Clinical trial NCT03084718
Conditions: Asthma
Sponsor: Chiesi Farmaceutici S.p.A.
Start date: 2017-07-28; Completion date: 2018-12-05
Enrollment: 610 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the dose-response of different doses of CHF 781 Pressurized Metered Dose Inhaler (pMDI) on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target patient population.

Detailed description:
This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose ranging 5-arm parallel group study to identify the optimal dose of CHF 781 pMDI with respect to lung function and other clinical efficacy and safety outcomes.

After a 2 week run-in period under rescue albuterol as needed and background inhaled corticosteroid (ICS), patients will be randomized to one of the 5 study treatment groups. After randomization, patients will be assessed after 4 and 8 weeks of study treatment at the center. A follow-up phone call will be performed a week after the last visit.

During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication will be recorded via subject diary. Treatment-Emergent Adverse Events (TEAEs) will be assessed and recorded throughout the study. At screening and subsequent visits, patients will undergo physical and vital signs examinations, spirometry measurements, and 12-lead ECG. Routine hematology, blood chemistry, and pregnancy testing will be performed before enrollment and at end of study. 24-hr urine cortisol and creatinine will be assessed before and after the first dose and just before the last dose of study treatment.

Arms: arm 1: CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID); arm 2: CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID; arm 3: CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID; arm 4: Placebo Control, Placebo; CHF 718 pMDI matched Placebo: 4 inhalations BID; arm 5: Beclomethasone dipropionate (BDP) Hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR® 80 μg/actuation: 2 inhalations BID;
Interventions: intervention 1: CHF 718 pMDI intervention 2: Placebo pMDI intervention 3: Beclomethasone Dipropionate (BDP)
Intervention descriptions: intervention 1: Dose Response: Test one of three different doses of CHF 718 pMDI intervention 2: Placebo Control intervention 3: Active Control

Protocol documents:
Prot_000.pdf: 
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CCD-05993AA3-01
An 8-week, randomized, double-blind, placebo and active-controlled, parallel group, dose ranging 
study to evaluate the efficacy and safety of 3 doses of CHF 718 pMDI (beclomethasone 
dipropionate) in asthmatic subjects
Version No.: 4.0
Date: 05Jun2018
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. : 133679
NCT no. NCT03084718


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


 
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VERSION HISTORY
Version
Date
Change History
1.0
24Feb2017
2.0
19May2017
Removal of morning serum total cortisol from V4, 
clarification of non-permitted conmeds, other changes as 
specified by Summary of Changes document.
3.0
18Oct2017
Increasing BMI range, increasing FEV1 range, other 
changes as specified by Summary of Changes document.
4.0
05Jun2018
Increasing basal morning serum cortisol level range, 
clarification on additional screening attempts, clarification 
on dosing at Visit 4 (none), other changes are specified by 
the Summary of Changes document. 


 
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PROTOCOL OUTLINE
Study Title
An 8-week, randomized, double-blind, placebo and active-controlled, 
parallel group, dose ranging study to evaluate the efficacy and safety of 3 
doses of CHF 718 pMDI (beclomethasone dipropionate) in asthmatic 
subjects
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
CHF 718 pMDI (beclomethasone dipropionate)
Center(s)
Multi-center, in approximately 105 sites
Indication 
Asthma
Study design
Randomized, double-blind, placebo and active-controlled, parallel group, 
dose ranging study
Study phase
II
Objectives
Primary objective:
To evaluate the efficacy of CHF 718 pMDI by comparison with 
placebo in terms of change from baseline in pre-dose morning FEV1 at 
Week 8. 
Secondary objectives:
To evaluate the effect of CHF 718 pMDI on other lung function 
parameters and clinical outcome measures.
To assess the safety and the tolerability of the study drug.
Treatment duration
A 2-week run-in period on ICS monotherapy followed by an 8-week 
randomized treatment period.
Test product 
dose/route/regimen  
CHF 718 pMDI: beclomethasone dipropionate pressurized metered 
dose inhaler (pMDI), available in 50µg per inhalation (BDP 50) and 
100µg per inhalation (BDP 100).
Treatment A: BDP 100µg Total Daily Dose (TDD)
BDP 50µg per inhalation, 1 inhalation bid*
Treatment B: BDP 400µg TDD
BDP 100µg per inhalation, 2 inhalations bid*
Treatment C: BDP 800µg TDD
BDP 100µg per inhalation, 4 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 718 pMDI
Treatment D: 


 
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Matched placebo, 4 inhalations bid
QVAR® 80µg (beclomethasone dipropionate HFA, 80µg) Inhalation 
Aerosol: Each canister contains 120 actuations.
Treatment E: BDP 320µg TDD
BDP 80µg per inhalation, 2 inhalations bid
QVAR® will be administered as open label.
Number of subjects
A total of approximately 585 subjects will be randomized in order to reach 
a total of 495 completed and evaluable subjects, considering a non-
evaluable rate of 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 ≥50% and <85% of their predicted normal 
value, after appropriate washout from bronchodilators, at the screening 
and randomization visits.
5. A documented positive response to a reversibility test (pre – post BD) 
within 1 year prior to or 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 (stable dose in the last 4 weeks) 
before screening visit.
ICS*
Low daily 
dose
Medium daily 
dose
BDP extrafine (HFA pMDI) - QVAR®
80-160µg
>160-320µg
Budesonide (DPI)
200-400µg
>400-800µg
Ciclesonide (HFA pMDI)
80-160µg
>160-320µg
Flunisolide (HFA pMDI)
160-320µg
>320-640µg
Fluticasone furoate (DPI)
100µg
200µg.
Fluticasone propionate (HFA pMDI/DPI)
100-250µg
>250-500µg
Mometasone furoate (DPI)
110-220µg
>220-440µg
*(Table adapted from GINA 2016) 


 
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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
› 160µg 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
› 160µg 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
› 160µg bid -  N/A†
SYMBICORT® 80/4.5
160/9µg bid
80µg bid
SYMBICORT® 160/4.5
320/9µg bid
160µg bid
† This ICS/LABA 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 
electronic diary, peak flow meter, and pMDI inhalers.
8. A basal morning (7-10 am) serum cortisol level between 5-28µg/dL at 
screening (V1).
9. A Body Mass Index: 18.5≤ BMI <35 kg/m2.
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 and met on the same day, 
and before reversibility test is conducted.
At randomization (V2), inclusion criteria # 3, 4 and 7 should also be re-
checked. 
Exclusion Criteria:
If a subject meets any of the following criteria, he/she will NOT be 
enrolled into the study:
1. Pregnant (as evident by a positive urine hCG or serum β-hCG test) or 
lactating women and all women physiologically capable of becoming 
pregnant (i.e. women of childbearing potential) UNLESS they are 
willing to use a highly effective birth control method such as:
a. Placement of an intrauterine device (IUD) or intrauterine releasing 
system (IUS).
b. Oral, intravaginal, transdermal combined estrogen and progesterone 
containing hormonal contraception or oral, injectable, implantable 
progesterone only hormonal contraception.
c. Bilateral tubal ligation.
d. Partner vasectomy (provided that partner is the sole sexual partner 
of the WOCBP trial participant and that the vasectomized partner 


 
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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 screening, at Visit 4 and at the early termination visit; 
urinary pregnancy test will be performed at screening, Visit 2 and 3.
Women of non-childbearing potential defined as physiologically 
incapable of becoming pregnant: post-menopausal (defined as no 
menses for 12 months without an alternative medical cause) or 
permanently sterile (hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy) are eligible.
If indicated, as per investigator’s request, post-menopausal status may 
be confirmed by follicle-stimulating hormone levels (according to 
local laboratory ranges) in women not using hormonal contraception 
or hormonal replacement therapy.
2. Subjects who suffer from COPD as defined by the GOLD Report, 
2017, or are suspected of having Asthma COPD Overlap Syndrome 
(ACOS) as defined 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 corticosteroids within 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 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.


 
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12.Subjects who have a clinically significant abnormal 12-lead ECG that 
results an active medical problem which may impact the safety of the 
subject according to Investigator’s judgment.
13.Subjects whose 12-lead ECG shows Fridericia corrected QT interval 
(QTcF) >450ms for males or QTcF >470ms for females at screening or 
randomization visits.
14.Subjects with known intolerance/hypersensitivity or contra-indication 
to 
treatment 
with 
inhaled 
ß2-adrenergic 
receptor 
agonists, 
corticosteroids or propellant gases/excipients.
15.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.
16.Use of potent cytochrome P450 3A4 inhibitors (e.g. ritonavir, 
ketoconazole, itraconazole) and inducers within 4 weeks prior to 
screening.
17.History of alcohol abuse and/or substance/drug abuse within 12 months 
prior to screening.
18.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.
19.Subjects who are mentally or legally incapacitated or subjects 
accommodated in an establishment as a result of an official or judicial 
order. 
20.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, 12 and 13 should be re-checked at the 
randomization visit (V2). 
Study plan
The details of the assessments that will be performed during the study are 
summarized in the study flow diagram in table 1.
After a 2-week run-in period, subjects will be randomized to one of the 5 
treatment arms and will enter a period of 8 weeks of study treatment.
The study will last approximately 12 weeks for each subject and a total of 5 
clinic visits will be performed during the study (see the flow chart below)  
A one week follow-up will be conducted.
A pre-screening visit (Visit 0) 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 (Visit 1) not more than 7 days after V0 will help 
establish the eligibility of subjects for inclusion in the study (including 
routine hematology and blood chemistry, morning serum cortisol, 
medical history, physical examination, weight/height/BMI, serum and 
urine pregnancy tests for female subjects of childbearing potential, a 
12-lead ECG, ACQ assessment, spirometry testing pre and post BD (to 
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year, vital signs and training for the use of inhalers).  Concomitant 
Medications and Adverse Events will be assessed.  Dispensing of 
subject diary will be done.  Eligible subjects will be provided with a 
container for the 24-h urine collection, to be returned to the site the day 
after completing the collection, 1-2 days before or on the date of their 
next visit (V2).  This visit will be followed by a 14±2 day 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 be instead prescribed an equivalent 
daily dose of ICS as beclomethasone dipropionate (QVAR® 40 or 
80µg/actuation) 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.
At randomization visit (Visit 2), inclusion/exclusion criteria, adverse 
events and concomitant medications will be reviewed.  Eligibility 
recheck will be completed.  Pre-dose vital signs and spirometry testing 
[FEV1, FVC] will be performed.  A 12-lead ECG, physical 
examination, urine pregnancy test will be performed, and training on 
the use of inhalers will be conducted.  The ACQ will be assessed.  The 
24-h urine collection container will be collected from the subject if not 
already done, and shipped to a central laboratory for 24-h urine free 
cortisol and creatinine measurement.  Eligible subjects will then be 
randomized to one of the treatment groups and will receive the 1st dose 
of study drug under medical supervision.  The subjects will then leave 
the clinical center and will be instructed to return in 4 weeks. 
At Week 4 (Visit 3) subjects will undergo a physical examination, urine 
pregnancy test, concomitant medications review, adverse events, study 
drug dispensation and vital signs assessment. Study drug will be 
returned and accountability will be performed.  Pre-dose spirometry 
testing (FEV1, FVC) will be performed and ACQ will be assessed. 
Subjects will be provided with a container for the 24-h urine collection, 
to be returned to the site the day after completing the collection, 1-2 
days before or on the date of their next visit (V4).  The subject will be 
instructed to return to the clinical center in 4 weeks.  
At Week 8 (Visit 4) subjects will come to the clinical center and will 
undergo a physical examination, hematology and blood chemistry, 
serum/urine pregnancy test and vital signs assessment. A 12-lead ECG 
will be performed. Concomitant medications and adverse events will be 
assessed.  Pre-dose spirometry testing [FEV1, FVC] will be performed.  
No administration of the study drug will take place at V4.   The 
ACQ will be assessed. The 24-h urine collection container will be 
collected from the subject if not already done, and shipped to a central 
laboratory for 24-h urine free cortisol and creatinine measurement.  
Study drug will be returned and accountability will be done.  Subject 
diary will be returned by the subject.  After the last assessment a 
follow-up phone call will be scheduled with the subject.
At Week 9 (Visit 5): A safety follow up phone call will be performed 
by the investigator or designated staff no later than 1 week after the 
final visit (V4) or Early Termination Visit to check the status of 
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after V4, as well as related concomitant medications.
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.
Nasal corticosteroids if already taken at stable doses for at least 2 
months prior to screening visit (the dose must remain constant for 
the whole study period) or taken in short courses (10 days) during 
the study period.
4.
Treatment for desensitization at the “maintenance” 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). 
5.
Antihistamines (intranasal, ocular or oral ± decongestant) at no 
greater than FDA-approved doses for the treatment of allergy 
symptoms.
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 “most 
relevant forbidden concomitant treatment”.
Most relevant forbidden 
concomitant treatments
Non-permitted concomitant medications (from V1)
1.
Inhaled corticosteroids other than the run-in medication and study 
drug.
2.
Inhaled short-acting muscarinic antagonists (SAMA), or long-
acting muscarinic antagonists (LAMA).
3.
Inhaled fixed or free combinations of ICS/LABAs. 
4.
Inhaled long-acting β2-agonist drugs (LABAs).
5.
Any other asthma treatments (e.g. cromolyn sodium, nedocromil 
sodium, leukotriene modifiers).


 
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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.
11. Non-cardioselective ß-blocking drugs (including eye drops), except 
if taken at stable regimen for at least 2 months before screening. 
12. Any drug known to prolong the QT interval (e.g. quinidine, 
procainamide, amiodarone) except if taken at a stable regimen for 
at least 2 months before screening. 
13. Any medication that could interact with the study drug, according 
to Investigator’s judgment. 
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
1 month
Intramuscular depot corticosteroid
3 months
Prior to other visits with spirometry (V2  V4), the following washout 
periods must be respected:
Inhaled short-acting β2-agonists
6 hours
Caffeinated substances
6 hours
Efficacy variables
(and/or pharmacokinetics 
variables)
Primary efficacy variable
Change from baseline in pre-dose morning FEV1 (average of pre-dose 
FEV1 measurements) at Week 8


 
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Secondary efficacy variables
Change from baseline in pre-dose morning FEV1 (average of pre-dose 
FEV1 measurements) at Week 4
Change from baseline in pre-dose morning FVC (average of pre-dose 
FVC measurements) at Week 4 and Week 8
Change from baseline in ACQ-7 score at Week 4 and Week 8
Change from baseline in average use of rescue medication during inter-
visit periods and entire treatment period
Change from baseline in percentage of rescue medication-free days 
during inter-visit periods and entire treatment period
Change from baseline in daily asthma symptoms score during inter-
visit periods and entire treatment period
Change from baseline in percentage of asthma symptoms-free days 
during inter-visit periods and entire treatment period
Change from baseline in percentage of asthma control days during 
inter-visit periods and entire treatment period
Change from baseline in morning and evening pre-dose PEF during 
inter-visit periods and entire treatment period
Safety variables
Adverse Events (AEs) and Adverse Drug Reactions (ADRs)
Vital signs (systolic and diastolic blood pressure) 
12-lead ECG parameters (HR, QTcF, QRS, PR)
Standard blood chemistry and hematology
24-h Urinary Free Cortisol and Creatinine
Sample size calculation
The sample size has been calculated to evaluate the superiority of CHF 718 
pMDI at different doses over placebo in terms of change from baseline in 
pre-dose morning FEV1 at Week 8.
A total of 495 evaluable subjects (99 per group) will provide 80% power to 
detect a mean difference of 200mL between each dose of CHF 718 pMDI 
and placebo at a two-sided significance level of 0.0167 (since 3 dose levels 
will be tested, the Bonferroni adjustment has been taken into account: 
0.0167 = 0.05/3), assuming a standard deviation of 430mL.
Considering a non-evaluable rate of 15%, a total of approximately 585 
subjects (117 per group) will be randomized.
Statistical methods
Primary efficacy variable
Change from baseline in pre-dose morning FEV1 will be analysed using a 
linear mixed model for repeated measurements including treatment, visit, 
treatment by visit interaction, ICS dose before study (low/medium daily 
dose) and US regions as fixed effects, and the baseline value (average of 
the pre-dose FEV1 measurements at Visit 2) and baseline by visit 
interaction as covariates. An unstructured covariance matrix will be 
assumed. 
The adjusted means in each treatment group, the adjusted mean difference 
between treatments and their 95% two-sided Confidence Intervals (CIs) at 
Week 8 will be estimated by the model. The CIs and the p-values of the 
comparisons between each dose of CHF 718 pMDI and placebo at Week 8 
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 718 pMDI over placebo will be demonstrated by a 


 
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statistically significant difference (adjusted p-value < 0.05) favoring CHF 
718 pMDI.
All the other comparisons between treatments will be performed as 
secondary efficacy analyses with no multiplicity adjustment.
Secondary efficacy variables
No multiplicity adjustment will be performed in the secondary efficacy 
analyses.

For change from baseline in pre-dose morning FEV1 at Week 4, the 
adjusted means in each treatment group and the adjusted mean 
differences between treatments at Week 4 will be estimated with their 
95% CIs and p-values by the same model used for the primary efficacy 
analysis. 

Change from baseline in pre-dose morning FVC at Week 4 and Week 
8 will be analyzed using a similar model as the one used for the 
primary efficacy analysis. 

Change from baseline in ACQ-7 score at Week 4 and Week 8 will be 
analyzed using a similar model as the one used for the primary 
efficacy analysis.

Change from baseline to each inter-visit period in average use of 
rescue medication, in percentage of rescue medication-free days, in 
daily asthma symptoms scores, in percentage of asthma symptoms-free 
days, in percentage of asthma control days and in morning and evening 
pre-dose PEF will be analyzed using a similar model as the one used 
for the primary efficacy analysis. The inter-visit period will be 
considered instead of visit in the model. Comparison between 
treatments over the entire treatment period will also be derived from 
this model.
Safety variables
Adverse Events
All adverse events starting on or after the time of first study drug intake 
will be classified as Treatment Emergent Adverse Events (TEAEs). Any 
adverse event started after the informed consent signature and before the 
time of first study drug intake will be classified as pre-treatment adverse 
event. Pre-treatment adverse events will be listed only.
The number of TEAEs and the number and percentage of subjects who 
experienced at least one TEAE will be presented by treatment for all AEs, 
ADRs, serious AEs, serious ADRs, severe AEs, AEs leading to study 
discontinuation and AEs leading to death. Summaries will be presented 
overall and by system organ class and preferred term based on the 
MedDRA dictionary. 
Vital signs
Vital signs (systolic and diastolic blood pressure) and their changes from 
baseline (Visit 2) will be summarized by treatment using descriptive 
statistics and the 95% CI of the mean.


 
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ECG
12-lead ECG parameters (HR, QTcF, QRS and PR) and their changes from 
baseline (Visit 2) 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). 
The number and the percentage of subjects with a: 

QTcF >450ms (males only), >470ms (females only), >480ms (males 
only) and >500ms

change from baseline (Visit 2) in QTcF >30ms and >60ms
at post-baseline visit will be presented by treatment group.
Laboratory parameters
Shift tables from screening to the end of treatment, based on normal 
ranges, will be presented by treatment group for the laboratory parameters.
Mean change from baseline (Visit 2) to the end of treatment in 24-h 
urinary cortisol and creatinine will be calculated with its 95% CI by 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ACI
Andersen Cascade Impactor 
ACQ
Asthma Control Questionnaire  
ADR
Adverse Drug Reaction
AE
Adverse Event
AF
Atrial Fibrillation
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BD
Bronchodilator
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
CRA
Clinical Research Associate
(e-) CRF
(Electronic) Case Report Form
CRO
Contract Research Organization
DBP
Diastolic Blood Pressure
DPI
Dry Powder Inhaler
ECG
ElectroCardioGram
FEF
Forced Expiratory Flow
FEV1
Forced Expiratory Volume in the 1st second 
FF
Formoterol Fumarate
FPFV
First Patient First Visit
FVC
Forced Vital Capacity
GB
Glycopyrronium Bromide
GCP
Good Clinical Practices
GINA 
Global Initiative for Asthma
GMP
Good Manufacturing Practices
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GSD
Geometric Standard Deviation
h
hour
hCG
human Chorionic Gonadotropin hormone
HFA
Hydrofluoroalkane
HR
Heart Rate
IB
Investigator Brochure
IC
Inspiratory Capacity
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroid
IgE
Immunoglobulin E
IL5
Interleukin 5
IRT
Interactive Response Technology
ISO
International Organization for Standardization
ITT
Intention to Treat


 
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IU (D or S)
Intra Uterine (Device or System)
L
Liter
LABA
Long Acting β2-adrenergic receptor Agonist
LDH
Lactate dehydrogenase
LABD
Long-acting bronchodilators
LAMA
Long Acting Muscarinic Antagonist
LLN
Lower Limit of Normal
LPLV
Last Patient Last Visit
LS
Least Square
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
MMAD
Mass Median Aerodynamic Diameter
mMRC
modified Medical Research Council
NYHA
New York Heart Association
OCS
Oral Corticosteroid
PEF
Peak Expiratory Flow
PIL
Patient Information Leaflet
pMDI
Pressurized Metered Dose Inhaler
PP
Per-Protocol
PR
Time Interval from the beginning of the upslope of the P wave to the beginning 
of the QRS wave in the ECG
PRO
Patient Reported Outcome
prn
Pro re nata (as-needed)
qd
Every Day
Q
Quaque (every so-,any hours)
QRS
Time Interval from  the end of the PR interval to the end of the S wave in the 
ECG
QTc
Time interval between the start of the Q wave and the end of the T wave in the 
ECG (corrected for HR)
QTcF
QT interval corrected for HR using Fridericia’s formula
RCT
Randomized Controlled Trial
SAE
Serious Adverse Event
SABA
Short-acting Beta Agonist
SABD
Short acting bronchodilators
SADR
Serious Adverse Drug Reaction
SAMA
Short-Acting Muscarinic Antagonist
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SGRQ
St. George’s Respiratory Questionnaire
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment Emergent Adverse Events


 
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TDD
Total Daily Dose
UFC
Urinary free cortisol
ULN
Upper Limit of Normal
VC (SVC / FVC)
Vital Capacity (Slow /Forced)
WHO
World Health Organization
WOCBP
Women of Child Bearing Potential


 
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CONTENTS
GENERAL INFORMATION ..............................................................................................................2
PROTOCOL OUTLINE.......................................................................................................................4
1. INTRODUCTION..........................................................................................................................22
2. STUDY OBJECTIVES..................................................................................................................27
2.1 Primary Objective(s) ....................................................................................................................27
2.2 Secondary Objective(s) ................................................................................................................27
3. STUDY DESIGN...........................................................................................................................27
4. SUBJECT SELECTION CRITERIA.............................................................................................28
4.1 Subject Recruitment .....................................................................................................................28
4.2 Inclusion Criteria..........................................................................................................................28
4.3 Exclusion Criteria.........................................................................................................................29
4.4 Subject Withdrawals.....................................................................................................................31
5. CONCOMITANT MEDICATIONS..............................................................................................32
5.1 Permitted Concomitant Medications............................................................................................32
5.2 Non-Permitted Concomitant Medications....................................................................................32
6. TREATMENT(S)...........................................................................................................................34
6.1 Appearance and Content ..............................................................................................................34
6.2 Dosage and Administration..........................................................................................................34
6.2.1 Selection of doses in the study ..................................................................................................34
6.2.2 Dosage.......................................................................................................................................35
6.2.3 Administration...........................................................................................................................36
6.2.3.1 Run-in period (from Visit 1 to 2): ..........................................................................................36
6.2.3.2 Randomized period (from Visit 2 to 4): .................................................................................37
6.2.3.3 Rescue medication..................................................................................................................38
6.2.4 Subject Training ........................................................................................................................38
6.2.5 Subject Training on QVAR®.....................................................................................................38
6.3 Packaging .....................................................................................................................................38
6.3.1 Training kits ..............................................................................................................................39
6.3.2 Run-in period.............................................................................................................................39
6.3.3 Treatment period .......................................................................................................................39
6.3.4 Rescue medication.....................................................................................................................39
6.4 Labeling........................................................................................................................................39
6.5 Treatment allocation.....................................................................................................................40
6.6 Treatment Code ............................................................................................................................40
6.7 Treatment compliance ..................................................................................................................41
6.8 Drug Storage.................................................................................................................................41
6.9 Drug Accountability.....................................................................................................................41
6.10 Provision of additional care........................................................................................................42
7. STUDY PLAN ...............................................................................................................................43
7.1 Study Schedule.............................................................................................................................43
7.1.1 Visit 0 (Pre-screening visit).......................................................................................................44
7.1.2 Visit 1 (Screening visit /Week -2).............................................................................................44
7.1.3 Visit 2 (Randomization/ Start of Treatment Period /Week 0)...................................................46
7.1.4 Visit 3 (Week 4 of Treatment Period).......................................................................................48


