Randomized, Double Blind, Placebo Controlled Study to Evaluate the Effect of Dupilumab on Airway Inflammation Through Assessments of Lung Function, Mucus Plugging and Other Lung Imaging Parameters in Patients With Asthma
Phase: PHASE4
Conditions: Asthma
Sponsor: Sanofi



Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 2
PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Country/countries 
impacted by amendment
Date, version
Amended Clinical Trial Protocol 03 
All 
13 April 2023, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
All 
15 March 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01  
All 
12 March 2020, version 1 (electronic 1.0) 
Original Protocol 
 
09 January 2020, version 2 (electronic 2.0) 
Amended protocol 03 (13 April 2023)
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
The main reason for amended protocol 03 is evolving interest to evaluate FeNO as an airway 
inflammatory biomarker related to structural lung changes. Therefore, the primary endpoint FEV1
is proposed to be replaced with the secondary endpoint of FeNO, leading to an overall reduction 
in sample size.
Protocol amendment summary of changes table
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 2 Introduction 
Information from various literature sources for 
FeNO assessment added. 
 
The following text is deleted 
"and effect on lung function, airway inflammation 
and the relationship between imaging dynamics 
and FeNO, and the link with asthma control as 
perceived by the patient” 
To support the rationale for promoting 
FeNO to a primary endpoint. 
The text has been deleted as it is a 
redundant information. 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
The primary endpoint pre-BD FEV1 has been 
replaced by FeNO. 
To update primary objective to assess 
the role of dupilumab on airway 
inflammation related to structural 
changes in the lung in addition to 
imaging. 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
Minor clarifications on the terminology of the 
primary and secondary functional respiratory 
imaging (FRI) endpoints.  
To more accurately describe the FRI 
endpoints. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 3
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
Following endpoint has been moved from primary 
to secondary 
x Change from baseline to Week 24 in pre-
bronchodilator FEV1 
To reflect the shift of this endpoint from 
primary to secondary. 
Section 1.1 Synopsis 
Section 3 Objectives and 
Endpoints 
Following endpoint has been moved from 
tertiary/exploratory to secondary and updated as 
follows: 
x Change from baseline to Week 24 in global 
lung mucus scoring (UCSF mucus scoring) 
This change is proposed due to the 
increased interest in the assessment of 
presence of mucus plugs in the 
airways. 
Section 1.1 Synopsis 
Section 9.2 Sample Size 
Determination and Preservation 
of Type I Error For The Primary 
Endpoints 
The text is updated for sample size calculation.  
New text added for power calculation and 
hypotheses for the new primary endpoint. 
Updates to the sample size calculation 
and hypotheses reflecting the change 
to the primary endpoint. 
Section 1.1 Synopsis 
Section 9.4.2 Safety analyses 
The statement of multiplicity control procedure 
and the selected list of secondary endpoints was 
simplified and the details will be reported in the 
Statistical Analysis Plan. 
According to the new template, details 
of testing for secondary endpoints are 
reported in the Statistical Analysis 
Plan. 
Section 2.3 
Benefit/Risk Assessment 
The section is updated with the most recent data 
on exposure to dupilumab and regulatory 
information. 
To incorporate the most recent 
exposure  data for dupilumab and 
regulatory information. 
Section 8.1 Efficacy 
Assessments 
Asthma Control Questionnaire 7-question version 
Details of clinic staff score for FEV1% predicted 
added. 
Text updated for Asthma Quality of Life 
Questionnaire with Standardized Activities (Self-
Administered) details on overall score calculation. 
Clarification on clinical staff score for 
FEV1% predicted. 
 
Clarifications on overall score 
calculation. 
Section 9.1 Statistical 
Hypotheses 
Section 9.2 Sample Size 
Determination and Preservation 
of Type I Error for the Primary 
Endpoints 
New text added for hypotheses for the updated 
primary endpoints, and simplified testing 
procedure.
Use sequential testing for the primary 
endpoints; according to new template, 
details of testing for secondary 
endpoints are reported in the Statistical 
Analysis Plan. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 4
Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.1 Efficacy analyses 
Table 7 Efficacy analyses 
Following sentence is added to the text 
Data may be logarithmically transformed prior to 
analysis if extreme skewness was observed 
based on blinded data review. 
