A Single-dose, Randomised, Double-blind, Controlled, 2-way Cross-over Study to Assess the Potential for Bronchoconstriction of the New Propellant HFA-152a Versus the Marketed HFA-134a Propellant, in Adult Subjects With Mild Asthma
Phase: PHASE2
Conditions: Asthma
Sponsor: Chiesi Farmaceutici S.p.A.

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CLINICAL STUDY PROTOCOL 
STUDY CODE No.: CLI-05993AB6-07
EUDRACT No.: 2022-000536-36
A SINGLE-DOSE, RANDOMISED, DOUBLE-BLIND, CONTROLLED, 2-WAY CROSS-OVER 
STUDY TO ASSESS THE POTENTIAL FOR BRONCHOCONSTRICTION OF THE NEW 
PROPELLANT HFA-152a VERSUS THE MARKETED HFA-134A PROPELLANT, IN ADULT 
SUBJECTS WITH MILD ASTHMA.
Version No.: 2.0
Date: 30 August 2022
The information contained in this document is confidential and will not be disclosed to others without written 
authorisation from Chiesi Farmaceutici S.p.A., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics 
Committee/Investigational Review Boards, or people participating in the conduct of the study.
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy
NCT05472662

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Clinical Study Code No.: CLI-05993AB6-07
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GENERAL INFORMATION
SPONSOR
Chiesi Farmaceutici S.p.A.* 
Via Palermo 26/A
43122 Parma - Italy
+ 39 0521 2791
*Also reported as Chiesi throughout 
the text
SPONSOR MEDICAL EXPERT
(Clinical Research Physician)
, MD
Clinical Research Physician
Global Clinical Development
Tel. 
Mob. 
e-mail: 
 
Readily available in case of medical 
questions
COORDINATING INVESTIGATOR
Dave Singh
Medicines Evaluation Unit 
The Langley Building
Southmoor Road, Wythenshawe
Manchester, 
M23 9QZ, United Kingdom
Tel. +44 (0) 161 946 4052
Fax. +44 (0)161 946 1459
e-mail: dsingh@meu.org.uk
MONITORING CRO
CENTRAL SPIROMETRY LABORATORY

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Clinical Study Code No.: CLI-05993AB6-07
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EUDRACT No.: 2022-000536-36
Date: 30 August 2022
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VERSION HISTORY
Version 
Date 
Change History
1.0
06 April 2022
First version
2.0
30 August 2022
Second Version
The following non-substantial changes applied to 
the study protocol:
-
Numbering of the exclusion criteria have 
been adjusted; 
-
Removal of the calibration for the 
centralized spirometer as the device is 
already calibrated; 
-
Clarification that the spirometry for 
eligibility is performed locally;
-
Clarification of the re-screening 
procedure;
-
Removal of the rest period before ECG 
as not required;
-
Clarification regarding the ECG and 
Vital signs assessment pre-dose;
-
Clarification that the pregnancy test is 
applicable only for WOCBP;
-
Inclusion of the possibility to perform 
the ACQ-5 questionnaire at pre-
screening visit.  

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PROTOCOL OUTLINE
Study title
A single-dose, randomised, double-blind, controlled, 2-way cross-over 
study to assess the potential for bronchoconstriction of the new 
propellant HFA-152a versus the marketed HFA-134a propellant, in 
adult subjects with mild asthma.
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
HFA-152a propellant via pressurised metered dose inhaler (pMDI).
Centres
Approximately 4 centres in the United Kingdom (UK).
Indication 
Not Applicable
Study design
Single-dose, randomised, double-blind, controlled, 2-way cross-over study.
(HFA = Hydrofluoroalkane; pMDI = Pressurised metered dose inhaler)
The study design proposed in the figure is just an example of one of the 
possible sequences.
Study phase
Phase IIa
Objectives
Primary objective:

To compare the potential for bronchoconstriction 
 
of the HFA-152a propellant versus 
 the HFA-134a 
propellant when administered alone (not in combination with other 
active compounds).
Secondary objective:

To evaluate the general safety and tolerability of the two different 
propellants.

Treatment duration
Two treatment periods, each with a single-dose administration 
(
) of the study treatment, separated by a wash-out period of 
2 to 7 days.
Test product 
dose/route/regimen 
Placebo HFA-152a propellant via pMDI:

Administration: Single-dose administration 

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Reference product 
dose/route/regimen 
Placebo HFA-134a propellant via pMDI: 

Administration: Single-dose administration 
. 
Number of subjects
24 randomised subjects in order to have 20 evaluable subjects.
Study population
Male and female adult subjects with mild asthma (Step 1 of the Global 
Initiative for Asthma [GINA] 2021 guidelines).
Inclusion criteria
Subjects must meet all of the following inclusion criteria at screening, to 
be eligible for enrolment into the study:
1.
Subject’s written informed consent obtained prior to any study 
related procedure;
2.
Gender and age: Male or female adults aged from 18 to 75 years 
old (inclusive);
3.
Diagnosis of asthma: documented established diagnosis of mild 
asthma for at least 6 months according to Step 1 of the GINA 2021 
guidelines;
4.
Lung function: subjects with a pre-bronchodilator forced expiratory 
volume in 1 second (FEV1) ≥60% of the predicted normal value and 
≥1.5 L at screening and prior to randomisation, after appropriate 
wash-out from bronchodilators;
Note: In case of FEV1 values <60% at screening, measures can be 
repeated once before randomisation in an unscheduled visit.
5.
Documented excessive variability in lung function (one or more 
of the following): positive bronchodilator reversibility test, defined 
as an increase in FEV1 of >12% and/or >200 mL from baseline 
within 30 minutes (min) after inhalation of 200‑400 µg salbutamol 
(albuterol) according to the American Thoracic Society (ATS) and 
European Respiratory Society (ERS) (ATS/ERS) standards; or 
positive bronchial challenge test, defined as a decrease from baseline 
in FEV1 of ≥20% with standard doses of methacholine, or a decrease 
of ≥15% with standardised hyperventilation, hypertonic saline or 
mannitol challenge. Excessive variability in lung function must be 
documented within the past 2 years (a copy of the original 
spirometry report must be included as source documentation). In 
case evidence of documented excessive variability in lung function 
is not available, the test (bronchodilator reversibility or bronchial 
challenge) should be performed at screening;
In case the criterion of excessive variability in lung function is not 
met at screening, the test can be repeated once before randomisation 
in an unscheduled visit. A bronchial challenge test can be performed, 
if a bronchodilator reversibility test was unsuccessful and vice versa.  
6.
Current 
asthma 
therapy: 
as 
needed 
low-dose 
inhaled 
corticosteroids 
(ICS)‑formoterol, 
as 
needed 
short-acting 
β2-agonists (SABA), or low-dose ICS whenever SABA is taken; 
taken not more than twice a week (2 events) in the 4 weeks prior to 
screening or in the 6 weeks prior to randomisation. For subjects using 
pMDI, spacer is allowed (as it improves delivery and reduces the risk 
of ICS local side‑effects);

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Low-dose ICS is defined by GINA 2021 (box 3-6) as follows:
Inhaled corticosteroid
Adults daily low dose
Beclometasone dipropionate (pMDI, standard 
particle, hydrofluoroalkane [HFA])
200-500 µg
Beclometasone 
dipropionate 
(dry 
powder 
inhaler [DPI] or pMDI, extrafine, HFA)
100-200 µg
Budesonide (DPI or pMDI, standard particle, 
HFA)
200-400 µg
Ciclesonide (pMDI, extrafine, HFA)
80-160 µg
Fluticasone furoate (DPI)
100 µg
Fluticasone propionate (DPI)
100-250 µg
Fluticasone 
propionate 
(pMDI, 
standard 
particle, HFA)
100-250 µg
Mometasone furoate (DPI)
See product 
information
Mometasone furoate (pMDI, standard particle, 
HFA)
200-400 µg
7.
Asthma control: controlled or partly controlled based on an Asthma 
Control Questionnaire© (ACQ-5) score <1.5 at screening (or pre-
screening) and prior to randomisation;
8.
Ability to use the inhalers: subjects must have a cooperative 
attitude and the ability to be trained to use correctly the pMDI 
inhalers at screening;
9.
Ability to comply with the protocol: subjects must have a 
cooperative attitude, the ability to perform the required outcome 
measurements, and the ability to understand the risks involved at 
screening and prior to randomisation;
10. Female subjects fulfilling one of the following criteria:
a)
Women of non-childbearing potential (WONCBP) defined as 
physiologically 
incapable 
of 
becoming 
pregnant 
(i.e. postmenopausal or permanently sterile, as per definitions 
given Section 4.1 of the Clinical Trials Facilitation and 
Coordination Group guidance). 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);
b)
Women of childbearing potential (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 
preferably with low user dependency, from the signature of 

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the informed consent form (ICF) and until the follow-up 
visit/call or;
ii.
WOCBP with non-fertile male partners (contraception is not 
required in this case).
Note: In case of hormonal contraception, an additional 
non-hormonal method (barrier method, preferably male condom) is 
required.
11. Male subjects fulfilling one of the following criteria:
a)
Fertile male subjects with pregnant or non-pregnant 
WOCBP partners: they must be willing to use male condom 
from the signature of the ICF and until the follow-up 
visit/call, or;
b)
Non-fertile male subjects (contraception is not required in 
this case), or;
c)
Fertile male subjects with WONCBP partner (contraception 
is not required in this case).
For the definition of WOCBP, fertile men and the list of highly 
effective birth control methods, refer to Section 4.1 of the Clinical 
Trials Facilitation and Coordination Group guidance.
The following criteria will be re-checked at randomisation: #4, #6, #7, #9.
Exclusion criteria
The presence of any of the following exclusion criteria will exclude a 
subject from study enrolment:
1.
History of “at risk” asthma: history of near fatal asthma, 
hospitalisation for asthma in intensive care unit which, in the 
judgement of the Investigator, may place the subject at undue risk;
2.
Recent exacerbation: asthma exacerbation requiring systemic 
corticosteroids or emergency room admission or hospitalisation 
within 4 weeks prior to screening and prior to randomisation;
3.
Asthma requiring use of biologics: asthma subjects treated with 
chronic systemic corticosteroids or anti-immunoglobulin E (IgE) or 
other monoclonal or polyclonal antibodies;
4.
Respiratory disorders other than asthma: subjects with known 
respiratory disorders other than asthma. This can include, but is not 
limited 
to, 
diagnosis 
of 
chronic 
obstructive 
pulmonary 
disease (COPD) as defined by the current guidelines (e.g. Global 
Initiative 
for 
Chronic 
Obstructive 
Lung 
Disease [GOLD] 
guidelines), known α1-antitrypsine deficiency, active tuberculosis, 
bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension 
and interstitial lung disease;
5.
Lung cancer or history of lung cancer: subject with a diagnosis of 
lung cancer or a history of lung cancer;
6.
Lung resection: subject with a history of lung volume resection;
7.
Lower respiratory tract infection: subject with lower respiratory 
tract infection that required use of antibiotics within 4 weeks prior to 
screening and prior to randomisation;
8.
Documented coronavirus disease 2019 (COVID-19) diagnosis 
within 
2 weeks 
prior 
to 
screening, 
or 
associated 

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complications/symptoms, which have not resolved within 2 weeks 
prior to screening;
9.
Smoking status: current smoker, or ex-smoker with a smoking 
history of ≥10 pack-years (pack-years = the number of cigarette 
packs per day times the number of years). 
To be eligible for the study, ex-smokers with a smoking history of 
<10 pack-years must have stopped smoking for ≥1 year (≥6 months 
for e-cigarettes);
10. Cancer or history of cancer (other than lung cancer): subject with 
active cancer or a history of cancer with less than 5 years disease-free 
survival time (whether or not there is evidence of local recurrence or 
metastases). Localised carcinoma (e.g. basal cell carcinoma, in situ 
carcinoma of the cervix adequately treated) is acceptable;
11. Cardiovascular diseases: subjects who have known and clinically 
significant (CS) cardiovascular conditions such as, but not limited 
to, unstable or acute ischemic heart disease experienced within one 
year prior to study entry, class III/IV heart failure (according to the 
classification by the New York Heart Association [NYHA]), history 
of atrial fibrillation, uncontrolled hypertension, history of sustained 
or non-sustained cardiac arrhythmias diagnosed within 6 months 
prior to study entry and not controlled with therapy according to the 
Investigator’s opinion;
12. Electrocardiogram (ECG) criteria: any CS abnormal 12‑lead 
ECG that, in the Investigator's opinion, would affect safety 
evaluations or place the subject at risk; 
Note: In case the criterion is not met at screening, the test can be 
repeated once before randomisation in an unscheduled visit
13. Central nervous system disorders: subjects with a history of 
symptoms or significant neurological disease such as but not limited 
to transient ischemic attack, stroke, seizure disorder or behavioural 
disturbances, according to the Investigator’s opinion;
14. Other concurrent diseases: subjects with historical or current 
evidence of uncontrolled concurrent disease such as, but not limited 
to, hyperthyroidism, diabetes mellitus or other endocrine disease, 
haematological disease, autoimmune disorders (e.g. rheumatoid 
arthritis), gastrointestinal disorders (e.g. poorly controlled peptic 
ulcer, gastroesophageal reflux disease), significant renal impairment 
or other disease or condition that might, in the judgement of the 
Investigator, place the subject at undue risk or potentially 
compromise the results or interpretations of the study;
15. Laboratory 
abnormalities: 
subjects 
with 
CS 
laboratory 
abnormalities indicating a significant or unstable concomitant 
disease that might, in the judgement of the Investigator, place the 
subject at undue risk or potentially compromise the results or 
interpretations of the study; 
Note: In case the criterion is not met at screening, the test can be 
repeated once before randomisation in an unscheduled visit

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16. Alcohol/drug abuse: subjects with a known or suspected history of 
alcohol and/or substance/drug abuse within 12 months prior to 
screening;
17. Participation to investigational trial: subjects who have received 
any investigational drug within the 30 days (60 days for biologics) 
prior to screening, or a more appropriate time as determined by the 
Investigator (e.g. approximately 5 half-lives of the investigational 
drug whatever is longer);
18. Hypersensitivity: history of hypersensitivity to any of the study 
medications components or a history of other allergy that, in the 
opinion of the Investigator, contraindicates the subject’s 
participation;
19. Subjects 
mentally 
or 
legally 
incapacitated 
or 
subjects 
accommodated in an establishment as a result of an official or 
judicial order;
20. Recent eye surgery or any condition where raised intracranial 
pressure (caused by forceful exhalation) would be harmful;
21. For female subjects only: pregnant or lactating women, where 
pregnancy is defined as the state of a female after conception and 
until termination of the gestation, confirmed by a positive serum 
human chorionic gonadotropin laboratory test.
Note: Serum pregnancy test to be performed at screening, and urine 
pregnancy test to be performed prior to randomisation to women of 
childbearing potential.
The following criteria will be re-checked at randomisation: #2, #7, #21.
Study plan
A total of 4 ambulatory study visits and a follow-up call will be performed 
during the trial, as follows:

A pre-screening visit (Visit 0) will be carried out 2 to 7 days before 
screening, to explain the study, obtain the written informed consent 
and to instruct the subject on screening visit procedures 
(e.g. wash-out from medication and restrictions). 

