Clinical trial NCT05472662
Conditions: Asthma
Sponsor: Chiesi Farmaceutici S.p.A.
Start date: 2022-08-03; Completion date: 2022-10-31
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase IIa, multicentre, 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 adults with mild asthma.

HFA=Hydrofluoroalkane

Detailed description:

Arms: arm 1: Placebo HFA-152a propellant via pressurised metered-dose inhaler (pMDI):

Administration: Single-dose administration. arm 2: Placebo HFA-134a propellant via pressurised metered-dose inhaler (pMDI):

Administration: Single-dose administration.
Interventions: intervention 1: Placebo 152a intervention 2: Placebo 134a
Intervention descriptions: intervention 1: Placebo pressurised metered-dose inhaler (pMDI) formulated with the 152a propellant intervention 2: Placebo pressurised metered-dose inhaler (pMDI) formulated with the 134a propellant

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL
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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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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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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 
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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 
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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, 
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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 
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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 
Report 
2014. 
https://www.unenvironment.org/resources/annual-report/unep-2014-annual-report. 
Accessed April 2021.
[7]
The 
Montreal 
Protocol 
on 
Substances 
that 
Deplete 
the 
Ozone 
Layer. 
https://ozone.unep.org/treaties/montreal-protocol-substances-deplete-ozone-layer/text. 
Accessed April 2021.
[8]
Myhre G, Shindell G, Bréon F-M, Collins W, Fuglestvedt J, Huang J, Koch D, Lamarque 
JD, Lee D, Mendoza B, Nakajima T, Robock A, Stephens G, Takemura T, Zhang H. 
2013: Anthropogenic and Natural Radiative Forcing. In: Climate Change 2013: The 
Physical Science Basis. Contribution of Working Group I to the Fifth Assessment Report 
of the Intergovernmental Panel on Climate Change. Stocker TF, Qin D, Plattner GK, 
Tignor M, Allen SK, Boschung J, Nauels A, Xia Y, Bex V, Midgley PM (eds.). 
Cambridge University Press, Cambridge, United Kingdom and New York, NY, USA. Pp. 
659-740.
[9]
Jeswani H, Corr S, Azapagic A. Reducing carbon footprints of metered dose inhalers. 
Inhalation. 2017;11(6).
[10] Panigone S, Sandri F, Ferri R, Volpato A, Nudo E, Nicolini G. Environmental impact of 
inhalers for respiratory diseases: decreasing the carbon footprint while preserving 
patient‑tailored treatment. BMJ Open Respir Res. 2020 Mar;7(1):e000571.
[11] Avella J, Kunaparaju N, Kumar S, Lehrer M, Zito SW, Barletta M. Uptake and 
distribution of the abused inhalant 1,1-difluoroethane in the rat. J Anal Toxicol. 
2010;34(7):381-388.
[12] Ernstgård L, Sjögren B, Dekant W, Schmidt T, Johanson G. Uptake and disposition of 
1,1-difluoroethane (HFC-152a) in humans. Toxicol Lett. 2012 February 25;209(1):21-29.
[13] Recommendations related to contraception and pregnancy testing in clinical trials 
(Clinical 
Trial 
Facilitation 
Group. 
Final 
version 
1.1 
dd. 
21/09/2020). 


Clinical Study Protocol 
Clinical Study Code No.: CLI-05993AB6-07
Version No.: 2.0
EUDRACT No.: 2022-000536-36
Date: 30 August 2022
CONFIDENTIAL
Page 62/65
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance
_Version_1.1_updated.pdf. Accessed April 2021.
[14] EudraLex. The Rules Governing Medicinal Products in the European Union. Volume 4 - 
EU Guidelines to Good Manufacturing Practice. Medicinal Products for Human and 
Veterinary Use. Annex 13 – Manufacture of Investigation Medicinal Products. 2010. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2009_06_annex13.pdf. 
Accessed March 2021. 
[15] COVID-19 Rapid guideline: arranging planned care in hospitals and diagnostic services. 
National Institute for Health and Care Excellence (NICE) guideline NG179. 
2020 July 27. Overview | COVID-19 rapid guideline: arranging planned care in hospitals 
and diagnostic services | Guidance | NICE. Accessed February 2022.
[16] Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, 
Hallstrand TS, Kaminsky DA, McCarthy K, McCormack MC, Oropez CE, Rosenfeld M, 
Stanojevic S, Swanney MP, Thompson BR. Standardization of Spirometry 2019 Update. 
An Official American Thoracic Society and European Respiratory Society Technical 
Statement. Am J Respir Crit Care Med. 2019;200(8):e70-e88.
[17] Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson 
JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-1343.
[18] Miller M.R., Hankinson J., Brusasco V., Burgos F., Casaburi R., Coates A., Crapo R., 
Enright P., van der Grinten C.P.M., Gustafsson P., Jensen R., Johnson D.C., MacIntyre 
N., McKay R., Navajas D., Pedersen O.F., Pellegrino R., Viegi G. and Wanger J. 
ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J 2005; 26: 319–338.
[19] Juniper E. Asthma Control Questionnaire (ACQ). ACQ-5 - United Kingdom/English 
Version. 22 Sep 2017. 


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).

SAP_001.pdf: 
Page 1 of 48 
STATISTICAL ANALYSIS PLAN 
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. 
Protocol: CLI-05993AB6-07
 Internal 
Reference: BE-80-2100847 
Development phase: IIa 
Sponsor: Chiesi Farmaceutici S.p.A. 
SAP version number: Final 1.0 
SAP version date: 22DEC2022 
- NCT05472662


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 2 of 48 
TABLE OF CONTENTS 
Table of contents .......................................................................................................... 2 
Protocol history ............................................................................................................ 5 
List of abbreviations .................................................................................................... 6 
Definition of terms ....................................................................................................... 8 
1. 
Introduction ......................................................................................................... 9 
1.1 
Study objectives............................................................................................... 9 
1.2 
Study design .................................................................................................... 9 
1.3 
Expected sample size ..................................................................................... 10 
1.4 
Randomisation and blinding .......................................................................... 10 
1.5 
Interim analysis ............................................................................................. 10 
1.6 
Software ......................................................................................................... 11 
1.7 
Validation model ........................................................................................... 11 
2. 
Safety analyses ................................................................................................... 12 
2.1 
Adverse events............................................................................................... 12 
2.1.1 
Available data .................................................................................. 12 
2.1.2 
Derivation rules ............................................................................... 12 
2.1.3 
Presentation of results ..................................................................... 13 
2.2 
Clinical laboratory evaluation ....................................................................... 14 
2.2.1 
Available data .................................................................................. 14 
2.2.2 
Presentation of results ..................................................................... 14 
2.3 
Vital signs ...................................................................................................... 14 
2.3.1 
Available data .................................................................................. 14 
2.3.2 
Derivation rules ............................................................................... 14 
2.3.3 
Presentation of results ..................................................................... 15 
2.4 
Electrocardiograms ........................................................................................ 15 
2.4.1 
Available data .................................................................................. 15 
2.4.2 
Derivation rules ............................................................................... 15 
2.4.3 
Presentation of results ..................................................................... 15 
2.5 
Lung function ................................................................................................ 16 
2.5.1 
Available data .................................................................................. 16 
2.5.2 
Derivation rules ............................................................................... 16 
2.5.3 
Inferential statistics ......................................................................... 17 
2.5.4 
Presentation of results ..................................................................... 18 


Statistical Analysis Plan 
 
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Final 1.0 of 22DEC2022 
 
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2.6 
Use of rescue medication............................................................................... 18 
2.6.1 
Available data .................................................................................. 18 
2.6.2 
Derivation rules ............................................................................... 18 
2.6.3 
Presentation of results ..................................................................... 18 
2.7 
Physical examinations ................................................................................... 19 
 
 
 
 
 
 
 
 
4. 
General characteristics analyses ...................................................................... 21 
4.1 
Subject disposition......................................................................................... 21 
4.2 
Protocol deviations and eligibility ................................................................. 21 
4.3 
Demographic and other baseline characteristics ........................................... 21 
4.3.1 
Available data .................................................................................. 21 
4.3.2 
Derivation rules ............................................................................... 22 
4.3.3 
Presentation of results ..................................................................... 22 
4.4 
Medical history and concomitant diseases .................................................... 23 
4.4.1 
Available data .................................................................................. 23 
4.4.2 
Presentation of results ..................................................................... 23 
4.5 
Procedures and Medications .......................................................................... 23 
4.5.1 
Available data .................................................................................. 23 
4.5.2 
Derivation rules ............................................................................... 23 
4.5.3 
Presentation of results ..................................................................... 24 
4.6 
Exposure to study drug .................................................................................. 24 
4.6.1 
Available data .................................................................................. 24 
4.6.2 
Presentation of results ..................................................................... 24 
5. 
General methodology......................................................................................... 25 
5.1 
Analysis sets .................................................................................................. 25 
5.1.1 
Analysis sets .................................................................................... 25 
5.1.2 
As planned versus as actual analysis ............................................... 25 
5.2 
Phases, periods and time points ..................................................................... 26 
5.2.1 
Phases and periods .......................................................................... 26 
5.2.2 
Baseline and change from baseline ................................................. 27 
5.2.3 
Relative day ..................................................................................... 27 


