A 12 Week, Randomized, Double-blind, Multicenter, Active Controlled, 2-Arm Parallel Group Study Testing the Superiority of CHF 1535 pMDI 800/24µg Total Daily Dose (Fixed Combination of Extrafine Beclomethasone Dipropionate Plus Formoterol Fumarate) Compared to CHF 718 pMDI 800µg Total Daily Dose (Extrafine Beclomethasone Dipropionate) in Adults With Asthma on Medium or High-Dose Inhaled Corticosteroid
Phase: PHASE3
Conditions: Asthma
Sponsor: Chiesi Farmaceutici S.p.A.

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CLINICAL STUDY PROTOCOL 
STUDY CODE No.: CLI-05993AB8-02
IND No: 153868
A 12 week, randomized, double-blind, multicenter, active controlled, 2-arm parallel group study 
testing the superiority of CHF 1535 pMDI 800/24µg total daily dose (fixed combination of 
extrafine beclomethasone dipropionate plus formoterol fumarate) compared to CHF 718 pMDI 
800µg total daily dose (extrafine beclomethasone dipropionate) in adults with asthma on medium 
or high-dose inhaled corticosteroid.
Version No.: 2.0
Date: 01Jun2023
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, Investigational 
Review Boards, or people participating in the conduct of the study.
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy
NCT05292586

Clinical Study Protocol
Clinical Study Code No.: CLI-05993AB8-02
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IND No.: 153868
Date: 01Jun2023
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PROTOCOL OUTLINE
Study title
A 12 week, randomized, double-blind, multicenter, active controlled, 2-arm 
parallel group study testing the superiority of CHF 1535 pMDI 800/24µg 
total daily dose (fixed combination of extrafine beclomethasone 
dipropionate plus formoterol fumarate) compared to CHF 718 pMDI 800µg 
total daily dose (extrafine beclomethasone dipropionate) in adults with 
asthma on medium or high-dose inhaled corticosteroid.
Sponsor
Chiesi Farmaceutici S.p.A. – Via Palermo 26/A 
43122 Parma – Italy 
Name of the Product
CHF 
1535 
200/6µg 
pressurized 
metered 
dose 
inhaler 
(pMDI) 
(beclomethasone dipropionate [BDP] plus formoterol fumarate [FF])
Centre(s)
Approximately 90 sites
Indication 
Asthma
Study design
Double-blind, randomized, multicenter, 2-arm parallel group study with 
active control group
Study phase
Phase III
Objectives
Primary Objectives 
•
To demonstrate the superiority of CHF 1535 pMDI 800/24µg total daily 
dose (TDD) compared to CHF 718 pMDI 800µg TDD in terms of 
change from baseline in FEV1 AUC0-12h at Week 12. 
Key Secondary Objective 
•
To demonstrate the superiority of CHF 1535 pMDI 800/24µg TDD 
compared to CHF 718 pMDI 800µg TDD in terms of change from 
baseline in peak FEV1 within the first 3 hours post-dose at Week 12.  
Secondary Objectives 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in FEV1 AUC0-12h 
at Week 0.
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in peak FEV1 
within the first 3 hours post-dose at Week 0.
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in trough FEV1 (i.e. 
average of 11.5h and 12h post-dose FEV1 value) at Week 12. 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in pre-dose 
morning FEV1 at Week 4, 8 and 12. 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in average morning 
PEF over 12-week treatment period. 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in average evening 
PEF over 12-week treatment period. 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of FEV1 responders (i.e. change ≥100mL) 
for pre-dose morning FEV1 at Week 4, 8 and 12. 

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•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of FEV1 responders (i.e. change ≥100mL) 
for trough FEV1 at Week 12. 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in terms of Asthma 
Control Questionnaire-7 (ACQ-7) and Asthma Control Questionnaire-5 
(ACQ-5) at Week 12. 
•
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in percentage of 
rescue medication free days and asthma symptom free days over 12-
week treatment period. 
•
To assess the safety and the tolerability of the study drugs.
Treatment duration
A 2-week run-in period on CHF 718 (BDP) pMDI 100µg, followed by a 12-
week double-blind, treatment period.  
Test product 
dose/route/regimen  
CHF 1535 pMDI 200/6µg 
Fixed combination of extrafine BDP 200µg plus FF 6µg (BDP/FF) 
Dose regimen: BDP/FF 200/6µg per actuation, 2 inhalations (puffs) BID, 
total daily dose (TDD) 800/24µg  
Reference product 
dose/route/regimen 
CHF 718 pMDI 100µg 
Beclomethasone dipropionate (BDP) 100µg 
Dose regimen: BDP 100µg per actuation, 4 inhalations (puffs) BID, total 
daily dose (TDD) 800µg  
Number of subjects
A total of about 580 subjects will be randomized according to a 1:1 ratio to 
either CHF 1535 pMDI 800/24µg TDD (290 subjects) or CHF 718 pMDI 
800µg TDD (290 subjects)
Study population
Adult subjects with asthma on medium or high dose inhaled corticosteroids 
(ICS) or on medium dose ICS plus long-acting β2-agonist (LABA)
Inclusion/exclusion criteria
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for 
participation into the study:  
1.
Informed consent: A signed and dated written informed consent 
obtained prior to any study-related procedures.
2.
Sex and age: Male or female aged ≥18 and ≤75 years.
3.
Diagnosis of asthma: A documented history of asthma for at least 1 
year, with onset before age 40
4.
Stable asthma therapy: Use of medium-dose ICS with or without 
a LABA or high-dose ICS alone for 3 months (at a stable dose for at 
least 4 weeks prior to screening).

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Estimated Comparative Total Daily Dosages for US Approved 
Inhaled Corticosteroids
Inhaled Corticosteroid*
Medium 
daily dose
High 
daily 
dose
Beclomethasone dipropionate 
(DPI or pMDI, extrafine particle, 
HFA)
>160-
320µg 
>320-
640µg
Budesonide DPI
>360-
720µg
>720µg
Ciclesonide (pMDI, extrafine 
particle, HFA)
>160-
320µg
>320µg
Fluticasone furoate (DPI)
100µg
200µg
Fluticasone propionate (pMDI, 
standard particle, HFA) *
>220-
440µg
>440µg
Fluticasone propionate (DPI)
>250-
500µg
>500µg
Mometasone furoate (DPI) 
220-440µg
>440µg
Mometasone furoate (pMDI, 
standard particle, HFA)
200-400µg
>400µg
* Note: This is not a table of equivalence. For questions on Inhaled 
corticosteroid + long-acting beta agonist (LABA) dual therapy 
where dose ranges do not fall within table ranges, please contact 
Medical Monitor for guidance. 
(Table adapted from Global Initiative for Asthma (2022) and 
Expert Panel Report 3: Guidelines for the Diagnosis and 
Management of Asthma (2007))
5.
Lung function: Subjects with a pre-bronchodilator FEV1 ≥40% and 
≤85% of predicted, after appropriate washout from bronchodilators, 
at the screening and randomization visits.  In addition, the absolute 
value of the first pre-dose FEV1 at randomization (V2) must be at 
least 80% of the pre-bronchodilator value attained at screening. 
6.
Reversibility post-bronchodilator: Subjects with a positive 
reversibility to bronchodilator at screening, defined as an increase in 
FEV1 > 12% and > 200mL compared to baseline within 30 minutes 
after 4 inhalations of albuterol HFA pMDI 90µg/actuation.
Note for IC#5 and IC#6: In case the reversibility and/or quality 
threshold is not met at screening, the test can be performed once before 
randomization.
7.
Female subjects:
a.
WOCBP fulfilling one of the following criteria: 
i.
WOCBP with fertile male partners: they and/or their 
partner must be willing to use a highly effective 
birth control method from the signing of the 

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informed consent form and until the follow-up 
contact 
or 
ii.
WOCBP 
with 
non-fertile 
male 
partners 
(contraception is not required in this case). 
For the definition of WOCBP and of fertile men and the 
list of highly effective birth control methods, refer to 
Appendix 2. Highly effective contraception should be 
maintained until the follow-up call. Subjects should then 
refer to the pregnancy recommendations and precautions,
related to their asthma treatment prescribed after the 
study drug discontinuation.
Or 
b.
Female subjects of non-childbearing potential defined as 
physiologically incapable of becoming pregnant (i.e. post-
menopausal or permanently sterile as per definitions given 
in Appendix 2). Tubal ligation or partial surgical 
interventions are not acceptable.  If indicated, as per 
investigator’s request, post-menopausal status may be 
confirmed by follicle-stimulating hormone levels (according 
to local laboratory ranges). 
 
8.
Cooperative attitude and ability to demonstrate correct use of the 
pMDI inhalers and eDiary/peak flow meter. 
The following inclusion criteria must be confirmed at the randomization visit 
prior to dosing: 5, 6, 7 and 8. 
Exclusion Criteria 
Any of the following will exclude a subject from participation:
 
1.
Pregnancy or lactation: where pregnancy is defined as the state of 
a female after conception and until termination of the gestation, 
confirmed by a positive pregnancy test (serum and urine pregnancy 
test to be performed at screening visit and urine pregnancy test to be 
performed prior to randomization).
2.
Poor compliance with run-in medication or eDiary completion 
<50% before randomization.
3.
History of “at risk” asthma: History of near-fatal asthma or of a 
past hospitalization for asthma in intensive care unit which, in the 
judgement of the investigator, may place the subject at undue risk. 
4.
Recent asthma exacerbation: Hospitalization, emergency room 
admission or use of systemic corticosteroids for an asthma 
exacerbation in the 4 weeks prior to screening visit or during the 
run-in period.  
5.
Unresolved respiratory tract infection (RTI) in the 4 weeks prior 
to the screening visit or during run-in period. Documented 
coronavirus disease 2019 (COVID-19) diagnosis within the last 8 

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weeks or complications from this disease, which have not resolved 
within 14 days prior to screening.   
6.
Unstable ICS dose during the 4 weeks prior to screening visit, 
including any change in dose, schedule, or formulation. 
7.
Use of systemic corticosteroid medication in the 4 weeks prior to 
screening or slow-release corticosteroids in the 12 weeks before 
screening. 
8.
Respiratory disorders other than asthma: History of a diagnosis 
of cystic fibrosis, bronchiectasis, COPD (as defined by the current 
GOLD Report), alpha-1 antitrypsin deficiency, interstitial lung 
disease, sarcoidosis, pulmonary hypertension, or any other 
significant lung disease which may interfere with study evaluations.
9.
Smoking status: Current smokers or ex-smokers with total 
cumulative exposure equal to or more than 10 pack-years (pack-
years = the number of cigarette packs per day times the number of 
years smoked) or having stopped smoking within one year prior to 
screening visit. 
10. E-cigarette status: Current e-cigarettes users at the time of the 
screening visit or having stopped ≤ 6 months prior to screening 
visit).
11. Cannabis usage: Current use of inhaled or oral cannabis products 
(e.g. marijuana). 
12. Substance abuse: Subjects with a history of alcohol or 
substance/drug abuse within 12 months prior to screening.
13. Cardiovascular diseases: 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.
Note: Subjects with Permanent Atrial Fibrillation (for at least 6 
months) with a resting ventricular rate <100/min, controlled with a 
rate control strategy (i.e., selective β-blocker, calcium channel blocker, 
pacemaker placement, digoxin, or ablation therapy) can be considered 
for the enrollment. 
14. ECG criteria: An abnormal and clinically significant 12-lead 
electrocardiogram (ECG) which may impact the safety of the 
subject according to Investigator’s judgement. In terms of the QTcF, 

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subjects with QTcF >450ms for males or QTcF >470ms for females 
at screening or at randomization visits (criterion not applicable for 
subject with pacemaker or permanent atrial fibrillation).
15. Other medical conditions: Other active severe acute or chronic 
medical or psychiatric condition or laboratory abnormality that may 
increase the risk associated with study participation or study drug 
administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the 
subject inappropriate for entry into this study. 
16. Vaccination: Subjects having received a vaccination within 2 
weeks prior to screening or during the run-in period.
17. Subjects’ wellbeing: Subjects mentally or legally incapacitated, 
including but not limited to subjects who are institutionalized or 
incarcerated.
18. Hypersensitivity: Subjects with known intolerance, 
hypersensitivity or contraindication to treatment with ß2-agonists, 
ICS, or propellant gases/excipients.
19. Surgery: Subjects with major surgery in the 3 months prior to the 
screening visit or planned surgery during the study.
20. Additional treatment: Subjects treated with non-potassium sparing 
diuretics (unless administered as a fixed-dose combination with a 
potassium conserving drug or changed to potassium sparing before 
the screening), non-selective beta-blocking drugs, quinidine, 
quinidine-like anti-arrhythmic, or any medication with a QTc 
prolongation potential or a history of QTc prolongation.
21. Subjects treated with monoamine oxidase inhibitors (MAOIs) and 
tricyclic antidepressants.
22. 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.
23. Subjects who are receiving any therapy that could interfere with the 
study drugs according to investigator’s opinion.
24. Participating in other investigational trial: 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.

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25. Spacer: The need to use a spacer for correct self-administration of 
a pMDI. 
Exclusion criteria # 1, 2, 4, 5, 14 and 16 must be confirmed at the 
randomization visit prior to dosing.
Study plan
A total of 6 clinic visits (V0 to V5) and a follow-up call will be performed 
during the study, as follows: 
•
A pre-screening visit (V0) will be carried out in order to fully explain 
the study to potential subjects, to obtain the written informed consent 
from the subject and to instruct the subject on screening visit procedures 
(such as medication restrictions). Eligible subjects entering the study 
will be instructed to refrain from taking their current asthma medication 
morning dose in addition to rescue medication as well as all non-
permitted medications in accordance with section 5.2 unless absolutely 
necessary prior to the screening visit (V1).
•
A screening visit (V1) will help establish the eligibility of subjects for 
inclusion in the study (including routine hematology and blood 
chemistry, medical history, physical examination, vital signs, a 12-lead 
ECG, spirometry including FEV1 reversibility after albuterol intake, and 
training for the use of inhalers and diary/peak flow meter). 
•
This visit will be followed by a 2-week open-label run-in period, where 
subjects entering the study on ICS/LABA therapy will be switched to a 
similar dose of extrafine BDP as the ICS dose contained in the 
ICS/LABA combination for the full run-in period. Subjects on ICS 
alone will be switched to similar dose of extrafine BDP during the run-
in. 
•
After the run-in period, eligible subjects will be randomized to one of 
the 2 study treatment arms (V2, Day 1). 
•
After the randomization visit (V2), subjects will be assessed after 4, 8 
and 12 weeks of treatment (from V3 to V5) at the clinic. At visit 2 (Week 
0) and visit 5 (Week 12), ACQ-7 will be performed prior to spirometry. 
Spirometry will be performed at -45 min and -15 min pre-dose and at 5 
min, 15 min, 30 min, 1hr, 2hr, 3hr, 6hr, 9hr, 11.5hr and 12hr post-dose. 
Vital signs and 12-lead ECG will be performed pre-dose and at 30 mins, 
1h, 4h, and 12h post-dose. At Visits 3 (Week 4) and 4 (Week 8), only 
pre-dose spirometry will be performed (i.e., no serial spirometry will be 
performed), pre-dose vital signs and 12 lead ECG, as well as ACQ-7 
will be performed. 
•
A safety follow-up phone call will be done by the investigator 1 week 
after V5 or Early Treatment Discontinuation visit to check the status of 
unresolved adverse events (AEs) and to record any new AEs that have 
occurred after the last visit as well as the related concomitant 
medications. 
•
AEs and SAEs will be monitored throughout the study. 
 
The study duration from V0 to V6 will be about 16 weeks. 
The subjects who discontinue study drug should not be considered 
automatically withdrawn from the study (except if the reason is consent 
withdrawal or lost to follow up). These subjects will be encouraged to remain 

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in the study and complete all remaining protocol-specified visits (while off 
study drug) to assess lung function, adverse events, serious adverse events 
(SAEs) and concomitant medications post investigational treatment.
Most relevant allowed 
concomitant treatments
The following medications are allowed during the study (run-in and 
randomization periods):
1.
Inhaled short-acting β2-agonist, SABA, (albuterol) as rescue 
medication.  A minimum of 6 hours should elapse between the use 
of rescue albuterol and the start of spirometric measurements, 
otherwise visits must be postponed. 
2.
Other asthma treatments (e.g., leukotriene modifiers, theophylline) 
if already taken at stable doses for at least 2 months prior to screening 
visit (the dose must remain constant for the entire study period).
3.
Nasal corticosteroids and antihistamines for the treatment of hay-
fever during the randomized treatment-period.
4.
Treatment for allergic 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 entire study period).
5.
One short course (<10 days) of oral/parenteral corticosteroid and/or 
brief use of short-acting β2-agonists, and/or ipratropium (via 
nebulizer or inhaler) and/or steroids (via nebulizer), for asthma 
exacerbation during the randomized treatment-period. 
In the case of a concomitant disease, appropriate treatment will be permitted 
if it does not interfere with the study drugs or the study evaluation parameters 
and does not qualify under the section “non permitted medications”.
Most relevant forbidden 
concomitant treatments
The following medications are not permitted during the study (run-in and 
randomized treatment periods). Intake of such a drug during run-in 
constitutes a screening failure and the subject will not be randomized into the 
study. If any of these medications are taken during the treatment period, the 
subject will be carefully evaluated by the Investigator if they may continue 
taking the study drug or not, but they may remain in the study.

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1.
Inhaled corticosteroids other than the study drugs
2.
Inhaled LABAs 
3.
Inhaled 
fixed 
combinations 
ICS/LABAs 
(e.g., 
fluticasone 
propionate/salmeterol, budesonide/formoterol other than the study 
drugs
4.
Oral β2-agonists
5.
Oral/parenteral corticosteroids (except to treat an asthma 
exacerbation as described above)
6.
Tricyclic antidepressants and Monoamine oxidase inhibitors 
(MAOIs)
7.
Long-acting anticholinergics and short-acting anticholinergics (with 
the exception of a short course of nebulized or inhaled ipratropium 
to treat an asthma exacerbation as described above) 
8.
Non-selective β-blocking drugs (including eye drops)
9.
Non-potassium sparing diuretics
10. Quinidine, quinidine-like anti-arrhythmic, or any medication with 
potential to prolong the QTc
11. Any biologic therapy for asthma (e.g., omalizumab, mepolizumab, 
reslizumab, benralizumab, dupilumab, tezepelumab) 
12. Any medication that could interact with the study drug, according to 
Investigator’s judgement
Efficacy variables
Primary Variable

Change from baseline in FEV1 AUC0-12h at Week 12.  
Key-Secondary Variable 

Change from baseline in peak FEV1 within the first 3 hours post 
dosing at Week 12.  
Secondary Variables 

Change from baseline in FEV1 AUC0-12h at Week 0.

Change from baseline in peak FEV1 within the first 3 hours post 
dosing at Week 0.

Change from baseline in trough FEV1 at Week 12. 

Change from baseline in pre-dose morning FEV1 at Week 4, 8 and 
12. 

Change from baseline in average morning PEF measured by subjects 
at home over the 12-week treatment period. 

Change from baseline in average evening PEF measured by subjects 
at home over the 12-week treatment period. 

Proportion of subjects classified as responder (change from baseline 
≥100mL) in pre-dose morning FEV1 at Week 4, 8 and 12. 

Proportion of subjects classified as responder (change from baseline 
≥100mL) in trough FEV1 at Week 12. 

Change from baseline in ACQ-7 and ACQ-5 score at Week 12. 

Change from baseline in percentage of rescue medication free days 
over 12-week treatment period. 

Change from baseline in percentage of asthma symptom free days 
over 12-week treatment period.

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Safety variables

Adverse Events (AEs), Adverse Drug Reactions (ADRs) and Class 
related Adverse Events. 

Vital signs (systolic and DBP). 

12-lead ECG parameters: HR, QTcF, PR and QRS. 