A screening visit (Visit 1) will be carried out 2 to 21 days before 
Treatment period 1 (TP1), to help establishing the eligibility of 
subjects for inclusion in the study. Eligible subjects will continue 
using their medications (including asthma medications) as needed, 
ensuring the required wash-out before TP1.
Note: Visit 0 and Visit 1 can be combined if the study restrictions 
and wash-out requirements are respected at Visit 0. 

The investigational phase comprises two one-day treatment 
periods, separated by a minimum of 2 days and up to 7 days of 
wash-out from the study treatment. Each treatment period consists 
of one ambulatory visit at the investigational site:
o
Treatment 
period 1 (TP1) 
including 
randomisation, 
followed by a single-dose administration of one of the two 
study treatments (HFA-152a or HFA-134a; according to 
each subject’s randomisation arm) and the assessment of its 
effects;

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o
Treatment period 2 (TP2) single-dose administration of 
the other study treatment and the assessment of its effects.
Note: for each subject, the study treatment administrations 
(at TP1 and TP2) will start at approximately the same time 
of the day. 
During the period of wash-out from the propellant (between 
TP1 and TP2), subjects will take the asthma medications that were 
taken before the study start, and will ensure the required wash-out 
period before the administration of the second treatment (at TP2).

A follow-up call (or visit, if deemed necessary by the Investigator) 
will be performed between 7 and 10 days from TP2. 
The expected duration of the clinical trial for the subjects is around 6 weeks.
Measures
The following safety measures will be evaluated at each treatment period 
(at TP1 and TP2):

Spirometry: Serial spirometries will be performed. Spirometry 
assessments (FEV1 and peak expiratory flow [PEF]) will be 
performed at the following timepoints (starting at approximately the 
same time of the day for each subject): 
o
Pre-dose: 45 min and 15 min before the first inhalation of 
the propellant (T0*)
o
Post-dose: 5 min, 15 min, 30 min, 1 hour (h), 1 h 30 min and 
3 h after the last 
 inhalation of the propellant (T1**). 

Vital Signs (duplicate systolic blood pressure [SBP] and diastolic 
blood pressure [DBP], assessed after 5 min in supine position) and 
single local 12-lead safety ECG (heart rate [HR], QRS 
interval [QRS], PR interval [PR] and QT interval corrected using 
Fridericia’s formula [QTcF]) will be evaluated at the following 
timepoints at each treatment period: 
o
Pre-dose: within 1 h before T0* (to be performed before the 
first pre-dose spirometry); 
o
Post-dose: 45 min, 1 h 45 min and 2 h 45 min after T1**.
*T0 is the time of the first inhalation of the study treatment, and must be used 
to calculate the pre-dose timepoints.
**T1 is the time of the last 
 inhalation of the study treatment, and must 
be used to calculate the post-dose timepoints.
Subjects must perform the 
 inhalations within 12 min.
Most relevant allowed 
concomitant treatments

Asthma treatment as needed (see Inclusion criterion #6 for the 
allowed treatments), with an appropriate wash-out before the 
spirometric assessments (the required wash-out periods are provided 
in the section below);

Systemic corticosteroid and/or nebulised treatment containing 
β2-agonists and/or corticosteroids, and/or antibiotics therapy for 
severe asthma exacerbation. In case of asthma exacerbation 
requiring treatment, the visit must be postponed (4 weeks after 
recovery and stopping the treatment);

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
Antihistamines 
(oral, 
ocular, 
intranasal) 
and 
intranasal 
corticosteroids for the treatment of allergy or rhinoconjunctivitis 
symptoms;

Allergen immunotherapy for the treatment of respiratory allergy, if 
already started before inclusion in the study;

Appropriate treatment for concomitant diseases, seasonal influenza 
and SARS-CoV-2 vaccination (1 week should elapse from 
vaccination to the treatment period) will be permitted if they do not 
interfere with the study treatment or the study evaluations, and if 
they are not listed among the “Non-permitted concomitant 
medications” (provided in the section below); 

Hormonal contraceptives;

Hormonal replacement treatment for postmenopausal women.
Most relevant forbidden 
concomitant treatments

Regular 
daily 
maintenance 
treatment 
with 
ICS, 
ICS/long‑acting β2‑agonist (LABA), 
leukotriene 
receptor 
antagonists (LTRA), or long-acting anti-muscarinic (LAMA), 
administered alone or in combination;

Systemic corticosteroids (see exceptions in the section above);

Monoclonal 
antibodies 
(e.g. 
anti-IgE 
or 
anti-immunoglobulin G [IgG] antibodies) or biological drugs used 
for the treatment of respiratory conditions, and for any other 
condition if impact on respiratory outcomes cannot be excluded;

Any medication that could interact with the asthma treatments 
administered as needed, according to Investigator’s judgement.
Prior to any spirometric study assessments, the following wash-out 
periods apply:

Inhaled/nebulised SABA: 6 h;

ICS (in combination with SABA): 24 h;

ICS-formoterol: 24 h.
Safety variables
Safety variable evaluating the potential for bronchoconstriction of each 
propellant:

Relative change from baseline* in FEV1 at the 15 min post-dose 
timepoint.
Safety variables completing the evaluation of the potential for 
bronchoconstriction of each propellant:

Relative change from baseline* in FEV1 at all the other post-dose 
timepoints (5 min, 30 min, 1 h, 1 h 30 min and 3 h after T1);

Absolute change from baseline* in FEV1 at all post-dose timepoints 
(5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1);

Number and percentage of subjects with a relative change from 
baseline* in FEV1 at each post-dose timepoint <-15%;

Number and percentage of subjects with a relative change from 
baseline* in FEV1 at any post-dose timepoint <-15%;

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
Change from baseline* in FEV1 area under the concentration-time 
curve from time zero to 3 hours (AUC0-3h);

Relative change from baseline* in PEF at all post-dose timepoints; 

Absolute change from baseline* in PEF at all post-dose timepoints;

Number and percentage of subjects with use of rescue medication in 
the 3 h after T1;

Mean use (puffs) of rescue medication in the 3 h after T1. 
* The baseline FEV1 and PEF values are the mean of the 2 pre-dose 
assessments (i.e. performed 45 min and 15 min before T0).
Safety variables evaluating the general safety and tolerability of the two 
propellants:

Adverse Events (AEs) and AEs of particular interest (bronchospasm, 
cough, dysphonia, hoarseness);

Vital signs (SBP and DBP);

12-lead ECG parameters: HR, QTcF, PR and QRS.

Sample size calculation
The sample size has been calculated to verify equivalence between the test 
treatment (HFA-152a) and the reference treatment (HFA-134a) for the 
relative change from baseline in FEV1 at the 15 min post-dose timepoint, 
with equivalence defined as a difference between the two treatments within 
the ±10%. 
A total of 20 evaluable subjects will ensure a 95% power to provide a 95% 
confidence interval (CI) of the mean difference of the relative change from 
baseline in FEV1 at 15 min post-dose within the above-mentioned 
equivalence limits (i.e. [-10%; +10%]) assuming a within-subject standard 
deviation (SD) of 8%.
Estimating a non-evaluable rate of 16%, a total of 24 subjects will be 
randomised.
Statistical methods
Safety variables
Variable assessing the primary objective of the study (potential for 
bronchoconstriction of each propellant): 

The relative change from baseline in FEV1 at the 15 min post-dose 
timepoint 
will 
be 
analysed 
using 
an 
analysis 
of 
covariance (ANCOVA) model, including treatment group, subject 
and period as fixed effects, and FEV1 baseline (mean of the two 
measurements at 45 min and 15 min pre-dose in each treatment 
period) as a covariate. 
The adjusted mean relative change from baseline obtained with each 
treatment and the adjusted mean difference between HFA-152a and 
HFA-134a with their 95% CIs and p-values will be estimated by the 
model.
Variables completing the evaluation of the potential for bronchoconstriction 
of each propellant:

The relative changes from baseline in FEV1 at all the other post-dose 
timepoints (5 min and 30 min, 1 h, 1 h 30 min and 3 h after T1) will 

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be analysed using the same model used for the relative change from 
baseline in FEV1 at 15 min post-dose;

The absolute changes from baseline in FEV1 at all post-dose 
timepoints (5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1) 
will be analysed using the same model used for the relative change 
from baseline in FEV1 at 15 min post-dose;

The number and percentage of subjects with a relative change from 
baseline in FEV1 at each post-dose timepoint (5 min, 15 min, 30 min, 
1 h, 1 h 30 min and 3 h after T1) and at any post-dose timepoint 
<‑15% will be summarised for each treatment;

The change from baseline in FEV1 AUC0-3h will be summarised 
using descriptive statistics;

The relative and absolute changes from baseline in PEF at all 
post-dose timepoints (5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h 
after T1) will be summarised for each treatment, using descriptive 
statistics;

The number and percentage of subjects with use of rescue 
medication in the 3 h post-dose will be summarised for each 
treatment;

The mean use (puffs) of rescue medication in the 3 h post-dose will 
be summarised for each treatment, using descriptive statistics.
Variables assessing the secondary objective of the study (general safety and 
tolerability of the two different propellants):

The number of subjects who experienced at least one 
treatment‑emergent adverse event (TEAE), adverse drug reaction 
(ADR), serious TEAE, serious ADR, TEAE leading to study 
discontinuation, and TEAE leading to death will be summarised for 
each treatment. Summaries will be presented overall (number and 
percentage of subjects having at least one event, total number of 
events) and by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
Specific summary tables will be provided for the AEs of particular 
interest.
All AEs will be listed.
Pre-treatment AEs will be listed only;

The mean absolute values and mean changes from baseline in each 
12-lead ECG parameter (HR, QRS, PR, and QTcF) will summarised 
for each treatment, using descriptive statistics. For QTcF, the 
following categories will also be analysed for each study treatment, 
by means of descriptive statistics: 
o
For male subjects: QTcF interval >450 ms, >480 ms and 
>500 ms;
o
For female subjects: QTcF interval >470 ms and >500 ms;
o
For both male and female subjects: Change from baseline 
>30 ms and >60 ms.
The analysis will be presented at each and any post-dose timepoint.
All data will be listed.

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
Vital signs (SBP and DBP) mean absolute values at each pre-dose 
and post-dose timepoint and change from baseline will be 
summarised for each study treatment, by means of descriptive 
statistics. 
All vital signs will be listed.

 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ACQ-5
Asthma Control Questionnaire©
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATS
American Thoracic Society
AUC
Area Under the Concentration-Time Curve
AUC0-3h
Area Under the Concentration-Time Curve from Time Zero to 3 Hours
BTPS
Body Temperature and Pressure Saturation
Ca
Calcium
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
Cl
Chloride Electrolyte
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Coronavirus Disease 2019
CRO
Contract Research Organisation
CS
Clinically Significant
DALY
Disability Adjusted Life Year
DBP
Diastolic Blood Pressure
DPI
Dry Powder Inhaler
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
ERS
European Respiratory Society
FEV1
Forced Expiratory Volume in 1 Second
FSH
Follicle-Stimulating Hormone
FVC
Forced Vital Capacity
γ-GT
Gamma-Glutamyl Transpeptidase
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
GMP
Good Manufacturing Practice

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GOLD
Global Initiative for Chronic Obstructive Lung Disease
GWP
Global Warming Potential
h
Hour
Hb
Haemoglobin
Hct
Haematocrit 
HFA
Hydrofluoroalkane
HR
Heart Rate
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICS
Inhaled Corticosteroid
ICSR
Individual Case Study Report
IgE
Immunoglobulin E
IgG
Immunoglobulin G
K
Potassium
LABA
Long-Acting β2-Agonist
LAMA
Long-acting anti-muscarinic
LTRA
Leukotriene receptor antagonist
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
min
Minute
Na
Sodium
No.
Number
NYHA
New York Heart Association
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PLT
Platelet
pMDI
Pressurised Metered Dose Inhaler
PP
Per-Protocol
PR
PR Interval
PT
Preferred Term
QRS
QRS Interval
QTcF
QT Interval Corrected Using Fridericia’s Formula
RBC
Red Blood Cell
R&D
Research and Development
SABA
Short-Acting β2-Agonists
SAE
Serious Adverse Event

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SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reaction
T0
Time of First Inhalation of the Study treatment
T1
Time of Last Inhalation of the Study treatment
TEAE
Treatment‑Emergent Adverse Event
TP
Treatment Period
UK
United Kingdom
WBC
White Blood Cell
WHO
World Health Organization
WOCBP
Women of Childbearing Potential
WONCBP
Women of Non-Childbearing Potential

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CONTENT
GENERAL INFORMATION................................................................................................................2
PROTOCOL OUTLINE........................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .....................................................15
CONTENT ............................................................................................................................................18
1.
INTRODUCTION......................................................................................................................21
1.1 Background Information..........................................................................................................21
1.2 Study Rationale..........................................................................................................................22
1.3 Risk/Benefit Assessment ...........................................................................................................23
2.
STUDY OBJECTIVES..............................................................................................................24
2.1 Primary Objective .....................................................................................................................24
2.2 Secondary Objective..................................................................................................................24
2.3 
...............................................................................................................24
3.
STUDY DESIGN........................................................................................................................24
4.
SUBJECT SELECTION CRITERIA.......................................................................................26
4.1 Subject Recruitment..................................................................................................................26
4.2 Inclusion Criteria.......................................................................................................................26
4.3 Exclusion Criteria......................................................................................................................28
4.4 Subject Withdrawals.................................................................................................................30
5.
CONCOMITANT MEDICATIONS ........................................................................................31
5.1 Permitted Concomitant Medications.......................................................................................31
5.2 Non-Permitted Concomitant Medications ..............................................................................32
6.
TREATMENTS..........................................................................................................................32
6.1 Appearance and Content ..........................................................................................................32
6.2 Dosage and Administration ......................................................................................................32
6.3 Packaging ...................................................................................................................................34
6.4 Labelling.....................................................................................................................................35
6.5 Treatment Allocation ................................................................................................................35
6.6 Treatment Code.........................................................................................................................36
6.7 Treatment Compliance .............................................................................................................36
6.8 Drug Storage..............................................................................................................................36
6.9 Drug Accountability..................................................................................................................37
6.10 Provision of Additional Care..................................................................................................37
7.
STUDY PLAN ............................................................................................................................37
7.1 Study Schedule...........................................................................................................................37
7.2 Study Restrictions and Standardisation..................................................................................43
7.3 Investigations .............................................................................................................................44