Statistical Analysis Plan 
 
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Final 1.0 of 22DEC2022 
 
Page 4 of 48 
5.2.4 
Analysis visits ................................................................................. 27 
5.2.5 
Worst-case ....................................................................................... 29 
5.3 
Imputation and rounding rules ....................................................................... 29 
5.3.1 
Missing values ................................................................................. 29 
5.3.2 
Handling partially or completely missing dates in calculations ...... 29 
5.3.3 
Values below or above a threshold ................................................. 30 
5.3.4 
Rounding of derived variables ........................................................ 30 
5.3.5 
Outliers ............................................................................................ 30 
5.4 
Presentation of results.................................................................................... 30 
5.4.1 
Calculation of descriptive statistics and percentages ...................... 30 
5.4.2 
Presentation of treatments ............................................................... 31 
5.4.3 
Ordering in tables, listings and figures ............................................ 31 
5.4.4 
Raw SAS output .............................................................................. 31 
6. 
Changes to the planned analysis ....................................................................... 33 
6.1 
Changes not covered by protocol amendments before unblinding ............... 33 
7. 
References ........................................................................................................... 34 
8. 
List of tables, listings and figures ..................................................................... 35 
8.1 
Tables ............................................................................................................ 35 
8.2 
Listings .......................................................................................................... 41 
8.3 
Figures ........................................................................................................... 45 
9. 
Appendices ......................................................................................................... 46 
9.1 
SAS code ....................................................................................................... 46 
9.2 
Schedule of assessments ................................................................................ 47 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 5 of 48 
PROTOCOL HISTORY 
Protocol: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the changes on the statistical 
analysis 
Final 1.0 
06APR2022 
NAP 
Final 2.0 
30AUG2022 
NAP 
 
Protocol amendments: 
Version or ID 
Date 
(ddMMMyyyy) 
Impact of the amendment on the 
statistical analysis 
NAP 
 
 
This statistical analysis plan (SAP) only considers the last version of the protocol, and 
of the protocol amendments, as listed above. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 6 of 48 
LIST OF ABBREVIATIONS 
ACQ-5 
Asthma Control Questionnaire© 
ADaM 
analysis data model 
ADR 
adverse drug reaction 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
AUC 
area under the curve 
AUC0-xh 
area under the curve, from 0 to x hours post-dose 
BMI 
body mass index 
CI 
confidence interval 
COVID-19 
coronavirus disease 2019 
CPU 
clinical pharmacology unit 
CRF 
case report form 
DBP 
diastolic blood pressure 
DRM 
data review meeting 
DRR 
data review report 
DY 
relative day 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ENR 
enrolled set 
FEV1 
forced expiratory volume in 1 second 
FSH 
follicle-stimulating hormone 
FVC 
forced vital capacity 
HFA 
hydrofluoroalkane 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
KFR 
key first results 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAP 
not applicable 
PEF 
peak expiratory flow 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 7 of 48 
pMDI 
pressurised metered dose inhaler 
PP 
per protocol 
QTc 
corrected QT interval 
QTcF 
Fridericia’s corrected QT interval 
RND 
randomised set 
SAF 
safety set 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SDTM 
study data tabulation model 
SE 
standard error 
 CR 
 Clinical Research 
SOP 
standard operating procedure 
STAT 
Statistics 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
VS 
vital signs 
WHO 
World Health Organisation 
WHODrug 
WHO drug dictionary 
WI 
work instruction 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 8 of 48 
DEFINITION OF TERMS 
bias 
The systematic tendency of any factors associated with the design, 
conduct, analysis and evaluation of the results of a clinical trial to 
make the estimate of a treatment effect deviate from its true value. 
Bias introduced through deviations in conduct is referred to as 
‘operational’ bias. The other sources of bias listed above are 
referred to as ‘statistical’. 
 
 
case report form 
(CRF) 
A printed, optical, or electronic document designed to record 
protocol required information to be reported to the sponsor for each 
trial subject. 
 
 
display 
Analysis table, listing or figure 
 
 
phase 
Interval of time in the planned conduct of a study associated with a 
specific purpose: for example, screening, treatment, follow-up. 
 
 
significant digit 
All digits of a number used to express it to the required degree of 
accuracy, starting from the first non-zero digit. 
 
 
standardised 
unit 
unit populating --STRESU in the clinical database 
 
 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 9 of 48 
1. 
INTRODUCTION 
This SAP describes the final statistical analysis to be performed for the CLI-
05993AB6-07 (BE-80-2100847) study. 
This SAP covers the safety, 
, and general characteristics parts of the 
statistical analysis. It specifies the analysis displays to be presented and describes the 
methods and procedures in a more elaborated way than in the statistical methods 
section of the protocol. 
The statistical analysis will process and present the results following the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) standards, in particular the ICH-E3, ICH-E6(R2), and ICH-E9 
guidelines. 
1.1 
STUDY OBJECTIVES 
According to the protocol, 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). 
According to the protocol, the secondary objective of this study is: 
• To evaluate the general safety and tolerability of the two different 
propellants. 
 
 
 
1.2 
STUDY DESIGN 
This is a Phase IIa, multicentre, 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. 
A double-blind design was chosen for this study to minimise the risk of bias in the 
study outcomes. 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 10 of 48 
The study design [1] is shown in the below figure: 
 
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. 
The schedule of assessments is in appendix 9.2. 
1.3 
EXPECTED 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 time point, 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. 
1.4 
RANDOMISATION AND BLINDING 
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 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. 
1.5 
INTERIM ANALYSIS 
No interim analyses are foreseen. 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 11 of 48 
1.6 
SOFTWARE 
SAS version 9.4 or later (SAS Institute Inc., Cary, NC, USA) will be used for 
programming. 
1.7 
VALIDATION MODEL 
 Statistics (STAT) standard operating procedures (SOPs) and work instructions 
(WIs) as effective at the time of the activity will be followed throughout the project, 
provided the applicable regulatory requirements are still met. 
The analysis tables/figures/listings will be validated according to model B (review by 
an independent person; see SOP.STAT.020). 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 12 of 48 
2. 
SAFETY ANALYSES 
2.1 
ADVERSE EVENTS 
2.1.1 
Available data 
Adverse events (AEs) are coded into system organ classes and preferred terms using 
the medical dictionary for regulatory activities (MedDRA). For each AE, start and 
stop date(time)s are collected as well as severity, a seriousness flag, treatment-
relationship, action taken towards the study drug and outcome. 
2.1.2 
Derivation rules 
Pre-treatment AEs are defined as AEs starting between date of informed consent with 
00:00 added as time part and the date(time) of first study drug administration – 1 
minute, extremes included. 
Treatment-emergent adverse events (TEAE) are defined as AEs starting on or after 
first administration of any study drug. 
Adverse drug reactions (ADRs) are defined as TEAEs related to study drug or with 
missing relationship. 
AEs of particular interest will be selected based on the following algorithms: 
• Bronchospasm: to select preferred terms or lowest level terms including 
the word “bronchospasm” 
• Cough: to select preferred terms or lowest level terms including the 
words “cough” or “coughing” 
• Dysphonia: to select preferred terms including the word “dysphonia” 
(excluding lowest level terms containing the word “hoarseness”) 
• Hoarseness: to select lowest level terms containing the word 
“hoarseness” 
Based on their start date(time), AEs will be allocated to the phase and period during 
which they started. Phases and periods are defined in section 5.2.1. In case the AE 
start date(time) is incomplete or missing and the AE could consequently be allocated 
to more than one phase or period, a worst-case allocation will be done as detailed 
below: 
• Treatment phase vs. non-treatment phase: AE will be allocated to the 
treatment phase. 
• Multiple treatment periods: AE will be allocated to all treatment 
periods, except periods for which the available parts of the AE start or 
stop date(time) provides evidence the AE did not occur during that 
period. 
A fatal AE is defined as an AE with outcome ‘fatal’. 
An AE for which the study drug was discontinued is defined as an AE with action 
taken ‘drug permanently withdrawn’. 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 13 of 48 
AE onset and duration will be calculated as follows: 
• AE onset day (vs. first administration) = 
o AE start date < date of first administration: AE start date – 
date of first administration 
o AE start date ≥ date of first administration: AE start date – 
date of first administration + 1 day 
• AE onset day (vs. start of period) = AE start date – analysis period start 
date + 1 day 
• AE duration (rounded as detailed in section 5.3.4) =  
o If start and stop date/time are available: 
- 
AE end date/time – AE start date/time + 1 minute 
Note: If AE duration is less than 1 hour, the duration will be presented in 
minutes. If the AE duration is 1 hour or more, but less than 1 day, it will be 
presented in hours. If AE duration is 1 day or more, it will be presented in 
days. 
o If only start and stop dates are available: 
- 
AE end date – AE start date + 1 day 
- 
date of last contact – AE start date + 1 day (when the AE start date 
is fully known but the AE is not resolved at the end of the study); 
in this case the duration will be presented as “>x days”. 
2.1.3 
Presentation of results 
Tables will present TEAEs only. Pre-treatment AEs will only be listed. 
An overview table will show the number and percentage of subjects with at least one 
event and the number of events by treatment and overall for the following: 
• TEAEs 
• Serious TEAEs 
• Non-serious TEAEs 
• ADRs 
• Serious ADRs 
• Severe TEAEs 
• TEAEs leading to study drug discontinuation  
• TEAEs leading to death 
• TEAEs of particular interest 
Separate summary tables by MedDRA system organ class and preferred term will 
show the number and percentage of subjects with at least one event and the number of 
events by treatment and overall for the aforementioned categories. Each AE record in 
the clinical database is considered as a distinct adverse event and is counted as such. 
Blank system organ classes and preferred terms, if any, will be shown as ‘Not 
Available’ in the tables and listings. 