Standard hematology and blood chemistry.
Sample size calculation
Sample Size 
The sample size has been calculated to demonstrate the superiority of CHF 
1535 pMDI 800/24µg TDD over CHF 718 pMDI 800µg TDD in terms of 
the primary and key secondary endpoint. 
A discontinuation rate from the randomized study drug of approximately 
10% at Week 12 has been considered. 
A total of 580 subjects will be randomized according to a 1:1 ratio to either 
CHF 1535 pMDI 800/24µg TDD or CHF 718 pMDI 800µg TDD (i.e., 290 
subjects per group). This sample size will provide, using the main estimand:

Approximately 89% power to detect a mean difference of 108mL in 
favor of CHF 1535 pMDI 800/24µg TDD on change from baseline 
in FEV1 AUC0-12h at Week 12 at a two-sided significance level of 
0.05, assuming a SD of 409mL. The assumed mean difference of 
108mL represents a weighted average between two means: a mean 
difference between groups of 120mL while on treatment (assuming 
90% of the randomized subjects) and a mean difference between 
groups of 0mL while off-treatment (assuming 10% of the 
randomized subjects).

Approximately 90% power to detect a mean difference of 117mL in 
favor of CHF 1535 pMDI 800/24µg TDD on change from baseline 
in peak FEV1 within the first 3 hours post dose at Week 12 at a two-
sided significance level of 0.05, assuming a SD of 434mL. The 
assumed mean difference of 117mL represents a weighted average 
between two means: a mean difference between groups of 130mL 
while on treatment (assuming 90% of the randomized subjects) and 
a mean difference between groups of 0mL while off treatment 
(assuming 10% of the randomized subjects).
Thus, considering the main estimand analysis, an overall study power of at 
least 80% for the primary and the key-secondary efficacy endpoint will be 
ensured.
Statistical methods
Analysis Sets 
The following analysis sets will be considered: 

Safety set: all randomized subjects who receive at least one dose of 
study drug (analyzed as treated).

ITT set: all randomized subjects who receive at least one dose of the 
study drug (analyzed as randomized).

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Primary efficacy variable
Main Estimand
Population: Subjects with asthma.
Treatment: Randomized study drug (CHF 1535 pMDI 800/24µg TDD or 
CHF 718 pMDI 800µg TDD) including rescue medication and any other 
asthma treatments that may be administered during the study.
Variable: Change from baseline in FEV1 AUC0-12h at Week 12.
Population-level summary: Adjusted between treatment difference 
comparing CHF 1535 pMDI 800/24µg TDD vs. CHF 718 pMDI 800µg 
TDD.
Strategy for intercurrent events and events leading to missing data:

Early discontinuation from the randomized study drug: Data 
collected after discontinuation from the randomized study drug (i.e. 
off-treatment data) will be included in the analysis (i.e. targeting a 
treatment policy strategy).

Early discontinuation from the study: The collected off-treatment 
data observed on all subjects will be used for the imputation of 
missing data after study discontinuation for both treatment arms [1]. 
Note: In case of collection of very few off-treatment data such that the 
planned imputation cannot be performed, the imputation of missing data 
after study discontinuation will be based on the Copy Reference (CR) 
approach (i.e. considering the data distribution of the CHF 718 pMDI 800µg 
TDD arm, including both on-treatment and off-treatment data) for both 
treatment arms.

Use of not allowed medications and other important protocol 
deviations: Data will be used regardless of whether or not the 
intercurrent event occurs (i.e. targeting a treatment policy strategy).

Wrong study drug intake: If a subject takes the wrong study drug, the 
data will be analyzed as if the intercurrent event had not occurred, 
thus considering the randomized study drug (i.e. targeting a 
treatment policy strategy).
Sensitivity analyses – Strategy for intercurrent events and events leading to 
missing data:

Early discontinuation from the study: A two-dimensional tipping 
point analysis varying assumptions about the missing outcomes in 
the two treatment arms will be performed to explore the plausibility 

Clinical Study Protocol
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of missing data assumptions under which the conclusions change 
(i.e. under which treatment effect is no longer statistically 
significant).
Analysis
Change from baseline in FEV1 AUC0-12h at Week 12 will be analyzed on the 
ITT set using an ANCOVA model including treatment, US region and prior 
asthma therapy as fixed effects and baseline (i.e. pre-dose FEV1 at Week 0) 
value as covariate. The adjusted means in each treatment group, the adjusted 
mean difference between treatments and their 95% CIs at Week 12 will be 
estimated by the model. Superiority of CHF 1535 pMDI 800/24µg TDD will 
demonstrated by a statistically significant difference between treatments at 
Week 12 (defined as p<0.05) favoring CHF 1535 pMDI 800/24µg TDD.
Key-secondary efficacy variable
Main Estimand
Population: Subjects with asthma.
Treatment: Randomized study drug (CHF 1535 pMDI 800/24µg TDD or 
CHF 718 pMDI 800µg TDD) including rescue medication and any other 
asthma treatments that may be administered during the study.
Variable: Change from baseline in peak FEV1 within the first 3 hours post-
dose at Week 12.
Population-level summary: Adjusted between treatment difference 
comparing CHF 1535 pMDI 800/24µg TDD vs. CHF 718 pMDI 800µg 
TDD.
Strategy for intercurrent events and events leading to missing data:

Early discontinuation from the randomized study drug: Data 
collected after discontinuation from the randomized study drug (i.e. 
off-treatment data) will be included in the analysis (i.e. targeting a 
treatment policy strategy).

Early discontinuation from the study: The collected off-treatment 
data observed on all subjects will be used for the imputation of 
missing data after study discontinuation for both treatment arms [1]. 
Note: In case of collection of very few off-treatment data such that the 
planned imputation cannot be performed, the imputation of missing data 
after study discontinuation will be based on the Copy Reference (CR) 
approach (i.e. considering the data distribution of the CHF 718 pMDI 800µg 
TDD arm, including both on-treatment and off-treatment data) for both 
treatment arms.

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
Use of not allowed medications and other important protocol 
deviations: Data will be used regardless of whether or not the 
intercurrent event occurs (i.e. targeting a treatment policy strategy).

Wrong study drug intake: If a subject takes the wrong study drug, the 
data will be analyzed as if the intercurrent event had not occurred, 
thus considering the randomized study drug (i.e. targeting a 
treatment policy strategy).
Sensitivity analyses – Strategy for intercurrent events and events leading to 
missing data:

Early discontinuation from the study: A two-dimensional tipping 
point analysis varying assumptions about the missing outcomes in 
the two treatment arms will be performed to explore the plausibility 
of missing data assumptions under which the conclusions change 
(i.e. under which treatment effect is no longer statistically 
significant).
Analysis
Change from baseline in peak FEV1 within the first 3 hours post-dose at 
Week 12 will be analyzed on the ITT set using an ANCOVA model 
including treatment,  US region and prior asthma therapy as fixed effects 
and baseline (i.e. pre-dose FEV1 at Week 0) value as covariate. The adjusted 
means in each treatment group, the adjusted mean difference between 
treatments and their 95% CIs at Week 12 will be estimated by the model. 
Superiority of CHF 1535 pMDI 800/24µg TDD will demonstrated by a 
statistically significant difference between treatments at Week 12 (defined 
as p<0.05) favoring CHF 1535 pMDI 800/24µg TDD.
Control Type 1 Error 
The primary and key-secondary efficacy variables will be tested following a 
hierarchical strategy to control the familywise type I error rate. Any p-values 
generated at each step will be considered exploratory in nature if at least one 
of the preceding steps in the hierarchy is not successful. The hierarchy for 
the primary and key secondary efficacy analyses is as follows:

Step 1: Change from baseline in FEV1 AUC0-12h at Week 12 using 
the main estimand.

Step 2: Change from baseline in peak FEV1 within 3 hours post dose 
at Week 12 using the main estimand.
Secondary efficacy and safety variables

Analyses of secondary efficacy variables are planned to target the 
same estimand as described for the primary and key-secondary 
efficacy variables in sections 12.3.4 and 12.3.5 (i.e. with collected 

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off-treatment data included in the analysis and used to impute 
possible missing off-treatment data).

Safety analysis will be based on Safety set. For subjects who 
discontinue the study drug but remain in the study, assessments 
conducted following 1 week after the last dose of study drug will not 
be considered in the analysis or presentation of safety data.
Details for the analysis of secondary efficacy and safety variables are 
defined in the Section 12 of protocol.

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ACQ
Asthma Control Questionnaire
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical Classification
AUC
Area Under the Curve
β-HCG
Beta Human Chorionic Gonadotropin
B17MP
Beclomethasone 17-Monoproprionate
BDP
Beclomethasone Diproponate
BID
Twice a Day
BTPS
Body Temperature, Pressure, Saturated with Water Vapor 
BUN
Blood Urea Nitrogen
CFC
Chlorofluorocarbon 
CFR
Code of Federal Regulations
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Coronavirus Disease 2019
CPK
Creatine Phosphokinase
CR
Copy Reference
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
DPB
Diastolic Blood Pressure
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
eDiary
Electronic Diary
ER
Emergency Room
ET
Early Termination
ETD
Early Treatment Discontinuation
EU
European Union
FDA
Food and Drug Administration
FDC
Fixed Dose Combination
FEV1
First Forced Expiratory Volume
FF
Formoterol Fumarate
FSH
Follicle Stimulating Hormone
FU
Follow-up
FVC
Forced Vital Capacity
GB
Glycopyrronium Bromide
GCP
Good Clinical Practices
GGT
Gamma-Glutamyl Transpeptidase
GMP
Good Manufacturing Practices
Hb
Hemoglobin
Hct
Hematocrit
HFA
Hydrofluoroalkane
HR
Heart Rate
ICF
Informed Consent Form

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ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroid
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISO
International Organization for Standardization
ITT
Intention to Treat
LABA
Long Acting β2-adrenergic receptor Agonist
LAMA
Long Acting Muscarinic Antagonist
LSLV
Last Subject Last Visit
MAOIs
Monoamine Oxidase Inhibitors
MART
Maintenance and Reliever Therapy
MedDRA
Medical Dictionary for Regulatory Activities
MMAD
Mass Median Aerodynamic Diameter
MMRM
Mixed Model for Repeated Measured
NDA
New Drug Application
NYHA
New York Heart Association 
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PLT
Platelet Count
pMDI
Pressurized Metered Dose Inhaler
PT
Preferred Term
QTc
QT Corrected for Heart Rate
QTcF
Corrected QT Interval by Fridericia
R&D
Research and Development
RBC
Red Blood Cells Count
RR
Respiratory Rate
RTI
Respiratory Tract Infection
SABA
Short Acting β2-adrenergic receptor Agonist
SAE
Serious Adverse Event
SAMA
Short Acting Muscarinic Antagonist
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SBP
Systolic Blood Pressure
SD
Standard Deviation
SITT
Single Inhaler Triple Therapy
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
TDD
Total Daily Dose
TEAE
Treatment Emergent Adverse Event
TLC
Total Lung Capacity
US
United States 
WBC
White Blood Cell Count
WOCBP
Women of Childbearing Potential

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TABLE OF CONTENTS
GENERAL INFORMATION..................................................................................................2
PROTOCOL OUTLINE ..........................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS........................................17
TABLE OF CONTENTS .......................................................................................................19
1.
INTRODUCTION...........................................................................................................22
1.1 BACKGROUND INFORMATION AND STUDY RATIONALE....................................................22
1.2 STUDY RATIONALE ..........................................................................................................23
1.3 RISK/BENEFIT ASSESSMENT.............................................................................................24
2.
STUDY OBJECTIVES...................................................................................................26
2.1 PRIMARY OBJECTIVE........................................................................................................26
2.2 KEY-SECONDARY OBJECTIVE ..........................................................................................27
2.3 SECONDARY OBJECTIVES.................................................................................................27
3.
STUDY DESIGN.............................................................................................................28
4.
SUBJECT SELECTION CRITERIA ...........................................................................29
4.1 SUBJECT RECRUITMENT...................................................................................................29
4.2 INCLUSION CRITERIA .......................................................................................................30
4.3 EXCLUSION CRITERIA ......................................................................................................31
4.4 DISCONTINUATION FROM STUDY DRUG............................................................................34
4.5 STUDY DISCONTINUATION ...............................................................................................36
5.
CONCOMITANT MEDICATIONS.............................................................................37
5.1 PERMITTED CONCOMITANT MEDICATIONS.......................................................................37
5.2 NON-PERMITTED CONCOMITANT MEDICATIONS..............................................................37
6.
TREATMENT(S)............................................................................................................38
6.1 APPEARANCE AND CONTENT............................................................................................38
6.2 DOSAGE AND ADMINISTRATION.......................................................................................39
6.2.1 Selection of doses in the study .................................................................................39
6.2.2 Dosage .....................................................................................................................39
6.2.3 Administration..........................................................................................................40
6.2.4 Subject Training.......................................................................................................42
6.3 PACKAGING......................................................................................................................42
6.3.1 Treatment Kits (Blinded)..........................................................................................42
6.3.2 Run-In Kit.................................................................................................................43
6.3.3 Training Kit..............................................................................................................43
6.4 LABELING ........................................................................................................................43
6.5 TREATMENT ALLOCATION................................................................................................43
6.6 TREATMENT CODE...........................................................................................................44
6.7 EMERGENCY UNBLINDING ...............................................................................................44
6.8 STUDY DRUG COMPLIANCE .............................................................................................44
6.9 DRUG STORAGE ...............................................................................................................45
6.10 DRUG ACCOUNTABILITY................................................................................................46
6.11 PROVISION OF ADDITIONAL CARE..................................................................................46

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7.
STUDY PLAN.................................................................................................................47
7.1 STUDY SCHEDULE............................................................................................................47
7.1.1 Visit 0 - Pre-screening visit......................................................................................48
7.1.2 Visit 1- Screening Visit (Week -2)............................................................................48
7.1.3 Visit 2 – Randomization Visit (Week 0), Serial Spirometry Visit.............................51
7.1.4 Visit 3 - (Week 4) and Visit 4 (Week 8)....................................................................53
7.1.5 Visit 5 – (Week 12) End of Treatment......................................................................55
7.1.6 Visit 6 - Follow-up Safety Visit................................................................................56
7.1.7 Early Termination Visit from Study.........................................................................56
7.1.8 Early Discontinuation Visit from Study Drug..........................................................57
7.2 STUDY ASSESSMENTS AND PROCEDURES.......................................................................58
7.2.1
Asthma Control Questionnaire (ACQ-7) ..............................................................58
7.2.2
Vital signs..............................................................................................................58
7.2.3
12-lead ECG .........................................................................................................59
7.2.4
Physical Examination (Visit 1 and Visit 5)...........................................................59
7.2.5
Serum and Urine Pregnancy Tests .......................................................................60
7.2.6
Blood Hematology and Chemistry........................................................................60
7.2.7
Daily PEF measurements with Electronic Peak Flow Meter...............................61
7.2.8
Electronic Diary (eDiary).....................................................................................62
7.2.9
Asthma exacerbations during the treatment period..............................................63
7.2.10
Spirometry.........................................................................................................65
7.2.11
Rescue medication ............................................................................................66
8.
EFFICACY ASSESSMENTS ........................................................................................66
9.
SAFETY ASSESSMENTS.............................................................................................67
9.2..........................................................................................................................................67
9.3..........................................................................................................................................67
9.1 SAFETY VARIABLES.......................................................................................................67
9.2 COVID-19 INFECTION...................................................................................................68
10.
ADVERSE EVENT REPORTING ...........................................................................68
10.1 DEFINITIONS ..................................................................................................................68
10.2 EXPECTEDNESS ..............................................................................................................70
10.3 INTENSITY OF ADVERSE EVENT .....................................................................................70
10.4 CAUSALITY ASSESSMENT...............................................................................................70
10.5 ACTION TAKEN WITH THE STUDY DRUG DUE TO AN AE..................................................71
10.6 OTHER ACTIONS TAKEN..................................................................................................71
10.7 OUTCOME ......................................................................................................................71
10.8 RECORDING ADVERSE EVENTS ......................................................................................71
10.9 REPORTING SERIOUS ADVERSE EVENTS TO CHIESI........................................................72
10.10 REPORTING SERIOUS ADVERSE EVENTS TO REGULATORY AUTHORITIES AND IRBS ...73
10.11 GENERAL NOTES..........................................................................................................73
11.
DATA MANAGEMENT............................................................................................74
12.
STATISTICAL METHODS ......................................................................................75
12.1 SAMPLE SIZE..................................................................................................................75
12.2 POPULATIONS FOR ANALYSIS .........................................................................................76

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12.3 STATISTICAL ANALYSIS..................................................................................................76
12.3.1 Descriptive Statistics..............................................................................................76
12.3.2 Missing data...........................................................................................................76
12.3.3 Subject demographics and baseline characteristics..............................................77
12.3.4 Primary efficacy variables.....................................................................................77
12.3.5 Key-Secondary efficacy variable ...........................................................................79
12.3.6 Secondary efficacy variable...................................................................................79
12.3.7 Safety variables......................................................................................................81
12.3.8 Interim analysis......................................................................................................84
13.
INSTITUTIONAL REVIEW BOARD APPROVAL..............................................84
14.
REGULATORY REQUIREMENTS........................................................................84
15.
INFORMED CONSENT............................................................................................85
16.
SOURCE DOCUMENTS/DATA ..............................................................................85
16.1 RECORDING OF SOURCE DATA........................................................................................85
16.2 DIRECT ACCESS TO SOURCE DOCUMENT/DATA...............................................................86
17.
STUDY MONITORING ............................................................................................86
18.
QUALITY ASSURANCE ..........................................................................................86
19.
INSURANCE AND INDEMNITY ............................................................................87
20.
CONFIDENTIALITY ................................................................................................87
21.
PREMATURE TERMINATION OF THE STUDY................................................87
22.
CLINICAL STUDY REPORT ..................................................................................87
23.
RECORD RETENTION ............................................................................................87
24.
PUBLICATION OF RESULTS.................................................................................88
25.
REFERENCES............................................................................................................89
APPENDIX 1 - APPROVAL OF THE PROTOCOL BY CLINICAL 
INVESTIGATOR(S)...............................................................................................................92
APPENDIX 2 – RECOMMENDATIONS RELATED TO CONTRACEPTION AND 
PREGNANCY TESTING IN CLINICAL TRIALS............................................................93

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1.
INTRODUCTION
1.1 Background Information and Study Rationale
Asthma is a chronic inflammatory disease of the airways characterized by heterogeneity in 
terms of phenotype and underlying mechanism(s) [2], [3]. Airway remodeling is also a cardinal 
histologic feature of asthma [3].  The clinical presentation typically includes a history of 
respiratory symptoms such as wheezing, shortness of breath, chest tightness, or cough and 
variable airflow obstruction.  Asthma symptoms can vary over time and in intensity depending 
upon the presence of classic triggers like exercise, environmental/occupational exposures or 
viral respiratory infections [4], [5].  
According to the World Health Organization, asthma affected an estimated 262 million people 
in 2019 and led to 461,000 deaths [6].  It impacts people of all races, ages and both sexes 
although there are ethnic and sex disparities with higher death rates in minority groups and in 
women [7], [8]. 
Current consensus guidelines for asthma management [9] have as a major goal to achieve 
disease control and to minimize future risk of asthma-related mortality, exacerbations, 
persistent airflow limitation and side effects of medications.  Figure 1 shows the step therapy 
for starting treatment in adults and adolescents who carry an asthma diagnosis.  It is apparent 
from the figure that the combination of Inhaled Corticosteroids (ICS) and Long Acting β2-
adrenergic receptor Agonists (LABA) plays an important role in asthma treatment as both 
maintenance and reliever therapy (MART).  Notably, formoterol is the only LABA 
recommended by the 2021 GINA Report as a reliever therapy in combination with an ICS due 
to its proven fast bronchodilator effect.
Despite adherence to ICS/LABA therapy, 30-50% of patients with asthma remain symptomatic 
and poorly controlled [10], [11], [12].  GINA 2021 guidelines recommend triple therapy 
[addition of long-acting muscarinic antagonists (LAMA) to ICS-LABA] for patients ≥18 years 
old at step 5.  Evidence suggests that addition of LAMA therapy to medium or high dose 
ICS/LABA can improve lung function and in some cases, lead to a reduction in exacerbations 
[13], [14]. Single inhaler triple therapy (SITT) is more convenient for patients than taking 
multiple inhalers and can potentially improve adherence [15].  Currently there is only one SITT 
marketed in the United States under the name of Trelegy® Ellipta® (fluticasone 
furoate/umeclidinium/vilanterol), a dry powder inhaler.
In January 2021, Chiesi’s SITT, CHF 5993 with the trade name of Trimbow® [medium strength 
(beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide, BDP/FF/GB 
100/6/12.5mcg) and high strength (BDP/FF/GB 200/6/12.5mcg)] pMDI was approved for the 
asthma indication in the European Union (EU).  Trimbow® is not yet approved for asthma in 
the United States.
A fixed dose combination (FDC) consisting of the ICS BDP at 100µg and LABA FF at 6µg 
(Foster® or CHF 1535) was developed by Chiesi in the same Hydrofluoroalkane (HFA) pMDI 
solution formulation as CHF 5993, with a high extrafine inhaled particle fraction (i.e., mass 
median aerodynamic diameter [MMAD] around 1.1µm) for both active ingredients. CHF 1535 
pMDI was nationally approved in Europe for asthma in 2006.