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8.
EFFICACY ASSESSMENTS....................................................................................................47
9.
SAFETY ASSESSMENTS ........................................................................................................47
9.1 
..........................................................................................................48
10.
ADVERSE EVENT REPORTING...........................................................................................48
10.1 Definitions ................................................................................................................................48
10.2 Expectedness ............................................................................................................................49
10.3 Intensity of Adverse Event......................................................................................................50
10.4 Causality Assessment ..............................................................................................................50
10.5 Action Taken with the Study Treatment Due to an Adverse Event ...................................50
10.6 Other Actions Taken...............................................................................................................51
10.7 Outcome....................................................................................................................................51
10.8 Recording Adverse Events......................................................................................................51
10.9 Reporting Serious Adverse Events to Chiesi.........................................................................51
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees.........52
10.11 General Notes.........................................................................................................................52
11.
DATA MANAGEMENT ...........................................................................................................53
12.
STATISTICAL METHODS......................................................................................................54
12.1 Sample Size...............................................................................................................................54
12.2 Populations for Analysis .........................................................................................................54
12.3 Statistical Analysis...................................................................................................................54
13.
ETHICS COMMITTEE............................................................................................................57
14.
REGULATORY REQUIREMENTS .......................................................................................58
15.
INFORMED CONSENT ...........................................................................................................58
16.
SOURCE DOCUMENTS/DATA..............................................................................................58
16.1 Recording of Source Data.......................................................................................................58
16.2 Direct Access to Source Document/Data...............................................................................58
17.
STUDY MONITORING............................................................................................................58
18.
QUALITY ASSURANCE..........................................................................................................59
19.
INSURANCE AND INDEMNITY............................................................................................59
20.
CONFIDENTIALITY................................................................................................................59
21.
PREMATURE TERMINATION OF THE STUDY...............................................................60
22.
CLINICAL STUDY REPORT..................................................................................................60
23.
RECORD RETENTION............................................................................................................60
24.
PUBLICATION OF RESULTS................................................................................................60
25.
REFERENCES...........................................................................................................................60
APPENDIX 1.........................................................................................................................................63
APPENDIX 2.........................................................................................................................................64

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APPENDIX 3.........................................................................................................................................65

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1.
INTRODUCTION
1.1 Background Information
Chronic respiratory diseases
Chronic respiratory diseases are among the leading causes of morbidity and mortality 
worldwide [1]. Among these, common chronic respiratory diseases include chronic obstructive 
pulmonary disease (COPD) with a global prevalence of 3.9% in 2017, and asthma with a global 
prevalence of 3.6% in 2017 [2].
COPD is an inflammatory disease of the airways characterised by persistent respiratory 
symptoms (e.g. cough, breathlessness, excess sputum production) and airway limitation, with 
a progressive decline in lung function. COPD has seen a recent increase in prevalence, and 
represents a substantial and increasing economic and social burden [3], [4].
Asthma is a serious, sometimes fatal disease affecting people of all ages. Asthma is 
characterised by chronic airway inflammation, respiratory symptoms (e.g. wheeze, shortness of 
breath, cough, chest tightness), and variable expiratory flow limitation. The number of disability 
adjusted life years (DALYs) lost due to asthma amounts to 26.2 million, representing about 1% 
of DALYs lost due to any disease, and is comparable to those lost due to diabetes or 
Alzheimer’s disease [5].
COPD and asthma treatments help dilate major air passages, improve shortness of breath and 
quality of life, and prevent disease escalation [2].
Use of propellants in inhaler devices
Pressurised metered dose inhalers (pMDIs) represent one of the most commonly used devices 
for inhaled drug delivery in the treatment of COPD and asthma. The propellant, a liquified gas, 
provides the force required to generate the aerosol cloud.
More than 630 million pMDIs are estimated to be manufactured annually worldwide using 
up-to 10,000 tons of propellants [6]. The adoption of the Montreal Protocol in 1989 initiated 
the development of the hydrofluoroalkane (HFA) propellants currently used in pMDIs 
(HFA-134a and HFA-227ea), which replaced ozone depleting substances [7]. However, there 
is growing concern regarding the global warming potential (GWP) of many 
hydrofluorocarbons, including HFA-134a. This led to the introduction of regulations in many 
parts of the world that place controls on the usage of these substances. Accordingly, 
manufacturers of aerosolised products have been looking for potential alternatives to these 
HFAs in both industrial and medical application sectors. The transition towards a low GWP 
propellant is also in line with Chiesi’s sustainability commitment.
A potential alternative to fluorocarbons with high ozone depleting potential and/or GWP in the 
pMDI application is HFA-152a (1,1 difluoroethane), designated by the United 
States Environmental Protection Agency as an acceptable replacement in certain applications, 
including as an aerosol propellant. HFA-152a has an environmental GWP one order of 
magnitude lower than HFA-134a or HFA-227ea, and a carbon footprint that is 90% reduced 
compared to an equivalent HFA-134a pMDI [8], [9], [10].
The toxicological properties of HFA-152a are well known in industrial applications and indicate 
a relatively low risk profile. However, additional data proving its safety for use as an inhaled 
drug are required before it can be approved as a novel excipient. 

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In non-clinical studies, the dose limiting effects of HFA-152a are associated with 
concentrations far greater than that delivered by a pMDI formulation, and the effects appear to 
resolve quickly following cessation of exposure [11]. HFA-152a essentially caused no other 
toxicities.
The pharmacokinetics (PK) of HFA-152a has been studied in healthy volunteers exposed to 
0, 200 or 1000 ppm of HFA-152a for 2 hours (h) during light exercise in an exposure 
chamber [12]. Symptom ratings and changes in inflammatory markers revealed no 
exposure-related effects.
 
 
 
 
 
 
This study aims to compare the potential for bronchoconstriction, the general safety and the 
tolerability of the new HFA-152a propellant administered alone (not in combination with active 
compounds) to those of the marketed HFA-134a propellant administered alone (not in 
combination with active compounds). 
1.2 Study Rationale
This clinical study has been designed to investigate the potential for bronchoconstriction of the 
new HFA-152a propellant, in comparison with the marketed HFA-134a propellant. 
This study was conceived following concerns from the European Medicines Agency’s (EMA) 
Committee for Medicinal Products for Human Use (CHMP) about the lack of data on the 
potential of the new HFA-152a propellant to cause bronchoconstriction in healthy subjects or 
asthma patients with hyperreactive airways. In fact, safety studies performed during the clinical 
development programme assessed the safety of the HFA-152a propellant when used for the 
administration of asthma treatments via pMDI. According to the CHMP, these studies were not 
capable of assessing the potential for bronchoconstriction of the new propellant, which may be 
clinically relevant but not detected, given that the HFA-152a propellant was administered in 
combination with bronchodilating agents. 
As this residual risk was deemed not adequately covered by the clinical development program, 
and as it cannot be predicted by in-vitro data, this appropriately designed clinical trial will 
adequately address this residual risk.
This randomised, double-blind, controlled, 2-way cross-over study will be conducted in male 
and female subjects with mild asthma (Step 1 of the Global Initiative for Asthma [GINA] 2021 
guidelines). Each subject will be administered a single-dose 
 of each of the two 
following treatments, according to an order pre-specified by the randomisation list:

Test treatment: placebo HFA-152a propellant via pMDI;

Reference treatment: placebo HFA-134a propellant via pMDI. 

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Subjects will be asked to wash-out from their asthma treatments before the administration of 
the study treatment and before the spirometry assessments, in order to suppress the 
bronchodilating effect of the asthma treatments. The following wash-out periods will apply: 

Inhaled/nebulised short-acting β2-agonists (SABA): 6 h;

Inhaled corticosteroids (ICS) (in combination with SABA): 24 h;

ICS-formoterol: 24 h.
The selected treatment dose (
) corresponds to the maximum total daily dose 
of propellant allowed for administration with the Clenil pMDI device. 
Subjects will perform 
 inhalations, with a minimum of 40 seconds between two consecutive 
inhalations (see Section 6.2.3.1). Subjects will be given up to 12 minutes (min) to perform the 
 inhalations, which will give them enough time to breath during treatment administration. To 
harmonise subjects’ pre-dose and post-dose timepoints, the time of the first inhalation (T0) will 
be used for the calculation of the pre-dose timepoints, and the time of the last 
 
inhalation (T1) will be used for the calculation of the post-dose timepoints. 
The potential for bronchoconstriction of the propellants will be evaluated throughout 
spirometry assessments, specifically by the change in the values of the forced expiratory volume 
in 1 second (FEV1) from baseline (pre-dose timepoints) to the post-dose timepoints. The 
spirometry schedule was designed to accurately characterise lung function. In particular, 
frequent sampling was planned around the predicted maximum effect of the propellant to 
inform about any post-dose bronchoconstriction.
1.3 Risk/Benefit Assessment
The toxicological properties of HFA-152a are well known in industrial applications and indicate 
a relatively low risk profile. Short-term inhalation of HFA-152a with light exercise did not have 
exposure effects in human subjects [12]. A comprehensive package of toxicology studies was 
conducted for the HFA-152a propellant alone, in conformance with the International Council 
for Harmonisation (ICH) M3(R2) requirements; results were described in the Investigator’s 
Brochure for CHF 5993 pMDI HFA-152a. The pre-clinical studies did not elicit any findings 
that could not be attributed to the expected pharmacological action of the test items, and were 
similar to those previously reported with the formulation of CHF 5993 HFA-134a propellant. 
It was therefore considered that the change of the propellant to HFA-152a had not produced 
any new effects. Of particular note, the results of bacterial mutagenicity, in-vitro micronucleus, 
and in-vivo micronucleus assays did not show HFA-152a to be mutagenic or genotoxic. 
However, the results of the embryofoetal toxicology study in rats were not available at the time 
of the study. Thus, considering the recommendations related to contraception and pregnancy 
testing in clinical trials from the Clinical Trial Facilitation and Coordination Group [13], the 
worst-case 
scenario 
was 
considered, 
i.e. 
“Demonstrated 
or 
suspected 
human 
teratogenicity/fetotoxicity in early pregnancy” and contraception measures were taken 
accordingly.
Subjects will be closely monitored throughout the study and evaluated by the Investigator. 
Therefore, the overall risk/benefit assessment for the proposed study is considered to be 
acceptable.
This study will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments), current Good Clinical Practice (GCP) ICH E6 and all other applicable laws and 
regulations.

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2.
STUDY OBJECTIVES
2.1 Primary Objective

To compare the potential for bronchoconstriction 
 of the HFA-152a 
propellant versus 
 the HFA-134a propellant when administered alone 
(not in combination with other active compounds).
2.2 Secondary Objective

To evaluate the general safety and tolerability of the two different propellants.
3.
STUDY DESIGN 
This is a Phase IIa, multicentre (approximately 4 centres in the United Kingdom [UK]), 
single-dose, randomised, double-blind, controlled, 2-way cross-over study to evaluate the 
potential for bronchoconstriction of the new HFA-152a propellant (single dose, 
) 
versus the marketed HFA-134a propellant (single dose, 
) in adult subjects with 
mild asthma (Step 1 of the GINA 2021 guidelines). 
A double-blind design was chosen for this study to minimise the risk of bias in the study 
outcomes.
The study design is shown in Figure 1.

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Figure 1. Study Design[1]
Study treatment
Approximately 24 adult subjects with mild asthma (Step 1 of the GINA 2021 guidelines) will 
be randomised to receive a single dose (
) of each of the following treatments, in 
an order determined by the randomisation list: 

HFA-152a propellant (also referred to as “test treatment”): placebo HFA-152a 
propellant alone (not in combination with other active compounds) via pMDI;

HFA-134a propellant (also referred to as “reference treatment”): placebo HFA-134a 
propellant alone (not in combination with other active compounds) via pMDI. 
Study visits
A total of 4 ambulatory study visits and a follow-up call will be performed during the study, as 
follows:

A pre-screening visit (Visit 0) will be carried out 2 to 7 days before screening, to 
explain the study, obtain the written informed consent and to instruct the subject on 
screening visit procedures (e.g. wash-out from medication and restrictions). 

A screening visit (Visit 1) will be carried out 2 to 21 days before Treatment 
period 1 (TP1), to help establishing the eligibility of a subject for inclusion in the study 
(including routine haematology and blood chemistry, medical history, physical 
examination, 12-lead electrocardiogram [ECG], lung function, vital signs and training 
for the use of inhalers). Eligible subjects will continue using their medications 
(including asthma medications) as needed, ensuring the required wash-out before TP1.
Note: Visit 0 and Visit 1 can be combined if the study restrictions and wash-out 
requirements are respected at Visit 0. 
HFA = Hydrofluoroalkane; pMDI = Pressurised metered dose inhaler.
[1] The study design proposed in the figure is just an example of one of the possible sequences.
[2] The pre-screening and screening visits can be combined in one visit if the study restrictions and wash-out 
requirements are respected at pre-screening. 
[3] A follow-up visit can be performed, if deemed necessary by the Investigator. 

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
The investigational phase comprises two one-day treatment periods, separated by a 
minimum of 2 days and up to 7 days of wash-out from the study treatment. Each 
treatment period consists of one ambulatory visit at the investigational centre:
o
Treatment period 1 (TP1) including randomisation, followed by a single-dose 
administration of one of the study treatments (HFA-152a or HFA-134a; 
according to each subject’s randomisation arm) and the assessment of its effects;
o
Treatment period 2 (TP2) single-dose administration of the other study 
treatment and the assessment of its effects.
Note: For each subject, the study treatment administrations (at TP1 and TP2) 
will start at approximately the same time of the day.
During the period of wash-out from the propellant (between TP1 and TP2), subjects will 
take the asthma medications that were taken before the study start and will ensure the 
required wash-out period before the administration of the second propellant (at TP2).