The table for efficacy analyses is updated. 
The efficacy analyses are updated 
based on changes to the endpoints. 
Section 10.1.7 Data Quality 
assurance 
Text for quality tolerance limits is removed. 
This paragraph is not applicable. 
Throughout the text 
Following sections are updated 
Section 6.3-Measures to minimize bias: 
Randomization and Blinding 
Section 8.3-Adverse events and serious adverse 
events 
Appendix 1 Section 10.1.4-Data protection 
Appendix 1 Section 10.1.6-Dissemination of 
clinical study data and results 
Appendix 1 Section 10.1.9-Study and site start 
and closure 
Appendix 9-Contingency Measures for a regional 
or national emergency that is declared by a 
governmental agency 
Template related changes 
Throughout the text 
Minor grammatical, editorial, and/or 
administrative changes. 
To improve the readability and/or clarity 
of the protocol. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 5
TABLE OF CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL 03 ..............................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................2 
TABLE OF CONTENTS..................................................................................................................................5 
LIST OF TABLES ...........................................................................................................................................9 
LIST OF FIGURES..........................................................................................................................................9 
1 
PROTOCOL SUMMARY ...............................................................................................................10 
1.1 
SYNOPSIS.....................................................................................................................................10 
1.2 
SCHEMA........................................................................................................................................17 
1.3 
SCHEDULE OF ACTIVITIES (SOA)..............................................................................................18 
2 
INTRODUCTION............................................................................................................................22 
2.1 
STUDY RATIONALE......................................................................................................................22 
2.2 
BACKGROUND
...........................................................................................................................23 
2.3 
BENEFIT/RISK ASSESSMENT.....................................................................................................24 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................28 
3.1 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................29 
4 
STUDY DESIGN ............................................................................................................................30 
4.1 
OVERALL DESIGN........................................................................................................................30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................30 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................31 
4.4 
END OF STUDY DEFINITION.......................................................................................................31 
5 
STUDY POPULATION ..................................................................................................................32 
5.1 
INCLUSION CRITERIA..................................................................................................................32 
5.2 
EXCLUSION CRITERIA ................................................................................................................33 
5.3 
LIFESTYLE CONSIDERATIONS...................................................................................................35 
5.4 
SCREEN FAILURES......................................................................................................................35 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 6
5.5 
CRITERIA FOR TEMPORARILY DELAYING SCREENING, RANDOMIZATION, OR 
STUDY INTERVENTION ADMINISTRATION ...............................................................................36 
6 
STUDY INTERVENTION ...............................................................................................................37 
6.1 
STUDY INTERVENTION(S) ADMINISTERED..............................................................................37 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY.......................................................39 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................40 
6.4 
STUDY INTERVENTION COMPLIANCE ......................................................................................42 
6.5 
CONCOMITANT THERAPY ..........................................................................................................42 
6.6 
RESCUE MEDICINE......................................................................................................................43 
6.7 
DOSE MODIFICATION..................................................................................................................43 
6.8 
INTERVENTION AFTER THE END OF THE STUDY...................................................................43 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...........................................................................................44 
7.1 
DISCONTINUATION OF STUDY INTERVENTION .....................................................................44 
7.1.1 
Definitive discontinuation ...............................................................................................................44 
7.1.2 
Temporary discontinuation.............................................................................................................45 
7.1.2.1 
Rechallenge ...................................................................................................................................45 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................46 
7.3 
LOST TO FOLLOW UP .................................................................................................................47 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................48 
8.1 
EFFICACY ASSESSMENTS ........................................................................................................48 
8.2 
SAFETY ASSESSMENTS ............................................................................................................55 
8.2.1 
Physical examinations ...................................................................................................................55 
8.2.2 
Vital signs.......................................................................................................................................56 
8.2.3 
Electrocardiograms ........................................................................................................................56 
8.2.4 
Clinical safety laboratory assessments..........................................................................................56 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................57 
8.3.1 
Time period and frequency for collecting AE and SAE information...............................................58 
8.3.2 
Method of detecting AEs and SAEs...............................................................................................58 
8.3.3 
Follow-up of AEs and SAEs...........................................................................................................58 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................................59 
8.3.5 
Pregnancy......................................................................................................................................59 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 7
8.3.6 
Guidelines for reporting product complaints ..................................................................................60 
8.4 
