Open Label, Prospective Study to Evaluate the Effect of Step-up From Non-extra Fine Inhaled Corticosteroids/Long Acting Beta2 Agonist (ICS/LABA) Dry Powder Inhaler (DPI) to Extra Fine Triple Therapy With CHF5993 DPI on Airway Geometry and Lung Ventilation Using Functional Respiratory Imaging (FRI) in Subjects With Advanced Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE3
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Chiesi Farmaceutici S.p.A.

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CLINICAL STUDY PROTOCOL 
STUDY CODE No.: CLI-05993BA1-08
EUDRACT No.: 2020-002356-20
Open label, prospective study to evaluate the effect of step-up from non-extra fine ICS/LABA 
DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and lung ventilation 
using FRI in subjects with advanced COPD
Version No.: 4.0
Date: 26 May 2021
The information contained in this document is confidential and will not be disclosed to others without written 
authorization from Chiesi Farmaceutici S.p.A., except to the extent necessary to obtain informed consent from those 
persons to whom the drug may be administered or for discussions with local regulatory authorities, Ethics Committee, 
or people participating in the conduct of the study.
Chiesi Farmaceutici S.p.A.
Via Palermo 26/A
43122 Parma - Italy
NCT04876677

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Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
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-
IMP storage conditions updated 
accordingly to EMA requirements;
-
Typo corrections.
4.0
26 May 2021
Fourth Version:
The following substantial changes have been 
implemented:
-
Blood chemistry updated considering the 
creatinine test replacing BUN analysis
-
RSI is now referred to Summary of 
Product Characteristics instead of IB
-
Sponsor medical expert contacts updated
-
Typo corrections

Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
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PROTOCOL OUTLINE
Study title
Open label, prospective study to evaluate the effect of step-up from non-extra 
fine ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on 
airway geometry and lung ventilation using FRI in subjects with advanced 
COPD
Sponsor
Chiesi Farmaceutici S.p.A. - Via Palermo 26/A 
43122 Parma - Italy 
Name of the Product
CHF 5993 DPI (fixed combination of Beclometasone Dipropionate (BDP) 
100 μg, Formoterol Fumarate (FF) 6 μg, Glycopyrronium Bromide (GB) 
12.5 μg)
Centre(s)
~ 8 centres in Europe
Indication 
COPD
Study design
Multicentre, open-label, single arm
Study phase
Phase IIIb
Objectives
Primary Objective
To assess the effect of stepping-up from SERETIDE™ DISKUS™ 
(fluticasone propionate/salmeterol or FP/SLM 500/50 µg) DPI to extra fine 
CHF 5993 (BDP/FF/GB 100/6/12.5 µg) DPI on airway geometry and lung 
ventilation 
Secondary Objective 
To assess therapeutic aerosol particles deposition, lung function following 
a switch from FP/SLM 500/50 µg (SERETIDE™ DISKUS™) DPI to 
extra fine BDP/FF/GB 100/6/12.5 µg (CHF5993) DPI.
Treatment duration
6 weeks
Test product 
dose/route/regimen  
CHF 5993 inhalation powder:
(BDP/FF/GB) 100/6/12.5 µg 
Dose regimen: 2 inhalations bid
Administration: via Dry Powder Inhaler (DPI)
Reference product 
dose/route/regimen 
NA
Number of subjects
30 subjects
Study population
Adult subjects with moderate to severe COPD
Inclusion/exclusion criteria
Inclusion Criteria:
1.
Subject’s signed Informed Consent Form obtained prior to any 
study-related procedure;
2.
Male or female ≥ 40 years of age;
3.
Current smokers and/or ex-smokers of at least 10 pack-years, 
calculated as (number of cigarettes/day * number of years)/20. (E-
cigarettes smoking cannot be used to calculate pack-year history);
4.
Established diagnosis of COPD according to the 2020 GOLD 
Report, prior to the Screening visit (V1);
5.
Post-BD FEV1/FVC < 0.7 and FEV1 ≤ 60% of predicted at V1 (Note: 
if the criterion is not met at screening, the measure can be repeated 
once before run-in day 1); 

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6.
On a stable dose of any non-extra fine ICS/LABA DPI twice daily 
regimen for at least 8 weeks before screening;
7.
Presence of lung hyperinflation based on the increase of Total Lung 
Capacity (TLC) exceeding either the upper limit of normal (ULN) or 
an empiric 120% of predicted, and/or a plethysmographic functional 
residual capacity (FRC) exceeding either ULN or 120 % of 
predicted;
8.
Symptomatic subjects with CAT score ≥ 10 at V1 and V2;
9.
Documented history of ≥ 1 moderate or severe COPD exacerbation 
in the previous 12 months prior to V1;
10. To have a cooperative attitude and the ability to be trained and use 
correctly the Dry Powder Inhalers (DPI);
11. To have a cooperative attitude and the ability to perform the required 
outcomes measurements (e.g. spirometry manoeuvres in sitting and 
supine position) and the ability to understand the risks involved;
12. WOCBP fulfilling one of the following criteria: 
a.
WOCBP with fertile male partners: they and/or their 
partner must be willing to use a highly effective birth 
control method from the signature of the informed consent 
and until the follow-up visit or
b.
WOCBP with non-fertile male partners (contraception is not 
required in this case)
13. Female subjects of non-childbearing potential defined as 
physiologically incapable of becoming pregnant (i.e. post-
menopausal or permanently sterile; e.g. amenorrhea for ≥ 12 
consecutive months without alternative medical cause). Permanent 
sterilisation methods include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy. If indicated, as per investigator’s 
request, post-menopausal status may be confirmed by follicle-
stimulating hormone levels (according to local laboratory ranges).
Exclusion Criteria:
1.
Pregnant or lactating woman; 
2.
Exacerbations defined as a sustained and acute deterioration of 
subject’s symptoms and signs (dyspnoea, cough and/or sputum 
production/purulence) that are either moderate, i.e. require treatment 
with systemic (oral/IV/IM) corticosteroids and/or antibiotics, or 
severe, 
i.e. 
require 
hospitalization, 
if 
their 
associated 
treatment/hospitalization occurred within the 30 days before V1 (or 
4 weeks in case the event was treated with just systemic 
corticosteroids) or if the event is recorded during the run-in period;
3.
A current asthma diagnosis;
4.
Respiratory disorders other than COPD: subjects with known 
respiratory disorders other than COPD that in the Investigator's 
opinion would affect efficacy and safety evaluation or place the 
subject at risk. This can include but is not limited to known α1-anti-
trypsine deficiency, active tuberculosis, bronchiectasis, sarcoidosis, 
lung fibrosis, pulmonary hypertension and interstitial lung disease;
5.
Cardiovascular diseases: subjects who have known clinically 
significant cardiovascular conditions such as but not limited to: 

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unstable or acute ischemic heart disease within one year prior to 
study entry, NYHA class IV heart failure, history of atrial 
fibrillation, history of sustained and non-sustained cardiac 
arrhythmias diagnosed within 6 months prior to study entry and not 
controlled with therapy according to the investigator’s opinion;
6.
Evidence or history of other concurrent disease such as but not 
limited to hyperthyroidism, diabetes mellitus or other endocrine 
disease; haematological disease; autoimmune disorders (e.g. 
rheumatoid arthritis), significant renal impairment, significant 
neurological disease 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 interpretation of the study;
7.
Medical history or current diagnosis of narrow-angle glaucoma, 
clinically relevant prostatic hypertrophy or bladder neck obstruction 
that in the opinion of the Investigator would have prevented use of 
anticholinergic agents;
8.
History of lung transplant or lung reduction surgery;
9.
ECG criteria: any clinically significant abnormal 12-lead ECG that 
in the investigator's opinion would affect efficacy or safety 
evaluation or place the subjects at risk. Male subjects with a QTcF 
>450msec and female subjects with a QTcF > 470msec at V1 are not 
eligible;
10. Laboratory abnormalities: subjects with clinically significant 
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 interpretation of the study;
11. Alcohol/drug abuse: subjects with a known or suspected history of 
alcohol and/or substance/drug abuse within 12 months prior to 
screening; or having a positive drug test at screening or V2;
12. Participation in investigational trial: subjects who have received any 
investigational drug within the 30 days or a more appropriate time 
as determined by the investigator (e.g. approximately 5 half-lives of 
the investigational drug, whatever is longer);
13. Contra-indications to IMPs, based on investigator judgement;
14. 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;
15. Subjects mentally or legally incapacitated or subjects accommodated 
in an establishment as a result of an official or judicial order;
16. Documented COVID-19 diagnosis or its complications which have 
not resolved within 14 days prior to screening;
17. Positive molecular COVID-19 test within the last 72 hours before 
the remaining of screening activities.
Study plan
Screening visit (Visit 1) will be performed 6 weeks ± 2 days before Visit 2.
Eligible subjects will undergo a 6-week run-in period with open-label 
FP/SLM DPI (SERETIDE™ DISKUS™). At the end of the run-in period 
(Visit 2), subjects will be switched to open-label treatment with BDP/FF/GB 
DPI (CHF5993) for 6 weeks (until Visit 3). 

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Please refer to Section 7 for additional details.
Most relevant allowed 
concomitant treatments
1. Inhaled salbutamol administered as rescue medication. A minimum period 
of 6 hours has to elapse between the use of rescue salbutamol and the 
Spirometry measurements;
2. Anti-histamines (oral, intranasal, ocular) and intranasal corticosteroids 
(INS) for the treatment of allergy or rhinoconjunctivitis symptoms;
3. Oral Xanthine derivatives (e.g. Theophylline) if taken at stable regimen 
for at least 1 month prior to screening and to be maintained constant during 
the study;
4. Nocturnal Oxygen Therapy (NOT) with HbO2 saturation ≥ 90% at rest;
5. Ambulatory Oxygen Therapy (AOT) with HbO2 saturation ≥ 90% at rest;
6. Non-Invasive Positive Pressure Ventilation (NIPPV) with diurnal HbO2 
saturation ≥ 90% at rest and at Investigator’s discretion;
7. Short courses (≤ 10 days) of nasal corticosteroids (maximum 4 courses) 
are allowed during the treatment period;
8. In case of a concomitant disease any appropriate treatment not interfering 
with the study evaluation parameters is allowed;
9. Paracetamol (maximum 2 g per day with a maximum of 10 g per 14 days).
Most relevant forbidden 
concomitant treatments
1. Long Term Oxygen Therapy (LTOT) prescribed for severe arterial 
hypoxemia, with HbO2 saturation ≤ 90% at rest;
2. Depot corticosteroids;
3. Oral/parenteral/IM corticosteroids;
4. Nebulized β2-agonists, anti-cholinergic and/or steroids; 
5. ICS (pMDI and DPI);
6. Inhaled LABAs or fixed combination of corticosteroids and LABAs other 
than study treatments (e.g. salmeterol plus fluticasone or Formoterol plus 
budesonide);
7. Inhaled LAMAs;
8. Inhaled SABAs (other than salbutamol as rescue medication);
9. Inhaled fixed combinations of a SABA and a SAMA;
10. Inhaled SAMAs (ipratropium and oxytropium);
11. Non-cardio-selective β-blockers;

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12. Tricyclic antidepressants, monoamine oxidase inhibitors, selective 
serotonin re-uptake inhibitors and other drugs known to prolong the QTc 
interval unless already taken at the time of screening;
13. PDE-4 inhibitors (e.g. roflumilast);
14. Leukotriene modifiers;
15. Non-potassium sparing diuretics (unless administrated as a fixed dose 
combination with a potassium conserving drug);
16. OTC medicines, homeopathic remedies, etc., in the 7 days before the 
screening visit and until the end of the study.
Efficacy variables
Primary endpoints:
The following FRI parameters are used as primary outcome parameters:

Percentage change from baseline (pre-dose V2) to pre-dose in 
untrimmed specific airway volume (siVaw) upon inspiration (at 
Total Lung Capacity, TLC) at Visit 3

Percentage change from baseline (pre-dose V2) to pre-dose in 
trimmed specific airway resistance (siRaw) upon inspiration (at 
TLC) at Visit 3
Data for these parameters will be recorded by lobar region and overall distal 
region.
Secondary endpoints:
Evaluation of the percentage change from baseline (V2) to post-dose at Visit 
3, the percentage change from pre-dose to post-dose at Visit 2, and the 
percentage change from pre-dose to post-dose at Visit 3 for the primary 
endpoints.
Values at pre-dose and post-dose for the following FRI parameters:

siVaw upon expiration (at Functional Residual Capacity, FRC)

siRaw upon expiration (at FRC) 

ventilation mapping

perfusion mapping

airway wall thickness upon inspiration (at TLC)

imaged lobe and lung volumes at TLC and FRC

air trapping at FRC

low attenuation score at TLC

Percentile 15th at TLC 

Regional lung deposition 
In addition, pre-dose spirometry, body plethysmography and CAT will be 
assessed at Visit 2 and Visit 3.
Safety variables

Adverse Events (AEs) and Adverse Drug Reactions (ADRs) 

Vital signs (systolic and diastolic blood pressure)
Sample size calculation
No formal sample size calculation has been performed since the nature of the 
study (i.e., exploratory study).
30 subjects will be enrolled in the study in order to have at least 25 
completed subjects.