A follow-up call (or visit, if deemed necessary by the Investigator) will be performed 
between 7 and 10 days from TP2.
A subject’s participation in the study will end with the follow-up call (or visit, if deemed 
necessary by the Investigator).
The end of the trial is defined as the last follow-up contact of the last subject in the trial. 
The expected duration of the clinical trial for the subjects is around 6 weeks
4.
SUBJECT SELECTION CRITERIA
4.1 Subject Recruitment
Subjects attending the hospital clinics/study centres will be recruited. Adult male and female 
subjects with mild asthma (Step 1 of the GINA 2021 guidelines), aged from 18 to 75 years old 
(inclusive) will be selected.
A total of 24 subjects will be randomised in accordance with the inclusion and exclusion 
criteria, in order to reach a total of 20 completed and evaluable subjects, considering a 
non-evaluable rate of approximately 16%.
4.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the 
study:
1. Subject’s written informed consent obtained prior to any study related procedure;
2. Gender and age: Male or female adults aged from 18 to 75 years old (inclusive);
3. Diagnosis of asthma: documented established diagnosis of mild asthma for at least 
6 months according to Step 1 of the GINA 2021 guidelines;

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4. Lung function: subjects with a pre-bronchodilator FEV1 ≥60% of the predicted normal 
value and ≥1.5 L at screening and prior to randomisation, after appropriate wash-out from 
bronchodilators;
Note: In case of FEV1 values <60% at screening, measures can be repeated once before 
randomisation in an unscheduled visit.
5. Documented excessive variability in lung function (one or more of the following): 
positive bronchodilator reversibility test, defined as an increase in FEV1 of >12% 
and/or >200 mL from baseline within 30 min after inhalation of 200‑400 µg salbutamol 
(albuterol) according to the American Thoracic Society (ATS) and European Respiratory 
Society (ERS) (ATS/ERS) standards; or positive bronchial challenge test, defined as a 
decrease from baseline in FEV1 of ≥20% with standard doses of methacholine, or a 
decrease of ≥15% with standardised hyperventilation, hypertonic saline or mannitol 
challenge. Excessive variability in lung function must be documented within the past 2 
years (a copy of the original spirometry report must be included as source 
documentation). In case evidence of documented excessive variability in lung function is 
not available, the test (bronchodilator reversibility or bronchial challenge) should be 
performed at screening;
In case the criterion of excessive variability in lung function is not met at screening, the 
test can be repeated once before randomisation in an unscheduled visit. A bronchial 
challenge test can be performed, if a bronchodilator reversibility test was unsuccessful 
and vice versa.  
6. Current asthma therapy: as needed low-dose ICS‑formoterol, as needed SABA, or 
low‑dose ICS whenever SABA is taken; taken not more than twice a week (2 events) in 
the 4 weeks prior to screening or in the 6 weeks prior to randomisation. For subjects using 
pMDI, spacer is allowed (as it improves delivery and reduces the risk of ICS local 
side‑effects);
Low-dose ICS is defined by GINA 2021 (box 3-6) as follows:
Inhaled corticosteroid
Adults daily low dose
Beclometasone dipropionate (pMDI, standard particle, 
HFA)
200-500 µg
Beclometasone dipropionate (DPI or pMDI, extrafine, HFA)
100-200 µg
Budesonide (DPI or pMDI, standard particle, HFA)
200-400 µg
Ciclesonide (pMDI, extrafine, HFA)
80-160 µg
Fluticasone furoate (DPI)
100 µg
Fluticasone propionate (DPI)
100-250 µg
Fluticasone propionate (pMDI, standard particle, HFA)
100-250 µg
Mometasone furoate (DPI)
See product information
Mometasone furoate (pMDI, standard particle, HFA)
200-400 µg

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7. Asthma control: controlled or partly controlled based on an Asthma Control 
Questionnaire© (ACQ-5) score <1.5 at screening (or pre-screening) and prior to 
randomisation;
8. Ability to use the inhalers: subjects must have a cooperative attitude and the ability to 
be trained to use correctly the pMDI inhalers at screening;
9. Ability to comply with the protocol: subjects must have a cooperative attitude, the 
ability to perform the required outcome measurements, and the ability to understand the 
risks involved at screening and prior to randomisation;
10. Female subjects fulfilling one of the following criteria:
a) Women of non-childbearing potential (WONCBP) defined as physiologically 
incapable of becoming pregnant (i.e. postmenopausal or permanently sterile, as per 
definitions given in Appendix 3 or Section 4.1 of the Clinical Trials Facilitation and 
Coordination Group guidance). 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 (FSH) levels (according to local laboratory 
ranges);
b) Women of childbearing potential (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 preferably with low user dependency, 
from the signature of the informed consent form (ICF) and until the follow-up 
call/visit or;
ii. WOCBP with non-fertile male partners (contraception is not required in this case).
Note: In case of hormonal contraception, an additional non-hormonal method (barrier 
method, preferably male condom) is required.
11. Male subjects fulfilling one of the following criteria:
a) Fertile male subjects with pregnant or non-pregnant WOCBP partners: they must be 
willing to use male condom from the signature of the ICF and until the follow-up 
call/visit, or;
b) Non-fertile male subjects (contraception is not required in this case), or;
c) Fertile male subjects with WONCBP partner (contraception is not required in this 
case).
For the definition of WOCBP, fertile men and the list of highly effective birth control 
methods, refer to Appendix 3 (or Section 4.1 of the Clinical Trials Facilitation and 
Coordination Group guidance). 
The following criteria will be re-checked at randomisation: #4, #6, #7, #9.
4.3 Exclusion Criteria
The presence of any of the following will exclude a subject from study enrolment: 
1. History of “at risk” asthma: history of near fatal asthma, hospitalisation for asthma in 
intensive care unit which, in the judgement of the Investigator, may place the subject at 
undue risk;
2. Recent exacerbation: asthma exacerbation requiring systemic corticosteroids or 
emergency room admission or hospitalisation within 4 weeks prior to screening and prior 
to randomisation;

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3. Asthma requiring use of biologics: asthma subjects treated with chronic systemic 
corticosteroids or anti-immunoglobulin E (IgE) or other monoclonal or polyclonal 
antibodies;
4. Respiratory disorders other than asthma: subjects with known respiratory disorders 
other than asthma. This can include, but is not limited to, diagnosis of COPD as defined 
by the current guidelines (e.g. Global Initiative for Chronic Obstructive Lung 
Disease [GOLD] guidelines), known α1-antitrypsine deficiency, active tuberculosis, 
bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung 
disease;
5. Lung cancer or history of lung cancer: subject with a diagnosis of lung cancer or a 
history of lung cancer;
6. Lung resection: subject with a history of lung volume resection;
7. Lower respiratory tract infection: subject with lower respiratory tract infection that 
required use of antibiotics within 4 weeks prior to screening and prior to randomisation;
8. Documented coronavirus disease 2019 (COVID-19) diagnosis within 2 weeks prior to 
screening, or associated complications/symptoms which have not resolved within 
2 weeks prior to screening;
9. Smoking status: current smoker, or ex-smoker with a smoking history of ≥10 pack-years 
(packyears = the number of cigarette packs per day times the number of years). 
To be eligible for the study, ex-smokers with a smoking history of <10 pack-years must 
have stopped smoking for ≥1 year (≥6 months for e-cigarettes);
10. Cancer or history of cancer (other than lung cancer): subject with active cancer or a 
history of cancer with less than 5 years disease-free survival time (whether or not there is 
evidence of local recurrence or metastases). Localised carcinoma (e.g. basal cell 
carcinoma, in situ carcinoma of the cervix adequately treated) is acceptable;
11. Cardiovascular diseases: subjects who have known and clinically significant (CS) 
cardiovascular conditions such as, but not limited to, unstable or acute ischemic heart 
disease experienced within one year prior to study entry, class III/IV heart failure 
(according to the classification by the New York Heart Association [NYHA]), history of 
atrial fibrillation, uncontrolled hypertension, history of sustained or non-sustained cardiac 
arrhythmias diagnosed within 6 months prior to study entry and not controlled with 
therapy according to the Investigator’s opinion;
12. ECG criteria: any CS abnormal 12-lead ECG that, in the Investigator's opinion, would 
affect safety evaluations or place the subject at risk; 
Note: In case the criterion is not met at screening, the test can be repeated once before 
randomisation in an unscheduled visit
13. Central nervous system disorders: subjects with a history of symptoms or significant 
neurological disease such as, but not limited to transient ischemic attack, stroke, seizure 
disorder or behavioural disturbances, according to the Investigator’s opinion;
14. Other concurrent diseases: subjects with historical or current evidence of uncontrolled 
concurrent disease such as, but not limited to, hyperthyroidism, diabetes mellitus or other 
endocrine disease, haematological disease, autoimmune disorders (e.g. rheumatoid 
arthritis), gastrointestinal disorders (e.g. poorly controlled peptic ulcer, gastroesophageal 
reflux disease), significant renal impairment or other disease or condition that might, in 

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the judgement of the Investigator, place the subject at undue risk or potentially 
compromise the results or interpretations of the study;
15. Laboratory abnormalities: subjects with CS laboratory abnormalities indicating a 
significant or unstable concomitant disease that might, in the judgement of the 
Investigator, place the subject at undue risk or potentially compromise the results or 
interpretations of the study; 
Note: In case the criterion is not met at screening, the test can be repeated once before 
randomisation in an unscheduled visit
16. Alcohol/drug abuse: subjects with a known or suspected history of alcohol and/or 
substance/drug abuse within 12 months prior to screening;
17. Participation to investigational trial: subjects who have received any investigational 
drug within the 30 days (60 days for biologics) prior to screening, or a more appropriate 
time as determined by the Investigator (e.g. approximately 5 half-lives of the 
investigational drug whatever is longer);
18. Hypersensitivity: history of hypersensitivity to any of the study medications 
components or a history of other allergy that, in the opinion of the Investigator, 
contraindicates the subject’s participation;
19. Subjects mentally or legally incapacitated or subjects accommodated in an 
establishment as a result of an official or judicial order;
20. Recent eye surgery or any condition where raised intracranial pressure (caused by 
forceful exhalation) would be harmful;
21. For female subjects only: pregnant or lactating women, where pregnancy is defined as 
the state of a female after conception and until termination of the gestation, confirmed by 
a positive serum human chorionic gonadotropin laboratory test.
Note: Serum pregnancy test to be performed at screening, and urine pregnancy test to 
be performed prior to randomisation to women of childbearing potential.
The following criteria will be re-checked at randomisation: #2, #7, #21. 
4.4 Subject Withdrawals
Subjects must be discontinued from the study for any of the following reasons:

An adverse event (AE) occurs that, in the opinion of the Investigator, makes it unsafe 
for the subject to continue in the study. In this case, the appropriate measures will be 
taken;

Occurrence of pregnancy;

The subject is lost to follow-up;

The subject withdraws consent;

The subject’s safety is affected by violation of inclusion or exclusion criteria or use of 
non-permitted concomitant medication;

The subject is unwilling or unable to adhere to the study requirements, 
i.e. non-compliance;

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
The Sponsor or the regulatory authorities or the Ethics Committee(s) (EC), for any 
reason, terminates the entire study, or terminates the study for this investigational site 
or this particular subject. 
It is understood by all concerned that an excessive rate of withdrawals can render the study 
uninterpretable. Therefore, unnecessary withdrawals of subjects should be avoided.
However, should a subject discontinue the study, all efforts will be made to complete and report 
the observations as thoroughly as possible.
In the event of early termination, if the subject has not withdrawn his/her consent, an Early 
Termination visit should be scheduled to perform the following safety assessments, as described 
in Table 1 and in section 7.1.6: 
Note: No follow-up call will be performed after the Early Termination visit.
In case of early withdrawal, the Investigator will have to fill in the “Study Termination” page 
in the electronic case report form (eCRF), reporting the main reason for withdrawal.
If a subject is withdrawn/drops-out of the study after randomisation, the subject’s study number 
and corresponding study treatments should not be reassigned to another subject.
Individuals who do not meet the criteria for participation in the study (screen failures) may be 
rescreened once. Rescreened participants should be assigned a new participant number for 
every screening/rescreening event.
5.
CONCOMITANT MEDICATIONS
5.1 Permitted Concomitant Medications
1. Asthma treatment as needed, (see Inclusion criterion # 6, Section 4.2 for the allowed 
treatments), with an appropriate wash-out before the spirometric assessments (see 
Section 5.2 for the wash-out periods, and Table 1 for the timepoints of spirometry 
assessments);
2. Systemic corticosteroid and/or nebulised treatment containing β2-agonists and/or 
corticosteroids, and/or antibiotics therapy for severe asthma exacerbation. In case of 
asthma exacerbation requiring treatment, the visit must be postponed (4 weeks after 
recovery and stopping the treatment);
3. Antihistamines (oral, ocular, intranasal) and intranasal corticosteroids for the treatment 
of allergy or rhinoconjunctivitis symptoms;
4. Allergen immunotherapy for the treatment of respiratory allergy, if already started 
before inclusion in the study;
5. Appropriate treatment for concomitant diseases, seasonal influenza and SARS-CoV-2 
vaccination (1 week should elapse from vaccination to the treatment period) will be 
permitted if they do not interfere with the study treatment or the study evaluations, and 
if they are not listed among the “Non-permitted concomitant medications” (see 
Section 5.2 below); 
6. Hormonal contraceptives;
7. Hormonal replacement treatment for postmenopausal women.