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All AEs, including pre-treatment events and all coding information will be listed. 
COVID-19 related AEs will be flagged. Separate listings will be prepared for the 
categories presented in the summary tables. 
2.2 
CLINICAL LABORATORY EVALUATION 
2.2.1 
Available data 
Per protocol, the following safety laboratory parameters are expected: 
• Biochemistry: creatinine, urea, phosphate, aspartate aminotransferase, 
alanine aminotransferase, gamma-glutamyl transpeptidase, total 
bilirubin, alkaline phosphatase, total cholesterol, triglycerides, sodium, 
potassium, calcium, chloride electrolytes. 
Note: only abnormal clinically significant results will be entered in the 
eCRF. 
• Haematology: red blood cells count, white blood cells count and 
differential count (absolute value and %), total haemoglobin, 
haematocrit, platelets count. 
Note: only abnormal clinically significant results will be entered in the 
eCRF. 
• Urinalysis: quantitative (proteins) and qualitative (proteins, ketones, 
microscopic examination of the sediment). 
Note: only abnormal clinically significant results will be entered in the 
eCRF. 
• Serum and urine pregnancy test and FSH. 
Normal ranges are available as provided by the laboratory. 
2.2.2 
Presentation of results 
All laboratory data will be listed. 
2.3 
VITAL SIGNS 
2.3.1 
Available data 
The following vital signs parameters are collected: 
• Systolic (SBP) and diastolic blood pressure (DBP) in supine position 
2.3.2 
Derivation rules 
Mean values of the duplicates will be calculated per time point and rounded as 
detailed in section 5.3.4. Records belonging to the same duplicate will be identified 
using the visit and time point. In case of only one assessment available for the 
specific time point, its result will be considered. Throughout the analysis the mean 
values will be used. Individual duplicate values will only be listed. 
Potential exclusion of vital signs parameters will be discussed during the review of 
the data by the Chiesi team. Decisions on whether values are to be excluded from the 
analysis will be fully documented in the DRR. 


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2.3.3 
Presentation of results 
Vital signs parameters will be summarised by means of descriptive statistics at each 
analysis time point by treatment. Actual values and changes from baseline will be 
tabulated. 
All vital signs data will be listed. 
2.4 
ELECTROCARDIOGRAMS 
2.4.1 
Available data 
The following electrocardiogram (ECG) parameters will be collected: 
• Triplicate local 12-lead ECG at Screening: heart rate (HR), PR interval, 
QRS interval, QT interval, corrected QT interval (Fridericia) and the 
corresponding interpretation 
• Local 12-lead single ECG: HR, PR interval, QRS interval, QT interval, 
corrected QT interval (Fridericia) and the corresponding interpretation 
2.4.2 
Derivation rules 
For QTcF interval (ms), the following abnormality categories are defined: 
• Actual values: 
o >450 ms (males) or >470 ms (females) 
o >480 ms (males) 
o >500 ms 
• Changes from pre-dose: 
o Increase from pre-dose >30 ms 
o Increase from pre-dose >60 ms 
Note: The worst-case, as defined in section 5.2.5, is the highest value and associated 
change. 
Potential exclusion of ECG parameters will be discussed during the review of the data 
by the Chiesi team. Decisions on whether values are to be excluded from the analysis 
will be fully documented in the DRR. 
2.4.3 
Presentation of results 
Local 12-lead single ECG parameters (HR, PR, QRS and QTcF) will be summarised 
by means of descriptive statistics at each analysis time point by treatment. Actual 
values (with their 95% CI) and changes from pre-dose (with their 90% CI) will be 
tabulated. 
For QTcF, the number and percentage of subjects with abnormal actual values will be 
presented at each post-dose analysis time point and at the worst-case post-dose 
analysis window by treatment. In addition, the number and percentage of subjects 
with abnormal changes from pre-dose will be presented at each post-dose analysis 
window and at the worst-case analysis time point by treatment. 
All local 12-lead ECG parameters will be listed. Uncorrected QT interval and the 
investigator’s interpretation will only be listed. 


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2.5 
LUNG FUNCTION 
2.5.1 
Available data 
The following lung function (spirometry) parameters are collected: Forced Expiratory 
volume in 1 second (FEV1), percent predicted FEV1, forced vital capacity (FVC), 
percent predicted FVC, FEV1/FVC ratio, percent predicted FEV1/FVC ratio, peak 
expiratory flow (PEF) and forced expiratory flow 25-75%. 
2.5.2 
Derivation rules 
Pre-dose: 
The mean values of the two measurements at 45 min and 15 min will be calculated in 
each treatment period and rounded as detailed in section 5.3.4. In case only one 
assessment is available, its result will be used as pre-dose. Throughout the analysis 
the mean values will be used. Individual duplicate values will only be listed. 
FEV1 AUC0-3h calculation: 
The area under the result vs. time curve observed from time 0 up to the last 
measurable value (i.e., 3h) will be computed using the linear trapezoidal rule. 
The change from baseline in area under the curve (AUC) normalised by time will be 
calculated as follows, using the trapezoidal summation rule: 
•  AUC normalised by time = 
{∑[(𝐭𝐢−𝐭𝐢−𝟏)(𝐅𝐄𝐕𝟏𝐢+ 𝐅𝐄𝐕𝟏𝐢−𝟏)/𝟐]
𝐢
} 𝐭𝐢𝐦𝐞
⁄
 
• Change from baseline in AUC = AUC normalised by time – baseline 
(FEV10). 
where: 
• for t0, FEV10 is the pre-dose average of t-45’ and t-15’ before study drug 
administration of each treatment period. 
• t0 is the actual time of first study drug administration, 
• for i = 5 min, 15 min, 30 min, 1h, 1.5h and 3h, FEV1i is the actual FEV1 
value at each time point and ti is the actual time of sample i. 
• time is the actual elapsed time from t0 until t3h. 
Per analysis window, only the timepoint closest to the target time will be considered 
for AUC calculation (as per analysis windows rules reported in section 5.2.4).  


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The following rules will be applied for the AUC0-3h calculation: 
• 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]); 
• In case no pre-dose measurements are available, the entire curve will be 
considered missing; 
• In case the last measurement for the AUC0-3h (i.e. 3h) is missing, the 
entire curve will be considered missing; 
• Single, isolated missing values (different from pre-dose or last value) 
will be replaced by linear interpolation using adjacent values; 
• In case of two or more consecutive missing time points, the entire curve 
will be considered missing; 
• In case of three or more missing time points, the entire curve will be 
considered missing. 
• If the date(time) is missing or incomplete for a specific post-dose time 
point, then it will be imputed as the date(time) of the previous time point 
+ the theoretical time interval between the two time points. 
• If 2 or more consecutive post-dose time points have a missing or 
incomplete date(time), then the AUC will also be set to missing. 
For FEV1, the following abnormality categories are defined: 
• Relative changes from baseline: 
o Decrease from Baseline >15 % 
Potential exclusion of lung function parameters based on time window not respected 
will be discussed during the review of the data by the Chiesi team. Decisions on 
whether values are to be excluded from the analysis will be fully documented in the 
DRR. 
2.5.3 
Inferential statistics 
Primary objective (i.e. evaluation of the potential for bronchoconstriction of each 
propellant): 
• The relative change from baseline in FEV1 at the 15 min post-dose time 
point 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. 


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Other 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 
time points (5 min, 30 min, 1 h, 1 h 30 min and 3 h) 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 time points 
(5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h) will be analysed using 
the same model used for the relative change from baseline in FEV1 at 15 
min post-dose. 
2.5.4 
Presentation of results 
Lung function parameters will be summarised by means of descriptive statistics at 
each analysis time point by treatment. Actual values, absolute and relative changes 
from baseline (FEV1 and PEF only) will be tabulated. 
For the ANCOVA models, adjusted mean in each treatment and the adjusted mean 
difference between HFA-152a and HFA-134a, their 95% CIs and related p-values 
will be provided and tabulated from the ANCOVA. This tables will also include the 
type III p-values associated to model effects. 
The number and percentage of subjects with FEV1 abnormal relative changes from 
baseline will be presented at each post-dose time point and at the worst-case analysis 
visit by treatment. 
The change from baseline in FEV1 AUC0-3h will be summarised by means of 
descriptive statistics by treatment. 
All lung function parameters will be listed. 
Graphs of the mean changes (both absolute and relative) from baseline over time will 
be prepared for FEV1 and PEF by treatment. 
2.6 
USE OF RESCUE MEDICATION 
2.6.1 
Available data 
For each administration of rescue medication, the start and end date(time) and the 
number of puffs will be recorded. 
2.6.2 
Derivation rules 
The following parameters will be derived: 
• Mean use of rescue medication (puffs) = total number of puffs of rescue 
medication during the first 3h post-dose 
2.6.3 
Presentation of results 
The number and percentage of subjects with use of rescue medication in the first 3h 
post-dose will be presented by treatment using frequency tabulations. 
Mean use of rescue medication in the first 3h post-dose will be summarised by means 
of descriptive statistics by treatment. 


