Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 67
Healthy volunteers: no

Brief summary:
To evaluate the dose-response of different doses of CHF 1531 pressurized metered dose inhaler (pMDI) containing formoterol fumarate, on lung function and other clinical outcomes and to identify the optimal dose(s) with regard to benefit/ risk ratio for further development in the target subject population.

Detailed description:
This is a phase II, randomized, double-blind, placebo and active controlled dose-ranging, 6 arm incomplete block cross-over study to identify the optimal dose of CHF 1531 pMDI (containing formoterol fumarate), with regard to lung function and other clinical efficacy and safety outcome measures.

After a 2 week run-in period under rescue albuterol 'as needed' and background inhaled corticosteroid (ICS), subjects qualifying for the study were required to complete 4 treatment intervals of 2 weeks each, separated by 2 week wash-out intervals.

During each treatment interval, the subject were randomly assigned to take one of 5 double-blind study treatments twice daily (BID) i.e. one of 4 doses of CHF 1531 pMDI or a matching placebo or the open-label active control treatment (Perforomist® Inhalation Solution \[IS\]) also BID. During the entire study, all subjects concomitantly received ICS treatment with QVAR® inhaler (beclomethasone dipropionate 40 or 80 µg /actuation) twice daily at a dose that matches their pre-enrollment ICS and an albuterol inhaler to use as asthma rescue medication on 'as needed' basis. The subjects visited the study center every 2 weeks to undergo study procedures, and received a safety follow-up phone call one week after their last visit. In total, the study lasted 18 weeks and required 10 visits to the study center.

During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. A full physical exam, routine hematology, blood chemistry, spirometry, vital signs measurement, 12-lead ECG, and pregnancy testing were performed before enrollment and at the end of the study. Furthermore, on Day 1 and 14 of each treatment interval, serial spirometry, 12-lead ECGs, blood pressure measurements (BP), serum potassium, and serum glucose were measured at the study center for up to 12 hours post-dose.

Arms:
arm 1: Treatment A, CHF 1531 pMDI:

CHF 1531 pMDI 6 μg total daily dose (TDD):

1 inhalation of CHF 1531 pMDI 3 μg/actuation plus 1 inhalation of CHF 1531 matched Placebo BID. arm 2: Treatment B, CHF 1531 pMDI:

CHF 1531 pMDI 12 μg TDD:

1 inhalation of CHF 1531 pMDI 6 μg/actuation plus 1 inhalation of CHF 1531 matched Placebo BID. arm 3: Treatment C, CHF 1531 pMDI:

CHF 1531 pMDI 24 μg TDD: 2 inhalations of CHF 1531 pMDI 6 μg/actuation BID. arm 4: Treatment D, CHF 1531 pMDI

CHF 1531 pMDI 48 μg TDD: 2 inhalations of CHF 1531 pMDI 12 μg/actuation BID. arm 5: Treatment E, Matched placebo

Placebo: 2 inhalations of CHF 1531 pMDI matched Placebo BID. arm 6: Treatment F, Formoterol fumarate inhalation solution (IS)

Perforomist® IS (active comparator, open-label) 40 μg TDD: 1 inhalation, 20 μg/ 2 mL vial, 1 vial BID.

Interventions: intervention 1: CHF 1531 pMDI intervention 2: Formoterol Inhalation Solution intervention 3: Placebo pMDI
Intervention descriptions: intervention 1: Dose Response: Test one of five different doses of CHF 1531 intervention 2: Active Control intervention 3: Matched Placebo

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL
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A randomized, double-blind, placebo and active-controlled, incomplete block cross-over, 
dose ranging study to evaluate the efficacy and safety of 4 doses of CHF 1531 pMDI 
(Formoterol Fumarate) in asthmatic subjects
Version No.: 3.0
Date: 31Oct2017
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 : 133680
CCD-05993AA3-03
ClinicalTrials.gov ID: NCT03086460


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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
Readily available in case of medical questions
MONITORING CRO
CENTRAL LABORATORY OF 
ANALYSIS:
OTHER CENTRAL TECHNICAL 
LABORATORIES
Spirometry:
Central ECG:


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VERSION HISTORY
Version
Date
Change History
1.0
16Mar2017
2.0
24Jul2017
Clarified non-permitted concomitant medications, other 
changes as specified by Summary of Changes document.
3.0
31Oct2017
Increasing FEV1 range, allowing concomitant treatment 
with INS and antihistamines for the treatment of allergy 
symptoms, other changes as specified by Summary of 
Changes document.


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PROTOCOL OUTLINE 
Study title
A randomized, double-blind, placebo and active-controlled, incomplete 
block cross-over, dose ranging study to evaluate the efficacy and safety of 
4 doses of CHF 1531 pMDI (Formoterol Fumarate) in asthmatic subjects.
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
CHF 1531 pMDI (Formoterol Fumarate)
Center(s)
Multi-center, in approximately 15 sites
Indication 
Asthma
Study design
Randomized, double-blind, placebo and active-controlled, incomplete 
block, cross-over, dose ranging study.
Study phase
II
Objectives
Primary objective:
To evaluate the efficacy of CHF 1531 pMDI by comparison with placebo in 
terms of acute bronchodilator effect (change from baseline in FEV1 AUC0-
12h normalized by time at Day 14).
Secondary objectives:

To evaluate the effect of CHF 1531 pMDI on other lung function 
parameters and clinical outcome measures.

To assess the safety and the tolerability of the study drug.
Treatment duration
4 treatment periods of 2 weeks, each separate by a 2-week washout period.
Test product 
dose/route/regimen  
CHF 1531 pMDI: formoterol fumarate administered via pressurized 
metered dose inhaler (pMDI), available in 3µg per inhalation (FF 3), 
6µg per inhalation (FF 6), 12µg per inhalation (FF 12).
Treatment A: FF 6µg Total Daily Dose

FF 3µg per inhalation, 1 inhalation bid*
Treatment B: FF 12µg Total Daily Dose

FF 6µg per inhalation, 1 inhalation bid*
Treatment C: FF 24µg Total Daily Dose

FF 6µg per inhalation, 2 inhalations bid
Treatment D: FF 48µg Total Daily Dose

FF 12µg per inhalation, 2 inhalations bid
*An adequate number of inhalations from Placebo inhalers will be 
performed to maintain a double blind design.
Reference product 
dose/route/regimen 
Matched Placebo for CHF 1531 pMDI
Treatment E: 
Matched placebo, 2 inhalations bid


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PERFOROMIST®: Formoterol Fumarate 20µg / 2mL vial inhalation 
solution administered by nebulization
Treatment F: FF 40µg Total Daily Dose

FF 20µg/2mL, 1 unit-dose vial bid
PERFOROMIST® will be administered as open label.
Number of subjects
A total of approximately 60 subjects will be randomized in order to reach a 
total of 51 completed and evaluable subjects, considering a non-evaluable 
rate of approximately 15%.
Study population
Subjects with poorly controlled or uncontrolled moderate asthma on 
low/medium doses of inhaled corticosteroids.
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 ≥18 and ≤75 years who have signed an 
Informed Consent Form prior to initiation of any study-related 
procedure.
2. A diagnosis of asthma as defined in the GINA Report, 2016, 
documented for at least 1 year prior to screening.
3. Poorly controlled or uncontrolled asthma evidenced by a score ≥1.5 on 
the Asthma Control Questionnaire 7 © (ACQ-7) this criterion must be 
met at screening and at randomization visits).
4. A pre-bronchodilator FEV1 ≥60% and <85% of their predicted normal 
value, after appropriate washout from bronchodilators, at the screening 
and randomization visits.
5. Subjects with a positive response to a reversibility test at screening, 
defined as ΔFEV1 ≥12% and ≥200mL over baseline within 30 minutes 
after inhaling 4 puffs of albuterol HFA 90µg/actuation.
Note: In case the reversibility threshold is not met at screening, the test 
can be performed once before randomization.
6. Use of ICS (low/medium dose according to GINA Report, 2016) with 
or without a LABD for 3 months (at a stable dose in the last 4 weeks) 
before screening visit.
ICS*
Low daily 
dose
Medium daily 
dose
BDP extrafine (HFA) - QVAR®
80-160µg
>160-320µg
Budesonide (DPI)
200-400µg
>400-800µg
Ciclesonide (HFA)
80-160µg
>160-320µg
Flunisolide (HFA)
160 – 320µg
>320-640µg
Fluticasone furoate (DPI)
100µg
200µg
Fluticasone propionate (HFA/DPI)
100-250µg
>250-500µg
Mometasone furoate (DPI)
110-220µg
>220-440µg
*(Table adapted from GINA Report, 2016) 


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† This ICS/LABA daily dose is not permitted as its ICS component exceeds 
Medium Daily Dose equivalent of QVAR®.
7. A cooperative attitude and ability to demonstrate correct use of the 
diary, peak flow meter and pMDI inhaler.
At randomization (V2), inclusion criteria # 3, 4 and 7 should also be re-
checked.
Exclusion Criteria:
If a patient 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 a 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.
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 
drugs.
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 Visit 1, Visit 9 and at the early termination visit, urinary 
pregnancy test will be performed at Visit 1- 8.
Women of non-childbearing potential defined as physiologically 
ICS/LABA for Asthma
ICS/LABA Daily 
Dose
QVAR® 
recommended 
Daily Dose
ADVAIR® DISKUS® 100/50
100/50µg bid
80µg bid
ADVAIR® DISKUS® 250/50
250/50µg bid
160µg bid
ADVAIR® DISKUS® 500/50
500/50µg bid†
N/A
ADVAIR® HFA 45/21
90/42µg bid
80µg bid
ADVAIR® HFA 115/21
230/42µg bid
160µg bid
ADVAIR® HFA 230/21
460/42µg bid†
N/A
BREO® ELLIPTA® 100/25
100/25µg qd
40-80µg bid
BREO® ELLIPTA® 200/25
200/25µg qd
80-160µg bid
DULERA® 100/5
200/10µg bid
160µg bid
DULERA® 200/5
400/10µg bid†
N/A
SYMBICORT® 80/4.5
160/9µg bid
80µg bid
SYMBICORT® 160/4.5
320/9µg bid
160µg bid


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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 
central laboratory ranges) in women not using hormonal contraception 
or hormonal replacement therapy.
2. Subjects who suffer from COPD as defined by the GOLD Report, 
2017, or are suspected of having Asthma COPD Overlap Syndrome 
(ACOS) as described in the GINA Report, 2016.
3. Inability to carry out pulmonary function testing, to comply with study 
procedures or with study drug intake.
4. Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) 
with a smoking history of >10 pack-years or having stopped smoking 
one year or less prior to screening visit.
5. History of life-threatening asthma, clinically significant uncontrolled 
disease or respiratory infection.
6. An asthma exacerbation requiring oral/intravenous corticosteroids ≤ 30 
days, intramuscular depot corticosteroid ≤3 months or hospitalization 
within 6 months prior to screening.
7. Subjects with unresolved bacterial or viral respiratory tract, sinus, or 
middle ear infection affecting asthma status within 2 weeks prior to 
screening.
8. Subjects who received a vaccination within 2 weeks prior to screening 
or during the run-in.
9. Subjects with oral candidiasis at screening and at randomization.
10.Subjects with any clinically significant, uncontrolled condition 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 conditions 
which may impact the feasibility or the results of the study according to 
Investigator’s judgment.
11.Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at 
screening.
12.Subjects who have 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.
13.Subjects who have a clinically significant abnormal 12-lead ECG that 
results in active medical problem which may impact the safety of the 
patient according to Investigator’s judgment.
14.Subjects whose 12-lead ECG shows Fridericia’s corrected QT interval 
(QTcF) >450ms for males or QTcF >470ms for females at screening or 


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randomization visits (criterion not applicable for subjects with a 
pacemaker or permanent atrial fibrillation).
15.Subjects with known intolerance/hypersensitivity or contra-indication 
to 
treatment 
with 
inhaled 
β2-adrenergic 
receptor 
agonists, 
corticosteroids or propellant gases/excipients.
16.Subjects with concomitant immunosuppressive therapy, use of oral or 
injected corticosteroids, anti-IgE, anti-IL5 or other monoclonal or 
polyclonal antibodies within 12 weeks prior to screening.
17.Use of potent cytochrome P450 3A4 inhibitors (e.g. ritonavir, 
ketoconazole, itraconazole) and inducers within 4 weeks prior to 
screening.
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 
screening visit or have a planned surgery during the trial.
Exclusion criteria # 1, 3, 8, 9, 13 and 14 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 followed during 4 treatment 
periods of 2 weeks each separated by 2 weeks washout period. The study 
will last approximately 18 weeks for each patient and a total of 10 clinic 
visits will be performed during the study, including a follow-up phone 
call/visit (see the flow chart below).
A pre-screening visit (V0) will be carried out in order to fully explain 
the study to potential participants, to obtain their written Informed 
Consent and to instruct them on screening visit procedures (such as 
medication restrictions).
A screening visit (V1) not more than 7 days after V0 will help establish 
the eligibility of subjects for inclusion in the study (including routine 
weight/height, 
hematology 
and 
blood 
chemistry, 
medical 
history/previous medications, serum and urine pregnancy tests for 
women of childbearing potential, physical examination, a 12-lead ECG, 
FEV1 reversibility testing, ACQ assessment spirometry testing pre and 
post BD (to determine post-BD reversibility), vital signs, review of 
concomitant medications, adverse events and training on the use of 
pMDI inhalers. The subject will be dispensed the paper diary. This visit 


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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 including current ICS (as monotherapy or as combination 
ICS/LABA). The subjects will instead be prescribed a daily dose of 
inhaled beclomethasone dipropionate (QVAR® 40 or 80µg/actuation) 
equipotent to their ICS and this treatment regimen should remain stable 
for the entire run-in period. Subjects will receive rescue medication 
(albuterol) with instructions for “on demand” use for the entire study 
period.
Subjects will be randomized at Visit 2 (V2), if all the eligibility criteria 
are confirmed, to one of the sequences comprising 4 out of 6 possible 
treatments: CHF 1531 pMDI (6, 12, 24 or 48µg daily) and placebo. The 
randomized subjects will be followed during 4 consecutive treatment 
periods of 2 weeks each, separated by 2-week washout intervals.
During each treatment period, a visit is scheduled on Day 1 and on Day 
14. At each study visit the patient will have pre-dose assessments (i.e. 
vital signs, urine pregnancy test for women of childbearing potential, 
ACQ questionnaire (at V2 only), concomitant medications, adverse 
events and paper diary dispensed/returned, 12-lead ECG, lung function 
testing) and will undergo pre-dose and 12 hours post-dose serial 
spirometry and serial serum potassium and blood glucose assessments. 
Post-dose lung function (FEV1, FVC) will be evaluated and recorded at 
the following time points: 15, 30, 45 min and 1h, 2h, 3h, 4h, 6h, 8h, 
10h, 11.5h and 12h after study drug intake. Post-dose vital signs and 
12-lead ECG will be performed at 30 mins, 1h, 4h, 8h and 12h time-
points. Post-dose Serum Potassium and Blood Glucose will be 
measured at 1.5h, 3h, 5h, 7h and 11h time-points. 
At Visit 9, the subject will be discharged from the study after 
completion of the last assessment of the serial spirometry, Hematology 
and Blood chemistry, physical examination, 12-lead ECG, review of 
AEs, concomitant medications, return and accountability of background 
and study drug, return of subject diary, serum pregnancy test for 
women of childbearing potential.
A safety follow-up phone call (V10) will be performed by the 
investigator or designated staff no later than 1 week after the final visit 
(V9) or Early Termination Visit to check the status of unresolved AEs 
and to record any new AEs that may have occurred after V9 as well as 
related concomitant medications.


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Most relevant allowed 
concomitant treatments
Permitted concomitant medications
1. 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.
2. Cardioselective beta-blocking drugs if taken at stable regimen for at 
least 2 months before screening.
3. Non-potassium sparing diuretics administered as a fixed-dose 
combination with a potassium conserving drug.
4. Nasal corticosteroids and oral, nasal, or ocular antihistamines at FDA-
approved doses for the treatment of allergy symptoms.
5. Immunotherapy for allergen desensitization at the “maintaining” phase 
if already taken at stable doses for at least 1 month prior to screening 
visit (the dose must remain constant for the whole study period). 
In the case of a concomitant disease, appropriate treatment will be 
permitted if it does not interfere with the study drugs or the study 
evaluation parameters and does not qualify under the section "Non-
Permitted Concomitant Medications".
Most relevant forbidden 
concomitant treatments
Non-permitted concomitant medications (from V1)
1.
Inhaled corticosteroids other than the QVAR® (ICS background 
treatment).
2.
Inhaled short-acting muscarinic antagonists (SAMA), or long-acting 
muscarinic antagonists (LAMA).
3.
Inhaled fixed or free combinations of ICS/LABAs. 
4.
Nebulized or inhaled long-acting β2-agonist drugs (LABAs) other 
than study drug.
5.
Any other asthma treatments (e.g. cromolyn sodium, nedocromil 
sodium, leukotriene modifiers).
6.
Any oral/parenteral/intramuscular (depot) corticosteroid therapy for 
asthma exacerbation or other medical condition.
Note: any subject requiring systemic corticosteroid treatments will 
be discontinued from the study.
7.
Xanthine derivative (e.g. theophylline).
8.
Anti-IgE, anti-IL5 monoclonal antibodies.
9.
Tricyclic antidepressants and Monoamine oxidase inhibitors 
(MAOIs). 
10. Systemic 
anticholinergics 
and 
sympathomimetics 
including 
immediate and sustained-release oral formulations of phenylephrine 
and pseudoephedrine.
11. Non-cardioselective ß-blocking drugs (including eye drops), except 
if taken at stable regimen for at least 2 months before screening. 
12. Non-potassium sparing diuretics, except if administered as a fixed-
dose combination with a potassium conserving drug. 
13. Any drug known to prolong the QT interval (e.g. quinidine, 
procainamide, amiodarone). 
14. Any medication that could interact with the study drug or procedures, 
according to Investigator’s judgment. 


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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
Ketotifen
7 days
Cromoglycate
7 days
Oral or parenteral (i.v.) corticosteroid
3 month
Intramuscular depot corticosteroid
3 months
Prior to other visits with spirometry (V2  V9), the following washout 
periods must be respected:
Inhaled short-acting β2-agonists
6 hours
Caffeinated substances
6 hours
Efficacy variables
Primary efficacy variable
Change from baseline in FEV1 AUC0-12h normalized by time at Day 14.
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 Day 14.
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 at Day 
14.
Change from baseline in pre-dose morning FEV1 (average of pre-dose 
FEV1 measurements) at Day 14.
Change from baseline in pre-dose morning FVC (average of pre-dose 
FVC measurements) at Day 14.
Time to onset of action (change from baseline in post-dose FEV1 ≥ 
12% and ≥ 200mL) at Day 1.
Safety variables
Adverse Events (AEs) and Adverse Drug Reactions (ADRs).
Vital signs (systolic and diastolic blood pressure).
12-lead ECG parameters (HR, QTcF, QRS, PR).
HR AUC0-4h normalized by time and HR peak0-4h.
Serum Potassium and Blood Glucose.


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Sample size calculation
The sample size has been calculated to evaluate the superiority of CHF 
1531 pMDI at different doses over placebo in terms of change from 
baseline in FEV1 AUC0-12h normalized by time at Day 14. The calculation is 
based on simulations.
A total of 51 evaluable subjects will provide 96% power to detect a mean 
difference of 200 mL between each dose of CHF 1531 pMDI and placebo 
at a two-sided significance level of 0.0125, assuming a within-subject 
standard deviation of 180mL.
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 60 
subjects (5 subjects for each of the 12 treatment sequences) will be 
randomized.
Statistical methods
Primary efficacy variable
Change from baseline in FEV1 AUC0-12h normalized by time at Day 14 will 
be analyzed using an Analysis of Covariance (ANCOVA) model including 
treatment, period and patient as fixed effects and baseline (average of the 
pre-dose FEV1 measurements on Day 1 of each treatment period) as a 
covariate. The adjusted means in each treatment group, the adjusted mean 
difference between treatments and their 95% Confidence Intervals (CIs) at 
Day 14 will be estimated by the model. The CIs and the p-values of the 
comparisons between each dose of FF pMDI and placebo 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 
1531 pMDI over placebo will be demonstrated by a statistically significant 
difference (adjusted p-value < 0.05) favoring CHF 1531 pMDI.
All the other comparisons between treatments will be performed as 
secondary efficacy analyzes with no multiplicity adjustment.
Secondary efficacy variables
No multiplicity adjustment will be performed in the secondary efficacy 
analyzes.

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 Day 14 and change from baseline in pre-
dose morning FEV1 at Day 14 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 Day 14 
and change from baseline in pre-dose morning FVC at Day 14 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 ≥ 


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12% and ≥ 200mL) at Day 1 will be analyzed using a Cox proportional 
hazard model stratified by patient and with treatment and period as 
factor and baseline FEV1 (average of the pre-dose FEV1 measurements 
on Day 1 of each treatment period) as covariate. A Kaplan-Meier plot 
will be presented. 
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 measurement on Day 1 of each treatment period) and 
from pre-dose on Day 14 will be summarized by treatment using 
descriptive statistics and the 95% CI of the mean.
ECG
12-lead ECG parameters (HR, QTcF, QRS and PR) and their changes from 
baseline (pre-dose measurement on Day 1 of each treatment period) and 
from pre-dose on Day 14 will be summarized by treatment using 
descriptive statistics and the CI of the mean (95% CI for absolute values 
and 90% CI for the changes from baseline/pre-dose).
The number and the percentage of subjects with a:

QTcF >450ms (males only), >470ms (females only), >480ms (males 
only) and >500ms;

change from baseline (pre-dose measurement on Day 1 of each 
treatment period) in QTcF >30ms and >60ms;

for post-dose time-points on Day 14: change from pre-dose on Day 14 
in QTcF >30ms and >60ms
At each post-dose time-point and at any post-dose time-point will be 
presented by treatment.
At each post-dose time-point, the change from baseline (pre-dose 
measurement on Day 1 of each treatment period) in 12-lead ECG 
parameters (HR, QTcF, QRS and PR) will be analyzed using an ANCOVA 
model including treatment, period and subject as fixed effects and baseline 
(pre-dose measurement on Day 1 of each treatment period) as a covariate. 
The adjusted means in each treatment and the adjusted mean differences 
between treatments will be estimated by the model with 90% CIs. 


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HR AUC0-4h normalized by time and HR peak0-4h on Day 1 and Day 14 and 
their changes from baseline (pre-dose measurement on Day 1 of each 
treatment period) and from pre-dose on Day 14 will be summarized by 
treatment using descriptive statistics and the CI of the mean (95% CI for 
absolute values and 90% CI for the changes from baseline/pre-dose).
Serum Potassium and Blood Glucose
Serum potassium and blood glucose and their changes from baseline (pre-
dose measurement on Day 1 of each treatment period) and from pre-dose 
on Day 14 will be summarized by treatment using descriptive statistics and 
the 95% CI of the mean.


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ACQ
Asthma Control Questionnaire
ADR
Adverse Drug Reaction
AE
Adverse Event
ANCOVA
ANalysis of COVAriance
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area Under the Curve
BDP
Beclomethasone dipropionate
bid
Bis in die (twice a day)
BMD
Bone Mineral Density
BTPS
Body Temperature and ambient Pressure Saturated with water vapor
BUN
Blood urea nitrogen 
CFC
Chlorofluorocarbon
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
(e-) CRF
(Electronic) Case Report Form
CRO
Contract Research Organization
DBP
Diastolic Blood Pressure
DPI
Dry Powder Inhaler
ECG
ElectroCardioGram
FA
FORADIL® AEROLIZER®
FEV1
Forced Expiratory Volume in the 1st second 
FF
Formoterol Fumarate
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
HFA
Hydrofluroalkane
HR
Heart Rate
IB
Investigator brochure
IC
Inspiratory Capacity
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroid
IgE
Immunoglobulin E
IL5
Interleukin 5
IRT
Interactive Response Technology
ITT
Intention to Treat
IU (D or S)
Intra Uterine (Device or System)
L
Liter
LABA
Long Acting β2 adrenergic receptor agonist
LABD
Long-acting bronchodilators


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LAMA
Long Acting Muscarinic Antagonist
LLN
Lower Limit of Normal
LTRA
Leuktriene Receptor Antagonist
µg
Microgram
mab
Monoclonal antibody
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
OCS
Oral Corticosteroid
PEF
Peak Expiratory Flow
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)
qd
Quaque die (once daily)
QRS
Time Interval from the end of the PR interval to the end of the  S wave in the 
ECG
QTc
Time interval from the beginning of the QRS complex to 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
SABA
Short-acting Beta Agonist
SABD
Short acting bronchodilators
SAP
Statistical Analyis Plan
SAE
Serious Adverse Event
SAMA
Short-Acting Muscarinic Antagonist
SBP
Systolic Blood Pressure
SD
Standard Deviation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment Emergent Adverse Events
TEADR
Treatment Emergent Adverse Drug Reaction
TDD
Total Daily Dose
VC (SVC / FVC)
Vital Capacity (Slow /Forced)
WOCBP
Women of Childbearing Potential


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CONTENTS
GENERAL INFORMATION ..............................................................................................................2
PROTOCOL OUTLINE.......................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................15
CONTENTS.......................................................................................................................................17
1. 
BACKGROUNG INFORMATION AND STUDY RATIONALE....................................21
2. 
STUDY OBJECTIVES.......................................................................................................30
2.1
Primary Objective(s) ...........................................................................................................30
2.2
Secondary Objective(s) .......................................................................................................30
3. 
STUDY DESIGN................................................................................................................30
4. 
SUBJECT SELECTION CRITERIA..................................................................................31
4.1 
Subject Recruitment ............................................................................................................31
4.2 
Inclusion Criteria.................................................................................................................31
4.3 
Exclusion Criteria................................................................................................................32
4.4
Subject Withdrawals............................................................................................................34
5. 
CONCOMITANT MEDICATIONS...................................................................................35
5.1 
Permitted Concomitant Medications...................................................................................35
5.2 
Non-Permitted Concomitant Medications...........................................................................35
5.3 
Washout Medication Visit 1................................................................................................36
5.4 
Washout Medication Visits 2-9...........................................................................................37
6. 
TREATMENT(S)................................................................................................................37
6.1 
Appearance and Content .....................................................................................................37
6.2 
Dosage and Administration.................................................................................................38
6.2.1 
Selection of doses in the study ............................................................................................38
6.2.2 
Dosage.................................................................................................................................39
6.2.3 
Administration.....................................................................................................................40
6.2.4
Subject Training ..................................................................................................................42
6.3
Packaging ............................................................................................................................43
6.3.1
Training kits ........................................................................................................................43
6.3.2
Rescue medication...............................................................................................................43
6.3.3
Treatment kit .......................................................................................................................43
6.4
Labeling...............................................................................................................................43
6.5
Treatment allocation............................................................................................................44
6.6
Treatment Code ...................................................................................................................44
6.7
Treatment compliance .........................................................................................................44
6.8
Drug Storage........................................................................................................................45
6.9
Drug Accountability............................................................................................................46
6.10
Provision of additional care.................................................................................................46
7.
STUDY PLAN ....................................................................................................................47
7.1
Study Schedule....................................................................................................................47
7.1.1
Visit 0 (Pre-screening visit).................................................................................................48
7.1.2
Visit 1 (Screening visit / Week -2)......................................................................................48
7.1.3
Visit 2 (Randomization / Period 1, Day 1)..........................................................................50
7.1.4
Visit 3 (Period 1, Day 14) ...................................................................................................52


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7.1.5
Visit 4 (Period 2, Day 1), Visit 6 (Period 3, Day 1) and Visit 8 (Period 4, Day 1).............54
7.1.6
Visit 5 (Period 2, Day 14) and Visit 7 (Period 3, Day 14) ..................................................56
7.1.7
Visit 9 (Period 4, Day 14) ...................................................................................................57
7.1.8
Follow-up Phone Call (Visit 10) .........................................................................................59
7.1.9
Early Termination Visit.......................................................................................................59
7.2
Investigations.......................................................................................................................60
7.2.1
ACQ Questionnaire .............................................................................................................60
7.2.2
Vital Signs...........................................................................................................................60
7.2.3
Physical Exam and assessment of oral candidiasis .............................................................61
7.2.4
12-lead ECG........................................................................................................................61
7.2.5
Pulmonary Function Test ....................................................................................................62
7.2.6
Subject Diaries ....................................................................................................................64
7.2.7
Serum Potassium and Glucose ............................................................................................64
7.2.8
Hematology, Chemistry, and Pregnancy Tests ...................................................................65
7.2.9
Asthma Action Plan and Handling of Asthma Exacerbations ............................................65
8
EFFICACY ASSESSMENTS.............................................................................................66
9
SAFETY ASSESSMENTS.................................................................................................66
10
ADVERSE EVENT REPORTING.....................................................................................66
10.1
Definitions...........................................................................................................................66
10.2
Expectedness .......................................................................................................................68
10.3
Intensity of Adverse Event..................................................................................................68
10.4
Causality Assessment..........................................................................................................68
10.5
Action taken with the study drug ........................................................................................69
10.6
Other actions taken..............................................................................................................69
10.7
Outcome ..............................................................................................................................69
10.8
Recording Adverse Events ..................................................................................................69
10.9
Reporting Serious Adverse Events to Chiesi ......................................................................70
10.10
Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRB.....71
10.11
General Notes......................................................................................................................71
11
DATA MANAGEMENT....................................................................................................72
12
STATISTICAL METHODS ...............................................................................................72
12.1
Sample Size .........................................................................................................................72
12.2
Populations for analysis.......................................................................................................72
12.3
Statistical analysis ...............................................................................................................73
12.3.1
Descriptive Statistics ...........................................................................................................73
12.3.2
Missing data ........................................................................................................................73
12.3.3
Patient demographics and baseline characteristics..............................................................74
12.3.4
Primary efficacy variables...................................................................................................74
12.3.5
Secondary efficacy variables...............................................................................................75
12.3.6
Safety variables ...................................................................................................................75
12.3.7
Interim analysis ...................................................................................................................76
13
ETHICS AND RESPONSIBILITY ....................................................................................76
14
INFORMED CONSENT.....................................................................................................76
15
INSTUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITTEE .............77
16
SOURCE DOCUMENTS/DATA.......................................................................................77
17
STUDY MONITORING.....................................................................................................77


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18
QUALITY ASSURANCE ..................................................................................................78
19
INSURANCE AND INDEMNITY.....................................................................................78
20
CONFIDENTIALITY.........................................................................................................78
21
PREMATURE TERMINATION OF THE STUDY...........................................................78
22
CLINICAL STUDY REPORT............................................................................................78
23
RECORD RETENTION .....................................................................................................78
24
PUBLICATION OF RESULTS..........................................................................................79
25
REFERENCES....................................................................................................................79
APPENDIX I......................................................................................................................................85
APPENDIX II.....................................................................................................................................86


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APPENDICES
APPENDIX I
Minimum list of Source Data Required
APPENDIX II Principal Investigator Signature Page 


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1. BACKGROUNG 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 mixtures of lung abnormalities are 
characteristic of COPD, including small airway and parenchymal disease (obstructive bronchiolitis; 
emphysema), with variable contributions in any given patient.[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 COPD modifies the long-term decline in 
lung function.  The mainstays 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. 