Clinical Study Protocol
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The FORCE2 study was designed as a pivotal clinical study to demonstrate the added benefit 
of the LABA component (FF) within BDP/FF to serve as a key piece of information to support 
a new drug application (NDA) for the BDP/FF/GB triple combination product for
asthma in the United States.
1.2 Study Rationale
CHF 1535 pMDI is a FDC consisting of the ICS beclomethasone dipropionate (BDP) and the 
LABA formoterol fumarate (FF) developed by Chiesi with a high extrafine inhaled particle 
fraction (i.e. mass median aerodynamic diameter [MMAD] around 1.1 µm) for both active 
ingredients. CHF 1535 pMDI has been approved in Europe first for adults with asthma in 2006 
and then, in 2014 via a Type II variation for adults with COPD under several brand names 
(Foster®, Fostair®). Currently the 100/6 mcg/actuation dose strength pMDI is approved in 77 
countries and the 200/6 mcg/actuation dose strength pMDI in 39 countries. CHF 1535 is not 
FDA-approved for any indication.
At the time of its initial development, CHF 1535 100/6μg was a new HFA134a pMDI 
formulation of known active constituents, BDP and formoterol, which were individually 
marketed as pMDIs (both CFC and HFA) and dry powder inhaler (DPI) products. A clinical 
“bridging” strategy undertaken within the CHF 1535 HFA pMDI 100/6μg clinical development 
program confirmed the suitability of the use of the comparators in the pivotal clinical trials 
CT03 and CT04.  CT03 demonstrated the non-inferiority of CHF 1535 HFA pMDI 100/6μg to 
corresponding equipotent daily doses of the free combination of BDP CFC pMDI plus 
formoterol DPI (as dry powder capsules), the superiority of CHF 1535 HFA pMDI 100/6μg 
over monotherapy with the corresponding equipotent daily dose of BDP CFC pMDI, and the 
safety and tolerability profile of CHF 1535 100/6μg.  CT04 established the superiority of CHF 
1535 HFA pMDI 100/6μg over double the equipotent corresponding daily dose of BDP CFC 
pMDI.

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During the CHF 1535 pMDI product development, two additional late-stage pre-market phase 
III clinical trials in asthma generated data on the comparative efficacy and safety compared to 
other marketed products and supported product reimbursement. In one study, CHF 1535 100/6 
μg 2 puffs bid (total daily dose BDP/FF 400/24μg) was demonstrated to be non-inferior to 
Symbicort® Turbuhaler® DPI (Budesonide/Formoterol Fumarate 640/18µg TDD) based on 
morning pre-dose peak expiratory flow (PEF) rate in adult patients with moderate-to-severe 
asthma without any difference in frequency of AEs [16].  CHF 1535 was also found to be non-
inferior to Seretide® pMDI (Fluticasone Propionate/Salmeterol 500/100µg TDD) in a second 
phase III trial based on changes in lung function measured by morning pre-dose peak expiratory 
flow (PEF) rate in adult patients with moderate-to-severe asthma [17].
The clinical program in support of the high strength CHF 1535 pMDI 200/6μg (developed as 
“step-up” in therapy in those patients not adequately controlled either on high dose ICS 
monotherapy or on moderate doses of ICS within a fixed combination ICS/LABA, with the aim 
to get better asthma control) was based on two single dose PK studies investigating the dose 
proportionality of Beclomethasone 17-Monopropionate (B17MP) total systemic exposure and 
lung bioavailability, respectively, after administration of CHF 1535 at increasing dose strengths 
(BDP/FF 50/6, 100/6 and 200/6μg per actuation) in healthy subjects and on the following two 
clinical studies: 1) A 6-month study demonstrated that CHF 1535 pMDI (BDP/FF 200/6μg per 
actuation, 2 puffs bid), administered at 800/24μg/day, is as safe as fluticasone 500μg + 
salmeterol 50μg/actuation (Seretide®) at 1000/100μg/day in patients with severe asthma [18], 
and 2) a 12-week clinical study that established the superiority of CHF1535 200/6µg 
(800/24µg/day) vs. extrafine BDP (QVAR®, 800µg/day) in terms of the primary lung function 
outcome [19]. Although this data package was acceptable at that time for a European 
registration of the FDC BDP/FF (CHF 1535 pMDI), it does not meet today’s FDA’s 
requirement of FDC product development due to the differences in the devices between 
QVAR® and CHF 1535 pMDI. 
FORCE2 was therefore designed to fulfil the FDA’s regulatory requirement for combination 
product development in order to adequately characterize BDP/FF as an acceptable ICS/LABA 
comparator as used in the pivotal phase III studies with the SITT BDP/FF/GB (CHF 5993 
pMDI) [20].  If the study meets its specified primary and key secondary endpoints, it will 
provide support for the NDA for the BDP/FF/GB triple combination product for asthma in the 
United States.  
1.3 Risk/Benefit Assessment
1.3.1 Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with CHF 1535 
can be found in the Investigator’s Brochure. Several findings were identified as potential risks 
associated with the mono-components of CHF 1535 which will be monitored in the study. 
 
Risk of Oropharyngeal Candidiasis with ICS: Local effects of ICS include oropharyngeal 
candidiasis and assessment for this will be performed on a regular basis at each study visit.  As 
a mitigation strategy, subjects will be instructed to gargle with water and to rinse out their 
mouths each time they use their ICS.

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Risk of Systemic Effects with ICS: Systemic effects such as bone disorders, bone mineral density 
decrease and associated fractures, and cortisol suppression have been described with the use of 
corticosteroids.  Although a decrease in bone mineral density and the risk of fractures is a class 
concern for ICS containing medications, the proposed dose of inhaled BDP in this study is 
considered unlikely to have a clinically significant impact on hypothalamic pituitary axis 
particularly given the short-term nature of the study and the fact that the described systemic 
effects will be monitored during ongoing assessment of AEs and SAEs. In addition, systemic 
ocular effects of corticosteroids, including glaucoma and cataract formation, have been 
described although these effects are much less likely to occur with inhaled corticosteroids 
compared with oral corticosteroids and will be monitored during AE/SAE reviews.
Risk of Cardiovascular Events with LABAs: Cardiovascular events are a documented class
effect associated with LABAs, including FF. The randomized controlled trial, TRIGGER, 
provides extensive long-term safety data to support the safety of FF 24µg TDD when used as a 
component of BDP/FF in subjects with uncontrolled asthma using high dose ICS in 
combination with a LABA [20].  This high range of ICS dose is consistent with other FDA-
approved ICS/LABA combination products for asthma (e.g., DULERA®, SYMBICORT®, 
ADVAIR® DISKUS®, and BREO® ELLIPTA®).  To mitigate potential cardiovascular risks 
associated with FF, subjects with clinically significant cardiovascular disease (as outlined in 
section 4.3, Exclusion Criteria) will be excluded from the study and ECGs and vital sign 
assessments will be performed as per protocol.
1.3.2 Benefit Assessment
A previously completed 12-week, multinational ex-US randomized phase III study with CHF 
1535 demonstrated the clinical benefit of using pMDI BDP/FF 200/6µg (two actuations bid) 
compared to BDP 100μg (QVAR®, four actuation bid) in a population of 376 adult asthmatics 
not adequately controlled with high dose of ICS or medium dose of ICS plus LABA (the 
primary endpoint was improvement in lung function) [19].  BDP/FF and BDP showed a 
comparable safety profile, with no adverse events of clinical concern observed with either 
treatment.  CHF1535 is commercialized as Foster® in more than 50 countries ex-US since it 
launched 15 years ago.
1.3.3 Overall Risk: Benefit Conclusion
Current risks that have been identified for the BDP/FF (200/6μg) combination are based on
the known pharmacology of the individual active components BDP and FF. These include risks 
of oropharyngeal candidiasis, ocular effects and bone disorders/fractures from ICS and the risk 
of adverse cardiovascular effects from LABA. The BDP/FF combination is widely 
commercialized ex-US.  A comprehensive safety monitoring strategy is being proposed for all 
the risks. Given the overall clinical experience with BDP and FF and the fact that that the 
associated risks with these compounds are anticipated from their known pharmacology, the 
risk: benefit ratio of using CHF 1535 in subjects with asthma on medium or high-dose ICS in 
order to provide support for the NDA for the BDP/FF/GB triple combination product for asthma 
seems justified.

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This trial will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments) current ICH E6 Good Clinical Practices and all other applicable laws and 
regulations.
2.
STUDY OBJECTIVES
2.1 Primary Objective
To demonstrate the superiority of CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in FEV1 AUC0-12h at Week 12.
The main estimand associated to the primary objective is defined by the following attributes:
Population
Subjects with asthma. Further details about the population are 
provided in Section 4.
Treatments
Randomized study drug (CHF 1535 pMDI 800/24µg TDD vs. CHF 
718 pMDI 800µg TDD) including rescue medication and any other 
asthma treatments that may be administered during the study.
Variable
Change from baseline in FEV1 AUC0-12h at Week 12.
Early discontinuation from the randomized study drug: Data 
collected after discontinuation from the randomized study drug (i.e. 
off-treatment data) will be included in the analysis (i.e. targeting a 
treatment policy strategy).
Early discontinuation from the study: The collected off-treatment 
data observed on all subjects will be used for the imputation of 
missing data after study discontinuation for both treatment arms [1]. 
Note: In case of collection of very few off-treatment data such that 
the planned imputation cannot be performed, the imputation of 
missing data after study discontinuation will be based on the Copy 
Reference (CR) approach (i.e. considering the data distribution of 
the CHF 718 pMDI 800µg TDD arm, including both on-treatment 
and off-treatment data) for both treatment arms.
Use of not allowed medications and other important protocol 
deviations: Data will be used regardless of whether or not the 
intercurrent event occurs (i.e. targeting a treatment policy strategy).
Strategy for 
intercurrent events 
/ events leading to 
missing data
Wrong study drug intake: If a subject takes the wrong study drug, 
the data will be analyzed as if the intercurrent event had not 
occurred, thus considering the randomized study drug (i.e. targeting 
a treatment policy strategy).
Population-level 
summary
Adjusted treatment difference comparing CHF 1535 pMDI 
800/24µg TDD vs. CHF 718 pMDI 800µg TDD

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2.2 Key-Secondary Objective
To demonstrate the superiority of CHF 1535 pMDI 800/24µg TDD compared to CHF 718 
pMDI 800µg TDD in terms of change from baseline in peak FEV1 within the first 3 hours post-
dose at Week 12.
The main estimand associated to the key-secondary objective is defined by the following 
attributes:
Population
Subjects with asthma. Further details about the population are 
provided in Section 4.
Treatments
Randomized study drug (CHF 1535 pMDI 800/24µg TDD vs. CHF 
718 pMDI 800µg TDD) including rescue medication and any other 
asthma treatments that may be administered during the study.
Variable
Change from baseline in peak FEV1 within the first 3 hours post-
dose at Week 12.
Early discontinuation from the randomized study drug: Data 
collected after discontinuation from the randomized study drug (i.e. 
off-treatment data) will be included in the analysis (i.e. targeting a 
treatment policy strategy).
Early discontinuation from the study: The collected off-treatment 
data observed on all subjects will be used for the imputation of 
missing data after study discontinuation for both treatment arms [1]. 
Note: In case of collection of very few off-treatment data such that 
the planned imputation cannot be performed, the imputation of 
missing data after study discontinuation will be based on the Copy 
Reference (CR) approach (i.e. considering the data distribution of 
the CHF 718 pMDI 800µg TDD arm, including both on-treatment 
and off-treatment data) for both treatment arms.
Use of not allowed medications and other important protocol 
deviations: Data will be used regardless of whether or not the 
intercurrent event occurs (i.e. targeting a treatment policy strategy).
Strategy for 
intercurrent events 
/ events leading to 
missing data
Wrong study drug intake: If a subject takes the wrong study drug, 
the data will be analyzed as if the intercurrent event had not 
occurred, thus considering the randomized study drug (i.e. targeting 
a treatment policy strategy).
Population-level 
summary
Adjusted treatment difference comparing CHF 1535 pMDI 
800/24µg TDD vs. CHF 718 pMDI 800µg TDD
2.3 Secondary Objectives

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in FEV1 AUC0-12h at Week 0.

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
To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in peak FEV1 within the first 3 hours post-dose at 
Week 0.

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in trough FEV1 at Week 12. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in pre-dose morning FEV1 at Week 4, 8 and 12. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in average morning PEF over 12-week treatment 
period. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in average evening PEF over 12-week treatment 
period. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of FEV1 responders (i.e. change ≥100 mL) for pre-dose morning FEV1 at Week 
4, 8 and 12. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of FEV1 responders (i.e. change ≥100 mL) for trough FEV1 at Week 12. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in terms of ACQ-7 and ACQ-5 at Week 12. 

To evaluate CHF 1535 pMDI 800/24µg TDD compared to CHF 718 pMDI 800µg TDD 
in terms of change from baseline in percentage of rescue medication free days and 
asthma symptom free days over 12-week treatment period. 

To assess the safety and the tolerability of the study drugs.
3.
STUDY DESIGN 
This is a phase III, randomized, double-blind, active controlled, 2-arm parallel group study to 
demonstrate the superiority of CHF 1535 pMDI 800/24µg total daily dose (TDD) compared 
to CHF 718 pMDI 800µg in terms of change from baseline in FEV1 AUC0-12 at Week 12.  
Approximately 580 subjects over the age of 18 will be randomized into the study.  
A total of 6 clinic visits (V0- V5) and a follow-up call (V6) will be performed during the 
study as noted in section 7.  
Screened subjects who were on a medium dose ICS or medium dose ICS-LABA prior to the 
study will be put on CHF 718 pMDI 100µg 2 inhalations BID (TDD 400µg) during the 2-
week run in period.  Screened subjects who were on a high dose ICS prior to the study will be 

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put on CHF 718 pMDI 100µg 4 inhalations BID (TDD 800µg) during the 2-week run in 
period.  
Following the run-in period, eligible subjects will be randomized to one of two study drug 
arms (using a 1:1 allocation ratio) for 12 weeks. 
 
The total study duration (V0 to FU call) is approximately 16 weeks for any subject completing 
the trial. 
The start of the trial is defined as the date of first site initiation visit in the trial.
The end of the study trial is defined as the last contact of the last subject in the trial: 
- Last follow-up contact 
- Last study visit if the last subject in the trial is discontinued from the study drug and agrees to 
remain in the study.
4.
SUBJECT SELECTION CRITERIA
4.1 Subject Recruitment
Approximately 580 subjects (290 subjects per group) will be randomized.  Recruitment will 
occur at participating outpatient study centers. 
The end of recruitment will be communicated to study sites by Chiesi (or designee).  
If a subject is screen failed, he/she can be rescreened (at least 1 month from the screen failure 
date) providing the medical conditions of the subject are appropriate with the inclusion in the 

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study according to the investigator judgement and after sponsor approval. The subject should 
sign a new informed consent and will be assigned with a new subject number. 
4.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for participation into the 
study:  
1. Informed consent: A signed and dated written informed consent obtained prior to any 
study-related procedures.
2. Sex and age: Male or female aged ≥18 and ≤75 years.
3. Diagnosis of asthma: A documented history of asthma for at least 1 year, with onset 
before age 40
4. Stable asthma therapy: Use of medium-dose ICS with or without a LABA or high-
dose ICS alone for 3 months (at a stable dose for at least 4 weeks prior to screening).
Estimated Comparative Total Daily Dosages for US Approved Inhaled Corticosteroids 
Inhaled Corticosteroid*
Medium daily dose
High daily dose
Beclomethasone dipropionate (DPI or pMDI, extrafine particle, HFA)
>160-320µg 
>320-640µg
Budesonide DPI
>360-720µg
>720µg
Ciclesonide (pMDI, extrafine particle, HFA)
>160-320µg
>320µg
Fluticasone furoate (DPI)
100µg
200µg
Fluticasone propionate (pMDI, standard particle, HFA) *
>220-440µg
>440µg
Fluticasone propionate (DPI)
>250-500µg
>500µg
Mometasone furoate (DPI) 
220-440µg
>440µg
Mometasone furoate (pMDI, standard particle, HFA)
200-400µg
>400µg
* Note: This is not a table of equivalence. For questions on Inhaled corticosteroid + 
long-acting beta agonist (LABA) dual therapy where dose ranges do not fall within 
table ranges, please contact Medical Monitor for guidance. 
(Table adapted from GINA 2022 and Expert Panel Report 3: Guidelines for the 
Diagnosis and Management of Asthma (2007))
5. Lung function: Subjects with a pre-bronchodilator FEV1 ≥40% and ≤85% of predicted, 
after appropriate washout from bronchodilators, at the screening and randomization 
visits.  In addition, the absolute value of the first pre-dose FEV1 at randomization (V2) 
must be at least 80% of the pre-bronchodilator value attained at screening. 
6. Reversibility post-bronchodilator: Subjects with a positive reversibility to 
bronchodilator at screening, defined as an increase in FEV1 > 12% and > 200mL 
compared to baseline within 30 minutes after 4 inhalations of albuterol HFA pMDI 
90µg/actuation.
Note for IC#5 and IC#6: In case the reversibility and /or quality threshold is not met at 
screening, the test can be performed once before randomization.

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7. Female subjects:
a.
WOCBP fulfilling one of the following criteria: 
i. WOCBP with fertile male partners: they and/or their partner must be 
willing to use a highly effective birth control method from the signing of 
the informed consent form and until the follow-up contact or 
ii. WOCBP with non-fertile male partners (contraception is not required in 
this case). 
For the definition of WOCBP and of fertile men and the list of highly 
effective birth control methods, refer to Appendix 2. Highly effective 
contraception should be maintained until the follow-up call. Subjects should 
then refer to the pregnancy recommendations and precautions,
related to their asthma treatment prescribed after the study drug 
discontinuation.
or 
b. Female subjects of non-childbearing potential defined as physiologically 
incapable of becoming pregnant (i.e. post-menopausal or permanently sterile as 
per definitions given in Appendix 2). Tubal ligation or partial surgical 
interventions are not acceptable.  If indicated, as per investigator’s request, post-
menopausal status may be confirmed by follicle-stimulating hormone levels 
(according to local laboratory ranges). 
 
8. Cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and 
eDiary/Peak Flow Meter. 
The following inclusion criteria must be confirmed at the randomization visit prior to dosing: 
5, 6, 7 and 8. 
4.3 Exclusion Criteria
Any of the following will exclude a subject from participation:
 
1. Pregnancy or lactation: where pregnancy is defined as the state of a female after 
conception and until termination of the gestation, confirmed by a positive pregnancy 
test (serum and urine pregnancy test to be performed at screening visit and urine 
pregnancy test to be performed prior to randomization).
2. Poor compliance with run-in medication or eDiary completion <50% before 
randomization.
3.  History of “at risk” asthma: History of near-fatal asthma or of a past hospitalization 
for asthma in intensive care unit which, in the judgement of the investigator, may place 
the subject at undue risk. 
4. Recent asthma exacerbation: Hospitalization, emergency room admission or use of 
systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening 
visit or during the run-in period.  