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All rescue medication data will be listed. 
2.7 
PHYSICAL EXAMINATIONS 
Abnormal physical examination findings will be listed. 


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4. 
GENERAL CHARACTERISTICS ANALYSES 
4.1 
SUBJECT DISPOSITION 
The following subject data will be tabulated by treatment sequence: 
• The number of screen failures 
• The number and percentage of subjects who completed or discontinued 
the study as documented on the study termination page and the number 
and percentage of subjects for each study discontinuation reason 
• The number of subjects in each analysis set per period 
• The number of subjects enrolled, randomised, completed, and 
discontinued by site  
• The number and percentage of subjects who entered, completed, or 
discontinued each study period 
All information collected in the CRF concerning allocation, code breaking, study 
discontinuation (discontinuations due to COVID-19 will be flagged) and information 
on phases and periods, dates of first signed informed consent, last visit and last 
contact (over the whole study) will be listed. 
4.2 
PROTOCOL DEVIATIONS AND ELIGIBILITY 
The number and percentage of subjects with important protocol deviations, per 
category and type, will be tabulated, by treatment and overall. 
All available information concerning protocol deviations (protocol deviations related 
to COVID-19 will be flagged), violations on eligibility criteria (only violated 
eligibility criteria having DV.DVCAT = 'INCLUSION/EXCLUSION CRITERIA') 
and restrictions will be listed. 
4.3 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
4.3.1 
Available data 
The following parameters will be available: 
• Demographics: women of childbearing potential (yes / no / post-
menopausal), age, sex, race, BMI, height and weight at screening, date 
of birth, and date of signing informed consent form (ICF), smoking 
status, duration and number of pack-years 
• Screening tests: vital signs, local 12-lead ECG, lung function, 
reversibility test and ACQ-5 
• Baseline disease characteristics: date of first diagnosis, asthma 
medication at study entry, exacerbation history (number of 
exacerbations in the 12 months before screening and date of the most 
recent exacerbation ended, treatment, hospitalisation, emergency room) 


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4.3.2 
Derivation rules 
The following parameters will be derived: 
• Age categories: 
o >=18 and <65 years 
o >=65 and <85 years 
• Time since first diagnosis (years): (date of ICF – date of first 
diagnosis)/365.25 
Note: Partially missing dates will be imputed as specified in section 
5.3.2 
• Time since most recent exacerbation (months): (date of ICF – date of 
most recent exacerbation ended)/30.4375 
Note: Partially missing dates will be imputed as specified in section 
5.3.2 
• Mean values of the duplicates (blood pressure parameters) will be 
calculated and rounded as detailed in section 5.3.4. Records belonging 
to the same duplicate will be identified using the visit and time point. In 
case of only one assessment available for the specific time point, its 
result will be considered. 
• Mean values of the triplicates (ECG parameters) will be calculated and 
rounded as detailed in section 5.3.4. Records belonging to the same 
triplicate will be identified using the visit and time point. All records of 
the triplicate will be used to calculate the mean, even if less or more 
than the expected three. 
4.3.3 
Presentation of results 
Demographics will be presented by treatment sequence and overall using descriptive 
statistics for age, height, weight, BMI, smoking duration and number of pack-years 
(current and ex-smokers only) and frequency tabulations for sex, race, age category 
and smoking status. 
Baseline disease characteristics will be presented by treatment sequence and overall 
using descriptive statistics for time since first diagnosis, time since most recent 
exacerbation ended and number of exacerbations in the last 12 months and frequency 
tabulations for asthma medication category at study entry, number of exacerbations in 
the last 12 months, last exacerbation treatments, hospitalization and emergency room. 
In addition, the following parameters will be presented by treatment sequence and 
overall using descriptive statistics: 
• vital signs at screening and Period 1 Day 1 pre-dose; 
• local 12-lead ECG at screening and Period 1 Day 1 pre-dose; 
• lung function at screening and Period 1 Day 1 pre-dose; 
• reversibility test at screening (FEV1 Reversibility (mL) and FEV1 
Reversibility (%)); 
• ACQ-5 at screening and Period 1 Day 1 pre-dose. 


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All demographic data, baseline disease characteristics and screening tests (except 
when listed in the safety part, i.e. vital signs, local 12-lead ECG, lung function) will 
be listed. 
4.4 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
4.4.1 
Available data 
Medical history and concomitant diseases findings are coded using the medical 
dictionary for regulatory activities (MedDRA) into system organ classes and 
preferred terms. For each finding (MH.MHCAT is ‘GENERAL MEDICAL 
HISTORY’), a start and stop date or ongoing flag is collected. 
The following selection will be performed: 
• Medical history finding: not ongoing at informed consent 
(MH.MHENRTPT is ‘BEFORE’) 
• Concomitant disease finding: still ongoing at informed consent 
(MH.MHENRTPT is ‘ONGOING’ or missing) 
4.4.2 
Presentation of results 
Medical history and concomitant diseases will be tabulated separately by treatment 
sequence and overall. Each table will show: 
• The number and percentage of subjects with findings 
• The number and percentage of subjects with findings by system organ 
class and preferred term 
All medical history and concomitant diseases data will be listed separately. 
4.5 
PROCEDURES AND MEDICATIONS 
4.5.1 
Available data 
All procedures are coded into system organ classes and preferred terms using the 
medical dictionary for regulatory activities (MedDRA). For each procedure, start and 
stop dates or ongoing flag are collected. 
All medications are coded using WHO Drug. ATC coding up to level 5 is available in 
the clinical database. For each medication, a start date(time) and stop date(time) or 
ongoing flag are collected. 
4.5.2 
Derivation rules 
Based on their start and stop date(time), procedures and medications will be allocated 
to each phase / period during which they were performed/administered. A 
procedure/medication can therefore be reported in more than one phase or period. 
Phases and periods are defined in section 5.2.1. Procedures/medications with 
(partially) missing dates will be allocated to each phase / period unless the available 
parts of the procedure/medication start or stop date(time) provide evidence that the 
procedure/medication was not performed/taken during that phase / period. 


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Based on their start and stop date(time) procedures and medications will be allocated 
to one of the following categories: 
• Prior: the procedure/medication stopped prior to first study drug 
administration 
• Maintained: the procedure/medication started before first study drug 
administration and was ongoing at first study drug administration 
• Concomitant: the procedure/medication started at or after first study 
drug administration 
For procedures/medications with (partially) missing date(time)s not allowing 
allocation to any of the categories, a worst-case allocation will be done based on the 
available parts of the medication/procedure start or stop date(time). The 
medication/procedure will be allocated to the first category allowed by the available 
data, according to the following order: 
• Concomitant 
• Maintained 
• Prior 
Note: these procedures/medications will only be allocated to the phases / periods that 
match the worst-case allocated category. 
4.5.3 
Presentation of results 
Procedures: 
All procedures data will be listed. 
Medications: 
The number and percentage of subjects with medications and the number and 
percentage of subjects with medications by anatomical main group (level 1), 
therapeutic subgroup (level 2), chemical subgroup (level 4), and preferred name will 
be tabulated per category (prior, maintained, and concomitant); by treatment 
(sequence for prior medications) and overall. Blank ATC levels and preferred names, 
if any, will be shown as ‘Not Available’ in the tables. 
Subjects having more than one medication allocated to the same category within the 
same treatment (sequence), anatomical main group, therapeutic subgroup, chemical 
subgroup, and preferred name will be counted only once. 
All medications data will be listed. 
4.6 
EXPOSURE TO STUDY DRUG 
4.6.1 
Available data 
For each study drug administration, the start date(time)s, the number of correct and 
incorrect inhalations and the reason for incorrect inhalations. In addition, data on 
training with inhalers is collected. 
4.6.2 
Presentation of results 
All exposure and training with inhalers data will be listed. 


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5. 
GENERAL METHODOLOGY 
5.1 
ANALYSIS SETS 
5.1.1 
Analysis sets 
The following analysis sets will be considered in the statistical analysis: 
Enrolled Set (ENR): 
subjects who signed an informed consent to participate 
in this study 
Randomised Set (RND): 
subjects who were randomised into this study 
Safety Set (SAF): 
subjects who were randomised and received at least one 
dose of study drug 
Per Protocol (PP) 
Analysis Set: 
subjects from the SAF, excluding the subjects having 
important protocol deviations impacting the analysis set 
Notes: 
• Having signed an informed consent is defined as having a complete 
informed consent signature date in the database. 
• Randomised is defined as having a randomisation date in the database or 
any information to confirm randomisation. 
• Having received at least one dose of study drug is defined as having an 
exposure date or any information confirming exposure. 
• Exact definition of important protocol deviations concerning PP will be 
discussed by the clinical team and described in the DRR. The subjects to 
be excluded from PP analysis set will be defined in the DRR. 
 