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Statistical methods
Efficacy variables
Primary and secondary efficacy endpoints will be presented using descriptive 
statistics at each timepoint. Change from baseline to pre-dose and post-dose 
at Visit 3 as well as change from pre-dose to post-dose at Visit 2 and Visit 3 
will also be presented for primary and secondary efficacy endpoints FRI-
related using descriptive statistics, while change from baseline to pre-dose at 
Visit 3 will be presented for other secondary endpoints.
Overall distal region value for primary endpoints will be log-transformed and 
analysed using an ANCOVA model including the logarithm of baseline 
(Visit 2) at TLC, logarithm of pre-dose lobar volume at FRC on Visit 3 as 
covariates. The adjusted % change from baseline to pre-dose at Visit 3 will 
be calculated with its 95% CI. 
Multiple data on lobar regions for primary endpoints will be log-transformed 
and analysed using the same model as for the overall distal region.
For the primary FRI parameters, the percentage change from baseline to post-
dose at Visit 3 and the percentage change from pre-dose to post-dose at Visit 
2 and Visit 3 will be analysed using the same models described for the 
primary efficacy endpoints.
For the other FRI parameters, analysed using the same model as for the 
primary endpoints, with exclusion of pre-dose lobar volume at FRC on Visit 
3 where appropriate.
For all FRI parameters, additional analyses using different models (e.g. 
mixed-effect models) and subgroup analyses will be performed to get better 
insights in regional effects. These analyses will be pre-specified and 
described in the statistical analysis plan (SAP).
For all other efficacy endpoints, change from baseline to pre-dose at Visit 3 
will be analysed presenting 95% CI of the mean change and using a paired t-
test.
Relevant correlations between variables will be evaluated using Spearman’s 
rank correlation coefficient.
Safety variables
Adverse Events
All adverse events starting on or after the time of first study drug intake will 
be classified as treatment emergent adverse event (TEAE). Any adverse 
events started after the informed consent signature and before the time of first 
study drug intake will be classified as pre-treatment adverse event.
The number of subjects who experienced at least one AE, drug-related AE, 
non-serious AE, serious AE, serious related AE, AE leading to study 
discontinuation, and AE leading to death will be summarized by treatment 
arm. Summaries will be presented overall (number and percentage of 
subjects having at least one event, total number of events) and by system 
organ class and preferred term (number and percentage of subjects having at 
least one occurrence of that event). 

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All adverse events will be listed. Pre-treatment adverse event will be listed 
only.
Vital signs
Vital signs (systolic and diastolic blood pressure) and their changes from
pre-dose to post-dose at Visit 2 and Visit 3 will be summarized using 
descriptive statistics and the 95% CI of the mean.
A detailed statistical analysis description will be provided in the SAP.

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Ab-HCV
Hepatitis C Virus Antibody
Ab-HIV
Human Immunodeficiency Virus Antibody
ADR
Adverse Drug Reaction
AE
Adverse Event 
ALT
Alanine Aminotransferase
anti-HBc 
hepatitis B core antibody
AOT
Ambulatory Oxygen Therapy
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical classification
ATS
American Thoracic Society
BD
Bronchodilator
BDP
Beclometasone Dipropionate
BTPS
Body Temperature Pressure Saturated
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CFD
Computational Fluid Dynamics
CI
Confidence Interval
COPD
Chronic obstructive pulmonary disease
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organization
CT
Computed Tomography
DPI
Dry-Powder Inhaler
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ERS
European Respiratory Society
EVC
Expiratory Vital Capacity
FDC
Fixed-Dose Combination
FET
Forced Expiratory Time
FF
Formoterol Fumarate
FEV1
Forced Expiratory Volume in one second
FPD
Fine Particle Dose
FRC
Functional Residual Capacity
FRI
Functional respiratory imaging
FSH
Follicle-Stimulating Hormone
FSFV
First Subject First Visit
FVC
Forced Vital Capacity
GB
Glycopyrronium Bromide
GOLD
Global Initiative for Chronic Obstructive Lung Disease
Hb
Haemoglobin
HBsAg
Hepatitis B Surface Antigen
Hct
Haematocrit
ICH
International Conference on Harmonization
IC
Inspiratory Capacity
ICS
Inhaled Corticosteroids
IM
Intra Muscular
IMP
Investigational Medical Product
ITGV
Intrathoracic Gas Volume

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ITT
Intention to Treat
IV
Intra Venous
iVlob
Lobar Volume
iVlung
Lung Volume
iVaw
Airway Volume
LABA
Long Acting Beta2 Agonist
LAMA
Long Acting Muscarinic Antagonist
LAS
Low Attenuation Score
LSLV
Last Subject Last Visit
LTOT
Long Term Oxygen Therapy
MDCT
Multi-slice with multidetector Compound Tomography
MedDRA
Medical Dictionary for Regulatory Activities
MEF
Maximal expiratory Flow
MEF25
Maximal expiratory flow at 25% of expired vital capacity
MEF50
Maximal expiratory flow at 50% of expired vital capacity
MMAD
Mass Median Aerodynamic Diameter
NIPPV
Non-Invasive Positive Pressure Ventilation
NOT
Nocturnal Oxygen Therapy
NYHA
New York Heart Association
OTC 
Over The Counter
PD15
Percentile 15th 
PDE-4
phosphodiesterase-4
PEF
Peak Expiratory Flow
PLT
Platelets
pMDI
Pressurized Metered-Dose Inhaler
PP
Per-Protocol
PRN
Pro Re Nata
Raw
Airway resistance
RBC
Red Blood Cells
RV
Residual Volume
SABA
Short Acting Beta Agonist
SAD
Small Airway Disease
SAE
Serious Adverse Event
SAMA
Short Acting Muscarinic Antagonist
SAP
Statistical Analysis Plan
sGaw
Specific conductance
SGRQ
St. George Respiratory Questionnaire
siRav
Specific Airway Resistance
siVaw
Specific Airway Volume
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment Emergent Adverse Events
TLC
Total Lung Capacity
UA
Upper Airway
ULN
Upper Limit of Normal
VC
Vital Capacity
WBC
White Blood Cells
WOCB
Women Of Childbearing Potential
γ-GT
Gammaglutamyl transpeptidase

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CONTENT
 
GENERAL INFORMATION ................................................................................................................................2
PROTOCOL OUTLINE ........................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................................................................11
CONTENT.............................................................................................................................................................13
1.
INTRODUCTION .......................................................................................................................................16
1.1 BACKGROUND INFORMATION........................................................................................................................16
1.2 STUDY RATIONALE........................................................................................................................................17
1.3 RISK/BENEFIT ASSESSMENT...........................................................................................................................19
2.
STUDY OBJECTIVES ...............................................................................................................................19
2.1 PRIMARY OBJECTIVE(S) ................................................................................................................................19
2.2 SECONDARY OBJECTIVE(S) ...........................................................................................................................19
3.
STUDY DESIGN .........................................................................................................................................19
4.
SUBJECT SELECTION CRITERIA........................................................................................................20
4.1 SUBJECT RECRUITMENT................................................................................................................................20
4.2 INCLUSION CRITERIA.....................................................................................................................................20
4.3 EXCLUSION CRITERIA ...................................................................................................................................22
4.4 SUBJECT WITHDRAWALS ..............................................................................................................................23
5.
CONCOMITANT MEDICATIONS..........................................................................................................24
5.1 PERMITTED CONCOMITANT MEDICATIONS....................................................................................................24
5.2 NON-PERMITTED CONCOMITANT MEDICATIONS ...........................................................................................24
6.
TREATMENT(S) ........................................................................................................................................25
6.1 APPEARANCE AND CONTENT.........................................................................................................................25
6.2 DOSAGE AND ADMINISTRATION....................................................................................................................26
6.2.1 Selection of doses in the study..............................................................................................................26
6.2.2 Dosage..................................................................................................................................................26
6.2.2.1 Run-in period...................................................................................................................................................26
6.2.2.2 Treatment period:............................................................................................................................................26
6.2.3 Administration ......................................................................................................................................26
6.2.3.1 Run-in period (from Visit 1 to 2):...................................................................................................................26
6.2.3.2 Treatment period (from Visit 2 to Visit 3):.....................................................................................................27
6.2.4 Subject Training ...................................................................................................................................27
6.2.4.1
Training with In-check Dial...................................................................................................................27
6.3 PACKAGING...................................................................................................................................................27
6.3.1 Run-in packaging..................................................................................................................................27
6.3.2 Treatment kit packaging.......................................................................................................................28
6.4 LABELING......................................................................................................................................................28
6.5 TREATMENT ALLOCATION.............................................................................................................................28
6.6 TREATMENT CODE ........................................................................................................................................28
6.7 TREATMENT COMPLIANCE.............................................................................................................................28
6.8 DRUG STORAGE ............................................................................................................................................28
6.9 DRUG ACCOUNTABILITY...............................................................................................................................29
6.10 PROVISION OF ADDITIONAL CARE................................................................................................................29
7.
STUDY PLAN..............................................................................................................................................30
7.1 STUDY SCHEDULE.........................................................................................................................................30
7.1.1 Visit 0....................................................................................................................................................31

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7.1.2 Visit 1 (screening).................................................................................................................................31
7.1.3 Visit 2....................................................................................................................................................32
7.1.4 Visit 3....................................................................................................................................................33
7.1.5 Follow-up visit......................................................................................................................................33
7.1.6 Early termination visit..........................................................................................................................33
7.2 INVESTIGATIONS ...........................................................................................................................................33
7.2.1 Multidetector Computed Tomography (MDCT) and FRI endpoints....................................................34
7.2.1.1
Specific Airway Volume (siVaw)..........................................................................................................34
7.2.1.2
Specific Airway Resistance (siRaw)......................................................................................................34
7.2.1.3
Ventilation mapping...............................................................................................................................35
7.2.1.4
Perfusion mapping .................................................................................................................................35
7.2.1.5
Airway wall thickness............................................................................................................................35
7.2.1.6
Lung and lobar Volume (iVlung and iVlobe)........................................................................................35
7.2.1.7
Air trapping............................................................................................................................................36
7.2.1.8
Low attenuation score (LAS).................................................................................................................36
7.2.1.9
Percentile 15th (PD15)...........................................................................................................................36
7.2.1.10
Regional lung deposition .......................................................................................................................36
7.2.2 Vital signs: Blood pressure ..................................................................................................................36
7.2.3 Blood and urine sample collection for safety laboratory test ..............................................................36
7.2.4 Body plethysmography .........................................................................................................................37
7.2.5 COPD Assessment Test (CAT) .............................................................................................................38
7.2.6 Spirometry ............................................................................................................................................38
7.2.7 Diary Card............................................................................................................................................40
8.
EFFICACY ASSESSMENTS.....................................................................................................................40
9.
SAFETY ASSESSMENTS..........................................................................................................................41
10.
ADVERSE EVENT REPORTING............................................................................................................41
10.1 DEFINITIONS................................................................................................................................................41
10.2 EXPECTEDNESS ...........................................................................................................................................42
10.3 INTENSITY OF ADVERSE EVENT ..................................................................................................................42
10.4 CAUSALITY ASSESSMENT............................................................................................................................43
10.5 ACTION TAKEN WITH THE STUDY DRUG DUE TO AN AE ..............................................................................43
10.6 OTHER ACTIONS TAKEN...............................................................................................................................43
10.7 OUTCOME....................................................................................................................................................43
10.8 RECORDING ADVERSE EVENTS ...................................................................................................................44
10.9 REPORTING SERIOUS ADVERSE EVENTS TO CHIESI.....................................................................................44
10.10 REPORTING SERIOUS ADVERSE EVENTS TO REGULATORY AUTHORITIES/ETHICS COMMITTEES..............45
10.11 GENERAL NOTES.......................................................................................................................................45
11.
DATA MANAGEMENT.............................................................................................................................46
12.
STATISTICAL METHODS.......................................................................................................................47
12.1 SAMPLE SIZE...............................................................................................................................................47
12.2 POPULATIONS FOR ANALYSIS ......................................................................................................................47
12.3 STATISTICAL ANALYSIS...............................................................................................................................47
12.4 DESCRIPTIVE STATISTICS............................................................................................................................47
12.5 MISSING DATA.............................................................................................................................................47
12.6 SUBJECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................................................47
12.7 EFFICACY VARIABLES .................................................................................................................................47
12.8 SAFETY VARIABLES.....................................................................................................................................48
12.9 INTERIM ANALYSIS......................................................................................................................................49
13.
ETHICS COMMITTEE APPROVAL......................................................................................................49
14.
REGULATORY REQUIREMENTS.........................................................................................................49
15.
INFORMED CONSENT.............................................................................................................................49
16.
SOURCE DOCUMENTS/DATA...............................................................................................................49
16.1 RECORDING OF SOURCE DATA.....................................................................................................................49