 
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7.1.5 Visit 4 (Week 8 of Treatment Period).......................................................................................49
7.1.6 (Visit 5) Follow-up Phone Call (Week 9) .................................................................................51
7.1.7 Early Termination Visit.............................................................................................................51
7.2 Investigations................................................................................................................................51
7.2.1 ACQ Questionnaire ...................................................................................................................51
7.2.2 Body Mass Index.......................................................................................................................52
7.2.3 Vital Signs.................................................................................................................................52
7.2.4 Physical Exam and assessment of oral candidiasis ...................................................................52
7.2.5 12-lead ECG..............................................................................................................................53
7.2.6 Pulmonary Function Test ..........................................................................................................54
7.2.7 Morning Serum Cortisol............................................................................................................55
7.2.8 24-h Urine Free Cortisol and Creatinine ...................................................................................55
7.2.9 Asthma Action Plan and Handling of Asthma Exacerbations ..................................................56
7.2.10 Blood Hematology and Chemistry..........................................................................................56
7.2.11 Urine Pregnancy Test ..............................................................................................................57
7.2.12 Subject Diaries ........................................................................................................................57
8. EFFICACY ASSESSMENTS........................................................................................................58
9. SAFETY ASSESSMENTS............................................................................................................59
10. ADVERSE EVENT REPORTING..............................................................................................59
10.1 Definitions..................................................................................................................................59
10.2 Expectedness ..............................................................................................................................60
10.3 Intensity of Adverse Event.........................................................................................................61
10.4 Causality Assessment.................................................................................................................61
10.5 Action taken with the study drug due to the AE ........................................................................62
10.6 Other actions taken.....................................................................................................................62
10.7 Outcome .....................................................................................................................................62
10.8 Recording Adverse Events .........................................................................................................62
10.9 Reporting Serious Adverse Events to Chiesi .............................................................................63
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRB..........63
10.11 General Notes...........................................................................................................................64
11. DATA MANAGEMENT.............................................................................................................64
12. STATISTICAL METHODS ........................................................................................................65
12.1 Sample Size ................................................................................................................................65
12.2 Populations for analysis..............................................................................................................65
12.3 Statistical analysis ......................................................................................................................66
12.3.1 Descriptive Statistics ...............................................................................................................66
12.3.2 Missing data ............................................................................................................................66
12.3.3 Subject demographics and baseline characteristics.................................................................66
12.3.4 Primary efficacy variables.......................................................................................................67
12.3.5 Secondary efficacy variables...................................................................................................67
12.3.6 Safety variables .......................................................................................................................67
12.3.7 Interim analysis .......................................................................................................................68
13. ETHICS AND RESPONSIBILITY .............................................................................................68
14. INFORMED CONSENT..............................................................................................................68
15. INSTUTIONAL REVIEW BOARD/ INDEPENDENT ETHICS COMMITTEE ......................69
16. SOURCE DOCUMENTS/DATA................................................................................................69


 
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17. STUDY MONITORING..............................................................................................................69
18. QUALITY ASSURANCE ...........................................................................................................70
19. INSURANCE AND INDEMNITY..............................................................................................70
20. CONFIDENTIALITY..................................................................................................................70
21. PREMATURE TERMINATION OF THE STUDY....................................................................70
22. CLINICAL STUDY REPORT.....................................................................................................70
23. RECORD RETENTION ..............................................................................................................71
24. PUBLICATION OF RESULTS...................................................................................................71
25. REFERENCES.............................................................................................................................71
APPENDIX I......................................................................................................................................77
APPENDIX II.....................................................................................................................................78


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


 
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1. INTRODUCTION
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 subject.[2]
The NHANES III national survey estimated the U.S. prevalence of COPD to be 10.2% to 20.9% 
based on whether pre- or post-bronchodilator values were used and which diagnostic criterion 
(fixed ratio or lower limit of normal {LLN}) was applied.[3][4] 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.[5]
Smoking cessation can have the greatest influence on stopping the progression of COPD, as well as 
increasing survival and reducing morbidity.[6]  However, long-term cessation success rates rarely 
exceed 25%.[2][7]
Existing pharmacologic therapy is used to improve airflow, symptoms, exercise capacity, health 
status, and reduce the frequency and severity of exacerbations in stable COPD. To date, there is no 
conclusive evidence that any available pharmacotherapy for COPD modifies the long-term decline 
in lung function.  The 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.[8][9][10] 
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,[11] 
effectiveness 
of 
pulmonary 
rehabilitation,[12][13] and to reduce exacerbations and related hospitalizations[14] 
compared to placebo. 


 
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
Adverse events of this class of medications are mainly due to their 
anticholinergic activities, and include dry mouth, constipation, urinary 
retention and increased intraocular pressure.
o
Combination Bronchodilators: Combining bronchodilators using a LABA and a 
LAMA increases FEV1, albeit not to the full additive effect of each individual 
component; improves PROs and reduces exacerbations vs monotherapy.  One study 
(FLAME trial) in subjects with post-BD FEV1 ≥ 25% and < 60% predicted, an 
mMRC score of ≥2, and a history of ≥1 exacerbation reported an 11% further 
reduction in COPD exacerbations with fixed combination of once daily indacaterol 
110µg + glycopyrronium 50µg (LABA+LAMA) compared to fixed combination 
twice daily fluticasone propionate 500µg + salmeterol 50µg (ICS+LABA).[15]  
Combining a SABA and a SAMA or a LABA and LAMA can be done using 
separate inhalers or using a single inhaler containing a fixed dose combination.  

Anti-inflammatory agents
o
Inhaled Corticosteroids (ICS) alone: The available evidence does not support a 
beneficial effect of ICS monotherapy in subjects with COPD.[16]
o
ICS in combination with LABD: Most studies in subjects with mod-severe COPD 
and history of exacerbations found a beneficial effect of ICS+LABA fixed dose 
combination over either component alone in improving lung function, health status, 
and in reducing exacerbations.  Studies that evaluated withdrawal of ICS have 
yielded equivocal results.

Post-hoc analyses suggest that sputum and blood eosinophil count may be a 
predictor of ICS efficacy, particularly in preventing exacerbations.[17]

High quality evidence has confirmed an increased rate of pneumonia, oral 
candidiasis, 
hoarseness 
and 
skin 
bruising 
with 
ICS 
treatment.[18][19][20][21][22]  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.[23][24] A meta-analysis suggested 
that subjects with COPD with lower blood eosinophil counts (<2%) had more 
pneumonia events than did those with higher counts.[25]

RCTs have reported variable outcomes regarding ICS effect on decreased 
bone mineral density (BMD)[26][27] and risk of fractures,[28] and 
observational studies suggest an increased risk of diabetes / poorly controlled 
diabetes,[29] cataracts,[30][31] and mycobacterial infections, including 
tuberculosis.[32]

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.[33][34][35][36][37][38] This step-up therapy can be achieved 
using various available approaches and products. More studies with this combination are 
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Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is 
characterized by variable symptoms of wheezing, shortness of breath, chest tightness and/or
cough, and by variable expiratory flow limitations.  Variations over time and intensity are often 
triggered by factors such as exercise, environmental/occupational exposures, or viral respiratory 
infections.[39] As of 2014, the Center for Disease Control (CDC) estimated that the prevalence of 
asthma in US adults is 7.4%.[40]
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 
future risks such as exacerbations and decline in lung function. The controller medication is 
adjusted up or down in a stepwise approach to achieve these 4 goals.

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:
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 
theophylline
Med-High 
dose ICS + 
LTRA
(or + theo)
Add tiotropium
High dose ICS 
+ LTRA
(or + theo)
Add low-dose 
OCS
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 


 
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2006 and is currently available in 35 countries worldwide including Russia and China, but not the 
US.  FOSTER® is dispensed as a Pressurized Inhalation Solution (pMDI, Modulite®) and as a dry 
powder for inhalation (DPI) by the NEXThaler® device, releasing extra-fine particles.[41] 
FOSTER® pMDI has been developed with a high “extrafine” (< 1.1µm) BDP particle size fraction, 
similarly to another HFA BDP marketed formulation (QVAR® Inhalation Aerosol, Teva 
Respiratory, LLC).
Chiesi Farmaceutici is also developing a fixed dose triple combination of an ICS/LABA/LAMA 
(CHF 5993) with beclomethasone dipropionate (BDP) + formoterol fumarate (FF) + 
glycopyrronium bromide (GB), and on Sep 29, 2016 became the first company to submit a 
marketing authorization application with this investigational product to the European Medicine 
Agency (EMEA) for the treatment of COPD.  The product is administered using a single 
pressurized metered dose inhaler (pMDI), specifically formulated to deliver extra-fine particles 
efficiently reaching both central and peripheral airways.
The submission of the EMEA dossier is based on the results of a large and comprehensive 
development program performed by Chiesi since 2009, which included 12 clinical studies involving 
more than 8,000 subjects.[42]
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. A dose-ranging study with Chiesi’s formulation of HFA 
BDP pMDI has not been previously done.  
The aim of this study is to characterize the dose-response of Chiesi’s BDP Pressurized Inhalation 
Solution delivered via a non-CFC-propelled metered-dose inhaler (CHF 718 pMDI) and containing 
the same excipients as in FOSTER®.  Three doses of CHF 718 pMDI: 50, 200, 400µg (ex-valve) 
twice daily will be assessed vs placebo, with QVAR® Inhalation Aerosol 320µg (400µg ex-valve) 
twice daily as an active comparator. 
Dose selection of ICS in COPD is challenging given the lack of efficacy for ICS monotherapy that 
has been observed to date.  Therefore, the study will be conducted in adult subjects with asthma, 
since asthmatics are thought to be more steroid-sensitive than subjects with COPD, using trough 
FEV1 as the primary endpoint. While exacerbations may be a more meaningful assessment of the 
added benefit of an ICS in an ICS/LABA combination in subjects with COPD, the design and 
conduct of an exacerbation trial for the purposes of dose selection are challenging.[43][44]
Beclomethasone dipropionate (BDP):
Description and Mechanism of Action:
BDP is a pro-drug with weak glucocorticosteroid receptor binding affinity that is rapidly activated 
by hydrolysis via esterase enzymes to an active metabolite beclomethasone 17 monopropionate (17-
BMP).  Beclomethasone 17 monopropionate has been shown in vitro to exhibit a binding affinity 
for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 


 
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times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of 
beclomethasone dipropionate. The clinical significance of these findings is unknown.[45]
The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an 
important component in the pathogenesis of asthma. Corticosteroids have been shown to have a 
wide range of actions on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, 
lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in 
inflammation. These anti-inflammatory actions of corticosteroids contribute to their efficacy in 
asthma. 
Though effective for the treatment of asthma, corticosteroids may not affect symptoms 
immediately. Individual subjects will experience a variable time to onset and degree of symptom 
relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. 
When corticosteroids are discontinued, asthma stability may persist for several days or longer.[46]
Beclomethasone dipropionate was first patented in 1962 and used medically in 1972. It was 
approved for medical use in the United States in 1976. It is on the World Health Organization's List 
of Essential Medicines, the most important medications needed in a basic health system.[47]
An HFA BDP inhalation aerosol was originally approved by the US FDA in Sep 2000 under the 
brand name QVAR®, as the first CFC-free metered dose inhaler containing a corticosteroid (a 
solution of beclomethasone dipropionate in propellant HFA-134a). It was the first inhaler designed 
to deliver smaller particle sized medication to the large, intermediate and small airways.  This 
allowed QVAR® to control asthma at a lower dose than conventional CFC-containing BDP 
inhalers.[48]
Today, in the US, QVAR® is indicated for 1) Maintenance treatment of asthma as prophylactic 
therapy in subjects 5 years of age and older; and 2) Treatment of asthma in subjects who require 
oral corticosteroid therapy, where QVAR® may reduce or eliminate the need for the systemic 
corticosteroids.  In May 2014, the FDA additionally approved the use of QVAR® with a dose 
counter for the ongoing treatment of asthma as a preventative therapy in subjects five years of age 
and older. QVAR® is supplied in two strengths: 40 and 80µg/actuation and contains 120 
actuations/canister.[45]
Clinical Efficacy of HFA BDP:
Previously, a bridging study established the clinical equipotency with CHF 718 (HFA BDP) pMDI 
100µg 2 puffs bid (TDD = 400µg) to CFC BDP 250µg 2 puffs bid (1,000µg) in adult subjects with 
mild-moderate symptomatic asthma, previously not well-controlled on low dose ICS.[49]
QVAR® 40, 160, and 320µg (ex-actuator) twice daily doses were evaluated vs. 42, 168 or 336µg 
CFC BDP twice-daily for 6 weeks in asthmatics who exhibited a deterioration in asthma control 
during an ICS washout period. Treatment with increasing doses of both QVAR® and CFC BDP 
resulted in increased improvement in FEV1, FEF25-75% and asthma symptoms.  Thus, in subjects 12 
years and older on ICS, the recommended starting dose of QVAR® was set as 40 – 160µg twice 
daily, and the maximum dose as 320µg twice daily.[50]


 
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Clinical Safety of HFA BDP:
In clinical trials, Adverse Events reported by at least 3% of the subjects on QVAR® included 
headache, pharyngitis, upper respiratory tract infection, rhinitis, increased asthma symptoms, oral 
symptoms inhalation route, sinusitis, pain, back pain, and dysphonia. Other adverse events that 
occurred in these clinical trials using QVAR® with an incidence of 1% to 3% and which occurred at 
a greater incidence than placebo were nausea, dysmenorrhea, and coughing. Oropharyngeal 
candidiasis occurred in <1% of subjects in both QVAR® and placebo treatment groups.
Warning and precautions in the QVAR® USPI include:

Localized infections with Candida albicans

Not indicated for relief of acute episodes of bronchospasm (i.e. not a reliever therapy)

Glaucoma, increased intraocular pressure, and cataracts 

Particular care is needed in transfering subjects from systemic corticosteroid therapy due to 
the potential for fatal adrenal insufficieny

Immunosuppression

Paradoxical bronchospasm

Immediate hypersensitivity reactions

Hypercorticism and adrenal suppression

Reduction in growth velocity in pediatric subjects

Reduction in bone mineral density
In addition to adverse reactions experienced in the clinical trials, the following adverse
events have been reported during post-approval use of QVAR®:  Localized infections with Candida 
albicans, aggression, depression, sleep disorders, psychomotor hyperactivity, and suicidal ideation 
(primarily in children)[45]
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 E6 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 718 pMDI by comparison with placebo in terms of change 
from baseline in pre-dose morning FEV1 at Week 8. 
2.2 Secondary Objective(s)

To evaluate the effect of CHF 718 pMDI on other lung function parameters and clinical 
outcome measures.

To assess the safety and the tolerability of the study drugs.
3. STUDY DESIGN 
This is a phase II, multi-center, randomized, double-blind, placebo and active-controlled, parallel 
group, dose ranging study to evaluate the efficacy and safety of 3 doses of CHF 718 pMDI (HFA 
beclomethasone dipropionate) in adult subjects with asthma. Following a 2-week run-in period on 


 
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ICS monotherapy, eligible subjects will be randomized to one of five study drugs (1:1:1:1:1) 
delivered twice-daily for 8 weeks. After the last assessment a follow-up phone call will be 
scheduled with the subject. The study will last approximately 12 weeks for each subject and a total 
of 5 clinic visits will be performed during the study.
The end of the trial is defined as the last follow-up contact with 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 975 subjects will be screened and 585 randomized (117 per group) to yield 495 
evaluable subjects. Recruitment will occur at approximately 105 participating outpatient study 
center(s) 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, documented for at least 1 year 
prior to screening.[39]
3. Poorly controlled or uncontrolled asthma evidenced by a score ≥1.5 on the Asthma Control 
Questionnaire 7 © (ACQ-7)[51] (this criterion must be met at screening and at randomization 
visits).
4. A pre-bronchodilator FEV1 ≥50% and <85% of their predicted normal value, after appropriate 
washout from bronchodilators, at the screening and randomization visits.
5. A documented positive response to a reversibility test (pre – post BD) within 1 year prior to or 
at screening, defined as ΔFEV1 ≥12% and ≥200mL[52] over baseline within 30 minutes after 
inhaling 4 puffs of albuterol HFA 90µg/inhalation. 


 
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Note: In case the reversibility threshold is not met at screening, the test can be performed once 
before randomization.[53]
6.  Use of ICS (low/medium dose according to GINA Report, 2016) with or without a LABD for 3 
months (stable dose in the last 4 weeks) before screening visit.
ICS*
Low daily dose
Medium daily dose
BDP extrafine (HFA pMDI) - QVAR®
80-160µg
>160-320µg
Budesonide (DPI)
200-400µg
>400-800µg
Ciclesonide (HFA pMDI)
80-160µg
>160-320µg
Flunisolide (HFA pMDI)
160 – 320µg
>320-640µg
Fluticasone furoate (DPI)
100µg
200µg
Fluticasone propionate (HFA pMDI/DPI)
100-250µg
>250-500µg
Mometasone furoate (DPI)
110-220µg
>220-440µg
*(Table adapted from GINA Report, 2016) 
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
› 160µg 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
› 160µg 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
› 160µg bid -  N/A†
SYMBICORT® 80/4.5
160/9µg bid
80µg bid
SYMBICORT® 160/4.5
320/9µg bid
160µg bid
† This ICS/LABA 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 electronic diary, peak flow 
meter, and the pMDI inhalers.
8. A basal morning (7-10 am) serum cortisol level between 5-28µg/dL at screening (V1).[54]
9. A Body Mass Index: 18.5≤ BMI <35kg/m2.[55][56][57]
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 and 
met on the same day, and before reversibility test is conducted.
At randomization (V2), inclusion criteria # 3, 4 and 7 should also be re-checked. 
4.3 Exclusion Criteria
If a subject meets any of the following criteria, he/she will NOT be enrolled into the study:


 
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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 method such as:
a. Placement of an intrauterine device (IUD) or intrauterine releasing system (IUS).
b. Oral, intravaginal, transdermal combined estrogen and progesterone containing hormonal 
contraception or oral, injectable, implantable progesterone only hormonal contraception.
c. Bilateral tubal occlusion ligation.
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 screening, at Visit 4 and at 
the early termination visit; urinary pregnancy test will be performed at screening, Visit 2 and 3.  
Women of non-childbearing potential defined as physiologically incapable of becoming 
pregnant: post-menopausal (defined as no menses for 12 months without an alternative medical 
cause) or permanently sterile (hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy) are eligible.
If indicated, as per investigator’s request, post-menopausal status may be confirmed by follicle-
stimulating hormone levels (according to local laboratory ranges) in women not using 
hormonal contraception or hormonal replacement therapy.
2. Subjects who suffer from COPD as defined by the GOLD Report, 2017,[2] or are suspected of 
having Asthma COPD Overlap Syndrome (ACOS) as described in GINA Report, 2016.[39]
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 corticosteroids within 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 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 


 
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and non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to screening, 
not controlled with a rate control strategy.
12. Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical 
problem which may impact the safety of the subject according to Investigator’s judgment.
13. Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450ms for males 
or QTcF >470ms for females at screening or randomization visits.
14. Subjects with known intolerance/hypersensitivity or contra-indication to treatment with inhaled 
ß2-adrenergic receptor agonists, corticosteroids or propellant gases/excipients.
15. 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.
16. Use of potent cytochrome P450 3A4 inhibitors (e.g. ritonavir, ketoconazole, itraconazole) and 
inducers within 4 weeks prior to screening.
17. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening.
18. 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.
19. Subjects who are mentally or legally incapacitated, or subjects accommodated in an 
establishment as a result of an official or judicial order. 
20. 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, 12 and 13 should be re-checked at the randomization visit (Visit 2). 
4.4 Subject Withdrawals
Subjects may be discontinued from the study for any of the following reasons:

An adverse event occurs that, in the opinion of the investigator, makes it unsafe for the 
subject to continue 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 non-
permitted concomitant medications.

The subject is unwilling or unable to adhere to the study requirements, i.e, non-compliance.


 
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
The sponsor or the regulatory authorities or the Ethics Committee(s), for any reason, 
terminates the entire study, or terminates the study for this trial site or this particular subject. 
It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable; therefore, unnecessary withdrawals of subjects should be avoided.  However, 
should a subject discontinue the study, all efforts will be made to complete and report the 
observations as thoroughly as possible.
In case of withdrawal, the Investigator must fill in the “Study Termination” page in the eCRF, 
reporting the main reason for withdrawal.   
If a subject is withdrawn/drops-out of the study after receiving the test treatment, the subject study 
number and corresponding test treatments should not be reassigned to another subject.
5. CONCOMITANT MEDICATIONS
5.1 Permitted Concomitant Medications
1. 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. Nasal corticosteroids if already taken at stable doses for at least 2 months prior to screening 
visit (the dose must remain constant for the whole study period) or taken in short courses (10 
days) during the study period.
4. Treatment for desensitization at the “maintenance” 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). 
5. Antihistamines (intranasal, ocular or oral ± decongestant) at no greater than FDA-approved 
doses for the treatment of allergy symptoms.
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 
“most relevant forbidden concomitant treatment”.
5.2 Non-Permitted Concomitant Medications
The following medications are not permitted during the total study period starting from Screening 
visit (V1).  Subjects who take any of these medications during the run-in period (V1-V2) should not 
be randomized into the study. Subjects who take any of these medications during the randomized 
treatment period (V2-V4) will be carefully evaluated by the investigator for Early Withdrawal on 
the basis of the potential impact on efficacy or safety evaluations and in the best interest of the 
subject.
1.
Inhaled corticosteroids other than the run-in medication and study drug
2.
Inhaled short-acting muscarinic antagonists (SAMA), or long-acting muscarinic antagonists 
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3.
Inhaled fixed or free combinations of ICS/LABAs
4.
Inhaled long-acting β2-agonist drugs (LABAs)
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 treatment will be discontinued from the 
study.
7.
Xanthine derivative (e.g. theophylline)
8.
Anti-IgE and anti-IL5 monoclonal antibodies
9.
Tricyclic antidepressants and Monoamine oxidase inhibitors (MAOIs)
10. Systemic anticholinergics
11. Non-cardioselective ß-blocking drugs (including eye drops), except if taken at stable regimen 
for at least 2 months before screening
12. Any drug known to prolong the QT interval (e.g. quinidine, procainamide, amiodarone), 
except if taken at a stable regimen for at least 2 months before screening 
13. Any medication that could interact with the study drug, according to Investigator’s judgment 
Prior to screening spirometry (Visit 1), the following washout periods must be respected:[58]
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
1 month
Intramuscular depot corticosteroid
3 months
Prior to other visits with spirometry (V2 to V4), the following washout periods must be respected:
Inhaled short-acting β2-agonists
6 hours
Caffeinated substances
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6. TREATMENT(S)
The study drug will be supplied to the clinical site under the responsibility of the Sponsor, who will 
also provide the Pharmacist/Investigator with appropriate certificates of analytical conformity.
6.1 Appearance and Content
Study drug
Chiesi has patented MODULITE®, a technology for the development of pMDI as HFA solution 
formulations. Since the non-CFC propellant Norflurane (HFA-134a) has poor solvency properties, 
ethanol has been included in the formulation to enhance the solubility of the active ingredients (co-
solvent).  All the included excipients are extensively used in pharmaceutical preparations.