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5. Unresolved respiratory tract infection (RTI) in the 4 weeks prior to the screening 
visit or during run-in period. Documented coronavirus disease 2019 (COVID-19) 
diagnosis within the last 8 weeks or complications from this disease, which have not 
resolved within 14 days prior to screening.   
6. Unstable ICS dose during the 4 weeks prior to screening visit, including any change 
in dose, schedule, or formulation. 
7. Use of systemic corticosteroid medication in the 4 weeks prior to screening or slow-
release corticosteroids in the 12 weeks before screening. 
8. Respiratory disorders other than asthma: History of a diagnosis of cystic fibrosis, 
bronchiectasis, COPD (as defined by the current GOLD Report), alpha-1 antitrypsin 
deficiency, interstitial lung disease, sarcoidosis, pulmonary hypertension, or any other 
significant lung disease which may interfere with study evaluations
9. Smoking status: Current smokers or ex-smokers with total cumulative exposure equal 
to or more than 10 pack-years (pack-years = the number of cigarette packs per day times 
the number of years smoked) or having stopped smoking within one year prior to 
screening visit. 
10. E-cigarette status: Current e-cigarettes users at the time of the screening visit or 
having stopped ≤ 6 months prior to screening visit).
11. Cannabis usage: Current use of inhaled or oral cannabis products (e.g. marijuana). 
12. Substance abuse: Subjects with a history of alcohol or substance/drug abuse within 12 
months prior to screening.
13. Cardiovascular diseases: 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.
Note: Subjects with Permanent Atrial Fibrillation (for at least 6 months) with a resting 
ventricular rate <100/min, controlled with a rate control strategy (i.e., selective β-blocker, 
calcium channel blocker, pacemaker placement, digoxin, or ablation therapy) can be 
considered for the enrollment. 
14. ECG criteria: An abnormal and clinically significant 12-lead electrocardiogram 
(ECG) which may impact the safety of the subject according to Investigator’s 
judgement. In terms of the QTcF, subjects with QTcF >450ms for males or QTcF 

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>470ms for females at screening or at randomization visits (criterion not applicable for 
subject with pacemaker or permanent atrial fibrillation).
15. Other medical conditions: Other active severe acute or chronic medical or psychiatric 
condition or laboratory abnormality that may increase the risk associated with study 
participation or study drug administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study. 
16. Vaccination: Subjects having received a vaccination within 2 weeks prior to screening 
or during the run-in period.
17. Subjects’ wellbeing: Subjects mentally or legally incapacitated, including but not 
limited to subjects who are institutionalized or incarcerated.
18. Hypersensitivity: Subjects with known intolerance, hypersensitivity or 
contraindication to treatment with ß2-agonists, ICS, or propellant gases/excipients.
19. Surgery: Subjects with major surgery in the 3 months prior to the screening visit or 
planned surgery during the study.
20. Additional treatment: Subjects treated with non-potassium sparing diuretics (unless 
administered as a fixed-dose combination with a potassium conserving drug or changed 
to potassium sparing before the screening), non-selective beta-blocking drugs, 
quinidine, quinidine-like anti-arrhythmic, or any medication with a QTc prolongation 
potential or a history of QTc prolongation.
21. Subjects treated with monoamine oxidase inhibitors (MAOIs) and tricyclic 
antidepressants.
22. 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.
23. Subjects who are receiving any therapy that could interfere with the study drugs 
according to investigator’s opinion.
24. Participating in other investigational trial: 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.
25. Spacer: The need to use a spacer for correct self-administration of a pMDI. 

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Exclusion criteria # 1, 2, 4, 5, 14 and 16 must be confirmed at the randomization visit prior to 
dosing.
4.4 Discontinuation from study drug
A subject who discontinues study drug should not be considered automatically withdrawn 
from the study (except if the reason is consent withdrawal or lost to follow up). The 
investigator and study staff must discuss with the subject who will be asked to continue 
attending the remaining study visits while off study drug.
Protocol Defined Criteria for Discontinuation from Study Drug:
Occurrence or initiation of an adverse event, non-permitted concomitant medication, 
pregnancy, premature unblinding or other event at the investigator’s discretion, for which 
remaining on study drug would create a safety risk for the subject. Any of the criteria listed in 
protocol section 4.5 may lead to discontinuation from study drug.
In accordance with ICH E9-R1 and corresponding guidance from regulatory agencies 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 drug, all efforts will be made to complete the 
study procedures per protocol and report the observations as thoroughly as possible.
It will be the Investigator’s judgement to withdraw the subject from the study drug if he/she 
deems it will place the subject at undue risk by continuing his/her participation.

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Actions following Permanent Discontinuation from Study Drug:
The investigator is responsible for assessing the optimal treatment prescription for each study 
subject after the study drug discontinuation. The post study drug asthma medications should be 
recorded in the eCRF.
The investigator/designee must register the subject’s Early Study Drug Discontinuation in 
the IRT (Interactive Response Technology) system. The Investigator/designee must report in 
the eCRF the main reason for Early treatment discontinuation.   
The follow-up call must be done one week after the Early Study Drug Discontinuation Visit, 
except for the subject who withdraws consent or is lost to follow-up.
Subject who consents to data collection till the planned V5 visit will continue attending study 
visits according to the study visit schedule. Before each visit, the wash-out periods for 

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concomitant medications detailed in section 5.2 must be respected. The following assessments 
will be performed: 

Spirometry (pre/post of the subject’s maintenance inhaled therapy for asthma, 
including the serial spirometry when planned by the study protocol).

The subject should continue to complete eDiary data (except for the study drug 
questions) and to measure PEF at home.

The investigator (or designee) will check the concomitant medications and adverse 
events that occurred since last visit.

Urine or serum pregnancy tests in all women of childbearing potential.

Questionnaires- subjects will complete the ACQ-7 questionnaire (section 7.2.1).
4.5 Study Discontinuation
Subject must be discontinued from the study for any of the following reasons:

The subject is lost to follow-up

The subject withdraws consent  

The subject experiences an adverse event which makes participation in the study not 
possible

Chiesi or the regulatory authorities or the Institutional Review Board(s),  for any 
reason, terminates the entire study, or terminates the study for this trial site or this 
particular subject. 

The subject is unwilling or unable to adhere to the study requirements, i.e. non-
compliance. 
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. Every effort 
will be made to retain the subject in the study.
The investigator must document the reason (if specified by the subject) for withdrawal of 
consent in the eCRF. Subjects who wish to withdraw from further participation in the study 
should be encouraged to return to the clinic as soon as possible to complete the Early 
Termination Visit and to complete the follow-up phone call in order to collect important safety 
information. If a subject is lost to follow-up or withdraws consent no further information will 
be collected.
If a subject is withdrawn/dropped-out of the study, the subject number should not be reassigned 
to another subject.  
The investigator is responsible for the optimal individual treatment prescription after the study 
discontinuation. The post study drug asthma medications should be recorded in the eCRF.

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5.
CONCOMITANT MEDICATIONS
5.1 Permitted concomitant Medications
The following medications are allowed during the study (run-in and randomization periods):
1. Inhaled Short-acting β2-agonist, SABA, (albuterol) as rescue medication.  A 
minimum of 6 hours should elapse between the use of rescue albuterol and the start 
of spirometric measurements, otherwise the visit must be postponed. 
2. Other asthma treatments (e.g., leukotriene modifiers, theophylline) if already taken 
at stable doses for at least 2 months prior to screening visit (the dose must remain 
constant for the entire study period).
3. Nasal corticosteroids and antihistamines for the treatment of hay-fever during the 
randomized treatment-period.
4. Treatment for allergic 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 entire study period).
5. One short course (<10 days) of oral/parenteral corticosteroid and/or brief use of 
short-acting β2-agonists, and/or ipratropium (via nebulizer or inhaler) and/or 
steroids (via nebulizer), for asthma exacerbation during the randomized treatment-
period. 
In the case of a concomitant disease, appropriate treatment will be permitted if it does not 
interfere with the study drugs or the study evaluation parameters and does not qualify under the 
section "non permitted medications".
5.2 Non-permitted Concomitant Medications
The following medications are not permitted during the study (run-in and randomized treatment 
periods). Intake of such a drug during run-in constitutes a screening failure and the subject will 
not be randomized into the study. If any of these medications are taken during the randomized 
treatment period, the subject will be carefully evaluated by the Investigator to determine if they 
may continue taking the study drug or not, but they may remain in the study.  
1. Inhaled corticosteroids other than the study drugs.
2. Inhaled LABAs. 
3. Inhaled fixed combinations ICS/LABAs (e.g., fluticasone propionate/salmeterol, 
budesonide/formoterol) other than the study drugs
4. Oral β-2-agonists.
5. Oral/parenteral corticosteroids (except to treat an asthma exacerbation as described 
above).
6. Tricyclic antidepressants and Monoamine oxidase inhibitors (MAOIs), 
7. Long-acting anticholinergics and short-acting anticholinergics (with the exception of a 
short course of nebulized or inhaled ipratropium to treat an asthma exacerbation as 
described above)      
8. Non-selective β-blocking drugs (including eye drops).
9. Non-potassium sparing diuretics.

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10. Quinidine, quinidine-like anti-arrhythmics, or any medication with potential to prolong 
the QTc.
11. Any biologic therapy for asthma (e.g., omalizumab, mepolizumab, reslizumab, 
benralizumab, dupilumab, tezepelumab) 
12. Any medication that could interact with the study drug, according to Investigator’s 
judgement.
Prior to screening spirometry at Visit 1 the following wash-out intervals for concomitant 
medications must be respected: 
Medication
No use within the following time 
intervals prior to Screening
Inhaled/nebulized short-acting β2-agonists
6 hours
Inhaled/nebulized short acting muscarinic antagonists
12 hours
Inhaled/nebulized SABA/SAMA fixed combinations
12 hours
Caffeinated substances
6 hours
During the treatment period, the following wash-out intervals for concomitant medications 
must be respected prior to spirometry: 
Medication
No use within the following time 
intervals prior to Spirometry
Inhaled and/or nebulized short-acting β2-agonists
6 hours
Caffeinated substances
6 hours
6.
TREATMENT(S)
The study drugs (randomized treatment, training medication and run-in medication) will be 
supplied to the clinical site under the responsibility of the Chiesi, who will also provide the 
pharmacist/investigator with appropriate certificates of analytical conformity.
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.
6.1 Appearance and Content
Both Test Treatments are administered via double-blinded pMDIs while Training and Run-in 
are administered via open label pMDIs.

CHF 1535 pMDI 200/6µg (Test product_Treatment A)
Active ingredients
Beclomethasone dipropionate/Formoterol fumarate 
200/6 µg per metered dose
Excipients:
HFA-134a propellant, ethanol anhydrous, hydrochloric acid
Presentation:
Each canister contains 120 doses 
Appearance:
Aluminum canister + white actuator

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
CHF 718 pMDI 100µg (Run-In and Reference product_ Treatment B)
Active ingredients
HFA Beclomethasone Dipropionate
Excipients:
HFA-134a propellant, ethanol anhydrous 
Presentation:
Each canister contains 120 doses
Appearance:
Aluminum canister + white actuator

CHF 5993 Placebo (Training kit and placebo_Treatment A)
Active ingredients: 
None
Excipients: 
HFA-134a propellant, ethanol anhydrous
Presentation: 
Each canister contains 120 doses
Appearance: 
Aluminum canister + white actuator
All the inhalers are identical so it will allow a complete double-blind design.
6.2 Dosage and Administration 
6.2.1 Selection of doses in the study
The selection of the dose for CHF 1535 200/6μg is the same as for the EU marketed product 
FOSTER®. 
CHF 718 100μg are based on the EU marketed dose of Clenil® Modulite® (beclomethasone 
dipropionate).
6.2.2 Dosage
6.2.2.1 Run-in period 

CHF 718 100μg: 2 or 4 inhalations BID (puffs); total daily dose of BDP 400 or 800μg  
according to the subject’s pre-trial asthma therapy ICS dose.
6.2.2.2 Randomized Treatment period
According to the allocation based on the randomization list, eligible subjects will be 
administered with one of the following study drugs:

Treatment A: 
CHF 1535 200/6μg and Placebo: 2 puffs from each inhaler BID: 8 total inhalations 
(puffs); total daily dose of BDP/FF: 800/24μg

Treatment B: 
CHF 718 100 μg:  2 puffs from each inhaler BID: 8 total inhalations (puffs); total daily 
dose of BDP: 800μg

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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 Priming of the pMDI inhalers and inhalation
Before using the pMDI inhaler for the first time, one inhalation must be released into the air 
after removing the protection cap.  Subjects will be instructed to perform priming of inhalers as 
reported in the packaging instruction leaflet. Additional information regarding instructions for 
use of the study drug and inhalers will be provided to sites/subjects in the packaging instruction 
leaflet.
6.2.3.2  Run-in kits
During the run-in period, each subject will receive 1 run-in kit (containing 2 inhalers of CHF 
718) covering the 2-week run-in period.
At screening visit (V1), the Investigator/designee, will contact the IRT system to assign each 
subject 1 run-in kit of CHF 718, to be taken as 2 or 4 inhalations BID, to replace the subject’s 
current asthma regimen of medium or high dose ICS.  
Note: The first dose of run-in medication must be administered at clinic at Visit 1.
The run-in medication will be administered BID from inhalers A and B as follows: 

Morning administration (preferably between 7 am and 9 am):
-
1 or 2 inhalations (puffs) from inhaler A and 1 or 2 inhalations (puffs) from inhaler 
B according to what the investigator prescribes.

Evening administration (preferably between 7 pm and 9 pm):
-
1 or 2 inhalations (puffs) from inhaler A and 1 or 2 inhalations (puffs) from inhaler 
B according to what the investigator prescribes.
 
To the extent possible, the time of dosing must remain constant for each subject for the 
whole duration of the study. 
For more details regarding the instructions for use of run-in treatment, please refer to packaging 
instruction leaflet.
On the morning of the randomization visit (V2), eligible subjects will be instructed to refrain 
from taking the run-in medication.

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6.2.3.3 Study treatment kits
At randomization visit (V2) after the confirmation of eligibility, the subject will be randomized 
to one of the double-blind study drugs. The investigator or designee will use the IRT system to 
assign the treatment kit.
From Visit 2 to Visit 4 each subject will receive:

One box containing 4 pMDIs (Treatment A: 2 CHF 1535 pMDIs and placebo pMDIs, 
or Treatment B: 4 CHF 718 pMDIs)
Each of the four canisters will be labeled with the letters A, B, C, D.  Subjects will be instructed 
to take the medication starting with inhalers A and B.  
He/she will switch to inhalers C and D after 2 weeks according to the date written on the labels 
by the study staff for inhalers A and B.
The study drug will be administered BID from the same inhalers (A, B, C, D):

Morning administration (preferably between 7 am and 9 am):
-
2 inhalations (puffs) from inhaler A and 2 inhalations (puffs) from inhaler B (until 
the subject switches to inhalers C and D after 2 weeks according to the date written 
by the study staff on the label of the inhalers A and B)

Evening administration (preferably between 7 pm and 9 pm):
-
2 inhalations (puffs) from inhaler A and 2 inhalations (puffs) from inhaler B (until 
the subject switches to inhalers C and D after 2 weeks according to the date written 
by the study staff on the label of the inhalers A and B)
 
To the extent possible, the time of dosing must remain constant for each subject for the duration 
of the study. 
Newly Assigned Kit
The first morning dose from inhalers A and B of each newly assigned kit will be taken at the 
site under the supervision of the Investigator/designee. 
Prior to dosing, study drug stored between 2°C and 8°C, should be removed from the 
refrigerator and the canister should be taken out of the actuator and warmed with hands for a 
few minutes before administration to the subject. The canister should never be warmed by 
artificial means. The subject should never inhale a cold medication (section 6.9 for storage 
conditions).
The priming of the inhalers “A” and “B” will be performed at site by Investigator/designee 
while for inhalers “C” and “D” the subjects will be instructed to perform the priming at home 
prior to start the administration with the new inhalers. 
On study visit days, study drug should not be taken before coming to the site.

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6.2.4 Subject Training
At screening visit (V1), the Investigator/designee will contact the IRT system to assign a 
training kit to each subject.   Subjects will use the same training kit at screening (V1) and 
randomization visit (V2) if applicable.
At screening (V1) and at randomization visit (V2), the correct use of the pMDI (according to 
the product leaflets provided by Chiesi) will be explained to the subjects and they will be trained 
by using training inhalers identical to the devices used for the administration of the study drug 
containing placebo. The investigator/designee should make sure the subject is properly using 
their study drug inhaler at each clinic visit. Additional re-training should be done if needed.
The training kit will be kept at the site by the investigator (will not be dispensed to the subjects) 
and they will be used again if needed in order to retrain the subject. 
For more details concerning the use of the pMDI please refer to the corresponding subject 
leaflets.
6.3 Packaging 
All investigational products will be prepared in accordance with Good Manufacturing Practices 
(GMP) as required by the current Good Clinical Practices (GCP).
6.3.1 Treatment Kits (Blinded)
Treatment A Kit:
One box will contain 4 pMDIs, labeled A-B-C-D (on the top of the canister).
Two CHF 1535 inhalers and two placebo inhalers (4 total inhalations BID). 
The label will include a space on inhalers A and B for the study staff to note the date for the 
subject to switch from inhalers A and B to inhalers C and D, after a 2-week period (since there 
is no dose counter).  

Primary packaging: 4 labeled canisters (with study label in English only) and 4 labeled 
actuators (with an English and Spanish label).  The four inhalers will be named with 
letters A-B-C-D. 

Secondary packaging: 1 carton box labeled (with an English and Spanish label) with a 
tear/peel off portion
Treatment B Kit:
One box will contain 4 pMDIs, labeled A-B-C-D (on the top of the canister).
Four CHF 718 inhalers (4 total inhalations BID)

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The label will include a space on inhalers A and B for the study staff to note the date for the 
subject to switch from inhalers A and B to inhalers C and D, after a 2-week period (since there 
is no dose counter).  

Primary packaging: 4 labeled canisters (with study label in English only) and 4 labeled 
actuators (with an English and Spanish label).  The four inhalers will be named with 
letters A-B-C-D. 

Secondary packaging: 1 carton box labeled (with an English and Spanish label) with a 
tear/peel off portion
6.3.2 Run-In Kit
One box will contain 2 CHF 718 inhalers labeled A and B (on the top of the canister).

Primary packaging: 2 labeled canisters (with a study label in English only) canister 
plus 2 labeled actuators (with an English and Spanish label).  The two inhalers will be 
named with letters A and B.

Secondary packaging: 1 carton box labeled (with an English and Spanish label) with a 
tear/peel off portion
6.3.3 Training Kit
One box will contain 1 CHF 5993 placebo pMDI.

Primary packaging: 1 labeled canister (with a study label in English only) plus 1 labeled 
actuator (with an English and Spanish label) 

Secondary packaging: 1 carton box (with a study label in English and Spanish) with a 
tear/peel off portion.
6.4 Labeling 
All labeling will be in local language and according to local law and regulatory requirements 
and will be compliant with Annex 13 to the Volume 4 of the GMP and 21 CFR 312.6 
“Labeling of an Investigational New Drug”.
6.5 Treatment allocation
A balanced block randomization scheme stratified by prior asthma therapy at screening/study 
entry (i.e., “medium dose ICS/LABA”, “medium dose ICS” and “high dose ICS”) and US 
region (i.e., “Northeast”, “Midwest”, “South” and “West”) will be prepared via a computerized 
system. Subject will be centrally assigned to one of the two treatment arms with a 1:1 ratio.
An Interactive Response Technology (IRT) system will be used at each visit (from pre-
screening to follow-up call) to record subject status.

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Subject number will be centrally assigned, through the IRT, during the pre-screening visit (Visit 
0). 
Subject numbers will consist of a 9 digit-number: 

the 6 first digits correspond to the centre number (first 3 digits for the country number 
corresponding to the ISO country codes and 3 last progressives for the site); 

the 3 last digits to the screening number (allocated in a chronological way in each site).
The Investigator, or designee, at the sites will call the IRT system to screen, randomize subjects 
and assign treatment kits according to the sequence described in the randomisation list. The 
IRT will track also subject screen failures and discontinuations from the treatment and from the 
study. 
6.6 Treatment Code
The study medication will be packaged and uniquely numbered. Each primary packaging in the 
medication kit will have a numbered label that matches the kit number on the label of the outside 
packaging. The IRT will be used to assign both initial and subsequent kits in order to have 
inventory control and subject dosing tracking. The IRT will also maintain quantities, kit 
numbers, kit status, 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. 
6.7 Emergency Unblinding
The randomization 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.  Chiesi’s clinical team will also 
be blinded during the study as they will not have direct access to the randomization list.
In case of emergency, where he/she considers it essential to know what treatment the subject 
was taking, unblinding of the treatment code will be done through IRT and the treatment group 
will be disclosed. 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, including unblinding. 
The IRT will also promptly notify the Sponsor and the Clinical Monitor whenever a treatment 
code is unblinded.
Users from Chiesi Global Pharmacovigilance will have their own credentials to unblind 
subjects in case of SUSARs to be reported to the IRB. 
6.8 Study Drug Compliance
Compliance will be evaluated on the basis of the information recorded daily by the subject on 
the eDiary as well as the information recorded in the eCRF during the treatment visits.