Unless stated otherwise, the SAF will be used for the general characteristics, safety 
 tables, listings and figures. The variables assessing the primary study 
objective will also be analysed considering the PP, for sensitivity purposes. 
Since a cross-over design will be used, the inclusion in the analysis sets will be 
defined at subject level on a per-period basis and at subject level overall (in case all 
periods are affected). In case of important protocol deviations impacting specific time 
points, only the affected data at the specific time point will be excluded from the 
applicable analysis sets. These cases will be documented in the DRR. 
5.1.2 
As planned versus as actual analysis 
For analyses done on the safety analysis set and on PP analysis set (excluding general 
characteristics analyses), the actual treatment of the subject will be considered. In 
addition, the actual treatment will be presented in all listings. 
For all other analyses, the planned treatment (sequence) will be used. 


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5.2 
PHASES, PERIODS AND TIME POINTS 
5.2.1 
Phases and periods 
Adverse events, medications, and procedures will be allocated to phases and periods. 
All other analyses will not be allocated to phases and periods. Instead, the visit and 
time point labels indicated on the subject’s case report form (CRF) will be used to 
allocate the assessments to the correct treatment. Early termination and follow-up 
visit assessment will be allocated to the last administered treatment. 
Adverse events and medications: 
Phase 
Period 
Start 
End 
Screening 
 
Date of signing the 
informed consent form 
(ICF), with 00:00 added as 
time part 
First administration 
date(time) in period 1 – 1 
minute 
Treatment Period 1 First administration 
date(time) in period 1 
First administration 
date(time) in period 2 – 1 
minute 
Period 2 First administration 
date(time) in period 2 
Date of last contact, with 
23:59 added as time part 
Per definition, and for each subject, the first phase starts on the date of the earliest 
available ICF signature, with 00:00 added as time part. The last available 
phase/period ends on the date of last contact, with 23:59 added as time part. 
Procedures: 
Phase 
Period 
Start 
End 
Screening 
 
Date of signing the 
informed consent form 
(ICF) 
First administration date in 
period 1 – 1 day 
Treatment Period 1 First administration date in 
period 1 
First administration date in 
period 2 – 1 day 
Period 2 First administration date in 
period 2 
Date of last contact 
Per definition, and for each subject, the first phase starts on the date of the earliest 
available ICF signature. The last available phase/period ends on the date of last 
contact. 
All tables and figures will present treatments/sequences rather than periods. 
AEs, medications and procedures will be allocated to phases and periods as described 
in sections 2.1.2 and 4.5.2 respectively. 


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5.2.2 
Baseline and change from baseline 
The baseline value is a non-missing value before the first administration of any study 
drug. 
The following table summarizes the baseline definition for each parameter: 
 
Parameter 
Baseline 
Vital signs 
Day 1 pre-dose (of each treatment period) 
ECG parameters 
Day 1 pre-dose (of each treatment period) 
Lung function 
Day 1 pre-dose (average of 45 min and 15 min pre-dose 
measurements of each treatment period) 
Note: decisions on whether a different baseline should be used in the analysis will be 
fully documented in the DRR. 
Change from baseline is defined as: 
Change from baseline at time point t = value at time point t – baseline value. 
Relative change from baseline at time point t is defined as follows: 
• When baseline value is not zero: 100*((value at time point t – baseline 
value) / baseline value) 
• When baseline value is zero: not calculated 
5.2.3 
Relative day 
Relative days (DY) will be calculated according to the following rule: 
• Concerned date < reference date: DY = concerned date – reference date 
• Concerned date ≥ reference date: DY = concerned date – reference date 
+ 1 
The reference date is the date of first administration of study drug (in the study and in 
each period). 
5.2.4 
Analysis visits 
The analysis will use the visits and time points indicated on the subject’s CRF, while 
for the timepoints related to the vital signs, ECG and spirometry assessments a 
windowing approach will be used (see time window definitions below). 
The screening value is the last available and non-missing value before Period 1 Day 
1. This value corresponds to the screening visit, except in case of retesting. Reason 
for this approach is the use of retest results for subject eligibility assessment. 
Unscheduled assessments will not be used in the analysis unless it is selected as 
screening value, or per time window definitions below. 
The unscheduled assessments will be checked during the DRM before database lock, 
and any different approach to the rule defined above will be documented in the DRR.  
Baseline is defined in section 5.2.2. 
All scheduled and unscheduled assessments will be listed. Early termination and 
follow-up visits will be listed only, unless otherwise specified. 


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Except when defined by time windows, the analysis visit labels will be assigned using 
the following rules: 
• All planned screening, re-screening, eligibility re-check, etc. visits 
occurred during the screening phase will be presented as ‘Screening’. 
• All planned visits occurred during a scheduled day, will be presented as 
‘Day x’ (x = study day, e.g. ‘Day -1’, ‘Day 1’, etc.) 
• Early termination visits will be presented as ‘Early Termination’ 
• Follow-up visits will be presented as ‘Follow-up’ 
• Unscheduled visits will be presented as ‘Unscheduled’ unless the 
decision to reallocate the visit is fully documented in the DRR. In case 
of reallocation, the unscheduled visit will be presented with the same 
label as the replaced planned visit (see rules above) 
• Other visits not covered by the rules above will be presented using 
similar labels to the ones used in SDTM (XX.VISIT) 
The analysis time point labels for spirometry, vital signs and ECG parameters, will be 
assigned using the following time windowing rules. 
Next to the screening value, all assessments, including unscheduled assessments, will 
be allocated to analysis windows. Tables will present the analysis windows as defined 
below and listings will present the analysis windows, as well as the CRF visits. 
Allocation of assessments will be done according to the following tables: 
Spirometry: 
Analysis time 
point window 
Target time from 
dose of study drug 
per period (minutes) 
Time interval (minutes) 
 
45min Pre-dose 
<0 
Day 1, before study drug 
15min Pre-dose 
<0 
Day 1, before study drug 
5min  
5 
[3 ; 10) 
15min 
15 
[10 ; 23) 
30min 
30 
[23 ; 45) 
1h 
60 
[45 ; 75) 
1.5h 
90 
[75 ; 135) 
3h 
180 
[135 ; 240] 
Notes:  
• Target time and time interval will be calculated in each treatment period 
from the first inhalation for pre-dose assessments and from the last 
inhalation for post-dose assessments. 
• The 45min pre-dose and 15min pre-dose assessments will first be 
allocated to analysis windows before calculation of the pre-dose mean 
value. 
 