CHF 718  pMDI 100µg - Test product 
Active ingredient:
beclomethasone dipropionate 100µg per inhalation
Excipient: 
HFA-134a propellant, ethanol anhydrous
Presentation: 
Each canister contains 120 doses

CHF 718  pMDI 50µg - Test product 
Active ingredient:
beclomethasone dipropionate 50µg per inhalation
Excipient: 
HFA-134a propellant, ethanol anhydrous 
Presentation: 
Each canister contains 120 doses

CHF 718 pMDI matched Placebo
Excipient: 
HFA-134a propellant, ethanol anhydrous 
Presentation:
Each canister contains 120 puffs
QVAR® Inhalation Aerosol (Teva Respiratory, LLC) - Reference product
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
An in-vitro assessment of HFA BDP (the ICS component in CHF 1535 or FOSTER®) has been 
undertaken in comparison with QVAR® Inhalation Aerosol (3M Healthcare) using the Andersen 
Cascade Impactor (ACI). A very similar deposition profile between extrafine HFA BDP and 
QVAR® was obtained in the therapeutically useful range 1.1-4.7µm, being 22.0µg for HFA BDP 
and 23.2µg for QVAR®. The Fine Particle Dose = 36.1µg for HFA BDP and 43.3µg for QVAR®. 
MMAD and its associated geometric standard deviation (GSD) evidenced comparable particle size 
distribution, being 1.34µm ± 2.11 for BDP component in CHF 1535 and 1.14µm ± 1.87 for 
QVAR®, respectively, smaller compared to the 3.5-4.0μm found with CFC BDP).[59]
Additionally, and as part of the clinical development plan for FOSTER® Pressurized Inhalation 
Solution, a bridging study was conducted to confirm the bioequivalence of HFA BDP pMDI 100µg 
2 puffs bid (TDD = 400µg) vs. BECLOFORTE® Inhaler (CFC BDP) 250µg 2 puffs bid (1,000µg) 


 
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in adult subjects with mild-moderate symptomatic asthma, previously not well-controlled on low 
dose ICS.  The equivalence limit was set at ± 25L/min for the change from baseline in morning pre-
dose Peak Expiratory Flow rate (AM PEF, primary endpoint),[49] similar to development studies 
with QVAR®,[60][61][62] and 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 results showed a LS mean 
difference in AM PEF and AM FEV1 of 10.06 L/min (95% CI 0.88 to 19.24) and 0.05 L (95% CI (-
0.04 to 0.14) respectively at the end of 8-week treatment between HFA BDP (n=115) and CFC 
BDP (n=118) in the ITT population, this confirming a clinical equipotency ratio of 1:2.5.
With QVAR®, clinical evidence confirms that adult and elderly subjects required approximately ½ 
the dose of extrafine HFA BDP to achieve the same degree of asthma control as with CFC 
BDP.[59]
Considering that the doses assessed in the QVAR® dose-ranging studies were 40, 160, and 320µg 
(ex-actuator) twice daily[50] (corresponding to 50, 200, and 400 ex-valve, respectively), The same 
ex-valve doses of CHF 718 pMDI will be used in this dose-ranging trial, namely 50µg, 200µg, and 
400µg twice daily.
6.2.2 Dosage
6.2.2.1 Run-in period: 
Standardized Run-in 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
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:

Treatment A: 
CHF 718 pMDI 50µg (Total daily dose: 100µg BDP)
An adequate number of inhalations from Placebo inhalers will be performed to maintain a double 
blind design.
o
One inhalation of CHF 718 pMDI 50µg plus three inhalations of CHF 718 pMDI 
matched placebo in the morning 
o
One inhalation of CHF 718 pMDI 50µg  plus three inhalations of CHF 718 pMDI 
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
Treatment B
CHF 718 pMDI 100µg (Total daily dose: 400µg BDP)
An adequate number of inhalations from Placebo inhalers will be performed to maintain a double 
blind design.
o
Two inhalations of CHF 718 pMDI 100µg plus two inhalations of CHF 718 pMDI 
matched placebo in the morning 
o
Two inhalations of CHF 718 pMDI 100µg plus two inhalations of CHF 718 pMDI 
matched placebo in the evening

Treatment C
CHF 718 pMDI 100µg (Total daily dose: 800µg BDP)
o
Four inhalations of CHF 718 pMDI 100µg and in the morning 
o
Four inhalations of CHF 718 pMDI 100µg and in the evening 

Treatment D
CHF 718 pMDI Matched Placebo 
o
Four inhalations of CHF 718 pMDI matched placebo in the morning 
o
Four inhalations of CHF 718 pMDI matched placebo in the evening 

Treatment E (Open label arm): 
QVAR® 80µg (HFA beclomethasone dipropionate, 80µg), (Total daily dose: 320µg) Inhalation 
Aerosol. 
o
Two inhalations from Qvar® in the morning  
o
Two inhalations from Qvar® in the evening 
Note: For the administration of treatment A, B, C, D, 4 separates inhalers will be dispensed in one 
box. Subject will take 1 inhalation from each inhaler in the morning and 1 inhalation from each 
inhaler in the evening. The same kit will be used for morning and evening administration. 
6.2.3 Administration
To the extent possible, the time of dosing of study drug must remain constant for each subject for 
the whole duration of the study.
6.2.3.1 Run-in period (from Visit 1 to 2):
At screening visit 1 (Visit 1), the Investigator, or designee, will contact the IRT system to dispense 
to each eligible subject one run-in ICS background medication kit. This kit will cover the needs 
in background maintenance medication until Visit 2. 
The recommended time of administration is between 8-10 am for the morning dose and between 
8-10 pm for the evening dose, at the same time every day.  At Visit 1 (screening visit), all subjects 
allowed to continue in the study, including those scheduled for Visit 1.1 for a repeat Reversibility 
test, will receive the following standard ICS medication to cover the 2-week run-in period:


 
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
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 background QVAR® medication should not be taken in the morning before coming to the clinic 
(at V1.1 and V2) and will be discontinued at V2.
6.2.3.2 Randomized period (from Visit 2 to 4):
At randomization visit (V2) after the confirmation of eligibility, the subject will be randomized to 
one of the 5 treatment arms (A, B, C, D, E). The investigator or designee will use the IRT system to 
allocate the treatment kit which will cover the period until V3. At Visit 3 the investigator or 
designee will use again the IRT system to allocate the subsequent treatment kit to cover the period 
until V4 (4 weeks).
For Treatment Arms A, B, C, D (CHF-718 pMDI treatments and placebo), each subject will receive 
one box at Visit 2 and one box at Visit 3 containing four pMDI inhalers of double-blinded study 
drug. Each canister will be labeled with a small label numbered 1, 2, 3 or 4 identifying the sequence 
to be followed during the administration. 
The study drug will be administered twice-a-day (in the morning and in the evening):
Morning administration (between 8-10 am):
One inhalation from the canister labeled 1
One inhalation from the canister labeled 2
One inhalation from the canister labeled 3
One inhalation from the canister labeled 4
Evening administration (between 8-10 pm):
One inhalation from the canister labeled 1
One inhalation from the canister labeled 2
One inhalation from the canister labeled 3
One inhalation from the canister labeled 4
For Treatment Arm E (Open Label arm), each subject will receive two QVAR® 80µg commercial 
pack carton at V2 and two QVAR®  80µg commercial pack  at V3.
The study drug will be administered twice-a-day (in the morning and in the evening):
Morning administration (between 8-10 am):
Two inhalations from QVAR® 80µg
Evening administration (between 8-10 pm):
            Two inhalations from QVAR® 80µg


 
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The first administration of study drug will take place at the clinic on visit 2 (V2), after pre-dose 
procedures have been completed.
To the extent possible, the time of dosing must remain constant for each subject for the 
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 Q4-6h as needed (prn). Albuterol may be re-supplied 
by the investigator to the subject at subsequent visits during the study as needed, based on 
assessment of used and remaining doses. The maximum dose allowed is 8 puffs per day.  If the 
subject’s needs exceed 4 puffs/day 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 the spirometric measurements.  Albuterol 
will not be provided by the study sponsor. 
6.2.4 Subject Training
During the V1 (screening), each subject will receive one training kit containing pMDI placebo.
With these kits, the subject will be instructed on how to use the pMDI according to the instructions 
for use. These training kits will be kept at the site by the Investigator (will not be dispensed to the 
subjects) and they will be used again at V2 (randomization) in order to check again the proper use 
of the inhalers.
6.2.5 Subject Training on QVAR® 
Investigator will instruct subjects on how to use the inhaler by reading together and showing the 
QVAR® leaflets 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
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 study drugs for the run-in period and the randomized treatment period.


 
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6.3.1 Training kits
The training kit is one box. The box will contain one CHF 718 pMDI placebo. 

Primary packaging: 1 labeled canister plus 1 labeled standard actuator

Secondary packaging: 1 labeled box containing one canister plus one actuator
6.3.2 Run-in period
At visit 1, the investigator will deliver to each eligible subject one commercial box containing 1 
canister of QVAR® metered dose inhaler: 

Primary packaging: 1 canister plus 1 actuator with a dose counter 

Secondary packaging:1 labeled commercial box containing 1 canister of QVAR® metered dose 
inhaler 
6.3.3 Treatment period
At randomization visit (V2) and at Visit 3, each subject will be provided with 1 box according to 
the randomization list.
Treatment A, B, C, D:

Primary packaging:  1 labeled canister of CHF 718 50µg, 100µg or placebo plus standard 
actuator

Secondary packaging: 1 box containing 4 canisters plus 4 standard actuators  
Treatment E (open label arm):

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 
6.3.4 Rescue medication
Starting at Visit 1, the rescue medication (albuterol) will be prescribed and provided by the 
Investigator to all subjects (purchased locally) for use throughout the study, according to the 
manufacturer’s instructions for use.
6.4 Labeling 
All the supplies provided by Chiesi will be labeled according to the 21 CFR 312.6 of the GMP as 
well as to local law and regulatory requirements. 


 
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6.5 Treatment allocation
A balanced block randomization scheme stratified by US Region (based on US Census Bureau 
Regions: West, Midwest, South, Northeast) and ICS dose before study (low/medium daily dose) 
will be prepared via a computerized system. Subjects will be centrally assigned to one of the five 
treatment arms at the end of the run-in period through an IRT system (Interactive Response 
Technology) with a 1:1:1:1:1 ratio.
The IRT will allocate the subject to a certain treatment group using a list-based randomization 
algorithm and will assign the study drug kit number corresponding to the treatment group assigned 
to the subject. The IRT will also generate a confirmation after every IRT transaction is performed.
The Investigator will call the IRT at each visit (from pre-screening to follow-up call) to record the 
subject number at pre-screening, to enroll and randomize the subject, to obtain the medication kit 
numbers and to register the subject status in the system. Detailed instructions for use of IRT will be 
provided to the site.
6.6 Treatment Code
Study drug will be packaged and uniquely numbered. Each primary packaging in the study drug 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 a username 
and password for randomization purposes and a separate username and password to unblind the 
study drug in case of emergency situations, where he/she considers it 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 Corporate 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 study site and Investigator to be 
called in case of emergency.


 
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6.7 Treatment compliance
Compliance will be evaluated on the basis of the information recorded daily by the subject on the 
digital diary as well as the information recorded in the eCRF during the treatment visits. 
The evaluation of compliance will be done using the following formula:
 DRUG
ED
ADMINISTER
OF
%
100
 DOSES
SCHEDULED
OF
NUMBER
TOTAL
 DOSES
ED
ADMINISTER
OF
NUMBER
TOTAL


The total number of scheduled doses will be calculated on the basis of the extent (days) of exposure 
of each subject. A range 65-135 % will be taken into account for a satisfactory level of compliance. 
Subjects with compliance level less than 75% will receive additional coaching during study visits 2 
and 3.
 
6.8 Drug Storage 
The Pharmacist/Investigator will be responsible for the safe storage of all medications assigned to 
this study, in a secure place with restricted access, and maintained within the appropriate ranges of 
temperature and humidity.
Run-in medication:
The boxes of QVAR® used as study drug for the run-in period and for treatment E 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 718 pMDI and matched placebo pMDI kits must be stored at ambient temperature, not above 
25°C (77°F) either by Pharmacist/Investigator at the study site and by subjects at home. 
Medication for training:
The training inhaler (pMDI) must be kept at site and not dispensed to the subjects. pMDI training 
kit  must be stored at ambient temperature, not above 25°C (77°F), by Pharmacist/Investigator at the 
study center.
The site must check the Min/Max temperatures once daily for adequate storage of ambient kits. 
The Min/Max temperatures must be recorded in a dedicated temperature tracking form. Any 
deviation to the requirement for storage will be promptly reported and 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 the study drugs to be used for the study. Study drugs that should be stored in a locked, secure 
storage facility with access limited to those individuals authorized to dispense the study drugs.
An inventory will be maintained by the Investigator or pharmacist (or other designated individual), 
to include a signed account of all the study drug(s) received, dispensed and returned by each subject 
during the trial.


 
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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 
Pre-
Screening
Screening
Treatment period
Follow-
Up
Visit
V0
V1
V2
V3
V4
V5
ET
Time (Weeks)
-2
0
4
8
9
Early
Termination
Window (days)
±2
±2
±2
±2
Informed consent form 

Demographic data

IRT visit confirmation call







Inclusion / exclusion criteria 

Asthma Action Plan Review



Eligibility recheck

Medical history/Previous medication 

Weight, Height and BMI

Physical examination





Hematology and Blood Chemistry



Morning serum cortisol assessment

Dispensing Container for 24-h Urine Collectiond


Collecting container for 24-h UFC & creatinine analysisd


Serum pregnancy test a



Urinary pregnancy test a



12-lead ECGf




Vital signs (SBP/DBP)e 





Spirometry pre and post-bronchodilator b

Pre-dose spirometry c




ACQ questionnaire 





Concomitant medications 






Adverse Events assessment 






Training on use of pMDI, e-diary and PEF meter 


e-diary, PEF meter completion
 (daily)
Dispensation (D) / Return (R) of run-in QVAR®
D
R
R
Dispensation of rescue albuterolg



Study Drug dispensation(D)/ return & Accountability (R)
D
D/R
R
R
Subject  diary dispensation (D) /return (R)
D
D/R
D/R
R
R
a In female subjects of childbearing potential only
b Spirometry will be carried out before and within 30 minutes after the inhalation of 4 puffs of albuterol to establish airway reversibility, if no documentation is available within 1 yr 
prior to V1.
c Pre-dose FEV1, FVC: T -45’ and T -15’ before study drug administration at V2,  V3, and at V4 and Early Termination at
approximately the same time as done on V2 (no study drug administration at V4 and Early Termination).
d At V1, eligible subjects will be provided with a container for the 24-h urine collection, to be returned to the site the day after
completing the collection, 1-2 days before or on the date of V2. At V3, subjects will be provided with a container for the 24-h urine
collection, to be returned to the site after completing the collection, 1-2 days before or on the date of V4.
e Vital signs (SBP/DBP) will be measured at each visit, before the spirometry, bronchodilator, run-in  ICS medication (QVAR®)
or study drug intake
f A 12-lead ECG will be measured at V1, V2 and V4 or Early Termination before the spirometry, bronchodilator,
run-in ICS medication (QVAR®) or study drug intake.
g One commercial albuterol HFA MDI (200 actuations) will be prescribed and supplied by the investigator to each subject at V1,
and resupplied as needed At V2-3 based on assessment of doses used between visits.


 
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7.1.1 Visit 0 (Pre-screening visit) 
A pre-screening visit will be carried out in order to fully explain the study to potential eligible 
subject. The following procedures will take place: 
-
The written informed consent signed by the subject will be collected after the study has been 
fully explained by the investigator. The investigator or his/her designee should provide them 
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 scheduled for the morning before 9:00 
am, within 1 week. The appointment day may vary depending on the washout period 
necessary for the subject prior to the screening visit. 
-
Subjects will be instructed:
To fast overnight (at least 10 hours) for the next visit in order to perform blood 
sampling (only water is allowed);
Not to take albuterol 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 be carried out in the morning (before 9:00 am) in order to identify eligible 
consenting subjects for the study.
If any of the washouts for non-permitted medications have not been respected, the visit needs to be 
re-scheduled within 2 days. Only one re-scheduling is allowed. If any of the relevant washouts is 
not respected again on the 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.
-
Weight, height and BMI will be recorded.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator and run-in ICS medication (QVAR®) administration, after 5 
minutes of rest, in resting position (see section 7.2.3).
-
A 12-lead ECG will be performed before spirometry, bronchodilator and run-in ICS 
medication (QVAR®) administration, after 5 minutes of rest (see section 7.2.5). A subject 
will not be eligible in case of QTcF >450ms for males or QTcF >470ms for females, or in 


 
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case of 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. 
-
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 7.2.10):
standard hematology and blood chemistry;
serum total cortisol test
a serum -HCG test (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 and FVC (see section 
7.2.6). To be eligible, FEV1 must be ≥50% and <85% of the subject’s predicted normal 
value.
-
If documented airway reversibility within 1 year prior to V1 is not available, post-
bronchodilator spirometry (reversibility) will be carried out within 30 minutes after intake 
of 4 puffs of albuterol HFA (90 µg/actuation). To be eligible, 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 and none of the 
exclusion criteria (screening failure) at V1 under protocol version 4.0 may be re-screened 
again, up to one additional time, after 2 weeks from the date of the initial screening failure.   
A re-screened subject will be treated as a new subject. Subjects who have failed (once or 
twice) to meet all inclusion and none of the exclusion criteria under a previous protocol 
version may be eligible for re-screening once more under this version of the study protocol 
(i.e. up to a total of 3 attempts for this study).
-
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. 


 
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-
The subject will be instructed on how to daily record the medications intake (run-in and 
rescue), and asthma symptoms in the electronic diary/portable electronic peak flow meter 
(see section 7.2.12).
-
The investigator will access IRT also in order to obtain the run-in ICS medication (one 
commercial box containing 1 canister of QVAR® 40 or 80 µg to be dispensed to the subject 
together with instructions for use). 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. 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 run-in ICS medication 
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 bring 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 it as rescue 
medication if necessary. 
-
An electronic diary will be dispensed. Subject must complete and transmit daily their 
electronic diary entries until Visit 2. It is important to ensure good compliance of the subject 
with the use of the electronic diary during the run-in period.
-
Asthma Action Plan will be communicated to the subject.
-
A container for the 24-h urine collection will be dispensed with instructions.  The container 
will be returned to the site at V2.
-
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:
Not to take albuterol or 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 run-in ICS medication (QVAR®) on the morning of the next visit.
To return the rescue medication (in their boxes), and the electronic Diary. 
7.1.3 Visit 2 (Randomization/ Start of Treatment Period /Week 0)
The Visit 2 will start in the morning (before 9:00 am).
If caffeine has been ingested, or rescue albuterol has been inhaled in the previous 6 hours, or the 
washout for non-permitted medications has not been respected, or the run-in ICS medication 
(QVAR®) has been taken in 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 


 
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washouts is not respected again on the morning of the re-scheduled visit, the subject will be 
discontinued and recorded as a screen failure in the IRT and eCRF.
The following pre-dose procedures will be performed:
-
The ACQ questionnaire will be completed.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, and study drug administration, after 5 minutes of rest, in resting 
position (see section 7.2.3).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, and study drug 
administration, after 5 minutes of rest (see section 7.2.5). 
-
The investigator will check in the electronic diary portal whether subject has been 
transmitting data daily since screening. In case of lack of compliance, instructions on how 
to use it will be provided again to the subject (see section 7.2.12).
-
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 a screen failure in the IRT. (see section 5.2).
-
A full physical examination will be performed including assessment for oral candidiasis.
-
A urine pregnancy test in women with childbearing potential will be performed.
-
24-hour urine sample will be processed for 24-hour urine cortisol and creatinine (see section 
7.2.8).
-
The occurrence of other adverse events will be checked and recorded if any.
-
The proper use of pressurized metered dose inhaler will be checked and subject will be 
retrained to the usage of the pMDI using the Training kit previously assigned at V1 (see 
section 6.2.4).
-
Run-in ICS medication (QVAR®) will be collected and disposed of per the study sponsor’s 
instructions.
-
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 min 
and T -15 min before 1st dose of study drug, and will constitute the baseline value (see 
section 7.2.6). Both T -15 and T -45 min assessments must be performed and FEV1 must be 
≥50% and <85% of predicted in order to meet Inclusion Criterion #4.
-
Eligibility criteria will be rechecked (Inclusion #3, 4 and 7 and Exclusion #1, 3, 8, 9, 12 and 
13).  At the discretion of the investigator, a subject who fails to meet all inclusion and none 
of the exclusion criteria (screening failure) at V2 under protocol version 4.0 may be re-
screened again, up to one additional time, after 2 weeks from the date of the initial screening 
failure. A re-screened subject will be treated as a new subject. Subjects who have failed 
(once or twice) to meet all inclusion and none of the exclusion criteria under a previous 
protocol version may be eligible for re-screening once more under this version of the study 
protocol (i.e. up to a total of 3 attempts for this study).


 
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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 4-week treatment period. 
-
The first administration of the study drug will take place at the clinic visit (before 10 
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. 
Before discharge
-
Study drug will be dispensed to the subject together with instructions for use. Study drug 
administration will be done according to section 6.2.3. Subject will be instructed to take 
albuterol as rescue medication if necessary. Investigator will also dispense albuterol if 
needed.
-
The electronic diary (the same given at V1) will be given back to the subject. Subject 
must continue to complete and transmit the data on a daily basis in the digital platform until 
Visit 3.
-
Asthma Action Plan will be reviewed with the subject.
-
An appointment for Visit 3 will be made at 4 weeks (±2 days) from Visit 2 (at 
approximately the same time as Visit 2, before 9:00 am). The subject will be instructed:
To return the study drug (in the box) and the e-diary at the next visit.
Not to take albuterol or caffeinated substances in the 6 hours preceding the next 
visit, and to abstain from taking the non-permitted medications listed in section 5.2 
unless absolutely necessary. 
Not to take the morning dose of the study drug before coming to the next clinic visit 
(it will be administered at the clinic visit).
7.1.4 Visit 3 (Week 4 of Treatment Period)
The visit 3 will start in the morning (before 9:00 am).
If caffeine has been ingested, or rescue albuterol has been inhaled in the previous 6 hours, or the 
study drug has been taken on the morning of the visit (prior to spirometry), or the washout for non-
permitted medications has not been respected, 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 Early Termination 
Visit performed and recorded in the IRT and eCRF.
The following pre-dose procedures will be performed:
-
The ACQ questionnaire will be completed.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, and study drug administration, after 5 minutes of rest, in resting 
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-
The investigator will check in the electronic diary portal whether subject has been 
transmitting data daily since screening. In case of lack of compliance, instructions on how 
to use it will be given again to the subject. (see section 7.2.12)
-
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 assessment of oral candidiasis.
-
A urine pregnancy test in women with childbearing potential will be performed.
-
The occurrence of other adverse events will be checked and recorded if any.
-
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 min and T -15 min before 
the expected time for the morning dose of study drug, at approximately the same time as 
done on V2. 
-
The administration of the study drug will take place at the clinic visit (before 10 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. 
Before discharge
-
Study drug will be dispensed to the subject together with instructions for use. Drug 
administration will be done according to section 6.2.3. Subject will be instructed to take 
albuterol as rescue if necessary. Investigator will also dispense albuterol if needed.
-
The electronic diary (the same given at V1) will be given back to the subject. Subject 
must continue to complete and transmit the data on a daily basis in the digital platform until 
Visit 4.
-
Asthma Action Plan will be reviewed with the subject.
-
A container for the 24-h urine collection will be dispensed. The container will be returned to 
the site at 1-2 days before or on the date of V4.
-
An appointment for Visit 4 will be made at 4 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 bring back the study drug (in the box) and the e-diary 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 before coming to the next clinic 
visit.
7.1.5 Visit 4 (Week 8 of Treatment Period)
The Visit 4 will start in the morning (before 9:00 am). 


 
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If caffeine has been ingested, or rescue albuterol has been inhaled in the previous 6 hours, or the 
study drug has been taken on the morning of the visit (before spirometry), or the washout for non-
permitted medications has not been respected, 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 Early Termination 
Visit performed and recorded in the IRT and eCRF.
The following pre-dose procedures will be performed:
-
The ACQ questionnaire will be completed.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, or study drug administration, after 5 minutes of rest, in resting 
position (see section 7.2.3).
-
A 12-lead ECG will be performed before spirometry, bronchodilator, or study drug 
administration, after 5 minutes of rest (see section 7.2.5). 
-
The investigator will check in the electronic diary portal whether subject has been 
transmitting data daily since Visit 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 Early Termination in the IRT. (see section 5.2).
-
A full physical examination will be performed, including assessment of oral candidiasis.
-
24-hour urine sample will be processed for 24-hour urine cortisol and creatinine
-
A blood sample will be collected, after an overnight fasting (at least 10h), for the 
assessments of (see section 7.2.10):
standard hematology and blood chemistry;
a serum -HCG test in women of childbearing potential.
The blood samples must be collected after vital signs and 12-lead ECG recording.
In case of non-interpretable data, another determination must be performed as soon as 
possible and prior to the follow up safety phone call (V5).
-
The occurrence of other adverse events will be checked and recorded if any.
-
Pre-dose spirometry: FVC pre-dose spirometry measurement will be then performed to 
assess FEV1 and FVC. This measurement will be taken at T -45 min and T -15 min before 
the expected time for the morning dose of study drug at approximately the same time as 
done on V2. 
-
No administration of study drug will take place at Visit 4. 
Before discharge at Visit 4
-
All study material (study drug, rescue medications, e-diary) will be collected.
-
The investigator will prescribe each subject an appropriate treatment or restore their initial 
therapy or refer them to their primary care physician.
-
An appointment will be made in 1 week time for the follow-up phone call.
 