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The evaluation of compliance will be done using the following formula:
 
The total number of scheduled doses will be calculated on the basis of the extent (days) of 
exposure of each subject. A range of 65-135 % will be taken into account for a satisfactory level 
of compliance, while a level of compliance equal or superior to 50 % will be considered as 
satisfactory for the run-in medication. Subjects with compliance levels less than 75% will 
receive additional coaching from the site staff. 
To optimize subjects’ compliance to study medication, a compliance check using metrics will 
be periodically reviewed. 
6.9 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.
Handling of the study drugs must be according to the package instruction leaflets. A package 
leaflet will be included in each kit.
•
Run-in and Treatment kits 
Run-In and Treatment kits must be stored between 2˚C (36˚F) and 8˚C (46˚F) by 
pharmacist/investigator at the hospital pharmacy or clinical site.
At the clinic visit, the kit to be dispensed must be removed from the refrigerator before priming 
and administration.  Once dispensed, the subjects will be instructed to keep the box at ambient 
temperature not above 25°C (77 ˚F).  At this temperature condition the residual shelf life of the 
pMDI kits will be three months (90 days).  Therefore, the pharmacist/investigator must write 
the use-by-date on the labels of each pMDI once the kit is removed from the refrigerator, before 
assigning it to the subject.  The use-by-date corresponds to the dispensing date plus three 
months (90 days). Please note that the use-by-date must not exceed the total shelf life of the 
product.
•
Training Kits 
Training kits must be kept on site and not dispensed to the subjects. Training kits must be stored 
between 2˚C (36 ˚F) and 8˚C (46 ˚F) by pharmacist/investigator and they must be removed from 
the refrigerator before priming and administration.
Once used, the training pMDI must be kept at the site at ambient temperature not above 25°C 
(77 ˚F), and outside the refrigerator. At this temperature condition the residual shelf life of the 
training pMDI will be four months (120 days).   Therefore, the pharmacist/investigator at the 
hospital or study site must write the use-by-date on the kit labels once the pMDI is removed 
TOTAL NUMBER OF ADMINISTERED DOSES
TOTAL NUMBER OF SCHEDULED DOSES
× 100 = % OF ADMINISTERED DRUG

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from the refrigerator, before using it. The use-by-date corresponds to the dispensing date plus 
4 months.  Please note that the use-by-date must not exceed the total shelf life of the product. 
The site must check the Min/Max temperatures once daily for adequate storage of refrigerated 
and ambient kits. Automated recorders may allow skipping daily records during weekends of 
bank holidays for no longer than 3 consecutive days. The Min/Max temperatures must be 
recorded in a dedicated temperature tracking form. Any deviation from the requirement for 
storage will be promptly reported and Chiesi shall assess if the affected study drug can still be 
used.
6.10 Drug Accountability
The Investigator, or the designated/authorized representative, is responsible for the 
management of all the study medications to be used for the study. Study medications that should 
be stored in a locked, secure storage facility with access limited to those individuals authorized 
to dispense the study medications.
An inventory will be maintained by the Investigator or pharmacist (or other designated 
individual), to include a signed account of all the study medication(s) received, dispensed and 
returned by each subject during the trial. 
At the conclusion or termination of the study, the Investigator or the pharmacist shall conduct 
and document a final drug supply (used and unused) inventory. An explanation will be given 
for any discrepancies.
All the study medications supplied, used or unused, will be returned to the designated distributor 
to be destroyed centrally or destroyed directly on site (according to the sites guidelines).  If 
destroyed on site, a destruction certificate must be provided by the site and filed both at the site 
and Chiesi.  The return of study medication(s) must be done only after full study medication 
accountability and reconciliation are completed. The destruction of study medication(s) will not 
occur until authorized by Chiesi.
6.11 Provision of Additional Care
At completion of subject’s study participation, it is the Investigator’s responsibility to prescribe 
the more appropriate treatment for the subject or to restore the initial therapy or to refer to the 
General Practitioner.

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7.
STUDY PLAN
7.1 Study Schedule
Pre-
screening
Run-in
Treatment Period
Follow Up 
Call
Visits
V0
V1
Screening
V2
Rand.*
V3
V4
V5
V6
Early** 
Term
Time (weeks)
-3
-2
0
4
8
12
13
Visit Windows (days)
± 2
± 2
± 2
±2
± 2
Informed Consent Form
✓
Demographic Data
✓
IRT Visit Confirmation Call
✓
✓
✓
✓
✓
✓
✓
✓
Inclusion/ Exclusion Criteria
✓
Eligibility Recheck1
✓
Medical History/ Previous Meds & 
Smoking History
✓
Concomitant Medications
✓
✓
✓
✓
✓
✓
✓
Adverse Events Assessment
✓
✓
✓
✓
✓
✓
✓
Full Physical examination
✓
✓
✓
Oropharyngeal examination
✓
✓
✓
✓
✓
✓
Hematology and Blood Chemistry
✓
✓
✓
Serum pregnancy test (WOCBP)
✓
✓
✓
Urine pregnancy test (WOCBP)
✓
✓
✓
✓
✓
✓6
Spirometry pre/post albuterol2,
Vital signs & ECG pre-albuterol
✓
Spirometry V2 & V5: serial4,5 
V3 & V4: pre-dose only
✓
✓
✓
✓
✓7
Vital signs V2 & V5: serial3 
V3 & V4: pre-dose vital signs only
✓
✓
✓
✓
✓7
ECG: V2 & V5: serial ECG3
V3 & V4: pre-dose ECG only
✓
✓
✓
✓
✓7
ACQ-7 Questionnaire
✓
✓
✓
✓
✓
Training (pMDI, eDiary, Peak Flow 
Meter)
✓
✓
eDiary/Peak Flow Meter completion
(daily)
 (daily)
(daily)
(daily)
Dispensation of rescue albuterol
D
D/R
D/R
R
Dispensation of run-in medication
✓
R
Study Drug dispensation (D)/ return & 
Accountability (R)
D
D/R
D/R
R
R
Subject eDiary/Peak Flow Meter 
dispensation (D)/ Return (R)
✓
D/R
D/R
D/R
R
R
Morning 
dose 
of 
Study 
Drug 
Administration 
✓
✓
✓
✓
✓
Review of eDiary/Peak Flow Meter 
and study drug compliance
✓
✓
✓
✓
✓
*Rand.: Randomization
        
 **Early Term: Early Termination for randomized subjects withdrawn from study treatment before week 12
1-
Eligibility re-check only for inclusion criteria 5, 7, 8. 9 and exclusion criteria 2, 3, 13, 16, 26.
2-
Spirometry will be carried out at baseline and repeated within 30 minutes after the inhalation of 4 puffs of albuterol.
3-
Vital signs and 12-Lead ECG- pre-dose and 30 min, 1h, 4 h and 12 h post-dose
4-
Pre-dose FEV1: -45min and -15min before administration of study drug at (V2 and V5/ET).
5-
Post-dose serial spirometry (FEV1): 5min, 15min, 30min, 1h, 2h, 3h, 6h, 9h, 11.5h, 12h (V2 and V5/ET)
6-
Urine pregnancy test to be done only if serum is not collected. 
7-
Early Termination visit – Pre-dose vital signs, ECG and spirometry.

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7.1.1 Visit 0 - Pre-screening visit
A pre-screening visit (Visit 0) will be carried out in order to fully explain the study to potential 
eligible asthmatic subjects. The investigator or his/her designee should provide the subject with 
ample time and opportunity to inquire about details of the trial and to decide whether or not to 
participate.
If subject agrees to participate, the signed and dated informed consent must be obtained before 
any study related procedures.
This visit can be the same day as Visit 1 (V1) if the washout period has been respected.  
The following procedures will take place:

As soon as the informed consent is signed, the investigator (or his/her designee) will 
connect to IRT to assign a unique subject number. This number will be sequentially 
assigned.

Demographic data: Recording of demographic data including sex, race date of birth 
(real or dummy depending on country privacy restrictions) and height (for spirometry 
purpose), and childbearing potential status (for female only).
Before leaving the site:

An appointment for Visit 1 will be made within 1 week (maximum) in the morning. 

A subject card with the Investigator’s contact details will be handed out to the subject.

Subjects will be instructed:
o
To fast overnight (at least 8 hours) before the next visit in order to perform blood 
sampling (only water is allowed);
o
To refrain from taking their current asthma regimen morning dose before the 
screening visit.
o
To refrain from taking rescue medications (albuterol), caffeinated substances in 
the 6 hours preceding the next visit, and to abstain from all non-permitted 
medications in accordance with section 5.2 unless absolutely necessary.
Note: Visit 0 and Visit 1 can be combined, in case the subject has not taken his/her usual 
asthma treatment when he/she arrives at the clinic, the wash-out period is respected as well 
as he/she has fasted overnight (at least 8 hours), 
7.1.2 Visit 1- Screening Visit (Week -2)
A screening visit will be carried out in order to identify eligible consenting subjects for the 
study (preferably before 7-9 am). 

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If any of the wash-out for asthma medications has not been respected (section 5.2), the visit 
needs to be re-scheduled within 2 days. Only one re-schedule is allowed. If wash-out is still not 
respected in the morning of the re-scheduled visit, the subjects will be recorded in the IRT as 
screening failure. 
The following procedures will take place:
Inclusion/exclusion criteria check
Medical History: The medical history including asthma history will be recorded.
Smoking history: smoking status with all the data needed to calculate the pack year will be 
recorded.
Previous and concomitant medication: all medications taken by the subjects in the last 3 
months will be recorded. Intake of non-permitted medication constitutes non-eligibility 
criterion for enrollment in the study.
Adverse Events (AEs): The occurrence of any AE between informed consent signature and 
screening visit will be checked. In case of any clinically significant abnormality revealed 
during the physical examination or screening procedures, it will be recorded in the subjects’ 
medical history, unless its onset date is after the informed consent signature date and it is not 
due to a pre-existing condition. In this case it will be recorded as an AE.
A full physical examination (section 7.2.4) will be performed.
Oropharyngeal examination (section 7.2.4)
Vital Signs: Pre-bronchodilator vital signs will be recorded (pulse rate, systolic [SBP] and 
diastolic [DBP] blood pressure, after 10 minutes of rest, in sitting position) (section 7.2.2). 
12-Lead ECG: Single pre-bronchodilator 12-lead ECG will be recorded after at least 10 
minutes of rest (section 7.2.3). 
Eligible subjects must have a mean QTcF ≤450 ms (males) and ≤470 ms (female). (criterion 
not applicable for subjects with pacemaker or permanent atrial fibrillation) (exclusion 
criterion #14).
Blood samples: A blood sample will be collected before albuterol administration and after 
an overnight fasting for the assessments of:
standard hematology and blood chemistry;
serum β-HCG tests in women of childbearing potential.
The blood samples must be collected after vital signs and 12-lead ECG recording. The 
central laboratory will analyze the samples and provide the subjects’ reports to the site. In 
case of non-interpretable data, another determination must be performed as soon as possible 
and prior to Visit 2 (randomization visit) (section 7.2.6). 

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A urine pregnancy test will be performed in women of childbearing potential. This test will 
allow confirmation that the woman tested is not pregnant before the serum pregnancy test 
results are made available by the central laboratory (section 7.2.5).
Pre-bronchodilator and Post-bronchodilator spirometry – pre- and post-albuterol, in 
order to assess eligibility and bronchodilator responsiveness (section 7.2.10)
If the subject is not eligible, the investigator or site staff will access IRT to record the subject 
as screening failure.
If the subject is eligible, the site staff will request a run-in kit from the IRT system.  One 
Run-in Medication kit (CHF 718 (BDP) pMDI 100µg 2 or 4 inhalations BID (TDD) 400 
or 800µg) for the run-in period will be dispensed with instructions for use.  The number of 
inhalations the subject should take and the use-by-date must be filled-in on the label by the 
site staff. 
The subject will be trained on the proper use of pMDI (section 6.2.4) using the training kit 
containing placebo. The corresponding tear-off label will be placed in the subject specific 
dispensation tracking form. The training kit will remain at the site. 
The morning dose of run-in medication (first administration) will be administered at the 
clinic visit (preferably before 10:00 am) under medical supervision. The run-in medication 
will be primed by site staff. 
eDiary/Peak Flow Meter dispensed - Subjects will be trained on how to record the run-in 
medications and rescue medication, respiratory symptoms in the eDiary (section 7.2.8) and 
the use of the Peak Flow Meter (section 7.2.7). 
Rescue Medication dispensed - Subjects will keep the rescue medication throughout the 
study period (will be re-supplied if needed); subject will be instructed to bring the rescue 
medication at each visit in order to check the need for replacement.
Before leaving the site:
An appointment for Visit 2 will be scheduled within 14 days (± 2-days) in the morning 
(approximately the same time of day). 
Subjects will be instructed:
o To inhale 1 or 2 puffs in the morning and evening from each run-in inhaler depending on 
what is prescribed (depending upon what ICS dose the subject was on prior to screening). 
In addition, subject will also be instructed to take albuterol as rescue if necessary (sections 
6.2.2 and 6.2.3).
o To answer twice daily eDiary questions on symptoms, medication intake (run-in and 
rescue). 
o To perform home PEF measurements twice daily (am/pm) (the morning PEF 
measurement should be done prior to visit 2).

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o Not to take the morning dose of run-in medication before coming to visit 2. 
o To refrain from taking rescue medications (albuterol), caffeinated substances in the 6 
hours preceding the next visit, and to abstain from all non-permitted medications in 
accordance with section 5.2 unless absolutely necessary.
o To bring back the run-in medication (in the boxes), and eDiary/Peak Flow Meter with 
them at the next visit.
7.1.3 Visit 2 – Randomization Visit (Week 0), Serial Spirometry Visit
The subjects will visit the site for the randomization visit (2 weeks (± 2 days) after Visit 1) in 
the morning, approximately the same time of day (preferably before 7-9 am).
 
PEF measurement is done at home in the morning before the visit.  
If the wash-out of the medications (including rescue and run-in) has not been respected (section 
5.2), the visit needs to be re-scheduled within 2 days. Only one re-schedule is allowed. If wash-
out is still not respected in the morning of the re-scheduled visit, the subjects will be recorded 
as screen failure in the IRT system.
The following assessments and procedures will take place:
Eligibility criteria will be rechecked: (inclusion criteria # 5, 6, 7, and 8 and exclusion criteria # 
1, 2, 4, 5, 14 and 16). At the discretion of the investigator, a subject who fails to meet all 
inclusion/exclusion criteria (screen failure) at V2 may be re-screened again, up to one additional 
time, after 1 month from the date of the initial screen failure. The screen failure should be 
entered into the IRT system. In case of rescreening, the subject should sign a new informed 
consent and will be assigned a new subject number; a link to prior subject number will be 
recorded in the eCRF.
 

Run-in Medication taken during the run-in period will be collected and accounted for. 

eDiary/Peak Flow Meter: The investigator (or designee) will check the eDiary/Peak 
Flow Meter portal whether the subject has completed the expected daily questions on 
symptoms and medications intake, as well as performing daily PEF measurements 
(am/pm) for compliance. 
In case of non-compliance, the investigator (or designee) will retrain the subjects on 
how to complete the eDiary, perform home PEF maneuvers, and the medication intake 
(rescue and study drug). While retraining the subjects, the investigator (or designee) will 
verify subjects’ cooperative attitude and ability to correctly use the eDiary/Peak Flow 
Meter. If the subjects are not cooperative and do not meet inclusion criteria #8, they will 
be recorded as screen failure in the IRT system.

Adverse Events assessment – the occurrence of any AE since the last visit will be 
recorded.  The status of ongoing AEs will be checked and updated. 

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
Concomitant Medications – the investigator or designee will check that the subject did 
not take any of the non-permitted medications since the screening visit.  Any change in 
medications will be recorded. 

Oropharyngeal Examination (section 7.2.4)

Questionnaire: Subjects will complete the ACQ-7 questionnaire (section 7.2.1). 

A urine pregnancy test will be performed in women of childbearing potential (section 
7.2.5).  

Pre-dose Spirometry- A spirometry measurement at -45 and -15 minutes pre-dose will 
be completed (section 7.2.10). 
Pre-dose Serial Vital signs (section 7.2.2) and Serial ECG (section 7.2.3) will be 
performed.
If eligibility criteria are confirmed:
The investigator (or designee) will randomize the subjects in the IRT system and dispense 
the study drug kit allocated by the IRT system.
The morning dose of study drug (first administration) will be administered at the clinic 
visit (before 9:00 am preferably) (the time of first inhalation corresponds to Time 0 of 
spirometry). Subjects will be instructed to inhale 2 puffs from the inhaler labeled A and 2 
puffs from inhaler labeled B.  
Post-dose spirometry- Serial spirometry will be conducted at the following time points:  5 
min, 15 min, 30 min, 1h, 2h, 3h, 6h, 9h, 11.5h and 12 hour
Post-dose Serial Vital signs and Serial ECG:  30 min, 1h, 4h, and 12-hour post-dose
Re-training on pMDI/eDiary/Peak Flow Meter (if necessary)
Dispensation of rescue medication if needed
Before leaving the site:
An appointment for Visit 3 will be scheduled in 4 weeks ± 2 days in the morning 
approximately between 7:00-9:00 am.
Study drug (1 kit containing 4 inhalers labeled as A-B-C-D) will be dispensed with 
instructions for use. The use-by-date must be filled-in on the label of study drug by the site 
staff. The site will provide the subject instructions when to switch to canisters labeled (C & 
D).
 

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Subjects will be instructed:
o To answer twice daily: questions on symptoms, study drug intake and rescue medication 
in the eDiary.
o To take the rescue medication as needed, but to refrain 6 hours prior to the next visit (if 
possible).
o To perform home PEF measurements twice daily (am/pm) (the morning PEF 
measurement should be done prior to visit 3).
o Not to take the morning dose of the study drug before coming to the next visit. 
o To bring back the study drug (in the boxes), and eDiary/Peak Flow Meter with them at 
the next visit.
o To refrain from taking caffeinated substances in the 6 hours preceding the next visit, and 
to abstain from all non-permitted medications in accordance with section 5.2 unless 
absolutely necessary.
7.1.4 Visit 3 - (Week 4) and Visit 4 (Week 8) 
The subject will visit the site for Visit 3 (Week 4) and/or Visit 4 (Week 8) 4 weeks (± 2 days) 
after the last visit in the morning, approximately the same time of day (preferably before 7-9 
am).
 
PEF measurement is done at home in the morning before the visit. 
If the wash-out of the medications has not been respected (section 5.2), the visit needs to be re-
scheduled within 2 days. Only one re-schedule is allowed. If wash-out is still not respected in 
the morning of the re-scheduled visit, the site should note the deviation from the protocol and 
the reason.
The following assessments and procedures will take place:

The subject will bring in their rescue medication for accountability.

The investigator (or designee) will update the IRT system with the current visit date and 
dispense the study drug kit allocated by the IRT system.

eDiary/Peak Flow Meter: The investigator (or designee) will check the eDiary/Peak 
Flow Meter portal to determine whether subject has completed the expected daily 
questions on symptoms and medications intake as well as performing daily PEF 
measurements (am/pm) for compliance. 
In case of non-compliance, the investigator (or designee) will retrain the subjects on 
how to complete the eDiary, perform PEF maneuvers, and the medication 
intake (rescue and study drug). 

Adverse Events assessment – the occurrence of any AE since the last visit will be 
recorded.  The status of ongoing AEs will be checked and updated.