Adverse event of this class of medications are mainly due to their 
anticholinergic activities, and include dry mouth, constipation, urinary 
retention and increased intraocular pressure.
o
Combination Bronchodilators: Combining bronchodilators using a LABA and a 
LAMA increases FEV1, albeit not to the full additive effect of each individual 


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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).[14]  
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 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.[15]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.[16][17][18][19][20] 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.[21][22] A meta-analysis suggested that subjects with 
COPD with lower blood eosinophil counts (<2%) had more pneumonia events than did 
those with higher counts.[23]RCTs have reported variable outcomes regarding ICS effect on 
decreased bone mineral density (BMD)[24][25] and risk of fractures,[26] and observational 
studies suggest an increased risk of diabetes / poorly controlled diabetes,[27] 
cataracts,[28][29] 
and 
mycobacterial 
infections, 
including 
tuberculosis.[30]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.[31][32][33][34][35][36]  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.
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is 
defined by variable symptoms of wheezing, shortness of breath, chest tightness and/or cough, and 
by variable expiratory flow limitation.  Variations over time and intensity are often triggered by 
factors such as exercise, environmental/occupational exposures, or viral respiratory infections.[37]  
As of 2014, the Center for Disease Control (CDC) estimated that the prevalence of asthma in US 
adults is 7.4%.[38]
The long-term goals of asthma management are to 1) achieve good symptom control, 2) to 
minimize future risk of exacerbations, 3) to minimize fixed airflow limitation and 4) to minimize 
side-effects of treatment. 
There are 3 types of asthma medications: Controllers, Relievers, and Add-ons.

Controller medications (e.g. ICS, ICS+LABA, LTRA, OCS): these are used for regular 
maintenance treatment. They reduce airway inflammation, control symptoms, and reduce 


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future risks such as exacerbations and decline in lung function. Controller medication is 
adjusted up or down in a stepwise approach to achieve these 4 goals.[37]
o
LABAs are drugs that have been associated with serious adverse asthma 
outcomes such as asthma-related hospitalization, need for intubation, and even 
death.[39][40] 
o
In February of 2010, the US FDA issued a re-labeling requirement for products 
containing LABAs to include a contraindication of LABA use without concomitant 
asthma-controller medication (e.g. ICS) and recommendations that LABAs be used 
only when necessary to achieve and maintain asthma control.[41][42] In April 2011, 
the FDA issued a requirement for all manufacturers of LABAs marketed in asthma 
in the US to conduct controlled clinical trials to assess the safety of a regimen of 
LABA+ICS vs ICS alone in asthma.[43]
o
A recently completed trial in 11,679 asthmatics age ≥12 yrs (AUSTRI trial) reported 
a 21% lower risk of severe asthma exacerbation in the FP+SLM (fluticasone 
propionate + salmeterol xinafoate fixed-dose 100/50; 250/50 or 500/50µg bid via the 
DISKUS® dry powder inhaler; GSK) group vs the FP (fluticasone propionate 100, 
250 or 500µg bid via the DISKUS® dry powder inhaler; GSK) alone group and no 
asthma-related deaths.[44]  In a second trial in asthmatic children age 4-11yr 
(VESTRI trial) FP+SLM (100/50 or 250/50µg bid) was non-inferior to FP (100 or 
250µg bid) alone in the risk of serious asthma-related event (HR 1.28; [CI] 0.73-
2.27).[45] There are similar ongoing trials with other ICS+LABAs which have not 
reported yet. 

Reliever (rescue) medications (e.g. SABA): these are provided to all subjects for as-needed 
relief of breakthrough symptoms, including during worsening asthma or exacerbations. They 
are also recommended for short-term prevention of exercise-induced bronchoconstriction. 
Reducing and, ideally, eliminating the need for reliever treatment is both an important goal 
in asthma management and a measure of the success of asthma treatment.

Add-on therapies for subjects with severe asthma (e.g. LAMA, anti-IgE mab, anti-IL-5 
mab): Some subjects with severe asthma may continue to have exacerbations despite well 
controlled symptoms, and for subjects with ongoing symptoms, side-effects may be an issue 
if ICS doses continue to be stepped up. Add-on medications may be considered when 
subjects have persistent symptoms and/or exacerbations despite optimized treatment with 
high dose controller medications (usually a high dose ICS+LABA).
According to the GINA Report, 2016, once asthma pharmacotherapy is prescribed, decisions are 
based on a cycle of assessment, adjustment of treatment (step up / step down), and review of 
response as shown in this table:[37]
Therapy
Step 1
Step 2
Step 3
Step 4
Step 5
Preferred 
Controller
Consider 
low dose 
ICS
Low dose 
ICS
Low dose 
ICS + 
LABA
Med-High ICS 
+ LABA
Refer to 
specialist for 
add-ons 
(LAMA, anti-
IgE mab, anti-
IL5 mab)
Other 
Controller
LTRA
Low dose 
Med-High 
dose ICS + 
Add 
tiotropium
Add low-dose 
OCS


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theophylline
LTRA
(or + theo)
High dose ICS 
+ LTRA
(or + theo)
Reliever
SABA prn
SABA prn
SABA prn
or low-dose ICS + formoterol
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 spray-formulated product (pMDI, Modulite®) and as a dry powder 
for inhalation (DPI) by the NEXThaler® device, releasing extra-fine particles.[46]
Chiesi Limited (Manchester, UK) currently also markets an inhaled formulation of the LABA 
formoterol fumarate in 20 European countries and over 20 non-European countries and has been 
marketed since 2004 under the brand name ATIMOS® Modulite pressurized inhalation solution[47] 
and other trade names.  The product is approved in Europe for the long-term symptomatic treatment 
of persistent, moderate-to-severe asthma in subjects aged ≥12 years requiring regular bronchodilator 
therapy in combination with long-term anti-inflammatory therapy (inhaled and / or oral 
glucocorticoids); and for the relief of broncho-obstructive symptoms in subjects with COPD.  Each 
actuation of ATIMOS® delivers 12µg (ex-valve) of formoterol fumarate dihydrate via an HFA-134a 
pressurized metered dose inhaler (pMDI).  The recommended range of dosing is 24-48µg per day.  
This product is not FDA-approved and is not available for use in the US. 
Chiesi Farmaceutici is also developing a fixed dose triple combination of a 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.[48]
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.
Since a dose-ranging study with CHF 1531 (HFA FF pMDI) has not been previously conducted, 
this study aims to characterize the dose-response to HFA FF pMDI using four doses: 3, 6, 12, 24µg 
(ex-valve) twice daily vs placebo in adult subjects with asthma.  


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Formoterol Fumarate HFA will not be indicated as monotherapy for asthma, however, the dose 
selection will be primarily based upon the results from this dose-ranging trial in asthmatics, as an 
asthma population is the most responsive to β2-agonist bronchodilation and is most likely to 
demonstrate a dose response. At the request of the FDA, an active comparator arm will be included, 
for benchmarking purposes.  Since FORADIL® AEOLIZER® is no longer marketed in the US, 
PERFOROMIST® (formoterol fumarate) Inhalation Solution (Mylan Specialty, L.P., Morgantown, 
WV, USA) will be used as the active comparator.
Formoterol Fumarate:
Description and Mechanism of Action:
Formoterol fumarate is a long-acting β2-adrenergic receptor agonist (LABA). Inhaled formoterol 
fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has 
more than 200-fold greater agonist activity at β2-receptors than at β1-receptors. Although β2-
receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors 
are the predominant receptors in the heart, there are also β2-receptors in the human heart 
comprising 10%-50% of the total beta-adrenergic receptors. The precise function of these receptors 
has not been established, but they raise the possibility that even highly selective β2-agonists may 
have cardiac effects.
The pharmacologic effects of β2-adrenoceptor agonist drugs, including formoterol, are at least in 
part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the 
conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic 
AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of 
release of mediators of immediate hypersensitivity from cells, especially from mast cells.[49]
Clinical Efficacy:[50][51]
A full description of the prescribing information and efficacy data for FORADIL® AEROLIZER® 
and PERFOROMIST®, can be found in their respective FDA-approved Product Information sheets.
FORADIL® AEROLIZER® (formoterol fumarate inhalation powder) was first approved by US 
FDA in Feb 2001 for the maintenance treatment of asthma and the prevention of bronchospasm in 
reversible obstructive airways disease, and for the acute prevention of exercise-induced 
bronchospasm (EIB), when administered on an occasional, as needed basis. In September 2001, a 
second FDA approval was obtained for the long term administration in the maintenance treatment 
of bronchoconstriction in patients with COPD, including chronic bronchitis and emphysema.[52]  
Manufacturing of this product was discontinued in Oct 2015, and is no longer distributed in the US 
as of January 2016.[53] 
In Adults and Adolescents with Asthma:
Two doses of FA DPI 12 and 24µg bid have been compared to albuterol 180µg QID and to placebo 
in two (n=541; n=554) 12-week multi-center, randomized, double-blind, parallel-group trials in 
adults and adolescents ≥12 years of age with mild-moderate asthma.  Both doses of FA DPI 
demonstrated statistically significant improvements vs placebo and albuterol in the primary 
endpoint (serial FEV1) and in many secondary efficacy endpoints, including improved combined 
and nocturnal asthma symptom scores, fewer night-time awakenings, fewer nights in which subjects 


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used rescue medication, and higher morning and evening peak flow rates. Onset of bronchodilation 
(ΔFEV1 ≥15%) after the 1st dose was within 5 min for FA DPI 12µg, 24µg, and albuterol. 
FA DPI 24µg twice daily did not provide any additional improvements in the primary or secondary 
endpoints compared to FA DPI 12µg twice daily, but serious asthma exacerbations occurred more 
commonly in the higher dose group.[54][55]
In COPD:
FA DPI was studied in two phase III, double-blind, placebo-controlled, randomized, multi-center, 
parallel-group trials in a total of 1634 adult patients with COPD. These studies included 
approximately equal numbers of patients with and without baseline bronchodilator reversibility, 
(ΔFEV1 ≥ 15%) after inhalation of 200mcg of albuterol sulfate. A total of 405 patients received 
FORADIL® AEROLIZER® 12µg bid. Each trial compared FA DPI 12 and 24µg bid with placebo 
and an active control drug.[49] The active control drug was ipratropium bromide 40µg qid in Trial 
A[56] (n = 780; 12 weeks) and slow-release theophylline (Theo-Dur 200 or 300mg bid) in  Trial 
B[57] (n = 854; 12 months). The results showed that FA DPI 12µg bid resulted in significantly 
greater bronchodilation (as measured by post-dose FEV1 AUC0-12h - the primary efficacy analysis) 
compared to placebo after 12 weeks of treatment in both trials, and after 12 months of treatment in 
the 12-month trial. Compared to FA-DPI 12µg bid, FA DPI 24µg bid did not provide any additional 
benefit on a variety of endpoints including FEV1.
PERFOROMIST® (formoterol fumarate) Inhalation Solution (FFIS) received US FDA approval in 
May 2007[58] for the long-term, twice daily (morning and evening) administration in the 
maintenance treatment of bronchoconstriction in patients with COPD, including chronic bronchitis 
and emphysema. PERFOROMIST® Inhalation Solution is not indicated to treat acute deteriorations 
of COPD and is not indicated to treat asthma. As with all LABAs, PERFORMIST® is 
contraindicated in patients with asthma without use of a long-term asthma control medication. 
PERFOROMIST® Inhalation Solution is currently marketed in the US by Mylan Specialty L.P., 
Morgantown, WV.[59]
PERFOROMIST® was evaluated in one phase III, 12-week, double-blind, placebo- and active-
controlled, randomized, parallel-group, multi-center trial conducted in the United States. A total of 
351 adults with mod-severe COPD (≤ 30% %predFEV1 < 70%) were enrolled and 237 were 
randomized to FF IS 20µg or placebo, administered bid via a PARI-LC Plus® nebulizer with a 
PRONEB® Ultra compressor. Fifty eight percent (58%) of patients had bronchodilator reversibility, 
defined as a ≥10% increase in FEV1 after inhalation of 2 actuations (180µg) of albuterol. FF IS 
20µg bid resulted in significantly greater post-dose bronchodilation (as measured by serial FEV1 for 
12 hours post-dose, with 78% of subjects achieving a 15% increase from baseline FEV1 following 
the first dose.  In these subjects, the median time to onset of bronchodilation, defined as 15% 
increase in FEV1, was 11.7 minutes. When defined as an increase in FEV1 of 12% and 200mL, the 
time to onset of bronchodilation was 13.1 minutes after dosing. The median time to peak 
bronchodilator effect was 2 hours after dosing.[60]
CHF 1531 (HFA FF pMDI) was especially designed to be equipotent to standard and established 
doses of FORADIL® AEROLIZER® (formoterol fumarate inhalation powder).[49][61]  As part of 


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the clinical development plan for FOSTER® Pressurized Inhalation Solution, a bridging study 
(CT04) was conducted to test the equivalent efficacy and safety of a single dose CHF 1531 24µg, 
(12µg/actuation) to FORADIL® AEROLIZER® 24µg (FA DPI, 12µg/capsule) and to compare the 
efficacy of 12 and 24µg doses administered via CHF 1531.  The study followed a randomized, 
double-blind, double-dummy, cross-over design with 4 treatments (3 active and placebo) and 4 
treatment periods.[62] The equivalence limit was set at ± 0.2L for FEV1, because the upper limit of 
the normal variability of the FEV1 measurement is known to approximate this value.[63]  The 
primary efficacy variable was the 12-hour average FEV1 following morning dosing (i.e. FEV1 
AUC0-12hr ÷ 12).
Fifty one (51) adult subjects with moderate-severe asthma (FEV1 50-80% of predicted normal) were 
randomized and 46 were evaluated in the per protocol population. All three active treatments 
produced a greater mean 12h average FEV1 when compared to placebo after first dose.  
Administration of FORADIL® AEROLIZER® 24µg and CHF 1531 24µg improved FEV1 by similar 
amounts.  Conversely, the improvement was less marked after administration of CHF 1531 12µg. 
The maximum effect (i.e. peak FEV1) was achieved at 2 hours after administration, regardless of the 
formulation used.
Maximum changes from baseline of FEV1 after the administration of CHF 1531 24µg or 
FORADIL® AEROLIZER® 24µg were identical, and were higher than after administration of CHF 
1531 12µg. Maximum changes from baseline of FEV1 after the placebo administration were lower 
than after each of the three active treatments. Onset of bronchodilation was comparable between 
CHF 1531 24µg and FORADIL® AEROLIZER® 24µg. The numbers of patients with a first FEV1 
improvement ≥ 15% before 20 minutes were 36 with CHF 1531 24µg and 40 with FORADIL® 
AEROLIZER® 24µg. The duration of action appeared to be comparable between CHF 1531 24µg 
and FORADIL® AEROLIZER® 24µg. Conversely, the duration of action of CHF 1531 12µg was 
shorter than that of CHF 1531 24µg or FORADIL® AEROLIZER® 24µg.
Another randomized, double-blind, double-dummy, placebo-controlled cross-over study (CT03) 
evaluated the bronchoprotective and bronchodilator effects of 12µg formoterol delivered via FF-
HFA pMDI (Chiesi Farmaceutici S.p.A, Parma, Italy) compared to FORADIL® AEROLIZER® 
12µg Inhalation powder (FA -DPI, 1 inhalation) and CFC FORADIL® inhaler (both by Novartis, 
Health consumer, Basel, Switzerland) in 38 adult subjects with mild-moderate asthma. The primary 
endpoint was methacholine challenge provocative dose required for 20% fall in the FEV1 PD20 90 
min post dose. The three formoterol formulations demonstrated significant (P ≤ 0.05) improvements 
in bronchoprotection compared to placebo and non-inferiority of the HFA preparation compared to 
the CFC and DPI preparations. Serum potassium, glucose and formoterol plasma profiles were 
comparable for the CFC, HFA and DPI devices.[64]
Clinical Safety:[50][51]
A full description of the safety, contraindications, warnings and precautions and drug interactions 
with FORADIL® AEROLIZER® and PERFOROMIST®, can be found in their respective FDA-
approved Product Information sheets.


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Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death.  All 
LABA are contraindicated in patients with asthma without use of a long-term asthma control 
medication.
Adverse reactions with β2-adrenergic receptor agonists including: angina, hypertension or 
hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, muscle cramps, 
palpitations, nausea, dizziness, fatigue, malaise, insomnia, hypokalemia, hyperglycemia, and 
metabolic acidosis.
FORADIL® AEROLIZER®:[49]
In Adults and Adolescents with Asthma:
Of the 5,824 patients in multiple-dose controlled clinical trials, 1,985 were treated with FORADIL® 
AEROLIZER® at the recommended dose of 12µg bid.  TEADRs where the frequency was ≥1% in 
the FORADIL® bid group and where the rates in the FORADIL® group exceeded placebo included: 
viral infection, bronchitis, chest infection, dyspnea, chest pain, tremor, dizziness, insomnia, 
tonsillitis, rash, and dysphonia.
A 16-week, randomized, multi-center, double-blind, parallel-group trial enrolled 1568 patients 12 
years of age and older with mild-to-moderate asthma (%predFEV1 ≥40%) in three treatment 
groups: FORADIL® AEROLIZER® 12 and 24µg bid, and placebo. The trial’s primary endpoint was 
the incidence of serious asthma-related adverse events. Serious asthma exacerbations occurred in 3 
(0.6%) patients who received FORADIL® AEROLIZER® 12µg bid, 2 (0.4%) patients who received 
FORADIL® AEROLIZER® 24µg bid, and 1 (0.2%) patient who received placebo. The size of this 
trial was not adequate to precisely quantify the differences in serious asthma exacerbation rates 
between treatment groups. All serious asthma exacerbations resulted in hospitalizations. While 
there were no deaths in the trial, the duration and size of this trial were not adequate to quantify the 
rate of asthma-related death.
In adults with COPD: 
Of the 1634 patients in two pivotal multiple-dose COPD controlled trials, 405 were treated with 
FORADIL® AEROLIZER® 12µg bid. TEADRs where the frequency was ≥1% in the FORADIL® 
AEROLIZER® group and where the rates in the FORADIL® AEROLIZER® group exceeded 
placebo included: upper respiratory tract infection, back pain, pharyngitis, chest pain, sinusitis, 
fever, leg cramps, muscle cramps, anxiety, pruritis, increased sputum, and dry mouth.
Post-Marketing Experience:
In extensive worldwide marketing experience with FORADIL®, serious exacerbations of asthma, 
including some that have been fatal, have been reported. While most of these cases have been in 
patients with severe or acutely deteriorating asthma, a few have occurred in patients with less severe 
asthma. It is not possible to determine from these individual case reports whether FORADIL® 
AEROLIZER® contributed to the events: rare reports of anaphylactic reactions, including severe 
hypotension and angioedema, hypokalemia, hyperglycemia, cough, rash, angina pectoris, cardiac 
arrhythmias, e.g. atrial fibrillation, ventricular extrasystoles, tachyarrhythmia,  QT prolonged, blood 
pressure increased (including hypertension).


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PERFOROMIST®:[59]
In Adults with COPD:
Adverse reactions from the 12-week, double-blind, placebo-controlled trial where the frequency 
was ≥ 2% in the PERFOROMIST® Inhalation Solution group (n = 123) and where the rate in the 
PERFOROMIST® Inhalation Solution group exceeded the rate in the placebo group were: diarrhea, 
nausea, nasopharyngitis, dry mouth, vomiting, dizziness, and insomnia. 
Patients treated with PERFOROMIST® Inhalation Solution 20µg bid in a 52-week open-label trial 
(n = 463) did not experience an increase in specific clinically significant AEs above the number 
expected based on the medical condition and age of the patients.
Post-Marketing Experience:
The following adverse reactions have been reported during post-approval use of PERFOROMIST® 
Inhalation Solution. Because these reactions are reported voluntarily from a population of uncertain 
size, it is not always possible to reliably estimate their frequency or establish a causal relationship to 
drug exposure: Anaphylactic reactions, urticaria, angioedema (presenting as face, lip, tongue, eye, 
pharyngeal, or mouth edema), rash, and bronchospasm.
CHF 1531 (HFA FF pMDI): 
CT04: No serious adverse events occurred during the study. Overall, 58 treatment-emergent adverse 
events were reported by 32 patients. Of these, 21 AEs (36.2%) occurred with CHF 1531 24µg, 17 
AEs (29.3%) occurred with FORADIL® AEROLIZER® 2µg, 12 AEs (20.7%) occurred with CHF 
1531 12µg, and 8 AEs (13.8%) occurred with placebo. The most commonly reported adverse event 
was hand tremor, which was reported by 9 patients with CHF 1531 24µg (18.8%), by 7 patients 
with FORADIL® AEROLIZER® 24µg (14.3%), by 5 patients with CHF 1531 12µg (10.4%) and by 
2 patients with placebo (4.1%). All adverse events were of mild or moderate intensity. The 
relationship to the treatment was mostly "likely" with CHF 1531 24µg and mostly "possible" with 
FORADIL® AEROLIZER® 24µg. All adverse events resolved spontaneously except for one 
pneumopathy, one asthma exacerbation and one vagal syndrome, which led to patient withdrawal.
The evaluation of the effects of formoterol on the duration of QTc interval showed similar increases 
with CHF 1531 24µg and FORADIL® AEROLIZER® 24µg formulations, while the QTc interval 
remained close to baseline with CHF 1531 12µg and with placebo. The maximum changes from 
baseline were 29.08 msec for CHF 1531 24µg and 23.08 msec for FORADIL® AEROLIZER® 24µg 
as opposed to 16.06 msec and 15.02 msec for CHF 1531 12µg and placebo respectively. The 
maximum changes from baseline were mostly seen 2 hours after administration of CHF 1531 24µg 
or FORADIL® AEROLIZER® 24µg.
A moderate increase in heart rate was recorded 2 hours after administration of each of the three 
active treatments and this was slightly higher with CHF 1531 24µg and FORADIL® AEROLIZER® 
24µg formulations than with CHF 1531 12µg and placebo. The maximum changes from baseline 
were 11.21 bpm for CHF 1531 24µg and 11.88 bpm for FORADIL® AEROLIZER® 24µg as 
opposed to 9.52 bpm and 9.23 bpm for CHF 1531 12µg and placebo respectively.


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A slight decrease in systolic blood pressure was seen between 2 hours and 4 hours post-dose and a 
slight decrease in diastolic blood pressure was seen between 1 and 2 hours post-dose regardless of 
the treatment. The maximum changes from baseline for SBP were 13.38 mmHg for CHF 1531 
24µg, 11.65 mmHg for FORADIL® AEROLIZER® 24µg, 12.33 mmHg with CHF 1531 12, and 
13.77 mmHg with placebo. The maximum changes from baseline for DBP were -11.8 mmHg for 
CHF 1531 24µg, -9.69 mmHg for FORADIL® AEROLIZER® 24µg, -10.2 mmHg for CHF 1531 
12µg and -11.2 mmHg for placebo. However, these modest variations were regarded as not 
clinically relevant.
As far as the biological safety is concerned, the three formoterol treatments lowered the serum 
potassium concentrations and increased glucose concentrations as expected. The maximum change 
in serum potassium from baseline reached -0.369 mmol/L with CHF 1531 24µg, and was 
-0.264 mmol/L for FORADIL® AEROLIZER® 24µg, -0.250 mmol/L for CHF 1531 12µg, and 
-0.239 mmol/L for placebo.  Blood glucose showed a similar peak in concentration 2 hours after 
administration of each of the three active treatments. The maximum change from baseline reached 
2.145 mmol/L with CHF 1531 24µg, and was 1.916 mmol/L for FORADIL® AEROLIZER® 24µg, 
1.860 mmol/L for CHF 1531 12µg, and 1.253 mmol/L for placebo.
This study will be conducted in compliance with the protocol, the Sponsor’s standard operation 
procedures and/or guidelines, the United States FDA regulations, the ICH GCP guidelines, the 
Declaration of Helsinki, and other local regulations, as applicable.
2. STUDY OBJECTIVES
2.1 Primary Objective(s)
To evaluate the efficacy of CHF 1531 pMDI by comparison with placebo in terms of acute 
bronchodilator effect (change from baseline in FEV1 AUC0-12h normalized by time at Day 14).
2.2 Secondary Objective(s)
To evaluate the effect of CHF 1531 pMDI on other lung function parameters and clinical 
outcome measures.
To assess the safety and the tolerability of the study drug.
3. STUDY DESIGN 
This is a phase II, multi-center, randomized, double-blind, placebo and active-controlled, 
incomplete block cross-over, dose-ranging study to evaluate the efficacy and safety of 4 doses of 
CHF 1531 pMDI (Formoterol Fumarate) in adult subjects with asthma.
Following a 2-week run-in period, subjects will be enrolled into 4 consecutive treatment periods of 
2 weeks each, separated by 2-week washout period. A follow-up phone contact for adverse events 
and concomitant medication assessment will be conducted approximately 1 week after the last study 
visit. The study will last approximately 18 weeks for each patient and a total of 10 clinic visits will 
be performed during the study, including a follow-up phone call. 


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The end of the trial is defined as the last follow-up contact with 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 100 subjects will be screened, 60 randomized to yield 51 evaluable subjects. 
Recruitment will occur across approximately 15 participating outpatient study centers within the 
US.  
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 ≥18 and ≤75 years who have signed an Informed Consent 
Form prior to initiation of any study-related procedure.
2. A diagnosis of asthma as defined in the GINA Report, 2016,[37] documented for at least 1 
year prior to screening.
3. Poorly controlled or uncontrolled asthma evidenced by a score ≥1.5 on the Asthma Control 
Questionnaire 7© (ACQ-7) [65] (this criterion must be met at screening and at 
randomization visits).
4. A pre-bronchodilator FEV1 ≥60% and <85% of their predicted normal value, after 
appropriate washout from bronchodilators, at the screening and randomization visits.
5. A positive response to a reversibility test at screening, defined as ΔFEV1 ≥12% and ≥200mL 
over baseline within 30 minutes after inhaling 4 puffs of albuterol HFA (90µg/actuation).66
Note: In case the reversibility threshold is not met at screening, the test can be performed 
once before randomization.
6. Use of ICS (low/medium dose according to GINA Report, 2016) with or without a LABD 
for 3 months (at a stable dose in the last 4 weeks) before screening visit.
ICS*
Low daily 
dose
Medium daily 
dose
BDP extrafine (HFA) - QVAR®
80-160µg
>160-320µg
Budesonide (DPI)
200-400µg
>400-800µg
Ciclesonide (HFA)
80-160µg
>160-320µg
Flunisolide (HFA)
160 – 320µg
>320-640µg
Fluticasone furoate (DPI)
100µg
200µg
Fluticasone propionate (HFA/DPI)
100-250µg
>250-500µg
Mometasone furoate (DPI)
110-220µg
>220-440µg
*(Table adapted from GINA Report, 2016) 


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† This ICS/LABA daily dose is not permitted as its ICS component exceeds Medium Daily Dose equivalent of QVAR®.
7. A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter 
and pMDI inhaler.
If at Visit 1 the inclusion criterion #5 (reversibility) is not met, the subject may return to repeat the 
procedure once before randomization.  If this occurs, criteria # 3 and 4 must also be repeated on the 
same day, and before reversibility test is conducted.
At randomization (Visit 2), inclusion criteria # 3, 4 and 7 should also be re-checked.
4.3 Exclusion Criteria
If a patient 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 a 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.
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 drug.
ICS/LABA for Asthma
ICS/LABA Daily 
Dose
QVAR® 
recommended Daily 
Dose
ADVAIR® DISKUS® 100/50
100/50µg bid
80µg bid
ADVAIR® DISKUS® 250/50
250/50µg bid
160µg bid
ADVAIR® DISKUS® 500/50
500/50µg bid†
N/A
ADVAIR® HFA 45/21
90/42µg bid
80µg bid
ADVAIR® HFA 115/21
230/42µg bid
160µg bid
ADVAIR® HFA 230/21
460/42µg bid†
N/A
BREO® ELLIPTA® 100/25
100/25µg qd
40-80µg bid
BREO® ELLIPTA® 200/25
200/25µg qd
80-160µg bid
DULERA® 100/5
200/10µg bid
160µg bid
DULERA® 200/5
400/10µg bid†
N/A
SYMBICORT® 80/4.5
160/9µg bid
80µg bid
SYMBICORT® 160/4.5
320/9µg bid
160µg bid


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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 V1, V9 and at the Early 
Termination visit; urinary pregnancy test will be performed at Visits 1-8. 
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 central 
laboratory ranges) in women not using hormonal contraception or hormonal replacement 
therapy.
2. Subjects who suffer from COPD as defined by the GOLD Report, 2017, or are suspected of 
having Asthma COPD Overlap Syndrome (ACOS) as described in the GINA Report, 2016.
3. Inability to carry out pulmonary lung function testing, to comply with study procedures or 
with study drug intake.
4. Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) with a smoking 
history of >10 pack-years or having stopped smoking one year or less prior to screening 
visit.
5. History of life-threatening asthma, clinically significant uncontrolled disease or respiratory 
infection.
6. An asthma exacerbation requiring oral/intravenous corticosteroids ≤ 30 days, intramuscular 
depot corticosteroid ≤ 3 months or hospitalization within 6 months prior to screening.
7. Subjects with unresolved bacterial or viral respiratory tract, sinus, or middle ear infection 
affecting asthma status within 2 weeks prior to screening. 
8. Subjects who received a vaccination within 2 weeks prior to screening or during the run-in.
9. Subjects with oral candidiasis at screening or at randomization.
10. Subjects with any clinically significant, uncontrolled condition 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 
conditions which may impact the feasibility or the results of the study according to 
Investigator’s judgment.
11. Subjects with serum potassium levels <3.5 mEq/L (or 3.5 mmol/L) at screening.
12. Subjects who have 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.
13. Subjects who have a clinically significant abnormal 12-lead ECG that results in active 
medical problem which may impact the safety of the patient according to Investigator’s 
judgment.
14. Subjects whose 12-lead ECG shows Fridericia’s corrected QT interval (QTcF) >450ms for 
males or QTcF >470ms for females at screening or randomization visits (criterion not 
applicable for subjects with a pacemaker or permanent atrial fibrillation).