 
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7.1.6 (Visit 5) Follow-up Phone Call (Week 9)
A safety follow up phone call will be performed by the investigator or designated staff no later than 
1 week after the final visit (V4) or Early Termination Visit to check the status of unresolved AEs 
and to record any new AEs that may have occurred after V4, as well as related concomitant 
medications.
7.1.7 Early Termination Visit
If a subject prematurely discontinues the study after randomization, all efforts will be made to 
perform an early termination visit which will include the following assessments, providing there are 
no safety issues for the subject and in accordance with the subject’s agreement:
-
All study material (Study and rescue medications, subject diary) will be collected.
-
No administration of study drug will take place at the Early Termination Visit.
-
Site to update IRT.
-
The ACQ questionnaire will be completed.
-
Vitals signs [systolic (SBP) and diastolic (DBP) blood pressure] will be measured before 
spirometry, bronchodilator, or study drug administration, after 5 minutes of rest, in resting 
position (see section 7.2.3).
-
A 12-lead ECG will be performed before spirometry and/or bronchodilator, after 5 minutes 
of rest (see section 7.2.5). 
-
The investigator will check in the electronic diary portal whether subject has been 
transmitting data daily since previous visit. 
-
Changes of concomitant medications being taken by the subject will be recorded. 
-
A full physical examination will be performed, including assessment of oral candidiasis.
-
A blood sample will be collected, after an overnight fasting (at least 10h, when possible), for 
the assessments of (see section 7.2.10):
standard hematology and blood chemistry;
a serum -HCG test in women of childbearing potential.
The blood samples must be collected after vital signs and 12-lead ECG recording.
-
The occurrence of other adverse events will be checked and recorded if any.
-
Spirometry: FVC spirometry measurement will be then performed to assess FEV1 and FVC. 
This measurement will be taken at T -45 min and T -15 min before the expected time for the 
morning dose of study drug at approximately the same time as done on V2. 
-
The investigator will prescribe each subject an appropriate treatment or restore their initial 
therapy or refer them to their primary care physician.
-
An appointment will be made in 1 week time for the follow-up phone call.
7.2 Investigations 
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 


 
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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.[51][64]  
The ACQ will be completed on site, at every Study Visit. 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 considering the pre-BD FEV1 assessment at V1 and V1.1 
and the T-15 min* pre-dose FEV1 assessment at V2, 3, 4 and ET.
The ACQ-7 is provided on paper and should be completed by the subject 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 
subject, 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).
* If the FEV1 from the T -15 min assessment is not available at V3, V4, or ET, the FEV1 from the T -
45 min assessment will be used.
7.2.2 Body Mass Index
Body Mass index (kg/m2) will be calculated at Visit 1 using the following equation:
Body weight (in kilograms) ÷ by height (in meters)2. Only subjects with a BMI 18.5 ≤ BMI <35 
kg/m2 will be enrolled, to limit the potential impact of obesity on the ICS-treatment response, 
[55][56], and also to accommodate for the rising rate of obesity in the US, especially in the non-
Hispanic Blacks and Hispanic populations.[57] 
7.2.3 Vital Signs
Systolic and diastolic blood pressure will be measured before spirometry, bronchodilator, QVAR® 
or study drug administration, after 5 min rest in resting position. The measurements will be done 
before administration of run-in ICS (V1) and study drug (V2, V3, V4). 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 the same time. 
7.2.4 Physical Exam and assessment of oral candidiasis
A full physical examination will be performed at V1-V4 and Early Termination, including an 
assessment of oral candidiasis. 
Oropharyngeal candidiasis is a condition commonly associated with the use of ICS, and is cause by 
the Candida fungus. This side effect may be attributed to the topical effects of these medications on 
the oral mucosa.[21] Generalized immunosuppressive and anti-inflammatory effects of steroids are 
thought to play a major role in the pathogenesis of candidiasis.[65] Asthmatics who are using β-2 


 
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agonists show a decreased salivary flow rate, which in turn can be associated with higher oral 
Candida counts.[66] 
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.
7.2.5 12-lead ECG
A local ECG instrument will be used. A single ten-second 12-lead ECG will be performed before 
spirometry, bronchodilator, administration of run-in ICS (V1) and study drug (V2, V4) to verify the 
subject’s cardiac safety parameters and his/her eligibility. Prior to recording, the subject should be 
at rest for at least 5 minutes.
Safety ECGs will be taken using the site’s own instrument. 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 by the investigator/sub-investigator on-site for any 
abnormality and clinical significance.
QTc value will be calculated using the Fridericia formula (Fridericia-corrected QTc=
). It will 
𝑄𝑇
3 𝑅𝑅
be calculated automatically by the ECG recorder. Heart rate (HR), PR and QRS values will be also 
evaluated from ECGs at all visits.
ECGs with computerized protocol interpretation are considered normal if 
-
40 bpm ≤ Heart rate ≤ 110 bpm, 
-
120 ms ≤ PR ≤ 210 ms, 
-
QRS ≤ 120 ms.
For eligible subjects, QTcF values must be QTcF ≤ 450ms (for males) and 470ms (for females) (as 
per Exclusion Criterion 13).
In case of relevant ECG abnormalities, the inclusion of the subject will be judged by the 
investigator. For any doubts the Investigator may consult the study’s 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.


 
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7.2.6 Pulmonary Function Test
All pulmonary function tests including FEV1 and FVC will be performed in accordance with 
ATS/ERS spirometry criteria,[67] 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 maneuver and the reports must 
be kept with the source study documents.
Throughout the study (after randomization), the clinic visits will start before 9 a.m. and the 
pulmonary function measurements will be conducted between 7 – 10 a.m., approximately at the 
same time of the day for each subject.
The following parameters will be recorded at Visit 1, 2, 3 and 4 or Early Termination Visit:
Forced Expiratory Volume in the 1st second (FEV1, L)
o
The volume exhaled during the first second of a forced expiratory maneuver starting 
from the level of total lung capacity. FEV1 is decreased in obstructive lung diseases.
Forced Vital Capacity (FVC, L)
o
The maximal volume of gas that can be exhaled from full inhalation by exhaling as 
forcefully and rapidly as possible.
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.[68]
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 forced vital capacity 
maneuvers.  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).[69] 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 subject safety.
The rescue medication (albuterol) must be withheld as much as possible for at least 6 hours prior to 


 
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starting the pre-dose assessment at each visit. If the subject requires rescue medication within this 
timeframe, the visit should be rescheduled once within the next two days.
The run-in 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, if documentation of airway reversibility within 1 year prior to V1 is not available, 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/actuation, 
total dose 360µg) at 30-sec intervals. An increase in FEV1 ≥12% of control and ≥200mL constitutes 
a positive bronchodilator response.[52]
At Visits 2, 3, 4 and Early Termination, spirometry will be conducted at T -45 and T -15 minutes 
before the expected time of study drug administration.
7.2.7 Morning Serum Cortisol
On the morning of Visit 1, a blood sample (5mL) will be collected between 7-10 AM to measure 
basal serum total cortisol level. Serum samples will be analyzed in duplicate in a blinded manner 
for serum cortisol using solid-phase extraction in combination with liquid chromatography tandem 
mass spectrometry.[70] 
The specific procedures for serum processing and shipping will be provided to the investigator by 
the laboratory.
7.2.8 24-h Urine Free Cortisol and Creatinine
Cortisol is a steroid hormone synthesized from cholesterol by a multi-enzyme cascade in the adrenal 
glands. It is the main glucocorticoid in humans. Its production is under hypothalamic-pituitary 
feedback control. Only a small percentage of circulating cortisol is biologically active (free), with 
the majority of cortisol inactive (protein bound). As plasma cortisol values increase, free cortisol 
(ie, unconjugated cortisol or hydrocortisone) increases and is filtered through the kidney’s 
glomerulus. Urinary free cortisol (UFC) correlates well with the concentration of plasma free 
cortisol. UFC represents excretion of the circulating, biologically active, free cortisol that is 
responsible for the signs and symptoms of hypercortisolism. UFC is a sensitive test for the various 
types of adrenocortical dysfunction, particularly hypercortisolism (Cushing syndrome). Subjects 
with Cushing syndrome due to intake of synthetic glucocorticoids should have suppressed UFC.[71]  
A measurement of 24-hour UFC excretion, by liquid chromatography-tandem mass spectrometry 
(LC-MS/MS), is the preferred screening test for Cushing syndrome.[72] LC-MS/MS methodology 
eliminates 
analytical 
interferences 
including 
carbamazepine 
(Tegretol) 
and 
synthetic 
corticosteroids, which can affect immunoassay-based cortisol results.
24-hour urine samples will be collected for the measurement of UFC concentration and creatinine 
excretion. At V1, eligible subjects will be provided with a container for the 24-h urine collection, to 
be returned to the site the day after completing the collection, 1-2 days before or on the date of V2. 
At V3, subjects will be provided with a container for the 24-h urine collection, to be returned to the 
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study, a normal range for UFC in subjects ≥18 years of age is considered between 4.0 – 50 µg/24 
hs, and the normal range in adults for 24-h Urine creatinine = 0.63-2.50 g/24hs.[73]
The specific procedures for 24-h urine collection, processing and shipping will be provided to the 
investigator by the laboratory.
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 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 subject 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 1 of the following:

Initiation of systemic corticosteroids (tablets, suspension, or injection), or an increase (e.g. 
doubling) from a stable maintenance dose, for ≥ 3 consecutive 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 
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. 
*Any change in treatment should be reviewed with the subject, and all concomitant medications 
should be recorded in the CRF.
7.2.10 Blood Hematology and Chemistry
Blood samples of approximately 12 mL will be collected for hematology and serum chemistry at 
Visit 1 (screening), Visit 4 and Early Termination in the morning, after an overnight fasting of at 
least 10 hours (only water is allowed during the night). At V1, the blood draw should be performed 
after vital signs and 12-lead ECG recording, but before administration of albuterol and background 


 
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QVAR®.  An additional blood sample will be collected for serum pregnancy test in women of 
childbearing potential at visits 1 and 4 (including an early termination visit).
The following evaluations will be performed using a laboratory:

A hematology test: red blood cells count (RBC), white blood cells count (WBC) and 
differential, total hemoglobin (Hb), hematocrit (Hct), and 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, and electrolytes (sodium, potassium, calcium, and chloride). 

Fasting blood glucose

A serum pregnancy test (serum β-hCG) in women of child-bearing potential.
Blood collection and sample preparation will be performed according to procedures provided by the 
laboratory which will be in charge to transmit the results to the Investigator. In case of clinically 
significant abnormality, findings will be reported in the medical history (if occurred at V1), or as an 
Adverse Event (if occurred after V1).  
7.2.11  Urine Pregnancy Test
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 
at V1, V2 and V3.
7.2.12 Subject Diaries
Using the ePRO diary (system details to be provided by selected vendor) dispensed at V1, and with 
time and date stamped, subjects will be instructed to: 

Enter a daily record of daytime 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


 
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
The derived variable of Asthma Control Days[76] will be calculated according to the 
following definition: 
o
Days (night-time plus daytime) with a total asthma score = 0
o
No rescue medication use.

Perform Peak Expiratory Flow rate (PEF, L/min) measurements twice daily, in triplicate, 
starting at V1 using using a portable electronic peak flow meter. (Instrument description 
TBD).  The device will be customised with a specific program, according to the parameters 
required by the study protocol. 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 run-in ICS 
medication or study drug) the subject will perform 3 exhalations. Data will be recorded in 
the device. 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. An alarm will remind the subjects to perform measurements. Data from the 
electronic peak flow meter will be automatically transmitted from home to the Vendor’s 
database on a daily basis. A regular check of the recorded data will be done by the 
Investigator (or designee) through a dedicated portal to verify the correct use of the device, 
to detect any clinical abnormality and to check subject’s compliance. In case of bad 
compliance and/or worsening of asthma control during the study, phone call(s) to the subject 
will be done by the site and instructions will be given again to the subject if appropriate.
 

Enter their daily intake of run-in ICS medication and Study Drug, twice daily.
8. EFFICACY ASSESSMENTS
Primary efficacy variable
Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) 
at Week 8
Secondary efficacy variables
Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) 
at Week 4
Change from baseline in pre-dose morning FVC  (average of pre-dose FVC measurements) at 
Week 4 and Week 8
Change from baseline in ACQ-7 score at Week 4 and Week 8
Change from baseline in average use of rescue medication during inter-visit periods and entire 
treatment period
Change from baseline in percentage of rescue medication-free days during inter-visit periods 
and entire treatment period
Change from baseline in daily asthma symptoms scores during inter-visit periods and entire 
treatment period
Change from baseline in percentage of asthma symptoms-free days during inter-visit periods 
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Change from baseline in percentage of asthma control days during inter-visit periods and 
entire treatment period
Change from baseline in morning and evening pre-dose PEF during inter-visit periods and 
entire treatment period
9. SAFETY ASSESSMENTS
Adverse Events (AEs), Adverse Drug Reactions (ADRs)
Vital signs (systolic and diastolic blood pressure)
12-lead ECG parameters (HR, QTcF, QRS, PR)
Standard blood chemistry and hematology
24-h Urinary Free Cortisol and Creatinine
10. ADVERSE EVENT REPORTING
10.1 Definitions
An Adverse Event is “any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment”.
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 
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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 an 
AE. Complications that occur during the hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE. Emergency room visits that do not result in a formal admission 
into hospital should be evaluated for one of the other seriousness criteria (e.g., life-threatening; 
persistent or significant disability or incapacity; medically significant).
-
Results in persistent or significant disability or incapacity.
The term significant disability should be viewed as any situation whereby an AE has a clinically 
important effect on the subject’s physical or psychological well-being to the extent that the subject 
is unable to function normally.
-
Is a congenital anomaly or birth defect
-
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.
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 product information (Investigator’s Brochure for an CHF 718 pMDI or US-FDA 
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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.
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.


 
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10.5 Action taken with the study drug due to the AE 
Dose not changed
Drug withdrawn
Drug interrupted
Not applicable
Unknown
10.6  Other actions taken
Specific therapy/medication
Concomitant procedure
Not applicable
10.7 Outcome
Each Adverse Event must be rated by choosing among:
Recovered/resolved
Recovering/resolving
Not recovered/not resolved
Recovered with sequelae/resolved with sequelae
Fatal
Unknown
10.8 Recording Adverse Events
All Adverse Events occurring during the course of the study must be documented in the Adverse 
Event page of the electronic Case Report Form (eCRF).  Moreover, if the Adverse Event is serious, 
the Serious Adverse Event Form must also be completed. 
It is responsibility of the Investigator to collect all adverse events (both serious and non-serious) 
derived by spontaneous, unsolicited reports of subjects, by observation and by routine open 
questionings.
The recording period for Adverse Events is the period starting from the Informed Consent signature 
until the subject’s study participation ends.
Clinically significant abnormalities detected at Visit 1 not due to a pre-existing condition or 
clinically significant changes at the following visits in the medical opinion of the investigator must 
be reported as adverse events in the eCRF.
If a clinically significant abnormal laboratory finding or other abnormal assessment meets the 
definition of an AE, then the AE eCRF page must be completed, as appropriate. A diagnosis, if 
known, or clinical signs and symptoms if diagnosis is unknown, rather than the clinically significant 
abnormal laboratory finding, should be reported on AE eCRF page. If no diagnosis is known and 
clinical signs and symptoms are not present, then the abnormal finding should be recorded.


 
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For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as 
completely and practically as possible their nature and/or causality until resolution of all queries, 
clinical recovery is complete, laboratory results have returned to normal, stable condition is reached 
or until the subject is lost to follow-up. Follow-up may therefore continue after the subject has left 
the study. In this case, the follow-up will continue with no timelines for related SAEs, while for 
unrelated SAEs the type and extent of follow-up undertaken will be determined for each individual 
case and will depend upon the nature (e.g. events with poor prognosis or which do not resolve), 
severity and medical significance of the event.
10.9 Reporting Serious Adverse Events to Chiesi
The Investigator must report all Serious Adverse Events to the 
 Safety Contact 
listed below within 24 hours of awareness. The information must be sent by providing the 
completed Serious Adverse Event form. At a later date, the 
 Safety Contact will 
report all information to Chiesi Global Pharmacovigilance, the Clinical Project Manager and the 
Clinical Research Physician. 
Name and Title
Telephone no.
Fax no.
E-mail
, MD
Medical Safety Officer
Global Pharmacovigilance Operation Specialist
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 event occurring after the site is closed should be reported 
directly to the Chiesi Safety Contact.
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees/IRB
The Sponsor or designated CRO will report adverse events to the regulatory authorities in 
compliance with the timelines and standards of reporting according to local regulations (Guidance 
for industry and Investigators-Safety Reporting Requirements for INDs and BA/BE studies, 
December 2012). All suspected unexpected serious adverse reactions (SUSARs), which occur with 
the investigational medicinal product or marketed active comparator, within or outside the 
concerned clinical trial, will be reported by the Sponsor or designated CRO to regulatory 
authorities, as required, as well as to the Investigators and Central IRB, if applicable, by 
MedWatch/CIOMS form. The Investigator (or Sponsor/CRO where required) must inform the IRB 
per Sponsor instruction upon receipt of the SUSAR notification. An IND and/or NDA Safety 
Report will be submitted to regulatory authorities unblinded. Participating Investigators and IRB 
will receive a blinded IND Safety Report, unless otherwise specified.
With regard to regulations in force for Pharmacovigilance, the Investigator must fulfil his/her 
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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 the 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 or of the run-in ICS 
/rescue medication, the pregnancy does not need to be reported; it is only required that the 
subject is immediately withdrawn from the study.
11. DATA MANAGEMENT
An electronic CRF (eCRF) will be filled-in by the Investigator and/or his/her designee. 
All subjects who sign the informed consent will be 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.
Subject’s questionnaire (ACQ) answers will be databased.
Front-end edit checks will run at the time of data collection and back-end edit checks will be used 
by the Data Manager to check for discrepancies and to ensure consistency and completeness of the 
data. 
Medical history, Concomitant Procedures and Adverse Events will be coded using the MedDRA 
dictionary; medications will be coded using the WHO Drug dictionary and Anatomical Therapeutic 
Chemical classification (ATC).
External data (IRT, Spirometry, e-diary, Laboratory) will be processed centrally and reconciled 
against data recorded in the eCRF as part of cleaning activities.  After cleaning of data, a review 


 
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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 718 pMDI at different doses 
over placebo in terms of change from baseline in pre-dose morning FEV1 at Week 8.
A total of 495 evaluable subjects (99 per group) will provide 80% power to detect a mean 
difference of 200mL between each dose of CHF 718 pMDI and placebo at a two-sided significance 
level of 0.0167, assuming a standard deviation of 430mL.
Since three 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 (0.0167 = 0.05/3). 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 585 subjects (117 per group) will 
be randomized.
12.2 Populations for analysis
Safety population: all randomized subjects who receive at least one dose of study drug.
Intention-to-Treat population (ITT): all randomized subjects who receive at least one dose of 
the study drug and with at least one available evaluation of efficacy (primary or secondary 
efficacy variables) after the baseline.
Per-protocol population (PP): all subjects from the ITT population without any major 
protocol deviation (i.e., wrong inclusions, poor compliance, non-permitted medications). Exact 
definition of major protocol deviations will be discussed by the study team during the blind 
review of the data and described in the Data Review Report.
Since the superiority of CHF 718 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 analysed in the ITT population.
The safety variables will be analysed in the Safety population. 
In case of deviation between randomized treatment and treatment actually received, the treatment 
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12.3 Statistical analysis
A detailed statistical analysis plan will be described in a separate document. The plan might be 
reviewed and updated as a result of the blind review of the data and will be finalized before 
breaking the blind. 
12.3.1 Descriptive Statistics 
Descriptive statistics will be provided in summary tables by treatment group according to the type 
of variable summarized.
Descriptive statistics for quantitative variables will include n (the number of non-missing values), 
mean, SD, median, minimum and maximum values. 
Categorical variables will be summarized by using frequency count and percent distribution.
12.3.2 Missing data
For the primary efficacy analysis, a linear mixed model for repeated measures will be used to 
handle missing data. Under the Missing At Random (MAR) assumption, this model provides an 
unbiased estimate of the treatment effect that would have been observed if all subjects had 
continued on treatment for the full study duration. This approach addresses efficacy (or de jure) 
hypotheses, estimating the causal effects of the initially randomized drug if taken as directed 
(in contrast with effectiveness, or de facto, hypotheses, evaluating the effect of the drug as 
actually taken).[77] The efficacy estimand is considered appropriate in the context of a phase II 
study aiming at characterising dose-response.[78][79][80]
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.
A minimum of 7 days with available measurements will be required for each inter-visit period 
(including run-in period) to consider the following variables as non-missing: average use of 
rescue medication, percentage of rescue medication-free days, daily asthma symptoms, and 
percentage of asthma symptom-free days, percentage of asthma control days, morning and 
evening PEF.
For ACQ-7 questionnaire, the total score will be calculated only if all the scores derived from 
all the seven items are recorded.
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 Subject demographics and baseline characteristics
The following variables will be summarized by treatment group on the ITT population (and on the 
Safety or PP populations, if relevant): demographic characteristics, medical history and concomitant 
diseases, previous and concomitant medications, efficacy and safety parameters at screening and/or 
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12.3.4 Primary efficacy variables
Change from baseline in pre-dose morning FEV1 will be analysed using a linear mixed model for 
repeated measurements including treatment, visit, treatment by visit interaction, ICS dose before 
study (low/medium daily dose) and US regions as fixed effects, and the baseline value (average of 
the pre-dose FEV1 measurements at Visit 2) and baseline by visit interaction as covariates. An 
unstructured covariance matrix will be assumed. 
The adjusted means in each treatment group, the adjusted mean difference between treatments and 
their 95% two-sided Confidence Intervals (CIs) at Week 8 will be estimated by the model. The CIs 
and the p-values of the comparisons between each dose of CHF 718 pMDI and placebo at Week 8 
will be adjusted for multiplicity. The adjustment will be based on the parametric simulation method 
by Edwards and Berry.[81] At each dose level, the superiority of CHF 718 pMDI over placebo will 
be demonstrated by a statistically significant difference (adjusted p-value < 0.05) favoring CHF 718 
pMDI.
All the other comparisons between treatments will be performed as secondary efficacy analyses 
with no multiplicity adjustment.
12.3.5 Secondary efficacy variables
No multiplicity adjustment will be performed in the secondary efficacy analyses.
For change from baseline in pre-dose morning FEV1 at Week 4, the adjusted means in each 
treatment group and the adjusted mean differences between treatments at Week 4 will be 
estimated with their 95% CIs and p-values by the same model used for the primary efficacy 
analysis. 
Change from baseline in pre-dose morning FVC at Week 4 and Week 8 will be analysed using 
a similar model as the one used for the primary efficacy analysis. 
Change from baseline in ACQ-7 score at Week 4 and Week 8 will be analysed using a similar 
model as the one used for the primary efficacy analysis.
Change from baseline to each inter-visit period in average use of rescue medication, in 
percentage of rescue medication-free days, in daily asthma symptoms scores, in percentage of 
asthma symptoms-free days, in percentage of asthma control days and in morning and evening 
pre-dose PEF will be analysed using a similar model as the one used for the primary efficacy 
analysis. The inter-visit period will be considered instead of visit in the model. Comparison 
between treatments over the entire treatment period will also be derived from this model.
12.3.6 Safety variables
Adverse Events
All adverse events starting on or after the time of first study drug intake will be classified as 
Treatment Emergent Adverse Events (TEAEs). Any adverse event started after the informed 
consent signature and before the time of first study drug intake will be classified as pre-treatment 
adverse event. Pre-treatment adverse events will be listed only.