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
Concomitant Medications – the investigator or designee will check that the subject did 
not take any of the non-permitted medications since the screening visit.  Any change in 
medications will be recorded.

Oropharyngeal Examination (section 7.2.4).

Questionnaire: Subjects will complete the ACQ-7 questionnaire (section 7.2.1). 

A urine pregnancy test will be performed in women of childbearing potential (section 
7.2.5). 

Pre-dose Spirometry only (section 7.2.10) 

Vital signs and ECG – pre-dose only (section 7.2.2 and section 7.2.3) 
The morning dose of new study drug will be administered at the clinic visit (before 9:00 am 
preferably) (the time of first inhalation corresponds to Time 0 of spirometry). Subjects will be 
instructed to inhale 2 puffs from the inhaler A and 2 puffs from inhaler B.  
Dispensation of rescue medication if needed
Before leaving the site:
An appointment for the next visit will be scheduled in 4 weeks ± 2 days in the morning 
approximately between 7:00-9:00 am.
Study drug (1 kit containing 4 inhalers labeled as A-B-C-D) will be dispensed with 
instructions for use. The use-by-date must be filled-in on the label of study drug by the site 
staff. The site will provide the subject instructions when to switch to canisters labeled (C & 
D).
Subjects will be instructed:
o To answer twice daily: questions on symptoms, study drug intake and rescue medication 
in the eDiary.
o To take the rescue medication as needed
o To perform home PEF measurements twice daily (am/pm) (the morning PEF 
measurement should be done prior to next visit).
o Not to take the morning dose of the study drug before coming to the next visit. 
o To bring back the study drug (in the boxes), and eDiary/Peak Flow meter with them at 
the next visit.
o To refrain from taking rescue medications (albuterol), caffeinated substances in the 6 
hours preceding the next visit, and to abstain from all non-permitted medications in 
accordance with section 5.2 unless absolutely necessary.

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o To fast overnight (at least 8 hours) before Visit 5 in order to perform blood sampling 
(only water is allowed).
7.1.5 Visit 5 – (Week 12) End of Treatment
The subjects will visit the site for Visit 5 (End of Treatment) 4 weeks (± 2 days) after Visit 4 in 
the morning, approximately the same time of day (preferably before 7-9 am).
 
PEF measurement is done at home in the morning before the visit. 
If the wash-out of the medications has not been respected (section 5.2), the visit needs to be re-
scheduled within 2 days. Only one re-schedule is allowed. If wash-out is still not respected in 
the morning of the re-scheduled visit, the site should note the deviation from the protocol and 
the reason.
The following assessments and procedures will take place:

eDiary/Peak Flow Meter: The investigator (or designee) will check the eDiary/Peak Flow 
Meter portal to determine whether subject has completed the expected daily questions on 
symptoms and medications intake as well as performing daily PEF measurements (am/pm) 
for compliance. 

The investigator (or designee) will update the IRT system with the current visit date.

Subject will return the eDiary/Peak Flow Meter and Study Drug kit 

Adverse Events assessment

Concomitant Medications will be reviewed

A full physical examination (section 7.2.4) will be performed.

Oropharyngeal Examination (section 7.2.4)

Questionnaire: Subjects will complete the ACQ-7 questionnaire (section 7.2.1).
Blood samples: A blood sample will be collected before study drug administration and after 
an overnight fasting for the assessments of (section 7.2.6) :
standard hematology and blood chemistry.
serum β-HCG tests in women of childbearing potential (section 7.2.5).
The blood samples must be collected before serial spirometry. The central laboratory will 
analyze the samples and provide the subjects’ reports to the site. 

A urine pregnancy test will be performed in women of childbearing potential (if the serum 
pregnancy test is not conducted).  

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Pre-dose Spirometry- A spirometry measurement -45 and -15 minutes pre-dose will be 
completed (section 7.2.10). 
Pre-dose Serial Vital signs and Serial ECG (section 7.2.2 and section 7.2.3)
The morning dose of study drug will be administered on site (from kit dispensed at Visit 
4/Week 8) (before 9:00 am preferably) (the time of first inhalation corresponds to Time 0 of 
spirometry). Subjects will be instructed to inhale 2 puffs from the inhaler labeled C and 2 
puffs from inhaler labeled D.  
Post-dose spirometry- Serial spirometry will be conducted at the following time points: 5 
min, 15 min, 30 min, 1h, 2h, 3h, 6h, 9h, 11.5h and 12 hour
Post-dose Serial Vital signs and Serial ECG: 30 min, 1h, 4h, and 12-hour post-dose
Before discharge:
A follow-up safety phone call (Visit 6) will be scheduled approximately 1 week after Visit 
5/End of Treatment. 
The investigator will prescribe the most appropriate treatment or restore the initial therapy 
the subject was taking prior to the study.   
7.1.6 Visit 6 - Follow-up Safety Visit
A follow-up safety phone call will be performed by the investigator or designated staff no later 
than 1 week after the final visit (Visit 5) or Early Termination from study drug visit to check 
the status of unresolved AEs/SAEs and to record any new AEs/SAEs that may have occurred 
after Visit 5 (or last visit), as well as related concomitant medications. 
Investigator will access IRT in order to record completion of the study visit.
7.1.7 Early Termination Visit from Study 
If a subject prematurely withdraws from the study, all efforts will be made to perform an Early 
Termination visit at the time of discontinuation from study. This visit will include the following 
assessments, providing there are no safety issues for the subject and in accordance with the 
subject’s agreement:

At the investigator’s discretion, the subject will resume their pre-study therapy regimen or 
change if appropriate

eDiary/Peak Flow Meter: The investigator (or designee) will check the eDiary/Peak Flow 
Meter portal to determine whether subject has completed the expected daily questions on 
symptoms and medications intake as well as performing daily PEF measurements (am/pm) 
for compliance. 

Investigator or designee will update the IRT system

Subject will return the eDiary/Peak Flow Meter and Study Drug kit 

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
Adverse Events assessment 

Concomitant Medications will be reviewed

A full physical examination (section 7.2.4) will be performed.

Oropharyngeal Examination (section 7.2.4)

Questionnaire: Subjects will complete the ACQ-7 questionnaire (section 7.2.1).

A blood sample will be collected, after an overnight fasting (at least 10h, when possible) 
after vital signs and 12-lead ECG recordings and before dosing, for the assessments of 
(section 7.2.6):
standard hematology and blood chemistry
a serum β-HCG test in women of childbearing potential
The following (pre-dose) procedures will be performed (the administration of the morning dose 
of study drug will take place during the clinic visit, if possible):

Spirometry (section 7.2.10) 

Vital signs and ECG: An appointment will be made 1-week from the Early Termination 
visit for the follow-up safety phone call (section 7.2.2 and section 7.2.3)
7.1.8 Early Discontinuation Visit from Study Drug
If a subject prematurely discontinues from study drug but remains in the study after 
randomization (Visit 2), all efforts will be made to perform an Early Termination visit at the 
time of discontinuation from study drug and the follow-up safety call will be conducted. 
Subjects who consent to data collection until the planned V5 visit will continue attending study 
visits according to the study visit schedule. Before each visit, the wash-out periods for 
concomitant medications detailed in section 5.2 must be respected. The following assessments 
will be performed: 

Spirometry (pre/post of the subject’s maintenance inhaled therapy for asthma, 
including the serial spirometry when planned by the study protocol).

The subject should continue to complete eDiary data (except for the study drug 
questions) and to measure PEF at home.

The investigator (or designee) will check the concomitant medications, adverse 
events that occurred since last visit.

Urine pregnancy tests in all women of childbearing potential.

Questionnaires- subjects will complete the ACQ-7 questionnaire (section 7.2.1).

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7.2 Study Assessments and Procedures
7.2.1
Asthma Control Questionnaire (ACQ-7)
Asthma control will be evaluated by the completion of the Asthma Control Questionnaire© 
(ACQ-7) [21], [22]. The ACQ-7 is able to identify the adequacy of asthma control in individual 
subjects. The first 6 items of the questionnaire refer to symptoms and rescue use in the previous 
7 days while the 7th item (related to FEV1), is completed by the clinical staff.
The ACQ-7 is administered at Visit 2, Visit 3, Visit 4 and Visit 5/ET. 
Subjects are asked to recall how their asthma has been during the previous week and to respond 
to the symptom and bronchodilator use questions on a 7-point scale (0=no impairment, 6= 
maximum impairment).
Item 7 should be populated using the pre-dose FEV1 % predicted (-15 minutes from V2 to 
V5). If the -15 minute FEV1 % predicted is missing, the -45 minute assessment will be used as 
item 7.
The ACQ-7 will be completed by subjects on an electronic device 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. 
Missing data should be avoided; therefore, the investigator (or designated site-personnel) will 
check the questionnaire for completeness before the subjects leave the clinic and if necessary, 
encourage the subjects to complete any missing responses. Anyway, the response to each item 
should not be questioned. 
The ACQ-5 score will be derived and analyzed from the ACQ-7 questionnaire data, considering 
the first five questions of the ACQ-7 questionnaire administered to subjects.
7.2.2
Vital signs
Pulse rate, systolic and diastolic blood pressure (SBP, DBP) will be measured after 10 min rest 
in sitting position:

Visit 1 - pre-albuterol 

Visit 2 & 5 pre-dose and 30 min, 1h, 4h, and 12h post-dose

Visit 3 & 4 pre-dose spirometry

ET visit (if applicable, pre-dose)
The vital signs should be assessed before the blood sampling.

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7.2.3
12-lead ECG
A centralized vendor will provide standardized ECG equipment to all the sites.  A 12-lead ECG 
will be performed at the site for eligibility check (all subjects). The evaluation will be done by 
the site.

Visit 1 - pre-albuterol 

Visit 2 & 5 pre-dose and 30 min, 1h, 4h, and 12h post-dose

Visit 3 & 4 pre-dose spirometry

ET visit (if applicable, pre-dose)
Before recording, subjects should be resting in a quiet setting with minimal stimulation (e.g. no 
television, loud music, computer games) and in a resting position for 10 minutes at least before 
ECG. The ECG must be performed (with the subject in the supine position) before the 
blood sampling.
Standard electrode placement will be used for these ECG, including placing the limb leads, dual 
snap electrodes will be used for the precordial leads. 
Single 12-lead ECG tracing will be recorded according to the study schedule. QTc value will 
be calculated using the Fridericia formula (Fridericia-corrected QTc=QT/3√RR). It will be 
calculated automatically by the ECG recorder. Heart rate (HR), PR and QRS values will be also 
evaluated from ECG at all visits.
ECGs with computerized protocol interpretation are considered normal if: 
-
45≤ Heart rate ≤110 bpm
-
120 ms ≤ PR ≤210 ms
-
QRS ≤120 ms
ECG will be evaluated and interpreted at ERT and in case of any abnormality requiring urgent 
action ECG should be also evaluated on site (before sending to central vendor).
In case of clinically significant ECG abnormalities (as reported by the investigator) not set as 
exclusion criteria, the inclusion of the subjects will be judged by the investigator and 
consultation with the medical monitor. ECG abnormalities in eligible subjects may be 
investigated at all times by the medical monitors and Sponsor. In any case, the trace must have 
QTcF values ≤ 450ms (males) and ≤ 470ms (females) at screening and randomization. The 
final decision for enrollment would be documented in the source documentation.
Clinically significant abnormalities evaluated by the investigator at Visit 1 not due to a pre-
existing condition or clinically significant changes at subsequent visits, in the medical opinion 
of the investigator, will be reported as adverse events in the eCRF.
7.2.4
Physical Examination (Visit 1 and Visit 5)
A full physical examination including body weight, height (height only at visit 1) an assessment 
of general appearance, eyes, ears, nose, skin, head and neck, mouth and throat, respiratory, 

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cardiovascular, renal and urinary, lymph nodes, gastrointestinal, musculoskeletal, and nervous 
systems will be performed at the site by the investigator or designee. 
Oropharyngeal Examination:
Oropharyngeal candidiasis is a condition commonly associated with the use of ICS and is 
caused by the Candida fungus. This side effect may be attributed to the topical effects of these 
medications on the oral mucosa [23]. Generalized immunosuppressive and anti-inflammatory 
effects of steroids are thought to play a major role in the pathogenesis of candidiasis [24]. 
The subject’s mouth and throat will be visually inspected by the investigator at V1- V5/ET 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
Serum and Urine Pregnancy Tests
Serum pregnancy tests will be performed at V1 and V5 for WOCBP.  
A urine pregnancy test will be administered at V1 to V4 (V5 only if serum is not collected) for 
WOCBP, using a commercial urine β-HCG pregnancy test strip. This test strip is used to obtain 
a quick (within a few minutes), visual, qualitative result for the early detection of pregnancy. 
The test performed at V1 will allow confirmation that the woman tested is not pregnant before 
the serum pregnancy results are made available by the central laboratory.  
7.2.6
Blood Hematology and Chemistry
Blood samples of approximately 9 mL (total) will be collected at the site for hematology and 
serum chemistry, after an overnight fast of at least 10 hours. The blood withdrawal should be 
performed after vital signs and 12-lead ECG recording and before administration of albuterol 
or study drug.  An additional blood sample will be collected for serum pregnancy test in women 
of childbearing potential.
The following evaluations will be performed in a central laboratory:

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7.2.6.1 Table. Laboratory Assessments
Serum chemistry
Blood urea nitrogen (BUN), cholesterol, triglycerides, creatinine, creatine 
phosphokinase (CPK), uric acid, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), Gamma-glutamyl transpeptidase (GGT), total 
bilirubin, bilirubin direct and indirect, alkaline phosphatases, albumin, total 
serum protein, and electrolytes (sodium, potassium, calcium, and chloride), 
fasting glucose, phosphate 
Hematology
Red blood cells count (RBC), white blood cell count (WBC), with 
differential (neutrophils, basophils, eosinophils, lymphocytes, monocytes - 
absolute and %), total hemoglobin (Hb), hematocrit (Hct), platelet count 
(PLT) 
Other 
Serum pregnancy test (serum β-HCG) in WOCBP
COVID-19 diagnostic swab test (as needed)
Blood collection and sample preparation will be performed according to procedures provided 
by the central 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 or as 
AE (section 10.8).
7.2.7
Daily PEF measurements with Electronic Peak Flow Meter
PEF (L/min) will be monitored twice daily in the morning and in the evening (during the run-
in and the study periods, from V1 to V4) by subjects at home using a portable electronic Peak 
Flow Meter. 
This will be done before the intake of the study drug for both morning and evening PEF 
assessments.
A specific question will be included in the eDiary to ask if PEF measurements have been 
performed before the intake of study medication.
Subjects will be educated on the purpose and technique of PEF measurements. Specific 
instructions for use will be made available to the subjects.
During each measurement session (morning or evening before the intake of the study drug) the 
subjects will perform 3 blows. Data will be recorded in the device.
Morning measurements should be done between approximately 7:00 am and 9:00 am and 
evening measurements should be done between approximately 7:00 pm and 9:00 pm. An alarm 
will remind the subjects to perform measurements.
Data from the Peak Flow Meter will be automatically transmitted from subjects’ home to ERT’s 
central 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 subjects’ compliance. In case of poor compliance 

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and/or worsening of asthma control during the study, phone call(s) to the subjects will be 
done by the site and instructions will be given again to the subjects if appropriate.
In case of Early Treatment Discontinuation, if the subject agrees to continue with the study 
assessments as planned in the study protocol, PEF measurements will continue to be monitored 
twice daily in the morning and in the evening by the subject at home as previously described.
7.2.8
Electronic Diary (eDiary)
Asthma symptoms, study drug and rescue medication
During the run-in and study periods (from V1 to V4), the subjects will answer the following 
questions in the electronic diary twice daily in the morning and in the evening before the PEF 
measurements:
- the asthma symptom scores;
- the nocturnal awakening occurrence due to asthma requiring rescue medication;
- the use of study medication (rescue and study treatment).
In case of Early Treatment Discontinuation, if the subject agrees to continue with the study 
assessments as planned in the study protocol, the subjects will answer twice a day in the 
morning and in the evening and before the PEF measurements the following questions in the 
electronic diary:
- the asthma symptom scores;
- the nocturnal awakening occurrence due to asthma requiring rescue medication;
- the use of rescue medication.
The data will be automatically transmitted from the subjects’ home to the ERT’s central 
database on a daily basis and checked by the Investigator on a regular basis.
Asthma symptoms (overall symptoms, cough, wheeze, chest tightness and 
breathlessness) will be scored, as occurred respectively during the night and during the 
day, 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
Nocturnal awakening occurrence due to asthma requiring rescue medication

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The subjects will confirm, answering once a day simple question whether nocturnal 
awakening occurred due to asthma requiring rescue medication.
Study Drug
The intake of study drug will be recorded twice daily as follows: the number of puffs 
taken in the morning and in the evening. Note: These questions are not applicable after 
the early treatment discontinuation, even if the subject agrees to continue with the study 
assessments as planned in the study protocol. 
 Rescue medication
The daily use of rescue medication will be recorded 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, before taking the study 
drug. 
Asthma control day
The derived variable of asthma control days will be calculated according to the following 
definition (both the two conditions below should occur to define an asthma control day): 
Days (night-time plus daytime) with a total asthma symptom score = 0.
Days with no rescue medication use.
7.2.9
Asthma exacerbations during the treatment period
In a case of an asthma exacerbation, treatment needs to be delivered in the way that the treating 
physician deems appropriate and in the best interest of the subject. Subjects will be instructed 
on recognition of symptoms and signs signaling a developing asthma exacerbation.
Asthma exacerbations (as per ATS/ERS guidelines and Virchow paper [25], [26]) are defined 
as follows: 
A moderate asthma 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 or 
increase of ≥ 0.75 from baseline in daily symptom score on 2 consecutive days.
b)
Increase from baseline in occasions of SABA use on 2 consecutive days (minimum 
increase: 4 puffs/day)
c)
≥ 20% decrease in PEF from baseline on at least 2 consecutive mornings/evenings 
or ≥ 20% decrease in FEV1 from baseline
d)
Visit to the ER/trial site for asthma treatment not requiring systemic corticosteroids
* A sustained increase of at least 1 puff of SABA for 2 consecutive days is considered 
as a change in treatment. Asthma worsening requiring the initiation of treatment with 
systemic corticosteroids for < 3 days is considered a moderate exacerbation.