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Vital signs and ECG: 
Analysis time 
point window 
Target time from dose 
of study drug per 
period (minutes) 
Time interval (minutes) 
Pre-dose 
<0 
Day 1, before study drug 
45min 
45 
[15 ; 75) 
1h 45min 
105 
[75 ; 135) 
2h 45min 
165 
[135 ; 240] 
Note: Target time and time interval will be calculated in each treatment period from 
the first inhalation for pre-dose assessments and from the last inhalation for post-dose 
assessments. 
Per parameter and analysis window, the value closest to the target time will be used in 
analysis tables and figures, other values will only be listed. If more than one value is 
located at the same distance from the target, then the latest in time will be selected. 
The value latest in time will be identified using, in order of preference, the assessment 
time, the visit and time point label or the group identifier. Missing values are 
removed before the selection is made. 
Partially missing assessment dates or times disabling allocation to analysis windows 
will not be imputed and thus these assessments will not be considered in the 
per-time point analysis, except for the derivation of the worst-case. 
5.2.5 
Worst-case 
A worst-case analysis visit (presented in the analysis as ‘At Any Time Point’, or 
similar) will be created for parameters for which abnormalities are defined to 
summarise values considered as the worst-case. 
The worst-case analysis visit will be derived within each treatment period, including 
scheduled and unscheduled assessments as well as the early termination and follow-
up visit assessments. Only post-dose assessments will be considered for the worst-
case analysis visit. 
5.3 
IMPUTATION AND ROUNDING RULES 
5.3.1 
Missing values 
No imputation of missing values will be done (i.e. observed cases analysis). 
5.3.2 
Handling partially or completely missing dates in 
calculations 
In case of missing date(time)s for FEV1 assessments, needed for the calculation of 
AUC0-3h, these cases will be discussed and documented in the DRR. 
Partially missing date of first diagnosis event will be imputed as follows for the 
calculation of time since event: 
• Missing day will be imputed with the first day of the month 
• Missing day and month will be imputed with 1st JAN 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 30 of 48 
Partially missing date of most recent exacerbation event will be imputed as follows 
for the calculation of time since event: 
• Missing day will be imputed with the last day of the given month 
• Missing day and month will be imputed with 31st DEC 
5.3.3 
Values below or above a threshold 
Safety values expressed as below (or above) the limit of quantification will be 
imputed by the value of the quantification limit itself. Listings will always show the 
non-imputed values. 
5.3.4 
Rounding of derived variables 
Derived variables will be rounded at display level: 
• AE duration will be presented with 1 decimal. 
• Mean of duplicates (blood pressure)/triplicates (ECG) will be rounded 
to the nearest integer. 
Note: since the rounding is applied at display level, in the listings, the 
change from baseline could be slightly different to the listed value at 
time point t – baseline value 
• Mean of duplicates (lung function) will be rounded to same number of 
decimal places as the individual values. 
Note: since the rounding is applied at display level, in the listings, the 
change from baseline could be slightly different to the listed value at 
time point t – baseline value 
• FEV1 AUC0-3h will be rounded to the same number of decimal places as 
the actual FEV1 values. 
• Relative change from baseline will be presented with 1 decimal. 
• Time since first diagnosis and most recent exacerbation will be 
presented with 1 decimal. 
5.3.5 
Outliers 
Potential outliers will be discussed during the review of the data by the Chiesi team. 
Decisions on whether values are to be excluded from the analysis will be fully 
documented in the DRR. 
5.4 
PRESENTATION OF RESULTS 
5.4.1 
Calculation of descriptive statistics and percentages 
For continuous parameters, full descriptive statistics will only be presented if there 
are at least 2 non-missing observations. Alternatively, only the number of non-
missing data points and mean are shown. 
Descriptive statistics will include the number of non-missing data points, the 
arithmetic mean, the standard deviation (SD), the median, minimum and maximum. 
Descriptive statistics of safety parameters will additionally include 95% (or 90%) 
confidence interval (CI) on the mean (based on t-distribution, without continuity 
correction). 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 31 of 48 
Mean, median, SD and CI will be presented with one more decimal place than the 
individual values. Minimum and maximum will be presented with the same number 
of decimal places than the individual values. 
For event-type data, the denominator will be all subjects in the analysis set and phase 
and period. All treatments will be shown, even if no events are present. 
P-values will be presented with three decimal places (Note: any p-value less than 
0.001 will be presented as <0.001 and any p-value greater than 0.999 will be 
presented as >0.999) and test statistics with two decimal places. 
For frequency tabulations, missing values will not be included in the denominator 
count when computing percentages. 
Percentages will be shown with one decimal place. 
5.4.2 
Presentation of treatments 
The following treatment labels will be used in the tables, listings and figures: 
When presented by treatment: 
• HFA-152a 
• HFA-134a 
When presented by treatment sequence: 
• HFA-152a-HFA-134a 
• HFA-134a-HFA-152a 
Unless specified otherwise, an overall column, to summarise all subjects over 
treatments, will be presented only in tables showing data that are not affected by the 
study treatment, as well as in the AEs summaries. The overall column will be shown 
last. 
5.4.3 
Ordering in tables, listings and figures 
If the treatments are presented as columns, tables will be sorted by analysis visit and 
time point. Otherwise, tables will be sorted first by treatment, then by analysis visit 
and time point. 
The test treatment will be shown first, and then reference treatment: HFA-152a, HFA-
134a. 
In the analysis of general characteristics, results will be presented by treatment 
sequence except where stated otherwise. For all other analyses (safety, 
), 
results will be presented by treatment. 
All listings will be ordered by subject and then by analysis visit and time point 
(chronologically), unless specified otherwise. 
In tables showing several parameters, each parameter will begin on a new page and 
parameters will be sorted alphabetically, within the parameter category if applicable. 
5.4.4 
Raw SAS output 
In addition to the statistical output as described in section 8, raw SAS output will be 
delivered in separate files as ‘Appendix to Table 14.x.x.x’ for all tables presenting 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 32 of 48 
inferential statistics. The layout of the appendices will be similar to the table (study 
identifier, SAS program name, production date, page count); presenting the raw SAS 
output in the body section. 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 33 of 48 
6. 
CHANGES TO THE PLANNED ANALYSIS 
6.1 
CHANGES NOT COVERED BY PROTOCOL AMENDMENTS BEFORE 
UNBLINDING 
Not applicable 


Statistical Analysis Plan 
 
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Final 1.0 of 22DEC2022 
 
Page 34 of 48 
7. 
REFERENCES 
• ICH Topic E6(R2) Guideline for Good Clinical Practice – Step 4, 9 
November 2016. 
• ICH Topic E9 Statistical Principles for Clinical Trials – Step 5 – Note 
for Guidance on Statistical Principles for Clinical Trials 
(CPMP/ICH/363/96), September 1998. 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 35 of 48 
8. 
LIST OF TABLES, LISTINGS AND FIGURES 
8.1 
TABLES 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
GENERAL CHARACTERISTICS 
14.1.1.1 
Screen Failures (Enrolled Set) 
ENR 
DST001 
 
Tabulation of the reason for screening failures. 
 
 
14.1.1.2 
Disposition by Treatment Sequence (Randomised Set) 
RND 
DST002 
 
Tabulation of completion/discontinuation and the reason for 
discontinuation. 
 
 
14.1.1.3 
Disposition by Treatment (Randomised Set) 
RND 
DST003 
 
Tabulation of completion/discontinuation and the reason for 
discontinuation by treatment period. 
 
 
14.1.1.4 
Disposition by Site (Randomised Set) 
RND 
DST004 
 
Tabulation of completion/discontinuation and the reason for 
discontinuation per site. 
 
 
14.1.1.5 
Analysis Sets per Period by Treatment (Randomised Set) [KFR] 
RND 
DST006 
 
Tabulation of the number of subjects per period in each of the analysis 
sets defined in the SAP. 
 
 
14.1.1.6 
Attendance at Treatment Periods by Sequence (Randomised Set) 
RND 
SVT002 
 
Tabulation of the number and percentage of subjects that entered, 
completed or discontinued each treatment period. 
 
 
14.1.1.7 
Important Protocol Deviations (Safety Set) 
SAF 
DVT001 
 
Tabulation of the important protocol deviations (at least one), deviation 
category and deviation type by treatment and overall. 
 
 
14.1.1.8 
Important Protocol Deviations Leading to Exclusion from PP 
Analysis Set (Safety Set) 
SAF 
DVT001 
 
Tabulation of the important protocol deviations (at least one) leading to 
exclusion from the PP analysis set, deviation category and deviation type 
by treatment and overall. 
 
 
14.1.2.1.1 
Demographic Characteristics (Safety Set) [KFR] 
SAF 
DMT001 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 
14.1.2.1.2 
Demographic Characteristics (PP Analysis Set) 
PP 
DMT001 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 
14.1.2.2.1 
Asthma History (Safety Set) 
SAF 
SCT002 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 36 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
14.1.2.2.2 
Asthma History (PP Analysis Set) 
PP 
SCT002 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 
14.1.2.3.1 
Exacerbation History (Safety Set) 
SAF 
SCT003 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 
14.1.2.3.2 
Exacerbation History (PP Analysis Set) 
PP 
SCT003 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 
14.1.2.4 
Smoking Status (Safety Set) 
SAF 
SUT001 
 
Descriptive statistics of continuous parameters and frequency tabulation 
of categorical parameters. 
 
 
14.1.2.5 
Vital Signs at Screening and Period 1 Day 1 Pre-dose (Safety Set) 
SAF 
BLT002 
 
Descriptive statistics of vital signs (DBP and SBP) results at Screening 
and Period 1 Day 1 pre-dose. 
 
 
14.1.2.6 
Local 12-Lead ECG at Screening and Period 1 Day 1 Pre-dose (Safety 
Set) 
SAF 
BLT002 
 
Descriptive statistics of all local triplicate 12-lead ECG results at 
Screening and single ECG at Period 1 Day 1 pre-dose. 
 
 
14.1.2.7.1 
Lung Functions at Screening and Period 1 Day 1 Pre-dose (Safety Set) 
SAF 
BLT002 
 
Descriptive statistics of lung function parameters at Screening and Period 
1 Day 1 pre-dose. 
 
 
14.1.2.7.2 
Lung Functions at Screening and Period 1 Day 1 Pre-dose (PP 
Analysis Set) 
PP 
BLT002 
 
Descriptive statistics of lung function parameters at Screening and Period 
1 Day 1 pre-dose. 
 
 
14.1.2.8.1 
Reversibility Test (Safety Set) 
SAF 
RET001 
 
Descriptive statistics of reversibility test at Screening. 
 
 
14.1.2.8.2 
Reversibility Test (PP Analysis Set) 
PP 
RET001 
 
Descriptive statistics of reversibility test at Screening. 
 
 
14.1.2.9 
ACQ-5 at Screening and Period 1 Day 1 Pre-dose (Safety Set) 
SAF 
BLT002 
 
Descriptive statistics of ACQ-5 (overall score) at Screening and Period 1 
Day 1 pre-dose. 
 
 
14.1.2.10 
Medical History (Safety Set) 
SAF 
MHT001 
 
Tabulation of the number and percentage of subjects with medical history 
findings and number and percentage of subjects with medical history 
findings by system organ class and preferred term. 
 
 
14.1.2.11 
Concomitant Diseases (Safety Set) 
SAF 
MHT001 
 
Tabulation of the number and percentage of subjects with concomitant 
diseases and number and percentage of subjects with concomitant diseases 
by system organ class and preferred term. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 37 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
14.1.2.12 
Prior Medications (Safety Set) 
SAF 
CMT001 
 
Tabulation of the number and percentage of subjects with prior 
medications and number and percentage of subjects with medications by 
ATC class (level 1), ATC class (level 2), ATC class (level 4) and 
preferred name. 
 