 
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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 (Visit 2) 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 (Visit 2) 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). 
The number and the percentage of subjects with a: 
QTcF >450ms (males only), >470ms (females only), >480ms (males only) and >500ms

change from baseline (Visit 2) in QTcF >30ms and >60ms

at post-baseline visit will be presented by treatment group.
Laboratory parameters
Shift tables from screening to the end of treatment, based on normal ranges, will be presented by 
treatment group for the laboratory parameters.
Mean change from baseline (Visit 2) to the end of treatment in 24-h urinary free cortisol and 
creatinine will be calculated with its 95% CI by treatment group.
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.


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


 
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23. RECORD RETENTION
After completion of the study, all documents and data relating to the study will be kept in an orderly 
manner by the Investigator in a secure study file. 
Regulations require that essential documents must be retained for at least two years after the final 
marketing approval in an ICH region or until two years have elapsed since the formal interruption 
of the clinical development of the product under study.
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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APPENDIX I
An 8-week, randomized, double-blind, placebo and active-controlled, parallel group, dose ranging 
study to evaluate the efficacy and safety of 3 doses of CHF 718 pMDI (beclomethasone 
dipropionate) in asthmatic subjects
Product: CHF 718 pMDI (beclomethasone dipropionate)
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), ICH E6 Good Clinical Practices and with all the other 
local laws and regulations relevant to the use of new and approved therapeutic agents in subjects.
Principal Investigator’s Name:   
    
                 , MD
Center No.: 
Signature
             Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy


-Clinical Study Protocol Appendix II-
Clinical Study Code: CCD-05993AA3-01
Version No.: 3.0  
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APPENDIX II
MINIMUM LIST OF SOURCE DATA REQUIRED
The following list should be considered as an example (not exhaustive list): 
-
Subjects demography file
-
Subjects medical file
-
Study number
-
Subject identity/number
-
Randomization number
-
Medical and surgery history
-
Previous and concomitant medications
-
Weight, height
-
Date of informed consent signature
-
Date of specific study visits
-
Labels of study drugs
-
Examination or assessments carried out during the study
-
Laboratory reports
-
Adverse events / serious adverse events
-
If subject is withdrawn, reason for withdrawal

SAP_001.pdf: 
Page 1 of 55 
CHIESI 
BEAM 
A 8-WEEK, RANDOMIZED, DOUBLE-BLIND, PLACEBO AND ACTIVE-
CONTROLLED, PARALLEL GROUP, DOSE RANGING STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF 3 DOSES OF CHF 718 
PMDI (BECLOMETHASONE DIPROPIONATE) IN ASTHMATIC 
SUBJECTS 
Protocol: CCD-05993AA3-01 
IND No: 133679 
Statistical Analysis Plan 
Version 1.0 
Final 
30 JAN 2019 
Author: 
 
 
NCT no. NCT03084718


 
Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-01 
Final Version 1.0, 30JAN2019 
 
Page 2 of 55 
 
Table of Contents 
1 SOPs to be followed ............................................................................................................................. 5 
2 Abbreviations ....................................................................................................................................... 6 
3 Protocol / Clinical Investigation Plan ................................................................................................... 8 
3.1 Study Objectives .................................................................................................. 8 
3.2 Study Design ........................................................................................................ 8 
3.3 Study Schedule .................................................................................................... 9 
3.4 Randomization................................................................................................... 11 
3.5 Sample Size Calculation ..................................................................................... 11 
3.6 Efficacy and Safety Variables ............................................................................. 11 
3.7 Interim Analyses ................................................................................................ 12 
3.8 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol .................................................................................................................. 12 
4 General Definitions ............................................................................................................................ 13 
4.1 Report Language ............................................................................................... 13 
4.2 Analysis Software .............................................................................................. 13 
5 Data Preparation ................................................................................................................................. 14 
5.1 Data Handling and Medical Coding .................................................................... 14 
5.1.1 Data Handling ................................................................................................ 14 
5.1.2 Coding ........................................................................................................... 14 
5.2 CDISC ............................................................................................................... 14 
5.3 SAS-Programming Quality Level ....................................................................... 14 
5.4 Data from third parties ...................................................................................... 15 
6 Analysis Populations and Subgroups ................................................................................................. 16 
6.1 Analysis Populations .......................................................................................... 16 
6.2 Treatment Misallocation .................................................................................... 16 
6.3 Subgroup Definitions ......................................................................................... 17 
7 Definition of Time Points and Analysis Variables ............................................................................. 18 
7.1 Definition of Time Points .................................................................................... 18 
7.2 Baseline Characteristics and Derived Analysis Variables .................................... 20 
7.2.1 Demographic Characteristics ............................................................................ 20 
7.2.2 Asthma History and Pre-Study Smoking Habits ................................................. 20 
7.2.3 Screening and Baseline Subject Characteristics .................................................. 21 
7.2.4 Spirometry and ACQ at Screening .................................................................... 21 


 
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7.2.5 Previous and Concomitant Medications ............................................................. 21 
7.2.6 Previous and Concomitant Procedures .............................................................. 22 
7.2.7 Treatment Exposure and Compliance – Background Medication .......................... 23 
7.2.8 Treatment Exposure and Compliance - Study Drug Administration ...................... 24 
7.2.9 Compliance with the use of e-Diary .................................................................. 27 
7.2.10 Efficacy Variables ......................................................................................... 28 
7.2.11 Safety Assessments ....................................................................................... 32 
8 Analysis Methods ............................................................................................................................... 36 
8.1 General Methods ............................................................................................... 36 
8.1.1 Rules for Handling Missing Data ...................................................................... 38 
8.2 Specific Methods for Efficacy Analyses ............................................................... 38 
8.2.1 Statistical/Analytical Issues .............................................................................. 41 
9 Interim analyses .................................................................................................................................. 41 
10 Overview of Tables, Listings and Figures ........................................................................................ 42 
10.1 Disposition of Subjects ..................................................................................... 42 
10.2 Protocol Deviations .......................................................................................... 42 
10.3 Data Sets to be Analyzed .................................................................................. 42 
10.4 Demographic and Other Baseline Characteristics ............................................. 42 
10.4.1 Demographic Characteristics .......................................................................... 42 
10.4.2 Medical History ............................................................................................ 43 
10.4.3 Screening and Baseline Subject Characteristics ................................................ 43 
10.4.4 Prior, Maintained and Concomitant Medications .............................................. 43 
10.5 Study drug / Investigational Medicinal Product ................................................ 43 
10.5.1 Background medication ................................................................................. 43 
10.5.2 Study drug .................................................................................................... 44 
10.5.3 Compliance with the use of Diary ................................................................... 44 
10.6 Efficacy Results ................................................................................................ 44 
10.6.1 Primary efficacy variable ............................................................................... 44 
10.6.2 Secondary efficacy variables .......................................................................... 45 
10.7 Safety Analyses ................................................................................................ 47 
10.7.1 Adverse Events ............................................................................................. 47 
10.7.2 Vital Signs ................................................................................................... 47 
10.7.3 ECGs ........................................................................................................... 48 
10.7.4 Clinical Laboratory Evaluation ....................................................................... 48 


 
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10.8 Early Termination and Unscheduled Visits ....................................................... 49 
11 Table of Contents for the Tables, Listings and Figures .................................................................... 51 
 
 
 


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


 
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2 Abbreviations 
Abbreviation 
Description 
ACQ  
Asthma Control Questionnaire 
ADAM 
Analysis Data Model 
ADR  
Adverse Drug Reaction  
AE  
Adverse Event  
BID 
Bis in die (twice a day)  
BMI 
Body Mass Index 
BDP 
Beclomethasone dipropionate 
CDISC 
Clinical Data Interchange Standards Consortium 
Cm 
Centimeters 
CRF 
Cases Report Form 
CSR 
Clinical Study Report 
DBP  
Diastolic Blood Pressure 
ECG  
ElectroCardioGram  
eCRF  
Electronic Case Report Form  
E-RS 
EXACT-Respiratory Symptom 
FEV1  
Forced Expiratory Volume in the 1st second  
FVC 
Forced Vital Capacity 
H 
Hours 
HR  
Heart Rate  
IC 
Inspiratory Capacity 
ICS 
Inhaled Corticosteroid 
IRT  
Interactive Response Technology  
ITT  
Intention-to-Treat (analysis population) 
Kg 
Kilograms 
L 
Liters 
LABA 
Long-Acting β2-adrenergic receptor Agonist 
LAMA  
Long Acting Muscarinic Antagonist  
µg 
Micrograms 
M 
Meters 
ms 
Milliseconds 
MedDRA  
Medical Dictionary for Regulatory Activities  
min 
Minute 
mL 
Milliliter 
PEF 
Peak Expiratory Flow 
pMDI  
Pressurized Metered Dose Inhaler  
PP  
Per-Protocol (analysis population) 
PR 
PR Interval width (ECG) 
PT 
Preferred Term (MedDRA) 
QC 
Quality Control 
Qd 
Once a day 
QRS 
QRS interval width (ECG) 
QTcF 
QT interval width corrected according to Fridericia (ECG) 
SAE  
Serious Adverse Event  


 
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SAP  
Statistical Analysis Plan  
SBP  
Systolic Blood Pressure 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class (MedDRA) 
SOP  
Standard Operating Procedure 
TEAE 
Treatment Emergent Adverse Event 
WHO  
World Health Organization 
WHO-DRL 
World Health Organization – Drug Reference List 
 
 


 
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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-05993AA3-01: A 8-week, randomized, double-blind, placebo and active-
controlled, parallel group, dose ranging study to evaluate the efficacy and safety of 3 doses of 
CHF 718 pMDI (beclomethasone dipropionate) in asthmatic subjects. This analysis plan is 
based on the final protocol (version 3.0) dated 19 OCT 2017 and the final electronic case report 
form (eCRF) (version 3.0) dated 26 OCT 2017. Text copied from Protocol is reported in this 
document in Italics to avoid unnecessary alterations to text approved in the Protocol. 
The SAP provides the description of the final analyses. In case of deviations from the SAP, 
explanations will be provided in the Clinical Study Report (CSR). 
3.1 Study Objectives 
The primary objective of this clinical trial is  
• To evaluate the efficacy of CHF 718 pMDI by comparison with placebo in terms of 
change from baseline in pre-dose morning FEV1 at Week 8. 
There are 2 secondary objectives: 
• To evaluate the effect of CHF 718 pMDI on other lung function parameters and 
clinical outcome measures. 
• To assess the safety and the tolerability of the study drug. 
3.2 Study Design 
This is a phase II, multi-center, randomized, double-blind, placebo and active-controlled, 
parallel group, dose ranging study to evaluate the efficacy and safety of 3 doses of CHF 718 
pMDI (HFA beclomethasone dipropionate) in adult subjects with asthma. Following a 2-week 
run-in period on ICS monotherapy, eligible subjects will be randomized to one of five study 
drugs (1:1:1:1:1) delivered twice-daily for 8 weeks. After the last assessment a follow-up phone 
call will be scheduled with the subject. The study will last approximately 12 weeks for each 
subject and a total of 5 clinic visits will be performed during the study. Subject will be 
randomized into 1 to 5 treatment groups presented below. 
• Treatment A*: BDP 100μg Total Daily Dose (BDP 50μg per inhalation, 1 inhalation 
bid) 
• Treatment B*: BDP 400μg Total Daily Dose (BDP 100μg per inhalation, 2 inhalation 
bid) 
• Treatment C: BDP 800μg Total Daily Dose (BDP 100μg per inhalation,  4 inhalations 
bid) 
• Treatment D: Matched placebo ( 4 inhalations bid) 
• Treatment E: QVAR® 320μg Total Daily Dose (HFA beclomethasone dipropionate 
80μg per ihhalation, 2 inhalations bid)  
 
*An adequate number of inhalations from Placebo inhalers will be performed to maintain a 
double blind design. 
 


 
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Background Medication for the Run-in Period 
At the screening visit (Visit 1), treatments that are disallowed by the protocol are to be 
discontinued, including current ICS (as monotherapy or as combination ICS/LABA). The 
subjects will be instead prescribed an equivalent daily dose of ICS as beclomethasone 
dipropionate (QVAR® 40 or 80µg/actuation) and this treatment regimen should remain stable 
for the entire run-in period. 
3.3 Study Schedule 
 
Pre-
Screening Screening 
Treatment period 
Follow-
Up 
ET 
Visit 
V0 
V1 
V2 
V3 
V4 
V5 
Time (Weeks) 
 
-2 
0 
4 
8 
9 
Early 
Termination 
Window (days) 
 
 
±2 
±2 
±2 
±2 
 
Informed consent form  
 
 
 
 
 
 
 
Demographic data 
 
 
 
 
 
 
 
IRT visit confirmation call 
 
 
 
 
 
 
 
Inclusion / exclusion criteria  
 
 
 
 
 
 
 
Asthma Action Plan Review 
 
 
 
 
 
 
 
Eligibility recheck 
 
 
 
 
 
 
 
Medical history/Previous medication  
 
 
 
 
 
 
 
Weight, Height and BMI 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
Hematology and Blood Chemistry 
 
 
 
 
 
 
 
Morning serum cortisol assessment 
 
 
 
 
 
 
 
Dispensing Container for 24-h Urine Collectiond 
 
 
 
 
 
 
 
Collecting container for 24-h UFC & creatinine 
analysisd 
 
 
 
 
 
 
 
Serum pregnancy test a 
 
 
 
 
 
 
 
Urinary pregnancy test a 
 
 
 
 
 
 
 
12-lead ECGf 
 
 
 
 
 
 
 
Vital signs (SBP/DBP)e  
 
 
 
 
 
 
 
Spirometry pre and post-bronchodilator b 
 
 
 
 
 
 
 
Pre-dose spirometry c 
 
 
 
 
 
 
 
ACQ questionnaire  
 
 
 
 
 
 
 
Concomitant medications  
 
 
 
 
 
 
 
Adverse Events assessment  
 
 
 
 
 
 
 
Training on use of pMDI, e-diary and PEF meter  
 
 
 
 
 
 
 
e-diary, PEF meter completion 
 
 (daily) 
 
 
Dispensation (D) / Return (R) of run-in QVAR® 
 
D 
R 
 
 
 
R 
Dispensation of rescue albuterolg 
 
 
 
 
 
 
 
Study Drug dispensation(D)/ return & Accountability 
(R) 
 
 
D 
D/R 
R 
 
R 


 
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Subject  diary dispensation (D) /return (R) 
 
D 
D/R 
D/R 
R 
 
R 
a In female subjects of childbearing potential only 
b Spirometry will be carried out before and within 30 minutes after the inhalation of 4 puffs of albuterol to establish airway reversibility, if no 
documentation is available within 1 yr prior to V1. 
c Pre-dose FEV1, FVC: T -45’ and T -15’ before study drug administration at V2, V3, V4 and Early Termination at approximately the same time as 
done on V2. 
d At V1, eligible subjects will be provided with a container for the 24-h urine collection, to be returned to the site the day after completing the 
collection, 1-2 days before or on the date of V2. At V3, subjects will be provided with a container for the 24-h urine collection, to be returned to the 
site after completing the collection, 1-2 days before or on the date of V4. 
e Vital signs (SBP/DBP) will be measured at each visit, before the spirometry, bronchodilator, run-in ICS medication (QVAR®) or study drug intake. 
f A 12-lead ECG will be measured at V1, V2 and V4 or Early Termination before the spirometry, bronchodilator, run-in ICS medication (QVAR®) 
or study drug intake. 
g One commercial albuterol HFA MDI (200 actuations) will be prescribed and supplied by the investigator to each subject at V1, and resupplied as needed At V2-3 based 
on assessment of doses used between visits. 
 
 
 


 
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3.4 Randomization 
A balanced block randomization scheme stratified by US Region (based on US Census Bureau 
Regions: West, Midwest, South, Northeast) and ICS dose before study (low/medium daily dose) 
will be prepared via a computerized system. Subjects will be centrally assigned to one of the 
five treatment arms at the end of the run-in period through an IRT system (Interactive Response 
Technology) with a 1:1:1:1:1 ratio. 
The IRT will allocate the subject to a certain treatment group using a list-based randomization 
algorithm and will assign the study drug kit number corresponding to the treatment group 
assigned to the subject. The IRT will also generate a confirmation after every IRT transaction 
is performed. 
The Investigator will call the IRT at each visit (from pre-screening to follow-up call) to record 
the subject number at pre-screening, to enroll and randomize the subject, to obtain the 
medication kit numbers and to register the subject status in the system. Detailed instructions 
for use of IRT will be provided to the site. 
3.5 Sample Size Calculation 
The sample size has been calculated to evaluate the superiority of CHF 718 pMDI at different 
doses over placebo in terms of change from baseline in pre-dose morning FEV1 at Week 8. 
A total of 495 evaluable subjects (99 per group) will provide 80% power to detect a mean 
difference of 200mL between each dose of CHF 718 pMDI and placebo at a two-sided 
significance level of 0.0167, assuming a standard deviation of 430mL. 
Since three 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 (0.0167 = 0.05/3). 
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 585 subjects (117 per group) 
will be randomized. 
3.6 Efficacy and Safety Variables 
Primary Efficacy Variable 
Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) at 
Week 8. 
 
Secondary Efficacy Variables 
 Secondary Efficacy Variables are: 
• Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 
measurements) at Week 4 
• Change from baseline in pre-dose morning FVC  (average of pre-dose FVC 
measurements) at Week 4 and Week 8 
• Change from baseline in ACQ-7 score at Week 4 and Week 8 


 
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• Change from baseline in average use of rescue medication during inter-visit periods 
and entire treatment period 
• Change from baseline in percentage of rescue medication-free days during inter-visit 
periods and entire treatment period 
• Change from baseline in daily asthma symptoms scores during inter-visit periods and 
entire treatment period 
• Change from baseline in percentage of asthma symptoms-free days during inter-visit 
periods and entire treatment period 
• Change from baseline in percentage of asthma control days during inter-visit periods 
and entire treatment period 
• Change from baseline in morning and evening pre-dose PEF during inter-visit periods 
and entire treatment period 
 
Safety Variable 
The list of safety assessments are:  
• Adverse Events (AEs) and Adverse Drug Reactions (ADRs) 
• Vital signs (systolic and diastolic blood pressure) 
• 12-lead ECG parameters (HR, QTcF, QRS, PR) 
• Standard blood chemistry and hematology 
• 24-h Urinary Free Cortisol and Creatinine 
3.7 Interim Analyses 
No interim analyses are planned for this clinical investigation. 
3.8 Changes in the Conduct of Study or Planned Analysis compared to the Study 
Protocol 
No changes in conduct between the Statistical Analysis Plan (SAP) and the study protocol 
have been noted. 


 
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4 General Definitions 
4.1 Report Language 
The output of the analyses (tables, figures, listings and inferential analysis) 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). 


 
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5 Data Preparation 
5.1 Data Handling and Medical Coding 
5.1.1 Data Handling 
For data quality control, please refer to the Data Management Plan (Version 1.0 from 22 JUN 
2017) including the Data Validation Plan (Version 3.0 from 26 OCT 2017). 
5.1.2 Coding 
The following codes will be used 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 Reference List (WHO-DRL) 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. 
 


 
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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. These third parties are: 
• 
: central laboratory data. 
• 
: drug intake details, PEF values, compliance values, spirometry data, rescue 
medication and Asthma Symptom Score results. 
• 
: supplies the randomization numbers and treatment codes to 
. 
• 
: randomization data from the IRT system. 


 
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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, 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 primary efficacy analysis will be based on the ITT population. The primary efficacy 
analysis will be also performed on the PP populations for sensitivity purpose. 
The secondary efficacy variables will be analyzed in the ITT population. 
All 3 populations (Safety, ITT, and PP) will be used for the presentation of demographics, 
asthma history and smoking, and spirometry and reversibility.   
The medical history/concomitant diseases and exposure/compliance to treatment results will be 
presented using the ITT and Safety populations.   
Medications, compliance with the use of e-diary, and protocol deviations will be reported using 
the ITT population.   
The safety data will be summarized and reported using the Safety population.   
6.2 Treatment Misallocation 
In case of deviation between the as-randomized treatment and the treatment actually received, 
the treatment actually received will be used in the safety analyses (i.e. an as-treated analysis 
will be performed). The following rules will be applied in the construct of the populations: 
• Subjects randomized but not treated will be excluded from the Safety, ITT and PP 
populations.  
• Subjects treated but not randomized will be excluded from the ITT and PP populations, 
given there will be no randomized treatment. These subjects will be summarized based 
on the treatment they received and will be counted in the Safety population. 
• Subjects who were randomized, but took the incorrect study drug for the duration of the 
study, will be summarized based on their randomized treatment for the ITT population 
and excluded from the PP population. These subjects will be summarized based on the 
treatment that they received for the safety analyses.   


 
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• Subjects who were randomized, but took the incorrect study drug for part of the study 
(e.g. the subject began the study by taking the incorrect study drug at Visit 2 but 
switched to randomized study drug at Visit 3) will be discussed during the Blind Data 
Review Meeting, 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. 


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


 
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• Inter-visit Period 1: Inter-visit Period 1 starts on the evening assessment of the date 
of the Start of the Randomized Treatment Period and runs through the morning 
assessment on the date of Visit 3.If the subject withdraws prematurely after Visit 2 
and before Visit 3 any value collected from Visit 2 until the End of the Randomized 
Treatment Period will be considered for the Inter-visit Period 1. By default Inter-
visit Period 2 is missing. 
• Inter-visit Period 2: Inter-visit Period 2 starts on the evening assessment of the day 
the subject returns to the clinic at Visit 3 and runs through the morning assessment 
of the date of Visit 4.   
If the subject withdraws prematurely after Visit 3 and before Visit 4 any value 
collected from Visit 3 until the End of the Randomized Treatment Period will be 
considered for the Inter-visit Period 2.  
 
Date of first/last study drug intake  
Date of first randomized study drug intake is derived as the minimum of ‘Date/Time of 
administration’ between the 4 inhalations (puffs) of the Morning Dose collected on the ‘Study 
drug administration at the clinic’ eCRF page. While subjects randomized to open-label 
QVAR® will only receive 1 inhaler, patients are required to take 2 inhalations of the content of 
1 inhaler on site, the morning of Visit 2. For these patients, no minimum is required, since only 
1 time is recorded. 
Note: The date and time of drug administration at each visit are mandatory variables to be 
reported in the CRF; no missing or partial data can be accepted. Only CRF data will be 
considered for the date of first randomized study drug intake. 
Date of last randomized study drug intake is derived as ‘Date/Time of last intake of study drug’ 
variable collected on the ‘Study Termination form’ eCRF page. If the date of the last intake of  
study drug is missing or partially missing, but the date of at least one dose of the study drug is 
recorded in the diaries or at the clinic, the date of the last randomized study drug intake will be 
imputed using the following rule: 
 max [date of last study drug intake in the diaries, date of last study drug intake at the clinic 
visits] 
The need for deviations from these rules in single cases will be evaluated during the data review 
and documented in the Data Review Report. 
 
 
Time to discontinuation from the study 
Time to discontinuation/completion 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 for lost to follow up or early 
withdrawal. Patients completing the study will be censored at the Date of Completion.  Patients 


 
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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) / 7 
 
Baseline definitions 
Demographic data will be recorded during Visit 0 (Pre-Screening visit). All other baseline 
characteristics (medical history, concomitant diseases, previous and concomitant medications) 
will be recorded during Visit 1 (Screening).  
For the primary efficacy endpoint, the baseline value is defined as the average of the FEV1 pre-
dose measurements on Visit 2 (45 min and 15 min pre-dose). In the same manner, for FVC the 
average of the FVC pre-dose measurements recorded at Visit 2 on Day 1 will be used as the 
baseline. 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 used in the analysis of PEF and diary data is the result recorded during the Run-
in Period. Depending on the structure of the specific variable, this may be an average value, or 
a percentage.  
Baseline ACQ-7 score is the ACQ score recorded at Visit 2, before randomization.    
For vital signs, 12-lead ECG and urinary cortisol and creatinine, baseline values are those 
recorded pre-dose at Visit 2. 
For laboratory the baseline values are the ones collected at Visit 1. 
7.2 Baseline Characteristics 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 eCRF system based on the date of birth and 
date of Pre-Screening (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: 
   (Visit 1 - 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  
as: (smoking stop date - smoking start date + 1)/365.25 


 
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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 Screening and Baseline Subject Characteristics 
• Asthma Control Questionnaire (ACQ) score at Visit 1 and Visit 2will be calculated 
within the eCRF. 
• 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 collected at Visit 1 and calculated as Weight (kg) / 
[Height (m)]² 
• Use of rescue medication, asthma symptoms, and PEF are collected twice daily during 
the run-in period via subject eDiary. For derivation of summary statistics for rescue 
medication, asthma symptoms, and PEF during the run-in period, a minimum of 7 days 
with some non-missing data is required. 
• Spirometry will be performed prior to and following bronchodilator at Visit 1 and prior 
to dosing at Visit 2. 
 