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A severe asthma exacerbation is defined as an asthma worsening requiring the initiation of 
treatment with systemic corticosteroids for at least 3 days.
Note: courses of corticosteroids separated by 1 week or more should be treated as separate 
severe exacerbations. A severe exacerbation requiring an emergency room visit or a 
hospitalization will be documented accordingly. Asthma worsening treated with depot 
corticosteroids (for sustained systemic effect of at least 3 days) are considered as severe 
exacerbations.
Eligible subjects should remain free of exacerbation requiring hospitalization, emergency room 
admission or use of systemic corticosteroids within 4 weeks prior to screening and during the 
run-in period (according to exclusion criterion #4).
During the run-in period, if the subject experiences any asthma exacerbation the subject will 
not be randomized in the study. In this case, the subject could be re-selected at a later stage (one 
month minimum after recovering) with a new subject number (the subject should sign a new 
informed consent), providing the subject meets the inclusion criteria for the study according to 
the investigator. 
After randomization, if the subject experiences a severe asthma exacerbation requiring systemic 
corticosteroid and/or use of nebulizer containing β2-agonists and/or corticosteroids and/or 
antibiotic therapy, hospitalization or emergency care visit, the following study visit should only 
occur after subject’s stabilization. In addition, a minimum timeframe of 2 weeks between the 
end of the exacerbation and the clinic visit should elapse. Otherwise, the clinic visit should be 
delayed.
In case of repeated severe asthma exacerbations during the study which may jeopardize the 
safety of the subject, it is up to the investigator to decide whether or not to withdraw the subject 
from the study treatment.
At each visit (starting Visit 1), the investigator will assess the occurrence of any asthma 
exacerbation since the last visit. If not already notified by the subject, the investigator will also 
check whether the subject has taken systemic corticosteroids meeting the criteria for a severe 
exacerbation or whether the subject has been in the emergency room or been hospitalized due 
to asthma. 
The investigator should detect any asthma worsening during the study and decide whether to 
ask the subjects to come to the clinic for an unscheduled visit and whether the subjects are 
experiencing a moderate or severe exacerbation as per protocol definitions.
The investigator is supported in the detection of asthma worsening by the eDiary data. 
In case of asthma exacerbations during the study, the subjects will be allowed to receive short 
courses (≤ 10 days) of systemic corticosteroids (section 5.1). 
The intake of study medication should be maintained in case of asthma exacerbation to the 
extent possible. Only in case of absolute need, a temporary discontinuation of study treatment 
intake no longer than 2 weeks is allowed (if longer, the subjects will be withdrawn). The 

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investigators will carefully record all additional treatments taken for the exacerbation. Any 
necessary unscheduled visit will be performed in order to evaluate the subjects’ clinical 
condition. 
In the recovery period from the exacerbation episode, if the condition of the subjects allows, 
every possible effort should be made to remove all additional medications used in the treatment 
of the exacerbation and to restart the treatment of the subjects according to the protocol as early 
as possible.
An asthma exacerbation is not a reason to withdraw the subject from the study treatment, unless 
the investigator deems it necessary.  The decision to withdraw the subject from the study drug 
will be at the investigator’s discretion, however the subject may stay on study, but off study 
drug.
Asthma exacerbations interpreted as due to lack of efficacy of the study medication should not 
be classified as “drug related.”
7.2.10 Spirometry
Lung function measurements and daily calibration of the spirometer will be done according to 
the recommendation of the Official Statement of the European Respiratory Society and 
American Thoracic Society [27]. All sites will be provided with a spirometer. It is 
recommended that, in each center, the same spirometer is used for a given subject during the 
course of the study. Calibration of the spirometer must be performed by the same 
investigator or designee (to the extent possible) at each visit prior to any spirometry 
maneuvers and the reports must be kept with the source documents.
The specific procedures for centralized spirometry will be provided to the investigator by the 
centralized spirometry vendor.
Throughout the study, the clinic visits and the lung function measurements will start in the 
morning between 7:00 and 09:00 a.m., approximately at the same time of the day for each 
subject.
The following parameters will be recorded at Visits V1 to V5/ET (if applicable):
Forced Expiratory Volume in the 1st second (FEV1, L)
Forced Vital Capacity (FVC, L)
Predicted values of FEV1 and FVC will be calculated according to formulas reported by Quanjer 
et al [28]. 
Subjects should be relaxed (shoulders down and relaxed) with the nose clipped after at least 10 
minutes rest 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) and exhale forcefully without hesitation. FEV1 
and FVC will be recorded at each clinic visit from a forced vital capacity maneuver.  The highest 

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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 [27]. Acceptable 
repeatability, for the purposes of this study, is achieved when the difference between the two 
largest FEV1 and the two largest FVC values is ≤ 200mL). If these criteria are not met in 3 
maneuvers, additional trials should be attempted, up to, but usually no more than 8.
The rescue medication (albuterol) must be withheld as much as possible for at least 6 
hours prior to starting the pre-dose assessment at each visit.
The run-in or the study drug should not be taken at home in the morning of the visit. If 
the drug is taken at home, the measurements should be deferred (i.e. the visit needs to be 
re-scheduled to take place within 2 days). If rescue or study drug intake occurs again in the 
previous 6 hours before the re-scheduled visit:
-
at V1 and V2, the subject will be a screen failure
-
from V3 to V5, the visit will be performed and details of the intake (time and quantity) 
documented. 
At Visits 2 and 5, serial spirometry will be conducted at T-45 and T-15 minutes pre-morning 
dose and 5, 15, 30, 1h, 2h, 3h, 6h, 9h, 11.5h and 12h post-morning dose. Time points for serial 
spirometry should be followed as closely as possible.  
Visits 3 and 4 pre-dose spirometry only (i.e. no serial spirometry will be performed). 
ET (if applicable) pre-dose spirometry only
7.2.11 Rescue medication
The daily use of rescue medication will be recorded as follows: the number of puffs taken during 
the night will be recorded each morning on awakening before taking the morning dose of the 
study drug while the number of puffs taken during the day will be recorded each evening before 
taking the evening dose of the study drugs.
In case of Early Treatment Discontinuation, if the subject agrees to continue with the study 
assessments as planned in the study protocol, the daily use of rescue medication will continue 
to be recorded by the subject as previously described.
8.
EFFICACY ASSESSMENTS
Primary efficacy variable:

Change from baseline in FEV1 AUC0-12h at Week 12.

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Key-Secondary efficacy variable:

Change from baseline in peak FEV1 within the first 3 hours post-dose at Week 12.
Secondary efficacy variables:

Change from baseline in FEV1 AUC0-12h at Week 0.

Change from baseline in peak FEV1 within the first 3 hours post-dose at Week 0.

Change from baseline in trough FEV1 at Week 12.

Change from baseline in pre-dose morning FEV1 at Week 4, 8 and 12.

Change from baseline in average morning PEF over 12-week treatment period.

Change from baseline in average evening PEF over 12-week treatment period.

Responder analysis (i.e. change ≥100 mL) for pre-dose morning FEV1 at Week 4, 8 and 
12.

Responder analysis (i.e. change ≥100 mL) for trough FEV1 at Week 12.

Change from baseline in terms of ACQ-7 and ACQ-5 at Week 12.

Change from baseline in percentage of rescue medication free days over 12-week 
treatment period.

Change from baseline in percentage of asthma symptom free days over 12-week 
treatment period.
9.
SAFETY ASSESSMENTS
9.1 Safety Variables

Adverse Events (AEs), Adverse Drug Reactions (ADRs), Class-related Adverse Events.

Vital signs (systolic and diastolic blood pressure).

12-lead ECG parameters: heart rate (HR), QTcF, PR and QRS.

Standard hematology and blood chemistry.

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9.2 COVID-19 Infection 
COVID-19 is a contagious illness caused by a coronavirus.  It may present with a wide range 
of symptoms from mild to severe and the investigator/site staff should maintain vigilance in 
detecting these symptoms which include, but are not limited to cough, shortness of breath, 
difficulty breathing, fever, chills, muscle pain, sore throat, and new loss of taste or smell.  
A person can become infected from respiratory droplets transmitted when an infected person 
coughs, sneezes, or talks or from inhalation of the aerosolized particles that may linger in the 
air for extended periods of time. One may also be able to get it by touching a surface or object 
that has the virus on it, and then by touching their mouth, nose, or eyes. Everyone is at risk of 
getting COVID-19. Older adults and people of any age who have serious underlying medical 
conditions may be at higher risk for more severe illness.
The investigator/site staff must take all necessary precautions to minimize and avoid the risk of 
transmission and exposure to study subjects and site staff, according to local guidelines. 
Every effort should be made by the site to confirm all suspected incidences of COVID-19 in 
accordance with local diagnostic guidelines. Documentation of testing and results obtained 
outside the clinical site, should be collected within 14 days of confirmed diagnosis (or whenever 
possible) and recorded in the eCRF. All incidences of COVID-19 as well as the impact on study 
visits and subject completion must be captured in the eCRF.
Occurrence of COVID-19 infection during the study does not automatically lead to withdrawal 
of the subject or discontinuation of study treatment.  It will be up to the investigator’s judgement 
to withdraw the subject from the study if he/she deems that remaining in the study will place 
the subject and/or the clinical site at undue risk by continuing their participation.  All efforts 
should be made to keep the subject on study treatment, if possible. 
In case study visits or procedures are modified or missed due to COVID-19, the relevant 
information will be recorded in the eCRF.  
To date, there are several vaccines approved for prevention of COVID-19 caused by SARS-
CoV-2. For all confirmed cases of COVID-19/SARS-CoV-2 the investigator must follow the 
standard of care in accordance with local treatment guidelines. COVID-19 vaccination status 
and all concomitant treatments must be recorded in the eCRF.
10.
ADVERSE EVENT REPORTING
10.1 Definitions
An Adverse Event is “any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment”.
An adverse event can therefore be any unfavourable 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”.

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All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression “reasonable causal relationship” means to convey in general that there are facts 
(evidence), or arguments meant to suggest a causal relationship.
The definition covers also medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.
A Serious Adverse Event (SAE)/Serious Adverse Drug Reaction is any untoward medical 
occurrence or effect that at any dose falls in one or more of the following categories:
-
Results in death
Death is not an adverse event but an outcome. It is the cause of death that should be regarded 
as the adverse event. The only exception to this rule is “sudden death” where no cause has been 
established; in this latter instance, “sudden death” should be regarded as the adverse event and 
“fatal” as its reason for being serious.
-
Is life-threatening
Life-threatening refers to an event in which the subject was at risk of death at the time of the 
event (e.g., aplastic anemia, acute renal failure, and anaphylaxis). The term does not refer to an 
event which hypothetically might have caused death if it were more severe.
-
Requires hospitalization or prolongation of existing hospitalization
Hospitalization refers to a situation whereby an AE is associated with unplanned formal 
overnight admission into hospital, usually for purpose of investigating and/or treating the AE. 
Hospitalization for the treatment of a medical condition that occurs on an “elective” or 
“scheduled” basis or for a pre-existing condition that did not worsen during the study should 
not necessarily be regarded as an AE. Complications that occur during the hospitalization are 
AEs. If a complication prolongs hospitalization, the event is an SAE. Emergency room visits 
that do not result in a formal admission into hospital should be evaluated for one of the other 
seriousness criteria (e.g., life-threatening; persistent or significant disability or incapacity; 
medically significant).
-
Results in persistent or significant disability or incapacity.
The term significant disability should be viewed as any situation whereby an AE has a clinically 
important effect on the subject’s physical or psychological well-being to the extent that the 
subject is unable to function normally.
- Is a congenital anomaly or birth defect
-
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 jeopardize 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 hospitalisation; or 
development of drug dependency or drug abuse.

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Medical and scientific judgment should be exercised in deciding whether an event is serious 
because medically significant.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
A Non-Serious Adverse Event/Non-Serious Adverse Drug Reaction is an adverse event or 
adverse drug reaction that does not meet the criteria listed above for a serious adverse 
event/serious adverse drug reaction.
10.2 Expectedness
An expected adverse reaction is an adverse reaction, the nature or severity of which is consistent 
with the applicable reference safety information (included in the Investigator’s Brochure for 
CHF 1535 pMDI and CHF 718 pMDI). Otherwise, it is considered unexpected.
Reports which add significant information on specificity or severity of a known, already 
documented serious adverse drug reaction constitute unexpected events. For example, an event 
more specific or more severe than described in the reference safety information 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

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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 treatment(s);
Mechanism of action of the study drug;
Class effects;
Other treatments-concomitant or previous;
Withdrawal of study treatment(s);
Lack of efficacy/worsening of existing condition;
Erroneous treatment with study medication (or concomitant);
Protocol related process.
10.5 Action taken with the study drug due to an AE
Dose not changed
Drug permanently withdrawn
Drug temporarily interrupted
Unknown
Not applicable
10.6  Other actions taken
Specific therapy/Medication
Concomitant Procedure
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 eCRF. 
If the Adverse Event is serious, the Serious Adverse Event Form must also be completed. 

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reported if the investigator becomes aware of them and considers them related to study 
drug.
Up to the closure of the site, SAE reports should be reported to the Parexel Safety Contact. 
New serious adverse events occurring after the site is closed should be reported directly 
to the Chiesi Safety Contact.
10.10 Reporting Serious Adverse Events to Regulatory Authorities and IRBs
All SUSARs/IND safety reports which occur with the investigational medicinal products within 
or outside the concerned clinical trial, if required, will be reported to Regulatory Authority  in 
compliance with the timelines and standards for reporting SUSARs/IND safety reports set out 
in the 21CFR Part 312.32 IND Safety Reporting and linked FDA guidance [Guidance for 
Industry and Investigators, Safety Reporting Requirements for INDS and BA/BE Studies] and 
according to local reporting requirements. 
Investigational Review Boards/Ethic Committees and Investigators will also receive the report, 
if required. 
With regard to regulations in force for Pharmacovigilance, the Investigator must fulfill his/her 
obligation according to the law in force in his country.
10.11 General Notes
In case of death, a comprehensive narrative report of the case should be prepared by the 
Investigator and sent to the Parexel Safety Contact together with the Serious Adverse 
Event form, retaining a copy on site.
If an autopsy is performed, copy of autopsy report should be actively sought by the 
Investigator and sent to the Parexel Safety Contact as soon as available, retaining a copy 
on site.
All documents provided by the Investigator or site staff to the Parexel Safety Contact 
must be carefully checked for respect of confidentiality. All personal subject’s data must 
be redacted.
In case of pregnancy, the subject will be immediately discontinued from the study drug 
and she will be asked (with a separate consent) to be followed with due diligence until 
the outcome of the pregnancy is known and until the age of one year to detect any 
congenital anomaly or birth defect. The pregnancy must be reported by the investigator 
within 24 hours by fax/e-mail/via Monitor to the Parexel Safety Contact using the paper 
Pregnancy Report Form. The Parexel 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 Parexel Safety Contact. Information 
collected in specific sections relative to the pregnancy will be recorded in the form only 
upon signature of the specific ICF by the subject/subject’s partner. 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 

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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, but the subject participating to the study should not be discontinued from 
the study. 
If the pregnancy is discovered before taking any dose either of study drug or of the run-
in/rescue medication, or if the pregnancy occurs after the follow-up call (i.e, at least 7 
days after the last study drug intake) the pregnancy does not need to be reported and 
followed.
Any Adverse Drug Reaction occurring with any marketed non-investigational medicinal 
product and/or concomitant medication during the study must be reported by the 
Investigator to his/her concerned Health Authority and/or to the relevant Marketing 
Authorisation Holders of the involved medicinal products, according to the applicable 
laws. Additionally, also conditions of use outside the marketing authorisation of the 
medicinal products (i.e. off-label, overdose, misuse, abuse and medication errors) or from 
occupational exposure, as well as cases of suspected drug interaction, pregnancy, breast-
feeding exposure and lack of efficacy should be reported.
11.
DATA MANAGEMENT
An electronic CRF (eCRF) will be filled-in by the Investigator and/or his/her representative 
designee.
All subjects who sign the informed consent will be databased. For subjects who are screened 
but not randomized a minimum set of information is required: date of informed consent signed, 
demography, assessment of inclusion/exclusion criteria when applicable, primary reason for 
not continuing, adverse events and concomitant medications if taken due to an adverse event or 
if they are the reason of discontinuation.
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, adverse events and concomitant procedures will be coded using the MedDRA 
dictionary; medications will be coded using the WHO Drug dictionary and Anatomical 
Therapeutic Chemical classification (ATC).
External data (ECG readings, spirometry, laboratory samples, eDiaries, electronic 
questionnaires and IRT) will be processed centrally, sent to the designated CRO and reconciled 
with the corresponding information recorded in the CRF. Access to electronic systems used for 
data collection will be granted to the study personnel only after appropriate training.
After the completion of data collection and cleaning, a review meeting will be held to determine 
the occurrence of any protocol violation and to define the subject populations for the analysis. 
Once the database has been declared to be complete and accurate, it will be locked, the 
randomization codes will be opened, and the planned statistical analysis will be performed.

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If the database is unlocked after the initial lock, the process must be carefully controlled and 
documented; updates to the study data must be authorized by Chiesi.
At the study conclusion, a complete copy of the study data will be created for archival purposes 
at Chiesi. The investigators will receive copies of the subject data for retention at the 
investigational sites.
12.
STATISTICAL METHODS
12.1  Sample Size
The sample size has been calculated to demonstrate the superiority of CHF 1535 pMDI 
800/24µg TDD over CHF 718 pMDI 800µg TDD in terms of the primary and key secondary 
endpoint. 
A discontinuation rate from the randomized study drug of approximately 10% at Week 12 has 
been considered. 
A total of 580 subjects will be randomized according to a 1:1 ratio to either CHF 1535 pMDI 
800/24µg TDD or CHF 718 pMDI 800µg TDD (i.e., 290 subjects per group). This sample size 
will provide, using the main estimand:

Approximately 89% power to detect a mean difference of 108 mL in favor of CHF 1535 
pMDI 800/24µg TDD on change from baseline in FEV1 AUC0-12h at Week 12 at a two-
sided significance level of 0.05, assuming a SD of 409 mL. The assumed mean 
difference of 108 mL represents a weighted average between two means: a mean 
difference between groups of 120 mL while on treatment (assuming 90% of the 
randomized subjects) and a mean difference between groups of 0 mL while off-
treatment (assuming 10% of the randomized subjects).

Approximately 90% power to detect a mean difference of 117 mL in favor of CHF 1535 
pMDI 800/24µg TDD on change from baseline in peak FEV1 within the first 3 hours 
post dose at Week 12 at a two-sided significance level of 0.05, assuming a SD of 434mL. 
The assumed mean difference of 117 mL represents a weighted average between two 
means: a mean difference between groups of 130mL while on treatment (assuming 90% 
of the randomized subjects) and a mean difference between groups of 0mL while off 
treatment (assuming 10% of the randomized subjects).
Thus, considering the main estimand analysis, an overall study power of at least 80% for the 
primary and the key-secondary efficacy endpoint will be ensured.
The primary and key secondary efficacy endpoints will be tested for statistical significance 
following a hierarchical strategy to control the familywise type I error rate using the main 
estimand. Each test will be considered confirmatory only if the tests at all the previous steps are 
successful. The hierarchy for the primary and key secondary endpoints is as follows:

Step 1:  Primary endpoint (i.e. change from baseline in FEV1 AUC0-12h at Week 12) 
using the main estimand - Tested at a 2-sided 5% significance level.

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
Step 2: Key-secondary endpoint (i.e. change from baseline in peak FEV1 within the first 
3 hours post dose at Week 12) using the main estimand - Tested at a 2-sided 5% 
significance level.
12.2 Populations for analysis
Safety set: All randomized subjects who receive at least one dose of study drug (analyzed 
as treated).
ITT set: All randomized subjects who receive at least one dose of the study drug (analyzed 
as randomized).
12.3 Statistical analysis
A detailed statistical analysis plan will be described in the Statistical Analysis Plan (SAP). 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 
General descriptive statistics for numeric variables will include the n (number of observed 
values), the mean, the standard deviation, the median, the minimum, and the maximum values. 
For categorical variables, the number and percent of subjects with a specific level of the variable 
will be presented.
12.3.2 Missing data

FEV1 AUC0-12h: In the calculation of FEV1 AUC0-12h normalised by time, missing values 
will be replaced as follows:
o
If the pre-dose FEV1 value is not available, the entire curve will be considered 
as missing.
o
In case the 12h value is missing, the value of the previous timepoint will be 
carried over; the time associated with this timepoint will be the time of study 
medication intake plus 12 hours.
o
Single, isolated missing FEV1 values (not pre-dose or last value) will be replaced 
by linear interpolation using the adjacent values.
o
If 2 or more consecutive post-dose time points have missing FEV1 values, the 
FEV1 AUC0-12h will be considered as missing.
o
If in total 3 or more of the post-dose time points have missing FEV1 values, the 
FEV1 AUC0-12h will be considered as missing.

Pre-dose FEV1: Pre-dose FEV1 is defined as the mean of 45 minutes and 15 minutes 
pre-dose FEV1 measurements. If one of the measurements at 45 minutes and 15 minutes 
pre-dose is not available, then the non-missing measurement will be taken as the pre-
dose value. If no pre-dose measurement is available, then the pre-dose FEV1 value will 
be considered as missing.

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
Trough FEV1: Trough FEV1 is defined as the mean of 11.5h and 12h post-dose FEV1 
measurements. If one of the FEV1 measurements at 11.5h and 12h post-dose is not 
available, then the non-missing measurement will be taken as the trough FEV1 value. If 
no measurement is available, then the trough FEV1 value will be considered as missing.

Peak FEV1: Peak FEV1 is defined as the maximum value among those collected at 5 
min, 15 min, 30 min, 1h, 2h and 3h post-dose. If 2 or more FEV1 measurements at 5 
min, 15 min, 30 min, 1h, 2h and 3h post-dose are not available, then the peak FEV1 
value will be considered as missing.

Daily data: A minimum of 7 days with available measurements will be required in the 
run-in period and in each inter-visit period (i.e. [Week 0 – Week 4]; [Week 4 – Week 
8] and [Week 8 – Week 12]) to consider the following variables as non-missing: 
morning and evening PEF, use of rescue medication, daily asthma symptoms, 
percentage of rescue medication free days and asthma symptom free days.