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15. Subjects with known intolerance/hypersensitivity or contra-indication to treatment with β2-
adrenergic receptor agonists, inhaled corticosteroids or propellant gases/excipients.
16. Subjects with concomitant immunosuppressive therapy, use of oral or injected 
corticosteroids, anti-IgE, anti-IL5 or other monoclonal or polyclonal antibodies within 12 
weeks prior to screening.
17. Use of potent cytochrome P450 3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole) 
and inducers within 4 weeks prior to screening.
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 five 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 screening visit or have 
a planned surgery during the trial.
Exclusion criteria # 1, 3, 8, 9, 13 and 14 should be re-checked at the randomization visit. 
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 with the study drug or study procedures. In this case, the appropriate measures will 
be taken.
o Subjects who experience a severe asthma 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 asthma exacerbation will be ensured by the 
study investigator, with the aim to preserve the research subject’s well-being at all times.
The subject receives systemic corticosteroid treatment.
The subject is lost to follow-up.
The subject withdraws consent.
The subject's safety is affected by violation of inclusion or exclusion criteria or use of not-
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.


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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. Short-acting β2-adrenergic receptor agonist (albuterol) as rescue medication. A minimum 
period of 6 hours should elapse between the use of rescue medication and the spirometric 
measurements.
2. Cardioselective beta-blocking drugs if taken at stable regimen for at least 2 months before 
screening.
3. Non-potassium sparing diuretics administered as a fixed-dose combination with a potassium 
conserving drug.
4. Nasal corticosteroids and oral, nasal, or ocular antihistamines at FDA-approved doses for 
the treatment of allergy symptoms.
5. Immunotherapy  for allergen desensitization at the “maintaining” phase if already taken at 
stable doses for at least 1 month prior to screening visit (the dose must remain constant for 
the whole study period). 
In the case of a concomitant disease, appropriate treatment will be permitted if it does not interfere 
with the study drugs or the study evaluation parameters and does not qualify under the section 
“Non-Permitted Concomitant Medications”.
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-V9) 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 corticosteroids other than the QVAR® (ICS background treatment).
2. Inhaled short-acting muscarinic antagonists (SAMA), or long-acting muscarinic antagonists 
(LAMA).
3. Inhaled fixed or free combinations of ICS/LABAs. 
4. Nebulized or inhaled long-acting β2-agonist drugs (LABAs) other than study drug.
5. Any other asthma treatments (e.g. cromolyn sodium, nedocromil sodium, leukotriene 
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6. Any oral/parenteral/intramuscular (depot) corticosteroid therapy for asthma exacerbation or 
other medical condition.
Note: any subject requiring systemic corticosteroid treatments will be discontinued from the 
study.
7. Xanthine derivative (e.g. theophylline).
8. Anti-IgE, anti-IL5 monoclonal antibodies.
9. Tricyclic antidepressants and Monoamine oxidase inhibitors (MAOIs). 
10. Systemic anticholinergics and sympathomimetics including immediate and sustained-release 
oral formulations of phenylephrine and pseudoephedrine.
11. Non-cardioselective ß-blocking drugs (including eye drops), except if taken at stable 
regimen for at least 2 months before screening. 
12. Non-potassium sparing diuretics, except if administered as a fixed-dose combination with a 
potassium conserving drug. 
13. Any drug known to prolong the QT interval (e.g. quinidine, procainamide, amiodarone) 
14. Any medication that could interact with the study drug or procedures, according to 
Investigator’s judgment. 
5.3 Washout Medication Visit 1
Prior to screening spirometry (Visit 1), the following washout periods must be respected:[67]
Caffeinated substances
6 hours
Inhaled and/or nebulized short-acting β2-agonists
6 hours
Caffeinated substances
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
Ketotifen
7 days
Cromoglycate
7 days
Oral or parenteral (i.v.) corticosteroid
3 month
Intramuscular depot corticosteroid
3 months


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5.4 Washout Medication Visits 2-9
Prior to other visits with spirometry (V2  V9), the following washout periods must be respected:
Inhaled short-acting β2-agonists
6 hours
Caffeinated substances
6 hours
6. TREATMENT(S)
The study medication 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 1531 pMDI 3µg – test product
Active ingredient: Formoterol Fumarate 3µg per inhalation
Excipient: Ethanol, HFA-134a propellant, hydrochloric acid
Presentation: each canister contains 120 doses

CHF 1531 pMDI 6µg - test product
Active ingredient: Formoterol Fumarate 6µg per inhalation
Excipient: Ethanol, HFA-134a propellant, hydrochloric acid
Presentation: each canister contains 120 doses

CHF 1531 pMDI 12µg - test product
Active ingredient: Formoterol Fumarate 12µg per inhalation
Excipient: Ethanol, HFA-134a propellant, hydrochloric acid
Presentation: each canister contains 120 doses

CHF 1531 pMDI matched placebo
Active ingredient: None
Excipient: Ethanol, HFA-134a propellant, hydrochloric acid
Presentation: each canister contains 120 doses

PERFOROMIST® Inhalation Solution (Mylan Specialty L.P.) – Reference product – 
Open-label
Active ingredient: Formoterol Fumarate 20µg /2mL
Excipient: water, citric acid, sodium citrate, NaCl
Presentation: 2mL unit dose vials


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
QVAR® Inhalation Aerosol (Teva Respiratory, LLC) – Background ICS medication
Active ingredient: beclomethasone dipropionate 40µg per inhalation 
Excipient: Propellant HFA-134a (Norflurane), Ethanol
Presentation: Each canister contains 120 doses

QVAR® Inhalation Aerosol (Teva Respiratory, LLC) - Background ICS medication
Active ingredient: beclomethasone dipropionate 80µg per inhalation 
Excipient: Propellant HFA-134a (Norflurane), Ethanol
Presentation: Each canister contains 120 doses
6.2 Dosage and Administration 
6.2.1 Selection of doses in the study
FORADIL® AEROLIZER®:  The PK and PD effects of inhaled formoterol fumarate (FF) have 
been tested in healthy volunteers using single doses ranging from 12 to 120µg. A linear relationship 
was observed between urinary excretion of formoterol and decreases in serum potassium, increases 
in plasma glucose, and increases in heart rate.  Maximum increase in plasma potassium was 
observed 1-3h after peak formoterol plasma concentration and a mean max increase in HR at 6h 
post-dose.  Formoterol plasma concentrations were weakly correlated with increased HR and QTc 
duration. QTc prolongation were transient and returned to baseline within 12-24h post-dosing. 
In the asthma clinical development plan, 3 TEADRs showed dose ordering among tested doses of 6, 
12 and 24µg bid; tremor, dizziness and dysphonia. In two 12-week controlled trials with combined 
enrollment of 1095 patients 12 years of age and older, serious asthma exacerbations (acute 
worsening of asthma resulting in hospitalization) occurred more commonly with FORADIL® 
AEROLIZER® (FA DPI) 24µg bid than with the recommended dose of FORADIL® AEROLIZER® 
12µg bid, albuterol, or placebo.  In a 16-week, randomized, multi-center, double-blind, parallel-
group trial, patients who received either 24µg or 12µg bid doses of FORADIL® AEROLIZER® 
experienced more serious asthma exacerbations than patients who received placebo.
In the COPD clinical development plan, FA DPI 24µg bid did not provide any additional benefit on 
a variety of endpoints including FEV1 compared to FA DPI 12µg bid.  Seven TEADRs showed 
dose ordering among tested doses of 12 and 24mcg administered twice daily; pharyngitis, fever, 
muscle cramps, increased sputum, dysphonia, myalgia, and tremor.
The US FDA-approved dosage of FORADIL® AEROLIZER® Inhalation Powder is 12µg bid.[49]
PERFOROMIST®:  Dose selection for the PERFORMIST® (FF IS) clinical program was based on 
two single-dose PD (bronchodilation) studies vs. FORADIL® AEROLIZER® (FA DPI) in patients 
with COPD.[68] 

DL-02: FEV1 dose-response of FF IS 40 and 80µg and FA DPI 12 & 24µg.  Results failed to 
match either FF IS dose with the approved dose of FA DPI (12µg).

DL-057: was the primary dose-finding study in 47 subjects with mod-severe COPD 
(FEV1/FVC ratio < 0.7 and 30% ≤ FEV1 <70%).  The primary endpoint was FEV1 AUC0-12h. 
The doses evaluated were FF IS 2.5, 5, 10, 20 & 40µg vs FA DPI 12µg and PBO. The study 
Showed comparable BD effect between FF IS 20µg and FA DPI 12µg doses. The FF IS 


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12µg dose was taken into the Phase III program. The FF IS 10µg dose also matched the FA 
DPI 12µg dose but was not chosen because the statistical evaluation plan used a descending 
order approach from highest to lower FF IS dose.[69]
The US FDA-approved dosage of PERFOROMIST® Inhalation Solution is one 20µg/2mL vial 
every 12 hours.
CHF 1531 (HFA FF pMDI): The clinical equivalence of single dose CHF 1531 (HFA FF pMDI) 
6µg (2 X 6μg/actuation) to the once US-marketed formulation of FORADIL® AEROLIZER® 12μg 
Inhalation Powder (FA DPI) has been previously established in adult subjects with moderate to 
severe asthma.  Therefore, considering the above evidence and the FDA’s recommendations, this 
dose-ranging study will assess 4 doses of CHF 1531: (3, 6, 12, and 24µg bid) vs placebo. 
PERFOROMIST® Inhalation Solution will be used as the active comparator, at the same dose 
indicated for COPD.
6.2.2 Dosage
6.2.2.1 Background medication for run-in and treatment periods: 
Standardized Background ICS therapy – Open label:
QVAR® 40µg (HFA beclomethasone dipropionate, 40µg), Inhalation Aerosol. Each canister 
contains 120 actuations.
OR:
QVAR® 80µg (HFA beclomethasone dipropionate, 80µg), Inhalation Aerosol. Each canister 
contains 120 actuations.
Both dose strengths of QVAR® will be provided by the study sponsor to be dispensed as 
prescribed by the investigator. The subjects will be prescribed a daily dose of (QVAR® 40 or 
80µg/actuation; 1-2 puffs bid) between 80 – 320µg, equipotent to their previous ICS (ref. inclusion 
criterion #6) and this treatment regimen should remain stable for the entire study period. The 
subject will be asked to not use any other ICS throughout the study. 
6.2.2.2 Randomized Treatment period:
An adequate number of inhalations from the Placebo inhalers will be performed to maintain a 
double blind design.  Randomized subjects will receive four of the six following Study Treatments 
according to the sequence assigned by the randomization list:

Treatment A: 
1 inhalation of CHF 1531 3µg pMDI plus 1 inhalation of CHF1531 matched placebo in the 
morning and in the evening, giving a total daily dose of 6µg. 

Treatment B: 
1 inhalation of CHF 1531 6µg pMDI plus 1 inhalation of CHF1531 matched placebo in the 
morning and in the evening, giving a total daily dose of 12µg. 


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
Treatment C: 
2 inhalations of CHF1531 6µg in the morning and in the evening, giving a total daily dose 
of 24µg.

Treatment D: 
2 inhalations of CHF1531 12µg in the morning and in the evening, giving a total daily dose 
of 48µg.

Treatment E:  
2 inhalations of CHF1531 matched placebo in the morning and in the evening, giving a 
total daily dose of 0µg.

Treatment F:  
1 inhalation in the morning and in the evening of PERFOROMIST® giving a total daily 
dose of 40µg. PERFOROMIST® will be administered as open label. 
6.2.3 Administration
6.2.3.1 : Background ICS medication kit for run-in period (from Visit 1 to Visit 2)
At screening visit 1 (Visit 1), the Investigator, or designee, will contact the IRT system to dispense 
to each eligible patient one background ICS medication kit (QVAR®). This kit will cover the 
needs in background ICS maintenance medication until Visit 2. 
At Visit 1 (screening visit), all subjects allowed to continue in the study, including those scheduled 
for V1.1 for a repeat Reversibility test, will receive the following standard ICS medication to cover 
the 2-week run-in period:

One commercial pack of  QVAR® 40 or 80µg containing Beclomethasone dipropionate HFA 
40 or 80µg per actuation, respectively, 120 actuations per canister 
The investigator will prescribe the subject QVAR® 40µg or QVAR® 80µg 1-2 puffs bid (80 – 
320µg/d) at an equipotent dose to replace the subject’s prior ICS. The 1st dose of QVAR® will be 
administered on-site at V1.  Subsequently, the subject will be instructed to discontinue the use of 
any other ICS for the duration of the study.
The recommended time of administration is between 8-10 am for morning dose and between 8-10 
pm for evening dose. 
All enrolled subjects will be instructed to:
1. take the same dose of QVAR®, daily, as prescribed on V1
2. refrain from taking their morning dose of QVAR® before reporting to the study site at V1.1 
and V2
3. return the QVAR® with the rest of their study drug and study material on the next visit.


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6.2.3.2 : Randomized Period (from Visit 2 to Visit 8)
Background ICS medication kit (from Visit 2 to Visit 8)
At Visit 2, the Investigator, or designee, will contact the IRT system to dispense to each 
randomized subject background ICS medication (QVAR®) at the same dose prescribed at V1, 
according to the following schedule: 

One commercial pack of QVAR® will be dispensed at V2, V4, V6 and V8 to each subject 
prescribed 1 puff bid of either QVAR® 40 or 80µg dose strength, OR

Two commercial packs of QVAR® will be dispensed at V2, V4, V6 and V8 to each subject 
prescribed 2 puffs bid of QVAR® 80µg dose strength.
The recommended time of administration is between 8-10 am for morning dose and between 8-10 
pm for evening dose. The morning dose of QVAR® will be administered on-site at V2-V9, 
immediately after study drug administration. The evening dose of QVAR® will be administered on-
site at V2-V8, immediately after all other procedures.
All randomized subjects will be instructed to:
1. take the same dose of QVAR®, daily, as prescribed on V2 until study completion at V9
2. refrain from taking their morning dose of QVAR® before reporting to the study site at each 
study visit
3. return QVAR® with the rest of their study drug and study material at each visit. 
Study Drug Administration (from V2 to V8):
At randomization visit (Visit 2), after the confirmation of the eligibility, the patient will be 
randomized to one of 12 treatment sequences. 
At Visit 2, 4, 6 and 8 the patient will receive 1 box with the randomized study drug. Each box will 
contain 2 actuators and 2 canisters for subjects randomized to Treatment Arms A to E, or 40 vials of 
PERFOROMIST® for subjects randomized to Treatment Arm F.
Patient randomized in Treatment F Arm will also receive a standard jet nebulizer equipped with a 
facemask or mouthpiece.
The first administration of study drug will take place at the clinic on visit 2 (V2) after pre-dose 
procedures have been completed and before the background medication (QVAR®) intake.
The study drug will be administered twice-a-day (in the morning and in the evening):
Morning administration (between 8-10 am):
Treatment Arms A – E: 1 inhalation from canister numbered 1 and 1 inhalation from 
canister numbered 2
Treatment Arm F: One (2mL) vial to be inhaled through standard jet nebulizer 


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Evening administration (between 8-10 pm):
Treatment Arms A – E: 1 inhalation from canister numbered 1 and 1 inhalation from 
canister numbered 2
Treatment Arm F: One (2mL) vial to be inhaled through standard jet nebulizer 
To the extent possible, the time of dosing must remain constant for each patient for the whole 
duration of the study.  On study visit days, study drug should not be taken before coming to 
the clinic.
6.2.3.3  Rescue medication
Asthma 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 through local 
procurement each subject with 1 canister of albuterol to use as asthma rescue treatment for the 
treatment of bronchospasm, as 1-2 inhalations q4-6 hours 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 for ≥ 2 consecutive days during the run-in period, or uses ≥ 4 
puffs/day above their run-in average for ≥ 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 spirometric measurements.  Albuterol will 
not be provided by the study sponsor. 
6.2.4
Subject Training
At screening visit (V1), Investigator or designee will contact IRT system to dispense a pMDI 
training kit containing one placebo canister plus one actuator for each patient (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 kits 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 pMDI. If needed, training can be repeated at following clinical visits. 
The Investigator will instruct subjects on how to use QVAR® by reading together and showing the 
QVAR® leaflet to the subjects. At each visit, the morning administration of QVAR® will be closely 
supervised by the Investigator to check whether it is conducted in accordance with the leaflet 
instruction.
When the subject is assigned to Treatment Arm F, the Investigator or designee will instruct them on 
how to use PERFOROMIST® Inhalation Solution in a standard jet nebulizer machine connected to 
an air compressor, by reading together and showing the PERFOROMIST® patient leaflet to the 
subjects. At visits requiring the administration of PERFOROMIST®, the subjects will be closely 
supervised by the Investigator or designee to check that PERFORMIST® administration is 
conducted in accordance with the leaflet instruction. 


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6.3 Packaging 
All study drug(s) will be prepared in accordance with Good Manufacturing Practices (GMP) 
requirements as required by the current Good Clinical Practices (GCP).
Chiesi will supply the background medication (for run-in and treatment period) 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 1531 pMDI placebo.

Primary packaging: One labeled aluminium canister of CHF 1531 placebo plus labeled standard 
actuator 

Secondary packaging: One carton box labeled with a study label 
6.3.2
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. 
6.3.3
Treatment kit
Treatment A, B, C, D, E

Primary packaging: Two aluminium canisters labeled with a study label plus standard actuator 
labeled with a study label. The two inhalers will be numbered 1 and 2. 

Secondary packaging: Carton box labeled with a study label.
Treatment F (Open label arm)

Primary packaging: Unit dose vials sealed in an aluminium wrap labeled. 

Secondary packaging: Carton box labeled with a study label.
6.3.4
Background medication kit for run in and treatment period

Primary packaging: One canister of QVAR® plus labeled actuator with a dose counter

Secondary packaging: One labeled commercial pack containing 1 canister plus 1 actuator with a 
dose counter.
6.4
Labeling 
All labeling will be in English language and according to local law and regulatory requirements and 
will be compliant with 21 CFR 312.6 “Labeling of an Investigational New Drug”.


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6.5
Treatment allocation
An Interactive Response Technology (IRT) system will be used at each visit (from pre-screening to 
follow-up call) to record patient status.  Patient number will be centrally assigned, through the IRT, 
during the pre-screening visit (Visit 0). 
The Investigator, or designee, at the sites will call the IRT system to screen, randomize subjects and 
assign treatment kits according to the sequence described in the randomization list.  The 
randomization list will be prepared by a specialised external provider and the whole study team, the 
investigators and the subjects will be blind to sequence assignment.  Subjects will be randomized to 
one of the 12 possible treatment sequences, according to a balanced incomplete block 
randomization scheme.
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.
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 study treatment code will be done through 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 study 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 Global Pharmacovigilance will have their own passwords to unblind subjects in 
case of SUSARs to be reported to the competent Regulatory Authorities and IRB. 
The subject will be provided with a card with the phone numbers of Hospital 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 
diary as well as the information recorded in the eCRF during the treatment visits.


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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 
to 8.
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. 
Run-in and Background medication:

The boxes of QVAR® used as run-in and background medication must be stored not above 
25˚C (77°F) by Pharmacist/Investigator at the study site and by subjects at home. 
Study drug for randomized treatment period:

CHF 1531 pMDI treatment kits and matched placebo must be stored between 2°C (36˚F) and 
8°C (46˚F) by the Investigator/Pharmacist at site. At the time of drug intake at site, the study 
drug should be removed from the refrigerator and the canister should be taken out of the 
mouthpiece and warmed with the hands for few minutes before administration to the patient. 
The canister should never be warmed by artificial means. The patient should never inhale a 
cold study drug.
Once delivered to subjects, the treatment kits must be stored at ambient temperature (not above 
25˚C [77˚F]) at home.  At this temperature condition, the actual use-by-date of the treatment 
kits will be three months (90 days). Therefore, the Pharmacist/Investigator at the hospital must 
write the use-by-date on the kit labels once the kits are removed from the refrigerator, before 
assigning to the subjects.

PERFOROMIST® treatment kits must be stored in a refrigerator, between 2°C (36˚F) to 8°C 
(46˚F). Once delivered to subjects, the treatment kits must be stored at home, between 2°C 
(36˚F) to 25˚C [77˚F]) for up to 3 months. 
Medication for training:

The pMDI training kits must be stored between 2°C (36˚F) and 8°C (46˚F) by the 
Investigator/Pharmacist at the site. At the time of the training, the training medication should be 
removed from the refrigerator and the canister should be taken out of the mouthpiece and 
warmed with the hands for few minutes before administration to the patient. The canister 


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should never be warmed by artificial means. The patient should never inhale a cold 
medication.
After usage, the training kit must be stored at room temperature (not above 25ºC [77˚F]) at the 
study sites.  At this temperature condition the actual use-by-date of the training kits will be 
three months (90 days) from the date of removal from refrigerator. The Pharmacist/Investigator 
at the hospital must write the use-by-date on the kit labels once the kits are removed from the 
refrigerator, before assigning to the subjects.
The site must check the Min/Max temperatures once daily for adequate storage conditions for the 
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 the Sponsor shall assess if 
the affected study drugs can still be used.
6.9
Drug Accountability
The Investigator, or the designated/authorized representative, is responsible for the management of 
all study drug(s). 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 the Investigator’s responsibility to prescribe the 
appropriate treatment for the subject or to restore their initial therapy or to refer them to their 
primary care physician. 


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7. STUDY PLAN
7.1 Study Schedule
Table 1: Study Flow Diagram
a In women of childbearing potential only 
b At V1: before administration of QVAR®;  and at V2-V9 : before study drug dosing  and at 30min, 1h, 4h, 8h and 12h post-dose.
c Spirometry will be carried out before and within 30 minutes after the inhalation of 4 puffs  of albuterol.
d Pre-dose FEV1, FVC: T -45’and T -15’ before administration of study drug at V2-V9 and ET.
e Post-dose serial spirometry (FEV1, FVC): 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 11.5h, 12h (V2-V9).
f Serum potassium and glucose: Pre-dose before administration of study drug at V2-V9; and Post-dose at 1.5h, 3h, 5h, 7h, and 11h at V2-V9.
g One commercial albuterol HFA pMDI (200 actuations) will be prescribed and supplied by the investigator to each subject at V1,and resupplied as needed at V2-8 based on 
   assessment of doses used between visits.
h Only Inclusion criteria #3, 4 and Exclusion criteria #1, 3, 8, 9, 13, 14.
i  Training on pMDI use will occur on V1 and V2.  Training on PERFOROMIST® use will occur when a subject is scheduled to receive Study Treatment F.
Period 1
Period 2
Period 3
Period 4
Pre-
screening
Screening
D 1
D 14
D 1
D 14
D 1
D 14
D 1
D 14
F/up 
Call
Visit
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
ET
Time (weeks)
- 2
0
2
4
6
8
10
12
14
15
Early 
Termination
Time window (days)
-
± 2
-
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
Informed Consent Form 

Demographic data

IRT visit confirmation call












Inclusion / exclusion criteria 

Asthma Action Plan Review








Eligibility recheckh

Medical history/Previous 
medication 

Weight and Height

Physical Examination



Assessment for Oral Candidiasis




Hematology and Blood 
Chemistry



Serum pregnancy test a



Urinary pregnancy test a








12-lead ECG b










Vital signs (DBP/SBP) b










Training on the use of pMDI, 
diary, PEF,  PERFOROMIST® i  





Randomization

Spirometry pre and post-BD c

Pre-dose spirometry d









Post-dose 12h serial spirometry e








Pre and post-dose Serum 
Potassium & Glucose f








ACQ questionnaire


Concomitant medications 











Adverse Events assessment 











Rescue Medication dispensationg

Dispensation / Return of 
background ICS: QVAR®
D
D/R
D/R
D/R
D/R
R
R
Study drug dispensation / return 
and Accountability
D
R
D
R
D
R
D
R
R
Subject diary/PEF dispensation 
(D) /return (R)
D
D/R
D/R
D/R
D/R
D/R
D/R
D/R
R
R
Schedule next appointment













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7.1.1
Visit 0 (Pre-screening visit)
A pre-screening visit will be carried out in order to identify eligible subjects and to fully explain the 
study.  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 next screening visit (V1) 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 (V1) will be taken in the morning before 9:00 am, 
within 1 week. The appointment day may vary depending on the washout subject shall 
respect for 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 and caffeinated substances, in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 5.2, 
unless absolutely necessary;
7.1.2
Visit 1 (Screening visit / Week -2)
A screening visit will start 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 morning of the rescheduled visit, the subject will be discontinued and 
recorded in the IRT and eCRF as screen failure.
The following procedures will take place:
-
Confirm that the diagnosis of asthma as defined in the GINA Report, 2016 has been 
documented for at least 1 year prior to screening.
-
The ACQ questionnaire will be completed (see section 7.2.1).
-
Weight and height will be recorded.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator and background ICS medication (QVAR®) administration, after 
5 minutes of rest, in resting position (see section 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator and run-in medication 
(QVAR®) administration, after 5 minutes of rest (see section 7.2.4). A subject will not be 
eligible in case of QTcF >450ms for males or QTcF >470ms 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 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 for oral candidiasis.
-
A urine pregnancy test in women with childbearing potential will be performed.
-
A blood sample will be collected before albuterol administration, after an overnight fasting 
(at least 10h), for the assessments of (see section 7.2.8):
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 carried out: to assess FEV1, FVC (see section 7.2.5). 
To be eligible, FEV1 must be ≥60% and <85% of the subject’s predicted normal value.
-
Post-bronchodilator spirometry (reversibility) will be carried out within 30 minutes after 
intake of 4 puffs of albuterol HFA (90µg/actuation). To be eligible, the post-bronchodilator 
increase in FEV1 must be ≥12% and ≥200mL from subject’s pre-bronchodilator baseline. 
-
If the reversibility criteria are not met at V1, this test can be performed once more before 
Visit 2 after an appropriate washout from bronchodilators. If this occurs, inclusion criteria 
# 3 and 4 must also be repeated and met on the same day, and before reversibility test is 
conducted.
-
Any AE occurring since the signature of the Informed Consent will be assessed 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, 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 daily record the medications intake (background ICS 
and rescue), and adverse events in the paper Diary (see section 7.2.6).
-
The investigator will access IRT also in order to obtain the background ICS medication (one 
commercial box containing 1 canister of QVAR® 40 or 80µg to be dispensed to the subject 
together with instructions for use. The investigator will prescribe the subject QVAR® 40µg 


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or QVAR® 80µg 1-2 puffs bid (80 – 320µg/d) at an equipotent dose to replace the subject’s 
prior ICS. Subject will be instructed to take the QVAR® in the morning (between 8-10 am) 
and in the evening (between 8-10 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 medications (including any other ICS, 
LABA, or LAMA) in accordance with section 5.2.
-
Rescue albuterol, for use as needed, will be dispensed by the Investigator. Subjects will keep 
this rescue albuterol throughout the study period (will be re-supplied if needed); 
nevertheless subject will be instructed to return this medication at each visit in order to 
check the need for replacement.
Before discharge:
-
Rescue albuterol will be dispensed and the subject will be instructed to take albuterol as 
rescue if necessary. 
-
A paper diary will be dispensed along with a peak flow meter. Subject must complete the 
diary on a daily basis through Visit 2. It is important to ensure a good compliance of the 
subject to the use of the paper Diary during the run-in period and throughout the study.
-
Asthma Action Plan will be communicated to the subject.
-
An appointment for Visit 2 will be made within 2 week (+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:
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 and caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 5.2 
unless absolutely necessary.
Not to take background ICS medication (QVAR®) in the morning of the next visit.
To return the rescue medication (in their boxes), and the paper Diary. 
7.1.3
Visit 2 (Randomization / Period 1, Day 1) 
The Visit 2 will start in the morning (before 9:00 am).
If caffeine was ingested, or rescue albuterol was inhaled in the previous 6 hours, or the washout for 
non-permitted medications was not respected, or the background ICS medication (QVAR®) was 
taken the morning of the visit (before 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 ACQ questionnaire will be completed (see section 7.2.1).