TREATMENT OF OVERDOSE......................................................................................................60 
8.5 
PHARMACOKINETICS..................................................................................................................60 
8.6 
PHARMACODYNAMICS ...............................................................................................................60 
8.7 
GENETICS.....................................................................................................................................61 
8.8 
BIOMARKERS ...............................................................................................................................61 
8.9 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ...........................................61 
8.10 
USE OF DATA FOR FUTURE RESEARCH..................................................................................61 
9 
STATISTICAL CONSIDERATIONS..............................................................................................62 
9.1 
STATISTICAL HYPOTHESES.......................................................................................................62 
9.2 
SAMPLE SIZE DETERMINATION AND PRESERVATION OF TYPE I ERROR FOR THE 
PRIMARY ENDPOINTS.................................................................................................................62 
9.3 
POPULATIONS FOR ANALYSES.................................................................................................63 
9.4 
STATISTICAL ANALYSES ............................................................................................................63 
9.4.1 
Efficacy analyses ...........................................................................................................................63 
9.4.2 
Safety analyses..............................................................................................................................65 
9.4.3 
Other analyses...............................................................................................................................66 
9.5 
INTERIM ANALYSES ...................................................................................................................66 
9.5.1 
Data Monitoring Committee (DMC)................................................................................................66 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................67 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......67 
10.1.1 
Regulatory and ethical considerations...........................................................................................67 
10.1.2 
Financial disclosure........................................................................................................................68 
10.1.3 
Informed consent process..............................................................................................................68 
10.1.4 
Data protection...............................................................................................................................69 
10.1.5 
Committees structure.....................................................................................................................71 
10.1.6 
Dissemination of clinical study data and results ............................................................................71 
10.1.7 
Data quality assurance ..................................................................................................................72 
10.1.8 
Source documents .........................................................................................................................72 
10.1.9 
Study and site closure....................................................................................................................73 
10.1.10 Publication policy ...........................................................................................................................74 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 8
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................74 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................75 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................80 
10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ...........................................................................................................................84 
10.6 
APPENDIX 6: LIST OF PROHIBITED LIVE ATTENTUATED VACCINES ...................................85 
10.7 
APPENDIX 7: 7-ITEM ASTHMA CONTROL QUESTIONNAIRE (ACQ-7) AND ASTHMA 
QUALITY OF LIFE QUESTIONNAIRE WITH STANDARDISED ACTIVITIES (AQLQ[S])............86 
10.8 
APPENDIX 8: COUNTRY SPECIFIC REQUIREMENTS ..............................................................95 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ...................................96 
10.10 
APPENDIX 10: RADIATION EXPOSURE .....................................................................................98 
10.11 
APPENDIX 11: ABBREVIATIONS ..............................................................................................104 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ..............................................................106 
10.12.1 Amended protocol 02 (15 March 2021) .......................................................................................106 
10.12.2 Amended protocol 01 (12 March 2020) .......................................................................................110 
11 
REFERENCES.............................................................................................................................111 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 9
LIST OF TABLES
Table 1 - Objectives and endpoints...............................................................................................................28 
Table 2 - Overview of study interventions administered ...............................................................................37 
Table 3 - Low, medium and high daily doses of inhaled corticosteroids (mcg).............................................39 
Table 4 - Wash out period of asthma controllers and rescue medication before HRCT scan and lung 
function assessments....................................................................................................................................48 
Table 5 - Clinic staff score for FEV1% ...........................................................................................................50 
Table 6 - Populations for analyses ................................................................................................................63 
Table 7 - Efficacy analyses ...........................................................................................................................64 
Table 8 - Safety analyses..............................................................................................................................65 
Table 9 - Protocol-required laboratory assessments ....................................................................................74 
LIST OF FIGURES
Figure 1 - Graphical study design .................................................................................................................17 
Figure 2 - Correlation between FEV1 and FRI-based airway volumes..........................................................53 
Figure 3 - Correlation between FEV1 and FRI-based airway resistance ......................................................54 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 10
1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Protocol title:
Randomized, double blind, placebo controlled study to evaluate the effect of dupilumab on airway 
inflammation through assessments of lung function, mucus plugging and other lung imaging 
parameters in patients with asthma
Short title:
VESTIGE
Rationale:
Chronic airway inflammation is a characteristic feature of asthma (1). Chronic inflammation is 
associated with mucus production, airway smooth muscle contraction and hypertrophy, airway 
hyperresponsiveness, and structural airway remodeling (2).