7.2.4 Spirometry and ACQ at Screening 
At Visit 1, if documentation of airway reversibility within 1 year prior to V1 is not available, 
airway reversibility will be assessed with spirometry in triplicate maneuvers before and within 
30 minutes after administration of 4 separate doses of albuterol HFA (90μg/actuation, total 
dose 360μg) at 30-sec intervals. The reversibility parameters (i.e., ΔFEV1 (mL), % ΔFEV1 ) 
will be calculated in the eCRF. Historical reversibility will be presented separately from 
reversibility calculated during the study. 
If the reversibility test of Visit 1 is repeated in a (pre-randomization) rescheduled visit (called 
Visit 1.1 in the eCRF), then all spirometry values of the rescheduled visit will be used for the 
analysis. The same approach will be applied to ACQ. 
7.2.5 Previous and Concomitant Medications 
Medications will be split into four categories: 
• Previous medications are those medications started and stopped prior to the initial 
exposure to the study drug (medication start date < date of first study drug intake and 
medication stop date ≤date of first study drug intake). 
• Maintained medications are all medications started before initial exposure to the study 
drug and ongoing at initial exposure to the study drug (medication start date < date of 
first study drug intake and medication stop date > date of first study drug intake). 
• Concomitant medications are all medications started during the treatment period (date 
of first study drug intake <= medication start date < date of last study drug intake). 


 
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• Post-treatment medications are all medications started on or after the last dose of study 
drug (medication start date >= date of last study drug intake). 
 
In case of missing or incomplete dates not directly allowing allocation to any of the four 
categories of medications, a worst-case allocation will be performed according to the available 
parts of the start and the stop dates. The medications will be allocated to the first category 
allowed by the available data, according to the following order: 
1. concomitant medication; 
2. maintained medication; 
3. post-treatment medication; 
4. prior medication. 
Information on previous and concomitant medications is retrieved from the ‘Prior and 
Concomitant medications’ eCRF page. 
In the analyses, some Preferred Names will be presented under a common name in order to 
improve the readability of the tables. The common name will be presented instead of the 
associated preferred names in the tables and the frequency distribution will be evaluated 
considering the common names (e.g., if one patient took two medications with different 
Preferred Names but the same common name, he/she will be counted only once under the 
common name in the tables). In the listing, the Preferred Names will not be replaced by the 
common names. The common name and the associated Preferred Names considered in the 
analyses are summarised in the table below. 
Common name 
Preferred Names 
“BUDESONIDE” 
“BUDESONIDE” 
“FLUTICASONE 
W/SALMETEROL” 
“FLUTICASONE W/SALMETEROL” 
“SERETIDE” 
“FLUTICASONE PROPIONATE 
W/SALMETEROL” 
“BUDESONIDE 
W/FORMOTEROL” 
“BUDESONIDE W/FORMOTEROL” 
“BUDESONIDE W/FORMOTEROL 
FUMARATE” 
“FLUTICASONE 
W/VILANTEROL” 
 
“BREO ELLIPTA” 
“FLUTICASONE FUROATE W/VILANTEROL” 
 
“MOMETASONE 
W/FORMOTEROL” 
 “DULERA” 
“IPRATROPIUM 
W/SALBUTAMOL” 
“COMBIVENT” “IPRATROPIUM 
W/SALBUTAMOL” 
7.2.6 Previous and Concomitant Procedures 
Procedures will be split into two categories: 
• Previous procedures are all procedures started and stopped prior to the treatment 
period (procedures start date < date of first study drug intake and procedures stop date 
≤ date of first study drug intake). 


 
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• Maintained procedures are all procedures started before initial exposure to the study 
drug and ongoing at initial exposure to the study drug (procedures start date < date of 
first study drug intake and procedures stop date > date of date of first study drug intake). 
• Concomitant procedures are all procedures started during the treatment period (date 
of first study drug intake <= procedures start date < date of last study drug intake). 
• Post-treatment procedures are all procedures started on or after the end of randomized 
period (procedures start date >= date of last study drug intake). 
In case of missing or incomplete dates not directly allowing allocation to the any of 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. maintained procedures; 
3. post-treatment procedures; 
4. previous procedures. 
Information on concomitant procedures is retrieved from the ‘Concomitant procedures’ eCRF 
page. Procedures will be listed only. 
7.2.7 Treatment Exposure and Compliance – Background Medication 
Run-In Period / Exposure and Compliance 
At Visit 1, 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 background QVAR® 
medication should not be taken in the morning before coming to the clinic (at V1.1 and V2) and 
will be discontinued at V2. This treatment regimen should remain stable for the entire run-in 
period.  
The Run-In Period starts at Visit 1 and runs through the day before Day 1 (Day -1). Note that 
the morning diary questions refer to the previous evening.  Therefore, assessments related to 
the evening of the day before Day 1 (Day -1) will be answered in the diary on the morning of 
Day 1.  Exposure during the Run-in Period are based on actual dosing date/times and not visit 
dates. Exposure will be calculated using the: 
 date of last dose of the Run-in Period – date of first dose of the Run-in Period + 1 day. 
Compliance to background medication during the run-in period is based on eCRF and diary 
data. If visit 1 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  Background Medication Administration eCRF page)
Total number of scheduled puffs
𝑥 100% 


 
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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 (days)] x [scheduled number of puffs per day] 
The approach above defined for the calculation of compliance assumes no intake of the 
background medication in case of missing data. 
The compliance will be summarized using the following categories: 
• Treatment compliance < 65%  
• 65% ≤ Treatment compliance ≤ 135%  
• Treatment compliance > 135%. 
and the following categories: 
• [0%-10%] 
• (10%-20%] 
• (20%-30%] 
• (30%-40%] 
• (40%-50%] 
• (50%-60%] 
• (60%-70%] 
• (70%-80%] 
• (80%-90%] 
• (90%-100%] 
• (100%-110%] 
• (110%-120%] 
• (120%-130%] 
• (130%-140%] 
• >140% 
 
7.2.8 Treatment Exposure and Compliance - Study Drug Administration 
The actual date and time of study drug administration will be used to calculate exposure. The 
following dosing schedule will be followed for the 8-week treatment period; study drug will be 
administered twice-a-day (in the morning and in the evening), with the last dose taken the 
evening before Visit 4. Note that the morning diary questions refer to the previous evening. 
Therefore, assessments related to the evening of the day before Day 1 (Day -1) will be answered 
in the diary on the morning of Day 1. 
For Treatment Arms A, B, C and D dosing schedule is:  
Morning administration (between 8-10 am): 
One inhalation from the canister labeled 1 
One inhalation from the canister labeled 2 
One inhalation from the canister labeled 3 
One inhalation from the canister labeled 4 
 


 
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Evening administration (between 8-10 pm):  
One inhalation from the canister labeled 1 
One inhalation from the canister labeled 2 
One inhalation from the canister labeled 3 
One inhalation from the canister labeled 4 
 
For Treatment Arm E dosing schedule is: 
Morning administration (between 8-10 am): 
Two inhalations from QVAR® 80 µg pMDI 
 
Evening administration (between 8-10 pm):  
Two inhalations from QVAR® 80 µg pMDI 
 
If the settings in the electronic diary are incorrect at randomization for a subject (e.g., Run-in 
period settings are applied during the treatment period), such that data is not collected for study 
drug administration during some days during the treatment period, then compliance and 
exposure will not be calculated for that subject for sessions (morning/evening) on which the 
settings were incorrect. Instead, compliance will be calculated based on sessions during which 
the settings were correct. The information recorded at the study clinic will always be considered 
in the calculation (i.e. day will be considered in calculation if exposure is recorded at clinic in 
a day where diary has an incorrect setting).  For these subjects, the duration of the treatment 
period (as used for calculation of scheduled puffs) will be reduced by the number of days during 
which the settings were incorrect. In other words, days with incorrect diary settings will be 
excluded from the numerator and denominator of the compliance calculation for these subjects. 
If the diary settings were incorrect during the entire treatment period, then compliance and 
exposure will not be calculated for the subject.  To be considered as incorrect, diary data should 
be nonmissing and questions answered consistent with a different period. For example 
(I=incorrect questions, C=correct questions, M=missing data): 
• Day 1: I 
• Day 2: I 
• Day 3: M 
• Day 4: M 
• Day 5: C. 
In this case, the last “incorrect day” is Day 2. 
The same approach will be applied to sessions for which any questions related to the wrong 
treatment arm (ABCD vs E) were asked, that will not be used in the calculation of compliance. 
Notably, these sessions will not contribute to the numerator (number of administered puffs) or 
the denominator (number of scheduled puffs).  For these subjects, the total number of scheduled 
puffs will be based on treatment exposure days, excluding sessions with any incorrect diary 
questions.  This includes sessions where duplicate questions were answered.  In these cases, all 
data at the session is considered unreliable, so even the correct questions will be excluded. 
The dosing occasions for study drug are expected to be taken during the visit dates, however 
exposure and compliance are based on actual dosing date/times and not visit dates. See Section 
7.1 for the definition of the study periods and period durations (days). 


 
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For the calculation of the number of administered and scheduled doses, the dosing occasions 
from the first to the last study drug intake will be taken into account (i.e. any study drug 
recorded in the Subject Diary after the date of last dose (as recorded on the ‘Study Termination’ 
eCRF page) will be ignored for study drug compliance calculations).  
If Date of last intake of study drug (as recorded on the ‘Study Termination’ eCRF page) is 
missing or partially missing, dosing occasions of the study drug recorded in the diaries or at the 
clinic will be taken into account until the ‘last randomized study drug intake’ as defined in 
Section 7.1. 
Exposure will be calculated as the Date of last intake of study drug – date of first intake of study 
drug + 1 day. 
The evaluation of compliance is done using the following formula: 
 
Total number of administered puffs (as recorded in the Subject Diary 
and  Study Drug Administration at 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 the Treatment period, as recorded in the Subject Diary and ‘Study Drug 
Administration at the Clinic’ eCRF page. 
Information on study drug intake is retrieved from the eCRF (on visit days) and subject diaries. 
If on a visit day information (morning or evening session) is available from both eCRF and 
diaries, data entered by the investigator in the eCRF will be taken into account. 
It should be noted that 4 puffs (for Arms A, B, C, and D) or 2 puffs (for Arm E) should be taken 
twice a day during the Treatment period (from the morning of Day 1 (V2) until the evening of 
the day before V4). No study treatment is to be administered on the morning of Visit 4.  
The approach above defined for the calculation of compliance assumes no intake of the study 
drug in case of missing data. 
The total number of scheduled puffs is defined during the treatment period as:  
 
• 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]. 
 
Any level of compliance with study treatment in the interval [65%; 135%] is considered as 
satisfactory after randomization. Therefore, the following categories will be discerned for 
Treatment Period: 
• Treatment compliance < 65% 
• 65% ≤ Treatment compliance ≤ 135% 
• Treatment compliance > 135%. 
The compliance will also be summarized as per following categories: 


 
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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% 
 
7.2.9 Compliance with the use of e-Diary 
If the setting in the electronic diary are incorrect for a subject (e.g., Run-in settings applied 
during treatment period or vice-versa), then compliance with use of e-Diary will still be 
considered.   
 In these cases, if any questions were answered, the session will count as “data recorded in the 
 device”.   
Compliance with the use of e-Diary is based on visit dates. See Section 7.1 for the definition of 
the study periods and period durations (days). Period duration will be calculated differently for 
completed subjects and discontinued subjects as defined in Section 7.1. 
Of note, the Visit 2 morning session relates to the run-in period, so this session is considered in 
the total number of sessions expected during the run-in. 
The evaluation of compliance per period (Run-in/Treatment Period) is done using the following 
formula: 
 
Total number of sessions in the treatment period with data recorded in eDiary 
Total number of sessions expected per Period
 𝑥 100% 
 
The following categories will be discerned for compliance: 
•  [0%-10%] 
• (10%-20%] 
• (20%-30%] 
• (30%-40%] 
• (40%-50%] 
• (50%-60%] 
• (60%-70%] 
• (70%-80%] 


 
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• (80%-90%] 
• (90%-100%] 
 
7.2.10 Efficacy Variables 
● Overview 
All spirometry results will be graded by an independent reviewer at 
. The grades after the 
Best Test Review are: U = Unacceptable, A = Acceptable, and B = Borderline Acceptable.  All 
spirometry values, including the values scored with a grade “Unacceptable”, will be considered 
in the calculation of the derived variables. This follows the approach recommended by the paper 
by Hankinson et al. (Eur Respir J 2015), 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 case of historical reversibility data are reported in eCRF only. 
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 pre-dose morning FEV1 at Week 
8. 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 (
).  
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. 
 
In case of rescue medication intake on a visit day, all spirometry data recorded from the time 
of rescue medication intake onwards for 6 hours will be analyzed as part of the ITT Population 
with no exception, but they will be excluded from the analysis of primary efficacy endpoint for 
the PP population. 
 
 
Secondary Efficacy Variables 
In case of rescue medication intake on a visit day, all spirometry data recorded will be analyzed 
as part of the ITT Population with no exception. 
For the derivations of secondary efficacy variables like, average use of rescue medication 
percentage of rescue medication-free days, daily asthma symptoms scores, number and 
percentage of asthma symptoms-free days, number and percentage of asthma control days, a 
minimum of 7 days with available measurements will be required for each inter-visit period 
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“day” is considered as the evening diary session (for which questions relate to the morning) and 
the following morning diary session (for which questions relate to the prior evening). 
 
• Change from baseline in pre-dose morning FEV1 at Week 4 
FEV1 is a continuous variable derived from spirometry data (
). The baseline value is the 
average of the T-45 and T-15 min pre-dose FEV1 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. 
 
• Change from baseline in pre-dose morning FVC at Week 4 and Week 8 
FVC is a continuous variable derived from spirometry data (
). The baseline value is the 
average of the T-45 and T-15 min 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. 
 
• Change from baseline in ACQ-7 score at Week 4 and Week 8  
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.  
ACQ mean score is recorded on ‘Asthma Control Questionnaire” eCRF page. Baseline ACQ-
7 score is the ACQ score recorded at Day 1, before randomization. 
 
• Change from baseline in average use of rescue medication (number of puffs/day) during 
inter-visit periods and entire treatment period 
Information on rescue medication use is collected in the subject- e-diary and in the eCRF at 
clinic. The change from baseline in the average use of rescue medication is a continuous 
variable. The average use of rescue medication is calculated as 
∑Number of puffs of rescue medication taken
Number of days with available data
 
In case of duplicates information reported at clinic and in diary, the greatest information will 
be used. The average use of rescue medication of the entire treatment period will be derived 
only if both inter-visit period are non-missing. See Section 7.1 for the definition of the inter-
visit and entire treatment periods. 
If only a single diary session is missing for a given day (evening session or morning session), 
then the non-missing session will be used.  If both sessions are missing, the day will be 
considered as missing. 


 
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• Change from baseline in percentage of rescue medication-free days during inter-visit 
periods and entire treatment period. 
Information on rescue medication use is collected in the subject-completed e-diary and in the 
eCRF at clinic. A patient is assumed to have used rescue medication if the answer to either of 
the following questions is >0: 
• How many times did you take rescue medication during the nighttime/daytime?  
• How many inhalations of rescue medication did you take during the nighttime/daytime?  
In case of duplicates information reported at clinic and in diary, the greatest information will 
be used. The change from baseline in the percentage of rescue medication-free days is a 
continuous variable. The percentage of rescue medication-free days is calculated as 
Number of rescue medication −free days
Number of days with available data
𝑥100% 
The percentage of rescue medication-free days during the entire treatment period will be 
derived only if both inter-visit period are non-missing. See Section 7.1 for the definition of the 
inter-visit and entire treatment periods. 
If only a single diary session is missing for a given day (evening session or morning session), 
then the non-missing session will be used.  If both sessions are missing, the day will be 
considered as missing. 
• Change from baseline in daily asthma symptoms scores during inter-visit periods and entire 
treatment period 
The change from baseline in daily asthma symptoms score is a continuous variable. Subjects 
have to record asthma symptom score (overall symptoms, cough, wheeze, chest tightness and 
breathlessness) in the morning (night-time asthma symptom score) and in the evening (daytime 
asthma symptom score). These data are collected on the subject’s diary. 
Daily asthma symptoms score are performed separately for morning score and evening score 
and also as a total, where the total equal the sum of the morning and evening scores. 
The daily morning asthma symptoms score is calculate as 
∑Daily Asthma Symptoms score (𝑚𝑜𝑟𝑛𝑖𝑛𝑔)
Number of days with available data
 
where “Daily Asthma Symptoms scores (morning)” is considered separately for “Cough”, 
“Wheeze”, “Chest Tightness”, “Breathlessness” and “overall symptoms” morning individual 
scores.  
Degree of each asthma symptoms is evaluated using a 4-point scale from 0 to 3: None (0), Mild 
(1), Moderate (2) and Severe (3). 
Daily asthma symptoms score during the entire treatment period will be derived only if both 
inter-visit period are non-missing. See Section 7.1 for the definition of the inter-visit and entire 
treatment periods. 
 
The daily evening asthma symptom score will be computed as defined for morning score using 
evening individual symptom scores. 


 
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For cough, wheeze, chest tightness, breathlessness, and overall symptoms scores, a day will be 
constituted by the data recorded in the evening session of that day plus the data recorded in the 
morning session of the next day.  
For each day of the treatment period, for each symptom, the “daily symptom score” will be 
calculated as the mean of the evening symptom score of the day and morning symptoms score 
of the next day. 
If one of the two sessions (evening or morning) associated with the day is missing, the daily 
symptom score will be calculated on the available session only.  
 
• Change from baseline in percentage of asthma symptoms-free days during inter-visit 
periods and entire treatment period 
The change from baseline in the percentage of asthma symptoms-free days is a continuous 
variable. The percentage of asthma symptoms-free days is calculated as 
Number of asthma symptoms −free days
Number of days with available data
𝑥100% 
Asthma symptoms-free days is the number of days with a total asthma score = 0 (daily morning 
plus evening asthma score). 
If only a single diary session is missing for a given day (evening session or morning session), 
then the non-missing session will be used. If both sessions are missing, the day will be 
considered as missing. The percentage of asthma symptoms-free days during the entire 
treatment period will be derived only if both inter-visit period are non-missing. See Section 7.1 
for the definition of the inter-visit and entire treatment periods. 
 
• Change from baseline in percentage of asthma control days during inter-visit periods and 
entire treatment period 
The change from baseline in percentage of asthma control day is a continuous variable. The 
percentage of asthma control day is calculated as 
Number of asthma control days
Number of days with available data 𝑥100% 
The derived variable of Asthma Control Days will be calculated according to the following 
definition:  
 
Days with a total daily morning + evening asthma score = 0  
 
AND no rescue medication use.  
If only a single diary session is missing for a given day (evening session or morning session), 
then the non-missing session will be used.  If both sessions are missing, the day will be 
considered as missing. The percentage of asthma control days -free days during the entire 
treatment period will be derived only if both inter-visit period are non-missing. See Section 7.1 
for the definition of the inter-visit and entire treatment periods. 
 
 


 
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• Change from baseline in morning and evening pre-dose PEF during inter-visit periods and 
entire treatment period 
PEF measurement is a continuous variable derived from an electronic peak flow meter. During 
each measurement session (morning or evening before the intake of the run-in ICS medication 
or study drug) the subject will perform 3 exhalations. Data will be recorded in the 
 device 
(e-diary). For analysis, the derived PEF to be used will be the highest value of the available 
PEF measurements for the given time point.   
A minimum of 2 PEF values should be available at a given time point in order to calculate the 
derived PEF for analysis.  Otherwise, if fewer than 2 PEF values are available for a given time 
point, that time point will be considered as missing for analysis of PEF. A minimum of 7 days 
with available measurements will be required for each inter-visit period (including the run-in 
period) to consider the morning and evening pre-dose PEF as non-missing. The morning and 
evening pre-dose PEF during the entire treatment period will be derived only if both inter-visit 
period are non-missing. See Section 7.1 for the definition of the inter-visit and entire treatment 
periods. 
 
7.2.11 Safety Assessments 
There are 5 sets of safety variables identified in the protocol. A description of each variable, 
and the timing of the recording of the information is presented below. 
 
• 1: Treatment Emergent Adverse Events (TEAEs)  
Three categories of AEs will be presented: Pre-Treatment, Treatment Emergent, and Post-
Study. An AE will be classified as: 
• pre-treatment AE: if AE starts before the first randomized study medication intake (AE 
onset date < date of first randomized study medication intake).   
• Treatment emergent AEs (TEAEs): all adverse events starting on or after the first study 
drug intake, up to study completion/discontinuation. TEAEs are defined as AEs with 
date of first randomized study drug intake ≤ AE onset date ≤ date of study 
completion/discontinuation.  
• post-study AE: if AE starts after the date of completion/discontinuation (AE onset date 
> date of completion/discontinuation).   
 


 
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Additional variables to define an adverse event include the following: 
• Serious AE (SAE) is defined as any AE that has the question “Is the AE serious?” 
marked as “Yes” on the eCRF.  
• ADR is defined as any AE that has the question “Is the AE Related to Study Drug?” 
marked as “Yes” on the eCRF.  
• Serious ADR is defined as any ADR that are also SAE   
• Severe AE, defined as any AE that has intensity marked as “Severe” on the eCRF. 
• AE leading to study drug discontinuation, defined as a TEAE where the action taken 
on the eCRF is marked as “Drug withdrawn”.  
• AE leading to death, defined as a TEAE where the outcome is marked as “Fatal” on 
the eCRF. 
• Relative day of AE onset, defined as  the AE onset date – Date of first study drug intake 
+ 1 if the AE onset date is greater or equal to date of first study drug intake.  For pre-
treatment AEs, the relative day is defined as the AE onset date – Date of first study drug 
intake.  Relative day will not be calculated in case of partial/missing date of AE onset. 
• Duration of AE, defined as the AE end date – AE onset date + 1 when the AE is resolved.  
If the AE is not resolved, the duration is defined as study completion date – AE onset 
date + 1 and the duration will be reported as “>x” in the listing. 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) 
Vital signs (systolic and diastolic blood pressure) will be measured pre-dose from Visit 1 to 
Visit 4. Blood pressure measurements are continuous variables and recorded in mmHg.  Change 
from baseline will be calculated using the pre-dose assessment on Day 1 as the baseline value.  
 
• 3:  12-lead ECG parameters (HR, QTcF, QRS, PR) 
The following parameters from 12-lead ECG will be measured at Visits 1, 2 and 4 and at the 
Early Termination visit: 
• Heart rate (HR) (bpm); 
• PR interval (msec) 
• QRS interval (msec) 
• QTcF interval (msec). 
 


 
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QTc value will be calculated using the Friderica formula (Fridericia-corrected QTc=
𝑄𝑇
√𝑅𝑅
3
) It will 
be calculated automatically by the ECG recorder. 
The changes from baseline will be based on the pre-dose assessment on Day 1.  
 
 
• 4: Standard blood chemistry and hematology 
Blood samples will be collected for hematology and serum chemistry at Screening and Week 
8. Blood samples will also be collected at Early Termination in the morning.   
The following evaluations will be performed using a central laboratory: 
• Hematology test: red blood cells count (RBC), white blood cells count (WBC) and 
differential, total hemoglobin (Hb), hematocrit (Hct), platelets count (PLT). 
• Serum chemistry test: blood urea nitrogen (BUN), cholesterol, triglycerides, creatinine, 
uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), Gamma-
glutamyl transferase (γ-GT), total bilirubin, alkaline phosphatases, albumin, total 
proteins, and electrolytes (sodium, potassium, calcium, and chloride).  
• Fasting blood glucose 
• Serum pregnancy test (serum β-hCG) in women of child-bearing potential; results will 
be presented as positive or negative. Urine β-hCG from visits 1, 2, and 3 will also be 
presented as positive or negative. 
 