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5.2 Non-Permitted Concomitant Medications
1. Regular daily maintenance treatment with ICS, ICS/long-acting β2-agonists (LABA), 
leukotriene receptor antagonists (LTRA), or long-acting anti-muscarinic (LAMA), 
administered alone or in combination;
2. Systemic corticosteroids (see exceptions in Section 5.1 above);
3. Monoclonal antibodies (e.g. anti-IgE or anti-immunoglobulin G [IgG] antibodies) or 
biological drugs used for the treatment of respiratory conditions, and for any other 
condition if impact on respiratory outcomes cannot be excluded;
4. Any medication that could interact with the asthma treatments administered as needed, 
according to Investigator’s judgement.
Prior to any spirometric study assessments, the following wash-out periods must be 
respected:

Inhaled/nebulised SABA: 6 h;

ICS (in combination with SABA): 24 h;

ICS-formoterol: 24 h.
6.
TREATMENTS
The study treatments will be supplied to the investigational centres under the responsibility of 
the Sponsor, who will also provide the Pharmacist/Investigator with appropriate certificates of 
analytical conformity. 
Any rescue medications used during the study will be purchased locally, by the investigational 
centres. The investigational centres will then be reimbursed by the Sponsor.
6.1 Appearance and Content
Test treatment: placebo HFA-152a propellant pMDI, presented as:

Active ingredients: none;

Excipients: HFA-152a propellant, 
;

Presentation: each canister contains 120 doses;

Appearance: aluminium canister + grey dose counter actuator.
Reference treatment and training kit: CHF1535 placebo HFA-134a propellant pMDI, 
presented as:

Active ingredients: none;

Excipients: HFA-134a propellant, 
;

Presentation: each canister contains 120 doses;

Appearance: aluminium canister + grey dose counter actuator.
6.2 Dosage and Administration 
6.2.1 Selection of Doses in the Study
The dose of test treatment and reference treatments administered in this study 
 corresponds to the maximum total daily dose of propellant allowed for 

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administration with the Clenil pMDI device at 200 mg/inhalation 
 
.
6.2.2 Dosage
Subjects will receive a single dose 
 of each of the following products:

Test treatment: placebo HFA-152a propellant pMDI;

Reference treatment: placebo HFA-134a propellant pMDI.
The administration of the study treatment will occur using two pMDI canisters and two 
actuators (one for each of the two treatment periods) for each subject. For each treatment period, 
each subject will take 
 (single-dose administration) from one of the pMDIs.
6.2.2.1 Concomitant Medication for Asthma
Subjects will preserve their current asthma therapy, which may include low‑dose 
ICS-formoterol, SABA or low‑dose ICS whenever SABA is taken (low‑dose SABA is defined 
in Inclusion criterion #6, Section 4.2). Subjects can take their asthma therapy as needed, but no 
more than twice a week in the 4 weeks prior to screening and randomisation or between TP1 
and TP2.
Prior to the spirometry assessments (see Table 1), subjects will be asked to wash-out from 
inhaled/nebulised SABA (6 h), ICS (in combination with SABA; 24 h) and 
ICS-formoterol (24 h).
6.2.2.2 Investigational Phase
According to the allocation based on the randomisation list, eligible subjects will be 
administered one single dose 
 of each of the following study treatments in a 
cross-over design:

Test treatment: placebo HFA-152a propellant via pMDI;

Reference treatment: placebo HFA-134a propellant via pMDI. 
6.2.3 Administration
Treatment administration will take place at the investigational sites, during TP1 and TP2 (see 
Table 1). The two treatment administrations will be separated by a 2- to 7-day wash-out period, 
and must be performed at approximately the same time of the day. The treatment will be 
administered according to the instructions for use (provided in a separate document) and under 
the supervision of the Investigator or his/her designee.
Before study treatment administration, restrictions related to treatment administration and study 
assessments will be checked (see Section 7.2), and the pre-dose assessments will be performed 
(see Table 1). 
6.2.3.1 Administration with Pressurised Metered Dose Inhaler
The study treatment will be administered by inhalation using the pMDI device, according to the 
following instructions:

Position: subjects must be in an upright position;

Duration of treatment administration: the 
 inhalations should be performed within 
12 min;

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o
T0 is defined as the moment when the first inhalation takes place, and will 
be used to calculate the pre-dose timepoints;
o
T1 is defined as the moment when the last 
 inhalation takes place, and 
will be used to calculate the post-dose timepoints. 
Subjects performing the 
 inhalations in more than 12 min will be considered as 
protocol deviations;

Time between two consecutive inhalations: two consecutive inhalations must be 
separated by 40 seconds minimum, during which subjects must:
o
Hold their breath for the 10 seconds following the inhalation;
o
Wait approximately 30 seconds before taking the next inhalation.
If a subject coughs during the 
 inhalations, the Investigator must wait until the cough is 
resolved and then resume treatment administration. If the cough is severe and does not resolve 
spontaneously, the subject must stop treatment intake in the interest of his/her safety. The 
appropriate measures should be taken. 
An incorrect inhalation is defined as “a significant reduction of delivered dose that reaches the 
lungs based on Investigator or designee judgement”. Even if this is the case, no extra inhalations 
(i.e. more than the 
 inhalations required) will be administered.
Treatment administration will be recorded in the eCRF by the Investigator or designee. Any 
issues occurring during the inhalations as evaluated by the Investigator or designee will be 
reported in the eCRF.
6.2.4 Subject Training
6.2.4.1 Training with Pressurised Metered Dose Inhaler Placebo
At screening, the correct use of the pMDI device will be explained to the subjects according to 
the instructions for use (provided in separate documents).
Subjects will be trained by using a placebo HFA-134a inhaler, which is identical from a 
functional point of view to the device used for the administration of the study treatment (see 
Section 6.3.1). Therefore, the training will be done with the pMDI device, with the inhalation 
repeated four times or as many times as necessary until the subject is properly trained.
The training kits will be kept at the investigational site by the Investigator and will not be 
dispensed to the subjects. The training kit will be assigned to the subject at screening. 
The subject will not be included in the study if the training is not completed successfully. 
Training evidence will be recorded in the eCRF by the Investigator or designee.
6.3 Packaging 
All investigational products will be prepared in accordance with Good Manufacturing 
Practices (GMP) as required by the current GCP. Chiesi will supply the material described in 
the following sections.
6.3.1 Training Kit
The training kits will be supplied to the investigational sites. Each kit will consist of one box 
containing placebo HFA-134a propellant pMDI. The training kits will be used at screening only 
(see Table 1) and must be stored as specified in Section 6.8. 

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Training kits will be supplied in the following packages:

Primary packaging: one labelled canister containing CHF1535 placebo HFA-134a 
propellant pMDI, plus one labelled dose counter actuator;

Secondary packaging (subject box): labelled box containing one labelled canister and 
one labelled dose counter actuator.
6.3.2 Study Treatment Kits
Treatment kits will be supplied to the Investigator as subject boxes containing two period boxes, 
each containing one pMDI device. For each treatment kit, “Reserve” kits will be prepared in 
case of drop-out or device malfunctioning; they will be exactly the same as the treatment kit, 
but will be identified with a specific printed label “Reserve” (this will allow an easier 
management of the reserve kits, avoiding any mistakes by the Investigator).
Treatment kits will be supplied in the following packages:

Primary packaging: one labelled canister containing placebo HFA-152a propellant or 
placebo HFA-134a propellant for inhalation, plus one labelled dose counter actuator;

Secondary packaging (period box): labelled box containing one canister and one 
actuator to be used at one treatment period;

Tertiary packaging (subject box): one labelled box containing two period boxes.
6.4 Labelling 
All labelling of primary/secondary/tertiary for training, treatment and reserve kits will be in 
English and will be compliant with Annex 13 of Volume 4 in the GMP [14] and according to 
local law and regulatory requirements.
6.5 Treatment Allocation
A balanced block randomisation list will be prepared using a computerised system. Each subject 
will be assigned to one of the two possible treatment sequences arranged in a 2x2 William 
design.
Each subject will be identified by a unique five-digit code (two digits specific to the 
investigational centre and three digits specific to each subject [XXYYY]) assigned at screening.
At randomisation (TP1), each eligible subject will be assigned the lowest randomisation number 
available at the investigational centre according to a pre-established randomisation list:

Subjects who do not meet inclusion and/or exclusion criteria at screening or prior to 
randomisation will not be eligible to enter the study. They will be considered as “screen 
failure subjects”;

Subjects who fully meet inclusion and/or exclusion criteria at screening or before 
randomisation will be eligible to enter the study;

Subjects who prematurely terminate the study will be considered as “drop-out subjects”. 
These subjects cannot be screened again.
Note: If a subject is withdrawn or discontinued from the study after randomisation, the subject 
code and randomisation number will not be reassigned to another subject.

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6.6 Treatment Code
The randomisation list will be provided to the labelling facility but will not be available to 
subjects, Investigators, monitors or employees of the investigational centre involved in the 
management of the trial before unblinding of the data, unless in case of emergency.
The Sponsor’s clinical team will also be blinded during the study as they will not have direct 
access to the randomisation list.
An individual disclosure envelope will be supplied to the Investigator for each subject and will 
contain the medication assignment for that subject.
The Investigator will keep the treatment code envelopes in a locked, secure storage facility. A 
treatment code envelope can only be opened in an emergency situation, where the Investigator 
considers it essential to know what treatment the subject was taking. The Sponsor and the 
clinical monitor shall be notified promptly if a treatment code envelope is opened. 
The Investigator shall provide a signed explanation in the eCRF, explaining the reasons for 
which the treatment code was opened.
All treatment code envelopes, either unopened or opened, will be returned to the contract 
research organisation (CRO) upon termination of the study or will be destroyed at site after a 
full reconciliation.
A second set of code break envelopes will be supplied to the Chiesi Global Pharmacovigilance, 
to be opened before reporting a Suspected Unexpected Serious Adverse Reaction (SUSAR) to 
the Regulatory Authorities and the EC.
Subjects will receive a card on which the investigator name, the site address and the phone 
numbers of the investigational site are reported. These can be contacted in case of emergency. 
6.7 Treatment Compliance
For each subject, the number of correct and incorrect inhalations taken in each treatment period 
will be recorded in the eCRF.
6.8 Drug Storage 
The Pharmacist/Investigator will be responsible for the safe storage of all medications assigned 
to this study, in a secure place with restricted access, and maintained within the appropriate 
ranges of temperature.
The following storage conditions must be respected: 

Training kit (placebo HFA-134a propellant pMDI): before the use, kits must be stored 
in a refrigerator at a temperature between 2°C and 8°C; 

Treatment kits (and Reserve kits) (placebo HFA-152a propellant pMDI and placebo 
HFA-134a propellant pMDI): the subject box must be stored in a refrigerator at a 
temperature between 2˚C and 8˚C. At study visits, only the period box must be removed 
from the refrigerator on the day of usage, while the subject box must be maintained in 
the refrigerator until the next treatment administration period. 
Note: the product administered to the subjects should be at room temperature (not cold). 
Any deviation from the required storage conditions must be reported promptly, and the Sponsor 
will assess whether the affected kits can still be used. 

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6.9 Drug Accountability
The Investigator, or the designated/authorised representative, is responsible for the 
management of all the study treatments to be used for the study. Study treatments should be 
stored in a locked, secure storage facility with access limited to those individuals authorised to 
dispense the study treatments.
An inventory will be maintained by the Investigator or Pharmacist (or other designated 
individual), to include a signed account of all the study treatments received 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 treatments, supplied, used or unused, will be destroyed by the Investigator, directly 
at the investigational site. In this case, a destruction certificate must be requested from the 
investigational site and must be filed, both at the investigational site and by the Sponsor. 
Destruction will not occur until authorised by Chiesi.
6.10 Provision of Additional Care
At study completion or early termination, it is under the Investigator’s responsibility to 
recommend subjects to continue using their usual asthma therapy or to refer them to the General 
Practitioner.
7.
STUDY PLAN
7.1 Study Schedule
The study will be conducted as described in Section 3 and Table 1.
Current UK national laws and site-specific recommendations for the prevention of the 
coronavirus disease 2019 (COVID-19) pandemic will be strictly adhered to. These include 
subjects’ monitoring for COVID-19 symptoms and the adherence to the appropriate measures 
to control the transmission of the virus in the hospital setting [15].The study plan and scheduled 
tests are summarised in Table 1.

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Table 1. Schedule of Assessments
Investigational Phase
Pre-screening 
visit
(Visit 0)[1]
Screening 
visit
(Visit 1)[1]
TP1
TP2
Follow-up 
call[2]
Early 
Termination 
visit
Date
2-7 days 
before 
screening
2-21 days 
before TP1
Day 1
2-7 days 
after TP1
7-10 days 
after TP2
Informed consent
X
Randomisation
X
Ambulatory visit
X
X
X
X
X[2]
X
Treatment intake
Treatment administration[3]
X
X
Training
Placebo training
X
Subject Health Evaluation
Inclusion/Exclusion criteria
X
X
Medical history, 
concomitant diseases and 
previous medications
X
Demographic data
X
Height and weight
X
Physical examination
X
X
X
X
ACQ-5
X*
X
X
Adverse events recording
X
X
X
X
X
Restrictions
X
X
X
Concomitant medications
X
X
X
X
X 
X
Safety assessment in blood
Clinical chemistry
X
Haematology
X
FSH or pregnancy test
X
Generic assessments in urine
Urinalysis
X
Pregnancy test 
X
X
X
Cardiac assessments[4]
12-lead ECG
X
X
X
X
Vital signs - Blood pressure
X
X
X
X
Pulmonary Assessments
Bronchodilator reversibility 
or bronchial challenge test[5] 
X
Lung function[6]
X
X
X
Other Assessments
X
X
ACQ-5 = Asthma Control Questionnaire©; DBP = Diastolic blood pressure; ECG = Electrocardiogram; FEV1 = Forced 
expiratory volume in 1 second; FSH = Follicle-stimulating hormone; h = hour; min = minute; PEF = Peak expiratory flow; 

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SBP = Systolic blood pressure; T0 = Time of the first inhalation of the study treatment; T1 = Time of the last 
 inhalation 
of the study treatment; TP = Treatment period. 
[1] Visit 0 and Visit 1 can be combined in a single visit if the study restrictions and wash-out requirements are respected at 
Visit 0. 
[2] A follow-up visit can be performed, if deemed necessary by the Investigator. A follow-up call (or visit) is not required in 
case of early withdrawal.
[3] A single dose 
 will be administered. Subjects must perform the 
inhalations within 12 min. For each 
subject, the two treatment administrations (at TP1 and TP2) must start at approximately the same time of the day. 
[4] Cardiac assessments will be performed as follows:

Vital signs: duplicate SBP and DBP will be evaluated after 5 min in supine position and before the spirometry 
assessments and blood tests, at screening (Visit 1), and at the following timepoints on TP1 and TP2: 
o
Pre-dose: within 1 h before T0;
o
Post-dose: 45 min, 1 h 45 min and 2 h 45 min after T1.

Local 12-lead safety ECG: a triplicate ECG will be performed to assess eligibility at screening (Visit 1), before the 
spirometry assessments and blood tests and a single ECG will be evaluated on TP1 and TP2, at the same timepoints 
as the vital signs.
[5] The bronchodilator reversibility or bronchial challenge test will be performed to assess a subject’s eligibility, in case 
documented evidence of excessive variability in lung function is not available or in case the documentation is older than 2 years. 
In case the criterion of excessive lung function variability is not met at screening, the test (bronchodilator reversibility or 
bronchial challenge) can be repeated once before randomisation (performed at TP1). 
[6] Lung function assessments (spirometry [FEV1 and PEF]) will be performed as follows: 

Screening (Visit 1): single spirometry to assess the subject’s eligibility; 

TP1 and TP2:
o
Pre-dose: 45 min and 15 min before T0;
o
Post-dose: 5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1.
 
* ACQ-5 questionnaire can be administered at pre-screening or at screening visit. 
7.1.1 Pre-screening (Visit 0) 
A pre-screening visit will be carried out 2 to 7 days before screening, in order to fully explain 
the study to the subject by the Investigator or his/her designee. The Investigator or his/her 
designee should provide subject ample time and opportunity to inquire about details of the trial 
and to decide whether or not to participate in the trial.
If subject agrees to participate, the signed and dated informed consent must be obtained before 
any study related procedures.
The following procedures will take place at pre-screening:

Concomitant medications: any medication taken regularly at the time of the ICF 
signature will be recorded.