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-
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 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest (see section 
7.2.3). 
-
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).
-
The investigator (or designee) will check the subject diary whether the subject has recorded 
rescue medication intake since the screening. The investigator/designee will also check to 
see if the subject recorded the PEF measurements.  In case of lack of compliance in the 
diary use, instructions on how to fill the diary will be provided again to the subject.
-
A urine pregnancy test in women with childbearing potential will be performed.
-
A pre-dose serum potassium and glucose will be conducted before study drug administration 
(see section 7.2.7)
-
The occurrence of adverse events will be checked and recorded if any.
-
The proper use of pressurized metered dose inhaler (pMDI) will be checked and subject will 
be retrained on the usage of the pMDI using the Training kit previously assigned at V1 (see 
section 6.2.4). 
-
Pre-dose spirometry: Pre-dose spirometry measurement will then be performed to assess 
FEV1 and FVC prior to subject randomization.  This measurement will be taken at T -45’ 
and T -15’ before 1st dose of study drug and will constitute the baseline value (see section 
7.2.5). Both T -15 min and T -45 min assessments must be performed and the selected best 
FEV1 at each timepoint must be ≥60% and <85% of predicted in order to meet Inclusion 
Criterion #4.
-
Assessment for oral candidiasis.
-
Eligibility criteria will be rechecked (Inclusion #3, 4, 7; Exclusion #1, 3, 8, 9, 13, 14). 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 additional time, after 1 month 
from the date of the initial screening failure. A rescreened 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 2-week treatment period. 
-
For subjects randomized to receive open-label PERFOROMIST® Inhalation Solution (Study 
Treatment F), the Investigator will instruct subjects on how to use PERFOROMIST® 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 (for this treatment period) will take 
place at the clinic visit (before 10:00 am) under supervision of the Investigator. The 


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corresponding tear-off labels will be placed in the dispensation tracking form and the kit 
number will be recorded in the corresponding electronic CRF (e-CRF). The use-by-date 
must be filled-in on the labels. Drug administration will be done according to section 6.2.3.
-
The morning dose of the background ICS QVAR® will be administered immediately after 
the study drug, at the dose prescribed at V1.
-
Post-dose spirometry will be performed (FEV1, FVC) at 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 
10h, 11.5h, 12h. For each time point, spirometry consists in three acceptable maneuvers (see 
section 7.2.5).
-
Post-dose SBP/DBP assessments will be conducted after 5 minutes of rest at 30min, 1h, 4h, 
8h and 12h (see section 7.2.2).
-
Post-dose 12-lead ECG assessments will be conducted after 5 minutes of rest at 30min, 1h, 
4h, 8h and 12h (see section 7.2.4).
-
Post-dose serum potassium and glucose assessments will be conducted at 1.5h, 3h, 5h, 7h, 
and 11h (see section 7.2.7)
-
The evening dose of study drug will be administered at the clinic under supervision, 
followed by immediately by the evening dose of the background ICS (QVAR®) once the 
12h spirometry and all other procedures have been completed.
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.
-
A paper diary will be dispensed along with the same peak flow meter. Subject must 
complete the diary on a daily basis and return the completed diary at the next visit.  
-
Asthma Action Plan will be reviewed with the subject.
-
An appointment for Visit 3 will be made at 2 weeks (±2 days) from Visit 2 (at 
approximately the same time as Visit 2, before 9:00 am). The subject will be instructed:
To fast overnight (at least 10 hours) for the next visit in order to perform blood 
sampling (only water is allowed);
To return the paper Diary, the study medication and rescue medication (in the boxes) at 
the next visit.
Not to take albuterol and caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 
5.2 unless absolutely necessary. 
Not to take the morning dose of the study drug and background ICS (QVAR®) 
before coming to the next clinic visit (they will be administered at the clinic visit).
7.1.4
Visit 3 (Period 1, Day 14)
Visit 3 will start in the morning (before 9:00 am).
If caffeine was ingested, or rescue albuterol was inhaled in the previous 6 hours, or the washout for 
non-permitted medications was not respected, or QVAR® or the study drug was taken the morning 


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of the visit (before 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:
-
Study drug from visit 2 will be reviewed for accountability and provided back to the subject.
-
Pre-dose vital 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 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest (see section 
7.2.4). 
-
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.
-
A pre-dose serum potassium and blood glucose will be conducted.
-
The occurrence of other adverse events will be checked and recorded if any.
-
The investigator (or designee) will check the subject diary whether the subject has recorded 
rescue medication intake since the last visit. The investigator/designee will also check to see 
if the subject recorded the PEF measurements.  In case of lack of compliance in the diary 
use, instructions on how to fill the diary will be provided again to the subject.
-
The Investigator will access IRT to record the visit.
-
Pre-dose spirometry: FVC pre-dose spirometry measurement will then be performed to 
assess FEV1 and FVC. This measurement will be taken at T -45’ and T -15’ prior to study 
drug intake.  
-
The administration of the last dose of study drug (for this treatment period) will take 
place at the clinic visit (before 10:00 am) under supervision of the Investigator.
-
The morning dose of the background ICS QVAR® will be administered immediately after 
the study drug, at the dose prescribed at V1.
-
Post-dose spirometry will be performed 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 11.5h, and 
12h. For each time point, spirometry consists in three acceptable maneuvers (see 
section 7.2.5).
-
Post-dose SBP/DBP assessments will be conducted after 5 minutes of rest at 30min, 1h, 4h, 
8h and 12h (see section 7.2.2).
-
Post-dose 12-lead ECG assessments will be conducted after 5 minutes of rest at 30min, 1h, 
4h, 8h and 12h (see section 7.2.4).
-
Post-dose serum potassium and glucose assessments will be conducted at 1.5h, 3h, 5h, 7h, 
and 11h (see section 7.2.7).
-
The evening dose of the background ICS QVAR® will be administered at the clinic under 
supervision, once the 12h spirometry and all other procedures have been completed.


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Before discharge
-
If needed, additional rescue medication will be dispensed to the subject together with 
instructions for use. 
-
A paper diary will be dispensed along with the same peak flow meter. Subject must 
complete the diary on a daily basis and return the completed diary at the next visit.  
-
Asthma Action Plan will be reviewed with the subject.
-
An appointment for Visit 4 will be made at 2 weeks (±2 days) from Visit 3 (at 
approximately the same time as Visit 3, before 9:00 am). The subject will be instructed:
To fast overnight (at least 10 hours) for the next visit in order to perform blood 
sampling (only water is allowed);
To return the paper Diary, and rescue medication at the next visit.
Not to take albuterol and caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 
5.2 unless absolutely necessary.
Not to take the morning dose of the background ICS (QVAR®) before coming to 
the next clinic visit (it will be administered at the clinic visit).
7.1.5
Visit 4 (Period 2, Day 1), Visit 6 (Period 3, Day 1) and Visit 8 (Period 4, Day 1)
The Visit will start in the morning (before 9:00 am), and will begin the applicable period, Day 1.
If caffeine was ingested, or rescue albuterol was inhaled in the previous 6 hours, or the washout for 
non-permitted medications was not respected, or QVAR® was taken the morning of the visit (before 
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:
-
Study drug from the previous visit will be collected and reviewed for accountability. 
-
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 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest (see section 
7.2.4). 
-
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).
-
The investigator (or designee) will check the subject diary whether the subject has recorded 
rescue medication intake since the last visit. The investigator/designee will also check to see 


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if the subject recorded the PEF measurements.  In case of lack of compliance in the diary 
use, instructions on how to fill the diary will be provided again to the subject.
-
A urine pregnancy test in women with childbearing potential will be performed.
-
A pre-dose serum potassium and glucose will be conducted.
-
The occurrence of adverse events will be checked and recorded if any.
-
The Investigator will access IRT to record the visit and to obtain the appropriate kit number 
for the corresponding 2-week treatment period.
-
Pre-dose spirometry:  FVC pre-dose spirometry measurement will then be performed to 
assess FEV1 and FVC. This measurement will be taken at T -45’ and T -15’ (see section 
7.2.5). 
-
The administration of the 1st dose of study drug from the new kit (for this treatment 
period) 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 (e-CRF). The 
use-by-date must be filled-in on the labels. Drug administration will be done according to 
section 6.2.3.
-
For subjects randomized to receive open-label PERFOROMIST® Inhalation Solution 
(Study Treatment F), the Investigator will instruct subjects on how to use 
PERFOROMIST® by reading together and showing the FDA-approved Patient Information 
Leaflet to the subjects, in accordance with section 6.2.4.
-
The morning dose of the background ICS QVAR® will be administered immediately after 
the study drug, at the dose prescribed at V1.
-
Post-dose spirometry will be performed (FEV1, FVC) at 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 
10h, 11.5h, and 12h. For each time point, spirometry consists in three acceptable maneuvers 
(see section 7.2.5).
-
Post-dose SBP/DBP assessments will be conducted after 5 minutes of rest at 30min, 1h, 4h, 
8h and 12h (see section 7.2.2).
-
Post-dose 12-lead ECG assessments will be conducted after 5 minutes of rest at 30min, 1h, 
4h, 8h and 12h (see section 7.2.4).
-
Post-dose serum potassium and glucose assessments will be conducted at 1.5h, 3h, 5h, 7h, 
and 11h (see section 7.2.7).
-
The evening dose of study drug will be administered at the clinic under supervision, 
followed by immediately by the evening dose of the background ICS (QVAR®) once the 
12h spirometry and all other procedures have been completed (see section 7.2).
Before discharge
-
Study drug will be dispensed to the subject together with instructions for use. Drug 
administration will be done according to section 6.2.2. Subject will be instructed to take 
albuterol as rescue if necessary. Investigator will also dispense albuterol if needed.
-
A paper diary will be dispensed along with the same peak flow meter. Subject must 
complete the diary on a daily basis and return the completed diary at the next visit.  
-
Asthma Action Plan will be reviewed with the subject.


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-
An appointment for the next visit will be made at 2 weeks (±2 days) from current visit (at 
approximately the same time as current visit, before 9:00 am). The subject will be 
instructed:
To fast overnight (at least 10 hours) for the next visit in order to perform blood 
sampling (only water is allowed);
To return the paper Diary, the study drug and rescue medication (in the boxes) at the 
next visit.
Not to take albuterol and caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 
5.2 unless absolutely necessary. 
Not to take the morning dose of the study drug and the background ICS (QVAR®) 
before coming to the next clinic visit (they will be administered at the clinic visit).
7.1.6
Visit 5 (Period 2, Day 14) and Visit 7 (Period 3, Day 14)
The Visit will start in the morning (before 9:00 am).
If caffeine was ingested, or rescue albuterol was inhaled in the previous 6 hours, or the washout for 
non-permitted medications was not respected, or QVAR® or the study drug was taken the morning 
of the visit (before 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 procedures will be performed:
-
Study drug from the previous visit will be reviewed for accountability and provided back to 
the subject.
-
Pre-dose vital 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 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, background ICS  
medication (QVAR®) or study drug administration, after 5 minutes of rest (see section 
7.2.4). 
-
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.
-
A pre-dose serum potassium and blood glucose will be conducted.
-
The occurrence of adverse events will be checked and recorded if any.
-
The investigator (or designee) will check the subject diary whether the subject has recorded 
rescue medication intake since the last visit. The investigator/designee will also check to see 
if the subject recorded the PEF measurements.  In case of lack of compliance in the diary 
use, instructions on how to fill the diary will be provided again to the subject.


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The Investigator will access IRT to record the visit.
-
Pre-dose spirometry:  FVC pre-dose spirometry measurement will then be performed to 
assess FEV1 and FVC. This measurement will be taken at T -45’ and T -15’ prior to study 
drug intake.  
-
The administration of the last dose of study drug (for this treatment period) will take 
place at the clinic visit (before 10:00 am) under supervision of the Investigator.
-
The morning dose of the background ICS QVAR® will be administered immediately after 
the study drug, at the dose prescribed at V1
-
Post-dose spirometry will be performed 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 11.5h, and 
12h. For each time point, spirometry consists in three acceptable maneuvers (see 
section 7.2.5).
-
Post-dose SBP/DBP assessments will be conducted after 5 minutes of rest at 30min, 1h, 4h, 
8h and 12h (see section 7.2.2).
-
Post-dose 12-lead ECG assessments will be conducted after 5 minutes of rest at 30min, 1h, 
4h, 8h and 12h (see section 7.2.4).
-
Post-dose serum potassium and glucose assessments will be conducted at 1.5h, 3h, 5h, 7h, 
and 11h (see section 7.2.7).
-
The evening dose of the background ICS QVAR® will be administered at the clinic under 
supervision, once the 12h spirometry and all other procedures have been completed.
Before discharge
-
If needed, additional rescue medication will be dispensed to the subject together with 
instructions for use. 
-
A paper diary will be dispensed along with the same peak flow meter. Subject must 
complete the diary on a daily basis and return the completed diary at the next visit.  
-
Asthma Action Plan will be reviewed with the subject.
-
An appointment for the next visit will be made at 2 weeks (±2 days) from current visit (at 
approximately the same time as current visit, before 9:00 am). The subject will be 
instructed:
To fast overnight (at least 10 hours) for the next visit in order to perform blood 
sampling (only water is allowed);
To return the paper Diary and rescue medication at the next visit.
Not to take albuterol and caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 5.2 
unless absolutely necessary.
7.1.7
Visit 9 (Period 4, Day 14)
The Visit 9 will start in the morning (before 9:00 am).
If caffeine was ingested, or rescue albuterol was inhaled in the previous 6 hours, or the washout for 
non-permitted medications was not respected, or QVAR® or the study drug was taken the morning 
of the visit (before spirometry), the visit needs to be re-scheduled to take place within 2 days. Only 


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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 procedures will be performed:
-
Study drug from Visit 8 will be collected and reviewed for accountability.
-
Pre-dose vital 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 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest (see section 
7.2.4). 
-
The investigator (or designee) will check the subject diary whether the subject has recorded 
rescue medication intake since the last visit. The investigator/designee will also check to see 
if the subject recorded the PEF measurements.  
-
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 full physical examination will be performed, including an assessment of the 
presence/absence of oral candidiasis.
-
A blood sample will be collected before bronchodilator, background ICS medication 
(QVAR®) or study drug administration, after an overnight fasting (at least 10h), for the 
assessments of (see section 7.2.8):
standard hematology and blood chemistry;
serum -HCG test in women of childbearing potential.
pre-dose serum potassium and glucose.
The blood samples must be collected after vital signs and 12-lead ECG recording.
-
The occurrence of adverse events will be checked and recorded if any.
-
The investigator will collect the paper diary to verify the study drug compliance and rescue 
medication intake.
-
The investigator will access IRT to record the visit.
-
Pre-dose spirometry: FVC pre-dose spirometry measurement will then be performed to 
assess FEV1 and FVC. This measurement will be taken at T -45’ and T -15’ prior to study 
drug intake.  
-
The administration of the last and final dose of study drug will take place at the clinic 
visit (before 10:00 am) under supervision of the Investigator. 
-
The morning dose of the background ICS QVAR® will be administered immediately after 
the study drug, at the dose prescribed at V1.
-
Post-dose spirometry will be performed 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 11.5h, and 
12h. For each time point, spirometry consists in three acceptable maneuvers (see 
section 7.2.5).


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-
Post-dose SBP/DBP assessments will be conducted after 5 minutes of rest at 30min, 1h, 4h, 
8h and 12h (see section 7.2.2).
-
Post-dose 12-lead ECG assessments will be conducted after 5 minutes of rest at 30min, 1h, 
4h, 8h and 12h (see section 7.2.4).
-
Post-dose serum potassium and blood glucose assessments will be conducted at 1.5h, 3h, 5h, 
7h, and 11h (see section 7.2.7).
Before discharge at Visit 9
-
All study material (study and rescue medications, subject diary including Peak Flow 
meter) will be collected.
-
The investigator will prescribe the most appropriate treatment or restore the initial therapy 
or refer the subject to their primary care physician.
-
An appointment will be made in 1 week time for the follow-up phone call.
7.1.8
Follow-up Phone Call (Visit 10)
A safety follow-up phone call will be performed by the investigator or designated staff no later than 
1 week after the final visit (V9) or Early Termination Visit to check the status of unresolved AEs 
and to record any new AEs that may have occurred after V9, as well as related concomitant 
medications. 
7.1.9
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 including Peak Flow meter) 
will be collected.
-
Site to update IRT .
-
Vital 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 7.2.2).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, background ICS 
medication (QVAR®) or study drug administration, after 5 minutes of rest (see section 
7.2.4). 
-
Changes of concomitant medications being taken by the subject will be recorded. 
-
A full physical examination will be performed, including an assessment of the 
presence/absence of oral candidiasis.
-
A blood sample will be collected before bronchodilator, background ICS medication 
(QVAR®) or study drug administration, after an overnight fasting (at least 10h, when 
possible), for the assessments of (see section 7.2.8):
standard hematology and blood chemistry;


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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 adverse events will be checked and recorded if any.
-
The investigator will collect the paper diary to verify the study drug compliance and rescue 
medication intake.
-
Spirometry: FVC pre-dose spirometry measurement will then be performed to assess FEV1 
and FVC. This measurement will be taken before the expected time of dosing (T-45 and T-
15) (the subject will not be dosed).  
-
The investigator will prescribe the most appropriate treatment or restore the initial therapy 
or refer the subject to their primary care physician.
-
An appointment will be made in 1 week time for the follow-up phone call.
7.2 Investigations
7.2.1
ACQ Questionnaire
The Asthma Control Questionnaire (ACQ) is a validated questionnaire that measures the adequacy 
of asthma control and change in asthma control which occurs either spontaneously or as a result of 
treatment. The ACQ consists of 7 items: six simple, self-administered questions referring to asthma 
control and rescue treatment usage with one week recall, and a seventh item consisting of the % 
predicted FEV1 completed by clinic staff. Scoring uses a 7-point scale, with 0 indicating “totally 
controlled” and 6 indicating “severely uncontrolled”. The ACQ score will be calculated as the 
average of all 7 items. A score of 0.0–0.75 is classified as well-controlled asthma; 0.75–1.5 as a 
grey zone; and >1.5 as poorly controlled asthma. The MCID is considered to be a change of 0.5 
unit.[65][70]  The ACQ will be completed on site, at Visit1 and Visit 2. Only subjects with an 
ACQ-7 score 1.5 are eligible for randomization (the criteria must be met at screening and at the 
end of the run-in period).  The 7th item should be populated using the pre-BD FEV1 at the visit 
when reversibility is met (V1 or V1.1) and the T-15 minutes FEV1 assessment at V2.
The ACQ-7 is provided on paper and should be completed by the patient in a quiet place before the 
pulmonary function testing, only question 7 will be completed after the testing. The investigator (or 
designated site-personnel) should check that all items have been completed by the patient, but the 
response to each item should not be questioned. The scores will then be transcribed into the eCRF 
by the Investigator (or designated site personnel).
7.2.2
Vital Signs
Systolic and diastolic blood pressure will be measured after 5 min rest in resting position. The 
measurements will be done before morning dose of study drug and background ICS medication 
(QVAR®) at all visits,  and 30 mins, 1h, 4h, 8h and 12h post-dose (V2-V9). SBP and DBP has 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 approximately the same time.


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7.2.3
Physical Exam and assessment of oral candidiasis 
A full physical examination including an assessment of the presence/absence of oral candidiasis 
will be performed at V1, V9 and Early Termination. These examinations shall be completed before 
spirometry testing, administration of study drug, bronchodilator, or background ICS (QVAR®) 
medication.
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. Generalized immunosuppressive and anti-inflammatory effects of steroids are 
thought to play a major role in the pathogenesis of candidiasis. Asthmatics who are using β-2 
agonists show a decreased salivary flow rate, which in turn can be associated with higher oral 
Candida counts. 
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.
7.2.4
12-lead ECG
A 12-lead ECG will be performed before morning dose of study drug and background ICS 
medication (QVAR®) at all visits to verify the patient’s cardiac safety parameters and his/her 
eligibility. Subjects will be instructed to refrain from the intake of any caffeinated beverages or 
foods past midnight before each visit. At Visits 2-9, the ECG will be performed also at 30 min, 1h, 
4h, 8h and 12h after the morning dose of study drug. Prior to recording, the patient should be at rest 
for at least 5 minutes. A 10-second strip will be recorded in triplicate, at 30-sec intervals at each 
time-point.
Standard electrode placement will be used for these ECG, including placing the limb leads, dual 
snap electrodes will be used for the precordial leads. 
ECG will be evaluated and interpreted at a central laboratory and in case of any abnormality 
requiring urgent action ECG should be also evaluated on site (before sending to central laboratory).
The specific procedures for ECG recording, reading and transmission of the results will be provided 
to the investigator by the central laboratory.
QT interval corrections (QTc) will be done using the following formulae:

QTcF (Fridericia’s correction) = 
.  This will be done by both the centralized ECG service 
𝑄𝑇
3 𝑅𝑅
provider and by the on-site investigator to confirm if the subject meets the 
Inclusion/Exclusion criteria at V1, and for safety monitoring at subsequent visits. 


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Digitalized 12-lead ECG will be measured in supine position after at least 5 min rest. ECGs will be 
digitally recorded and sent to a central laboratory for a high resolution digital manual measurement 
of the cardiac intervals and morphological changes (HR, PR, QRS, QTcF). ECG measurements will 
be performed by experienced technicians using digitization software with magnification of the ECG 
and point to point determination on the digitizing pad and by a centralized cardiologist.
ECGs with computerized protocol interpretation are considered normal if 
-
40 ≤ Heart rate ≤ 110bpm, 
-
120ms ≤ PR ≤ 210ms, 
-
QRS ≤ 120ms.
For eligible subjects, QTcF values must be QTcF ≤ 450ms (for males) and ≤ 470ms (for females) 
(as per Exclusion Criterion 14).
In case of relevant ECG abnormalities, the inclusion of the patient will be judged by the 
investigator. For any doubts the Investigator may consult the study clinical monitor. The final 
decision for enrollment 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.  A review and interpretation of all ECGs will be performed 
by the cardiologist of the central laboratory. Any discrepancy observed between the cardiologist and 
the investigator assessment will be discussed during the study as part of the on-going medical 
review activities. 
7.2.5
Pulmonary Function Test
All pulmonary function tests including FEV1 and FVC will be performed in accordance with 
ATS/ERS spirometry criteria,[71] 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. 
Pulmonary function measurements will be done with subjects sitting with the nose clipped after at 
least 10 minutes rest. Calibration of the spirometer must be performed by the same investigator or 
designee (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 patient.
The following parameters will be recorded at Visit 1-9 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.


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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.
Note: some additional standard parameters (for instance PEF, FEF25-75%, or ratio FEV1/FVC) will be 
assessed by the spirometer during the visit only for the investigator’s informational purpose.
Predicted normal value for FEV1 will be calculated using the Third National Health and Nutrition 
Examination Survey (NHANES III) reference equations.[72].
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 (≤ 100mL when FVC is < 1L).[73] If these criteria are not met in 3 maneuvers, 
additional trials should be attempted, up to, but usually no more than 8.
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 patient 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 patient requires rescue medication within this 
timeframe, the visit should be rescheduled once within the next two days.
The background ICS 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).
At Visit 1, airway reversibility will be assessed with spirometry in triplicate maneuvers (as 
described above) before and within 30 minutes after administration of 4 separate doses of albuterol 
HFA (90µg of albuterol/actuation, total dose 360µg) at 30-sec intervals. An increase in FEV1 ≥12% 
of control and ≥200mL constitutes a positive bronchodilator response.[66]
At Visits 2-9, serial spirometry will be conducted at T-45 and T-15 minutes pre-morning dose and 
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.


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At the Early Termination Visit, pre-dose spirometry measurement will be performed to assess FEV1 
and FVC. Measurements will be taken at 15 and 45 min before the expected time of dosing (T-45 
and T-15). The subject will not be dosed.  
7.2.6
Subject Diaries
Using paper diary dispensed at visits V1 – V8, subjects will be instructed to: 

Enter a daily record of day-time and night-time Asthma Symptom Score (overall 
symptoms, cough, wheeze, chest tightness and breathlessness), as follows: 

Morning (night-time asthma symptom score):
0 No symptom
1 Mild: symptoms not causing awakening
2 Moderate: discomfort enough to cause awakenings
3 Severe: causing awakenings for most of the night / do not allow to sleep at all

Evening (daytime asthma symptom score):
0 No symptom
1 Mild: aware of symptoms which can be easily tolerated
2 Moderate: discomfort enough to cause interference with daily activity 
3 Severe: incapacitating with inability to work/take part in usual activity

Record the daily use of Asthma Rescue Medication as follows: the number of puffs taken 
during the night will be recorded each morning on awakening, while the number of puffs 
taken during the day will be recorded each evening, both before taking the study drug

Perform Peak Expiratory Flow rate (PEF, L/min) measurements twice daily, in triplicate, 
starting at V1 using a portable electronic peak flow meter. (Vitalograph asma-1™). Subjects 
will be educated on the purpose and technique of PEF home monitoring. Specific 
instructions for use will be made available to the subjects.  During each measurement 
session (morning or evening before the intake of the background ICS medication QVAR® or 
the study drug) the patient will perform 3 exhalations and will record the best measurement 
in the diary. Morning measurements should be done approximately between 7:00 am and 
9:00 am and evening measurements should be done approximately between 7:00 pm and 
9:00 pm. 

Enter twice daily (am and pm) the number of study drug doses taken.  

Record twice daily all doses of QVAR® background medication.
7.2.7
Serum Potassium and Glucose
β-adrenergic receptor agonist medications may produce significant hypokalemia in some subjects, 
possibly through intracellular shunting, which has the potential to produce adverse cardiovascular 
effects The decrease in serum potassium is usually transient, not requiring supplementation. β-
adrenergic receptor agonist medications may also produce transient hyperglycemia in some 
subjects.[59]  At V2-9, blood samples of about 2.5 mL will be collected for measuring serum 
potassium and glucose pre-dose and at 1.5, 3, 5, 7 and 11h post-dose (total blood volume = 15 
mL/Visit).


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7.2.8
Hematology, Chemistry, and Pregnancy Tests
Blood samples of about 12 mL will be collected for hematology and serum chemistry at Visit 1, 
Visit 9 and Early Termination in the morning, after an overnight fasting of at least 10 hours (only 
water is allowed during the night) and before administration of albuterol, QVAR® or study drug. 
The blood withdrawal should be performed after vital signs and 12-lead ECG recording. An 
additional blood sample will be collected for serum pregnancy test in women of childbearing 
potential at these Visits, and a urine pregnancy test will be performed at visits (V1-8).
The following evaluations will be performed using a central laboratory:

A hematology test: red blood cells count (RBC), white blood cells count (WBC) and 
differential, total hemoglobin (Hb), hematocrit (Hct), platelets count (PLT).

A 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, glucose and electrolytes (sodium, potassium, calcium, and chloride). 

A serum pregnancy test (serum β-hCG) in women of child-bearing potential.

A urine pregnancy test 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.
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 V1), or as an 
Adverse Event (if occurred after V1).  
7.2.9
Asthma Action Plan and Handling of Asthma Exacerbations
The subject will be instructed to contact the site immediately if they experience a moderate or 
severe asthma exacerbation based on the following definitions:
Severe Asthma Exacerbation[74]
Severe asthma exacerbations are events that require urgent action on the part of the patient and 
physician to prevent a serious outcome, such as hospitalization or death from asthma. The definition 
of a severe asthma exacerbation for clinical trials should include at least one of the following:

Use of systemic corticosteroids (tablets, suspension, or injection), or an increase from a 
stable maintenance dose, for ≥ consecutive 3 days.
o
For consistency, courses of corticosteroids separated by 1 week or more should be 
treated as separate severe exacerbations.

A hospitalization or ER visit because of asthma, requiring systemic corticosteroids.
Moderate Asthma Exacerbation[75]
A moderate exacerbation is defined as ≥1 of criteria fulfilled and leading to a change in treatment*:
a) Nocturnal awakening(s) due to asthma requiring SABA for 2 consecutive nights 


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b) Increase from baseline in occasions of SABA use on 2 consecutive days (minimum increase: 
4 puffs/day)
c) ≥20% decrease in am or pm PEF from respective baseline on ≥ 2 consecutive 
mornings/evenings or ≥20% decrease in FEV1 from baseline
d) Visit to the emergency room/trial site for asthma treatment not requiring systemic 
corticosteroids
Subjects who experience a severe asthma exacerbation will be instructed to visit the site as soon as 
possible for an Early Termination Visit and will be withdrawn permanently from the study.  
Appropriate medical management of all asthma exacerbations will be ensured by the study 
investigator with the aim to preserve the research subject’s well-being at all times. 
*A change in treatment should be reviewed with the subject for any non-permitted concomitant 
medication that may trigger Early Termination from the study.
8
EFFICACY ASSESSMENTS
Primary efficacy variable

Change from baseline in FEV1 AUC0-12h normalized by time at Day 14
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 Day 14

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 at Day 14

Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) 
at Day 14

Change from baseline in pre-dose morning FVC (average of pre-dose FVC measurements) 
at Day 14

Time to onset of action (change from baseline in post-dose FEV1 ≥ 12% and ≥ 200 mL) at 
Day 1
9
SAFETY ASSESSMENTS

Adverse Events (AEs) and Adverse Drug Reactions (ADRs)

Vital signs (systolic and diastolic blood pressure)

12-lead ECG parameters (HR, QTcF, QRS, PR)

HR AUC0-4h normalized by time and HR peak0-4h 

Serum potassium and blood glucose
10 ADVERSE EVENT REPORTING
10.1
Definitions
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 


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this treatment”.  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 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 anaemia, 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 overnight formal 
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 a 
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
-
Is a medically significant adverse event
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.


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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 infectious agent is 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 1531 pMDI   or 
US-FDA approved Product Information for PERFOROMIST®), 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.
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.


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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 
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
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 


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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 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 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.
E-mail
, MD
Medical Safety Officer
Global Pharmacovigilance, Chiesi Farmaceutici S.p.A.
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 events occurring after the site is closed should be reported 
directly to the Chiesi Safety Contact.


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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. 
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 
medications 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 
SAEs. 
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, the background 
ICS, or the rescue medication, the pregnancy does not need to be reported; it is only required 
that the subject is immediately withdrawn from the study.