Although the pathophysiology of airway remodeling in asthma remains to be fully elucidated, key 
type 2 cytokines are believed to be involved in this process: IL-13 upregulate levels of fractional 
exhaled nitric oxide (FeNO) (3), which also affects airway smooth muscle function and mucus 
production, and may influence subepithelial fibrosis by secretion of periostin and other 
pro-fibrotic mediators. These effects may contribute to airway remodeling and obstruction (4).
IL-13 is implicated in tissue effects on goblet cells and airways smooth muscle cells, which 
impact on mucus secretion, smooth muscle contractility, and basement membrane thickening (5).
Airway remodeling in established asthma is poorly responsive to current therapies, such as 
inhalation of corticosteroids and administration of β2-agonists, anti-leukotrienes, theophylline, 
and biologics (6, 7). It is plausible that some potentially meaningful airway responses/changes 
involved in airway remodeling could fail to be detected or demonstrated due to the poor
sensitivity of the conventional parameters utilized in these previous clinical studies. 
Patients with normal forced expiratory volume in 1 second (FEV1) can have regional airway 
structure changes. Functional imaging (FI) is a useful tool for sensitive assessment of structural 
and functional changes in the lungs after asthma treatment (8). According to previous studies 
(8, 9, 10, 11) functional respiratory imaging (FRI) technology has demonstrated a higher 
sensitivity to detect the effect of treatment on lung function than conventional assessments like 
FEV1.
Type 2 biomarkers such as peripheral blood eosinophils and FeNO have been shown to identify 
different aspects of type-2 airway inflammation. Fractional exhaled nitric oxide is a simple, 
non-invasive biomarker that identifies IL-4/13 mediated airway inflammation at the level of the 
respiratory epithelium, leading to increased production of NO, which can be measured as FeNO, 
and is associated with pro-inflammatory effects, including excess mucus production, airway 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 11
remodeling, and increased bronchoconstriction (12, 13, 14). This inflammatory cascade could be 
identified via imaging including reduced airflow and increased airway wall thickness, as well as 
IL-13-mediated goblet cell production. Therefore, airway structural changes and FeNO levels 
could represent different biomarker components of IL-4 and IL-13 driven inflammation. FeNO 
has been shown to be a possible predictor of exacerbation risk and accelerated lung function 
decline and may indicate ongoing damage, although further investigations into this process are 
warranted (15, 16, 17, 18, 19, 20).
It is hypothesized that the changes in FEV1 observed with dupilumab treatment are potentially 
related to reduction in airway inflammation and changes in airway volumes detectable by 
functional respiratory imaging.
The goal of this study is to gain further insight into the effect of dupilumab on lung inflammation, 
and also explore the effect on airway changes, biomarkers, and gain preliminary understanding of 
the potential interrelationships between these parameters.
A combination of classical lung function, patient-reported outcome parameters, and FI methods 
has the potential to enhance the description of the mode of action of new compounds (8). In 
addition, results from the recently published ATLANTIS study suggest that a combination of 
biomarkers (FeNO), physiological testing (FEV1), and imaging approaches provides a
comprehensive assessment of small airway dysfunction (SAD) in asthma (21).
The QUEST study (22) has shown significant and clinically meaningful effects of dupilumab on 
FEV1 improvement, particularly in the high blood eosinophil count (≥300 cells/mm3) population 
at baseline, as early as Week 2 and was sustained throughout 52 weeks.
Dupilumab also has the potential to exert an unplugging effect on the airways by reducing mucus 
production, due to the anti-inflammatory effect via direct inhibition of IL-13 signaling (3, 4, 5).