Complete Blood Count (abbreviation followed by the full name and units) 
HCT:  
Hematocrit (L/L) 
HGB:  
Hemoglobin (g/L) 
PLATE: 
Platelets (10^9/L) 
RBC:  
Erythrocytes (10^12/L) 
WBC:  
Leucocytes (10^9/L) 
 
Differential (abbreviation followed by the full name and units)  
BASO: 
Basophil (10^9/L) and (%) 
EOSIN:  
Eosinophil (10^9/L) and (%) 
LYMPH: 
Lymphocyte (10^9/L) and (%) 
MONO: 
Monocyte (10^9/L) and (%) 
NEUT:  
Neutrophil (10^9/L) and (%) 
 
Blood Chemistry (abbreviation followed by the full name and units) 
ALB:  
Albumin (g/L) 
ALKPH: 
Alkaline Phosphatase (U/L) 
ALT:  
ALT (U/L) 
AST:  
AST (U/L) 
BUN:  
Blood Urea Nitrogen (mmol/L) 
BILDIR: 
Direct Bilirubin (μmol/L) 
CA: 
 
Calcium (mmol/L) 
CHOL: 
Cholesterol (mmol/L) 
CL:  
 
Chloride (mmol/L) 


 
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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.   
 
• 5: 24-h Urinary Free Cortisol and Creatinine 
24-hour urine sample will be collected at Visit 2 and at Visit 4 for the measurement of urinary 
free cortisol and creatinine excretion. 
 
 


 
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8 Analysis Methods 
8.1 General Methods 
Hypothesis testing will be carried out at the alpha = 0.05 level (two-sided). Statistical 
significance will be declared if the p-value is less than 0.05, with p-values for the primary 
efficacy analysis adjusted for multiplicity as described in Section 8.2.  
For continuous variables, summary statistics will include the number of non-missing 
observations, mean, standard deviation, 95% (or otherwise) confidence interval of the mean 
(only in the efficacy and safety analyses, unless otherwise specified), minimum, median and 
maximum.  
For qualitative variables, the number (n) and percentage (%) of subjects with non-missing 
data per category will be the default summary presentation, and where appropriate and present, 
the number of missing values as a “Missing” category. Unless otherwise specified, the 
denominator for each percentage will be the number of non-missing observations within the 
analysis set and treatment group. 
 
General rules to be used for reporting the number of decimal places for derived variables in the 
listings (in the analyses rounding will not be performed): 
• BMI, treatment exposure (days): whole numbers; 
• Time to discontinuation (weeks), duration of smoking (years), time since first asthma 
diagnosis (years), compliance, average use of rescue medication (number of puffs/day), 
percentage of rescue medication-free days, asthma symptoms scores, percentage of 
asthma symptoms-free days, percentage of asthma control days: 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; 
 
• P-values: 3 decimal places; if the p-value is less than 0.001, it will be presented as 
<0.001. 
 
In general, additional to the analysis model results presented in TLFs, the full SAS output 
generated for all the analyses will be presented to the sponsor as a standalone document. SAS 
output results will be delivered only after DB lock. 
 
 
Calculation of adjusted means (least squares means): 
The approach described below will ensure that the least squares means calculated by SAS 
will be based on: 


 
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– coefficients for classification effects (i.e., the effects of categorical covariates) 
proportional to the margins observed in the group of subjects analysed; 
– effects of quantitative covariates set equal to their mean values in the group of 
subjects analysed. 
The analysis is based on the following steps: 
1. generate a dataset by selecting: 
– in case of repeated post-randomisation measurements (e.g., FEV1 at each 
visit, analysed using a linear mixed model for repeated measures): all the 
post-randomisation records for subjects with at least one available and valid 
post-randomisation measurement and no missing covariates; 
2. in case of repeated post-randomisation measurements, add to the dataset generated 
in step 1 the records for missing post-randomisation visits of the subjects included 
in the dataset. In the added records the value of the response variable will be missing, 
but the full information on covariates has to be included; 
3. use the dataset obtained as the input dataset for the MIXED procedure, specifying 
the following options in the LSMEANS statement: 
– in case of repeated post-randomisation measurements: OM AT MEANS; 
 
Example: analysis of change from baseline (Visit 2) at all visits (Visits 3 to 5) based on a 
mixed model for repeated measures including the effects of treatment, visit (categorical 
variable), treatment by visit interaction, baseline and another covariate. Visit 1 represents 
the screening visit. 
Original dataset (X = available value, . = missing or invalid value): 
Patient 
Treatment Covariate 
Baseline 
Visit Change from baseline 
1 
A 
X 
X 
1 
. 
1 
A 
X 
X 
2 
. 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
2 
B 
X 
X 
1 
. 
2 
B 
X 
X 
2 
. 
2 
B 
X 
X 
3 
X 
3 
A 
X 
X 
1 
. 
3 
A 
X 
X 
2 
. 
3 
A 
X 
X 
3 
X 
3 
A 
X 
X 
4 
. 
3 
A 
X 
X 
5 
X 
4 
B 
X 
X 
1 
. 
4 
B 
X 
X 
2 
. 
5 
A 
. 
X 
1 
. 
5 
A 
. 
X 
2 
. 
5 
A 
. 
X 
3 
X 
 
Step 1 (visits 1 and 2 not selected since pre-randomisation, subject 4 not selected due to 
missing post-randomisation measurements, subject 5 not selected due to missing covariate): 


 
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Subject Treatment Covariate Baseline Visit 
Change from baseline 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
2 
B 
X 
X 
3 
X 
3 
A 
X 
X 
3 
X 
3 
A 
X 
X 
4 
. 
3 
A 
X 
X 
5 
X 
 
Step 2 (added records in italic): 
Subject Treatment Covariate Baseline Visit 
Change from baseline 
1 
A 
X 
X 
3 
X 
1 
A 
X 
X 
4 
X 
1 
A 
X 
X 
5 
X 
2 
B 
X 
X 
3 
X 
2 
B 
X 
X 
4 
. 
2 
B 
X 
X 
5 
. 
3 
A 
X 
X 
3 
X 
3 
A 
X 
X 
4 
. 
3 
A 
X 
X 
5 
X 
 
8.1.1 Rules for Handling Missing Data 
Handling of missing data for the statistical analysis is described below:  
For the primary efficacy analysis, a linear mixed model for repeated measures will be used to 
handle missing data. Under the Missing At Random (MAR) assumption, this model provides an 
unbiased estimate of the treatment effect that would have been observed if all subjects had 
continued on treatment for the full study duration. This approach addresses efficacy (or de jure) 
hypotheses, estimating the causal effects of the initially randomized drug if taken as directed 
(in contrast with effectiveness, or de facto, hypotheses, evaluating the effect of the drug as 
actually taken). The efficacy estimand is considered appropriate in the context of a phase II 
study aiming at characterizing dose-response.  
The specific ways how to deal with missing data, in particular with partial or missing dates 
(e.g., of medication use), missing spirometry data and missing questionnaire data, is 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 
● Primary Model for Analysis 


 
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The change from baseline in pre-dose morning FEV1 at week 8 will be analyzed using a linear 
mixed model for repeated measurements including treatment, visit, treatment by visit 
interaction, ICS dose before study (low/medium daily dose) and US regions as fixed effects, 
and the baseline value (average of the pre-dose FEV1 measurements on Day 1) and baseline by 
visit interaction as covariates. An unstructured covariance matrix will be assumed; the generic 
code for the model is presented below.  
 
proc mixed data = <xxx>; 
  class subject treatment visit usregion ICSdose; 
  model <response> = treatment  visit  treatment*visit  usregion ICSdose fev1base fev1base*visit / DDFM=KR;  
  repeated  visit / subject=subject  type=UN; 
  lsmeans treatment*visit / cl OM AT MEANS; 
  lsmestimate treatment*visit ‘Trt A vs Placebo week 8’ 0 1 0 0 0 0 0 -1 0 0, 
                      ‘Trt B vs Placebo week 8’ 0 0 0 1 0 0 0 -1 0 0, 
                      ‘Trt C vs Placebo week 8’ 0 0 0 0 0 1 0 -1 0 0 / cl adjust=simulate (seed=12311980 acc=0.0001); 
  lsmestimate treatment*visit  ‘Trt B vs Trt A week 8’ 0 -1 0 1 0 0 0 0 0 0 /cl; 
  lsmestimate treatment*visit ‘Trt C vs Trt A week 8’ 0 -1 0 0 0 1 0 0 0 0 /cl; 
  lsmestimate treatment*visit ‘Trt C vs Trt B week 8’ 0 0 0 -1 0 1 0 0 0 0 /cl; 
  lsmestimate treatment*visit  ‘Trt E vs Placebo week 8’ 0 0 0 0 0 0 0 -1 0 1 /cl; 
 
run; 
 
where: 
• treatment is the randomized treatment variable, codified and sorted as follow: 
1. Treatment A (BDP 100µg) 
2. Treatment B (BDP 400µg) 
3. Treatment C (BDP 800µg) 
4. Placebo 
5. Treatment E (QVAR 320 µg) 
• visit is the visit variable (Visit 3 [week 4] and Visit 4 [week 8]) 
• treatment*visit is the treatment by visit interaction 
• usregion is the region in the United States from which the subject entered the study 
(Midwest, Northeast, South and West Regions). 
• 
 ICSdose is the ICS dose before the study (low/medium daily dose) 
• fev1base is the baseline FEV1 result 
• fev1base*visit is the baseline FEV1 result by visit interaction. 
 
The adjusted means in each treatment group, the adjusted mean difference between treatments 
and their 95% Confidence Intervals (CIs) will be estimated by the model. The CIs and the p-
values of the comparisons between each dose of CHF 718 pMDI and placebo at Week 8 will 
be adjusted for multiplicity. For the primary endpoint, the adjustment will be based on the 
parametric simulation method by Edwards and Berry (adjust=simulate in the MODEL 
statement). The random number seed will be set equal to 12311980, and 0.0001 will be used 
for the target accuracy radius gamma (i.e. ACC=0.0001). At each dose level, the superiority of 
CHF 718 pMDI will be demonstrated by a statistically significant difference (adjusted p-value 
< 0.05) favoring CHF 718 pMDI. 
The model will include also pairwise comparisons of treatment A through treatment C, 
comparing each dose with a lower dose, and treatment E versus Placebo. The CIs and the p-
values of these comparisons at Week 8 will not be adjusted for multiplicity.  


 
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Kenward Roger’s method will be used to approximate denominator degrees of freedom 
(/DDFM=KR in the MODEL statement); OM and AT MEANS in LSMEANS statement will 
be used to account for unbalanced population (see details in 8.1). 
Sensitivity analysis: 
Primary analysis will be repeated for sensitivity analysis considering the ICS dose as reported 
in the IVRS system at randomization.  
Another sensitivity analysis, exactly as the primary analysis, will be repeated incorporating only 
the spirometry with Grade=”Acceptable”. 
Secondary efficacy endpoints 
For the secondary efficacy analyses (pre-dose morning FEV1 at Week 4, pre-dose morning FVC 
at Week 4 and Week 8, ACQ-7 score at Week 4 and Week 8, average use of rescue medication, 
percentage of rescue medication-free days, daily asthma symptoms scores, percentage of 
asthma symptoms-free days, percentage of asthma control days, morning and evening pre-dose 
PEF) the same model as above defined for the primary efficacy variable will be used with no 
multiplicity adjustment.  
The adjusted means in each treatment group, the adjusted mean difference between treatments 
and their 95% Confidence Intervals (CIs) will be estimated by the model. The CIs and the p-
values of the comparisons between treatments at Week 4 or Week 8 will not be adjusted for 
multiplicity. 
For analysis of use of rescue medication, rescue-medication free days, daily asthma symptoms 
scores, asthma symptoms-free days, asthma control days, morning and evening pre-dose PEF 
the inter-visit period will be considered instead of visit in the model. Comparison between 
treatments over the entire treatment period will also be derived from this model. The generic 
code for the model is presented below. 
proc mixed data = <xxx>; 
  class subject treatment inter_visit usregion ICSdose; 
  model <response> = treatment inter_visit treatment*inter_visit usregion ICSdose base base*inter_visit / 
DDFM=KR;  
  repeated  inter_visit / subject=subject  type=UN; 
  lsmeans treatment  treatment*inter_visit / cl OM AT MEANS; 
  lsmestimate treatment  "Trt A vs Placebo entire tmt period"  1 0 0 -1 0  /cl; 
  lsmestimate treatment  "Trt B vs Placebo entire tmt period"  0 1 0 -1 0  /cl; 
  lsmestimate treatment  "Trt C vs Placebo entire tmt period"  0 0 1 -1 0  /cl; 
  lsmestimate treatment  "Trt B vs Trt A entire tmt period"    -1 1 0 0 0  /cl; 
  lsmestimate treatment  "Trt C vs Trt A entire tmt period"    -1 0 1 0 0  /cl; 
  lsmestimate treatment  "Trt C vs Trt B entire tmt period"    0 -1 1 0 0  /cl; 
  lsmestimate treatment  "Trt E vs Placebo entire tmt period"  0 0 0 -1 1  /cl; 
  lsmestimate treatment*inter_visit ‘Trt A vs Placebo period 1’ 1 0 0 0 0 0 -1 0 0 0 /cl; 
  lsmestimate treatment*inter_visit ‘Trt B vs Placebo period 1’ 0 0 1 0 0 0 -1 0 0 0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt C vs Placebo period 1’ 0 0 0 0 1 0 -1 0 0 0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt B vs Trt A period 1’     -1 0 1 0 0 0 0 0 0 0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt C vs Trt A period 1’     -1 0 0 0 1 0 0 0 0 0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt C vs Trt B period 1’     0 0 -1 0 1 0 0 0 0 0 /cl; 
  lsmestimate treatment* inter_visit ‘Trt E vs Placebo period 1’ 0 0 0 0 0 0 -1 0 1 0 /cl; 
 lsmestimate  treatment* inter_visit "Trt A vs Placebo period 2" 0 1 0 0 0 0 0 -1 0 0 /cl; 
 … 
 lsmestimate treatment* inter_visit  "Trt E vs Placebo period 2" 0 0 0 0 0 0 0 -1 0 1 /cl; 
run; 


 
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8.2.1 Statistical/Analytical Issues  
8.2.1.1 Handling of Dropouts or Missing Data 
The rules to address missing data rules for specific variables are described in Section 7.2 and 
8.1.1. 
 
8.2.1.2 Blind Review 
A Blind Data Review Meeting is organized just before database 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 which cannot be resolved prior to database lock. 
The Data Review Plan will describe the tables, listings and figures used during this meeting, 
and falls outside the scope of the SAP. 
8.2.1.3 Multi-center Studies 
No adjustment is done for the multiple centers, and no analysis per center is carried out. The 
adjustment in the model will be US region. 
8.2.1.4 Multiple Comparisons/Multiplicity 
Adjustment for multiplicity is applicable only to the primary efficacy analysis. The CIs and the 
p-values of the comparisons between each dose of CHF 718 pMDI and placebo for the primary 
efficacy endpoint at Week 8 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 718 pMDI will be demonstrated by a statistically significant difference (adjusted p-value 
< 0.05) favoring CHF 718p MDI.  
 
8.2.1.5 Patients Randomized to Incorrect Inhaled Corticosteroid Dose Stratum 
If, during randomization, a patient was incorrectly randomized to the wrong stratum for Inhaled 
Corticosteroid Dose, then the patient will be analysed as if he/she had been assigned to the 
correct stratum.  For example, Subject was stratified to MEDIUM ICS stratum.  
According to the ICS dosage taken before the study entry the correct stratum was LOW.  Subject 
will be analysed as if he/she had been assigned to the LOW stratum. 
 
9 Interim analyses 
Not applicable. 
 
 
 


 
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10 Overview of Tables, Listings and Figures 
Demographics, asthma and smoking history, spirometry and reversibility will be presented 
using all three populations (ITT, Safety, PP). Medical history/concomitant diseases and 
compliance with study treatment will be presented using the ITT and Safety populations.  
Medications, ACQ score, efficacy variables derived from diary data, compliance use of e-diary, 
compliance with background medication and protocol deviations will be presented using the 
ITT population. vital signs, ECG, AEs and laboratory data will be presented using the Safety 
population. 
 
10.1 Disposition of Subjects 
A summary of the number of screened subjects, the number of screening failures and reasons 
for screening failure will be produced for all enrolled subjects. 
A disposition summary of subjects by treatment and overall will include the number (N) of 
subjects randomized with the number (n) and percentage (%) of subjects who completed or 
discontinued the study. A subject is considered as completed if the Study Termination Form in 
the eCRF has “Completed” checked for the question “Specify the subject’s status”. All 
percentages will be based on the number of subjects randomized.  
The reasons for study discontinuation will be also summarized by treatment using absolute 
counts and percentages, based on the number of subjects randomized. A Kaplan Meier plot will 
be reported by treatment. 
10.2 Protocol Deviations 
The number of subjects who had at least one Major Protocol Deviation and all Major Protocol 
Deviations will be summarized by absolute counts (n) and percentages (%) by treatment for the 
ITT population. Percentages will be based on the number of subjects in the ITT population. The 
summary will be repeated for Major and Minor Protocol Deviations.   
10.3 Data Sets to be Analyzed  
The number of subjects in each population will be summarized by treatment and overall, by 
absolute counts (n) and percentages (%) for each treatment group. Percentages will be based on 
the number of randomized subjects.  The summary will be repeated by treatment and regions. 
 
10.4 Demographic and Other Baseline Characteristics 
10.4.1 Demographic Characteristics 
Demographic data, asthma history and smoking habits will be summarized by summary 
statistics and absolute counts (n) and percentages (%) by treatment and overall for the Safety 
population, the ITT population and PP population. 


 
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10.4.2 Medical History 
Medical and Surgical History and Concomitant Diseases will be summarized on a per-subject 
basis (i.e. if a subject reported the same event repeatedly the event will be counted only once at 
the specific level of display). Absolute counts (n) and percentages (%) by treatment and overall 
will be presented for the number of subjects with at least one Medical or Surgical History or 
Concomitant Disease, and per SOC and per PT within SOC, for the ITT and Safety population. 
Percentages will be based on the number of subjects in the population. 
10.4.3 Screening and Baseline Subject Characteristics 
Central spirometry and reversibility test data, Vital signs, ECG results, and Asthma Control 
Questionnaire at Visit 1 and Visit 2 will be summarized with summary statistics and absolute 
counts (n) and percentages (%) by treatment and overall for populations as described in Section 
6 above.  
Reversibility test data will be presented overall and also separately for reversibility calculated 
during the study and historical reversibility.  
Use of rescue medication, asthma symptoms, asthma control days, and PEF during the run-in 
period will be presented using summary statistics. For these summaries, a minimum of 7 days 
with some non-missing data during the run-in period are required. 
Physical examination results will be only listed. 
10.4.4 Prior, Maintained and Concomitant Medications 
Previous medications will be summarized by treatment and overall, while maintained and 
concomitant medications will be summarized by treatment (for the assignment of medications 
to a category, see section 7.2.5). 
All previous, maintained and concomitant medications will be presented in the tables and the 
listings.  
Post-treatment medications will be only presented in a listing. 
Previous, maintained and concomitant medications will be summarized on the ITT population 
according to Anatomical Main Group (1st level of ATC), Therapeutic Subgroup (2nd level of 
ATC), Chemical Subgroup (4th level of ATC) and preferred name. 
Absolute counts (n) and percentages (%) will be presented for the number of subjects taking at 
least one medication, and per Anatomical Main Group and per Therapeutic Subgroup within 
Anatomical Main Group and per Chemical Subgroup within Therapeutic Subgroup, for the 
Safety and ITT populations. Percentages will be based on the number of subjects in the 
population.  
10.5 Study drug / Investigational Medicinal Product  
10.5.1 Background medication 
Daily dose of previous ICS treatment for Asthma will be summarized by summary statistics 
and absolute counts (n) of subjects according to the dose category (Low Daily Dose and 
Medium Daily Dose), and the number of morning and evening puffs that the subject was 
instructed to take, both for QVAR 40 µg and QVAR 80 µg for ITT population. The clinically 


 
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comparable dose assigned will also be described categorically (Low Daily Dose, Medium Daily 
Dose). 
Exposure and compliance will be summarized by summary statistics and absolute counts (n) 
and percentages (%) by the treatment that the subject will be randomized to and overall during 
the Run-in Period for the ITT populations. In addition, the number and percentage of subjects 
with the following compliance categories: satisfactory (65% - 135%) and unsatisfactory (<65%; 
>135%) levels of compliance and 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%], >140%) to the 
background medication will be summarized by treatment and overall during the Run-in Period.  
10.5.2 Study drug 
Treatment exposure and compliance during the Treatment Period will be summarized by 
summary statistics and absolute counts (n) by treatment using the ITT and Safety populations. 
In addition the number and percentage of subjects with satisfactory (65% - 135%) and 
unsatisfactory (<65%; >135%) levels of compliance to the study drug will be summarized by 
treatment. 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%], 
>140%). 
10.5.3 Compliance with the use of Diary 
Compliance with the use of Diary in Run-in Period and Treatment period 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.  
10.6 Efficacy Results 
10.6.1 Primary efficacy variable 
The primary endpoint is the change from baseline in pre-dose morning FEV1 at Week 8. The 
change from baseline in FEV1 will be analyzed using a linear mixed model for repeated 
measurements as outlined in Section 8.2. The adjusted means in each treatment group and their 
corresponding 95% confidence intervals (CI), the adjusted mean difference between treatments 
(active – placebo) and their 95% CIs will be estimated by the model. The CIs and the p-values 
of the comparisons between each dose of CHF 718 pMDI and placebo at Week 8 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 718 pMDI versus placebo will 
be demonstrated by a statistically significant difference (adjusted p-value < 0.05) favoring CHF 
718 pMDI. 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 mean absolute FEV1 values will be plotted over time for each of the treatment groups. 
These figures will be based on data from subjects in both ITT and PP populations (separate 
graphs for ITT and PP). 


 
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The mean change from baseline and adjusted mean change from baseline FEV1 values will be 
plotted over time for each of the treatment groups. These figures will be based on data from 
subjects in both ITT and PP populations (separate graphs for ITT and PP). 
10.6.2 Secondary efficacy variables 
The secondary efficacy endpoints will be summarized using descriptive statistics with the 95% 
CI of the mean and will be presented by treatment for the ITT population; in addition the 
following analyses will be performed. There will be no adjustment for multiplicity to the CIs 
or the p-values for any of the secondary efficacy endpoints. 
 
Analysis of Secondary Efficacy Variable: 
• Change from baseline in pre-dose morning FEV1 at Week 4  
The change from baseline in pre-dose morning FEV1 at Week 4 will be analyzed using a linear 
mixed model for repeated measurements as outlined in Section 8.2. The adjusted means in each 
treatment group with their corresponding 95% CIs, and the adjusted mean difference between 
treatments with their corresponding 95% CIs will be estimated by the model. In addition, the 
p-values for each of the factors in the model will be displayed. The mean change from baseline 
and adjusted mean change from baseline FEV1 values will be plotted over time for each of the 
treatment groups. 
 
• Change from baseline in pre-dose morning FVC at Week 4 and Week 8  
The change from baseline in pre-dose morning FVC at Week 4 and Week 8 will be analyzed 
using a linear mixed model for repeated measurements as outlined in Section 8.2. The adjusted 
means in each treatment group with their corresponding 95% CIs, and the adjusted mean 
difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. The 
adjusted mean change from baseline FVC values will be plotted over time for each of the 
treatment groups. 
 
• Change from baseline in ACQ-7 score at Week 4 and Week 8  
The change from baseline in ACQ-7 score at Week 4 and Week 8 will be analyzed using a 
linear mixed model for repeated measurements as outlined in Section 8.2. The adjusted means 
in each treatment group with their corresponding 95% CIs, and the adjusted mean difference 
between treatments with their corresponding 95% CIs will be estimated by the model. In 
addition, the p-values for each of the factors in the model will be displayed. The adjusted mean 
change from baseline in ACQ-7 score will be plotted over time for each of the treatment groups. 
 