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11 DATA MANAGEMENT
An electronic CRF (eCRF) will be filled-in by the Investigator and/or his/her designee. 
All subjects who will sign the Informed Consent will be entered into the database. 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.
Questionnaire (ACQ) patient’s answers and daily diary 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, 12-Lead ECG, Central Laboratory) 
will be processed centrally and results will be sent electronically to the designated CRO.  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 patient 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 1531 pMDI at different 
doses over placebo in terms of change from baseline in FEV1 AUC0-12h normalized by time at Day 
14. The calculation is based on simulations.
A total of 51 evaluable subjects will provide 96% power to detect a mean difference of 200 mL 
between each dose of CHF 1531 pMDI and placebo at a two-sided significance level of 0.0125, 
assuming a within-subject standard deviation of 180 mL.  Since four dose levels will be tested, the 
Edwards and Berry method[76]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[76] method is uniformly more powerful than the Bonferroni 
procedure.
Considering a non-evaluable rate of 15%, a total of approximately 60 subjects (5 subjects for each 
of the 12 treatment sequences) will be randomized.
12.2 Populations for analysis
Safety population: all randomized subjects who receive at least one dose of study drug.


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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.
The inclusion in each population will be defined on a per-period basis.  Since the superiority of 
CHF 1531 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 analyzes (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 (except for baseline 
characteristics which will be provided overall) 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.
12.3.2 Missing data
If one of the spirometry measurements at T-45 min and T-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 for spirometry data, 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 12h post-dose is missing, it will be replaced by the value at 11.5h;
o In case of two or more consecutive missing values or more than three missing values, the 
entire curve will be missing.


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In case of rescue medication intake during the serial spirometry (from pre-dose to 12h 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 45min, 
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 time-point with change from baseline in FEV1 ≥ 12% and ≥ 
200 mL, then Time to onset of action will be equal to the first post-dose time-point with change 
from baseline in FEV1 ≥ 12% and ≥ 200mL in the time interval considered (12h). In case of no 
time-point with change from baseline in FEV1 ≥ 12% and ≥ 200mL, and less than four missing 
values among post-dose spirometry measurements at 15min, 30min, 45min, 1h, 2h, 3h and 4h, 
then Time to onset of action will be equal to the last available post-dose time-point with non-
missing data and the subject will be considered as censored in the analysis.
HR AUC0-4h will be calculated only if HR data are recorded on each time-point (pre-dose, and 
30 minutes, 1h, 4h post-dose).
HR peak0-4h will be calculated only if HR data are recorded on each post-dose time-point (30 
minutes, 1h, 4h post-dose).
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.
12.3.3 Patient demographics and baseline characteristics
The following variables will be summarized overall 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 at Day 14 will be analyzed using an 
Analysis of Covariance (ANCOVA) model including treatment, period and subject as fixed effects 
and baseline (average of the pre-dose FEV1 measurements on Day 1 of each treatment period) as a 
covariate. The adjusted means in each treatment group, the adjusted mean difference between 
treatments and their 95% Confidence Intervals (CIs) at Day 14 will be estimated by the model. The 
CIs and the p-values of the comparisons between each dose of FF pMDI and placebo will be 
adjusted for multiplicity. The adjustment will be based on the parametric simulation method by 
Edwards and Berry.[75] At each dose level, the superiority of CHF 1531 pMDI over placebo will be 
demonstrated by a statistically significant difference (adjusted p-value < 0.05) favoring CHF 1531 
pMDI.
All the other comparisons between treatments will be performed as secondary efficacy analyzes 
with no multiplicity adjustment.


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12.3.5 Secondary efficacy variables
No multiplicity adjustment will be performed in the secondary efficacy analyzes.
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 Day 14 and change from 
baseline in pre-dose morning FEV1 at Day 14 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 Day 14 and change from baseline in pre-dose morning 
FVC at Day 14 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 ≥ 12% and ≥ 200 mL) at 
Day 1 will be analyzed using a Cox proportional hazard model stratified by subject and with 
treatment and period as factor and baseline FEV1 (average of the pre-dose FEV1 measurements 
on Day 1 of each treatment period) as covariate. A Kaplan-Meier plot will be presented. 
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 
measurement on Day 1 of each treatment period) and from pre-dose on Day 14 will be summarized 
by treatment using descriptive statistics and the 95% CI of the mean.
ECG
12-lead ECG parameters (HR, QTcF, QRS and PR) and their changes from baseline (pre-dose 
measurement on Day 1 of each treatment period) and from pre-dose on Day 14 will be summarized 
by treatment using descriptive statistics and the CI of the mean (95% CI for absolute values and 
90% CI for the changes from baseline/pre-dose).
The number and the percentage of subjects with a:
QTcF >450ms (males only), >470ms (females only), >480ms (males only) and >500ms;
change from baseline (pre-dose measurement on Day 1 of each treatment period) in QTcF >30 
ms and >60ms;
for post-dose time-points on Day 14: change from pre-dose on Day 14 in QTcF >30ms and 
>60ms


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At each post-dose time-point and at any post-dose time-point will be presented by treatment.  At 
each post-dose time-point, the change from baseline (pre-dose measurement on Day 1 of each 
treatment period) in 12-lead ECG parameters (HR, QTcF, QRS and PR) will be analyzed using an 
ANCOVA model including treatment, period and subject as fixed effects and baseline (pre-dose 
measurement on Day 1 of each treatment period) as a covariate. The adjusted means in each 
treatment and the adjusted mean differences between treatments will be estimated by the model 
with 90% CIs. 
HR AUC0-4h normalized by time and HR peak0-4h on Day 1 and Day 14 and their changes from 
baseline (pre-dose measurement on Day 1 of each treatment period) and from pre-dose on Day 14 
will be summarized by treatment using descriptive statistics and the CI of the mean (95% CI for 
absolute values and 90% CI for the changes from baseline/pre-dose).
Serum potassium and blood glucose
Serum potassium and blood glucose and their changes from baseline (pre-dose measurement on 
Day 1 of each treatment period) and from pre-dose on Day 14 will be summarized by treatment 
using descriptive statistics and the 95% CI of the mean.
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 pre-treatment 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 SOURCE DOCUMENTS/DATA
The Investigators or designated 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 regulatory 
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 designee 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 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 to all Institutional 
Review Boards, to the US Competent Authority 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. 


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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.
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. 
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Med. 2012;12(74). doi: 10.1186/1471-2466-12-74.
[68]
Center for Drug Evaluation and Research Medical Review. Clinical Team Leader 
Memorandum: Formoterol fumarate inhalation solution 20mcg/2mL; NDA # 22-007: 2007 
Mar 15.
[69]
Gross NJ, Kerwin E, Levine B, Kim KT, Denis-Mize K, Hamizavi M, et al. Nebulized 
formoterol fumarate: Dose selection and pharmacokinetics. Pulm Pharmacol Ther. 2008 
Oct;21(5):818-23. doi: 10.1016/j.pupt.2008.07.002.
[70]
Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J. 1999 Oct;41(4):902-7.
[71]
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005 Aug;26(2):319-38.
[72]
Hankinson JL, Kawut SM, Shahar E, Smith LJ, Hinckley Stukovsky K, Barr RG.   
Performance of American Thoracic Society-Recommended Spirometry Reference Values in 
a Multiethnic Sample of Adults. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung 
Study. CHEST 2010; 137(1):138–145.
[73]
Hankinson JL, Moon Bang KI. Acceptability and reproducibility criteria of the American 
thoracic society as observed in a sample of the general population. Am Rev Respir Dis. 
1991 Mar;143(3):516-21.
[74]
Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An 
official American Thoracic Society/European Respiratory Society statement: asthma control 
and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. 
Am J Respir Crit Care Med. 2009 Jul 1;180(1):59-99.
[75]
Virchow JC, Backer V, de Blay F, Kuna P, Ljorring C, Prieto JL, et al. Defining moderate 
asthma exacerbations in clinical trials based on ATS/ERS joint statement. Respir Med. 2015 
May;109(5):547-56. doi: 10.1016/j.rmed.2015.01.012.
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Edwards D, Berry JJ. The efficiency of simulation-based multiple comparisons. Biometrics. 
1987 Dec;43(4):913-28.


- Clinical Study Protocol Appendix I -
Clinical Study Code: CCD-05993AA3-03
Version No.: 3.0 
IND No.: 133680
Date: 31Oct2017 
CONFIDENTIAL
Page 85/86
APPENDIX I
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


- Clinical Study Protocol Appendix II -
Clinical Study Code: CCD-05993AA3-03
Version No.: 3.0 
IND No.: 133680
Date: 31Oct2017 
CONFIDENTIAL
Page 86/86
APPENDIX II
PRINCIPAL INVESTIGATOR SIGNATURE PAGE
A randomized, double-blind, placebo and active-controlled, incomplete block cross-over, dose ranging study 
to evaluate the efficacy and safety of 4 doses of CHF 1531 pMDI (Formoterol Fumarate) in asthmatic 
subjects
Product: CHF 1531 pMDI (Formoterol Fumarate)
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

SAP_001.pdf: 
Page 1 of 69 
CHIESI 
FLASH 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO AND ACTIVE-
CONTROLLED, INCOMPLETE BLOCK CROSS-OVER, DOSE RANGING 
STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 4 DOSES OF 
CHF 1531 PMDI (FORMOTEROL FUMARATE) IN ASTHMATIC 
SUBJECTS 
Protocol: CCD-05993AA3-03 
IND No: 133680 
Statistical Analysis Plan 
Amendment 
FINAL 2.0 Version 
11 APR 2019 
 
ClinicalTrials.gov ID: NCT03086460


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Table of Contents 
1 SOPs to be followed ............................................................................................................................. 5 
2 Abbreviations ....................................................................................................................................... 6 
3 Protocol / Clinical Investigation Plan ................................................................................................... 8 
3.1 Study Design ........................................................................................................ 8 
3.2 Study Schedule .................................................................................................. 10 
3.3 Randomization................................................................................................... 11 
3.3.1 Planned Randomization ................................................................................... 11 
3.3.2 Randomization Error ....................................................................................... 11 
3.4 Sample Size Calculation ..................................................................................... 12 
3.5 Efficacy and Safety Variables ............................................................................. 12 
3.6 Interim Analyses ................................................................................................ 13 
3.7 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol .................................................................................................................. 13 
3.8 Changes in SAP version 2.0 compared to SAP version 1.0. .................................. 13 
3.8 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol .................................................................................................................. 14 
6.1 Analysis Populations .......................................................................................... 14 
4 General Definitions ............................................................................................................................ 18 
4.1 Report Language ............................................................................................... 18 
4.2 Analysis Software .............................................................................................. 18 
5 Data Preparation ................................................................................................................................. 19 
5.1 Data Handling and Medical Coding .................................................................... 19 
5.1.1 Data Handling ................................................................................................ 19 
5.1.2 Coding ........................................................................................................... 19 
5.2 CDISC ............................................................................................................... 19 
5.3 SAS-Programming Quality Level ....................................................................... 19 
5.4 Data from third parties ...................................................................................... 20 
6 Analysis Populations and Subgroups ................................................................................................. 21 
6.1 Analysis Populations .......................................................................................... 21 
6.2 Treatment Misallocation .................................................................................... 21 
6.3 Subgroup Definitions ......................................................................................... 22 
7 Definition of Time Points and Analysis Variables ............................................................................. 23 
7.1 Definition of Time Points .................................................................................... 23 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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7.2 Baseline and Derived Analysis Variables ............................................................ 26 
7.2.1 Demographic Characteristics ............................................................................ 26 
7.2.2 Asthma History and Pre-Study Smoking Habits ................................................. 26 
7.2.3 Baseline Subject Characteristics ....................................................................... 26 
7.2.4 Spirometry Performed at Screening .................................................................. 26 
7.2.5 Medications.................................................................................................... 27 
7.2.6 Concomitant Medications and Treatment Assignment ......................................... 27 
7.2.7 Concomitant Procedures .................................................................................. 28 
7.2.8 Treatment Exposure and Compliance – Background ICS Medication ................... 29 
7.2.9 Treatment Exposure and Compliance - Study Drug Administration ...................... 31 
7.2.10 Compliance with the use of Diary ................................................................... 33 
7.2.11 Efficacy Variables ......................................................................................... 34 
7.2.12 Safety Variables ............................................................................................ 38 
8 Analysis Methods ............................................................................................................................... 41 
8.1 General Methods ............................................................................................... 41 
8.1.1 Rules for Patients Receiving the Same Treatment in Two Periods ........................ 42 
8.1.2 Rules for Handling Missing Data ...................................................................... 43 
8.2 Specific Methods for Efficacy Analyses ............................................................... 43 
8.2.1 Statistical/Analytical Issues .............................................................................. 50 
8.3 Specific Methods for Safety Analyses .................................................................. 51 
9 Interim analyses .................................................................................................................................. 52 
10 Overview of Tables, Listings and Figures ........................................................................................ 52 
10.1 Disposition of Subjects ..................................................................................... 52 
10.2 Protocol Deviations .......................................................................................... 53 
10.3 Analysis Sets .................................................................................................... 53 
10.4 Demographic and Other Baseline Characteristics ............................................. 54 
10.4.1 Demographic Characteristics, Asthma History, and Smoking Habits .................. 54 
10.4.2 Medical History ............................................................................................ 54 
10.4.3 Baseline Subject Characteristics ..................................................................... 54 
10.4.4 Previous, Maintained and Concomitant Medications ......................................... 54 
10.5 Study drug / Investigational Medicinal Product ................................................ 55 
10.5.1 Background ICS medication ........................................................................... 55 
10.5.2 Study drug .................................................................................................... 55 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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10.5.3 Compliance with the use of Diary ................................................................... 56 
10.6 Efficacy Results ................................................................................................ 56 
10.6.1 Primary efficacy variable ............................................................................... 56 
10.6.2 Secondary efficacy variables .......................................................................... 57 
10.6.3 Other efficacy variables ................................................................................. 59 
10.7 Safety Analyses ................................................................................................ 59 
10.7.1 Adverse Events ............................................................................................. 60 
10.7.2 Vital Signs ................................................................................................... 60 
10.7.3 ECGs ........................................................................................................... 60 
10.7.4 Clinical Laboratory Evaluation ....................................................................... 62 
10.8 Early Termination and Unscheduled Visits ....................................................... 62 
11 Table of Contents for the Tables, Listings and Figures .................................................................... 64 
 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-03 
 
 
 
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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. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-03 
 
 
 
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2 Abbreviations 
ACQ 
Asthma Control Questionnaire 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANCOVA 
ANalysis of COVAriance 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
bid 
Bis in die (twice a day) 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
(e) CRF 
(Electronic) Case Report Form 
CRO 
Contract Research Organization 
DBP 
Diastolic Blood Pressure 
ECG 
ElectroCardioGram 
FEV1 
Forced Expiratory Volume in the 1st second 
FF 
Formoterol Fumarate 
FVC 
Forced Vital Capacity 
h 
hour 
HFA 
Hydrofluroalkane 
HR 
Heart Rate 
ICS 
Inhaled Corticosteroid 
IRT 
Interactive Response Technology 
ITT 
Intention to Treat 
L 
Liter 
LABA 
Long Acting β2 adrenergic receptor agonist 
LABD 
Long-acting bronchodilators 
LAMA 
Long Acting Muscarinic Antagonist 
μg 
Microgram 
MAR 
Missing at Random 
MCID 
Minimal Clinically Important Difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minutes 
mL 
Milliliters 
PEF 
Peak Expiratory Flow 
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 
QRS 
Time Interval from the end of the PR interval to the end of the  S wave in the 
ECG 
QTc 
Time interval from the beginning of the QRS complex to the end of the T wave 
in the ECG (corrected for HR) 
QTcF 
QT interval corrected for HR using Fridericia’s formula 
SAP 
Statistical Analyis Plan 
SAE 
Serious Adverse Event 
SAMA 
Short-Acting Muscarinic Antagonist 
SBP 
Systolic Blood Pressure 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-03 
 
 
 
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SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Events 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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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-05993AA3-03: A randomized, double-blind, placebo and active-controlled, 
incomplete block cross-over, dose ranging study to evaluate the efficacy and safety of 4 doses 
of CHF 1531 pMDI (Formoterol Fumarate) in asthmatic subjects. This analysis plan is based 
on the final protocol (version 3.0) dated 31 OCT 2017 and the final electronic case report form 
(eCRF) (version 3.0) dated 14 NOV 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.  Of note, the SAP Version 1.0 (25 October 2018) 
was amended after database lock and unblinding, when it was learned that the randomization 
had not occurred according to the original randomization plan (see section 3.4.2). Considering 
the error, some patients received the same treatment during two periods. For this reason, the 
SAP and mock TFLs have been modified in order to properly consider these cases in the 
statistical analyses, to summarize the data transparently (e.g., showing also the number of 
treatment periods included in each analysis) and to add additional sensitivity analyses in order 
to evaluate the impact of patients receiving the same treatment in more than one period. The 
relevant changes from Version 1.0 of the SAP are described in section 3.8 and will be reported 
in the Clinical Study Report (CSR).Study Objectives. 
The primary objective of this clinical trial is  
• To evaluate the efficacy of CHF 1531 pMDI by comparison with placebo in terms 
of acute bronchodilator effect (change from baseline in FEV1 AUC0-12h normalized 
by time at Day 14).  
There are 2 secondary objectives: 
• To evaluate the effect of CHF 1531 pMDI on other lung function parameters and 
clinical outcome measures. 
• To assess the safety and the tolerability of the study treatments. 
3.1 Study Design 
The study is a Phase II multi-center, randomized, double-blind, placebo and active-controlled, 
incomplete block, cross-over, dose ranging study. Randomized subjects will receive four of the 
six following Study Treatments 
• Treatment A*: FF 6μg Total Daily Dose (FF 3μg per inhalation, 1 inhalation bid) 
• Treatment B*: FF 12μg Total Daily Dose (FF 6μg per inhalation, 1 inhalation bid) 
• Treatment C: FF 24μg Total Daily Dose (FF 6μg per inhalation, 2 inhalations bid) 
• Treatment D: FF 48μg Total Daily Dose (FF 12μg per inhalation, 2 inhalations bid) 
• Treatment E: Matched placebo for CHF 1531 pMDI (2 inhalations bid)* 
• Treatment F**: PERFOROMIST® (formoterol fumarate) Inhalation Solution, 40μg 
Total Daily Dose (FF 20μg/2mL, 1 unit-dose vial bid administered by nebulization). 
 
*An adequate number of inhalations from Placebo inhalers will be performed to maintain a 
double blind design.  
** Open label. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Background Medication for the Run-in and Treatment Periods 
Standardized Background ICS therapy – Open label: 
QVAR® 40μg (HFA beclomethasone dipropionate, 40μg), Inhalation Aerosol. Each 
canister contains 120 actuations. 
OR: 
QVAR® 80μg (HFA beclomethasone dipropionate, 80μg), Inhalation Aerosol. Each 
canister contains 120 actuations. 
Both dose strengths of QVAR® will be provided by the study sponsor to be dispensed as 
prescribed by the investigator. The subjects will be prescribed a daily dose of (QVAR® 40 or 
80μg/actuation; 1-2 puffs bid) between 80 – 320μg/day, equipotent to their previous ICS (ref. 
inclusion criterion #6) and this treatment regimen should remain stable for the entire study 
period. The subject will be asked to not use any other ICS throughout the study. 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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3.2 Study Schedule 
 
 
a    In women of childbearing potential only  
b   At V1 before administration of QVAR®; and at V2-V9: before study-drug dosing and at 30min, 1h, 4h, 8h and 12h post-dose. 
c    Spirometry will be carried out before and within 30 minutes after the inhalation of 4 puffs of albuterol. 
d   Pre-dose FEV1, FVC: T -45’and T -15’ before administration of study drug at V2-V9 and ET. 
e    Post-dose serial spirometry (FEV1, FVC): 15’, 30’, 45’, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 11.5h, 12h (V2-V9). 
f Serum potassium and glucose: Pre-dose before administration of study drug at V2-V9; and Post-dose at 1.5h, 3h, 5h, 7h, and 11h at V2-V9. 
g One commercial albuterol HFA pMDI (200 actuations) will be prescribed and supplied by the investigator to each subject at V1,and 
resupplied as needed at V2-8 based on assessment of doses used between visits. 
h Only Inclusion criteria #3, 4 and Exclusion criteria #1, 3, 8, 9, 13, 14. 
i Training on pMDI use will occur on V1 and V2. Training on PERFOROMIST® use will occur when a subject is scheduled to receive 
Study Treatment F. 
Pre- 
screenin
g 
Screening 
Period 1 
Period 2 
Period 3 
Period 4 
F/u
p 
Cal
ET 
D 1 
D 14 
D 1 
D 14 
D 1 
D 14 
D 1 
D 14 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
Time (weeks) 
- 2 
0 
2 
4 
6 
8 
10 
12 
14 
15 
Early 
Terminatio
Time window (days) 
- 
± 2 
- 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
Informed Consent Form 
 
Demographic data 
 
IRT visit confirmation call 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria 
 
Asthma Action Plan Review 
 
 
 
 
 
 
 
 
Eligibility recheckh 
 
Medical 
history/Previous 
medication 
 
Weight and Height 
 
Physical Examination 
 
 
 
Assessment for Oral 
 
 
 
 
Hematology and 
Blood Chemistry 
 
 
 
Serum pregnancy test a 
 
 
 
Urinary pregnancy test a 
 
 
 
 
 
 
 
 
12-lead ECG b 
 
 
 
 
 
 
 
 
 
 
Vital signs (DBP/SBP) b 
 
 
 
 
 
 
 
 
 
 
Training on the use of 
pMDI, diary, PEF, 
PERFOROMIST® i 
 
 
 
 
 
Randomization 
 
Spirometry pre and post-BD c 
 
Pre-dose spirometry d 
 
 
 
 
 
 
 
 
 
Post-dose 12h serial spirometry 
 
 
 
 
 
 
 
 
Pre and post-dose 
Serum Potassium & 
 
 
 
 
 
 
 
 
ACQ questionnaire 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events assessment 
 
 
 
 
 
 
 
 
 
 
 
Rescue Medication 
 
Dispensation / Return 
of background ICS: 
D 
D/R 
D/R 
D/R 
D/R 
R 
R 
Study drug dispensation / 
return and Accountability 
D 
R 
D 
R 
D 
R 
D 
R 
R 
Subject diary/PEF dispensation 
(D) /return (R) 
D 
D/R 
D/R 
D/R 
D/R 
D/R 
D/R 
D/R 
R 
R 
Schedule next appointment 
 
 
 
 
 
 
 
 
 
 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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3.3 Randomization 
3.3.1 Planned Randomization 
An Interactive Response Technology (IRT) system will be used at each visit (from pre-
screening to follow-up call) to record patient status. Patient number will be centrally 
assigned, through the IRT, during the pre-screening visit (Visit 0).  
The Investigator, or designee, at the sites will call the IRT system to screen, randomize subjects 
and assign treatment kits according to the sequence described in the randomization list. The 
randomization list will be prepared by a specialized external provider and the whole study 
team, the investigators and the subjects will be blind to sequence assignment. Subjects will be 
randomized to one of the 12 possible treatment sequences, according to a balanced incomplete 
block randomization scheme. For further details refer to Randomization Plan (version 1.0 from 
04 JUL 2017). Each randomized sequence will be identified with a number from 1 to 12 until 
unblinding will be completed. Then the treatment sequence actually randomized (eg.. ABCD) 
will be used instead of numbers for the analysis. 
3.3.2 Randomization Error 
An error occurred during a system update to the randomization system on 
. Of 
note, the randomization files were in 2 parts.  Both files were blinded to the study team: 
1. Randomization List – This is a list of the treatment sequences, with the 6 treatments 
coded as 1-2-3-4-5-6.  There is one record for each randomization number. 
2. Decode List – This is a list which assigns a treatment to each of the codes.  There are 6 
records, one record for each treatment. 
The update which was required was related to shipping and was not intended to have any 
impact to the randomization. During planning for the system update, the system update was 
tested in a Test Environment using a dummy Randomization List and a dummy Decode List. 
The Randomization List was not changed during the update – in either the Test or Production 
environment.  The Decode List was contained within a table that also contained shipping 
information (referred to as “CTM Types Table”).  The CTM Types table was updated to 
change shipping specifications (no changes to randomization were made).  The update was 
originally made in the Test Environment, which contained the dummy Decode List.  The 
updated CTM types table was then copied from the Test Environment to the Production 
Environment.  After the copy from Test to Production, the dummy Decode List should have 
been replaced with the actual Decode List.  However, this step was erroneously missed, and 
the dummy Decode List remained within the production environment after the update was 
completed. After the system update, patients received kits according to the original 
Randomization List and the dummy Decode List.  Patients who were ongoing in the study on 
 may have received the same treatment during more than one period.   
The update was made relatively early in the study, such that no patient received treatment 
assignments for all 4 periods prior to the update.  For patients who were ongoing in the study 
at the time of the update, there was a potential to receive the same treatment twice, since these 
patients received some treatment assignments (those assigned prior to the update) according 
the original planned Decode List and also some treatment assignments (those assigned after 
the update) according to the Dummy Decode List.   


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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3.4 Sample Size Calculation 
The sample size has been calculated to evaluate the superiority of CHF 1531 pMDI at different 
doses over placebo in terms of change from baseline in FEV1 AUC0-12h normalized by time at 
Day 14. The calculation is based on simulations. 
A total of 51 evaluable subjects will provide 96% power to detect a mean difference of 200 mL 
between each dose of CHF 1531 pMDI and placebo at a two-sided significance level of 0.0125, 
assuming a within-subject standard deviation of 180 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 60 subjects (5 subjects for 
each of the 12 treatment sequences) will be randomized. 
3.5 Efficacy and Safety Variables 
Primary Efficacy Variable 
Change from baseline in FEV1 AUC0-12h normalized by time at Day 14. 
 
Secondary Efficacy Variables 
The protocol defines 10 unique secondary efficacy variables but groups them into 3 bullet points 
in Section 12.3.5 of the protocol and 6 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 10 unique secondary efficacy variables but provide the traceability back to the 3 
bullet points as outlined in the protocol: 
• 
1a: Change from baseline in FEV1 AUC0-12h normalized by time at Day 1. 
• 
1b: Change from baseline in FEV1 AUC0-4h normalized by time at Day 1 and Day 14  
• 
1c: Change from baseline in FEV1 peak0-4h at Day 1 and Day 14. 
• 
1d: Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) 
at Day 14. 
• 
2a: Change from baseline in FVC AUC0-12h normalized by time at Day 1 and at Day 14. 
• 
2b: Change from baseline in FVC AUC0-4h normalized by time at Day 1 and at Day 14. 
• 
2c: Change from baseline in FVC peak0-4h at Day 1 and at Day 14. 
• 
2d: Change from baseline in pre-dose morning FVC (average of pre-dose FVC measurements) 
at Day 14. 
• 
3: Time to onset of action (change from baseline in post-dose FEV1 ≥ 12% and  ≥ 200mL) at 
Day 1. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Safety Assessments 
The list of safety assessments presented below is from Section 9 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) 
• 12-lead ECG parameters (HR, QTcF, QRS, PR)  
• HR AUC0-4h normalized by time and HR peak0-4h  
• Serum potassium and blood glucose 
3.6 Interim Analyses 
No interim analyses are planned for this clinical investigation. 
3.7 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol 
 The original study design expected that each randomized subject received four of the six Study 
Treatments. Not in accordance to the Study Protocol, some randomized subjects received the 
same treatment twice due to the error occurred during the randomization process (see section 
3.4.2). The originally planned analyses has been updated in this document to properly handle 
the cases of patients receiving a treatment during more than one period, which was not foreseen 
until after database lock and unblinding when the error was identified. Specifically, updates 
have been made in order to summarize clearly both the number of patients and the number of 
periods which are included in each analysis.  Sensitivity analyses have also been added in order 
to verify the results of the primary efficacy analysis, which has not been altered.  The SAP 
version 2.0 it is based on the same statistical models as specified in SAP version 1.0, ensuring 
consistency with the pre-specified analysis models. 
 
3.8 Changes in SAP version 2.0 compared to SAP version 1.0. 
All the updates implemented in this version of the SAP, compared to the Final SAP version1.0, 
are listed in the following table. For each modified section, a summary of the change is reported. 
 
Section 
SAP version 2.0 
3 Protocol / Clinical 
Investigation Plan 
Added text to describe why an Amendment to SAP 1.0 was needed.  
3.4 Randomization 
“Section 
3.4 
Randomization” 
became 
“3.4.1 
Planned 
Randomization”. Added section “3.4.2 Randomization Error” 
where the error occurred during the randomization process is 
described in details. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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3.8 Changes in the Conduct 
of Study or Planned 
Analysis compared to the 
Study Protocol 
Updated the text to describe why an amendment to the SAP 1.0 
was needed. Added section “3.8.1 Changes in SAP version 2.0 
compared to SAP version 1.0” where the list of all changes is 
reported. 
6.1 Analysis Populations 
Added text to specify that sensitivity analysis (added with SAP 
version 2.0) will be performed on the ITT population. 
6.2 Treatment Misallocation 
Added text to state that the treatment sequence assigned by the 
randomization system will be used in the statistical analysis instead 
of the one originally planned. Furthermore, inconsistency between 
the originally planned randomization and the actual implemented 
randomization has not be considered as a reason for exclusion from 
any analysis. 
8.1 General Methods 
General methods for continuous and categorical variable moved in 
the new section “8.1.1 Rules for Patients Receiving the Same 
Treatment in Two Periods”. General Methods to handle patients 
receiving the same treatments in more than one period have been 
added for both continuous and categorical variables.  
8.2 Specific Methods for 
Efficacy Analyses- Analyses 
Based on Mixed Models 
The way to handle patients receiving the same treatment in multiple 
periods in the analysis based on mixed models (primary and 
secondary efficacy endpoints) has been added to this section with 
an example. The model has not been modified. Three sensitivity 
analyses have been added. 
 