The subject will be informed about the study restrictions and the wash outs to be 
respected prior to screening visit. 

ACQ5 questionnaire can be performed at this visit or at the following one. 
If the study restrictions and wash-out requirements (see Section 7.2) are respected at Visit 0, 
Visit 0 and Visit 1 can be combined in one visit.
7.1.2 Screening (Visit 1)
A screening visit will be carried out in order to confirm a subject’s eligibility for the study. 

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The visit will take place 2 to 7 days after the pre-screening visit, and 2 to 21 days before 
TP1 (i.e. randomisation and administration of the first study treatment). In case the restrictions 
are not respected the visit can be rescheduled once
The following procedures will take place at screening:

Demographic data collection: demographic data including age, gender and race will be 
recorded;

Physical examination: a comprehensive physical examination will be performed;

Medical/surgical history, concomitant diseases and previous medications: subject’s 
medical and surgical history, as well as concomitant diseases (i.e. diseases pre-existing 
at the time of the ICF signature) will be recorded. Any medications taken in the month 
preceding the pre-screening visit will be recorded;

Study restrictions: study restriction criteria will be checked according to Section 7.2;

Concomitant medications: any medication taken regularly at the time of this visit will 
be recorded;

AE recording: the occurrence of any AEs since the pre-screening visit (ICF signature) 
will be checked, AEs will be recorded in the eCRF, along with the related concomitant 
medications.
In cases where CS abnormalities are revealed during the physical examination or 
screening procedures, these will be recorded in the subject’s eCRF as medical history, 
unless the start date/time is after the ICF signature date/time and it is not due to a 
pre‑existing condition. In the latter case, it will be recorded in the eCRF as an AE;

Local safety ECG: triplicate 12-lead ECG will be used to measure heart rate (HR), QRS 
interval (QRS), PR interval (PR) and QT interval corrected using Fridericia’s 
formula (QTcF). The assessment will be performed according to Section 7.3.3;

Blood pressure: SBP and DBP will be measured according to Section 7.3.2;

Blood test: blood samples will be collected for safety evaluations (clinical chemistry 
and haematology), after the 12-lead ECG and blood pressure assessments, according to 
Section 7.3.4;

FSH or pregnancy tests: blood samples will be collected from female subjects for FSH  
(for not childbearing potential women) and serum pregnancy tests (for childbearing 
potential women), according to Section 7.3.4;

Urine test: urine samples will be collected for urinalysis, according to Section 7.3.5;

Height and weight: will be recorded;

Lung function: single spirometry will be performed (after the ECG records and the 
assessment of the Vital signs) according to Section 7.3.1;

Bronchodilator reversibility or bronchial challenge test: will be performed in case 
documented evidence of excessive variability in lung function is not provided, or in case 
the documentation is older than 2 years;

Asthma Control Questionnaire© (ACQ-5): asthma control level will be assessed using 
the ACQ-5 questionnaire, according to Section 7.3.6.1;

Training: subjects will receive training on the proper use of the inhaler with a pMDI 
placebo, according to Section 6.2.4.1;

Subject selection: inclusion/exclusion criteria will be checked (see Section 4.2 and 
Section 4.3, respectively).

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7.1.3 Treatment Period 1 (TP1)
TP1 is the first visit of the investigational phase and takes place 2 to 21 days after screening. 
The following procedures and assessments will take place during this ambulatory visit:

Subject selection: inclusion and exclusion criteria will be re-checked (see Section 4.2 
and Section 4.3, respectively). Subjects not fulfilling the inclusion criteria or meeting 
any of the exclusion criteria will be recorded as screening failures;

Study restrictions: study restriction criteria will be checked, according to Section 7.2;

ACQ-5: asthma control level will be re-assessed using the ACQ-5, according to 
Section 7.3.6.1;

Randomisation: subjects will be randomised according to Section 6.5. 

Concomitant medications: concomitant medications taken by the subject since the 
screening visit and during TP1 will be checked and recorded;

AE recording: the status of AEs ongoing at the screening visit will be checked and 
updated in the eCRF when applicable. Any new AE occurring since the previous visit 
will be checked and recorded in the eCRF, as well as the related concomitant 
medications. Any AE occurring during the study visit must also be monitored and 
recorded in the eCRF;

Pregnancy test: urine samples will be collected from childbearing potential female 
subjects for pregnancy testing, according to Section 7.3.5;

Physical examination: a full physical examination will be performed, and any new CS 
abnormality revealed since the screening visit will be recorded as an AE;

12-lead ECG: a single ECG will be recorded to assess ECG parameters (HR, PR, QRS 
and QTcF), according to Section 7.3.3. The assessment will be performed in pre-dose: 
within 1 h before T0; and in post-dose: 45 min, 1 h 45 min and 2 h 45 min after T1;

Blood pressure: SBP and DBP will be measured after 5 min in supine position, as 
described in Section 7.3.2. The assessment will be performed before or after the 12-lead 
ECG assessment, in pre-dose: within 1 h before T0; and in post-dose: 45 min, 
1 h 45 min and 2 h 45 mins after T1;

Lung function: serial spirometries will be performed according to Section 7.3.1. 
Spirometry assessments will be collected in pre-dose: 45 min and 15 min before T0; and 
in post-dose: 5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1;

Study treatment administration: single-dose (
) treatment administration 
according to Section 6.2.3, based on each subject’s randomisation arm;

 
 
TP1 will be followed by a 2- to 7-day wash-out period from the propellant. 
7.1.4 Treatment Period 2 (TP2)
TP2 is the second visit of the investigational phase. It takes place 2 to 7 days after TP1. 
The following procedures and assessments will take place during this ambulatory visit:

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
Study restrictions: study restriction criteria will be checked, according to Section 7.2;

Concomitant medications: concomitant medications taken by the subject since TP1 and 
during TP2 will be checked and recorded;

AE recording: the status of AEs ongoing at TP1 will be checked and updated in the 
eCRF when applicable. Any new AE occurring since the previous visit will be checked 
and recorded in the eCRF, as well as the related concomitant medications. Any AE 
occurring during the study visit must also be monitored and recorded in the eCRF;

Pregnancy test: urine samples will be collected from childbearing potential female 
subjects for pregnancy testing, according to Section 7.3.5;

Physical examination: a full physical examination will be performed and any new CS 
abnormality revealed since TP1 will be recorded as an AE;

12-lead ECG: a single ECG will be recorded to assess ECG parameters (HR, PR, QRS 
and QTcF), according to Section 7.3.3. The assessment will be performed in pre-dose: 
within 1 h before T0; and in post-dose: 45 min, 1 h 45 min and 2 h 45 min after T1;

Blood pressure: SBP and DBP will be measured after 5 min in supine position, as 
described in Section 7.3.2. The assessment will be performed before or after the 12-lead 
ECG assessment, in pre-dose: within 1 h before T0; and in post-dose: 45 min, 
1 h 45 min and 2 h 45 min after T1;

Lung function: serial spirometries will be performed according to Section 7.3.1. For 
each subject, the assessments will start at approximately the same time of the day as at 
TP1. Spirometry assessments will be collected in pre-dose: 45 min and 15 min before 
T0; and in post-dose: 5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1;

Study treatment administration: single-dose (
) administration of the 
second propellant (based on each subject’s randomisation arm, following a cross-over 
design), according to Section 6.2.3. For each subject, treatment administration will start 
at approximately the same time of the day as at TP1;

 
 
A follow-up call (or visit, if deemed necessary by the Investigator) will be performed 
7 to 10 days after TP2. 
7.1.5 Follow-up Call
A follow-up call (or visit, if deemed necessary by the Investigator) will be performed 
7 to 10 days after TP2, for a safety follow-up. 
The following assessments will be performed during this call: 

AE recording: the status of any AEs ongoing at TP2 will be checked and updated in the 
eCRF, along with the related concomitant medications. Any new AE occurring since 
TP2 will be checked and recorded in the eCRF, as well as the related concomitant 
medications;

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
Concomitant medications: concomitant medications taken by the subject since TP2 will 
be checked and recorded.
7.1.6 Early Termination Visit
In the case of early discontinuation, an Early Termination visit will be performed in order to 
assess the subject’s safety. 
The following assessments will be performed: 

Concomitant medications: concomitant medications taken by the subject since the last 
study visit and during the Early Termination visit will be checked and recorded;

AE recording: the status of any AEs ongoing at the previous visit will be checked and 
updated in the eCRF, along with the related concomitant medications. Any new AE 
occurring since the previous visit will be checked and recorded in the eCRF, as well as 
the related concomitant medications. Any AE occurring during the study visit must also 
be monitored and recorded in the eCRF;

Pregnancy test: urine samples will be collected from childbearing potential female 
subjects for pregnancy testing, according to Section 7.3.5;

Physical examination: a full physical examination will be performed and any new CS 
abnormality revealed since the previous visit will be recorded as an AE;

12-lead ECG: a single ECG will be recorded to assess ECG parameters (HR, PR, QRS 
and QTcF), according to Section 7.3.3;

Blood pressure: SBP and DBP will be measured after 5 min in supine position, as 
described in Section 7.3.2. 
7.2 Study Restrictions and Standardisation
The following restrictions should be applied and should be checked at each visit at the 
investigational site:

No smoking or intake of substances containing nicotine: up to the end of the 
investigational phase (for the eligibility of ex-smokers, see Exclusion criterion #9, 
Section 4.3);

Current asthma therapy: low‑dose ICS‑formoterol, SABA, or low‑dose ICS (whenever 
SABA is taken) should be taken as needed, but not more than twice a week (2 events) 
in the 4 weeks prior to screening or in the 6 weeks prior to randomisation, and between 
the treatment periods. 
A definition of low‑dose ICS is provided in Inclusion criterion #6, Section 4.2.
The following restrictions should be applied before spirometry assessments (i.e. before 
screening, TP1 and TP2) [16]: 

Wash-out period: 
o
Inhaled/nebulised SABA: 6 h;
o
ICS (in combination with SABA): 24 h;
o
ICS-formoterol: 24 h.

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
No intake of intoxicants such as alcohol, caffeine/xanthine containing beverages or food 
(coffee, tea, chocolate, cola) within 8 h. Decaffeinated products are permitted;

No strenuous activities within 1 h;

Avoiding wearing clothes that substantially restrict full chest and abdominal expansion. 
7.3 Investigations
7.3.1 Lung Function Assessment
Lung function will be evaluated at the timepoints specified in Table 1.
Centralised spirometry will be used for the assessment performed during TP1 and TP2 for this 
trial while the local spirometer is used for the eligibility lung function assessments. The specific 
procedures for centralised spirometry will be provided to the Investigator by the centralised 
spirometry company. 
Calibration of the local spirometer must be performed at each screening visit prior to spirometry 
manoeuvres and the reports must be kept at the investigational sites and be accessible to the 
clinical research associate and the Sponsor. Personnel using the spirometer will be adequately 
trained to follow the commonly accepted procedures. The predicted values will be calculated 
according to the formulas reported by Quanjer et al. [17].
The same brand and model of spirometer will be provided by the centralised spirometry 
company for all measurements during TP1 and TP2and adjusted for the ATS/ERS standards 
[16]. The predicted values will be calculated according to the formulas reported by Quanjer et 
al. [17]. Personnel using the spirometer will be adequately trained to follow the commonly 
accepted procedures. The spirometer provided by the centralized spirometry company do not 
need the calibration procedure. 
Subjects should be at rest before each lung function test. All measurements are to be made with 
the subjects in sitting or standing position (for the same subject, the position must be consistent 
throughout the study) with the nose clipped. Values will be corrected for body temperature and 
pressure saturation (BTPS) conditions [18].
At each timepoint specified in Table 1, subjects will perform three attempts for the 
measurement of FEV1 and peak expiratory flow (PEF). In order to be considered as technically 
satisfactory attempts, measurements should be free from cough and false-start. The highest 
value (in L) of FEV1 and PEF from three technically satisfactory attempts (not necessarily 
coming from the same curve) will be recorded. The two largest FEV1 measurements must be 
within 150 mL of each other (or 100 mL, if the forced vital capacity [FVC] value is ≤1L). If the 
difference is larger, additional spirometry assessments (up to 8) will be made until the above 
criterion is met. If, at the end, the tests are not within 150 mL, the highest value of FEV1 and 
PEF will be recorded and used for eligibility or continuation criteria.
In case lung function measurements obtained at screening were below the expected value, (see 
Inclusion criterion #4 in Section 4.2), the subject will be asked to return to the investigational 
site once before randomisation to repeat the test. If, at that time, FEV1 ≥60% of the predicted 
normal value and ≥1.5 L, the subject can be included in the study. Otherwise, the subject will 
be discharged and recorded as a screening failure.
If a subject shows a progressive reduction in FEV1 with each subsequent blow, with cumulative 
drop above 15% of the starting value, the test procedure may be terminated in the interest of 
the subject’s safety. During the 3 h post-dose serial spirometry, the use of rescue medication should 

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be as limited as possible and rescue medication intake must be under medical control. The serial 
spirometries can be discontinued after the intake of rescue medication, based on the Investigator’s 
judgement. In this case and if deemed necessary, a safety spirometry can be performed by the site. 
Details on intake of rescue medication during the treatment periods will be recorded in the eCRF.
The restrictions to be applied before spirometry assessments are described in Section 7.2, [16]. 
In case any of the restrictions is not respected, the study visit should be rescheduled once, to be 
performed within the allowed time window between the previous and the current visit. 
For the post-dose lung function assessments, the following time deviations from the theoretical 
post-T1 times will be allowed (actual time to be recorded is the time when the first lung function 
manoeuvre starts): 

5 min and 15 min post-dose: ± 2 min;

30 min and 1 h post-dose: ± 5 min;

1h 30 min and 3 h post-dose: ± 15 min.
Longer time deviations will be evaluated on a case-by-case basis during the Blind Data Review 
meeting. 
7.3.2 Vital Signs (blood pressure)
SBP and DBP will be evaluated at the timepoints specified in Table 1. 
All measurements will be made in duplicate within a 5-min interval. Subjects should be resting 
in a quiet, supervised setting with minimal stimulation (e.g. no television, loud music, computer 
games) and lay in a supine position for 5 min (whenever possible) before each measurement. 
Blood pressure measurements must be performed before the lung function assessments and the 
blood tests, as specified in Table 1.
Acceptable time deviations from theoretical post-dose timepoints are ± 10 min.
7.3.3 Electrocardiogram Assessments
ECG assessments will be performed at the timepoints specified in Table 1.
Subjects should be resting in a quiet supervised setting with minimal stimulation (e.g. no 
television, loud music, computer games). ECG recordings will be performed either before or 
after blood pressure measurements, and must be performed before the lung function 
assessments and the blood tests, as specified in Table 1. 
At screening, a triplicate 12-lead digitised ECG recording will be performed. The values of all 
ECG parameters and the overall ECG evaluation will be reported in the eCRF. The average of 
the triplicate recordings will be used to assess the subjects’ eligibility (see Exclusion 
criterion #12 in Section 4.3). In case abnormal CS ECG results are obtained at screening, the 
subject will be asked to return to the investigational site once before randomisation to repeat 
the ECG measurement. If, at that time, ECG interpretation is not considered abnormal clinically 
significant, the subject can be included in the study. Otherwise, the subject will be discharged 
and recorded as a screening failure.
During the Investigational Phase (TP1 and TP2) and the Early Termination visit, single ECGs 
will be performed for safety assessments. Acceptable time deviations from theoretical post-dose 
timepoints are ± 10 min.
7.3.4 Blood Sample Collection
Blood samples will be collected at screening, as specified in Table 1.