Therefore, by utilizing imaging results, coupled with clinical outcomes (FEV1), biomarkers
(FeNO), and patient-reported outcomes (Asthma Control Questionnaire [ACQ] and Asthma 
Quality of Life Questionnaire with Standardized Activities [AQLQ(S)]), the study is expected to 
further characterize dupilumab’s unique mechanism of action (MoA).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 12
Objectives and endpoints
Objectives
Endpoints
Primary
x
To assess the effect of dupilumab on 
lung inflammation and related changes in 
airway volumes detectable by functional 
respiratory imaging.  
x
Proportion of participants achieving FeNO <25 parts per 
billion (ppb) at Week 24 
x
Percent change from baseline to Week 24 in untrimmed distal 
airway volumes corrected for lung volume ([s]iVaw) at total 
lung capacity (TLC) 
Secondary
x
To evaluate the effect of dupilumab at 
Week 24 on bronchodynamics, 
hyperinflation, airway resistance, airway 
wall thickness, ventilation defects and 
mucus plugging derived from high-
resolution computed tomography (HRCT) 
scans, patient-reported outcomes, FeNO 
and spirometry.  
Efficacy endpoints: 
x
Percent change from baseline to Week 24 in untrimmed distal 
airway volumes corrected for lung volume ([s]iVaw) at 
functional residual capacity (FRC) 
x
Percent change from baseline to Week 24 in trimmed distal 
airway resistance corrected for lung volume ([s]iRaw) at TLC 
x
Percent change from baseline to Week 24 in trimmed distal 
airway resistance corrected for lung volume ([s]iRaw) at FRC 
x
Change from baseline to Week 24 in global lung lobar 
volumes (iVlobes) at TLC 
x
Change from baseline to Week 24 in HRCT-based internal 
airflow distribution (IAD) for each lung zone 
x
Change from baseline to Week 24 in image-based 
ventilation/perfusion (iV/Q) at TLC for each lung zone 
x
Change from baseline to Week 24 in global lung mucus 
scoring (UCSF mucus scoring) 
x
Change from baseline to Week 24 in FeNO 
x
Change from baseline to Week 24 in pre-bronchodilator FEV1   
x
Change from baseline to Week 24 in post-bronchodilator 
FEV1 
x
Change from baseline to Week 24 in ACQ-7 
x
To evaluate safety of dupilumab 
Safety:  
x
Incidence of treatment emergent adverse events (TEAE) and 
serious adverse events (SAE) including clinically significant 
changes in vital signs and laboratory abnormalities  
x
Incidence of adverse events of special interest (AESI) 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 13
Objectives
Endpoints
Overall design:
A Phase 4 randomized, multinational study with 24-week double-blind placebo-controlled period 
to assess the effect of dupilumab on airway inflammation through assessments of biomarkers,
mucus plugging, and other lung imaging parameters in participants with asthma. 
Disclosure Statement: This is a Parallel Treatment study with 2 arms that is blinded for
participants and/or caregivers and investigators.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 14
Number of participants:
Approximately 97 participants will be randomly assigned to study intervention, respectively in a 
2:1 ratio for dupilumab: placebo, such that 87 evaluable participants (58 to dupilumab group and 
29 to placebo group) complete the study. Randomization will be stratified by dose level 
(medium/high - no less than 40% in ‘high ICS’ stratum) of inhaled corticosteroids (ICS) and 
region (Eastern Europe/ROW). In total, no more than 40% participants should be in "Eastern 
Europe" strata.
Intervention groups and duration:
Study participation for each participant will be a total of minimum 29 weeks and up to 41 weeks.
The study includes 3 study periods:
x
Screening period: 4 weeks (±1 week), from signed informed consent to randomization.
x
Randomized, placebo-controlled treatment period: 24 weeks from baseline (Day 1).
x
Post treatment follow-up period: up to 12 weeks or until the participants switch to 
commercialized dupilumab (or other biologic products), whatever comes first.