 
14.1.2.13 
Maintained Medications (Safety Set) 
SAF 
CMT001 
 
Tabulation of the number and percentage of subjects with maintained 
medications and number and percentage of subjects with maintained 
medications by ATC class (level 1), ATC class (level 2), ATC class (level 
4) and preferred name. 
 
 
14.1.2.14 
Concomitant Medications (Safety Set) 
SAF 
CMT002 
 
Tabulation of the number and percentage of subjects with concomitant 
medications and number and percentage of subjects with concomitant 
medications by ATC class (level 1), ATC class (level 2), ATC class (level 
4) and preferred name. 
 
 
SAFETY 
 
ADVERSE EVENTS 
 
14.3.1.1 
Summary of TEAEs (Safety Set) [KFR] 
SAF 
AET001 
 
Tabulation of the number and percentage of subjects with at least one of 
the events described in the SAP. The number of events will also be shown. 
 
 
14.3.1.2 
TEAEs by System Organ Class and Preferred Term (Safety Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with TEAEs by 
MedDRA system organ class and preferred term. The number of events 
will also be shown. 
 
 
14.3.1.3 
Serious TEAEs by System Organ Class and Preferred Term (Safety 
Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with serious TEAEs 
by MedDRA system organ class and preferred term. The number of events 
will also be shown. 
 
 
14.3.1.4 
Non-Serious TEAEs by System Organ Class and Preferred Term 
(Safety Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with non-serious 
TEAEs by MedDRA system organ class and preferred term. The number 
of events will also be shown. 
 
 
14.3.1.5 
ADRs by System Organ Class and Preferred Term (Safety Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with ADRs by 
MedDRA system organ class and preferred term. The number of events 
will also be shown. 
 
 
14.3.1.6 
Serious ADRs by System Organ Class and Preferred Term (Safety 
Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with serious ADRs by 
MedDRA system organ class and preferred term. The number of events 
will also be shown. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 38 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
14.3.1.7 
Severe TEAEs by System Organ Class and Preferred Term (Safety 
Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with severe TEAEs 
by MedDRA system organ class and preferred term. The number of events 
will also be shown. 
 
 
14.3.1.8 
TEAEs Leading to Study Drug Discontinuation by System Organ 
Class and Preferred Term (Safety Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with TEAEs leading 
to study drug discontinuation by MedDRA system organ class and 
preferred term. The number of events will also be shown. 
 
 
14.3.1.9 
TEAEs Leading to Death by System Organ Class and Preferred Term 
(Safety Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with TEAEs leading 
to death by MedDRA system organ class and preferred term. The number 
of events will also be shown. 
 
 
14.3.1.10 
TEAEs of Particular Interest (Safety Set) 
SAF 
AET003 
 
Tabulation of the number and percentage of subjects with TEAEs of 
particular interest (as defined in section 2.1.2) by MedDRA system organ 
class and preferred term. The number of events will also be shown. 
 
 
VITAL SIGNS 
 
14.3.5.1 
Vital Signs: Summary of Actual Values and Changes from Baseline 
(Safety Set) 
SAF 
VST001 
 
Descriptive statistics of vital signs actual values and changes from baseline 
per parameter and analysis time point. Table sorted by analysis time point. 
Each parameter will begin on a new page. 
 
 
ECG 
 
14.3.6.1 
Local 12-Lead ECG: Summary of Actual Values and Changes from 
Baseline (Safety Set) 
SAF 
EGT002 
 
Descriptive statistics of continuous 12-lead ECG (HR, PR, QRS, QTcF) 
actual values and changes from baseline per analysis time point. Table 
sorted by analysis time point. Each parameter will begin on a new page. 
 
 
14.3.6.2 
QTcF: Abnormalities (Safety Set) 
SAF 
EGT007 
 
Tabulation of the abnormalities as defined in section 2.4.2 at baseline and 
each post-dose analysis time point and at the worst-case analysis time-
point. Table sorted by analysis time point. Only baseline and post-dose 
analysis time points are shown. 
 
 
14.3.6.3 
QTcF: Abnormal Changes from Baseline (Safety Set) 
SAF 
EGT008 
 
Tabulation of the QTcF change abnormalities as defined in 2.4.2 at each 
post-dose analysis time point and at the worst-case analysis time point. 
Table sorted by analysis time point. Only post-dose analysis time points 
are shown. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 39 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
LUNG FUNCTION 
 
14.3.7.1.1 
Lung Functions: Summary of Actual Values and Changes from 
Baseline (Safety Set) [KFR] 
SAF 
TPT001 
 
Descriptive statistics of actual values and changes from baseline in FEV1 
and PEF results per parameter and analysis time point. Table sorted by 
analysis time point. Each parameter will begin on a new page. 
 
 
14.3.7.1.2 
Lung Functions: Summary of Actual Values and Changes from 
Baseline (PP Analysis Set) 
PP 
TPT001 
 
Descriptive statistics of actual values and changes from baseline in FEV1 
and PEF results per parameter and analysis time point. Table sorted by 
analysis time point. Each parameter will begin on a new page. 
 
 
14.3.7.2.1 
Lung Functions: Summary of Relative Changes from Baseline (Safety 
Set) [KFR] 
SAF 
TPT004 
 
Descriptive statistics of relative changes from baseline in FEV1 and PEF 
results per parameter and analysis time point. Table sorted by analysis time 
point. Only post-baseline analysis time points are shown. 
 
 
14.3.7.2.2 
Lung Functions: Summary of Relative Changes from Baseline (PP 
Analysis Set) [KFR] 
PP 
TPT004 
 
Descriptive statistics of relative changes from baseline in FEV1 and PEF 
results per parameter and analysis time point. Table sorted by analysis time 
point. Only post-baseline analysis time points are shown. 
 
 
14.3.7.3.1 
Primary Objective: Statistical Analysis of Relative Change from 
Baseline in FEV1 at 15 Min Post-dose (Safety Set) [KFR] 
SAF 
ANT001 
 
Results from the primary objective ANCOVA on relative change from 
baseline in FEV1 at the 15 min post-dose time point as described in 
section 2.5.3. 
 
 
14.3.7.3.2 
Statistical Analysis of Relative Change from Baseline in FEV1 at 15 
Min Post-dose (PP Analysis Set) [KFR] 
PP 
ANT001 
 
Results from the ANCOVA on relative change from baseline in FEV1 at 
the 15 min post-dose time point as described in section 2.5.3. 
 
 
14.3.7.4 
Statistical Analysis of Relative Change from Baseline in FEV1 at Other 
Time Points (Safety Set) [KFR] 
SAF 
ANT002 
 
Results from the ANCOVA on relative change from baseline in FEV1 at all 
other post-dose time points (5 min, 30 min, 1 h, 1 h 30 min and 3 h) as 
described in section 2.5.3. 
 
 
14.3.7.5 
Statistical Analysis of Change from Baseline in FEV1 (Safety Set) 
[KFR] 
SAF 
ANT002 
 
Results from the ANCOVA on absolute change from baseline in FEV1 at 
all post-dose time points (5 min, 15 min, 30 min, 1 h, 1 h 30 min and 3 h) 
as described in section 2.5.3. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 40 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
14.3.7.6 
FEV1: Abnormal Relative Changes from Baseline (Safety Set) 
SAF 
EGT008 
 
Tabulation of the FEV1 relative change abnormalities as defined in section 
2.5.2 at each post-dose analysis time point and at the worst-case analysis 
time point. Table sorted by analysis time point. Only post-dose analysis 
time points are shown. 
Template EGT008 is used, using the FEV1 relative change abnormalities 
instead. 
 
 
14.3.7.7 
FEV1: Changes from Baseline in AUC0-3h (Safety Set) 
SAF 
TPT002 
 
Descriptive statistics of change from baseline in FEV1 AUC0-3h. 
 
 
USE OF RESCUE MEDICATION 
 
14.3.8.1 
Rescue Medication Use (Safety Set) 
SAF 
XRT001 
 
Descriptive statistics of mean use of rescue medication in the first 3h 
post-dose by treatment and frequency tabulation of use of rescue 
medication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 41 of 48 
8.2 
LISTINGS 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
GENERAL CHARACTERISTICS 
 
16.1.7 
Randomisation Schedule (Randomised Set) 
RND 
DSL001 
 
Listing of subject numbers and randomisation information  
All discrepancies (as-randomised versus as-treated) will be presented. 
 
 
16.2.1.1 
Screening Failures (Enrolled Set) 
ENR 
DSL002 
 
Listing of all subjects not randomised. The study discontinuation reason 
and demographic data will be listed. 
 
 
16.2.1.2 
Study Discontinuation After Randomisation (Randomised Set) 
RND 
DSL003 
 
Listing of all subjects that discontinued after randomisation. The study 
discontinuation reason will also be listed. 
 
 
16.2.1.3 
Subject Disposition (Randomised Set) 
RND 
DSL004 
 
Listing of the reasons for completion / discontinuation and the number of 
days since first study drug administration at study discontinuation. In case 
the discontinuation was due to AE, the AE will be presented in this listing. 
If there is another explanation on the discontinuation reason collected in 
the CRF, this will also be presented in this listing. 
 