• Change from baseline in average use of rescue medication (number of puffs/day) 
during inter-visit periods and entire treatment period  
The change from baseline to each inter-visit period and to the entire treatment period in the 
average use of rescue medication will be analyzed using a linear mixed model for repeated 
measurements as outlined in Section 8.2. See Section 7.1 for the definition of the inter-visit 
periods. The adjusted means in each treatment group with their corresponding 95% CIs, and 
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estimated by the model. In addition, the p-values for each of the factors in the model will be 
displayed. The adjusted mean change from baseline in use of rescue medication will be plotted 
over time for each of the treatment groups. 
 
• Change from baseline in percentage of rescue medication-free days during inter-visit 
periods and entire treatment period  
The change from baseline to each inter-visit period and to the entire treatment period in the 
percentage of rescue medication-free days will be analyzed using a linear mixed model for 
repeated measurements as outlined in Section 8.2. See Section 7.1 for the definition of the inter-
visit periods. The adjusted means in each treatment group with their corresponding 95% CIs, 
and the adjusted mean difference between treatments with their corresponding 95% CIs will be 
estimated by the model. In addition, the p-values for each of the factors in the model will be 
displayed. The adjusted mean change from baseline in percentage of rescue medication free 
days will be plotted over time for each of the treatment groups. 
 
• Change from baseline in daily asthma symptoms scores during inter-visit periods and 
entire treatment period  
The change from baseline to each inter-visit period and to the entire treatment period in daily 
asthma symptoms score will be analyzed separately for morning and evening and also as a total 
(considering both morning and evening) using a linear mixed model for repeated measurements 
as outlined in Section 8.2. See Section 7.1 for the definition of inter-visit periods. The adjusted 
means in each treatment group with their corresponding 95% CIs, and the adjusted mean 
difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed. The 
adjusted mean change from baseline in daily asthma symptoms scores will be plotted over time 
for each of the treatment groups. 
 
• Change from baseline in percentage of asthma symptoms-free days during inter-visit 
periods and entire treatment period 
The change from baseline to each inter-visit period and to the entire treatment period in 
percentage of asthma symptoms-free days will be analyzed using a linear mixed model for 
repeated measurements as outlined in Section 8.2. See Section 7.1 for the definition of inter-
visit periods. The adjusted means in each treatment group with their corresponding 95% CIs, 
and the adjusted mean difference between treatments with their corresponding 95% CIs will be 
estimated by the model. In addition, the p-values for each of the factors in the model will be 
displayed. The adjusted mean change from baseline in percentage of asthma symptoms-free 
days will be plotted over time for each of the treatment groups. 
 
• Change from baseline in percentage of asthma control days during inter-visit periods 
and entire treatment period 
The change from baseline to each inter-visit period and to the entire treatment period in 
percentage of asthma control days will be analyzed using a linear mixed model for repeated 
measurements as outlined in Section 8.2. See Section 7.1 for the definition of inter-visit periods. 
The adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 


 
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model. In addition, the p-values for each of the factors in the model will be displayed. The 
adjusted mean change from baseline in percentage of asthma control days will be plotted over 
time for each of the treatment groups. 
 
• Change from baseline in morning and evening pre-dose PEF during inter-visit periods 
and entire treatment period 
The change from baseline to each inter-visit period and to the entire treatment period in morning 
and evening pre-dose PEF will be analyzed using a linear mixed model for repeated 
measurements as outlined in Section 8.2. See Section 7.1 for the definition of inter-visit periods. 
The adjusted means in each treatment group with their corresponding 95% CIs, and the adjusted 
mean difference between treatments with their corresponding 95% CIs will be estimated by the 
model. In addition, the p-values for each of the factors in the model will be displayed.  
 
10.7 Safety Analyses 
All safety analyses described below will be performed on the Safety population. 
10.7.1 Adverse Events 
As defined in the protocol, all AEs starting on or after the date of first study drug intake will be 
classified as a TEAE.  Only TEAEs will be included in the tables. 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, serious TEAEs, ADRs, serious ADRs, severe TEAEs, TEAEs leading 
to study drug discontinuation and TEAEs leading to death, and the number and the percentage 
of subjects experiencing TEAEs, ADRs, serious TEAEs, serious ADRs, severe TEAEs, TEAEs 
leading to study drug discontinuation and TEAEs leading to death will be summarized by 
treatment and overall.  
The number and percentage of subjects with at least one AE and the number of AEs will be 
presented by SOC and PT by treatment and overall for treatment-emergent AEs, ADRs, serious 
TEAEs, serious ADRs, severe TEAEs, TEAEs leading to study drug discontinuation and 
TEAEs leading to death. 
Subjects who have multiple events in the same system organ class (SOC) and preferred term 
(PT) will be counted only once in the subject counts. 
 
10.7.2 Vital Signs 
Vital signs (systolic and diastolic blood pressure) and their changes from baseline (pre-dose 
on Day 1) on Week 4 and Week 8 will be summarized by treatment using descriptive statistics 
and the 95% CI of the mean. 
 


 
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10.7.3 ECGs  
10.7.3.1 12-Lead ECGs  
ECG parameters (HR, QTcF, QRS, and PR) will be summarized on Day 1 and Week 8 by 
treatment using descriptive statistics and the 95% CI of the mean. The nominal recorded value 
will be used in the calculation. In addition, their changes from baseline will be summarized 
using descriptive statistics and 90% CI.   
In addition, the number and percentage of subjects with prolonged QTcF will be summarized 
using counts and percentages on Day 1, and Week 8 using the following thresholds: 
• QTcF >450 ms for males and >470 ms for females 
• QTcF >480 ms for males only 
• QTcF >500 ms 
• Change from baseline in QTcF >30 ms 
• Change from baseline in QTcF >60 ms 
12-lead ECG numerical parameters (HR, QTcF, PR and QRS) will not be included in the 
statistical analysis in the following cases:  
• 
patients with a pacemaker already in place at study entry, identified by the presence of at 
least one of the following Preferred Terms in the medical/surgical history or concomitant 
diseases: “Cardiac pacemaker battery replacement”, “Cardiac pacemaker evaluation”, 
“Cardiac pacemaker insertion”, “Cardiac pacemaker replacement”, “Electrocardiogram 
pacemaker spike”, “Pacemaker generated arrhythmia”, “Pacemaker generated rhythm”, 
“Pacemaker syndrome”, “Cardiac assistance device user”;  
• 
patients with a pacemaker implanted during the study, identified by a procedure coded with 
the Preferred Term “Cardiac pacemaker insertion” (other relevant cases may be identified 
in the Data Review Report). In this case, only the parameters assessed in a date ≥ start date 
of the procedure will be excluded from the statistical analysis;  
• 
patients with atrial fibrillation as concomitant disease, identified by the presence of at least 
one of the following Preferred Term: “Atrial fibrillation”, “Cardiac fibrillation”;  
• 
ECGs with PR=0, since this is indicative of poor quality or inevaluble ECG result. Note 
that this does not apply to all ECGs for the patient, but only the ECGs with PR=0. 
 
10.7.4 Clinical Laboratory Evaluation 
Shift tables will be presented for hematology and biochemistry parameters  by treatment group 
at Day 1 and Week 8.  
The categories for the shift tables are as follows: 
• Low clinically significant 
• Low not clinically significant 
• Normal 
• High clinically significant 
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In addition, all laboratory data will be listed, with abnormal values flagged. Mean change from 
baseline (Visit 2) to the end of treatment in 24-h urinary free cortisol and creatinine will be 
calculated with its 95% CI by treatment group. 
 
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, will be evaluated case by case during the Data 
Review Meeting. 
The following rules on data re-allocation will be considered: 
• Data collected at multiple visits (spirometry, ACQ score, vital signs, laboratory data, and 
ECG) recorded at the study termination visit for discontinued patients will be re-allocated 
by selecting the next visit at which the assessment was planned. For each assessment, only 
the visits at which the assessment was scheduled will be considered for re-allocation. This 
means that ECG and laboratory data can be re-allocated only to Visit 4. For example, if the 
last visit performed before the study termination visit was Visit 2, the data recorded at the 
study termination visit will be re-allocated to Visit 3 for spirometry, ACQ score, and vital 
signs, and to Visit 4 for 12-lead ECG and laboratory data.  If the study termination visit was 
performed less than 7 days after the preceding visit, then the data recorded at the study 
termination visit will not be re-allocated and they will excluded from the statistical analysis.  
• For discontinued patients, efficacy data recorded in the diaries from the last visit performed 
before the study termination visit or the date of discontinuation onwards will be reallocated 
to the next expected inter-visit period;  
• in case of missing intermediate visit not due to the re-allocation of data collected at the 
study termination visit (e.g., Visit 3 missing, but Visits 2 and 4 performed), an expected 
date for the missing Visit 3 will be imputed in order to define the inter-visit periods for diary 
data. The expected date for the missing Visit 3 will be imputed as follows: Visit 3 expected 
date = Visit 2 date + 28 days. 
• Additional unscheduled/optional assessments 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. 
• 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 
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11 Table of Contents for the Tables, Listings and Figures 
Key Frist Results (KFR) are identified with an “*”. 
Post-Text Tables 
CSR Section 14.1: Demographic data 
Table 14.1.1.1: Screening Failures (All Enrolled Subjects)  
* Table 14.1.1.2.1: Patient Disposition (All Randomized Subjects) 
Table 14.1.1.2.2: Summary of Subjects by Visit (All Randomized Subjects)
 
Table 14.1.1.3.1: Major Protocol Deviations (ITT Population)  
Table 14.1.1.3.2: Minor Protocol Deviations (ITT Population)  
* Table 14.1.1.4.1: Summary of Analysis Sets (All Randomized Patients) 
Table 14.1.1.4.2: Summary of Analysis Sets by US Region (All Randomized Patients)
 
Table 14.1.2.1: Demographic Characteristics (Safety Population)  
Table 14.1.2.2: Demographic Characteristics (ITT Population)  
Table 14.1.2.3: Demographic Characteristics (PP Population)  
Table 14.1.3.1: Asthma History and Smoking Habits (Safety Population)  
Table 14.1.3.2: Asthma History and Smoking Habits (ITT Population)
 
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 at Visits 1 and 2 and Reversibility at Visit 1 (Safety Population)  
Table 14.1.6.2: Central Spirometry at Visits 1 and 2 and Reversibility at Visit 1 (ITT Population)  
Table 14.1.6.3: Central Spirometry at Visits 1 and 2 and Reversibility at Visit 1 (PP Population)  
Table 14.1.7.1: Screening and Baseline Characteristics (Safety Population)  
Table 14.1.7.2: Screening and Baseline Characteristics (ITT Population) 
Table 14.1.7.3: Screening and Baseline Characteristics (PP Population) 
Table 14.1.8.1: Vital Signs Results at Visit 1 and Visit 2 (Safety Population)  
Table 14.1.8.2: Lead ECG at Visit 1 and Visit 2 (Safety Population) 
Table 14.1.9.1: Previous Medications (ITT Population)  
Table 14.1.9.2: Maintained Medications (ITT Population)  
Table 14.1.9.3: Concomitant Medications (ITT Population)  
Table 14.1.10.1: Background Medication (ITT Population)  
Table 14.1.10.2: Background Medication Exposure and Compliance during Run-in Period (ITT Population)  
Table 14.1.11.1: Study Treatment Exposure and Compliance (ITT Population)  
Table 14.1.11.2: Study Treatment Exposure and Compliance (Safety Population) 
Table 14.1.12: Compliance with the use of e-Diary (ITT Population)  
CSR Section 14.2: Efficacy Data 
Table 14.2.1.1: Summary of Pre-dose Morning FEV1 and the Change from Baseline at Week 8 (ITT Population)  
* Table 14.2.1.2: Analysis of Change form Baseline in Pre-dose Morning FEV1 at Week 8 (ITT population) 
Table 14.2.1.3: Summary of Pre-dose Morning FEV1 and the Change from Baseline at Week 8 (PP Population)
 
* Table 14.2.1.4: Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 8 (PP Population) 


 
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*Table 14.2.1.5: Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 8 – Sensitivity analysis 
(ICS dose as randomized) (ITT Population) 
*Table 14.2.1.6: Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 8 – Sensitivity analysis 
(only Acceptable Grade) (ITT Population) 
Table 14.2.2.1: Summary of Change from Baseline in Pre-dose Morning FEV1 at Week 4 (ITT Population)  
* Table 14.2.2.2: Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 4 (ITT Population) 
Table 14.2.2.3: Summary of Change from Baseline in Pre-dose Morning FEV1 at Week 4 (PP Population) 
Table 14.2.2.4: Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 4 (PP Population) 
Table 14.2.3.1: Summary of Pre-dose Morning FVC and the Change from Baseline at Week 4 and Week 8 (ITT 
Population)  
* Table 14.2.3.2: Analysis of Change from Baseline in Pre-dose Morning FVC at Week 4 and Week 8 (ITT 
Population) 
Table 14.2.4.1: Summary of ACQ-7 score and the Change from Baseline at Week 4 and Week 8 (ITT Population)
 
* Table 14.2.4.2: Analysis of Change from Baseline in ACQ-7 score at Week 4 and Week 8 (ITT Population) 
Table 14.2.5.1: Summary of the Average Use of Rescue Medication during Inter-Visit Periods and the Entire 
Treatment Period (ITT Population)  
* Table 14.2.5.2: Analysis of the Average Use of Rescue Medication during Inter-Visit Periods and the Entire 
Treatment Period (ITT Population) 
Table 14.2.6.1: Summary of the Percentage of Rescue Medication-free Days during Inter-Visit Periods and the 
Entire Treatment Period (ITT Population)  
* Table 14.2.6.2: Analysis of the Percentage of Rescue Medication-free Days during Inter-Visit Periods and the 
Entire Treatment Period (ITT Population) 
Table 14.2.7.1: Summary of Daily Asthma Symptoms Scores (morning and evening) during Inter-Visit Periods and 
the Entire Treatment Period (ITT Population)
 
* Table 14.2.7.2: Analysis of the Daily Asthma Symptoms Score (morning and evening) during Inter-Visit Periods 
and the Entire Treatment Period (ITT Population) 
Table 14.2.7.3: Summary of Daily Asthma Symptoms Scores during Inter-Visit Periods and the Entire Treatment 
Period (ITT Population) 
*Table 14.2.7.4: Analysis of the Daily Asthma Symptoms Score during Inter-Visit Periods and the Entire 
Treatment Period (ITT Population) 
Table 14.2.8.1: Summary of the Percentage of Asthma Symptoms-free Days during Inter-Visit Periods and the 
Entire Treatment Period (ITT Population)  
* Table 14.2.8.2: Analysis of the Percentage of Asthma Symptoms-free Days during Inter-Visit Periods and the 
Entire Treatment Period (ITT Population) 
Table 14.2.9.1: Summary of the Percentage of Asthma Control Days during Inter-Visit Periods and the Entire 
Treatment Period (ITT Population)  
* Table 14.2.9.2: Analysis of the Percentage of Asthma Control Days during Inter-Visit Periods and the Entire 
Treatment Period (ITT Population) 
Table 14.2.10.1: Summary of Morning Pre-dose PEF during Inter-Visit Periods and the Entire Treatment Period 
(ITT Population)  
* Table 14.2.10.2: Analysis of Morning Pre-dose PEF during Inter-Visit Periods and the Entire Treatment Period 
(ITT Population) 
Table 14.2.11.1: Summary of Evening Pre-dose PEF during Inter-Visit Periods and the Entire Treatment Period 
(ITT Population)  
* Table 14.2.11.2: Analysis of Evening Pre-dose PEF during Inter-Visit Periods and the Entire Treatment Period 
(ITT Population) 
CSR Section 14.3: Safety 
* Table 14.3.1.1.1: Summary of Treatment Emergent Adverse Events (Safety Population) 
Table 14.3.1.2.1: Treatment Emergent Adverse Events by System Organ Class and Preferred Term (Safety 
Population)  
Table 14.3.1.2.2: Serious Treatment Emergent Adverse Events by System Organ Class and Preferred Term (Safety 
Population)  
* Table 14.3.1.3.1: Adverse Drug Reactions by System Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.3.2: Serious Adverse Drug Reactions by System Organ Class and Preferred Term (Safety Population)
 


 
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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 and Changes from Baseline (Safety Population)  
Table 14.3.5.1: Summary of ECG Results and Changes from Baseline (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 14.3.6: Shift Table of Hematology Results (Safety Population)
 
Table 14.3.7: Shift Table of Biochemistry Results (Safety Population)
 
Table 14.3.8: 24-h urinary free Cortisol and Creatinine and Changes from Baseline (Safety Population) 
CSR Section Listing 16: 
General Programmer Notes for Listings  
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: Concomitant Procedures (All Randomized Subjects)  
Listing 16.2.4.9: Reversibility Test (All Randomized Subjects)  
Listing 16.2.5.1: Background Medication Administration (All Randomized Subjects)
 
Listing 16.2.5.2: Study Drug Administration (All Randomized Subjects)
 
Listing 16.2.5.3: Rescue Medication Administration (All Randomized Subjects)
 
Listing 16.2.5.4: Background Medication Exposure and Compliance (All Randomized Subjects)
 
Listing 16.2.5.5: Study Drug Exposure and Compliance (All Randomized Subjects)
 
Listing 16.2.5.6: Compliance with the use of e-Diary (All Randomized Subjects)  
Listing 16.2.6.1: Spirometry Results (All Randomized Subjects)  
Listing 16.2.6.2: Average Daily PEF Values (Morning and Evening) (All Randomized Subjects)  
Listing 16.2.6.3: Asthma Control Questionnaire – Single Items and Total Score (All Randomized Subjects)  
Listing 16.2.6.4: Rescue Medication Administration — Derived Variables (All Randomized Subjects)  
Listing 16.2.6.5.1: E-RS Questionnaire (All Randomized Subjects)  
Listing 16.2.6.5.2: E-RS Questionnaire - Daily Average Symptom score (All Randomized Subjects) 
Listing 16.2.6.5.3: E-RS Questionnaire - Period Average Symptom score (All Randomized Subjects) 


 
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Listing 16.2.6.5.4: Asthma Symptoms-free Days and Asthma Control Days (All Randomized Subjects) 
Listing 16.2.7.1: Pre-Treatment Adverse Events (All Randomized Subjects)
 
Listing 16.2.7.2: Treatment Emergent Adverse Events (All Randomized Subjects)
 
Listing 16.2.7.3: Serious Treatment Emergent Adverse Events (All Randomized Subjects)
 
Listing 16.2.7.4: Adverse Drug Reactions (All Randomized Subjects)  
Listing 16.2.7.5: Serious Adverse Drug Reactions (All Randomized Subjects)
 
Listing 16.2.7.6: Severe Treatment Emergent Adverse Events (All Randomized Subjects)
 
Listing 16.2.7.7: Treatment Emergent Adverse Events Leading to Study Drug Discontinuation (All Randomized 
Subjects) 
Listing 16.2.7.8: Treatment Emergent Adverse Events Leading to Death (All Randomized Subjects)
 
Listing 16.2.7.9: Post-study Adverse Events (All Randomized Subjects)  
Listing 16.2.8.1: Vital Signs (All Randomized Subjects)
 
Listing 16.2.8.2.1: 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: 12-lead ECG Investigator’s Interpretation (All Randomized Subjects)  
Listing 16.2.8.3.1: Laboratory Results – Hematology (All Randomized Subjects)  
Listing 16.2.8.3.2: Laboratory Results – Biochemistry (All Randomized Subjects)  
Listing 16.2.8.3.3: Laboratory Results – Pregnancy Test (All Randomized Females)  
Listing 16.2.8.3.4: 24-h urinary free Cortisol and Creatinine Results (All Randomized Subjects) 
Listing 16.2.8.4: Abnormal Physical Examination (All Randomized Subjects)
 
Listing 16.2.9: Comments (All Randomized Subjects)  
CSR Section Figure 14: 
Figure 14.1.1: Kaplan-Meier Curves for Time to Discontinuation (All Randomized Subject)  
Figure 14.2.1.1.1: Mean Absolute in Pre-dose Morning FEV1 values (ITT Population)  
Figure 14.2.1.1.2: Mean Absolute in Pre-dose Morning FEV1 values (PP Population)  
Figure 14.2.1.2.1: Mean Change from Baseline in Pre-dose Morning FEV1 values (ITT Population)
 
Figure 14.2.1.2.2: Mean Change from Baseline in Pre-dose Morning FEV1 values (PP Population)  
Figure 14.2.2.1.1: Adjusted Mean Change from Baseline in Pre-dose Morning FEV1 values (ITT Population)  
Figure 14.2.2.1.2: Adjusted Mean Change from Baseline in Pre-dose Morning FEV1 values (PP Population)  
Figure 14.2.3: Adjusted Mean Change from Baseline in Pre-dose Morning FVC values (ITT Population)  
Figure 14.2.4: Adjusted Mean Change from Baseline in ACQ-7scores values (ITT Population)  
Figure 14.2.5: Adjusted Mean Change from Baseline in Use of Rescue Medication (ITT Population)
 
Figure 14.2.6: Adjusted Mean Change from Baseline in Percentage of Rescue Medication-free Days (ITT 
Population)  
Figure 14.2.7.1: Adjusted Mean Change from Baseline in Daily Asthma Symptoms Score (morning and evening) 
(ITT Population)  
Figure 14.2.7.2: Adjusted Mean Change from Baseline in Daily Asthma Symptoms Score (ITT Population) 
Figure 14.2.8: Adjusted Mean Change from Baseline in Percentage of Asthma Symptoms-free Days (ITT 
Population)  
Figure 14.2.9: Adjusted Mean Change from Baseline in Percentage of Asthma Control Days (ITT Population)  
Figure 14.2.10.1: Adjusted Mean Change from Baseline in Morning Pre-dose PEF (ITT Population) 
Figure 14.2.10.2: Adjusted Mean Change from Baseline in Evening Pre-dose PEF (ITT Population) 
 
 
 


 
Statistical Analysis Plan 
Clinical Study Code: CCD-05993AA3-01 
Final Version 1.0, 30JAN2019 
 
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SAS Outputs Listings: 
 
Listing 16.1.9.1.1: SAS Output of Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 8 
(ITT population) 
Listing 16.1.9.1.2: SAS Output of Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 8 
(PP population)  
Listing 16.1.9.1.3: SAS Output of Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 8 
(ITT population) –Sensitivity analysis 
Listing 16.1.9.2.1: SAS Output of Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 4 
(ITT Population)  
Listing 16.1.9.2.2: SAS Output of Analysis of Change from Baseline in Pre-dose Morning FEV1 at Week 4 
(PP Population) 
Listing 16.1.9.3: SAS Output of Analysis of Change from Baseline in Pre-dose Morning FVC at Week 4 and 
Week 8 (ITT Population)  
Listing 16.1.9.4: SAS Output of Analysis of Change from Baseline in ACQ-7 score at Week 4 and Week 8 
(ITT Population)  
Listing 16.1.9.5: SAS Output of Analysis of the Average Use of Rescue Medication during Inter-Visit Periods 
and the Entire Treatment Period (ITT Population)  
Listing 16.1.9.6: SAS Output of Analysis of the Percentage of Rescue Medication-free Days during Inter-Visit 
Periods and the Entire Treatment Period (ITT Population)  
Listing 16.1.9.7.1: SAS Output of Analysis the Daily Asthma Symptoms Scores (morning and evening) 
during Inter-Visit Periods and the Entire Treatment Period (ITT Population)  
Listing 16.1.9.7.2: SAS Output of Analysis the Daily Asthma Symptoms Scores during Inter-Visit Periods 
and the Entire Treatment Period (PP Population) 
Listing 16.1.9.8: SAS Output of Analysis of the Percentage of Asthma Symptoms-free Days during Inter-Visit 
Periods and the Entire Treatment Period (ITT Population)  
Listing 16.1.9.9: SAS Output of Analysis of the Percentage of Asthma Control Days during Inter-Visit 
Periods and the Entire Treatment Period (ITT Population)  
Listing 16.1.9.10.1: SAS Output of Analysis of Morning Pre-dose PEF during Inter-Visit Periods and the 
Entire Treatment Period (ITT Population)  
Listing 16.1.9.10.2: SAS Output of Analysis of Evening Pre-dose PEF during Inter-Visit Periods and the 
Entire Treatment Period (ITT Population)