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16.2 DIRECT ACCESS TO SOURCE DOCUMENT/DATA............................................................................................50
17.
STUDY MONITORING.............................................................................................................................50
18.
QUALITY ASSURANCE...........................................................................................................................50
19.
INSURANCE AND INDEMNITY.............................................................................................................50
20.
CONFIDENTIALITY.................................................................................................................................50
21.
PREMATURE TERMINATION OF THE STUDY ................................................................................51
22.
CLINICAL STUDY REPORT...................................................................................................................51
23.
RECORD RETENTION.............................................................................................................................51
24.
PUBLICATION OF RESULTS .................................................................................................................51
25.
REFERENCES ............................................................................................................................................51
APPENDIX 1 - APPROVAL OF THE PROTOCOL BY CLINICAL INVESTIGATOR(S).......................54
APPENDIX 1 - APPROVAL OF THE PROTOCOL BY CLINICAL INVESTIGATOR(S).......................55
APPENDIX 2 - INSTRUCTION FOR USE OF IN-CHECK DIAL ................................................................56

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1.
INTRODUCTION
1.1 Background information
Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable 
disease that is characterised by persistent respiratory symptoms and airflow limitations that are 
due to large, small airways and/or alveolar abnormalities usually caused by significant exposure 
to noxious particles or gases. The chronic air flow limitation that is characteristic of COPD is 
caused by a mixture of small airway disease (e.g., obstructive bronchiolitis) and parenchymal 
destruction (emphysema), the relative contributions of each vary from person to person. 
Chronic inflammation causes structural changes, such as narrowing of the small airways, and 
destruction of the lung parenchyma that leads to the loss of alveolar attachments to the small 
airways and decreases lung elastic recoil.
The goal of treatment is to slow disease progression and to control symptoms by recourse to 
both non-pharmacological (e.g., diet, smoking cessation, exercise, pulmonary rehabilitation, 
oxygen) and pharmacologic therapy.
Pharmacologic therapy for COPD is used to reduce symptoms, reduce the frequency and 
severity of exacerbations and improve exercise tolerance and health status. The mainstays of 
drug therapy used in stable COPD are inhaled bronchodilators (BDs) (β2-agonists, 
anticholinergics and less often theophylline). As the disease state progresses and exacerbations 
become frequent, inhaled corticosteroids (ICS) and oral phosphodiesterase-4 (PDE-4) 
inhibitors can be used in combination with long-acting bronchodilators. In some subjects who 
remain symptomatic on ICS/LABA or continue to experience  exacerbations despite treatment 
with an ICS/LABA or a LABA/LAMA, triple therapy with a combination of ICS with a long-
acting β2-agonist (LABA) and a long-acting muscarinic (M3) antagonist (LAMA) is 
recommended [1].
CHF 5993 is a fixed-dose triple combination (FDC) of three known active substances: an ICS 
(beclometasone dipropionate [BDP]), a LABA (formoterol fumarate [FF]), and a LAMA 
(glycopyrronium bromide [GB]), first formulated to be delivered via a pressurised metered dose 
inhaler (pMDI) [2]. 
CHF 5993 was first granted marketing authorisation in 2017 by the European Commission for 
the treatment of COPD (Trimbow® 100/6/12.5 μg pressurised inhalation solution). Following 
indication extension authorised in January 2019, the current authorised indication is 
“maintenance treatment in adult subjects with moderate to severe COPD who are not 
adequately treated by a combination of an ICS and a LABA or a combination of a LABA and a 
LAMA” [3]. The authorised posology is two inhalations twice a day for a total daily dose of 400 
μg BDP, 24 μg FF, and 50 μg GB. 
Three 12-month Phase III/IIIb studies have formed the basis of the EMA-approved indication,
generating evidence of the superior efficacy of CHF 5993 over different comparators that were 
representative of the main therapeutic classes deployed in the COPD treatment paradigm 
(Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2019): TRILOGY, TRINITY, 
and TRIBUTE, [4], [5], [6].
The NEXThaler® device is currently marketed in Europe for the administration of Chiesi’s 
fixed dose ICS/LABA combination CHF 1535 (BDP/FF) 100 μg/6 μg dry powder inhaler 
(Foster® NEXThaler® and other tradenames). It contains extra fine formulations of 
Beclometasone Dipropionate Anhydrous (BDP) at 100 μg, and Formoterol Fumarate Dihydrate 
(FF) at 6 μg [3].

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Chiesi has developed a dry powder formulation of CHF 5993 (BDP/FF/GB) using the same 
NEXThaler device, and on 29 January 2021 has received a positive CHMP opinion for the same 
COPD indication as the pMDI.
Currently, the bulk of the clinical evidence with CHF 5993 has been generated with the pMDI 
formulation, and there is a need for evidence specific to the DPI formulation, especially in 
patients who are currently using a DPI for their COPD and who may benefit from a step-up to 
triple therapy using a DPI device. 
In this proposed study, the aim is to explore the changes in peripheral airway volume, resistance, 
lobar ventilation and the regional deposition of BDP/FF/GB DPI in subjects with moderate to 
severe COPD by means of Functional Respiratory Imaging (FRI), which is a validated 
technology alternative to the gold standard technology of lung scintigraphy. FRI uses a three-
dimensional (3D) airway model and computational fluid dynamics (CFD) to simulate changes 
within airways and predict delivery of therapeutic aerosols from extra-thoracic all the way to 
alveolar region by integrating the effects of device characteristics, aerosols formulations (i.e. 
mass median aerodynamic diameter or MMAD, fine particle dose or FPD), inhalation duration, 
and specific subject’s airway geometry. Upper Airway (UA) CT scan is performed at V2 (pre-
dose). The inter-subject small airway variability is also accounted for by this technology by 
using 4 low dose thorax CT scans obtained at 2 respiratory levels (inspiration and expiration), 
before and after a treatment [7]. 
1.2 Study rationale
 Chronic obstructive pulmonary disease is an umbrella term for conditions including 
emphysema, chronic bronchitis, and sometimes prominent small airway disease (SAD). The 
pathological effects of SAD contribute to the evolution of airway obstruction in subjects with 
COPD [8], and quantifying the regional bronchodilation effects of therapeutic aerosols at 
peripheral airway levels, their central and peripheral deposition, and the changes in lung 
ventilation is key in subjects with COPD and small airways dysfunction.
Unfortunately, spirometry is not suitable to differentiate large from small airway obstruction. 
Thus, evaluating the small airways has been better achieved by means of morphologic-
functional comparisons [9]. 
Nowadays, quantitative computed tomography (CT) of the chest affords us detailed imaging 
that enables accurate measurement of airway thickness, diameter, volume, as well as regional 
(central and distal) ventilation and perfusion patterns. This technology can be highly useful 
when characterizing the effects of various pharmacotherapies on the lung and enables a 
pathophysiologic correlation with subjects’ perception of respiratory symptoms [10]. 
Probing the effects of therapeutic aerosols which deliver extra fine particles that target the small 
airways and the measurement of the therapeutic aerosol regional deposition in individual 
subject’s airway geometry is now possible by implementing dedicated airway modelling and 
CFD techniques based on CT scan airway geometry measurements [11]. Briefly, the 3D 
reconstruction of the pharynx, trachea, and bronchial tree is obtained after the acquisition of 
inspiratory and expiratory chest CT scans by using a new generation low dose multi-detector 
scanner. It also allows measurement of many signatures of airway physiology such as extent of 
emphysema, airway wall thickness, lobar and segmental volumes and internal airway 
dimensions. The ensuing CFD analysis provides the ability to simulate flow in the individual 
subjects’ airway geometry, and to estimate the regional deposition of therapeutic aerosols in 
the lung of subjects based on each aerosol particle’s dimensions and subject’s outflow boundary 

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conditions. By repeating measurements after an intervention, this approach yields a 
personalised assessment of changes in airway volume and CFD-based resistance. 
A recently published FRI simulation study [12] compared the lung deposition of ICS, LABA 
and LAMA components from two fixed-dose triple inhaled therapies, Trimbow® 
(BDP/FF/GB), a pMDI delivering extra fine particles and Trelegy® Ellipta® (FluF/VI/UMEC) 
a DPI delivering non-extra fine particles. The results showed a higher peripheral (small airways) 
deposition of all three components (ICS, LABA, and LAMA) with BDP/FF/GB) pMDI than 
with FluF/VI/UMEC DPI, based on profiles from patients with moderate to very severe COPD. 
This finding is consistent with the extra fine particle engineering of BDP/FF/GB pMDI. Other 
studies have shown that FRI could be used to assess the acute bronchodilation effects of 
therapeutic FDC aerosols delivered via pMDI device in asthma [13] and COPD [14], [15], while 
information available with DPI is limited to date. 
Therefore, this study aims to explore the effect of stepping up symptomatic subjects with COPD 
from non-extra fine ICS/LABA (FP/SLM) fixed-dose combination to extra fine 
ICS/LABA/LAMA 
(BDP/FF/GB) 
fixed-dose 
combination 
on 
peripheral 
airway 
bronchodilation and peripheral aerosol deposition. Both products will be delivered via a DPI 
device (NEXThaler® for BDP/FF/GB and (DISKUS™), for FP/SLM) where spray 
aerosolization is accomplished by a subject-generated flow rate which induces shear 
fluidization of the active pharmacological ingredient particles aggregated to carrier particles 
such as lactose [16]. 
We chose to use FRI technology to prospectively explore the changes over baseline airway 
dimensions and resistances, lobar ventilation, and aerosol particle deposition to peripheral 
airways by allowing for device characteristics and subjects’ specific flow boundary conditions 
in an open label study design [17]. 
The rationale for the 6-week treatment duration on extra fine BDP/FF/GB DPI is supported by 
a prospective pharmacology study by Montuschi et al. [18], showing that a short-term (4-week) 
treatment with extra fine beclomethasone/formoterol (100/6 µg b.i.d) in patients who previously 
were on an 8-week maintenance treatment with fluticasone dipropionate/salmeterol (500/50 µg 
b.i.d) was associated with different breath-prints compared with regular fluticasone 
propionate/salmeterol. This signals that a differential effect on airway inflammation may be 
detected in as little as a 4-week time following a switch from a fine high-dose ICS regimen to 
an extra fine medium-dose ICS treatment. The rationale for the total daily dose selection of 
FP/SLM (1000/100 µg) and BDP/FF/GB (400/24/50 µg) is based on the approved label of 
SERETIDE™ DISKUS™ and the proposed label for CHF5993 DPI for the treatment of COPD, 
respectively. This indeed means that treatment with FP/SLM would result in exposure to high-
dose of ICS whereas treatment with BDP/FF/GB would deliver exposure to a medium-dose 
ICS. This approach avoids off-label use of these products and will help to investigate if 
switching from a maintenance treatment with a high-dose non-extra fine ICS-containing 
ICS/LABA combination (FP/SLM) to a medium-dose extra fine ICS-containing formulation 
(BDP/FF/GB) would result in a different bronchodilation effects at peripheral airway level.
Furthermore, the additive effect of the LAMA component to ICS/LABA has been studied in a 
52-week randomized controlled trial conducted with pMDI [4] device, with peak effect on FEV1 
evident within 4 weeks of treatment initiation. The effect at 4 weeks was consistent also for 
DPI device [19].

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The presence of lung hyperinflation based on the increase of Total Lung Capacity (TLC) 
exceeding either the upper limit of normal (ULN) or an empiric 120% of predicted, and/or an 
increase in plethysmographic functional residual capacity (FRC) above either ULN or 120 % 
of predicted [20] are also desirable screening characteristics among the study participants, 
because the additive effect of a LAMA in combination with LABA in terms of improving 
hyperinflation is well documented in patients with COPD and lung hyperinflation [21].   
1.3 Risk/benefit assessment
Current risks that have been identified for the BDP/FF/GB (100/6/12.5 µg) combination are 
based on known pharmacology of the individual active components BDP, FF, and GB, and they 
can be found in the Investigation Brochure (IB). These include risks of pneumonia, 
oropharyngeal candidiasis, and bone disorders/fractures from ICS-containing combinations, 
and the risk of adverse cardiovascular effects from LAMA and LABA-containing 
combinations. 
In this study, both FP/SLM (SERETIDE™ DISKUS™), and BDP/FF/GB (CHF5993) are both 
approved for the maintenance treatment of COPD. 
A significant advantage of a single inhaler triple therapy in COPD is convenience for the 
subjects as this reduces the need for using separate inhalers that are often of a differing type 
and therefore need to be used differently [22]. This is critical since most symptomatic subjects 
(CAT score >10) with COPD show poor adherence with regular inhaled therapy [23]. 
The main rationale for the development of CHF 5993 DPI is to make the extra fine single -
inhaler triple therapy option (BDP/FF/GB) available for patients who prefer the use of a DPI, 
or who are unable to use a pMDI correctly.
This trial will be conducted in compliance with the Declaration of Helsinki (1964 and 
amendments) current ICH E6 Good Clinical Practices and all other applicable laws and 
regulations.
2.
STUDY OBJECTIVES
2.1 Primary Objective(s)
To assess the effect of stepping-up from FP/SLM DPI (SERETIDE™ DISKUS™) to extra fine 
BDP/FF/GB DPI (CHF5993) on airway geometry and lung ventilation. 
2.2 Secondary Objective(s)
To assess therapeutic aerosol particles deposition and lung function following a switch from 
FP/SLM DPI (SERETIDE™ DISKUS™) to extra fine BDP/FF/GB DPI (CHF5993).
3.
STUDY DESIGN 
This is a multicenter, open-label, single arm study.
After the screening visit that will be performed 6 weeks ± 2 days before Visit 2, eligible subjects 
will undergo a 6 weeks run-in period with FP/SLM 500/50 µg (SERETIDE™ DISKUS™). 
At the end of the run-in period (Visit 2), subjects will be switched to the treatment period with 
BDP/FF/GB DPI (CHF5993) for 6 weeks (until Visit 3). 