8.2 Specific Methods for 
Efficacy Analyses- Analyses 
Based on the Time to Onset 
The way to handle patients receiving the same treatment in multiple 
periods in the analysis based on Time to Onset has been added to 
this section with an example. 
8.3 Specific Methods for 
Safety Analyses 
The way to handle patients receiving the same treatment in multiple 
periods has been added to this section. 
10 Overview of Tables, 
Listings and Figures 
The text has been updated to specify that no table will be presented 
by sequence, listings including sequences will report sequences as 
assigned by the randomization system and all listings will be sorted 
by patient ID. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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10.1 Dispositions of subjects The disposition summary table originally planned to be reported by 
treatment sequence, will be reported overall only. The disposition 
summary table originally planned to be reported by study treatment 
will be presented on a period-level, counting each treatment period 
once and including the number of periods as the denominator. The 
randomization schedule listing will be updated to show the original 
intended randomization schedule and how it differs from the 
randomization which was 
actually implemented by the 
randomization system and the treatments administered. 
10.2 Protocol Deviations 
The summary of Major Protocol Deviations has been updated to 
include patients receiving a treatment twice. The summary will be 
based on a per-period level and patients receiving a treatment twice 
will be considered twice in the corresponding treatment column. 
10.3 Analysis Sets  
The summary of analysis sets will include also the number of 
patients in each population, regardless of the number of periods 
(counted only once) and the total number of periods in each 
population. Percentages will be based on the total number of 
periods. 
10.4.1 Demographic 
Characteristics, Asthma 
History, and Smoking Habits 
The summaries of Demographic Characteristics, Asthma History, 
and Smoking Habits, originally planned to be reported by treatment 
sequence, will be reported overall only. 
10.4.2 Medical History 
The summary of Medical History, originally planned to be reported 
by treatment sequence, will be reported overall only. 
10.4.3 Baseline Subject 
Characteristics 
The summaries of Baseline Subject Characteristics (Central 
spirometry and reversibility test, ECG results at Visit 1, Vital signs 
at Visits 1 and 2, ACQ score at Visits 1 and 2) originally planned 
to be reported by treatment sequence, will be reported overall only. 
10.4.4 Previous, Maintained 
and Concomitant 
Medications 
Previous medication summary, originally planned to be reported by 
treatment sequence, will be reported overall only. Summaries of 
Maintained and Concomitant Medication have been updated to 
include patients receiving a treatment twice and they will be based 
on a per-period level; patients receiving a treatment twice will be 
considered twice in the corresponding treatment column.  
10.5.1 Background ICS 
medication 
Previous asthma treatment summary and summary of background 
medication exposure and compliance during run-in, originally 
planned to be reported by treatment sequence, will be reported 
overall only. Summaries of background medication exposure and 
compliance during treatment periods and washout periods have 
been updated to include patients receiving a treatment twice and 
they will be based on a per-period level; patients receiving a 
treatment twice will be considered twice in the corresponding 
treatment column.    


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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10.5.2 Study drug 
Summary of treatment exposure and compliance during the 
treatment periods has been updated to include patients receiving a 
treatment twice. Summary will be based on a per-period level and 
patients receiving a treatment twice will be considered twice in the 
corresponding treatment column.    
10.5.3 Compliance with the 
use of Diary 
Summary of compliance with the use of diary in run-in period, 
originally planned to be reported by treatment sequence, will be 
reported overall only. Compliance with the use of Diary in 
treatment and Washout periods summaries have been updated to 
include patients receiving a treatment twice. Summaries will be 
based on a per-period level and patients receiving a treatment twice 
will be considered twice in the corresponding treatment column.     
10.6.1 Primary efficacy 
variable 
Primary efficacy variable summary has been updated to include 
patients receiving a treatment twice. For patients receiving the same 
treatment in 2 periods, the 2 available data points will be averaged 
prior to calculation of the summary statistics for all subjects. The 
number of treatment periods considered will be added to the table. 
The same approach has been described also for the summary of 
FEV1 at each time point. The primary efficacy analysis has not 
been modified. A reference to the three sensitivity analyses defined 
in section 8.2 has been added.   
10.6.2 Secondary efficacy 
variables 
Summaries of secondary efficacy variables have been updated to 
include patients receiving a treatment twice. For patients receiving 
the same treatment in 2 periods, the 2 available data points will be 
averaged prior to calculation of the summary statistics for all 
subjects. The number of treatment periods considered will be added 
to the tables. The same approach has been described also for the 
summary of FVC at each time point.  
10.7.1 Adverse Events 
Summaries of TEAEs have been updated to include patients 
receiving a treatment twice. They will be considered twice in the 
corresponding treatment group. The number of subjects ("n"), the 
number of treatment periods ("n periods") and the number of events 
will be presented. The percentages will be based on the number of 
treatments periods in each group. 
10.7.2 Vital Signs  
Summary of vital signs has been updated to include patients 
receiving a treatment twice. For patients receiving the same 
treatment in 2 periods, the 2 available data points will be averaged 
prior to calculation of the summary statistics for all subjects. The 
number of treatment periods considered will be added to the table. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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10.7.3 ECGs 
Summary of continuous ECGs parameters has been updated to 
include patients receiving a treatment twice. For patients receiving 
the same treatment in 2 periods, the 2 available data points will be 
averaged prior to calculation of the summary statistics for all 
subjects. The number of treatment periods considered will be added 
to the table. Summary of QTcF values has also been updated such 
that patients receiving a treatment twice will contribute only once 
to the summary statistics, using the highest observed QTcF value. 
10.7.4 Clinical Laboratory 
Evaluation 
Summary of Clinical Laboratory data has been updated to include 
patients receiving a treatment twice. For patients receiving the same 
treatment in 2 periods, the 2 available data points will be averaged 
prior to calculation of the summary statistics for all subjects. The 
number of treatment periods considered will be added to the table. 
 
 


 
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 03 AUG 
2017) including the Data Validation Plan (Version 2.0 from 04 AUG 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 (SOP-ST-04) 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. Paper diary will contain drug intake details, PEF values, rescue medication 
and Asthma Symptom Score. Diary data will be databased. 
 
These third parties are: 
• 
: central laboratory data. 
• 
: ECG data, spirometry data. 
• 
: supplies the randomization schedule  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.  
 
The inclusion in the Safety, in the ITT and in the PP population will be defined on a per-period 
basis.  
Since the superiority of CHF 5259 pMDI at different doses over placebo will be tested, the 
primary efficacy analysis and the associated sensitivity analyses 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. 
All 3 populations (Safety, ITT, and PP) will be used for the presentation of demographics, 
Asthma history, Pre-Study Smoking Habits, spirometry and reversibility.   
The medical history/concomitant diseases, and exposure/compliance to study drug results will 
be presented using the ITT and Safety populations.   
Medications, ACQ score, compliance with use of the diary, exposure/compliance to 
background medication, and protocol deviations will be reported using the ITT population.   
6.2 Treatment Misallocation 
The majority of the subjects did not receive treatment assignments according to the originally 
planned treatment sequence. The randomization system erroneously assigned different 
treatments from to the originally planned ones (See section 3.4.2). For purposes of statistical 
analysis, ‘as randomized’ is considered to mean “as allocated by the randomization system”.  
While this differs from the original intended randomization plan, it accurately reflects the 
randomization which has occurred and therefore provides the most meaningful study results. 
Accordingly, the inconsistency observed between the originally planned randomization and the 
actual implemented randomization is not considered as a reason for exclusion from any 
analysis, as long as the treatment received corresponded to the treatment allocated by the 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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randomization system. Of note, one patient who received a treatment other than the one 
assigned by the randomization system (as documented in the DRR version 1.0, 26 October 
2018) will be considered as having received the wrong treatment.  
In case of deviation between the as-randomized (i.e., as allocated by the randomization system) 
treatments and the treatments actually received, the treatments 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 treatments they received and will be counted in the Safety population. 
• Subjects who were randomized, but took the incorrect study drug (i.e. study drug other 
than what was allocated by the randomization system) for the duration of one or more 
periods, will be summarized based on their assigned treatment for those periods for the 
ITT population and excluded from the PP population. These subjects will be 
summarized based on the treatments that they received for the safety analyses.   
• Subjects who were randomized, but took the incorrect study drug(i.e. study drug other 
than what was allocated by the randomization system)  for part of a period (e.g. the 
subject began the period by taking the incorrect study drug at Day 1 but switched to 
correct study drug before Day 14) 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.  
Period Definition 
Periods used in the analysis of this study are defined as below:  
• Run-in Period: Morning of Visit 1 through the evening of the day before Visit 2. 
• Treatment Period 1: from the morning of Visit 2 to the morning of Visit 3  
• Treatment Period 2: from the morning of Visit 4 to the morning of Visit 5  
• Treatment Period 3: from the morning of Visit 6 to the morning of Visit 7.  
• Treatment Period 4: from the morning of Visit 8 to the morning of Visit 9.  
Between each two consecutive treatment periods there is a Washout period, for a total of 
three Washout periods. 
Visits labels are assigned according to the eCRF visits as follow: 
eCRF Visit labels            
Study Period 
TLFs Visit labels  
Visit 1 
Run-in 
Visit 1 
Visit 2 
Treatment Period 1  
 
 Period 1 Day 1 
Visit 3 
Period 1 Day 14 
Visit 4 
Treatment Period 2  
 
Period 2 Day 1 
Visit 5 
Period 2 Day 14 
Visit 6 
Treatment Period 3  
 
Period 3 Day 1 
Visit 7 
Period 3 Day 14 
Visit 8 
Treatment Period 4   
 
Period 4  Day 1 
Visit 9 
Period 4  Day 14 
Visit 10 
Follow-up 
Visit 10 
 
Start/End of the Randomized Treatment Period (Study Level)  
Since many algorithms used in the statistical analyses require the start and/or the end of the 
randomized treatment periods to be identified, ad-hoc variables specifying these dates will be 
defined. Four treatment periods are defined. The date of start/end of the randomized treatment 
period will be set according to the following rule:  
• The date of Start of the Randomized Treatment Period (Study Level) 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 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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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 9 or Early Termination visit was completed, then the date of End of the 
Randomized Treatment Period (Study Level) will be defined as the date of Visit 
9/Early Termination.  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 
(excluding follow up phone call and any unscheduled visits after the last dose)]. 
 
Period durations (days) 
Treatment period duration is defined for each period using the following rule: 
• Treatment Period x: Date of Day 14 Visit – Date of Day 1 Visit + 1, per period. 
Between each two consecutive periods there is a Washout period. The duration of each 
Washout period is defined as: 
• Washout Period x: ((Date of the Day 1 visit of next period(x+1) -1) minus Date of Day 
14 visit of current period x) +1. 
For treatment period duration and washout period duration, if the period was started but not 
completed, then the end of period date will be replaced with the date of End of Randomized 
Treatment Period. 
 
 The duration of the Run-in Period is: 
• Run-in Period: (Date of Visit 2 -1) – Date of Visit 1 +1 
 
Date of first/last study drug intake per period   
Date of first study drug intake in each period 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 of Visit 2 for Period 1, Visit 4 for Period 2, Visit 
6 for Period 3, Visit 8 for Period 4. While subjects randomized to open-label PERFOROMIST® 
will receive a continuous nebulized treatment over approximately 10 minutes, the Date of first 
study drug intake for subjects treated with PERFOROMIST® coincide with the start ‘Date/Time 
of administration’ of the Morning Dose collected on the ‘Study drug administration at the clinic’ 
eCRF page.  
Note: The date and time of drug administration at each visit are mandatory variables to be 
reported in the CRF; no missing or partial data can be accepted.  Only eCRF data will be 
considered for the date of first study drug intake. 
Date of last study drug intake in each period is derived as the maximum of ‘Date/Time of 
administration’ between the inhalations (puffs) collected on the ‘Study drug administration at 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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the clinic’ eCRF page of Visit 3 for Period 1, Visit 5 for Period 2, Visit 7 for Period 3, Visit 9 
for Period 4. If the date of the last intake of study drug at Day 14 in a period is missing or 
partially missing, but the date of at least one dose of the study drug is recorded in the diaries, 
the date of the last study drug intake in that period will be imputed using the following rule: 
      max [date of study drug intake in the diaries per period] 
If a period is the last period in which the subject was treated then the date of last dose of that 
period will be set equal to the ‘Date of last intake of study drug’ on the ‘Study Termination’ 
eCRF page. If the date of 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.   
The time to completion/discontinuation from the study (weeks) is defined as: 
(date of completion/discontinuation - date of start of randomized Treatment Period 1 ) / 7 
Baseline definitions 
For FEV1 and FVC, the baseline value for each period is defined as the average of the pre-dose 
measurements on Day 1 (45 min and 15 min pre-dose) of the treatment period. If only a single 
value is recorded for FEV1 or FVC, the value will be used as the baseline value.    If no 
measurement is available, then the pre-dose value will be considered as missing (for FEV1, 
FVC) for that treatment period. 
For safety variables the baseline for each period is defined as pre-dose measurements on Day 1 
of each treatment period.  
For laboratory parameters the baseline values are the ones collected at Visit 1.   
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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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. 
 
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 (Visit 0) entered into the system. 
7.2.2 Asthma History and Pre-Study Smoking Habits  
• 
The time since first Asthma diagnosis (months) will be calculated as the (Visit 1 date minus 
the date of first diagnosis)/30.4375.   
• Age at First Asthma 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 
(smoking stop date - smoking start date + 1)/365.25). 
• 
The number of pack at year will be calculated within the eCRF   
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 
• Asthma Control Questionnaire (ACQ) at Visit 1, Visit 1.1 and Visit 2 will be 
calculated within the eCRF. If Asthma Control Questionnaire (ACQ) is repeated in a 
in a (pre-randomization) rescheduled visit (called Visit 1.1 in the eCRF) then the ACQ 
calculated at Visit 1.1 will be used for the analysis. 
• 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 (FEV1 and FVC) will be carried out before bronchodilator and within 30 minutes 
after intake of 4 puffs of albuterol HFA (90 µg/ actuation) at Visit 1 (screening). The 
reversibility parameters (ΔFEV1 (mL) and % ΔFEV1) will be calculated in the eCRF.  


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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If the reversibility test or any other screening assessments of Visit 1 are repeated in a (pre-
randomization) rescheduled visit (called Visit 1.1 in the eCRF), then all values of the 
rescheduled visit will be used for the analysis.   
 
 
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 of 
Period 1and medication stop date  ≤ date of first study drug intake of Period 1). 
• Concomitant medications are all medications started during the treatment period (date 
of first study drug intake of Period 1< medication start date < date of last study drug 
intake of last period attended, with the exception of medications taken only during 
Washout - see the definition below).  
• Medications taken only during washout are all medications started after the end of 
one randomized period and stopped before the start of the following randomized period. 
(For at least one treatment Period x  (Period 1, Period 2, Period 3): medication start date 
> date of last study drug intake in Period x and medication stop date < date of first study 
drug intake in Period x+1)  
• 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 of Period 1and medication stop date > date of first study drug 
intake of Period 1). 
• 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 of last period attended) 
 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. Medications taken only during washout 
4. post-treatment medication; 
5. previous medication. 
Information on concomitant medications is retrieved from the ‘Concomitant medications’ 
eCRF page. 
7.2.6 Concomitant Medications and Treatment Assignment 
The following rules are applied for assigning medications to a specific study treatment group: 
• Previous medications will not be assigned to study treatment groups since they will be 
summarized by sequence.  


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• Concomitant medications and maintained medications will be assigned to the study 
treatment(s) received by the patient whilst using the concomitant medication, by 
comparing the start and stop date of the concomitant medication with the start and stop 
dates of each study treatment. A concomitant/maintained medication could be assigned 
to more than one study treatment group. 
• Medications taken only during washout and post-treatment medications will be assigned 
to the last study treatment received prior to the Washout period or study 
completion/discontinuation. 
Where a medication start and/or stop date is fully or partially missing, so that it’s unclear 
as to which study treatment the medication is associated, the medication will be assigned to 
both treatments.  
7.2.7 Concomitant Procedures 
Procedures will be split into three 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 of 
Period 1 and procedures stop date ≤ date of first study drug intake of Period 1) 
• 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 of Period 1 and procedures stop date > date of date of first study 
drug intake of Period 1). 
• Concomitant procedures are all procedures started during the treatment period (date 
of first study drug intake of Period 1 ≤ procedures start date < date of last study drug 
intake of last period attended), with the exception of procedures received only during 
Washout (see the definition below).  
• Procedures performed only during Washout are all procedures started after the end 
of one randomized treatment period and before the start of the following randomized 
treatment period. (For at least one treatment Period x  (Period 1, Period 2, Period 3): 
procedure start date > date of last study drug intake in Period x and procedure stop 
date < date of first study drug intake in Period x+1)  
• Post-treatment procedures are all procedures started on or after the last dose of study 
drug (procedures start date >= date of last dose of study drug of last period attended) 
In case of missing or incomplete dates not directly allowing allocation to the four 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. procedures taken only during washout 
3. post-treatment procedures  
4. maintained procedures 
5. previous procedures. 
Information on concomitant procedures is retrieved from the ‘Concomitant procedures’ eCRF 
page. Procedures will be listed only. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Assignment of procedures to a study treatment group follows the same rules as stated in section 
7.2.6.  
7.2.8 Treatment Exposure and Compliance – Background ICS Medication 
The approach below defined for the calculation of compliance assumes no intake of the 
background medication in case of missing data. 
In each period a Diary Card is provided. It should be completed by the patients from the evening 
of Visit 1 to the morning of Visit 2 for Run-in period, from the evening of Day 1 to the morning 
of Day 14 for Treatment periods and from the evening of Day 14 to the morning of the following 
visit for Washout periods. In each period, all data recorded outside the pre-specified intervals 
will not be considered for the calculation of compliance. 
Run-In Period / Exposure and Compliance 
Background ICS medication (QVAR®) is prescribed to subjects during the Run-in Period. The 
Run-In Period starts at Visit 1 and runs through the day before Day 1 of Treatment Period 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 with background ICS 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
𝑥 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 
‘Background Medication Administration for Asthma’ eCRF page. 
The total scheduled number of puffs during the Run-in Period is defined as: 
Run-in Period duration x [scheduled number of puffs per day] 
 
Treatment Periods / Exposure and Compliance 
Compliance to background ICS medication during each Treatment Period should be calculated 
considering data recorded, from date of start of each randomized treatment period to date of 
end of each randomized treatment period.  
For each Treatment Period, exposure to background ICS medication (days) will be calculated 
as date of last background ICS medication intake during the treatment period- date of first 
background ICS medication intake during the treatment period+ 1 day. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Compliance to background ICS medication per 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 
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 for Run-in Period. 
The total scheduled number of puffs during each Treatment Period is defined as: 
– For subjects who had their last background ICS medication dose on the last 
scheduled dosing day of the Treatment Period [i.e. Day 14] the scheduled number 
of puffs = exposure to background ICS medication (days) x [scheduled puffs per 
day] minus [scheduled evening puffs on the last scheduled dosing day]  
 
– For subjects who had their last background ICS medication dose on any day before 
the last scheduled dosing day of the Treatment  Period [e.g. an  early 
discontinuation] the scheduled number of puffs = exposure to background ICS 
medication (days) x [scheduled puffs per day] 
 
If the date of the last dose of background ICS medication = date of first dose of background 
ICS medication, the scheduled number of puffs will be 1 day * [scheduled puffs per day].  
Washout Periods / Exposure and Compliance 
Exposure during each Washout Period are based on actual dosing date/times and not visit dates. 
For each Washout Period, exposure will be calculated as the date of last dose of the Washout 
Period – date of first dose of the Washout Period + 1 day. 
The evaluation of compliance will be based on the number of puffs following the formula 
presented for Run-in Period. The total number of scheduled puffs per day are derived as per 
Run-in Period. 
Compliance during Washout Periods will be evaluated by study treatment group. Compliance 
to background ICS medication will be assigned to the last study treatment received prior to the 
Washout Period. 
 
The total scheduled number of puffs during each Washout Periods is defined as: 
– Scheduled number of puffs = Washout Period duration x [scheduled puffs per day] 
minus [scheduled morning puffs on the first scheduled dosing day]. Subjects should 
receive their first background ICS medication dose of the washout period in the 
evening on the last dosing day of the Treatment Period [i.e. Day 14], so scheduled 
morning puffs should not be counted in the washout compliance calculation.  
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%. 
Compliance with background ICS medication will also be summarized using the following 
categories for the Run-in Period, Treatment Periods and Washout Periods: 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• 
[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% 
 
Exposure and compliance will be presented for the Run-in Period by sequence and for the 
Treatment and Washout Periods by study treatment group. 
 
7.2.9 Treatment Exposure and Compliance - Study Drug Administration 
The actual date and time of study drug administration will be used to calculate exposure. The 
following dosing schedule will be followed. Study drugs will be administered twice-a-day (in 
the morning and in the evening), according to the randomized treatment sequence, except for  
Day 14 of each Treatment Period (Visit 3, Visit 5, Visit 7, Visit 9) when only the morning dose 
is administered: 
Morning administration (between 8-10 am): 
• Study Treatments A – E: 
One puff from the canister numbered 1 
One puff from the canister numbered 2 
• Study Treatment F: 
One nebulized treatment of (2mL) vial to be inhaled through standard jet nebulizer 
 
Evening administration (between 8-10 pm):  
• Study Treatments A – E: 
One puff from the canister numbered 1 
One puff from the canister numbered 2 
• Study Treatment F: 
One nebulized treatment of (2mL) vial to be inhaled through standard jet nebulizer 
 
The first and last dosing occasions for study drug are expected to be taken during the visit dates, 
however exposure is 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). 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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For the calculation of the number of administered and scheduled puffs, the dosing occasions 
from the first to the last study drug intake for each period will be taken into account. In each 
period, all data recorded in subject diaries before Day 1-Evening and after Day 14-Morning 
will not be considered for the calculation of compliance. 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 for deriving the ‘last randomized study drug intake’ as defined 
in Section 7.1. 
 
During each Treatment Period, Treatment exposure will be calculated as the Date of last intake 
of study drug of the period – date of first intake of study drug of the period + 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
 𝑥 100% 
The total number of administered puffs will be calculated by adding up the number of puffs 
taken during each Treatment Period, as recorded in the Subject Diary or ‘Study Drug 
Administration at the Clinic’ eCRF page. 
It should be noted that 2 puffs (for treatment arms A-E) or 1 unit-dose vial nebulization (for 
Arm F)  should be taken twice a day during the Treatment Period (from Day 1 (V2, V4, V6, 
V8) until the day before V3, V5, V7, V9 respectively) and 2 puffs (for treatment arms A-E) or 
1 unit-dose vial nebulization (for Arm F)  should be taken once a day in the morning on V3, 
V5, V7 and V9 [On these end-of-Treatment Period visits, the morning dose occurs in the clinic 
and there is no evening dose]. The total number of scheduled puffs is defined during each 
Treatment Period as:  
• For subjects who had their last study drug dose on the last scheduled dosing day in the 
Treatment Period [i.e. Day 14 of Treatment Period], the scheduled number of puffs = 
Treatment exposure (days) x [scheduled puffs per day] minus [scheduled evening puffs] 
 
• For subjects who had their last study drug dose on any day before the last scheduled 
dosing day in the Treatment Period [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 
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 discerned for Study Treatment: 
• Treatment compliance < 65% 
• 65% ≤ Treatment compliance ≤ 135% 
• Treatment compliance > 135%. 
The Study Treatment 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% 
 
 
7.2.10 Compliance with the use of Diary 
Compliance with the use of Diary is based on visit dates. See Section 7.1 for the definition of 
the study periods and period durations (days).  On a given day, if any questions are answered 
in the diary (beyond a data, since these are not entered daily), then the diary is considered as 
used for that day, even if all questions are not completed. 
The evaluation of compliance per period, including Run-in, Treatment and Washout Periods, is 
done using the following formula: 
 
Total number of days in the period with data recorded in the Subject Diary 
Period duration
 𝑥 100% 
 
For Run-in and Washout periods, diary is expected to be completed also on the morning of the 
first day of the following Treatment Period. For this reason 1 day will be added to Run-in and 
Washout Period durations. 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Compliance during Washout periods will be assigned to treatments follow the same rules as for 
Medications taken only during Washout in paragraph 7.2.7. 
The compliance with the use of Diary will 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%] 
 
Compliance with the use of Diary will be presented by sequence for the Run-in Period and by 
study treatment group for the Treatment and Washout Periods. 
7.2.11 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 Day 14. The baseline value is the average of the T-45 and T-15 min pre-dose FEV1 
measurements on Day 1. FEV1 is a continuous variable derived from spirometry data (
). 
FEV1 AUC0-12h will be calculated at Day 14. AUC normalized by time will be calculated based 
on the actual times using the linear trapezoidal rule:  
 {∑[(𝐭𝐢−𝐭𝐢−𝟏)(𝐅𝐄𝐕𝟏𝐢+ 𝐅𝐄𝐕𝟏𝐢−𝟏)/𝟐]
𝐢
} 𝐭𝐢𝐦𝐞
⁄
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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where: 
for t0, FEV10 is the pre-dose average of T -45’ and T -15’ before study drug administration at 
Day 14 of each Treatment Period.  
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, 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 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 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. 
• 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 three or more 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 12-hour post-dose period during which the FEV1 
measurements are obtained at Day 14, 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 washout 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 
As the secondary efficacy variables will be analyzed in the ITT population, no data will be 
excluded from the analysis due to the intake of rescue medication during the serial spirometry 
or the 6 h washout pre-dose. 
• 1a: 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.  


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• 
1b: Change from baseline in FEV1 AUC0-4h normalized by time at Day 1 and Day 14  
 The baseline value is the average of the T-45 and T-15 min pre-dose FEV1 measurements on 
Day 1. The change from baseline in FEV1 AUC0-4h normalized by time at Day 1 and Day 14 
will be calculated using the following equation: 
 
{∑[(𝐭𝐢−𝐭𝐢−𝟏)(𝐅𝐄𝐕𝟏𝐢+ 𝐅𝐄𝐕𝟏𝐢−𝟏)/𝟐]
𝐢
} 𝐭𝐢𝐦𝐞
⁄
 
Where: 
for t0, FEV10 is the pre-dose average of T -45’ and T -15’ before the time of study drug 
administration at Day 14 or Day 1. 
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 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 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. 
 
• 1c: Change from baseline in FEV1 peak0-4h at Day 1 and Day 14 
FEV1 peak0-4h at Day 1 and Day 14 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.   In case of less than three missing values among post-dose spirometry 
measurements at 45min, 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. 
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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• 1d: Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 
measurements) at Day 14. 
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. The baseline value is the average of the 
T-45 and T-15 min pre-dose FEV1 measurements on Day 1. 
 
• 2a: Change from baseline in FVC AUC0-12h normalized by time at Day 1 and Day 14 
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 Day 14. The calculation of the FVC AUC0-12h will follow in the same manner as the 
calculation outlined above for the primary efficacy variable.  
 
• 2b: Change from baseline in FVC AUC0-4h normalized by time at Day 1 and Day 14 
FVC AUC0-4h will be calculated on Day 1 and Day 14. 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.  
 
• 2c: Change from baseline FVC peak0-4h at Day 1 and Day 14. 
FVC peak0-4h at Day 1 and Day 14 will be calculated using the following rule: 
(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. 
 
• 2d: Change from baseline in pre-dose morning FVC (average of pre-dose FVC 
measurements) at Day 14. 
The baseline value is the average of the pre-dose FVC measurements on Day 1. 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. 
 
• 3: Time to onset of action (change from baseline in post-dose FEV1 ≥ 12% and  ≥ 200mL) 
at Day 1 
In case of at least one post-dose timepoint with change from baseline in FEV1 ≥ 12% and ≥ 
200mL, then Time to onset of action will be equal to the first post-dose timepoint with change 
from baseline in FEV1 ≥ 12% and  ≥ 200mL 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 the start of dosing. In case of no time-point with change from baseline in FEV1 
≥12% and ≥ 200mL, 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 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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be equal to the last available post-dose time-point with non-missing data and the subject will 
be considered as censored in the analysis. In case of four or more missing values among post-
dose spirometry measurements at 15 min, 30 min, 45 min, 1h, 2h, 3h and 4h the subject will be 
excluded from the analysis of time to onset of action.  
7.2.12 Safety Variables 
There are 7 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 after signing the informed consent and before the first 
randomized study medication intake (AE onset date < date of first randomized study 
medication intake at the study-level).   
• 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 at the study-level ≤ 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).   
TEAEs will be assigned to the last randomized study drug received before the start of the TEAE. 
Therefore AEs started during the Washout Period will be assigned to the treatment received in 
the previous Period and AEs started during the Follow-up Period (i.e. from the day after Visit 
9 until the date of completion/discontinuation) will be assigned to the treatment received in 
Treatment Period 4. AEs occurring during the Washout and the Follow-up Periods will be 
flagged in the listings. 
 
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 
(of the associated treatment) + 1 if the AE onset date is greater or equal to date of first 


 
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study drug intake.  For pre-treatment AEs, the relative day is defined as the AE onset 
date – Date of first study drug intake (study-level). Relative day will not be calculated 
in case of partial/missing date of AE onset. The relative day of TEAEs is calculated 
considering the date of first study medication intake in the period associated with the 
start date of the TEAE. 
• 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.  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; 
2. post-study; 
3. pre-treatment. 
 
• 2: Vital signs (systolic and diastolic blood pressure) 
 
Blood pressure measurements are continuous variables and recorded in mmHg.  
 
Baseline of Vital signs, as defined in section 7.2.3, will be considered the pre-dose 
measurement on Day 1 of each Treatment Period. Change from pre-dose on Day 14 will also 
be evaluated. 
 
• 3:  12-lead ECG parameters (HR, QTcF, QRS, PR)  
 
12-lead ECG parameters are continuous variables. Heart rate (HR) is recorded in bpm; PR 
interval, QRS interval and QTcF interval are recorded in msec.  
QTc value will be calculated using the Fridericia formula (Fridericia-corrected QTc=
QT
√RR
3
).  
ECG parameters are provided by centralized ECG service provider, in eCRF only data, time 
and Investigator's Interpretation is collected. 
 