Participants who fulfill the inclusion criteria and do not meet any of the exclusion criteria will be 
randomized (2:1) to one of the following investigational medicinal products (IMP).
x
Dupilumab: participants will receive a loading dose of 600 mg of dupilumab (2 x 300 mg 
dupilumab SC on Day 1, followed by 300 mg every 2 weeks (Q2W) for 24 weeks.
x
Placebo: participants will receive 2 x 2 mL placebo injections SC on Day 1, then 1 placebo 
injection Q2W for 24 weeks.
Study intervention(s)
Investigational medicinal product(s)
Dupilumab and matching placebo will be supplied in prefilled syringes that are visually 
indistinguishable.
Dupilumab 300 mg:
x
Formulation: A 150 mg/mL dupilumab solution in a prefilled syringe to deliver 300 mg in 
a 2 mL injection.
x
Route of administration: SC injection.
x
Dose regimen: Q2W after an initial loading dose of 600 mg (2 injections of 300 mg) on 
Day 1.
Matching Placebo:
x
Formulation: Matching placebo will be supplied as an identical formulation to the active 
formulation without dupilumab, in a prefilled syringe to deliver placebo in a 2 mL
injection.
x
Route of administration: SC injection.
x
Dose regimen: Q2W after an initial loading dose (2 injections) on Day 1.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 15
Posttrial access to study medication: Posttrial access to study medication will be assessed in
accordance to the country requirements and the legislation in place.
Statistical considerations:
x
Sample size calculations and preservation of Type I error for the two primary 
endpoints
To control the type-I error rate for the 2 primary endpoints, a hierarchical testing 
procedure will be applied at a 2-sided 5% significance level, ie, each hypothesis will be 
formally tested only if the preceding one is significant at 5% level. The hierarchy of the 
tests for primary endpoints will be:
a) Proportion of participants achieving response of FeNO <25 ppb at Week 24
b) Percentage change from baseline to Week 24 in untrimmed distal [s]iVaw at TLC
 
x
Primary analysis:
For the primary endpoint proportion of participants achieving FeNO <25 pbb at Week 24, 
the analysis will be conducted by Cochran-Mantel-Haenszel (CMH) test adjusted by 
stratification factors. Comparison of the proportions of responders between dupilumab and 
placebo will be derived, and corresponding odds ratios and 95% CI along with the p-value 
will be reported. For participants who discontinued the study treatment, off-treatment data 
will be used to determine the responder/non-responder status. Missing data at Week 24 
will be considered as non-responders.
Percent change from baseline to Week 24 in distal [s]iVaw at TLC will be analyzed using 
a mixed model repeated measures model (MMRM). The model will include percent 
change from baseline values up to Week 24 as the response variable, and treatment group, 
region (Eastern Europe/ROW), ICS dose level (medium/high), visit, treatment-by-visit 
interaction, baseline value, and baseline-by-visit interaction as covariates. An unstructured 
covariance matrix will be used to model the within participants errors. No imputations for 
missing values will be carried out. The least square (LS) mean of each treatment group, the 
LS mean difference between the dupilumab group and placebo, and the corresponding 
95% CI of the differences and p-values will be provided. For participants who
discontinued the study treatment, off-treatment imaging data, as available, will be included 
in the analysis. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number:1
Property of the Sanofi group - strictly confidential
Page 16
x
Analysis of secondary endpoints:
Secondary endpoints relating to change or percent change from baseline will be analyzed
with MMRM model in a manner similar to that for the primary imaging endpoint.
x
Multiplicity considerations for the secondary endpoints:
A multiplicity control procedure and the selected list of secondary endpoints to be tested in 
the hierarchical order will be specified in the Statistical Analysis Plan. Regardless of 
eligibility to be declared significant, results for all comparisons will be presented. 
Descriptive statistics including number of participants, mean, standard deviation, and LS 
means will also be provided.
Safety analyses: All safety variables will be summarized using descriptive statistics.