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The end of the trial is defined as the last visit/last call of the last subject in the trial.
4.
SUBJECT SELECTION CRITERIA
4.1 Subject Recruitment
No formal sample size calculation has been performed since the nature of the study (i.e., 
exploratory study).
30 subjects will be enrolled in the study in order to have at least 25 completed subjects.
4.2 Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the 
study:
1. Subject’s signed Informed Consent Form obtained prior to any study-related procedure;
2. Male or female ≥ 40 years of age;
3. Current smokers or ex-smokers of at least 10 pack-years, calculated as (number of 
cigarettes/day * number of years)/20. (E-cigarettes smoking cannot be used to 
calculate pack-year history);
4. Established diagnosis of COPD according to the 2020 GOLD Report, prior to the 
Screening visit (V1);
5. Post-BD FEV1/FVC < 0.7 and FEV1 ≤ 60% of predicted at V1 (Note: if the criterion is 
not met at screening, the measure can be repeated once before run-in day 1); 
6. On a stable dose any non-extra fine ICS/LABA DPI twice daily regimen for at least 8 
weeks before screening;
7. Presence of lung hyperinflation based on the increase of Total Lung Capacity (TLC) 
exceeding either the upper limit of normal (ULN) or an empiric 120% of predicted, 
and/or a plethysmographic functional residual capacity (FRC) exceeding either ULN 
or 120 % of predicted;   
8. Symptomatic subjects with CAT score ≥ 10 at V1 and V2;
9. Documented history of ≥ 1 moderate or severe COPD exacerbation in the previous 12 
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10. To have a cooperative attitude and the ability to be trained and use correctly the Dry 
Powder Inhalers (DPI);
11. To have a cooperative attitude and the ability to perform the required outcomes 
measurements (e.g. spirometry manoeuvres in sitting and supine position) and the 
ability to understand the risks involved;
12. WOCBP fulfilling one of the following criteria: 
a.
WOCBP with fertile male partners: they and/or their partner must be willing to 
use a highly effective birth control method from the signature of the informed 
consent and until the follow-up visit or
b. WOCBP with non-fertile male partners (contraception is not required in this 
case).
13. Female subjects of non-childbearing potential defined as physiologically incapable of 
becoming pregnant (i.e. post-menopausal or permanently sterile; e.g. amenorrhea for 
≥12 consecutive months without alternative medical cause). Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  If 
indicated, as per investigator’s request, post-menopausal status may be confirmed by 
follicle-stimulating hormone levels (according to local laboratory ranges).
For the purpose of this document, a woman is considered of childbearing potential, i.e. fertile, 
following menarche and until becoming post-menopausal unless permanently sterile.
For the purpose of this document, a man is considered fertile after puberty unless permanently 
sterile by bilateral orchidectomy.
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test.
For the purpose of this document, methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly are considered as highly effective birth control 
methods. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation:
o
oral
o
injectable
o
implantable

intrauterine hormone-releasing system (IUS) 

intrauterine device

bilateral tubal occlusion/ligation

vasectomized partner

sexual abstinence

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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.
For the purpose of this document 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 
[24]. 
4.3 Exclusion Criteria
The presence of any of the following will exclude a subject from study enrolment: 
1. Pregnant or lactating woman;
2. Exacerbations defined as a sustained and acute deterioration of subject’s symptoms and 
signs (dyspnoea, cough and/or sputum production/purulence) that are either moderate, 
i.e. require treatment with systemic (oral/IV/IM) corticosteroids and/or antibiotics, or 
severe, i.e. require hospitalization, if their associated treatment/hospitalization occurred 
within the 30 days before V1 (or 4 weeks in case the event was treated with just systemic 
corticosteroids) or if the event is recorded during the run-in period;
3. A current asthma diagnosis;
4. Respiratory disorders other than COPD: subjects with known respiratory disorders other 
than COPD that in the Investigator's opinion would affect efficacy and safety evaluation 
or place the subject at risk. This can include but is not limited to known α1-anti-trypsine 
deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary 
hypertension and interstitial lung disease;
5. Cardiovascular diseases: subjects who have known clinically significant cardiovascular 
conditions such as but not limited to: unstable or acute ischemic heart disease within 
one year prior to study entry, NYHA class IV heart failure, history of atrial fibrillation, 
history of sustained and non-sustained cardiac arrhythmias diagnosed within 6 months 
prior to study entry and not controlled with therapy according to the investigator’s 
opinion;
6. Evidence or history of other concurrent disease  such as but not limited to 
hyperthyroidism, diabetes mellitus or other endocrine disease; haematological disease; 
autoimmune disorders (e.g. rheumatoid arthritis), significant renal impairment, 
significant neurological disease 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 interpretation of the study;
7. Medical history or current diagnosis of narrow-angle glaucoma, clinically relevant 
prostatic hypertrophy or bladder neck obstruction that in the opinion of the Investigator 
would have prevented use of anticholinergic agents;
8. History of lung transplant or lung reduction surgery;
9. ECG criteria: any clinically significant abnormal 12-lead ECG that in the investigator's 
opinion would affect efficacy or safety evaluation or place the subjects at risk. Male 
subjects with a QTcF > 450msec and female subjects with a QTcF > 470msec at V1 are 
not eligible;
10. Laboratory abnormalities: subjects with clinically significant laboratory abnormalities 
indicating a significant or unstable concomitant disease that might, in the judgement of 

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the investigator, place the subject at undue risk or potentially compromise the results or 
interpretation of the study;
11. Alcohol/drug abuse: subjects with a known or suspected history of alcohol and/or 
substance/drug abuse within 12 months prior to screening; or having a positive drug test 
at screening or V2;
12. Participation in investigational trial: subjects who have received any investigational 
drug within the 30 days or a more appropriate time as determined by the investigator 
(e.g. approximately 5 half-lives of the investigational drug, whatever is longer);
13. Contra-indications to IMPs, based on investigator judgement;
14. 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;
15. Subjects mentally or legally incapacitated or subjects accommodated in an 
establishment as a result of an official or judicial order;
16. Documented COVID-19 diagnosis or its complications which have not resolved within 
14 days prior to screening; 
17. Positive molecular COVID-19 test within the last 72 hours before the remaining of 
screening activities.
4.4 Subject Withdrawals
Subjects must be discontinued from the study for any of the following reasons:

An adverse event occurs that, in the opinion of the investigator, makes it unsafe for 
the subject to continue in the study. In this case, the appropriate measures will be 
taken

The subject is lost to follow-up

The subject withdraws consent

The subject's safety is affected by violation of inclusion or exclusion criteria or use 
of not-permitted concomitant medication

The subject is unwilling or unable to adhere to the study requirements, i.e., non-
compliance

The sponsor or the regulatory authorities or the Ethics Committee(s), for any reason, 
terminates the entire study, or terminates the study for this trial site or this particular 
subject

The subjects experienced a COPD exacerbation

Positive COVID-19 molecular test

Pregnancy 
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.

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In case of early withdrawal (except if the reason is lost to follow-up or consent withdrawal and 
subject is not willing to perform an early termination visit), an early termination visit will be 
performed 7 days after the last intake of the study drug.  
In case of withdrawal, the Investigator must fill in the “Study Termination” page in the eCRF, 
reporting the main reason for withdrawal.
If a subject is withdrawn/drops-out of the study after receiving the test treatment, the subject 
study number and corresponding test treatments should not be reassigned to another subject.
5.
CONCOMITANT MEDICATIONS
5.1 Permitted concomitant Medications
Inhaled salbutamol administered as rescue medication. A minimum period of 6 hours 
has to elapse between the use of rescue salbutamol and the Spirometric measurements
Anti-histamines (oral, intranasal, ocular) and intranasal corticosteroids (INS) for the 
treatment of allergy or rhinoconjunctivitis symptoms; Oral Xanthine derivatives (e.g. 
Theophylline) if taken at stable regimen for at least 1 month prior to screening and to 
be maintained constant during the study
Nocturnal Oxygen Therapy (NOT) with HbO2 saturation ≥ 90% at rest
Ambulatory Oxygen Therapy (AOT) with HbO2 saturation ≥ 90% at rest
Non-Invasive Positive Pressure Ventilation (NIPPV) with diurnal HbO2 saturation ≥ 
90% at rest and at Investigator’s discretion
Short courses (≤ 10 days) of nasal corticosteroids (maximum 4 courses) are allowed 
during the treatment period
In case of a concomitant disease any appropriate treatment not interfering with the study 
evaluation parameters is allowed
Paracetamol (maximum 2 g per day with a maximum of 10 g per 14 days)
5.2 Non-permitted concomitant Medications
Long Term Oxygen Therapy (LTOT) prescribed for severe arterial hypoxemia, with 
HbO2 saturation ≤ 90% at rest
Depot corticosteroids
Oral/parenteral/IM corticosteroids
Nebulized β2-agonists, anti-cholinergic and/or steroids 
ICS (pMDI and DPI)
Inhaled LABAs or fixed combination of corticosteroids and LABAs other than study 
treatments (e.g. salmeterol plus fluticasone or Formoterol plus budesonide)
Inhaled LAMAs
Inhaled SABAs (other than salbutamol as rescue medication)
Inhaled fixed combinations of a SABA and a SAMA

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Inhaled SAMAs (ipratropium and oxytropium)
Non-cardio-selective β-blockers
Tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin re-uptake 
inhibitors and other drugs known to prolong the QTc interval unless already taken at the 
time of screening
PDE-4 inhibitors (e.g. roflumilast)
Leukotriene modifiers
Non-potassium sparing diuretics (unless administrated as a fixed dose combination with 
a potassium conserving drug)
OTC medicines, homeopathic remedies, etc., in the 7 days before the screening visit and 
until the end of the study
Washout period prior to spirometry at Screening Visit:
Oral Xanthine derivates
72 hours
Inhaled ICS/LABA
12 hours
Systemic corticosteroids (oral, IM, IV)
4 weeks
Nasal corticosteroids
24 hours
Washout prior Visit 2 and Visit 3:
Rescue salbutamol
6 hours
6.
TREATMENT(S)
The study treatment CHF 5993 DPI and the run-in medication will be supplied to the clinical 
site under the responsibility of the Sponsor, who will also provide the Pharmacist/Investigator 
with appropriate certificates of analytical conformity.
6.1 Appearance and Content

CHF 5993 DPI NEXThaler® (Test product)
Active ingredients: Beclometasone Dipropionate (BDP) 100 μg/inhalation + 
Formoterol Fumarate (FF) 6 μg/inhalation + Glycopyrronium 
Bromide (GB) 12.5 µg/inhalation. 
Excipients: 
Lactose, Magnesium stearate. 
Presentation:
NEXThaler® inhaler containing 120 doses. 
Appearance: 
White inhaler with grey cover.

SERETIDE™ DISKUS™ (Run-in)  
Active ingredients: Fluticasone Propionate (FP) 500 μg/inhalation + Salmeterol 
Xinafoate (SLM) 50μg/inhalation.