The changes from baseline will be based on the pre-dose assessment on Day 1 of each 
Treatment Period. Change for pre-dose on Day 14 will also be evaluated.  
 
• 4:  HR AUC0-4h normalized by time. 
HR AUC0-4h will be calculated at Day 1 and Day 14. The calculation of the HR AUC0-4h will 
follow in the same manner as the calculation outlined above for the secondary efficacy 
variable 1b. 
HR AUC0-4h will be calculated only if HR data are recorded on each time-point (pre-dose, and 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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30 minutes, 1h, 4h post-dose). 
 
• 5: HR peak0-4h  
HR peak0-4h  will be calculated on Day 1 and Day 14. HR peak0-4h  will be calculated using the 
following formula: maximum value of all HR values at the time points 30 min, 1h, and 4h of 
the respective day.   
 
HR peak0-4h  will be calculated only if HR data are recorded on each post-dose time-point (30 
minutes, 1h, 4h post-dose). 
 
 
• 6:  Serum potassium and blood glucose 
 
From Visit 2 to Visit 9, blood samples of about 2.5 mL will be collected for measuring serum 
Potassium and glucose pre-dose and at 1.5, 3, 5, 7 and 11h post-dose (total blood volume = 15 
mL/Visit). The Baseline value is pre-dose measurement on Day 1 of each Treatment Period. 
Change for pre-dose on Day 14 will also be evaluated. 
 
• 7: Hematology, Chemistry, and Pregnancy Tests 
 
Blood samples of about 12mL will be collected for hematology and serum chemistry at 
Screening, Visit 9 and Early Termination in the morning. Data from hematology, chemistry, 
and Pregnancy Tests will only be listed. 
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).  
• Serum pregnancy test (serum β-hCG) in women of child-bearing potential; results will 
be presented as positive or negative. 
 
A urine pregnancy test using a commercial urine hCG pregnancy test strip will be conducted 
at each visit from V1-V8. Urine β-hCG from these visits will 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) 


 
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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) 
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.   
 
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 8.2.1.5.  
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): 


 
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• Age at First Asthma Diagnosis (years), BMI, treatment exposure (days): whole 
numbers; 
• Time to discontinuation (weeks), duration of smoking (years), Time since First Asthma 
Diagnosis (years), compliance, 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, 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 report. SAS output 
results will be generated only after DB lock. 
8.1.1 Rules for Patients Receiving the Same Treatment in Two Periods 
 
For continuous variables presented in tables for which both periods are considered for patients 
receiving the same treatment more than once, summary statistics will include the number of 
non-missing observations on the patient level (“n”), the number of non-missing observations 
on the treatment period level (“n periods”), 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.  The number of treatment periods considered (“n 
periods”) will not be presented in the summary tables on baseline characteristics. 
For patients receiving the same treatment in 2 periods, each subject will contribute once to the 
summary statistics.  Since 2 data points will be available, but the subject should only contribute 
once, the 2 available data points will be averaged for these subjects prior to calculation of the 
summary statistics for all subjects.   
 
Example: 
Parameter: Change from Baseline (CFB) in FEV1 AUC0-12 at Day 14 
Patient 123 receives Treatment A in Period 1 and receives Treatment A 
again in Period 2.  The values of CFB in FEV1 AUC0-12 at Day 14 are:  
Period 1:  100mL, Period 2: 110mL.   
For summary statistics of CFB FEV1 AUC0-12 at Day 14 for Treatment A, 
Patient 123 will contribute one value to the summary statistics of CFB in 


 
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FEV1 AUC0-12 at Day 14.  The value will be the average of the values from 
Period 1 and Period 2, which is 105mL. 
 
 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. For tables in which both periods are considered for patients 
receiving the same treatment more than once the following percentages will be compute: 
• For disposition, protocol deviations, maintained, concomitant medications, and 
exposure/compliance, the percentages will be based on the number of treatment periods 
and a footnote will be added to indicate this.  
• For safety variables, the percentages will be based on the number of patients in each 
treatment arm and a footnote will be added to specify this. 
 
For categorical analyses of QTcF, patients receiving a treatment twice will contribute only once 
to the summary statistics, using the highest QTcF value. 
Listings including sequence will present the sequence of treatment allocated by the 
randomization system.  A single listing will also be presented including the sequences based on 
the original Randomization and Decode Lists (described in Section 10.1, below).     
 
8.1.2 Rules for Handling Missing Data 
No adjustment for missing data is carried out. 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. 
 
8.2 Specific Methods for Efficacy Analyses 
Analyses Based on Mixed Models 
Primary efficacy endpoint 
Patients receiving the same treatment in more than one period will be included in the primary 
efficacy model including all available data. 
 
Example: 
Parameter: Change from Baseline (CFB) in FEV1 AUC0-12 at Day 14 
Patient 123 receives Treatment A in Period 1 and receives Treatment A 
again in Period 2.   


 
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For primary analysis of CFB FEV1 AUC0-12 at Day 14 for Treatment A, 
Patient 123 will contribute two values to the response variable CFB in FEV1 
AUC0-12 at Day 14 (one value from Period 1 and another value from Period 
2). 
 
● Model for Analysis 
Change from baseline in FEV1 AUC0-12h normalized by time at Day 14 will be analyzed using 
an Analysis of Covariance (ANCOVA) model including treatment, period and subject as fixed 
effects and baseline as a covariate.  
 
proc mixed data = <xxx>; 
  class subject treatment period;  
  model <response> = subject  treatment  period fev1base; 
  lsmeans treatment / cl ; 
  lsmestimate treatment ‘Treatment A vs Placebo: Day 14’ 1 0 0 0 -1 0,  
          ‘Treatment B vs Placebo: Day 14’ 0 1 0 0 -1 0,  
                                      ‘Treatment C vs Placebo: Day 14’ 0 0 1 0 -1 0,  
         ‘Treatment D vs Placebo: Day 14’ 0 0 0 1 -1 0  
          / cl adjust=simulate(seed=12311980 acc=0.0001); 
  lsmestimate  
treatment ‘Trt B vs Trt A: Day 14’ -1 1 0 0 0 0 / cl;  
  lsmestimate 
treatment ‘Trt C vs Trt A: Day 14’ -1 0 1 0 0 0/ cl; 
  lsmestimate 
treatment ‘Trt D vs Trt A: Day 14’ -1 0 0 1 0 0/ cl; 
  lsmestimate 
treatment ‘Trt C vs Trt B: Day 14’   0 -1 1 0 0 0 / cl; 
  lsmestimate  
treatment  ‘Trt D vs Trt B: Day 14’ 0 -1 0 1 0 0/cl; 
  lsmestimate 
treatment ‘Trt D vs Trt C: Day 14’ 0 0 -1 1 0 0/cl; 
  lsmestimate 
treatment ‘Trt F vs Placebo: Day 14’ 0 0 0 0 -1 1/cl; 
run; 
 
 
where: 
• Subject is the variable identifying subject. 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (FF 6 µg/d) 
2. Treatment B (FF 12 µg/d) 
3. Treatment C (FF 24 µg/d) 
4. Treatment D (FF 48 µg/d) 
5. Placebo 
6. Treatment F (PERFOROMIST® 40 µg/d) 
• period is the period variable (Treatment Period 1, Treatment  Period 2, Treatment 
Period 3, Treatment Period4) 
• fev1base is the baseline FEV1 result 
 
The adjusted means in each treatment group, the adjusted mean difference between treatments, 
their 95% Confidence Intervals (CIs) and their p-values at Day 14 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 1531pMDI and placebo 
will be adjusted for multiplicity. The adjustment will be based on the parametric simulation 


 
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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 1531 pMDI will be 
demonstrated by a statistically significant difference (adjusted p-value < 0.05) favoring CHF 
1531 pMDI.  
The adjusted mean pairwise differences between treatments A, B, C, and D and their 95% 
Confidence Intervals (CIs) will be estimated by the model, comparing each dose with a lower 
dose and treatment F versus placebo. The CIs and the p-values of the comparisons between 
each pairwise comparisons at Day 14 will not be adjusted for multiplicity.  
Sensitivity Analyses for the primary efficacy variable 
Additional sensitivity analyses will be performed on the primary efficacy endpoint only. 
Sensitivity Analysis 1: Incorporating Only the First Instance of Each Treatment 
Patients receiving the same treatment in more than one period will be included in the primary 
efficacy model including only data from the first instance of each treatment.   
 
Example: 
Parameter: Change from Baseline (CFB) in FEV1 AUC0-12 at Day 14 
Patient 123 receives Treatment A in Period 1 and receives Treatment A 
again in Period 2.   
For Sensitivity Analysis 1 of CFB FEV1 AUC0-12 at Day 14 for Treatment 
A, Patient 123 will contribute one value to the response variable CFB in 
FEV1 AUC0-12 at Day 14.  The value will be the result from Period 1.  The 
result obtained for Patient 123 during Period 2 will be ignored (considered 
as missing) for this sensitivity analysis. 
 
Sensitivity Analysis 2: Incorporating Only Treatment Periods for Which Treatment was 
Assigned After the IRT System Update 
Following the IRT system update on 
, the treatment allocation was changed for all 
patients.  Of note, the majority of treatment assignments occurred after the update to the 
randomization system on 
.  The file used after 
 would have provided 
an appropriate randomization had it been applied consistently across all patients.  With this in 
mind, the following sensitivity analysis is planned. 
The primary analysis will be repeated, incorporating only treatment periods for which treatment 
was allocated on or after 
.  Treatment periods for which treatment was allocated 
prior to 
 will be excluded from the analysis.  Of note, the system update occurred 
at 
 in the US Eastern time zone.  No allocation was performed on 
 prior 
to the update.  Therefore, allocations occurring on 
 all occurred after the update. 
 
Example: 


 
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Parameter: Change from Baseline (CFB) in FEV1 AUC0-12 at Day 14 
Patient 123 receives Treatment A in Period 1 and receives Treatment A 
again in Period 2.  The treatment allocation for period 1 occurred prior to 
  The treatment allocation for Period 2 occurred after 
 
For Sensitivity Analysis 2 of CFB FEV1 AUC0-12 at Day 14 for Treatment 
A, Patient 123 will contribute one values to the response variable CFB in 
FEV1 AUC0-12 at Day 14.  The value will be the result from Period 2.  The 
result obtained for Patient 123 during Period 1 will be ignored (considered 
as missing) for this sensitivity analysis. 
Sensitivity Analysis 3:  Incorporating Subject as a Random Effect 
The primary analysis will be repeated, incorporating subject as a random effect. As the period-
level baseline value is included as a covariate in the model, the approach proposed by Kenward 
and Roger (Kenward MG, Roger JH. The use of baseline covariates in crossover studies. 
Biostatistics. 2010 Jan;11(1):1-17) was adopted. This model assumes a joint multivariate 
normal distribution for Zik = (Xik1, Yik1, Xik2, …, Xikp, Yikp)T, where Xikp and Yikp denote 
the baseline measurement and the response, respectively, from the kth subject in sequence i in 
period p. The covariance matrix of Zik is given by: 
𝑉(Zik) = 𝚺𝐖 ⨂ 𝐈𝒑 + 𝚺𝐁 ⨂ 𝐉𝒑 . 
Ip and Jp denote the p x p identity matrix and matrix of ones, respectively. 𝚺𝐖 represents the 
covariance matrix for X and Y within a treatment period and 𝚺𝐁 the covariance matrix between 
baseline and response at the subject level. Two unstructured covariance matrices are assumed 
for 𝚺𝐖 and 𝚺𝐁: 
𝚺𝐖= (
𝝈𝒙𝒙
𝝈𝒙𝒚
𝝈𝒙𝒚
𝝈𝒚𝒚)     and     𝚺𝐁= (
𝜼𝒙𝒙
𝜼𝒙𝒚
𝜼𝒙𝒚
𝜼𝒚𝒚). 
The model includes a fixed period effect with 2p levels, one for each element of Z, and a fixed 
treatment effect that applies to the Ys only. 
 
The following SAS code will be used for this sensitivity analysis: 
 
proc mixed data=<XXX>; 
 
class subject treatment period type; 
 
model <response> = period*type treatment*type / ddfm=kr; 
 
random type / subject=subject type=un; 
 
repeated type / subject=subject*period type=un; 
 
lsmestimate treatment*type 'Chg from baseline: Treatment A'   -1 1 0 0 0 0 0, 
 
 
 
 
   'Chg from baseline: Treatment B'   -1 0 1 0 0 0 0, 
 
 
 
                 'Chg from baseline: Treatment C'   -1 0 0 1 0 0 0, 
 
 
 
 
   'Chg from baseline: Treatment D'   -1 0 0 0 1 0 0, 
 
 
 
 
   'Chg from baseline: Placebo' -1 0 0 0 0 1 0, 
 
 
 
 
   'Chg from baseline: Treatment F'   -1 0 0 0 0 0 1 / cl; 
 
lsmestimate treatment*type  
'Treatment A vs Placebo' 0 1 0 0 0 -1 0, 
 
 
 
 
 
'Treatment B vs Placebo' 0 0 1 0 0 -1 0, 


 
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'Treatment C vs Placebo' 0 0 0 1 0 -1 0, 
 
 
 
 
 
'Treatment D vs Placebo' 0 0 0 0 1 -1 0  
/ cl adjust=simulate(seed=12311980 acc=0.0001); 
   
lsmestimate  
treatment*type ‘Trt B vs Trt A: Day 14’    0 -1 1 0 0 0 0/cl;  
   
lsmestimate 
treatment*type ‘Trt C vs Trt A: Day 14’    0 -1 0 1 0 0 0/cl; 
   
lsmestimate 
treatment*type ‘Trt D vs Trt A: Day 14’    0 -1 0 0 1 0 0/cl; 
   
lsmestimate 
treatment*type ‘Trt C vs Trt B: Day 14’    0 0 -1 1 0 0 0/cl; 
   
lsmestimate  
treatment*type ‘Trt D vs Trt B: Day 14’    0 0 -1 0 1 0 0/cl; 
   
lsmestimate 
treatment*type ‘Trt D vs Trt C: Day 14’    0 0 0 -1 1 0 0/cl; 
 
lsmestimate         treatment*type ‘Treatment F vs Placebo‘   0 0 0 0 0 -1 1/cl; 
run; 
 
where: 
• subject is the variable identifying subject 
• treatment is the variable identifying the baseline measurement and the randomized 
treatment, codified and sorted as follow:  
o 0: baseline FEV1 measurement (irrespective of the treatment assigned in the 
period) 
o 1: Treatment A (FF 6 μg/d)  
o 2: Treatment B (FF 12 μg/d) 
o 3: Treatment C (FF 24 μg/d) 
o 4: Treatment D (FF 48 μg/d) 
o 5: Placebo 
o 6: Treatment F (PERFOROMIST® 40 μg/d) 
• period is the period variable (Treatment Period 1, Treatment Period 2, Treatment Period 
3, Treatment Period 4) 
• type is a variable identifying the baseline measurement and the response, codified as 
follow: 
o 0: baseline FEV1 measurement 
o 1: response (FEV1 AUC0-12 at Day 14). 
 
For each treatment period, the input data set for the MIXED procedure will include two records, 
as in the example below. The first record will include the baseline FEV1 measurement in the 
period, with treatment = 0 and type = 0. The second record will include the response (FEV1 
AUC0-12 at Day 14) in the period, with treatment = treatment assigned in the period and type = 
1. 
 
Subject 
Period 
Treatment 
Type 
Value 
001 
2 
0 
0 
xx.x 


 
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001 
2 
5 
1 
yy.y 
 
 
Secondary efficacy endpoints 
For secondary efficacy analyses the comparisons between treatments will be performed with 
no multiplicity adjustment. All the secondary efficacy variables except for Time to onset of 
action (i.e., change from baseline in post-dose FEV1 ≥ 12% and ≥ 200 mL) at Day 1 will be 
analyzed using the same model as the one used for the primary efficacy analysis. 
In case of patients receiving the same treatment in more than one period, the same approach 
will be used as for the primary efficacy analysis (including all available data). 
The SAS code for the secondary efficacy endpoints will be: 
 
proc mixed data = <xxx>; 
  class subject treatment period; 
  model <response> = subject  treatment  period fev1base ; 
  lsmeans treatment / cl; 
  lsmestimate ‘Trt A vs Placebo: day 1’ treatment 1 0 0 0 -1 0; 
  lsmestimate ‘Trt B vs Placebo: day 1’ treatment 0 1 0 0 -1 0; 
  lsmestimate ‘Trt C vs Placebo: day 1’ treatment 0 0 1 0 -1 0; 
  lsmestimate ‘Trt D vs Placebo: day 1’ treatment 0 0 0 1 -1 0; 
  lsmestimate treatment ‘Trt B vs Trt A: day 1’ -1 1 0 0 0 0; 
  lsmestimate treatment ‘Trt C vs Trt A: day 1’     -1 0 1 0 0 0; 
  lsmestimate treatment ‘Trt D vs Trt A: day 1’     -1 0 0 1 0 0; 
  lsmestimate treatment ‘Trt C vs Trt B: day 1’    0 -1 1 0 0 0; 
  lsmestimate treatment ‘Trt D vs Trt B: day 1’    0 -1 0 1 0 0; 
  lsmestimate treatment ‘Trt D vs Trt C: day 1’    0 0 -1 1 0 0; 
  lsmestimate treatment ‘Trt F vs Placebo: day 1’ 0 0 0 0 -1 1;  
run; 
• Subject is the variable identifying subjects. 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (FF 6 µg/d) 
2. Treatment B (FF 12 µg/d) 
3. Treatment C (FF 24 µg/d) 
4. Treatment D (FF 48 µg/d) 
5.  Placebo 
6. Treatment F (PERFOROMIST® 40 µg/d) 
• period is the period variable (Treatment Period 1, Treatment Period 2, Treatment 
Period 3, Treatment Period 4). 
• fev1base is the baseline FEV1 result 
 
The adjusted means in each treatment group, the adjusted mean difference between treatments, 
their 95% Confidence Intervals (CIs) and their p-values 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 treatments at Day 1 or Day 14, depending on with secondary 
variables we are analyzing, will not be adjusted for multiplicity. 


 
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Analyses Based on the Time to Onset 
Analyses based on time to onset will include only data from the first instance of each treatment 
for patients receiving the same treatment twice.    
 
Example: 
Parameter: Time to Onset of Action (Change from Baseline in Post-dose FEV1 ≥ 12% and ≥ 
200 ml) on Day 1 
Patient 123 receives Treatment A in Period 1 and receives Treatment A again in Period 2.   
For analysis of Time to Onset of Action (Change from Baseline in Post-dose FEV1 ≥ 12% and 
≥ 200 ml) on Day 1 for Treatment A, Patient 123 will contribute one values to the response 
variable.  The value will be the result from Period 1.  The result obtained for Patient 123 during 
Period 2 will be ignored (considered as missing) for this analysis. 
 
A Cox proportional hazards model will be utilized to analyze the time to onset of action in FEV1 
(i.e., change from baseline in post-dose FEV1 ≥ 12% and ≥ 200 mL). The Cox proportional 
hazards model will be stratified by subject and will include treatment and period as a factor, 
and baseline FEV1 as covariate. The generic code for the Cox model is: 
proc phreg data=<xxx>; 
   class  treatment  period subject ; 
   model time*censor(0) = treatment period fev1base / risklimits ties=exact; 
  strata subject;  contrast treatment “Treatment A vs. Placebo"        1 0 0 0 -1 /estimate=exp; 
  contrast treatment “Treatment B vs. Placebo"        0 1 0 0 -1 /estimate=exp; 
  contrast treatment “Treatment C vs. Placebo"        0 0 1 0 -1 /estimate=exp;; 
  contrast treatment “Treatment D vs. Placebo"        0 0 0 1 -1 /estimate=exp; 
  contrast treatment “Treatment B vs. Treatment A" -1 1 0 0 0 /estimate=exp; 
  contrast treatment “Treatment C vs. Treatment A" -1 0 1 0 0 /estimate=exp; 
  contrast treatment “Treatment D vs. Treatment A" -1 0 0 1 0 /estimate=exp; 
  contrast treatment “Treatment C vs. Treatment B" 0 -1 1 0 0 /estimate=exp; 
  contrast treatment “Treatment D vs. Treatment B" 0 -1 0 1 0 /estimate=exp; 
  contrast treatment “Treatment D vs. Treatment C" 0 0 -1 -1 0/estimate=exp; 
  contrast treatment “Treatment F vs. Placebo"         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: 
• Subject is the subject variable. 


 
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• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (FF 6 µg/d) 
2. Treatment B (FF 12 µg/d) 
3. Treatment C (FF 24 µg/d) 
4. Treatment D (FF 48 µg/d) 
5.  Placebo 
6. Treatment F (PERFOROMIST® 40 µg/d) 
• fev1base is the baseline FEV1 result 
• period is the visit period variable (Treatment Period 1, Treatment Period 2, Treatment 
Period 3, Treatment Period4). 
 
 
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 (i.e., change 
from baseline in post-dose FEV1 ≥ 12% and ≥ 200 mL) 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 pair of treatments 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. 
 
8.2.1 Statistical/Analytical Issues  
8.2.1.1 Adjustments for Covariates 
All linear models and time to event models will be adjusted for subject (used as a stratum in the 
Cox proportional hazards model), period and baseline value as covariate. 
8.2.1.2 Handling of Dropouts or Missing Data 
The rules to address missing data rules for specific variables are described in Section 7.2 and 
8.1.2.  
 
8.2.1.3 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. 


 
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8.2.1.4 Multi-center Studies 
As all the analyses will be based on within-subject comparisons, no adjustment is done for the 
multiple centers, and no analysis per center is carried out.  
8.2.1.5 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 1531pMDI and placebo for the primary 
efficacy endpoint at Day 14 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 1531 pMDI will be demonstrated by a statistically significant difference (adjusted p-
value < 0.05) favoring CHF 1531 pMDI.  
8.3 Specific Methods for Safety Analyses 
Analyses Based on ANCOVA 
The change from baseline (pre-dose measurement on Day 1 of each treatment period) and the 
change from pre-dose on Day 14 (only for Day 14 post-dose time points)  in post-dose 12-lead 
ECG parameters (HR, QTcF, QRS and PR) will be analyzed using an ANCOVA model for 
each time point including treatment, period and subject as fixed effects and baseline (pre-dose 
measurement on Day 1 of each treatment period/ change from pre-dose on Day 14) as a 
covariate. The SAS code will be: 
In case of patients receiving the same treatment in more than one period the same approach 
will be used as for the primary efficacy analysis (including all available data). 
 
proc mixed data = <xxx>; 
  class subject treatment period  
  model <response> = subject  treatment  period base  /  
  lsmeans treatment / cl alpha=0.10; 
  lsmestimate ‘Trt A vs Placebo: day 1’ treatment 1 0 0 0 -1 0/ cl alpha=0.10, 
  lsmestimate ‘Trt B vs Placebo: day 1’ treatment 0 1 0 0 -1 0/ cl alpha=0.10,   
  lsmestimate ‘Trt C vs Placebo: day 1’ treatment 0 0 1 0 -1 0/ cl alpha=0.10, 
  lsmestimate ‘Trt D vs Placebo: day 1’ treatment 0 0 0 1 -1 0/ cl alpha=0.10, 
  lsmestimate ‘Trt B vs Trt A: day 1’ treatment     -1 1 0 0 0 0/ cl alpha=0.10, 
  lsmestimate ‘Trt C vs Trt A: day 1’ treatment     -1 0 1 0 0 0/ cl alpha=0.10, 
  lsmestimate ‘Trt D vs Trt A: day 1’ treatment     -1 0 0 1 0 0/ cl alpha=0.10, 
  lsmestimate ‘Trt C vs Trt B: day 1’ treatment     0 -1 1 0 0 0/ cl alpha=0.10, 
  lsmestimate ‘Trt D vs Trt B: day 1’ treatment     0 -1 0 1 0 0/ cl alpha=0.10, 
  lsmestimate ‘Trt D vs Trt C: day 1’ treatment     0 0 -1 1 0 0/ cl alpha=0.10, 
  lsmestimate ‘Trt F vs Placebo: day 1’ treatment 0 0 0 0 -1 1/ cl alpha=0.10, 
run; 
 
 
where: 
• Subject is the variable identifying subject . 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (FF 6 µg/d) 
2. Treatment B (FF 12 µg/d) 
3. Treatment C (FF 24 µg/d) 
4. Treatment D (FF 48 µg/d) 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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5.  Placebo 
6. Treatment F (PERFOROMIST® 40 µg/d) 
• period is the period variable (Period 1, Period 2, Period 3, Period4).) 
• base is the baseline value (pre-dose measurement on Day 1 of each Treatment Period). 
 
The adjusted means in each treatment and the adjusted mean differences between treatments 
will be estimated by the model with 90% CIs and  their p-values. 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 treatments at Day 1 or Day 14, depending on with secondary variables we are 
analyzing, will not be adjusted for multiplicity.  
 
 
9 Interim analyses 
Not applicable. 
10 Overview of Tables, Listings and Figures 
Demographics, Asthma history, Pre-Study Smoking Habits, 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, ACQ score, compliance use of diary, and protocol deviations will 
be presented using the ITT population.  Vital signs, 12 lead ECG, AEs and laboratory data will 
be presented using the Safety population.  
 
 Since 32 treatment sequences were used in the randomization, no table will be presented by 
treatment sequence. 
Listings including sequence will present the sequence of treatment allocated by the 
randomization system. All listings will be sorted by patient ID, rather than sequence. 
 
 
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 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.  
The reasons for study discontinuation and number of subjects attending each study visit will be 
summarized overall (including all treatment sequences), using absolute counts and percentages, 


 
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based on the number of subjects randomized. 
 
A disposition summary of subjects will also be presented on period-level (counting each 
treatment period once and including the number of periods as the denominator). It will include 
both the number of patients (“n”) and the number of periods (“n periods”) with the percentage 
(%) of subjects who completed or discontinued the period based on the number of periods. For 
discontinuations occurring during a wash-out period, treatment assignment will be based on the 
most-recent treatment received prior to the discontinuation. The reasons for study 
discontinuation will be also summarized in the same way, using absolute counts and 
percentages.  
The time to discontinuation from study will be summarized overall using descriptive statistics. 
A listing will be presented to show the original intended randomization schedule and how it 
differs from the randomization which was actually implemented by the randomization system 
and the treatments administered. This listing will include columns for the original intended 
treatment assignment for each period, the actual treatment assigned by the IRT system for each 
period, the actual treatment administered/dispensed to the patient, a flag to highlight 
discrepancies between the intended treatment assignment and the actual treatment assignment, 
and a flag to highlight discrepancies between the actual treatment assignment and the treatment 
administered/dispensed to the patient. 
 
10.2 Protocol Deviations 
The number of subjects who had at least one Major Protocol Deviation in a treatment period 
(“Number of Treatment Periods with at Least One Major Deviation”) and all Major Protocol 
Deviations will be summarized by absolute counts (n) and percentages (%) by study treatment 
for the ITT population. Patients receiving a treatment twice will be considered twice in the 
corresponding column. Percentages will be based on the number of treatment periods (“n 
periods”) that will also be reported. 
When summarized by study treatment, Major Protocol Deviations will be assigned to the last 
study treatment received prior to the Major Protocol Deviation. 
The summary will be repeated for Minor Protocol Deviations.   
10.3 Analysis Sets  
The number of subjects in each population (each patient counted only once, regardless of the 
number of periods) will be summarized by absolute counts (n) and percentages (%) for each 
treatment group across periods and overall. Percentages will be based on the number of 
treatment periods which were assigned by the randomization system.  The number of periods 
(“n periods”) will be also summarized by treatment group by absolute counts (“n periods”) for 
each treatment group.   
 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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10.4 Demographic and Other Baseline Characteristics 
10.4.1 Demographic Characteristics, Asthma History, and Smoking Habits 
Demographic data, Asthma history and smoking habits will be summarized by summary 
statistics and absolute counts (n) and percentages (%) by treatment sequence and overall for the 
Safety population, the ITT population and PP population. Tables will be presented overall only 
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 (%) 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. Medical and Surgical History and Concomitant 
Diseases will be presented overall only. 
10.4.3 Baseline Subject Characteristics 
Central spirometry and reversibility test data, will be summarized at Visits 1 and 2 with 
summary statistics and absolute counts (n) for the Safety population, the ITT population and 
PP population. Central spirometry and reversibility test will be presented overall only. 
ECG results at Visit 1 and Vital signs at Visits 1 and 2 will be summarized with summary 
statistics and absolute counts (n) and percentages (%) for the Safety population. Results will be 
presented overall only.  
 
ACQ score will be summarized at Visits 1 and 2 with summary statistics and absolute counts 
(n) using the ITT population. ACQ score will be presented overall only. 
Physical examination results will only be listed.  
10.4.4 Previous, Maintained and Concomitant Medications 
Previous medications will be presented overall, while concomitant medications and maintained 
medications will be summarized by treatment and overall (for the assignment of medications to 
a treatment, see section 7.2.6).  For concomitant medications and maintained medications, 
patients receiving the same treatment during two different periods will be considered twice in 
the corresponding group and the number of periods (“n periods”) will be also reported. 
All previous medications will be presented in the tables and the listings.  
Post-treatment medications and medications taken only during washout 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 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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Anatomical Main Group and per Chemical Subgroup within Therapeutic Subgroup, for the ITT 
population. The number of subjects (“n”) and the number of periods (“n periods”) will be 
presented.  Percentages will be calculated based on the number of periods (“n periods”) for 
Concomitant and Maintained medications.  
.  
10.5 Study drug / Investigational Medicinal Product  
10.5.1 Background ICS medication 
Daily dose of previous ICS treatment for asthma will be summarized by descriptive statistics 
using absolute counts (n) and percentages (%) of subjects according to the dose category (Low 
Daily Dosage and Medium Daily Dosage), for the ITT population.  
In addition, daily dose of previous ICS treatment for Asthma in term of estimated clinically 
comparable daily dose of QVAR® and the number of morning and evening puffs that the subject 
was instructed to take, both for QVAR 40 µg and QVAR 80 µg will be summarized with 
summary statistics and absolute counts (n) for the ITT population. The table will be presented 
overall only. 
Exposure and compliance will be summarized overall (including all patients together) by 
summary statistics and absolute counts (n) for the run-in for the ITT population.  
During the treatment periods and the Washout period, exposure and compliance will be 
summarized by summary statistics and absolute counts (n) by treatment for the ITT population. 
Patients receiving a treatment twice will be considered twice in the corresponding group. The 
number of patients (“n) and also the number of periods (“n periods”) will be reported.  
In addition, for all periods, the number and percentage of subjects with satisfactory (65% - 
135%) and unsatisfactory (<65%; >135%) levels of compliance to the study drug will be 
summarized.  For treatment periods and Washout Periods, percentages will be based on the 
number of periods (“n periods”) while for run-in period, percentages will be based on the 
number of subjects in the ITT population.  The summary will be repeated by the following 
compliance 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%] and > 140%).  
 