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Laboratory tests can be repeated, if deemed necessary by the Investigator, to assess the subject’s 
safety or to confirm his/her eligibility.
Approximately 20 mL of blood will be collected according to the local procedures, to assess 
the following parameters:

Routine blood haematology: red blood cells (RBC) count, white blood cells (WBC) 
count and differential count (absolute value and %), total haemoglobin (Hb), 
haematocrit (Hct), platelets (PLT) count; 

Serum 
clinical 
chemistry: 
creatinine, 
urea, 
phosphate, 
aspartate 
aminotransferase (AST), 
alanine 
aminotransferase 
(ALT), 
gamma-glutamyl 
transpeptidase (γ-GT), total bilirubin, alkaline phosphatase, total cholesterol, 
triglycerides, sodium (Na), potassium (K), calcium (Ca), chloride electrolytes (Cl);

Serum pregnancy test (in case of WOCBP) and FSH test (in case of post-menopausal 
women, if the FSH value is deemed necessary by the investigator).
In case clinically significant abnormal laboratory values are obtained at screening that could 
indicate a temporary condition (see Exclusion criteria #13, #14 and #15 in Section 4.3 for 
details), the subject will be asked to return to the centre once before randomisation, to repeat 
the test. If, at that time, no clinically significative abnormalities are observed, the subject can 
be included in the study. Otherwise, the subject will be discharged and recorded as a screening 
failure.
Blood collection and sample preparation will be performed according to the procedures 
provided by the local laboratory, which will be in charge of transmitting the results to the 
Investigator for evaluation. Only CS abnormal values of laboratory results will be entered in 
the eCRF by the Investigator, and AEs/serious adverse events (SAEs) will be reported. The 
normal ranges will be provided by the local laboratory and included in the eCRF
7.3.5 Urine Sample Collection
A urine sample will be collected from all subjects at screening for the urinalysis (quantitative 
[proteins] and qualitative [ketones, microscopic examination of the sediment]). 
During the investigational phase (TP1 and TP2) and the Early Termination visit (if relevant), 
urine will be collected from childbearing potential female subjects for laboratory pregnancy 
tests.
7.3.6 Administered Questionnaires 
7.3.6.1 Asthma Control Questionnaire
The five-item ACQ-5 questionnaire will be used for the evaluation of each subject’s asthma 
control level [19]. The questionnaire will be administered at pre-screening or screening to assess 
eligibility, and at TP1 (before randomisation) to confirm eligibility.
The ACQ-5 is a self-administered questionnaire which includes five questions on asthma 
symptoms experienced during the past week. Subjects must score each of the questions on a 
scale of 0 to 6, where 0 represents excellent control of the symptom and 6 represents extremely 
poor control. The overall score of the ACQ-5 is the mean of the five responses [19]. 
Subjects must have an overall score of <1.5 to be eligible for inclusion in this study (see 
Inclusion criterion #7, Section 4.2).

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8.
EFFICACY ASSESSMENTS
No efficacy assessments are planned in this study.
9.
SAFETY ASSESSMENTS
The primary objective of this study is to compare the potential for bronchoconstriction 
 
 of the HFA-152a propellant versus 
 the HFA-134a propellant 
when administered alone (not in combination with other active compounds). 
The potential for bronchoconstriction will be assessed through centralised spirometry 
assessments performed at TP1 and TP2, as described in Section 7.3.1. At each treatment period, 
FEV1 and PEF will be assessed in pre-dose: 45 min and 15 min before T0; and in 
post-dose: 5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1. 
The following safety variable will be considered for the evaluation of the potential for 
bronchoconstriction of each propellant: 

Relative change from baseline* in FEV1 at the 15 min post-dose timepoint.
In addition, the following safety variables will be considered to complete the evaluation of the 
potential for bronchoconstriction of each propellant:

Relative change from baseline* in FEV1 at all the other post-dose timepoints (5 min and 
30 min, 1 h, 1 h 30 min and 3 h after T1);

Absolute change from baseline* in FEV1 at all post-dose timepoints (5 min, 15 min, 
30 min, 1 h, 1 h 30 min and 3 h after T1);

Number and percentage of subjects with a relative change from baseline* in FEV1 at 
each post-dose timepoint <-15%;

Number and percentage of subjects with a relative change from baseline* in FEV1 at 
any post-dose timepoint <-15%;

Change from baseline* in FEV1 area under the concentration-time curve from time zero 
to 3 hours (AUC0-3h);

Relative change from baseline* in PEF at all post-dose timepoints; 

Absolute change from baseline* in PEF at all post-dose timepoints;

Number and percentage of subjects with use of rescue medication in the 3 h after T1;

Mean use (puffs) of rescue medication in the 3 h after T1.
* The baseline FEV1 and PEF values are the mean of the 2 pre-dose assessments 
(i.e. performed 45 min and 15 min before T0).

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The secondary objective of the study is to evaluate the general safety and tolerability of the 
two propellants.
The general safety of the propellants will be assessed at TP1 and TP2, throughout local safety 
ECGs (as described in Section 7.3.3), vital signs (as described in Section 7.3.2), and recording 
of AEs and concomitant medications. 
The following safety variables will be considered for the evaluation of the general safety and 
tolerability of each propellant: 

AEs and AEs of particular interest (bronchospasm, cough, dysphonia, hoarseness);

Vital signs (SBP and DBP);

12-lead ECG parameters: HR, QTcF, PR and QRS.
 
 
 

10.
ADVERSE EVENT REPORTING
10.1 Definitions
An Adverse Event (AE) 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 AE 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 (ADR) is an “untoward and unintended response to an 
investigational medicinal product related to any dose administered”.
Within this trial the causality of an AE has to be considered with regards to the placebo and its 
excipients. 
All AEs 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 ADR 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 AE but an outcome. It is the cause of death that should be regarded as 
the AE. The only exception to this rule is “sudden death” where no cause has been 

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established; in this latter instance, “sudden death” should be regarded as the AE and 
“fatal” as its reason for being serious;

Is life-threatening
Life-threatening refers to an event in which the patient was at risk of death at the time 
of the event (e.g. aplastic anaemia, acute renal failure, and anaphylaxis). The term does 
not refer to an event which hypothetically might have caused death if it were more 
severe;

Requires hospitalisation or prolongation of existing hospitalisation
Hospitalisation 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. Hospitalisation 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 hospitalisation are AEs. If a complication prolongs hospitalisation, 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 AE
This criterion allows for any situations in which important AEs/reactions that are not 
immediately life-threatening or do not result in death or hospitalisation may jeopardise 
the subject’s health or may require intervention to prevent one of the above outcomes. 
Examples of such events are: intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; or development of drug dependency or drug abuse.
Medical and scientific judgment should be exercised in deciding whether an event is 
serious because medically significant.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious ADR.
A Non-Serious Adverse Event/Non-Serious ADR is an AE or ADR that does not meet the 
criteria listed above for an SAE/serious ADR.
10.2 Expectedness
Since no active ingredient will be included in the study treatment but only pMDI containing 
placebo propellant and excipients will be administered, there is no reference document for the 
assessment of the expectedness of AEs in this study. All AEs assessed as related to the study 
treatments and/or their excipients will be considered as unexpected AEs for safety reporting 
purposes. 

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10.3 Intensity of Adverse Event
Each AE must be rated on a 3-point scale of increasing intensity:

Mild: the event causes a minor discomfort or does not interfere with the daily activities 
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 patient 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 relatedness;

No reasonable possibility of relatedness.
The expression “reasonable possibility of relatedness” is meant to convey, in general, that there 
are facts (evidence) or arguments meant to suggest a causal relationship.
The Investigator will be asked to consider the following before reaching a decision on causality 
assessment:

Time relationship between study treatment intake and event’s onset;

Dechallenge (did the event abate after stopping the study treatment?);

Rechallenge (did the event reappear after reintroduction of the study treatment?);

Medical history;

Study treatment(s);

Mechanism of action of the study treatment;

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 Treatment Due to an Adverse Event

Dose not changed;

Treatment permanently withdrawn;

Unknown;

Not applicable.

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10.6  Other Actions Taken

Specific therapy/medication;

Concomitant procedure.
10.7 Outcome
Each AE 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 AEs occurring during the course of the study must be documented in the AE page of the 
eCRF. Moreover, if the AE is serious, the SAE Form must also be completed. 
It is the responsibility of the Investigator to collect all AEs (both serious and non-serious) 
derived by spontaneous, unsolicited reports of subjects, by observation and by routine open 
questionings.
The recording period for AEs is the period starting from the signature of the ICF until the 
subject’s study participation ends.
Any CS abnormalities detected at screening (Visit 1) not due to a pre-existing condition or CS 
changes at the following visits in the medical opinion of the Investigator must be reported as 
AEs in the eCRF.
If a CS abnormal laboratory finding or other abnormal assessment meets the definition of an 
AE, then the AE page of the eCRF must be completed, as appropriate. A diagnosis, if known, 
or clinical signs and symptoms if diagnosis is unknown, rather than the CS abnormal laboratory 
finding, should be reported on the AE page of the eCRF. If no diagnosis is known and clinical 
signs and symptoms are not present, then the abnormal finding should be recorded.
For pharmacovigilance purposes, all SAEs should be followed-up in order to elucidate as 
completely and practically as possible their nature and/or causality until resolution of all 
queries, clinical recovery is complete, laboratory results have returned to normal, stable 
condition is reached or until the subject is lost to follow-up. Follow-up may therefore continue 
after the subject has left the study. In this case, the follow-up will continue with no timelines 
for related SAEs, while for unrelated SAEs the type and extent of follow-up undertaken will be 
determined for each individual case and will depend upon the nature (e.g. events with poor 
prognosis or which do not resolve), severity and medical significance of the event. 
10.9 Reporting Serious Adverse Events to Chiesi
The Investigator must report all SAEs to the 
 Safety Contact listed below within 24 h of 
awareness. The information must be sent by providing the completed Serious Adverse Event 

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paper form. At a later date, the 
 Safety Contact will report all information to Chiesi Global 
Pharmacovigilance, the Clinical Project Manager and the Clinical Research Physician.
Safety Contact 
Fax no.
E-mail
 Safety Contact
Chiesi Safety Contact
Reporting of SAEs from the investigational site is from the time of a subject’s signature of the 
ICF and until the subject’s study participation ends. After this date, even if no active monitoring 
of subjects is required, SAEs occurring to a subject should be reported if the Investigator 
becomes aware of them.
Up to the closure of the investigational site, SAE reports should be reported to the 
 Safety 
Contact. New SAEs occurring after the site is closed should be reported directly to the Chiesi 
Safety Contact.
10.10 Reporting Serious Adverse Events to Regulatory Authorities/Ethics Committees
All SUSARs, which occur with the investigational medicinal products within or outside the 
concerned clinical trial, if required, will be reported in compliance with the timelines and 
standards for reporting SUSARs according to local UK regulations. The Medicines and 
Healthcare products Regulatory Agency (MHRA) will be informed through MHRA Individual 
Case Study Report (ICSR) Submission portal, while the EC and the Investigators by Council 
for International Organizations of Medical Sciences (CIOMS) I form or by periodic line-listings 
produced by Chiesi Global Pharmacovigilance.
With regard to regulations in force for Pharmacovigilance, the Investigator must fulfil his/her 
obligation according to the law in force in the UK.
10.11 General Notes

In case of death, a comprehensive narrative report of the case should be prepared by the 
Investigator and sent to the 
/Chiesi Safety Contact together with the SAE form, 
retaining a copy on site.

If an autopsy is performed, copy of autopsy report should be actively sought by the 
Investigator and sent to the 
/Chiesi Safety Contact as soon as available, retaining a 
copy on site.

All documents provided by the Investigator or site staff to the 
 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 withdrawn from the study and she 
will be asked (with a separate consent) to be followed with due diligence until the 
outcome of the pregnancy is known and till the age of one year of the child, to detect 
any congenital anomality or birth defect. The pregnancy must be reported by the 
Investigator within 24 h by fax/e-mail to the 
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Pregnancy Report Form. The 
 Safety Contact will inform Chiesi of the pregnancy 
within one working day of being notified. 
The first two pages of the Pregnancy Report Form should be completed by the 
Investigator with all the available information and sent to the 
/Chiesi Safety 
Contact. 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 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 of study treatment, the pregnancy 
does not need to be reported; it is only required that the subject is immediately 
withdrawn from the study.

Any ADR 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 according to the applicable laws. The Investigator is also 
recommended to report all ADRs to the relevant Marketing Authorisation Holders of 
the involved medicinal products. Additionally, 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 eCRF will be filled-in by the Investigator and/or his/her representative designee. 
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.
Questionnaires will be collected on paper and data will be entered in the database by trained 
and authorised site personnel.
Medical history, AEs and concomitant procedures will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA); medications will be coded using the World Health 
Organization (WHO) Drug dictionary and Anatomical Therapeutic Chemical (ATC) 
classification.
External data for spirometry assessments will be processed centrally, sent to the designated 
CRO and reconciled with the corresponding information recorded in the eCRF.
Access to electronic systems used for data collection will be granted to the study personnel only 
after appropriate training.