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Excipients:
Lactose monohydrate.
Presentation: 
Each Diskus™ contains 60 doses.
Appearance: 
Moulded purple plastic device with a dose counter.
6.2 Dosage and Administration 
6.2.1 Selection of doses in the study
An inhaled dose of CHF 5993 DPI 100/6/12.5 μg (Total daily dose: BDP 400 μg / FF 24 μg / 
GB 50 μg) was selected for the current study as it corresponds to the therapeutic daily dose. 
6.2.2 Dosage
CHF 5993 (BDP/FF/GB 100/6/12.5 μg per inhalation) DPI: 
Two inhalations bid: 4 inhalations; total daily dose of 400/24/50 μg BDP/FF/GB. 
6.2.2.1 Run-in period
SERETIDE™ DISKUS™ 500/50 μg
1 inhalation b.i.d (Total daily dose: FP 1 mg / SLM 100 µg)
6.2.2.2 Treatment period:
CHF 5993 DPI 100/6/12.5 µg 
2 inhalations b.i.d (Total daily dose: BDP 400 µg / FF 24 µg / GB 50 µg)
6.2.3 Administration
To the extent possible, the time of dosing of study medication must remain constant for each 
subject for the whole duration of the study.
All previous COPD medications will have to be withdrawn during the course of the study except 
as described in section 5.
6.2.3.1 Run-in period (from Visit 1 to 2):
At Visit 1 (screening visit), each eligible subject will receive the medication to cover the 6-
week run-in period:
Two commercial boxes containing one Diskus™ device of FP 500 µg / SLM 50 µg.
The administration will be b.i.d:
 1 inhalation in the morning and 1 inhalation in the evening from the same device.
Note: the first dose of run-in medication must be administered at clinic site at the end of Visit 
1.
Since the run-in period lasts 6 weeks, the administration will occur using 2 commercial devices: 
when the first Diskus™ is empty the subject will start to use the second with the same posology.

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6.2.3.2 Treatment period (from Visit 2 to Visit 3):
At Visit 2 each subject will receive 1 box with the study drug. The box contains 2 
NEXThaler® dry powder inhaler of CHF 5993 100/6/12.5 µg.
The study drug will be administered twice-a-day (in the morning and in the evening):
Morning administration (preferably at 8 am).
2 inhalations from NEXThaler® inhaler.
Evening administration (preferably at 8 pm).
2 inhalations from the same NEXThaler® inhaler used in the morning. 
The first administration of study drug will take place at clinic/hospital during the second 
visit.
Since the treatment period lasts 6 weeks, the administration will occur using 2 devices of DPI 
for each subject that will cover the entire period. 
Each inhaler and aluminium pouches are numbered 1 or 2 respectively. This indicates the order 
in which the aluminium pouches and inhalers will be used.
Subject will inhale four puffs a day (two puffs in the morning and two puffs in the evening) 
from the inhaler numbered 1, until the dose counter shows the number 0. When the first DPI is 
empty the subject will start to use the inhaler numbered 2 with the same posology.
6.2.4 Subject Training
6.2.4.1 Training with In-check Dial
All subjects should be well trained in the inhalation technique with In-check Dial at screening 
to familiarize with inhalation technique, in the attempt to yield repeatable inhalations.
During the V1 (screening) all subjects will be trained on the proper use of Seretide Diskus and 
CHF 5993 NEXThaler® by using In-Check DIAL.
During the training 2 different assessment will be performed: one set for Diskus™ resistance, 
and the second set for NEXThaler. The obtained successful PIF value (at least 30 L/min) will 
be recorded in the eCRF.
By comparing the subject's results and the “optimum” results, as reported in figure 10 
of Appendix 2, subjects can be trained to use their inhaler properly, continuing to use the same 
inspiratory flow rate while inhaling the study drug.
See Appendix 2 for instructions on how to use the In-Check Dial.  
6.3 Packaging 
All investigational products will be prepared in accordance with Good Manufacturing Practices 
(GMP) as required by the current Good Clinical Practices (GCP).
6.3.1 Run-in packaging
The run-in kit will consist of: 

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Primary packaging: 1 Diskus™ inhaler containing blisters of FP 500 µg / SLM 50 µg as 
powder for inhalation.
Secondary packaging: 1 commercial box containing 1 Diskus™ inhaler.
6.3.2 Treatment kit packaging
The treatment kit will consist of: 
Primary packaging: 2 NEXThaler® inhalers
Secondary packaging: 2 pouches containing 1 NEXThaler® inhaler each
Tertiary packaging: 1 box containing 2 pouches containing 1 NEXThaler® inhaler each
Each inhaler and aluminium pouches are numbered 1 or 2 respectively. This indicates the order 
in which the aluminium pouches and inhalers will be used.
6.4 Labeling 
All the supplies will be labelled in local language and according to Annex 13 to the Volume 4 
of the GMP as well as to local law and regulatory requirements.
6.5 Treatment allocation
All subjects will be administered with CHF 5993 DPI according to a non-randomized, open-
label design.
6.6 Treatment Code
This is an open-label, non-randomized study.
6.7 Treatment compliance
Compliance will be evaluated on the basis of the information recorded daily by the subject on 
the diary card.
The evaluation of compliance will be done using the following formula:
The total number of scheduled doses will be calculated on the basis of the extent (days) of 
exposure of each subject. A range 75-125 % will be taken into account for a satisfactory level 
of compliance.
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.
Run-in medication:
The box of Seretide™ Diskus™ used as study medication for the run-in period must not be 
stored above 30°C by Pharmacist/Investigator at the Hospital.
DRUG
ED
ADMINISTER
OF
%
100
DOSES
SCHEDULED
OF
NUMBER
TOTAL
DOSES
ED
ADMINISTER
OF
NUMBER
TOTAL



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Once dispensed the subjects will be instructed to keep the boxes at home at ambient temperature 
not above 30°C.
Treatment kits:
NEXThaler® inhaler prepared with CHF 5993:
-
Pouched inhaler: Store below 25°C; 
-
Unpouched inhaler: A maximum period of 6 weeks and stored in a dry place, below 
25°C is considered suitable for the unpouched inhaler. 
The use-by date shall therefore correspond to the dispensing date plus 6 weeks (42 days). 
Please note that the use-by-date must not exceed the total shelf life of the product. 
For pharmacist or investigator:
At clinic visits, remove the inhaler number 1 from the pouch number 1 and write the use-by-
date on the appropriate section on the label of pouch number 1.  
For the subject:
The remaining pouched inhaler number 2 must be opened at home. When the pouch number 
2 is opened, please write the use-by-date on the appropriate section of the pouch. The 
handwritten use-by date must not exceed the total shelf life of the product.
6.9 Drug Accountability
The Investigator, or the designated/authorized representative, is responsible for the 
management of all the study medications to be used for the study. Study medications that should 
be stored in a locked, secure storage facility with access limited to those individuals authorized 
to dispense the study medications.
An inventory will be maintained by the Investigator or pharmacist (or other designated 
individual), to include a signed account of all the study medication(s) received, dispensed and 
returned by each subject during the trial 
At the conclusion or termination of the study, the Investigator or the pharmacist shall conduct 
and document a final drug supply (used and unused) inventory. An explanation will be given 
for any discrepancies.
All the study medications supplied, used or unused, will be returned to Chiesi or to the 
designated CRO under Sponsor’s responsibility or destroyed directly from the Investigator by 
the centre. In this case, a destruction certificate must be asked to the investigational centre and 
filed both at site and at Sponsor. Return and destruction will not occur until authorized by 
Chiesi.
6.10 Provision of additional care
At completion of subject’s study participation, it is under the Investigator’s responsibility to 
prescribe the more appropriate treatment for the subject or to restore the initial therapy or to 
refer to the General Practitioner.

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7.
STUDY PLAN
7.1 Study Schedule
V0
Screening 
Visit
(V1)
-6weeks
Visit 2
6 weeks 
±2 days
Visit 3
6 weeks 
±2 days
Follow-up
2 weeks ±2 
days
Informed consent form

Medical history

Incl/Excl criteria check 
and/or confirmation


Demographic data

Vital 
Signs 
(blood 
pressure)1



*
Hematology 
and 
Chemistry2

Serology

COVID-19 test3



*
Physical examination4


*
Local safety ECG5

Training 
with 
In-check 
dial

Urinalysis

Urine pregnancy test6



*
Urine sample for drug test7


Body plethysmography8



CAT test



Spirometry9



Drug intake10



MDCT11


Diary dispensation12


Diary collection13


Concomitant medication




Adverse events assessment




* A follow-up phone call will be done 14 days after Visit 3. For WOCBP the follow-up visit 
will occur 30 days after Visit 3
Footnotes for schedule of events:
1.
Vital signs (BP): duplicate measurements at screening for checking inclusion/exclusion 
criteria; At Visit 2, Visit 3 and at follow-up visit, if applicable. BP after at least 5 min rest 
in sitting or supine. Duplicate assessment with at least 5 min in between
2. The blood samples will be collected after overnight fasting (i.e. at least 10 h fasting, 
water allowed).
3.
COVID-19 test: a molecular swab at screening and serological test at V2, V3 and 
Follow-up (if applicable). In case a serologic test for COVID-19 antibodies is positive, 
a molecular test must be performed.
4.
Physical Examination: Full physical examination at screening visit for checking the 
inclusion/exclusion criteria; at Visit 3 and follow-up visit (if applicable). 
5.
Safety ECG (single ECG): At screening visit pre-dose for checking the inclusion/exclusion 
criteria; ECG will be always recorded after at least 5 minutes of resting in supine position

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6.
Pregnancy test: for WOCBP a urine pregnancy test to be performed at screening, Visit 2, Visit 
3 and at Follow-up visit 
7.
Urine drug screen: at screening visit for checking the inclusion/exclusion criteria and at Visit 
2. 
8.
Body plethysmography: at screening, at Visit 2 and Visit 3 pre-dose
9.
Spirometry: at screening pre- and post-bronchodilator, at Visit 2 and Visit 3 pre-dose between 
7:00 and 10:00 a.m. preferably
10. Drug intake: Run-in medication dispensation at screening, the first dose will be taken at 
investigational site at Visit 1 in the morning. Study drug dispensation at Visit 2. Morning dose 
of Visit 2 and Visit 3 will be taken at the investigational site.
11. MDCT: multi-slice with multidetector computed tomography (inspiratory at TLC and 
expiratory at FRC) will be performed pre-dose and within 60– 120 min post-dose at Visit 2 
and Visit 3 as detailed in section 7.2.1. At Visit 2, Upper airway will be also scanned at TLC, 
pre-dose. 
12. Diary: the paper subject diary will be dispensed at screening for the run-in medication and at 
Visit 2 for the IMP. Information on concomitant medications and adverse events occurrences 
and study drug intake will be recorded. Diaries will be checked by the Investigator at Visit 2 
and Visit 3.
7.1.1 Visit 0 
During this visit the informed consent form will be obtained and a deep explanation on future 
screening visit procedures will be performed (such as medication restrictions and fasting 
conditions).
7.1.2 Visit 1 (screening) 
For logistical reason, it is also possible that the screening procedures are spread over different 
days. The actual date of each assessment will be recorded in the eCRF.
The following procedures will take place at the clinical site:
The following procedures will take place before run-in medication dispensation:

Pre-dose duplicate vital signs (systolic and diastolic blood pressure) will be evaluated 
after 5 min in supine position (see section 7.2.2); 

Pre-dose full physical examination;

Pre-dose safety ECG (12-lead electrocardiogram) will be recorded after 5 min in supine 
position; 

Pre-dose training with In-check dial; 

Pre-dose urine pregnancy test on women of childbearing potential;

Pre-dose urine drug test (see section 7.2.3);

Pre-dose urinalysis (see section 7.2.3);

Pre-dose blood sampling for hematology and chemistry, and serology (see section 
7.2.3);

Molecular COVID test;

Pre-dose body plethysmography (panting followed by acceptable and repeatable 
expiratory vital capacity [EVC]) (see section 7.2.4);

Pre-dose COPD Assessment Test (CAT) (see section 7.2.5);

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
Pre- and post-bronchodilator spirometry (3 repeatable and acceptable FVC expiratory-
inspiratory maneuvers per the 2019 Standardization of Spirometry Update, An Official 
ATS and ERS Technical Statement [25]  (see section 7.2.6);

Check of Inclusion/Exclusion Criteria;

Demographic Data; 

Medical History;

Run-in medication dispensation. The first morning dose will be taken at the 
investigational site at Visit 1 (in case spirometry needs to be reperformed to assess 
inclusion criterion 5, the dispensation and first intake of run-in medication will occur in 
that occasion);

Run-in paper Diary delivery to subject and instruction (see section 7.2.7);

Concomitant medication;

AEs since the signature of the informed consent will be checked and recorded.
In case of any clinically relevant abnormality revealed during the physical examination or 
screening procedures, it will be recorded in the subject’s medical history, unless its start 
date is after the informed consent signature date and it is not due to a pre-existing condition. 
In this case, it will be recorded as an adverse event.
A new appointment will be planned in 6 weeks: subject will be asked to come same time in 
the morning. Instruction to be given to the subject: bring back run in medication, diary card, 
and respect the washout prior Visit 2.
7.1.3 Visit 2
For logistical reason, it is also possible that the Visit 2 procedures are spread over different days 
within the allowed time window.
V2 should occur no more than 44 days after the last assessment for screening visit is completed.
The washout period from not allowed concomitant medication should be checked before 
starting the Visit (Refer to section 5.2). If the washout has not been respected, the Visit can be 
rescheduled once.
The following procedures will take place at the clinical site before study drug administration:

Pre-dose Duplicate vital signs (systolic and diastolic blood pressure) will be evaluated 
after 5 min in supine position; 

Pre-dose urine pregnancy test on women of childbearing potential; 

Pre-dose urine drug test;  

Pre-dose serological COVID test;

Pre-dose body plethysmography;

Pre-dose spirometry;

Return diary check prior to dosing to assess the compliance during run-in and delivery 
of new diary; 

Check of Inclusion/Exclusion Criteria;

Pre-dose CAT test; 

Study drug dispensation and morning dose will be taken at the investigational site; 

Multi-slice with multidetector computed tomography (MDCT) (see section 7.2.1);

AEs and concomitant medications check and recording, if any.