10.5.2 Study drug 
Treatment exposure and compliance during the Treatment Periods will be summarized by 
summary statistics and absolute counts (n) by treatment using the ITT population and the Safety 
population. 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 population and the Safety Population. The summary will be repeated 
by the following compliance 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%] and > 140%). Patients receiving a treatment twice 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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will be considered twice in the corresponding group. The number of periods (“n periods”) will 
be also reported. Percentages will be based on the number of periods (“n periods”).   
10.5.3 Compliance with the use of Diary 
Compliance with the use of Diary in Run-in Period will be summarized by summary statistics 
and absolute counts (n) using the ITT population. In addition the number and percentage of 
subjects with the following compliance categories ([0%-10%], (10%-20%], (20%-30%], (30%-
40%], (40%-50%], (50%-60%], (60%-70%], (70%-80%], (80%-90%], (90%-100%]) will be 
summarized using the ITT population.  
 
Compliance with the use of Diary in treatment and Washout periods will be summarized by 
summary statistics and absolute counts (n)by treatment using the ITT population. In addition 
the number and percentage of subjects with the following compliance categories ([0%-10%], 
(10%-20%], (20%-30%], (30%-40%], (40%-50%], (50%-60%], (60%-70%], (70%-80%], 
(80%-90%], (90%-100%]) will be summarized by treatment using the ITT population. Patients 
receiving a treatment twice will be considered twice in the corresponding group. The number 
of periods (“n periods”) will be also reported. Percentages will be based on the number of 
periods (“n periods”).   
 
 
10.6 Efficacy Results 
10.6.1 Primary efficacy variable 
FEV1 AUC0-12h normalized by time at Day 14 and change from baseline in FEV1 AUC0-12h  will 
be summarized with summary statistics with the 95% CI of the mean, number of treatment 
periods considered (“n periods”) and number of patients (“n”) by treatment for the ITT and the 
PP population. For patients receiving the same treatment in 2 periods, each subject will 
contribute once to the summary statistics.  Since 2 data points will be available, but the subject 
should only contribute once, the 2 available data points will be averaged for these subjects prior 
to calculation of the summary statistics for all subjects. 
The primary endpoint is the change from baseline in FEV1 AUC0-12h normalized by time at Day 
14.The change from baseline in FEV1 AUC0-12h normalized by time will be analyzed using an 
Analysis of Covariance (ANCOVA) 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 will be estimated by the 
model. The CIs and the p-values of the comparisons between each dose of CHF 1531 pMDI 
and placebo at Day 14 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 1531 pMDI versus placebo will be demonstrated by a statistically significant difference 
(adjusted p-value < 0.05) favoring CHF 1531 pMDI. The adjusted mean pairwise differences 
between treatments A, B, C, and D and their 95% Confidence Intervals (CIs) will be estimated 
by the model, comparing each dose with a lower dose and treatment F versus placebo. The CIs 
and the p-values of the comparisons between each pairwise comparisons at Day 14 will not be 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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adjusted for multiplicity. In addition, the p-values for each of the factors in the model will be 
displayed. 
The analysis will be performed using the ITT population (primary analysis) and will be repeated 
using the PP population. 
The primary analysis will be repeated for the three sensitivity analysis, as described in section 
8.2.  
The mean absolute FEV1 and the mean change from baseline at each time pointat Day 1 and 
Day 14 will be summarized with summary statistics with the 95% CI of the mean and absolute 
counts (n) and number of treatment periods considered (“n periods”)  by treatment for the ITT 
and the PP population. For patients receiving the same treatment in 2 periods, each subject will 
contribute once for each time point to the summary statistics.  Since 2 data points will be 
available for each time point, but the subject should only contribute once, the 2 available data 
points will be averaged for these subjects prior to calculation of the summary statistics for all 
subjects at each time point. The mean absolute FEV1 and the mean change from baseline at 
each time point will be plotted for each of the treatment groups at Day 1 and Day 14. 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.  For 
patients receiving the same treatment in 2 periods, each subject will contribute once to the 
summary statistics.  Since 2 data points will be available, but the subject should only contribute 
once, the 2 available data points will be averaged for these subjects prior to calculation of the 
summary statistics for all subjects. In addition to the summary statistics also the number of 
treatment periods considered (“n periods”) will be reported.  
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. 
 
Analysis of Secondary Efficacy Variable 1a: 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 an ANCOVA model 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 1b: Change from baseline in FEV1 AUC0-4h 
normalized by time at Day 1 and Day 14 
The change from baseline in FEV1 AUC0-4h normalized by time on Day 1 and Day 14 will be 
analyzed using an ANCOVA  model as outlined in Section 8.2. The adjusted means in each 
treatment group with their corresponding 95% CIs, and the adjusted mean difference between 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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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 1c: Change from baseline in FEV1 peak0-4h 
normalized by time at Day 1 and Day 14. 
The change from baseline in FEV1 peak0-4h normalized by time on Day 1 and Day 14 will be 
analyzed using an ANCOVA model 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 1d: Change from baseline in pre-dose morning 
FEV1 (average of pre-dose FEV1 measurements) Day 14 
The change from baseline in pre-dose morning FEV1 normalized by time at Day 14 will be 
analyzed using an ANCOVA model 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 2a: Change from baseline in FVC AUC0-12h 
normalized by time at Day 1 and Day 14 
The change from baseline in FVC AUC0-12h normalized by time on Day 1 and Day 14 will be 
analyzed using an ANCOVA model 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 and the mean change from baseline at each time point at Day 1 and 
Day 14 will be summarized with summary statistics with the 95% CI of the mean and absolute 
counts (n) by treatment for the ITT population. . For patients receiving the same treatment in 2 
periods, each subject will contribute once for each time point to the summary statistics.  Since 
2 data points will be available for each time point, but the subject should only contribute once, 
the 2 available data points will be averaged for these subjects prior to calculation of the 
summary statistics for all subjects at each time point. The mean absolute FVC and the mean 
change from baseline at each time point will be plotted for each of the treatment groups at Day 
1 and Day 14 for the ITT population.  
 
Analysis of Secondary Efficacy Variable 2b: Change from baseline in FVC AUC0-4h 
normalized by time at Day 1 and Day 14 
The change from baseline in FVC AUC0-4h normalized by time on Day 1 and Day 14 will be 
analyzed using an ANCOVA model as outlined in Section 8.2. The adjusted means in each 
treatment group with their corresponding 95% CIs, and the adjusted mean difference between 


 
Chiesi Farmaceutici S.p.A.                                                                                                    Statistical Analysis Plan 
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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 FVC peak0-4h at Day 1 
and Day 14 
The change from baseline in FVC peak0-4h normalized by time on Day 1 and Day 14 will be 
analyzed using an ANCOVA  model 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 2d: • 
Change from baseline in pre-dose morning 
FVC at Day 14. 
 
The change from baseline in in pre-dose morning FVC at Day 14 will be analyzed using an 
ANCOVA model 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: Time to onset of action (change from baseline 
in post-dose FEV1 ≥ 12% and ≥ 200 ml) at Day 1 (min) 
Time to onset of action (i.e., change from baseline in post-dose FEV1 ≥ 12% and ≥ 200 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 with their 
corresponding 95% CIs 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 treatments will be provided.  In addition, the p-values for each of the factors in the 
model will be provided. 
A Kaplan-Meier plot of the survival curves will also be presented. 
A summary of the number and percentage of subjects who achieved the threshold at each post-
dose time point on Day 1 will be provided.  
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. 
Rescue medication collected from eCRF and subject diaries will be will be presented in data 
listings only. 
 
10.7 Safety Analyses 
All safety analyses described below will be performed on the Safety population. 


 
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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 
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. 
All available data will be considered in the summary of TEAEs: patients receiving a treatment 
twice will be considered twice in the corresponding treatment group (data from both periods 
during which the subject received the corresponding treatment will be included). Subjects who 
have multiple events in the same system organ class (SOC) and preferred term (PT) during a 
single treatment period will be counted only once in the subject counts for the corresponding 
treatment period. The number of subjects ("n"), the number of treatment periods ("n periods") 
and the number of events will be presented.  Percentages will be based on the number of 
treatment periods in the Safety population. 
 
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 Day 14 (only for Day 14 post-dose time points) will be 
summarized by treatment using descriptive statistics and the 95% CI of the mean. 
Mean absolute Vital signs (systolic and diastolic blood pressure) and their changes from 
baseline (pre-dose on Day 1) will be plotted for each of the treatment groups at Day 1 and Day 
14. 
For patients receiving the same treatment in 2 periods, each subject will contribute once to the 
summary statistics.  Since 2 data points will be available, but the subject should only contribute 
once, the 2 available data points will be averaged for these subjects prior to calculation of the 
summary statistics for all subjects. In addition to the summary statistics also the number of 
treatment periods considered (“n periods”) will be reported. 
10.7.3 ECGs  
For continuous ECGs parameters, in case of patients receiving the same treatment in 2 periods, 
each subject will contribute once to the summary statistics.  Since 2 data points will be 
available, but the subject should only contribute once, the 2 available data points will be 
averaged for these subjects prior to calculation of the summary statistics for all subjects. In 


 
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addition to the summary statistics also the number of treatment periods considered (“n 
periods”) will be reported. 
 
ECG parameters (HR, QTcF, QRS, and PR) at each time point will be summarized on Day 1 
and Day 14 by treatment using descriptive statistics and the 95% CI of the mean. In addition, 
their changes from baseline and the changes from pre-dose on Day 14 (only for Day 14 post-
dose time points) will be summarized using descriptive statistics and 90% CI.   
 
In addition, the number and percentage of subjects with prolonged QTcF at any planned post 
dose time point will be summarized by treatment using counts and percentages on Day 1 and 
Day 14 Patients receiving a treatment twice will contribute only once to the summary statistics, 
using the highest QTcF value. The following thresholds will be used: 
• 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 and Change from baseline in QTcF >60 ms 
 
For post-dose time-points on Day 14:  
• change from pre-dose on Day 14 in QTcF >30ms and>60ms 
 
At each post-dose time-point at Day 1 and Day 14, the change from baseline (pre-dose 
measurement on Day 1 of each Treatment Period) in 12-lead ECG parameters (HR, QTcF, QRS 
and PR) will be analyzed using an ANCOVA as stated in section 8.3. The adjusted means in 
each treatment group with their corresponding 90% CIs, and the adjusted mean difference 
between treatments 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. 
 
Mean absolute ECG parameters (HR, QTcF, QRS, and PR) at each time point and the mean 
change from baseline (pre-dose measurement on Day 1) at each time point will be plotted for 
each of the treatment groups at Day 1 and Day 14. These figures will be based on data from 
subjects in ITT population. 
 
HR AUC0-4h normalized by time and HR peak0-4h on Day 1 and Day 14 and their changes 
from baseline (pre-dose measurement on Day 1 of each Treatment Period) and from pre-dose 
on Day 14 will be summarized by treatment using descriptive statistics and the CI of the mean 
(95% CI for absolute values and 90% CI for the changes from baseline/pre-dose). 
 
12-lead ECG Abnormalities will be presented in data listings only. 
 
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 


 
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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”, “Atrial flutter”. 
• 
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 
Serum potassium and blood glucose at each time point and their changes from baseline (pre-
dose measurement on Day 1 of each Treatment Period) and from pre-dose on Day 14 will be 
summarized by treatment using descriptive statistics and the 95% CI of the mean. 
Mean absolute Serum potassium and blood glucose at each time point and their changes from 
baseline (pre-dose on Day 1) will be plotted for each of the treatment groups at Day 1 and Day 
14 based on Safety population. 
 
For patients receiving the same treatment in 2 periods, each subject will contribute once to the 
summary statistics.  Since 2 data points will be available, but the subject should only 
contribute once, the 2 available data points will be averaged for these subjects prior to 
calculation of the summary statistics for all subjects. In addition to the summary statistics also 
the number of treatment periods considered (“n periods”) will be reported. 
 
In addition, all laboratory data will be listed, with abnormal values flagged. 
 
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: 


 
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• 
Data collected at Day 1 and Day 14 of each period (spirometry, vital signs, serum 
potassium/glucose, and ECG) which is recorded at the study termination visit for 
discontinued patients will be re-allocated to the Day 14 visit of the same period. 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.  
 
• 
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 calculations and as eligible for 
minimum/maximum assessments unless otherwise specified in the DRR.  
 
• 
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 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.  
 


 
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11 Table of Contents for the Tables, Listings and Figures 
Post-Text Tables 
[KFR] indicates table to be included with Key First Results. 
  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: Patient Disposition by Study Treatment (All Randomized Subjects) [KFR] 
Table 14.1.1.2.3: Summary of Subjects by Visit (All Randomized Subjects) 
Table 14.1.1.2.4: Summary of Time to Discontinuation from Study (All Randomized Subjects) 
Table 14.1.1.3.1: Major Protocol Deviations (ITT Population) 
Table 14.1.1.3.2: Minor Protocol Deviations (ITT Population) 
Table 14.1.1.4.1: Summary of Analysis Sets (All randomized patients) [KFR] 
Table 14.1.2.1: Demographic Characteristics (Safety Population) 
Table 14.1.2.2: Demographic Characteristics (ITT Population) [KFR] 
Table 14.1.2.3: Demographic Characteristics (PP Population) 
Table 14.1.3.1: Asthma History and Smoking Habits (Safety Population) 
Table 14.1.3.2: Asthma History and Smoking Habits (ITT Population) [KFR] 
Table 14.1.3.3: Asthma 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) [KFR] 
Table 14.1.6.3: Central Spirometry and Reversibility at Visit 1 (PP Population) 
Table 14.1.8: Vital Signs Results at Visit 1 (Safety Population) 
Table 14.1.9: Asthma Control Questionnaire (ACQ) at Visit 1 and Visit 2 (ITT Population) 
Table 14.1.10: 12-Lead ECG at Visit 1 (Safety Population) 
Table 14.1.11.1: Previous Medications (ITT Population) 
Table 14.1.11.2: Maintained Medications (ITT population)  
Table 14.1.11.3: Concomitant Medications (ITT population) 
Table 14.1.12.1: Background Medication – Previous Asthma Treatment (ITT population) 
Table 14.1.12.2: Background Medication Exposure and Compliance during Run-in (ITT population) 
Table 14.1.12.3: Background Medication Exposure and Compliance during Treatment Periods (ITT                    
population) 
Table 14.1.12.4: Background Medication Exposure and Compliance during Washout periods (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 14.1.14.2: Compliance with the use of Diary in Washout periods (ITT population) 
Table 14.1.14.2: Compliance with the use of Diary in Washout periods (ITT population) 
Table 14.1.14.3: : Compliance with the use of Diary during Treatment periods (ITT Population) 


 
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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 Day 14     
(ITT Population) 
Table 14.2.1.2: Analysis of FEV1 AUC0-12h Normalized by Time at Day 14 (ITT population) [KFR] 
Table 14.2.1.3: Summary of FEV1 AUC0-12h Normalized by Time and the Change from Baseline at Day 14 
(PP Population) 
Table 14.2.1.4: Analysis of FEV1 AUC0-12h Normalized by Time at Day 14 (PP Population) [KFR] 
Table 14.2.1.5: Analysis of FEV1 AUC0-12h Normalized by Time on Day 14 - Sensitivity analysis 1: 
Incorporating Only the First Instance of Each Treatment  (ITT Population) 
Table 14.2.1.6: Analysis of FEV1 AUC0-12h Normalized by Time on Day 14 - Sensitivity analysis 2: 
Incorporating Only Treatment Periods for Which Treatment was Assigned After the IRT System Update (ITT 
Population) 
Table 14.2.1.7: Analysis of FEV1 AUC0-12h Normalized by Time on Day 14 - Sensitivity Analysis 3: 
Incorporating Subject as a Random Effect 
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) [KFR] 
Table 14.2.3.1: Summary of FEV1 AUC0-4h Normalized by Time and the Change from Baseline on Day 1 
and Day 14 (ITT Population) 
Table 14.2.3.2: Analysis of FEV1 AUC0-4h Normalized by Time on Day 1 and Day 14 (ITT Population) 
[KFR] 
Table 14.2.4.1: Summary of FEV1 Peak0-4h and the Change from Baseline on Day 1 and Day 14 (ITT 
Population) 
Table 14.2.4.2: Analysis of FEV1 Peak0-4h on Day 1 and Day 14 (ITT Population) [KFR] 
Table 14.2.5.1: Summary of Pre-dose Morning FEV1 and the Change from Baseline at Day 14 (ITT 
Population) 
Table 14.2.5.2: Analysis of Pre-Dose Morning FEV1 Day 14 (ITT Population) [KFR] 
Table 14.2.5.3: Summary of FEV1 at Each Time Point on Day 1 and Day 14 (ITT Population) [KFR] 
Table 14.2.5.4: Summary of FEV1 at Each Time Point on Day 1 and Day 14 (PP Population) 
Table 14.2.5.5: Summary of Change from Baseline in FEV1 at Each Time Point on Day 1 and Day 14 (ITT 
Population) 
Table 14.2.5.6: Summary of Change from Baseline in FEV1 at Each Time Point on Day 1 and Day 14 (PP 
Population) 
Table 14.2.6.1: Summary of Time to Onset of Action (Change from Baseline in Post-dose FEV1 ≥ 12% and ≥ 
200 ml) on Day 1 (ITT Population)  
Table 14.2.6.2: Analysis of Time to Onset of Action (Change from Baseline in Post-dose FEV1 ≥ 12% and ≥ 
200 ml) on Day 1 (ITT Population) [KFR] 
Table 14.2.7.1: Summary of FVC AUC0-12h Normalized by Time and the Change from Baseline on Day 1 
and Day 14 (ITT Population) 
Table 14.2.7.2: Analysis of FVC AUC0-12h Normalized by Time on Day 1 and Day 14 (ITT Population) 
Table 14.2.8.1: Summary of FVC AUC0-4h Normalized by Time and the Change from Baseline on Day 1 and 
Day 14 (ITT Population) 
Table 14.2.8.2: Analysis of FVC AUC0-4h Normalized by Time on Day 1 and Day 14 (ITT Population) 
Table 14.2.9.1: Summary of FVC Peak0-4h and the Change from Baseline on Day 1 and Day 14 (ITT 
Population) 
Table 14.2.9.2: Analysis of FVC Peak0-4h on Day 1 and Day 14 (ITT Population) 
Table 14.2.10.1: Summary of Pre-dose Morning FVC and the Change from Baseline at Day 14 (ITT 
Population) 
Table 14.2.10.2: Analysis of Pre-Dose Morning FVC on Day 14 (ITT Population) 
Table 14.2.10.3: Summary of FVC at Each Time Point on Day 1 and Day 14 (ITT Population) 


 
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Table 14.2.10.4: Summary of Change from baseline FVC at Each Time Point on Day 1 and Day 14 (ITT 
Population) 
CSR Section 14.3: Safety 
Table 14.3.1.1.1: Summary of Treatment Emergent Adverse Events (Safety Population) [KFR] 
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 Treatment Emergent Adverse Events 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: Vital Signs Results, Changes from Baseline  (Safety Population) 
Table 14.3.4.1: Vital Signs Results, Changes from pre-dose at Day 14  (Safety Population) 
Table 14.3.5.1.1: Summary of the 12-lead ECG Results, Changes from Baseline. (Safety Population) 
Table 14.3.5.1.2: Summary of the 12-lead ECG Results, Changes from pre-dose at Day 14 (Safety Population) 
Table 14.3.5.2.1: 12-lead ECG – Prolonged QTcF (Safety Population - Males) 
Table 14.3.5.2.2: 12-lead ECG - Prolonged QTcF (Safety Population - Females) 
Table 14.3.5.2.3: 12-Lead ECG - Prolonged QTcF – Changes from Baseline (Safety Population) 
Table 14.3.5.2.4: 12-Lead ECG - Prolonged QTcF – Changes from pre-dose on Day 14 (Safety Population) 
Table 14.3.5.2.5: 12-Lead ECG– Summary of HR at each post-dose time point on Day 1 and Day 14 (Change 
from baseline) (Safety Population 
Table 14.3.5.2.6: 12-Lead ECG– Analysis of HR at each post-dose time point on Day 14 (Change from pre-
dose on Day 14) (Safety Population) 
able 14.3.5.2.7: 12-Lead ECG– Summary of QTcF at each post-dose time point on Day 1 and Day 14 (Change 
from baseline)(Safety Population 
Table 14.3.5.2.8: 12-Lead ECG– Analysis of QTcF at each post-dose time point on Day 14 (Change from pre-
dose on Day 14)   (Safety Population) 
Table 14.3.5.2.9: 12-Lead ECG– Summary of QRS at each post-dose time point on Day 1 and Day 14 
(Change from Baseline) (Safety Population) 
Table 14.3.5.2.10: 12-Lead ECG– Analysis of QRS at each post-dose time point on Day 14 (Change from pre-
dose on Day 14)   (Safety Population) 
Table 14.3.5.2.11: 12-Lead ECG– Summary of PR at each post-dose time point on Day 1 and Day 14 (Change 
from baseline)  (Safety Population) 
Table 14.3.5.2.12: 12-Lead ECG– Analysis of PR at each post-dose time point on Day 14 (Change from pre-
dose on Day 14)   (Safety Population) 
Table 14.3.5.3.1 Summary HR AUC0-4h normalized by time and the change from baseline on Day 1 and Day 
14 (Safety Population) 
Table 14.3.5.3.2 Summary of HR AUC0-4h normalized by time change from pre-dose on Day 14 (Safety 
Population) 
Table 14.3.5.4.1 Summary HR peak0-4h normalized by time and the change from baseline on Day 1 and Day 
14 (Safety Population) 
Table 14.3.5.4.2 Summary of HR peak0-4h normalized by time change from pre-dose on Day 14 (Safety 
Population) 
Table 14.3.5.5.1 Summary Serum potassium and Glucose Change from baseline on Day 1 and Day 14 (Safety 
Population) 


 
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Table 14.3.5.5.2 Summary Serum potassium and Glucose, Change from pre-dose on Day 14 
 
 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: Asthma 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) 
Listing 16.2.4.5: Concomitant Medications (All Randomized Subjects) 
Listing 16.2.4.6: Maintained Medications (All Randomized Subjects) 
Listing 16.2.4.7: Post-Treatment Medications (All Randomized Subjects) 
Listing 16.2.4.8: Medications Taken only during the Washout period (All Randomized Subjects) 
Listing 16.2.4.9: Concomitant Procedures (All Randomized Subjects) 
Listing 16.2.4.10: Post-Treatment Procedures (All Randomized Subjects) 
Listing 16.2.4.11: Procedures taken only during washout (All Randomized Subjects) 
Listing 16.2.4.12: Reversibility Test (All Randomized Subjects) 
Listing 16.2.4.13: Asthma Control Questionnaire – Single Items and Total Score (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 16.2.5.6: Compliance with the use of Subject Diary (All Randomized Subjects) 
Listing 16.2.6.1: Spirometry Results (All Randomized Subjects) 
Listing 16.2.6.2: Pre-dose Morning FEV1 and Pre-dose Morning FVC (All Randomized Subjects) 
Listing 16.2.6.3: FEV1 AUC0-12h, FEV1 AUC0-4h, FVC AUC0-12h, and FVC AUC0-4h Values (All 
Randomized Subjects) 
Listing 16.2.6.4 FEV1 Peak0-4h FVC Peak0-4h (All Randomized Subjects) 
Listing 16.2.6.5 Onset of Action (Change from baseline in FEV1≥ 12%) on Day 1(All Randomized Subjects) 
Listing 16.2.6.6: Daily PEF Values (Morning and Evening) (All Randomized Subjects) 
Listing 16.2.6.7: Asthma Symptoms 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) 


 
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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: 12-lead ECG Results (All Randomized Subjects) 
Listing 16.2.8.2.2: 12-lead ECG – Prolonged QTcF (All Randomized Subjects) 
Listing 16.2.8.2.3 HR AUC0-4h (All Randomized Subjects) 
Listing 16.2.8.2.4 HR peak0-4h (All Randomized Subjects) 
Listing 16.2.8.2.5: 12-lead 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 – Chemistry (All Randomized Subjects) 
Listing 16.2.8.3.3: Laboratory Results – Pregnancy Test (All Randomized Females) 
Listing 16.2.8.3.4: Laboratory Results – Potassium/Glucose (All Randomized Subjects) 
Listing 16.2.8.5: Physical Examination (All Randomized Subjects) 
Listing 16.2.9: Comments (All Randomized Subjects) 
CSR Section Figure 14: 
Figure 14.2.1.1.1: Mean absolute FEV1 values on Day 1 (ITT Population) 
Figure 14.2.1.1.2: Mean absolute FEV1 values on Day (PP Population) 
) 
Figure 14.2.1.2.1: Mean absolute FEV1 values on Day 14 (ITT Population) 
Figure 14.2.1.2.2: Mean absolute FEV1 values on Day 14 (PPPopulation) 
Figure 14.2.1.3.1: Mean Change from Baseline in FEV1 on Day 1 (ITT Population) 
Figure 14.2.1.3.2: Mean Change from Baseline in FEV1 on Day 1 (PP Population) 
Figure 14.2.1.4.1: Mean Change from Baseline in FEV1 on Day 14 (ITT population) 
Figure 14.2.1.4.2: Mean Change from Baseline in FEV1 on Day (PP population) 
Figure 14.2.1.5.1 Mean absolute FVC values on Day 1 (ITT Population) 
Figure 14.2.1.6.1: Mean absolute FVC values on Day 14 (ITT Population) 
Figure 14.2.1.7.1: Mean Change from Baseline in FVC on Day 1 (ITT Population) 
Figure 14.2.1.8.1: Mean Change from Baseline in FVC on Day 14 (ITT Population) 
Figure 14.3.1.1 Mean absolute Vital Signs (Systolic and Diastolic Blood Pressure) values (Safety 
Population) 
Figure 14.3.1.2: Mean Change from Baseline in Vital Signs (Systolic and Diastolic Blood Pressure) values 
(Safety Population) 
Figure 14.3.2.1: Mean absolute ECG parameters (HR, QTcF, PR interval and QRS interval) values (Safety 
Population) 
Figure 14.3.2.2: Mean Change from Baseline in ECG parameters (HR, QTcF, PR interval and QRS interval) 
values (Safety Population) 
Figure 14.3.3.1: Mean absolute Serum Potassium and Glucose values on Day 1 and Day 14 (Safety 
Population) 
Figure 14.3.3.2: Mean Change from Pre-dose in Serum Potassium and glucose on Day 1 and Day 14 Change 
on Day 14 (Safety Population) 
Figure 14.2.5.1: Kaplan-Meier Curves for Time to Onset of Action (FEV1 ≥ 12% and ≥ 200 mL) on Day 1 
(ITT population) 
SAS Outputs Listings: 
 
Listing 16.1.9.1.1: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time at Day 14 (ITT 
population)  


 
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Listing 16.1.9.1.2: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time at Day 14 (PP 
Population)  
Listing 16.1.9.1.3: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time on Day 14 - Sensitivity 
analysis 1: Incorporating Only the First Instance of Each Treatment  (ITT Population) 
Listing 16.1.9.1.4: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time on Day 14 - Sensitivity 
analysis 2: Incorporating Only Treatment Periods for Which Treatment was Assigned After the IRT System 
Update (ITT Population) 
Listing 16.1.9.1.5: SAS Output of Analysis of FEV1 AUC0-12h Normalized by Time on Day 14 - Sensitivity 
Analysis 3: Incorporating Subject as a Random Effect 
Listing 16.1.9.2.1: 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 AUC0-4h Normalized by Time on Day 1 and Day 14 (ITT 
Population)  
Listing 16.1.9.4: SAS Output of Analysis of FEV1 Peak0-4h on Day 1 and Day 14 (ITT Population)
 
Listing 16.1.9.5: SAS Output of Analysis of Pre-Dose Morning FEV1 Day 14 (ITT Population)  
Listing 16.1.9.6: SAS Output of Analysis of Time to Onset of Action (Change from Baseline in Post-dose 
FEV1 ≥ 12% and ≥ 200 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 Day 14 (ITT 
Population)  
Listing 16.1.9.9: SAS Output of Analysis of FVC AUC0-4h Normalized by Time on Day 1 and Day 14 (ITT 
Population)  
Listing 16.1.9.10: SAS Output of Analysis of FVC Peak0-4h on Day 1 and Day 14 (ITT Population)
 
Listing 16.1.9.11: SAS Output of Analysis of Pre-Dose Morning FVC on Day 14  
Listing 16.1.9.12: SAS Output of 12-Lead ECG– Analysis of HR at each post-dose time point  (Safety 
Population)  
Listing 16.1.9.13: SAS Output of 12-Lead ECG– Analysis of QTcF at each post-dose time point  (Safety 
Population)  
Listing 16.1.9.14: SAS Output of 12-Lead ECG– Analysis of QRS at each post-dose time point  (Safety 
Population)  
Listing 16.1.9.15: SAS Output of 12-Lead ECG– Analysis of PR at each post-dose time point  (Safety 
Population)