 
16.2.1.4 
Randomisation Code Broken (Randomised Set) 
RND 
DSL005 
 
Listing of the code breaking information. Only subjects for which the code 
was broken are presented in this listing. 
 
 
16.2.1.5 
Subject Disposition: Analysis Phases and Periods With Time 
(Randomised Set) 
RND 
DSL008 
 
Listing of the phases and periods in the study (definition with time for 
adverse events and medications), together with the start and end 
date(time)s. 
 
 
16.2.1.6 
Subject Disposition: Analysis Phases and Periods Without Time 
(Randomised Set) 
RND 
DSL008 
 
Listing of the phases and periods in the study (definition without time for 
procedures), together with the start and end dates. 
 
 
16.2.1.7 
Study Visits (Randomised Set) 
RND 
SVL001 
 
Listing per subject number of all subject visits, together with the start and 
end date of each visit. Listing is sorted chronologically by visit start date 
within each subject. 
 
 
16.2.1.8 
First and Last Contact in the Study (Enrolled Set) 
ENR 
 
 
List of the date of the first signed ICF, last visit date and last date of 
contact in the study. All dates are presented overall, not by treatment. 
 
 
16.2.2.1 
Violation of Eligibility Criteria (Randomised Set) 
RND 
DVL001 
 
Only violated in- and exclusion criteria will be listed. Only deviations with 
DVDECOD = “VIOLATION OF INCLUSION CRITERION” or 
“VIOLATION OF EXCLUSION CRITERION” will be selected. 
 
 
16.2.2.2 
Important Protocol Deviation (Randomised Set) 
RND 
DVL002 
 
Listing of all important protocol deviations information 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 42 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
16.2.2.3 
Restrictions (Randomised Set) 
RND 
 
 
Listing of all restrictions data available in the CRF. 
 
 
16.2.3.1 
Analysis Set Disposition (Randomised Set) 
RND 
DSL006 
 
Listing of all subjects and analysis set indicators. 
 
 
16.2.3.2 
Subjects Excluded from Safety/PP Analysis Set (Randomised Set) 
RND 
DSL007 
 
Listing of all subjects that were excluded from SAF/PP. 
 
 
16.2.4.1 
Demographic Characteristics (Randomised Set) 
RND 
DML001 
 
Listing of all demographic parameters 
 
 
16.2.4.2 
Asthma History (Randomised Set) 
RND 
SCL001 
 
Listing of all baseline disease characteristics. 
Adjust the columns of SCL001 according to the available data. 
 
 
16.2.4.3 
Smoking Status (Randomised Set) 
RND 
SUL001 
 
Listing of all smoking data available in the CRF 
 
 
16.2.4.4 
Reversibility Test (Randomised Set) 
RND 
REL001 
 
Listing of all reversibility test data available in the CRF 
 
 
16.2.4.5 
Medical/Surgical History (Randomised Set) 
RND 
MHL001 
 
Listing of the medical history data findings available in the CRF 
 
 
16.2.4.6 
Concomitant Diseases (Randomised Set) 
RND 
MHL002 
 
Listing of the concomitant diseases data findings available in the CRF 
 
 
16.2.4.7 
Procedures (Randomised Set) 
RND 
PRL001 
 
Listing of all data on prior, maintained and concomitant procedures 
 
 
16.2.4.8 
Medications (Randomised Set) 
RND 
CML001 
 
Listing of all data on prior, maintained and concomitant medications 
 
 
16.2.4.9 
Comments (Randomised Set) 
RND 
COL001 
 
Listing of all remarks and comments written in the CRF 
 
 
16.2.5.1 
Training with Inhalers (Randomised Set) 
RND 
 
 
Listing of all data related to training with inhalers 
 
 
16.2.5.2 
Exposure (Randomised Set) 
RND 
 
 
Listing of all data related to exposure 
 
 
SAFETY 
 
ADVERSE EVENTS 
 
16.2.7.1 
Pre-Treatment Adverse Events (Enrolled Set) 
ENR 
AEL001 
 
Listing of all pre-treatment AE information collected in the CRF and of the 
onset day and duration. All information of one AE will be presented on the 
same line. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 43 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
16.2.7.2 
Treatment Emergent Adverse Events (Randomised Set) 
RND 
AEL002 
 
Listing of all AE information collected in the CRF and of the phase / 
period dates and onset day and duration. All information of one AE will be 
presented on the same line. 
 
 
16.2.7.3 
Serious Treatment Emergent Adverse Events (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing serious TEAEs only 
 
 
16.2.7.4 
Non-Serious Treatment Emergent Adverse Events (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing non-serious TEAEs only 
 
 
16.2.7.5 
Adverse Drug Reactions (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing ADRs only 
 
 
16.2.7.6 
Serious Adverse Drug Reactions (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing serious ADRs only 
 
 
16.2.7.7 
Severe Treatment Emergent Adverse Events (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing severe TEAEs only 
 
 
16.2.7.8 
Treatment Emergent Adverse Events Leading to Study Drug 
Discontinuation (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing TEAEs leading to study drug 
discontinuation only 
 
 
16.2.7.9 
Treatment Emergent Adverse Events Leading to Death (Randomised 
Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing TEAEs leading to death only 
 
 
16.2.7.10 
Adverse Events of Particular Interest (Randomised Set) 
RND 
AEL002 
 
Same as listing 16.2.7.2, but listing TEAEs of particular interest only 
 
 
16.2.7.11 
Physical Examination Abnormalities (Randomised Set) 
RND 
PEL001 
 
Listing of all data on abnormal physical examinations findings 
 
 
LABORATORY DATA 
 
16.2.8.1.1 
Laboratory Results: Haematology Abnormalities (Randomised Set) 
RND 
LBL001 
 
Listing of all abnormal haematology results. The (non-imputed) values 
will be shown, as well as normal ranges, clinical significance flag and 
fasted flag. 
 
 
16.2.8.1.2 
Laboratory Results: Biochemistry Abnormalities (Randomised Set) 
RND 
LBL001 
 
Listing of all abnormal biochemistry results. The (non-imputed) values 
will be shown, as well as normal ranges, clinical significance flag and 
fasted flag. 
 
 
16.2.8.1.3 
Laboratory Results: Urinalysis (Randomised Set) 
RND 
LBL001 
 
Listing of all available urinalysis results. The (non-imputed) values will be 
shown, as well as normal ranges, abnormality flags, and clinical 
significance flag. 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 44 of 48 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
16.2.8.1.4 
Laboratory Results: Pregnancy Test (Randomised Set) 
RND 
LBL005 
 
Listing of all serum and urine pregnancy and FSH results. 
 
 
VITAL SIGNS 
 
16.2.8.2 
Vital Signs: Full Listing (Randomised Set) 
RND 
VSL001 
 
Listing of all vital signs results. The values will be shown, as well as 
changes from baseline. 
 
 
ECG 
 
16.2.8.3 
Local 12-Lead ECG: Full Listing (Randomised Set) 
RND 
EGL001 
 
Listing of all triplicate local 12-lead ECG results and the corresponding 
interpretation. The values will be shown, as well as changes from baseline 
and abnormality categories (for QTcF). 
 
 
LUNG FUNCTION 
 
16.2.8.4 
Lung Function: Full Listing (Randomised Set) 
RND 
VSL001 
 
Listing of all lung function results, except the reversibility test results. The 
values will be shown, as well as changes, relative changes from baseline 
and relative change abnormalities. 
Template VSL001 is used, presenting the lung function parameters 
instead. For layout purposes, VSL002 could be used instead. 
 
 
USE OF RESCUE MEDICATION 
 
16.2.8.5 
Rescue Medication Use (Randomised Set) 
RND 
 
 
Listing of all data related to rescue medication available in the CRF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 45 of 48 
8.3 
FIGURES 
Number 
Title 
Analysis 
Set 
TLFs Library 
Template 
Number 
LUNG FUNCTION 
14.3.7.1 
Mean Change from Baseline in Lung Functions (Safety Set) 
SAF 
TPF001 
 
Graph of mean absolute changes from baseline in FEV1 and PEF with 
“time” on the horizontal axis and a different plot symbol/colour/line 
pattern for each subject group. Each parameter will be presented 
separately. 
 
 
14.3.7.2 
Mean Relative Change from Baseline in Lung Functions (Safety Set) 
[KFR] 
SAF 
TPF001 
 
Graph of mean relative changes from baseline in FEV1 and PEF with 
“time” on the horizontal axis and a different plot symbol/colour/line 
pattern for each subject group. Each parameter will be presented 
separately. 
 
 
 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 46 of 48 
9. 
APPENDICES 
9.1 
SAS CODE 
The SAS code in this section is an example and might differ from the actual code 
used in the statistical analysis. 
Lung function ANCOVA models: 
 
proc mixed; 
   by param atptn; 
   class trtan subjid aperiod; 
   model (p)chg = trtan subjid aperiod base; 
   lsmeans trtan / diff alpha= 0.05; 
run; 
 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 47 of 48 
 
9.2 
SCHEDULE OF ASSESSMENTS 
 
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; 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. 


Statistical Analysis Plan 
 
CLI-05993AB6-07 
 
Final 1.0 of 22DEC2022 
 
Page 48 of 48 
 
[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.