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A new appointment will be plan in 6 weeks: subject will be asked to come same time in the 
morning. Instruction to be given to the subject: bring back medication, diary card, and 
respect the washout prior Visit 3.
7.1.4 Visit 3
For logistical reason, it is also possible that the Visit 3 procedures are spread over different days 
(2 days) within the allowed time window.

Pre-dose duplicate vital signs (systolic and diastolic blood pressure) will be evaluated 
after 5 min in supine position; 

Pre-dose full physical examination; 

Pre-dose urine pregnancy test on women of childbearing potential; 

Pre-dose Serological COVID test;

Pre-dose body plethysmography; 

Pre-dose spirometry;

Pre-dose CAT test;

Return diary check prior to dosing to assess the compliance during treatment period;

Study drug morning dose will be taken at the investigational site; 

Return of the dispensed inhalers;

Multi-slice with multidetector computed tomography (MDCT);

AEs and concomitant medications check and recording, if any.
7.1.5 Follow-up visit
A follow-up phone call will be done 14 days after Visit 3.
For WOCBP the follow-up visit will occur 30 days after Visit 3; the following procedures 
will be performed:

Duplicate vital sign;

Full physical examination;

A urine sample collection for pregnancy test; 

 Serological COVID test.
For both follow-ups, AEs and related concomitant medications check and recording, if any, 
including the status of any unresolved AE/SAE.
7.1.6 Early termination visit
During the Early termination visit the following procedures will take place:

Duplicate vital sign;

Full physical examination;

CAT test;

Spirometry. 
7.2 Investigations
The assessment should be performed following the order listed in the table below:
Pre-dose
Post-dose

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
Vital signs

Body-plethysmography

Spirometry

CAT

MDCT

MDCT
The exact time of each activity will be recorded in the eCRF. 
For both V2 and V3 assessments can be split over more than 1 day, however, Spirometry, Body 
plethysmography and MDCT must be performed on the same day.
7.2.1 Multidetector Computed Tomography (MDCT) and FRI endpoints 
Scan of the thorax multi-slice with multidetector computed tomography (inspiratory at TLC 
and expiratory at FRC) will be performed pre-dose and within 60– 120 min post-dose at Visit 
2 and Visit 3 At Visit 2, Upper airway will be also scanned at TLC, pre-dose.
Functional Respiratory Imaging (FRI) is a non-invasive quantification imaging methodology 
that provides detailed measurement, visualization, and evaluation of the lungs and airways, both 
regionally and in totality. FRI uses low-dose, high-resolution volumetric computerized 
tomography (CT) scans and quantitative imaging technology based on computational fluid 
dynamics (CFD) to model airflow and measure structural and functional characteristics of the 
respiratory system. FRI provides quantifiable measures of drug performance, contributing to 
clinical proof of concept and dose selection. A relative explanation of the FRI parameters that 
will be used as endpoints in this study is provided below.
The visible airway generations that comprise the lobes can vary over time. The airway related 
FRI measurements can thus be performed in two ways: 1) for each segment use all the 
generations visible at the particular study visit scan (“untrimmed”), or 2) for each segment use 
only generations of airways that are visible in the baseline scan and in the post scan 
(“trimmed”). For the two primary endpoints, the following approach will be used:
-
siVaw will be “untrimmed”
-
siRaw will be “trimmed”
7.2.1.1 Specific Airway Volume (siVaw)
The airways can be segmented up to the point where no distinction can be made between the 
intraluminal and alveolar air. This is where the airway diameter is around 1-2 mm, typically 
around the 7th-10th bifurcation, depending mainly on the disease state of the individual subject. 
From the resulting model, the central and distal airway volumes (iVaw) can be assessed at 
individual airways or in different regions. The distal airway volume is defined as the segmented 
airway volume starting from the 3rd bifurcation.
The specific Airway Volume as an FRI parameter is derived from the Airway Volume (iVaw). 
The specificity is calculated by dividing the airway volume with the lung volume. This way the 
airway volumes are normalized across subjects and become specific.
7.2.1.2 Specific Airway Resistance (siRaw)
The airway resistance (iRaw) is determined using Computational Fluid Dynamics (CFD). 
During the CFD calculations, the outflow to each lobe is adjusted iteratively for each subject to 
match the internal flow rate distributions obtained from the segmentation of the CT scans. As 
a result, iRaw accounts for the subject specific internal airflow distribution which might be 

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greatly altered by the lung disease. Hence, the airflow distribution in the CFD calculations 
reflects the airflow distribution as derived from the expansion of lung lobes from FRC to TLC. 
The iRaw is defined as the total pressure drop over an airway, divided by the flow rate through 
that airway.
The specific Airway Resistance as an FRI parameter is derived from the Airway Resistance 
(iRaw). The specificity is calculated by multiplying the airway resistances with the lung 
resistances. This way the airway resistances are normalized across subjects and become 
specific. Generally, when lung volumes (and thus airway volumes) increase, resistances 
decrease. 
7.2.1.3 Ventilation mapping
CT-based surrogates of regional ventilation, often referred to as ‘CT-ventilation maps’, are 
derived from pulmonary CT images acquired at different inflation levels, without the use of 
exogenous contrast, by assuming that regional changes in lung volume relate to regional 
ventilation.
7.2.1.4 Perfusion mapping
The blood vessel proportion can be measured using two thresholds, ultimately resulting in three 
categories: vessels less than 5mm2 in cross sectional area (BV5), vessels bigger than 5mm2 and 
less than 10mm2 in cross sectional area (BV5_10), and finally vessels bigger than 10mm2 in 
cross sectional area (BV10). These volumes are the combined volumes of the pulmonary 
arteries and veins, and because of variations in blood vessel volume based on overall body size, 
these measures are often expressed using the ratio of either BV5, BV5_10 or BV10 to TBV. 
This way each of the measures expresses the fraction of blood vessel caliber present in each 
category. Lower values in small vasculature (BV5 and BV5_10) suggest CT imaging evidence 
of vascular pruning, i.e. a smaller proportion of the blood vessel volume comprised of small 
peripheral pulmonary blood vessels. The BVX data is expressed as % of all regional blood 
vessel volume. BVXvol is the absolute volume, expressed in mL.
7.2.1.5 Airway wall thickness
This parameter consists of all visible tissue in the CT scan that encompasses the airway wall. 
The airway wall can typically be described to the same generation level as the volume 
description of the airway lumen. This is where the airway diameter is around 1-2 mm. This 
parameter will be described in multiple versions: the wall area as a percentage of the sum of 
wall area and airway area (WA%), as the square root of the wall area for a theoretical airway 
with an internal perimeter of 10 mm (Pi10), and as the wall area adjusted for BSA (Mosteller’s 
formula).
7.2.1.6 Lung and lobar Volume (iVlung and iVlobe)
Lobar Volume is an FRI-based ventilation parameter obtained by identifying and grouping 
voxels that represent the air in the lungs. The lung volume (L) can be determined from the scans 
at both FRC and TLC. During segmentation, identifying the fissure planes on the CT images 
and using these surfaces as cutting objects can separate lung lobes. This means that not only the 
total lung volume is determined, but also the volume of each lobe individually.

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7.2.1.7 Air trapping
Air trapping, also called gas trapping, is an abnormal retention of air in the lungs. FRI based air 
trapping is defined as all the intrapulmonary voxels with Hounsfield Units between -1024 and 
-850 using the expiratory scans at Functional Residual Capacity (FRC). 
7.2.1.8 Low attenuation score (LAS) 
The low attenuation areas on CT scans have been reported to represent emphysematous changes 
of the lung. Emphysema is a long-term, progressive disease of the lungs that primarily causes 
shortness of breath due to over-inflation of the alveoli. FRI-based emphysema calculations are 
defined as all the intrapulmonary voxels with Hounsfield Units between -1024 and -950 using 
the inspiratory scans at TLC.
7.2.1.9 Percentile 15th (PD15) 
The 15th percentile density (PD15) of the cumulative CT value distribution in HU indicates the 
HU value below which the lower 15% of all voxels are distributed. The percentile density (PD) 
can also be used to express emphysema.
7.2.1.10
Regional lung deposition
Regional aerosol deposition is determined by simulating the flow in the subject specific 
geometries using subject specific boundary conditions by means of CFD. While solving the 
flow equations, simultaneously particles are released in the flow and the force mass balance of 
the individual particles is determined through additional discrete phase computations. When a 
calculated particle trajectory intersects with the airway wall, the particle is trapped in that 
location. This allows for the determination of the regional concentration of inhaled aerosols and 
consequently the effective lung dose of inhaled medication as depicted in the figure below.
7.2.2 Vital signs: Blood pressure
Systolic and diastolic blood pressure will be measured after at least 5 min rest in sitting or 
supine position (for the same subject, the position must be consistent throughout the whole 
study). Duplicate BP measurements will be performed within a time window of 2 to 5 minutes 
between each measurement. Vital signs may be repeated at the discretion of the investigator for 
the purposes of safety or to confirm eligibility. If the investigator performed more assessments 
than expected a comment in the eCRF must be included.
In eCRF the single measurements and the average of duplicate blood pressure measurements 
will be recorded.
7.2.3 Blood and urine sample collection for safety laboratory test
The blood samples will be collected after overnight fasting (i.e. at least 10 h fasting, water 
allowed).
If the subjects attend the screening visit not in fasting conditions, laboratory test will be 
performed on another day within the allowed time window.
The following blood samples will be collected during the study by venipuncture:

5-mL sample at screening for clinical chemistry 

2-mL sample at screening for clinical haematology 

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
2-mL sample at screening for serology
Clinical hematology and chemistry:
The following parameters will be assessed in blood by a local laboratory:

Routine haematology: red blood cells count (RBC), white blood cells count (WBC) and 
differential count (absolute value and %), total haemoglobin (Hb), haematocrit (Hct), 
platelets count (PLT).

Blood Chemistry: creatinine, BUN (If BUN cannot be assessed it is acceptable that 
carbamide will be assessed instead), glucose (fasting), phosphate, aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase 
(ALT), 
gammaglutamyl 
transpeptidase (γ-GT), total bilirubin, alkaline phosphatase, total cholesterol, 
triglycerides and sodium, potassium, calcium.
FSH (if applicable): serum FSH levels may be indicated, as per investigator’s request, to 
confirm the post-menopausal status in female participants
Clinical serology:
The following parameters will be assessed in blood by the local laboratory:

Human Immunodeficiency Virus Antibody (Ab-HIV1 and 2), Hepatitis B Surface 
Antigen (HBsAg), hepatitis B core antibody (anti-HBc) and Hepatitis C Virus Antibody 
(Ab-HCV) 

COVID-19 (IgG, IgM)
Mid-stream urine sample of about 10 mL will be collected at screening for urinalysis, for drug 
test and pregnancy test (if applicable); at pre-dose on Visit 2 for drug test and pregnancy test 
(in women of childbearing potential) and at each subsequent Visit for pregnancy test in women 
of childbearing potential. Urine samples will be done by a local laboratory.
Urinalysis:
The following parameters will be assessed in urine by the local laboratory:

pH, specific gravity, proteins, glucose, ketones, bilirubin, nitrites and microscopic 
examination of the sediment (casts, erythrocytes, leucocytes).
Urine drug screen:

cannabinoids, opiates, cocaine, benzodiazepines, amphetamines, morphine, barbiturates 
and urine cotinine test. 
Blood collection and sample preparation will be performed according to procedures provided 
by the local laboratory which will be in charge of transmitting the results to the Investigator for 
entry in the eCRF. The normal ranges will be provided by the local laboratory and included into 
e CRF.
7.2.4 Body plethysmography
Body plethysmography is a well-established technique of lung function determination, 
providing measures of the lung that reflect a multitude of functional and structural aspects. 
It is an alternative method of measuring lung volume that takes advantage of the principle of 
Boyle's law, which states that the volume of gas at a constant temperature varies inversely with 
the pressure applied to it. The primary advantage of body plethysmography is that it can 
measure the total volume of air in the chest, including gas trapped in bullae. Another advantage 