Data Monitoring Committee: No
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 17
1.2
SCHEMA
Figure 1 - Graphical study design
 
ACQ-7= 7-item Asthma Control Questionnaire; AQLQ(S) =Asthma Quality of Life Questionnaire with Standardized Activities; D=Day; FeNO= Fractional exhaled nitric oxide; FU= Follow-up; HRCT= High-resolution 
computed tomography; ICF=Informed Consent Form; mg=milligram; ml=milliliter; Q2W= every 2 weeks; R=Randomization; V=Visit  
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 20
a
Participants who prematurely discontinue the study intervention (prior to completing the 24-week treatment period) should attend an Early Treatment Discontinuation (ETD) visit at earliest convenience with all the 
assessments planned for the End of Treatment visit (V5), except HRCT scans and IMP. In particular cases when the ETD visit is closed to a regular study visit, ETD could be merged and will replace the regular 
visit. In addition, the participants will be asked and encouraged to complete all the remaining study visits according to the visit schedule until and including the EOT visit (V5). Under exceptional circumstances 
when a participant cannot come to the site for the scheduled visit, a phone contact can be made after sponsor approval is given. During the phone contact, at least information about AEs and concomitant 
medication should be collected. 
b
Participants who prematurely discontinue the study should attend an Early Study Discontinuation (ESD) visit at earliest convenience with all the procedures planned for the End of Treatment Visit (Visit 5) except 
IMP. If the Investigator considers that the time from the last HRCT scan exposure is not acceptable, the investigation will not be done. 
c
Post-treatment Follow-up: up to 12 Weeks or until the participants switch to commercialized dupilumab (or other biologic products), whatever comes first.  
d
Visit 6 will be a telephone visit. For the participants who switch to commercialized dupilumab (or other biologic products), the call visit should be done prior to the first injection with commercialized dupilumab (or 
other biologic products). 
e
Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius).  
f
A complete physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal and neurological systems and will be performed at V1, V2 and V5. Body weight (kg) will 
be measured at V1, V2 and V5. Height (cm) will be measured only at V1. 
g
Reversibility test: Three attempts may be performed during the screening period to meet the qualifying criteria for reversibility before randomization. This is only required if a reversibility test meeting eligibility 
criterion was not performed within 6 months prior to Visit 1. 
h
Asthma Control Questionnaire-7 (ACQ-7): items 1 to 6 should be completed by the participant, independently from their physician, the study nurse or any other medical personnel and without any help from friends 
or relatives. The questionnaire should be completed by the participants before the consultation and/or clinical tests, in a quiet place. ACQ-5 scores (mean of the responses to the first 5 questions) and ACQ-6 
(mean of the responses to the first 6 questions) will be derived from ACQ-7. The local values of FEV1 will be considered for the ACQ-7 scores. For the statistical analysis we will use centrally read values. 
i
Asthma Quality of Life Questionnaire with Standardized Activities [AQLQ(S)] should be completed by the participant, independently from their physician, the study nurse or any other medical personnel and without 
any help from friends or relatives. The questionnaire should be completed by the participants before the consultation and/or clinical tests, in a quiet place. 
j
FeNO should be conducted prior to spirometry and the participant should refrain from eating and drinking for ≥1 hour before the procedure. The test will be performed after a wash out period of bronchodilators 
according to their action duration as detailed in Table 4 (Section 8.1). Retesting of FeNO can be done one additional time during screening if the eligibility criterion for FeNO was not met at V1. FeNO will be re-
checked at randomization visit (V2) for eligibility. Further details on the procedure for measuring FeNO will be provided in a separate instruction manual  
k
Centrally read. Scans are respiratory gated to avoid variations in lung and airway volume, as per scans protocol. Further details on the HRCT scan will be provided in a separate instruction manual. The wash out 
time of the asthma controllers and rescue medication before HRCT and lung function assessments is detailed in Table 4 (Section 8.1). If HRCT scan cannot be performed at D1 due to logistic reasons, it can be 
scheduled the next day. In this particular situation the investigator should ensure that the IMP loading dose is administered after the HRCT scan, at D1+1 day. At visits, the HRCT scan can be done before 
spirometry or before post-BD FEV1 or after (in the latter case the wash-out period of SABA should be ensured), as per Investigator's decision. 
l
FOT should be conducted prior to spirometry. Further details on FOT will be provided in a separate instruction manual. 
m
Centrally read. Spirometry test should be performed before IMP administration, in the morning if possible, but if testing can only be done at another time during the day, then the testing should be done at 
approximately the same time of day at each visit throughout the study. Spirometry will be performed after a wash out period of bronchodilators according to their action duration as detailed in Table 4 (Section 8.1). 