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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 
randomisation codes will be opened, and the planned statistical analyses will be performed.
If the database is unlocked after the initial lock, the process must be carefully controlled and 
documented; updates to the study data must be authorised 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 verify equivalence between the test 
treatment (HFA-152a) and the reference treatment (HFA-134a) for the relative change from 
baseline in FEV1 at the 15 min post-dose timepoint, with equivalence defined as a difference 
between the two treatments within the 10% (i.e. [-10%; +10%]). 
A total of 20 evaluable subjects will ensure a 95% power to provide a 95% confidence 
interval (CI) of the mean difference of the relative change from baseline in FEV1 at 15 min 
post-dose within the above-mentioned equivalence limits (i.e. [-10%; +10%]) assuming a 
within-subject standard deviation (SD) of 8%.
Estimating a non-evaluable rate of 16%, a total of 24 subjects will be randomised.
12.2 Populations for Analysis

Safety population: all randomised subjects who receive at least one dose of any of the 
two study treatments (analysed as treated);

Per-protocol population (PP): all subjects from the Safety population, except those 
subjects with important protocol deviations impacting the analysis population. Exact 
definition of important protocol deviations impacting the analysis population will be 
discussed by the study team during the blind review of the data and described in the 
Data Review Report.
Since a cross-over design will be used, the inclusion in the populations for analysis will be 
defined on a per-period basis. 
The Safety population will be used for the analysis of all safety variables. The variables 
assessing the primary study objective will also be analysed considering the PP population, for 
sensitivity purposes.
12.3 Statistical Analysis
A detailed statistical analysis plan will be described in the Statistical Analysis Plan (SAP), 
which will be finalised before breaking the blind. 
12.3.1 Descriptive Statistics 
General descriptive statistics for numeric variables will be summarised using n (number of 
observed values), the mean, the 95% CI of the mean, the SD, the median and the minimum and 

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maximum values. Categorical variables will be summarised using the number and percent of 
subjects with a specific level of the variable.
12.3.2 Missing Data
As a general rule, missing data will not be imputed.
For serial spirometry-derived parameters, the following rules will apply:

Pre-dose FEV1 and PEF:
o
In case only one pre-dose measurement is available, it will be used as pre-dose 
FEV1 and PEF;
o
In case no pre-dose measurements are available, the pre-dose FEV1 and PEF will 
be considered missing.

FEV1 AUC0-3h calculation:
o
In case only one pre-dose measurement is available, it will be used as pre-dose 
value (corresponding to time 0 for the calculation of the area under the 
concentration-time curve [AUC]);
o
In case no pre-dose measurements are available, the entire curve will be 
considered missing;
o
Single, isolated missing values (different from pre-dose) will be replaced by 
linear interpolation using adjacent values;
o
In case of two or more consecutive missing timepoints, the entire curve will be 
considered missing;
o
In case of three or more missing timepoints, the entire curve will be considered 
missing.
Further details on dealing with missing data, along with the handling of possible outliers, will 
be described in the SAP. Other critical missing data, if any, will be discussed during the review 
of the data. Decisions will be fully documented in the Data Review Report.
12.3.3 Subject Demographics and Baseline Characteristics
Demographics and baseline variables will be summarised by sequence and overall, using 
descriptive statistics for the Safety population.
The following variables will be presented: age, gender, race, height, weight, asthma history, 
medical history, prior medications, physical examination, vital signs, 12-lead ECG, ACQ-5, 
lung function, urinalysis, and safety blood assessments (routine haematology and clinical 
chemistry parameters). 
The following demographic and baseline variables will also be presented for the PP population: 
demographics (age, gender, race), asthma history and lung function.
12.3.4 Primary Efficacy Variables
No primary efficacy variables are considered in this study. 
12.3.5 Secondary Efficacy Variables
No secondary efficacy variables are considered in this study. 

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12.3.6 Safety Variables
Safety analyses will be based on the Safety population. For sensitivity purposes, the safety 
variables assessing the primary objective of the study will also be analysed in the PP population 
(see Section 12.2). 
The safety variables of the study are presented in Section 9.
The safety variable assessing the primary objective of the study (i.e. evaluation of the potential 
for bronchoconstriction of each propellant) will be analysed as follow: 

The relative change from baseline in FEV1 at the 15 min post-dose timepoint will be 
analysed using an analysis of covariance (ANCOVA) model, including treatment group, 
subject and period as fixed effects, and FEV1 baseline (mean of the two measurements 
at 45 min and 15 min pre-dose in each treatment period) as a covariate. 
The adjusted mean relative change from baseline obtained with each treatment and the 
adjusted mean difference between HFA-152a and HFA-134a with their 95% CIs and 
p-values will be estimated by the model.
The other safety variables completing the evaluation of the potential for bronchoconstriction of 
each propellant will be analysed as follows:

The relative changes from baseline in FEV1 at all the other post-dose timepoints (5 min, 
30 min, 1 h, 1 h 30 min and 3 h after T1) will be analysed using the same model used 
for the relative change from baseline in FEV1 at 15 min post-dose;

The absolute changes from baseline in FEV1 at all post-dose timepoints (5 min, 15 min, 
30 min, 1 h, 1 h 30 min and 3 h after T1) will be analysed using the same model used 
for the relative change from baseline in FEV1 at 15 min post-dose;

The number and percentage of subjects with a relative change from baseline in FEV1 at 
each post-dose timepoint (5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1) and 
at any post-dose timepoint <-15% will be summarised for each treatment;

The change from baseline in FEV1 AUC0-3h will be summarised using descriptive 
statistics;

The relative and absolute changes from baseline in PEF at all post-dose timepoints 
(5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h after T1) will be summarised for each 
treatment, using descriptive statistics;

The number and percentage of subjects with use of rescue medication in the 3 h 
post‑dose will be summarised for each treatment;

The mean use (puffs) of rescue medication in the 3 h post-dose will be summarised for 
each treatment, using descriptive statistics.
The safety variables assessing the secondary objective of the study (i.e. general safety and 
tolerability of the two different propellants) will be analysed as follow:

Adverse events and adverse events of particular interest: 
All AEs starting on or after the time of first study treatment intake will be classified as 
treatment-emergent adverse events (TEAE). Any AEs started after the informed consent 
signature and before the time of first study treatment intake will be classified as 
pre-treatment AEs.
The number of subjects who experienced at least one TEAE, ADR, serious TEAE, 
serious ADR, TEAE leading to study discontinuation, and TEAE leading to death will 

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be summarised for each treatment. Summaries will be presented overall (number and 
percentage of subjects having at least one event, total number of events) and by system 
organ class (SOC) and preferred term (PT) (number and percentage of subjects having 
at least one occurrence of that event) using the MedDRA. Specific summary tables will 
be provided for the AEs of particular interest (bronchospasm, cough, dysphonia, 
hoarseness). 
All AEs will be listed.
Pre-treatment AEs will be listed only.

ECG
For ECG parameters: HR, QRS, PR, and QTcF, mean absolute values and change from 
baseline will be summarised for each treatment using descriptive statistics. For QTcF, 
the following categories will also be analysed for each study treatment, by means of 
descriptive statistics: 
o
For male subjects: QTcF interval >450 ms, >480 ms and >500 ms;
o
For female subjects: QTcF interval >470 ms and >500 ms;
o
For both, male and female subjects: Change from baseline >30 ms and >60 ms.
The analysis will be presented at each post-dose timepoint and at any post-dose 
timepoint.
All data will be listed.

Vital signs
Vital signs (SBP and DBP) mean absolute values at each pre-dose and post-dose 
timepoint and change from baseline will be summarised for each study treatment, by 
means of descriptive statistics. 
All vital signs will be listed.
 
 

 
12.3.8 Interim Analysis
No interim analyses are planned.
13.
ETHICS COMMITTEE 
The study proposal will be submitted to the EC in accordance with the UK requirements.
The EC shall give its opinion in writing, clearly identifying the study number, study title and 
ICF approved; before the clinical trial commences.
A copy of all communications with the EC will be provided to the Sponsor.
The Investigator should provide written reports to the EC, annually or more frequently if 
requested, on any changes significantly affecting the conduct of the trial and/or increasing risk 
to the subjects (according to the UK requirements).

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14.
 REGULATORY REQUIREMENTS
The study will be notified to (or authorised by) the Health Authorities according to the legal 
requirements in the UK.
Selection of the subjects will not start before the approval of the EC has been obtained and the 
study has been notified to (or authorised by) the Health Authorities.
15.
INFORMED CONSENT 
The 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 EC‑approved version of the document.
Adequate time shall be given to the subject to enquiry the Investigator about any clarification 
needed and to consider his/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. Moreover, the Investigator must sign 
and date the informed consent form (ICF). A subject’s inclusion in the study, as well as the 
processing of his/her data is based on subject’s explicit consent, as pointed out within the 
informed consent.
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 to 
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.
Each subject’s signed informed consent must be kept on file by the Investigator. One copy must 
be given to the subject.
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 the data. 
Data recorded in the eCRF derived from source documents should be consistent with the data 
recorded on the source documents.
16.2 Direct Access to Source Document/Data
The Investigators or designated personnel must permit trial-related monitoring, audits, EC 
review or regulatory inspection, providing direct access to source data/documents.
17.
STUDY MONITORING
Monitoring will be performed by 
 who has been designated by Chiesi.
It is understood that the monitor(s) will contact and visit the Investigator/centre before the 
study, regularly throughout the study and after the study had been completed, and that they will 

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be permitted to inspect the various study records: eCRFs, 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 eCRFs for accuracy and completeness;

To validate the contents of the eCRFs against the source documents;

To assess the status of drug storage, dispensing and retrieval.
Prior to each monitoring visit, the Investigator or staff will record all data generated since the 
last visit on the eCRF. 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 Investigational sites 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 Research and Development (R&D) Quality Assurance Department of Chiesi may perform 
an audit at any time according to the Sponsor’s Standard Operating Procedures, in order to 
verify whether the study is being conducted in agreement with GCP and the protocol.
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 or damages arising 
out of the investigation, in excess of those covered by his/her own professional liability 
insurance, providing that the medication 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 will be 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 that 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 
(optionally) his/her address and telephone number. 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.

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21.
PREMATURE TERMINATION OF THE STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. 
Should this be necessary, the procedures for an early termination or temporary halt will be 
arranged after consultation by all involved parties.
The Sponsor should submit a written notification to the Regulatory Authority concerned and 
EC providing the justification of premature ending or of the temporary halt.
22.
CLINICAL STUDY REPORT
The Clinical Study Report, including the statistical and clinical evaluations, shall be prepared 
and sent to the Investigator for agreement and signature.
At the end of the trial, a summary of the CSR will be provided to all the ECs, to the UK 
Competent Authority and to the Investigators.
23.
RECORD RETENTION
After completion of the study, all documents and data relating to the study will be kept in an 
orderly manner by the Investigator in a secure study file.
Regulations require that essential documents must be retained for at least two years after the 
final marketing approval in an ICH region or until two years have elapsed since the formal 
interruption of the clinical development of the product under study.
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.
25.
REFERENCES
[1]
GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national 
deaths, prevalence, disability-adjusted life years, and years lived with disability for 
chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for 
the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691-706.

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[2]
GBD Chronic Respiratory Disease Collaborators. Prevalence and attributable health 
burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global 
Burden of Disease Study 2017. Lancet Respir Med. 2020 8(6):585-596.
[3]
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 
to 2030. PLoS Med. 2006;3(11):e442.
[4]
Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon 
JA, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and 
injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. 
Lancet. 2012;380(9859):2163-2196.
[5]
Croisant S. Epidemiology of asthma: prevalence and burden of disease. Adv Exp Med 
Biol. 2014;795:17-29.
[6]
UN 
Environment 
Programme 
(UNEP) 
Annual 
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Clinical Study Protocol 
Clinical Study Code No.: CLI-05993AB6-07
Version No.: 2.0
EUDRACT No.: 2022-000536-36
Date: 30 August 2022
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https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
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Clinical Study Protocol – Appendix 1
Clinical Study Code No.: CLI-05993AB6-07
Version No.: 2.0
EUDRACT No.: 2022-000536-36
Date: 30 August 2022
CONFIDENTIAL
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APPENDIX 1
APPENDIX 1
Approval of the protocol by the Coordinating Investigator
A SINGLE-DOSE, RANDOMISED, DOUBLE-BLIND, CONTROLLED, 2-WAY CROSS-OVER 
STUDY TO ASSESS THE POTENTIAL FOR BRONCHOCONSTRICTION OF THE NEW 
PROPELLANT HFA-152a VERSUS THE MARKETED HFA-134a PROPELLANT, IN ADULT 
SUBJECTS WITH MILD ASTHMA.
Product: 
Test product: Placebo HFA-152a propellant 
Reference product: Placebo HFA-134a propellant
Pharmaceutical Form: 
Test product: pressurised metered dose inhaler (pMDI) with HFA-152a
Reference product: pressurised metered dose inhaler (pMDI) with HFA-134a
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 Ethics Committee 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 enrolment 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.
Coordinating Investigator’s Name: ______________________, MD
Centre No.: 
_____________________
             Signature
Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy

Clinical Study Protocol – Appendix 2
Clinical Study Code No.: CLI-05993AB6-07
Version No.: 2.0
EUDRACT No.: 2022-000536-36
Date: 30 August 2022
CONFIDENTIAL
Page 64/65
APPENDIX 2
Approval of the protocol by the Principal Investigator
A SINGLE-DOSE, RANDOMISED, DOUBLE-BLIND, CONTROLLED, 2-WAY CROSS-OVER 
STUDY TO ASSESS THE POTENTIAL FOR BRONCHOCONSTRICTION OF THE NEW 
PROPELLANT HFA-152a VERSUS THE MARKETED HFA-134a PROPELLANT, IN ADULT 
SUBJECTS WITH MILD ASTHMA.
Product: 
Test product: Placebo HFA-152a propellant 
Reference product: Placebo HFA-134a propellant
Pharmaceutical Form: 
Test product: pressurised metered dose inhaler (pMDI) with HFA-152a
Reference product: pressurised metered dose inhaler (pMDI) with HFA-134a
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 Ethics Committee 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 enrolment 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.
Principal Investigator’s Name: ____________________, MD
Centre No.: 
__________________________
       Signature
Date
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy

Clinical Study Protocol – Appendix 3
Clinical Study Code No.: CLI-05993AB6-07
Version No.: 2.0
EUDRACT No.: 2022-000536-36
Date: 30 August 2022
CONFIDENTIAL
Page 65/65
APPENDIX 3
APPENDIX 2
Recommendations related to contraception and pregnancy testing in clinical trials
Definition of women of childbearing potential, postmenopausal state 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 postmenopausal unless permanently sterile. 
Permanent sterilisation 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 postmenopausal 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.
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 (oestrogen 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
Implantable 3;

Intrauterine device (IUD) 3;

Intrauterine hormone-releasing system (IUS) 3;

Bilateral tubal occlusion 3;

Vasectomised partner 1,3;

Sexual abstinence 2.
1 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP 
trial participant and that the vasectomised partner has received medical assessment of the surgical success.
2 Sexual abstinence is considered a 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.
3 Methods with lower user dependency.
Reference: Recommendations related to contraception and pregnancy testing in clinical trials 
(Clinical Trial Facilitation Group. Final version 1.1 dd. 21/09/2020).