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is that this test can be performed quickly. A subject is placed in a sitting position in a closed 
body box with a known volume. 
Body plethysmography allows to determinate functional residual capacity (FRC), lung residual 
volume (RV) and total lung capacity (TLC), airway resistance (Raw) and intrathoracic gas 
volume (ITGV).
These measures are recorded during breathing at rest and not by forced maneuvers. All 
procedures must be in accordance with the international recommendations European 
Respiratory Society and American Thoracic Society (ERS/ATS). 
Calibration of the body plethysmograph will be performed at each visit and the reports will be 
kept with the source study document. A series of 3 technically satisfactory panting manoeuvres 
will be recorded. Body plethysmography should meet the ATS/ERS guidelines criteria. 
Pre-dose body plethysmography will be performed after the vital signs assessment and before 
the spirometry.
The following parameters should be obtained from plethysmography [percent predicted values 
for FRC, RV and TLC will be derived from the ECSC 1993 reference equations [26]

Airway resistance (Raw), as absolute value

Specific conductance (sGaw), as absolute value

Functional Residual Capacity (FRC), as absolute value and percentage of predicted

Residual Volume (RV), as absolute value and percentage of predicted

Slow Expiratory Vital Capacity (EVC) maneuver will be performed at the end of 
panting, as absolute value and percentage of predicted, and measure the linked 
Inspiratory Capacity

Inspiratory capacity (IC), as absolute value 

Total Lung Capacity (TLC), as absolute value and percentage of predicted
7.2.5 COPD Assessment Test (CAT)
The COPD Assessment Test is an 8-items unidimensional questionnaire to measure health 
status impairment in COPD subjects. It was developed to be applicable worldwide and validated 
translations are available in a wide range of languages. The score ranges from 0-40, correlates 
very closely with the St. George’s Respiratory Questionnaire (SGRQ), and has been extensively 
documented.
It provides measure of symptomatic impact of COPD but does not categorize subjects into 
symptom severity groups for the purpose of treatment.
At Visit 1, Visit 2, and Visit 3, subjects will complete the CAT test and data collected by the 
Investigator on paper will be recorded in the eCRF. Only symptomatic subjects with a CAT 
score ≥10 are eligible.
7.2.6 Spirometry
Pulmonary function tests will be carried out under medical supervision in either a clinic or 
hospital and will be recorded using a computer-operated spirometer. 
Throughout the study, the clinic visits and the lung function measurements will start in the 
morning approximately between 7:00 and 10:00 a.m., preferably at the same time of the day for 
each subject, who should have only a light breakfast, refrain from smoking for four hours before 
the test and respect medication washout times.

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Calibration of the spirometer must be performed by the same investigator or deputy (to the 
extent possible) at each visit prior to spirometry maneuvers and the reports must be kept at the 
clinical site and be accessible to the CRA and the Sponsor. Personnel using the spirometer 
should be adequately trained to follow the commonly accepted procedures. The same make and 
model of spirometer will be used for all measurements and adjusted for the ATS/ERS standards. 
The predicted values will be calculated according to the Global Lung Function Initiative, ERS 
Task Force Lung Function Reference Values.
For the Forced Expiratory Volume in one second (FEV1), Forced Vital Capacity (FVC) and 
Maximal Expiratory Flow (MEF) the highest value (L) from three technically satisfactory 
attempts (1 minute apart) will be recorded (not necessarily coming from the same curve). In 
order to be considered as technically satisfactory attempts, measurements should be free from 
cough and false-start. The two largest FEV1 measurements must be within 150 mL of each other 
(or 100 mL, if the FEV1 value is ≤ 1L). If the difference is larger, additional tests will be made 
until the above criterion is met (up to 8 measurements). If at the end, the tests are not within 
150 mL, the highest value of FEV1 and FVC will be recorded and used for 
eligibility/continuation criteria. Please refer to the complete summary of acceptability, 
usability, and repeatability criteria for FEV1 and FVC in the 2019 Standardization of 
Spirometry Update.
If subjects show a progressive reduction in FEV1 with each subsequent blow, with cumulative 
drop above 20% of starting value, the test procedure may be terminated in the interest of the 
subject safety. Subjects should be at rest before each lung function test. All measurements are 
to be made with the subjects in sitting position. Values will be corrected for pressure saturation 
(BTPS) conditions.
At screening, the measurement of post-bronchodilator lung function test will be done starting 
from 20 to 30 minutes after inhalation of salbutamol pMDI 400 μg. 
Lung function tests can be repeated if the investigator deems it necessary to assess safety or to 
confirm eligibility. If the investigator performed more assessments than expected a comment 
in the eCRF should be included.
Pre-dose spirometry will be performed after the body plethysmography assessment and before 
the MDCT and CAT test.
The following parameters should be obtained from spirometry:

Forced Expiratory Volume in one second (FEV1);

Forced Vital Capacity (FVC);

Peak Expiratory Flow (PEF);

Maximal expiratory flow at 50% of expired vital capacity (MEF50);

Maximal expiratory flow at 25% of expired vital capacity (MEF25).
In case the restriction is not respected at screening, the visit should be rescheduled once to be 
performed within the allowed time window, as applicable. 

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7.2.7 Diary Card 
At screening and at Visit 2, a paper diary card will be handed out to the subject. Return will 
occur at Visit 2 for run-in diary card and Visit 3 for treatment period diary card. 
The subject should follow instructions for recording the study medication intake, concomitant 
treatments and adverse events. The information from the subject diary card will be entered into 
the clinical database by the Investigators. Investigator will check the diary for completeness 
before the subject leaves the centre. 
The following information will be recorded on the Diary:

Study drug intake

Concomitant treatments 

Adverse events
8.
EFFICACY ASSESSMENTS
Primary endpoints:
The following FRI parameters are used as primary outcome parameters:

Percentage change from baseline (pre-dose V2) to pre-dose in untrimmed specific 
airway volume (siVaw) upon inspiration (at TLC) at Visit 3

Percentage change from baseline (pre-dose V2) to pre-dose in trimmed specific airway 
resistance (siRaw) upon inspiration (at TLC) at Visit 3
Data for these parameters will be recorded by lobar region and overall distal region.
Secondary endpoints:
Evaluation of the percentage change from baseline (V2) to post-dose at Visit 3, the percentage 
change from pre-dose to post-dose at Visit 2, and the percentage change from pre-dose to post-
dose at Visit 3 in primary endpoints.
Values at pre-dose and post-dose for the following FRI parameters:

siVaw upon expiration (at FRC)

siRaw upon expiration (at FRC)

ventilation mapping

perfusion mapping

airway wall thickness upon inspiration (at TLC)

imaged lobe and lung volumes at TLC and FRC

air trapping

low attenuation score at TLC 

Percentile 15th at TLC

Regional lung deposition 
In addition, pre-dose spirometry, body plethysmography and CAT will be assessed at Visit 2 
and Visit 3.

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9.
SAFETY ASSESSMENTS
The drug safety will be evaluated in the study as follows:

Adverse Events (AEs) and Adverse Drug Reactions (ADRs) 

Vital signs (systolic and diastolic blood pressure)
10.
ADVERSE EVENT REPORTING
10.1 Definitions
An Adverse Event is “any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment”.
An adverse event can therefore be any unfavorable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
An Adverse Drug Reaction is an “untoward and unintended response to an investigational 
medicinal product related to any dose administered”.
All adverse events judged by either the reporting Investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression “reasonable causal relationship” means to convey in general that there are facts 
(evidence) or arguments meant to suggest a causal relationship.
The definition covers also medication errors and uses outside what is foreseen in the protocol, 
including misuse and abuse of the product.
A Serious Adverse Event (SAE)/Serious Adverse Drug Reaction is any untoward medical 
occurrence or effect that at any dose falls in one or more of the following categories:
-
Results in death
Death is not an adverse event but an outcome. It is the cause of death that should be regarded 
as the adverse event. The only exception to this rule is “sudden death” where no cause has been 
established; in this latter instance, “sudden death” should be regarded as the adverse event and 
“fatal” as its reason for being serious.
-
Is life-threatening
Life-threatening refers to an event in which the subject was at risk of death at the time of the 
event (e.g., aplastic anaemia, acute renal failure, and anaphylaxis). The term does not refer to 
an event which hypothetically might have caused death if it were more severe.
-
Requires hospitalisation or prolongation of existing hospitalisation
Hospitalization refers to a situation whereby an AE is associated with unplanned formal 
overnight admission into hospital, usually for purpose of investigating and/or treating the AE. 
Hospitalization for the treatment of a medical condition that occurs on an “elective” or 
“scheduled” basis or for a pre-existing condition that did not worsen during the study should 
not necessarily be regarded as an AE. Complications that occur during the 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 

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seriousness criteria (e.g., life-threatening; persistent or significant disability or incapacity; 
medically significant).
-
Results in persistent or significant disability or incapacity
The term significant disability should be viewed as any situation whereby an AE has a clinically 
important effect on the subject’s physical or psychological well-being to the extent that the 
subject is unable to function normally.
-
Is a congenital anomaly or birth defect
-
Is a medically significant adverse event
This criterion allows for any situations in which important adverse events/reactions that are not 
immediately life-threatening or do not result in death or 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 adverse reaction.
A Non-Serious Adverse Event/Non-Serious Adverse Drug Reaction is an adverse event or 
adverse drug reaction that does not meet the criteria listed above for a serious adverse 
event/serious adverse drug reaction.
10.2 Expectedness
An expected adverse reaction is an adverse reaction, the nature or severity of which is consistent 
with the applicable reference safety information (included in the Summary of Product 
Characteristics for TRIMBOW® DPI), otherwise it is considered unexpected.
Reports which add significant information on specificity or severity of a known, already 
documented serious adverse drug reaction constitute unexpected events. For example, an event 
more specific or more severe than described in the reference safety information would be 
considered as “unexpected”. Examples of such events are: (a) acute renal failure as a labelled 
ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report 
of fulminant hepatitis.
In the event an exacerbation is interpreted as due to lack of efficacy, it should not be classified 
as drug related.
10.3 Intensity of Adverse Event
Each Adverse Event must be rated on a 3-point scale of increasing intensity:
Mild: The event causes a minor discomfort or does not interfere with daily activity of the 
subject or does not lead to either modification of test treatment dosage or establishment 
of a correcting treatment.
Moderate: The event perturbs the usual activity of the subject and is of a sufficient 
severity to make the subject uncomfortable. The event leads to a diminution of dosage of 

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the test treatment, or a temporary interruption of its administration or to the establishment 
of a correcting treatment.
Severe: The event prevents any usual routine activity of the subject and causes severe 
discomfort. It may be of such severity to cause the definitive interruption of test treatment.
10.4 Causality Assessment
The following “binary” decision choice will be used by the Investigator to describe the causality 
assessment:
Reasonable possibility of a relatedness
No reasonable possibility of relatedness
The expression “reasonable possibility of relatedness” is meant to convey, in general, that there 
are facts (evidence) or arguments meant to suggest a causal relationship.
The Investigator will be asked to consider the following before reaching a decision on causality 
assessment:
Time relationship between study drug intake and event’s onset;
Dechallenge (did the event abate after stopping drug?);
Rechallenge (did the event reappear after reintroduction?);
Medical history;
Study treatment(s);
Mechanism of action of the study drug;
Class effects;
Other treatments-concomitant or previous;
Withdrawal of study treatment(s);
Lack of efficacy/worsening of existing condition;
Erroneous treatment with study medication (or concomitant);
Protocol related process.
10.5 Action taken with the study drug due to an AE
Dose not changed
Drug permanently withdrawn
Drug temporarily interrupted
Unknown
Not applicable
10.6  Other actions taken
Specific therapy/Medication
Concomitant Procedure
10.7 Outcome
Each Adverse Event must be rated by choosing among:
Recovered/resolved
Recovering/resolving
Not recovered/not resolved

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Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 47/61
12.
STATISTICAL METHODS
12.1 Sample Size
No formal sample size calculation has been performed since the nature of the study (i.e., 
exploratory study).
30 subjects will be enrolled in the study in order to have at least 25 completed subjects.
12.2 Populations for analysis
Safety population: all randomized subjects who receive at least one dose of study 
treatment.
Per-protocol population (PP): all subjects from the safety population, except subjects 
without any valid evaluation of FRI or with major protocol deviations (i.e., wrong 
inclusions, poor compliance, non-permitted medications). Exact definition of major 
protocol deviations will be discussed by the study team during the blind review of the 
data and described in the Data Review Report.
The Safety population will be used in the analysis of safety variables, while all the other 
variables will be analysed in the PP population.
12.3 Statistical analysis
A detailed statistical analysis plan (SAP) will be described in a separate document. The plan 
might be reviewed and updated as a result of the review of the data and will be finalized before 
locking the database. 
12.4 Descriptive Statistics 
Descriptive statistics will be provided in summary tables according to the type of variable 
summarised.
General descriptive statistics for numeric variables will include the n (number of observed 
values), the mean, the standard deviation, the median, the minimum, and the maximum values. 
For categorical variables, the number and percent of subjects with a specific level of the variable 
will be presented.
12.5 Missing data
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.
12.6 Subject demographics and baseline characteristics
The following variables will be summarised for the PP population (and for the Safety 
population, if relevant): demographic characteristics, medical history and concomitant diseases, 
previous and concomitant medications, efficacy and safety parameters at screening and/or at 
baseline.
12.7 Efficacy variables
 Primary and secondary efficacy endpoints will be presented using descriptive statistics at each 
timepoint. Change from baseline to pre-dose and post-dose at Visit 3 as well as change from 

Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 48/61
pre-dose to post-dose at Visit 2 and Visit 3 will also presented for primary and other secondary 
efficacy endpoints FRI-related using descriptive statistics, while change from baseline to pre-
dose at Visit 3 will be presented for other secondary endpoints.
Overall distal region value for primary endpoints will be log-transformed and analysed using 
an ANCOVA model including the logarithm of baseline (Visit 2) at TLC and logarithm of pre-
dose lobar volume at FRC on Visit 3 as covariates. The adjusted % change from baseline to 
pre-dose at Visit 3 will be calculated with its 95% CI. 
Multiple data on lobar regions for primary endpoints will be log-transformed and analysed 
using the same model as for the overall distal region.
For the primary FRI variables, the percentage change from baseline to post-dose at Visit 3 and 
the percentage change from pre-dose to post-dose at Visit 2 and Visit 3 will be analysed using 
the same models described for the primary efficacy endpoints.
For the other FRI parameters, analysed using the same model as for the primary endpoints, with 
exclusion of pre-dose lobar volume at FRC on Visit 3 where appropriate.
For all FRI parameters, additional analyses using different models (e.g. mixed-effect models) 
and subgroup analyses will be performed to get better insights in regional effects. These 
analyses will be pre-specified and described in the statistical analysis plan.
For all other efficacy endpoints, change from baseline to pre-dose at Visit 3 will be analysed 
presenting 95% CI of the mean change and using a paired t-test.
Relevant correlations between variables will be evaluated using Spearman’s rank correlation 
coefficient.
12.8 Safety variables
Adverse Events
All adverse events starting on or after the time of first study drug intake will be classified as 
treatment emergent adverse even (TEAE). Any adverse events started after the informed 
consent signature and before the time of first study drug intake will be classified as pre-
treatment adverse event.
The number of subjects who experienced at least one AE, drug-related AE, non-serious AE, 
serious AE, serious related AE, AE leading to study discontinuation, and AE leading to death 
will be summarized by treatment arm. Summaries will be presented overall (number and 
percentage of subjects having at least one event, total number of events) and by system organ 
class and preferred term (number and percentage of subjects having at least one occurrence of 
that event). 
All adverse events will be listed. Pre-treatment adverse event will be listed only.
Vital signs
Vital signs (systolic and diastolic blood pressure) and their changes from pre-dose to post-dose 
at Visit 2 and Visit 3 will be summarised using descriptive statistics and the 95% CI of the 
mean. 

Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 49/61
12.9 Interim analysis
Interim analysis not planned.
13.
ETHICS COMMITTEE APPROVAL 
The study proposal will be submitted to the Ethics Committee/ in accordance with the 
requirements of each country.
The EC shall give its opinion in writing -clearly identifying the study number, study title and 
informed consent form approved-, before the clinical trial commences.
A copy of all communications with the 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 requirements of each country).
14.
REGULATORY REQUIREMENTS
The study will be notified to the Health Authorities (or authorized by) according to the legal 
requirements in each participating country.
Selection of the subjects will not start before the approval of the Ethics Committee has been 
obtained and the study notified to Health Authorities (or authorized by).
15.
INFORMED CONSENT 
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 or from the 
subject’s legal representative 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 or his or her legal representative to enquiry the PI 
about any clarification needed and to consider his or her decision to participate to the trial.
If the subject and his/her legal representative are unable to read, the informed consent will be 
obtained in the presence of an impartial witness, e.g., a person independent of the study who 
will read the informed consent form and the written information for the subject.
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.
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 data.  
Data recorded in the electronic case report form (eCRF) derived from source documents should 
be consistent with the data recorded on the source documents.

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Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 51/61
21.
PREMATURE TERMINATION OF THE STUDY 
Both the Sponsor and the Investigator reserve the right to terminate the study at any time. 
Should this be necessary, the procedures for an early termination or temporary halt will be 
arranged after consultation by all involved parties.
The Sponsor should submit a written notification to the Regulatory Authority concerned and 
Ethics Committee 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 Co-ordinating Investigator’s for agreement and signature.
At the end of the trial a summary of the clinical study report will be provided to all Ethics 
Committees/, to the Competent Authority of the EU Member State.
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] The Global Initiative for Chronic Obstructive Lung Disease (GOLD) (updated 2016). 
Available from: https://goldcopd.org/.  
[2] Foster Summary of Product Characteristics, 2019.
[3] Trimbow Summary of Product Characteristics, 2019. 
[4] Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid 
plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): 

Clinical Study Protocol 
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 52/61
a double-blind, parallel group, randomized controlled trial. Lancet. 2016;388(10048):963-
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muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a 
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1929.
[6] Papi A, Vestbo J, Fabbri L, et.al. Extra fine inhaled triple therapy versus dual bronchodilator 
therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel 
group, randomised controlled trial. Lancet. 2018;391(10125):1076-1084.
[7] Walenga RL, Babiskin AH, Zhao L. In Silico Methods for Development of Generic Drug-
Device Combination Orally Inhaled Drug Products. CPT Pharmacometrics Syst Pharmacol. 
2019;8(6):359-370. doi:10.1002/psp4.12413
[8] Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic 
obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645‐2653.
[9]Leaver DG, Tatterfield AE, Pride NB. Contributions of loss of lung recoil and of enhanced 
airways collapsibility to the airflow obstruction of chronic bronchitis and emphysema. J 
Clin Invest. 1973;52(9):2117‐2128.
[10]
Postma DS, Brightling C, Baldi S, et al. Exploring the relevance and extent of small 
airways dysfunction in asthma (ATLANTIS): baseline data from a prospective cohort
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Med. 2019;7(5):402‐416.
[11]
Iwanaga T, Kozuka T, Nakanishi J, et al. Aerosol Deposition of Inhaled 
Corticosteroids/Long-Acting β2-Agonists in the Peripheral Airways of Patients with 
Asthma Using Functional Respiratory Imaging, a Novel Imaging Technology. Pulm Ther. 
2017;3:219-231.
[12]
Usmani OS, Mignot B, Kendall I, De Maria R, Cocconi D, Georges G, and Scichilone 
N. Airway Deposition of Extra fine Inhaled Triple Therapy in Patients with COPD: A Model 
Approach Based on Functional Respiratory Imaging Computer Simulations. International 
Journal of COPD 2020:15 2433–2440.
[13]
FRI technology. Available from: www.fluidda.com. 
[14]
De Backer JW, Vos WG, Vinchurkar SC, Claes R, Drollmann A, Wulfrank D, et al. 
Validation of computational fluid dynamics in CT-based airway models with SPECT/CT. 
Radiology. 2010;257(3):854-862. 
[15]
De Backer LA, Vos W, De Backer J, Van Holsbeke C, Vinchurkar S, De Backer W. 
The acute effect of budesonide/formoterol in COPD: a multi-slice computed tomography 
and lung function study. Eur Respir J. 2012;40(2):298-305.
[16]
Finlay WH. The mechanics of inhaled pharmaceutical aerosols: an introduction: 
Academic Press; 2001
[17]
De Backer W, De Backer J, Verlinden I, et al. Functional respiratory imaging 
assessment of glycopyrrolate and formoterol fumarate metered dose inhalers formulated 
using co-suspension delivery technology in patients with COPD. Ther Adv Respir Dis. 
2020;14:1753466620916990. doi:10.1177/1753466
[18]
Montuschi P, Santini G, Mores N, et al. Breathomics for Assessing the Effects of 
Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With 
COPD. Front Pharmacol. 2018;9:258. Published 2018 Apr 17. 
doi:10.3389/fphar.2018.00258.
[19]
Beeh KM, Kuna P, Corradi M, Viaud I, Guasconi A, Georges G. Comparison of Dry-
Powder Inhaler and Pressurized Metered-Dose Inhaler Formulations of Extra fine 

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Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
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Beclomethasone Dipropionate/Formoterol Fumarate/Glycopyrronium in Patients with 
COPD: The TRI-D Randomized Controlled Trial. Int J Chron Obstruct Pulmon Dis. 
2021;16:79-89
doi.org/10.2147/COPD.S291030
[20]
O’Donnell, D.E., Webb, K.A. & Neder, J.A. Lung hyperinflation in COPD: applying 
physiology to clinical practice. COPD Res Pract 1, 4 (2015). 
https://doi.org/10.1186/s40749-015-0008-8. 
[21]
Calzetta L, Ora J, Cavalli F, Rogliani P, O'Donnell DE, Cazzola M. Impact of 
LABA/LAMA combination on exercise endurance and lung hyperinflation in COPD: A 
pair-wise and network meta-analysis. Respir Med. 2017 Aug;129:189-198. 
[22]
Lavorini F, Magnan A, Dubus JC et al. Effect of incorrect use of dry powder inhalers 
on management of patients with asthma and COPD. Respir Med. 2008 Apr;102(4):593-604
[23]
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[accessed 10 July 2008]; Meeting report. 2001 Jun 4–5; Available at: 
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[24]
Clinical Trial Facilitation and Coordination Group (CTFG). Recommendations related 
to contraception and pregnancy testing in clinical trials. Version 1.1 
https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2020_09_HMA_CTFG_Contraception_guidance_V
ersion_1.1_updated.pdf 
[25]
Graham B.L., Steenbruggen I., Miller M.R., et al. Standardization of Spirometry 2019 
Update. Am J Respir Crit Care Med Vol 200, Iss 8, pp 963–971, Oct 15, 2019
[26]
Ph.H Quanjer, G.J. Tammeling, J.E. Cotes, O.F. Pedersen, R. Peslin, J-C. Yernault. 
Lung Volumes and Forced ventilatory flows. Eur Respir J 1993; 6, Suppl. 16:5-40

Clinical Study Protocol – Appendix 1
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 54/61
APPENDIX 1 - Approval of the protocol by clinical investigator(s)
Open label, prospective study to evaluate the effect of step-up from non-extra fine 
ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and 
lung ventilation using FRI in subjects with advanced COPD
Product: CHF 5993 BDP 100 μg / FF 6 μg / GB 12,5 μg 
Pharmaceutical Form: Dry Powder Inhaler
Approval of Clinical Study Protocol by the Investigator: 
I have carefully read this protocol and I agree that it contains all the necessary information 
required to conduct the study and I agree to conduct it as described.
I understand that this trial will not be initiated without 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 1
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 55/61
APPENDIX 1 - Approval of the protocol by clinical investigator(s)
Open label, prospective study to evaluate the effect of step-up from non-extra fine 
ICS/LABA DPI to extra fine triple therapy with CHF5993 DPI on airway geometry and 
lung ventilation using FRI in subjects with advanced COPD
Product: CHF 5993 BDP 100 μg / FF 6 μg / GB 12,5 μg
Pharmaceutical Form: Dry Powder Inhaler
Approval of Clinical Study Protocol by the Principal Investigator: 
I have carefully read this protocol and I agree that it contains all the necessary information 
required to conduct the study and I agree to conduct it as described.
I understand that this trial will not be initiated without Ethics 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 2
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 56/61
APPENDIX 2 - INSTRUCTION FOR USE OF IN-CHECK DIAL
1.
Reset the In-Check® Dial before each test
Figure 1
2.
Align the scale with the desired inhaler device - an audible "click" should be heard.
Figure 2
To correctly align the scale, the black arrow shown in the body of the In-check Dial (see red 
circle line in  Figure 3) must be put in correspondence of the “Med Low” and then of the “Med 
High” symbols (see Figure 4).

Clinical Study Protocol – Appendix 2
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 57/61
 
 Figure 3
It is very important to check that, after alignment, the hole is exactly in the right position 
as shown in Figure 4 (Diskus Medium-Low resistance and NEXThaler Medium-high 
resistance). 
Figure 4

Clinical Study Protocol – Appendix 2
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 58/61
3.
After alignment, take one mouthpiece, as shown in Figure 5. 
Figure 5
4.
Attach the mouthpiece to the In-Check Dial, as shown in Figure 6. 

Clinical Study Protocol – Appendix 2
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 59/61
Figure 6

Clinical Study Protocol – Appendix 2
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 60/61
5.
Ask the subject to exhale slowly and fully.
Figure 7
6.
Seal lips around the mouthpiece and ask subjects to inhale as quickly as they can. 
Figure 8

Clinical Study Protocol – Appendix 2
Clinical Study Code No.: CLI-05993BA1-08
Version No.: 4.0 
EUDRACT No.: 2020-002356-20
Date: 26 May 2021
CONFIDENTIAL
Page 61/61
7.
Record the inspiratory flow from the position of the red cursor against the scale. Reset, 
and repeat two more times per each test.
Figure 9
In order to ensure an optimum aerosol dispersion threshold using Plastiape RS-01®, a 
PIF of at least 30 L/min is required. No upper limit is set.
 
Figure 10