ACQ-7 and ACQ-5 questionnaire: For ACQ-7 and ACQ-5 questionnaire, the total score 
will be calculated only if all the scores derived from all the seven items (for ACQ-7) or 
from all the five items (for ACQ-5) 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 blinded 
review of the data. Decisions will be fully documented in the Data Review Report.
12.3.3 Subject demographics and baseline characteristics
Demographics and baseline variables will be summarized by treatment arm using descriptive 
statistics for the ITT population.
12.3.4 Primary efficacy variables
Main estimand
The attributes of the main estimand in terms of population, treatments, variable and population-
level summary are provided in section 2.1. The strategy for intercurrent events and events 
leading to missing data for the primary efficacy analyses and the sensitivity analyses targeting 
this estimand is summarized below.
Intercurrent event 
/ event leading to 
missing data
Strategy
Strategy for sensitivity 
analyses

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Early 
discontinuation 
from the 
randomized study 
drug
Treatment policy: Data collected after 
discontinuation from the randomized study 
drug (i.e. off-treatment data) will be included 
in the analysis.
Early 
discontinuation 
from the study
Hypothetical: The collected off-treatment data 
observed on all subjects will be used for the 
imputation of missing data after study 
discontinuation for both treatment arms [1].
This approach targets the off-treatment effect 
that would have been observed if all subjects 
discontinued from study drug had consented 
to continue the study.
Note: In case of collection of very few off-
treatment data such that the planned 
imputation cannot be performed, the 
imputation of missing data after study 
discontinuation will be based on the Copy 
Reference (CR) approach (i.e. considering the 
data distribution of the CHF 718 pMDI 800µg 
TDD arm, including both on-treatment and 
off-treatment data) for both treatment arms.
Sensitivity 1: A two-
dimensional tipping point 
analysis varying 
assumptions about the 
missing outcomes in the 
two treatment arms will be 
performed to explore the 
plausibility of missing data 
assumptions under which 
the conclusions change (i.e. 
under which treatment 
effect is no longer 
statistically significant).
Use of not allowed 
medications and 
other important 
protocol deviations
Treatment policy: Data will be used regardless 
of whether or not the intercurrent event 
occurs.
Wrong study drug 
intake
Treatment policy: If a subject takes the wrong 
study drug, the data will be analyzed as if the 
intercurrent event had not occurred, thus 
considering the randomized study drug.
Analysis
Change from baseline in FEV1 AUC0-12h at Week 12 will be analyzed on the ITT set using an 
ANCOVA model including treatment group, US region and prior asthma therapy as fixed 
effects and baseline value (i.e. Week 0, FEV1 pre-dose) as covariate.. The adjusted means in 
each treatment group, the adjusted mean difference between treatments and their 95% CIs at 
Week 12 will be estimated by the model. Superiority of CHF 1535 pMDI 800/24µg TDD will 
demonstrated by a statistically significant difference between treatments at Week 12 (defined 
as p<0.05) favoring CHF 1535 pMDI 800/24µg TDD.

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12.3.5 Key-Secondary efficacy variable
The attributes of the main estimand in terms of population, treatments, variable and population-
level summary are provided in section 2.1. The strategy for intercurrent events and events 
leading to missing data for the key-secondary efficacy analyses and the sensitivity analyses 
targeting this estimand is the same as the one reported for the primary efficacy variable (section 
12.3.4).
Analysis
Change from baseline in peak FEV1 within the first 3 hours post-dose at Week 12 will be 
analyzed on the ITT set using an ANCOVA model including treatment group, US region and 
prior asthma therapy as fixed effects and baseline value (i.e. Week 0, FEV1 pre-dose) as 
covariate.. The adjusted means in each treatment group, the adjusted mean difference between 
treatments and their 95% CIs at Week 12 will be estimated by the model. Superiority of CHF 
1535 pMDI 800/24µg TDD will demonstrated by a statistically significant difference between 
treatments at Week 12 (defined as p<0.05) favoring CHF 1535 pMDI 800/24µg TDD.
12.3.6 Secondary efficacy variable
Analyses of secondary efficacy variables are planned to target the same estimand as described 
for the primary and key-secondary efficacy variables in sections 12.3.4 and 12.3.5 (i.e., with 
collected off-treatment data included in the analysis and used to impute possible missing off-
treatment data) with:

Early discontinuation from the randomized study drug managed with a treatment 
policy strategy with off-treatment data included in the analysis.

Early discontinuation from the study managed with a hypothetical strategy with off-
treatment data observed on all subjects used for the imputation of missing data after 
study discontinuation for both treatment arms [1]. 
Note: In case of collection of very few off-treatment data such that the planned 
imputation cannot be performed, the imputation of missing data after study 
discontinuation will be based on the Copy Reference (CR) approach (i.e. considering 
the data distribution of the CHF 718 pMDI 800µg TDD arm, including both on-
treatment and off-treatment data) for both treatment arms

Use of not allowed medications and other important protocol deviations managed 
with a treatment policy strategy, with data used regardless of whether or not the 
intercurrent event occurs.

Wrong study drug intake managed with a treatment policy strategy, with data used 
regardless of whether or not the intercurrent event occurs (i.e. considering the 
randomized study drug).
No sensitivity analysis will be performed for the secondary efficacy analyses.

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Secondary efficacy variables will be analyzed as follows:

Change from baseline in FEV1 AUC0-12h at Week 0 will be analyzed with  an 
ANCOVA model as described for the analysis of the primary and key-secondary 
efficacy variable.

Change from baseline in peak FEV1 within the first 3 hours post-dose at Week 0 will 
be analyzed with an ANCOVA model as described for the analysis of the primary and 
key-secondary efficacy variable.

Change from baseline in trough FEV1 at Week 12 will be analyzed with an ANCOVA 
model as described for the analysis of the primary and key-secondary efficacy variable.

Change from baseline in pre-dose morning FEV1 at Week 4, 8 and 12 will be analyzed 
with an ANCOVA model as described for the analysis of the primary and key-secondary 
efficacy variable.

Change from baseline in average morning PEF over 12-week treatment period will 
be analyzed using an ANCOVA model including treatment group, US region and prior 
asthma therapy as fixed effects, and baseline value (i.e. average of the values collected 
during the run-in period) as covariate.

Change from baseline in average evening PEF over 12-week treatment period will be 
analyzed with an ANCOVA model as described for morning PEF.

Responder analysis (i.e. change from baseline ≥100 mL) for pre-dose morning FEV1 
at Week 4, 8 and 12 will be analyzed separately at each visit with a logistic regression 
model including treatment, US region and prior asthma therapy as factors and baseline 
FEV1 value (i.e. Week 0, FEV1 pre-dose) as covariate.

Responder analysis (i.e. change from baseline ≥100 mL) for trough FEV1 at Week 12 
will be analyzed with a logistic regression model including treatment,  US region and 
prior asthma therapy as factors and baseline FEV1 value (i.e. Week 0, FEV1 pre-dose) 
as covariate.

Change from baseline in terms of ACQ-7 and ACQ-5 at Week 12 will be analyzed 
with an ANCOVA model as described for the analysis of the primary and key-secondary 
efficacy variable, including baseline value (i.e. ACQ-7 or ACQ-5 at Week 0) as 
covariate.

Change from baseline in percentage of rescue medication free days over 12-week 
treatment period will be analyzed with an ANCOVA model as described for morning 
PEF.

Change from baseline in percentage of asthma symptom free days over 12-week 
treatment period will be analyzed with an ANCOVA model as described for morning 
PEF.

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12.3.7 Safety variables
Safety analysis will be based on Safety set. For subjects who discontinue the study drug but 
remain in the study, assessments conducted following 1 week after the last dose of study drug 
will not be considered in the analysis or presentation of safety data.
Adverse Events
Classification

All adverse events starting on or after the first study drug intake and up to 1 week after 
the last dose of study drug intake will be classified as treatment emergent adverse even 
(TEAE). 

Any adverse events started after the informed consent signature and before the first 
study drug intake will be classified as pre-treatment adverse events. 

Any adverse events started later than 1 week after the last dose of study drug will be 
considered as post-treatment adverse events.
Descriptive Analysis of TEAEs

The number of subjects who experienced: 
-
at least one TEAE
-
at least one drug related TEAE (i.e. ADR)
-
at least one serious TEAE
-
at least one non-serious TEAE
-
at least one serious related TEAE
-
at least one TEAE leading to study drug discontinuation
-
at least one TEAE leading to death 
will be summarized by treatment arm. Summaries will be presented overall (number 
and percentage of subjects having at least one event, total number of events and 
incidence density [i.e. number of subjects with at least one event divided by the total 
person-time of exposure to study drug]) and by System Organ Class (SOC) and 
Preferred Term (PT) (number and percentage of subjects having at least one occurrence 
of that event and incidence density):

Adverse events data will be also visualized with outputs including two-panels display 
with 1. proportions and incidence density and 2. plotted proportions.

All adverse events will be listed. 

Pre-treatment adverse event and post-treatment adverse events will be listed only.
Analysis of TEAEs comparing treatment groups

The number of subjects who experienced: 

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-
at least one TEAE
-
at least one drug related TEAE (i.e. ADR)
-
at least one serious TEAE
-
at least one non-serious TEAEs
-
at least one serious related TEAE
-
at least one TEAE leading to study drug discontinuation
-
at least one TEAE leading to death 
will be compared between treatment groups in terms of risk difference. The risk 
difference will be calculated considering the proportion of subjects with the selected 
event in the two treatment groups (i.e. number of subjects of the treatment group with 
the selected event / number of subjects of the treatment group). The 95% CIs for the 
risk difference will be calculated using the Newcombe hybrid score method [29]. Note: 
For each category defined above, the appropriateness of this analysis will be further 
evaluated in the SAP considering the actual number of events occurred in the overall 
safety set. 

The number of subjects who experienced: 
-
at least one TEAE by SOC
-
at least one serious TEAE by SOC
-
at least one TEAE by PT
-
at least one serious TEAE by PT
will be compared between treatment groups with the same methodology described in 
the previous bullet point.

Adverse events data will be also visualized with outputs including two-panels display 
with 1. plotted proportions and 2. forest plot with risk differences (95% CI).
Class-related Adverse Events
Class-related Adverse Events will be grouped into the following medical concepts according to 
the TEAE SOC and PT. The final categorization of TEAEs into medical concepts will be 
defined by the study team during the blinded review of the data, reported in the SAP and 
finalized before the database lock.
Class related Adverse Events
Medical concept 1
Medical concept 2
Lower Respiratory Tract Infections (including 
pneumonia)
Candidiasis
Ocular effects
Decreased bone density
ICS class related AEs
Adrenal suppression
LABA class related AEs
Cardiovascular effects

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Effects on glucose
Effects on potassium
Muscle spasms
Tremor
Descriptive Analysis of class related TEAEs

The number of subjects who experienced: 
-
at least one class related TEAE
-
at least one class related ADR
-
at least one serious class related TEAE
-
at least one non-serious class related TEAE
-
at least one serious class related ADR
-
at least one class related TEAE leading to study drug discontinuation
-
at least one class related TEAE leading to death 
will be summarized by treatment arm. Summaries will be presented overall (number 
and percentage of subjects having at least one event, total number of events and 
incidence density [i.e. number of subjects with at least one event divided by the total 
person-time of exposure to study drug]) and by medical concepts (number and 
percentage of subjects having at least one occurrence of that event and incidence 
density):

Adverse events data will be also visualized with outputs including two-panels display 
with 1. proportions and incidence density and 2. plotted proportions.
Analysis of class-related TEAEs comparing treatment groups

The number of subjects who experienced: 
-
at least one class related TEAE
-
at least one class related ADR
-
at least one serious class related TEAE
-
at least one non-serious class related TEAE
-
at least one serious class related ADR
-
at least one class related TEAE leading to study drug discontinuation
-
at least one class related TEAE leading to death 
will be compared between treatment groups with the same methodology described for 
the TEAEs. 

The number of subjects who experienced: 
-
at least one class related TEAE by medical concept 1
-
at least one serious class related TEAE by medical concept 1
-
at least one class related TEAE by medical concept 2
-
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will be compared between treatment groups with the same methodology described for 
the TEAEs.

Adverse events data will be also visualized with outputs including two-panels display 
with 1. plotted proportions and 2. forest plot with risk differences (95% CI).
ECG
ECG parameters and change from baseline will be summarised by treatment group using 
descriptive statistics. 
Vital signs
Vital signs and change from baseline will be summarised by treatment group using descriptive 
statistics.
Laboratory data
The laboratory values and the change from baseline for continuous laboratory will be 
summarised by treatment group using descriptive statistics.
12.3.8 Interim analysis
No interim analysis is planned.
13.
INSTITUTIONAL REVIEW BOARD APPROVAL 
The study proposal will be submitted to the Institutional Review Board in accordance with the 
requirements of each country. 
The IRB shall give its opinion in writing clearly identifying the study number, study title and 
informed consent form approved, before the clinical trial commences.
A copy of all communications with the IRB will be provided to the Chiesi.  
The investigator should provide written reports to the IRB annually or more frequently if 
requested on any changes significantly affecting the conduct of the trial and/or increasing risk 
to the subjects.
14.
 REGULATORY REQUIREMENTS
The study will be notified to the Health Authorities (or authorized by) according to the legal 
requirements in the participating country.
Selection of the subjects will not start before the approval of the Institutional Review Board has 
been obtained and the study notified to Health Authorities (or authorized by).

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15.
INFORMED CONSENT 
Written informed consent will be obtained from all subjects as per IRB guidelines before any 
study-related procedures are performed. Informed consent must be written in a language 
understandable to the subjects. It is the responsibility of the investigator to obtain written 
consent from each subject prior to any study related procedures taking place, by using the latest 
IRB approved version of the document. 
The processing of subjects’ data as well as subject inclusion in the study is based on subject’s 
explicit consent as pointed out within the informed consent.
Adequate time shall be given to the subject to ask the Investigator or designee about any 
clarification needed and to consider his or her decision to participate to the trial. 
Consent must be documented by the subject’s dated signature. The signature confirms that the 
consent is based on information that has been understood. The investigator must sign and date 
the informed consent form.
Each subject’s signed informed consent must be kept on file by the investigator. One copy must 
be given to the subject.
In case of rescreening, the subject should sign a new informed consent and will be assigned 
with a new subject number; a link to prior subject number will be recorded in the eCRF.
Female subjects becoming pregnant during the study and partner of a subject participating in 
the study becoming pregnant will have to sign a specific informed consent form to provide 
permission to Chiesi to collect information about the pregnancy, its outcome and the birth and 
health of the newborn child.
In case of pregnancy during the study, if the subject’s partner and his/her legal representative 
are unable to read, the specific informed consent for pregnancy follow-up will be obtained in 
the presence of an impartial witness, e.g., a person independent of the study who will read the 
informed consent form and the written information for the subject partner. The witness shall 
sign and date the informed consent document.
16.
SOURCE DOCUMENTS/DATA
16.1 Recording of source data
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data.  
Data recorded in the electronic case report form (eCRF) derived from source documents should 
be consistent with the data recorded on the source documents.

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16.2 Direct access to source document/data
The Investigator must permit trial-related monitoring, audits, Institutional Review Board(s) 
review or regulatory inspection, providing direct access to source data/documents.
17.
STUDY MONITORING
Monitoring will be performed by Parexel who has been designated by Chiesi.
It is understood that the monitor(s) will contact and visit the Investigator/center before the 
study, regularly throughout the study and after the study had been completed, and that they will 
be permitted to inspect the various study records: case reports form, Investigator study file and 
source data, 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 CRFs for legibility, accuracy and completeness;
to validate the contents of the CRFs against the source documents;
to assess the status of drug storage, dispensing and retrieval.
Prior to each monitoring visit, the Investigator or staff will record all data generated since the 
last visit on the case report forms. The Investigator and/or study staff will be expected to be 
available for at least a portion of the monitoring visit to answer questions and to provide any 
missing information.
It is possible that the Investigator site may be audited by Sponsor personnel or regulatory 
national and/or international regulatory agencies during and after the study has been completed.
18.
QUALITY ASSURANCE
The sponsor will implement processes to manage quality and oversight throughout all stages 
and activities of the trial based on data and processes identified as critical for the subjects’ 
rights and safety as well as data reliability and robustness. 
Quality management will include tools, and procedures for data collection, monitoring and 
processing, as well as the collection of information essential to decision making.
The quality management system will use a risk-based approach as described in ICH E6 with:

Critical Process and Data Identification

Risk Identification/Evaluation/Control/Communication and Review

Risk Reporting.
The R&D Quality Assurance Department of Chiesi may perform an audit at any time according 
to the Chiesi’s Standard Operating Procedures, in order to verify whether the study is being 
conducted in agreement with Good Clinical Practices and the protocol. 

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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 (according to country specific guidelines). 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 and Institutional 
Review Board providing the justification of premature ending or of the temporary halt.
22.
CLINICAL STUDY REPORT
At the end of the trial a summary of the clinical study report will be provided to all Institutional 
Review Boards and the FDA.
23.
RECORD RETENTION
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner by the Investigator in a secure study file.
Regulations require that essential documents must be retained for at least two years after the 
final marketing approval in an ICH region or until two years have elapsed since the formal 
interruption of the clinical development of the product under study.

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It is the responsibility of the Sponsor to inform the Investigator of when these documents can 
be destroyed. The Investigator must contact Chiesi before destroying any trial-related 
documentation. In addition, all subjects’ medical records and other source documentation will 
be kept for the maximum time permitted by the institution.
24.
PUBLICATION OF RESULTS
Chiesi is entitled to publish and/or present any results of this study at scientific meetings, and 
to submit the clinical trial data to national and international Regulatory Authorities and, if they 
fall under the Chiesi commitments on Clinical Trial Transparency, to make them available on 
www.chiesi.com website.
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 
according to the relevant regulatory requirements.

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25.
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Blake KV, Lang JE. Association of Inhaled Corticosteroids and Long-Acting 
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PMID: 29554174; PMCID: PMC5876909.

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to severe asthma. Allergy. 2007 Oct;62(10):1182-8.
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Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM; ICAT SE study group. 
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to severe asthma. Allergy. 2007 Oct;62(10):1182-8. 
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Version No. 2.0 
IND No.: 153868
Date: 01Jun2023
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IND No.: 153868
Date: 01Jun2023
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APPENDIX 1 - Approval of the protocol by clinical investigator(s)
A 12 week, randomized, double-blind, multicenter, active controlled, 2-arm parallel group 
study testing the superiority of CHF 1535 pMDI 800/24µg total daily dose (fixed 
combination of extrafine beclomethasone dipropionate plus formoterol fumarate) compared 
to CHF 718 pMDI 800µg total daily dose (extrafine beclomethasone dipropionate) in adults 
with asthma on medium or high-dose inhaled corticosteroid.
Product: CHF 1535
Pharmaceutical Form: Pressurized metered dose inhaler
Approval of Clinical Study Protocol by the 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 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 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.
Investigator’s Name: ______________________, MD
Centre No.: 
_____________________
             Signature
Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy

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 APPENDIX 2 – RECOMMENDATIONS RELATED TO 
CONTRACEPTION AND PREGNANCY TESTING IN 
CLINICAL TRIALS
Birth control methods, which may be considered as highly effective
For the purpose of this guidance, methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly are considered as highly effective birth control 
methods.  
Such methods include:

combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation:
o
oral
o
injectable
o
implantable3

intrauterine device (IUD)3

intrauterine hormone-releasing system (IUS)3

bilateral tubal occlusion3

vasectomized partner1,3

sexual abstience2
1Vasectomized partner is highly effective birth control method 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. 
2Sexual abstinence is considered as highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatments.  
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
3Methods with low user dependency.
Definition of women of childbearing potential and of fertile men
For the purpose of this document, a woman is considered of childbearing potential (WOCBP), 
i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile.  
Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy.  A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy.  However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.  For the purpose of this 
document, a man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy.  
Reference:  Recommendations related to contraception and pregnancy testing in clinical trials 
(Clinical Trial Facilitation Group, Final version 1.1 dd. 21/09/2020).