This will be verified before performing the measurements. A participant who is unable to complete a successful spirometry effort as defined by ATS criteria or evaluated by the investigator or did not meet the 
eligibility criterion for pre-BD FEV1 at V1 can be retested one additional time during the screening period. For spirometry the investigator will assess the eligibility based on the FEV1 local values from V1 and V2 
before randomization (the results from central reading will not be available on the same day). The recommendation is to perform the FeNO and FOT before spirometry  
n
Serum pregnancy test at screening visit (Visit 1) and urine pregnancy tests at the other visits using dipstick. A negative result must be obtained at Visits 1 and 2 for eligibility. In case of positive urinary test during 
the study, a serum pregnancy test should be performed as soon as possible to confirm the pregnancy. A urine pregnancy test will be performed at home at the end of follow-up visit.  
o
Retesting of eosinophil count is allowed up to three times during the screening period to meet inclusion criteria for showing eosinophil count ≥300 cells/microliter (cells/mL) (I 06) before randomization. This is only 
required if the participant does not have the blood eosinophil count measured within 6 months prior to V1 in the absence of OCS treatment.  
p
Hepatitis screening covering hepatitis B surface antigen (HBs Ag), total hepatitis B core antibody (total HBcAb) including IgM HBcAb; hepatitis C virus antibodies (HCVAb). In case of results showing HBsAg 
(negative) and HBcAb (positive), HBV DNA testing will be performed to rule out a false positivity or to clarify the serological status if the Investigator finds it unclear to interpret in absence of known HBV infection. 
In case of results showing HCVAb (positive), HCV RNA testing may be performed to rule out a false positivity. Human Immunodeficiency Virus (HIV) screening (Anti-HIV-1 and HIV-2 antibodies). 
q
 Tuberculosis (TB) testing would only be performed on a country by country basis according to the routine clinical practice and the local guidelines if required by Regulatory Authorities or Ethics Committees. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 21
r
Should be completed by participants regularly to record investigational (home dosing diary) and non-investigational product (asthma background therapy diary) information. Recorded data will be collected by the 
investigator at each onsite visit. 
s
Investigational product administrations (Q2W) should be separated by at least 11 days. The administration is performed on site during planned visits alternating with Q2W home administration (participant, 
caregiver, or health care professional) or in a health care facility. At D1, loading dose dupilumab arm 600 mg (300 mg x 2 syringes/injections); 2 placebo syringes for the placebo arm. In case that the HRCT scan 
is performed one day after D1 due to logistic reasons, the IMP loading dose should be administered after the completion of HRCT scan (D1 +1 Day).  
NOTE: 
x
The contingency measures for a regional or national emergency declared by a governmental agency are detailed in Appendix 9 (Section 10.9).  
x
In case of severe asthma exacerbations treated with systemic corticosteroids, the visits can be postponed up to 1 week to ensure the wash-out period (Table 4) is completed before performing HRCT scan, 
FeNO, FOT, and spirometry. In case this is not possible (eg, a participant experiences an exacerbation shortly before the scheduled visit), the procedures can be performed as planned, but it should be 
recorded that the participant had recently taken systemic corticosteroids. 
 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 22
2
INTRODUCTION
Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation (1).
Type 2 inflammation is an important disease mechanism in a large subgroup of individuals with 
asthma. Airway type 2 immune responses are mediated by cytokines such as IL-4, IL-5, and 
IL-13, which occur in approximately 50% of patients with asthma (10).
Dupilumab is a fully human anti-IL-4 receptor α monoclonal antibody that blocks both IL-4 and 
IL-13 signaling. The results of dupilumab pivotal studies have demonstrated its efficacy in 
moderate-to-severe asthma patients by decreasing the rates of severe asthma exacerbation, 
improving the lung function and asthma control (22) as well as reducing oral glucocorticoid use 
(23).
Dupilumab is approved for the treatment of patients with moderate-to-severe asthma in the United 
States, and for the treatment of patients with severe asthma in Europe and Japan.
2.1
STUDY RATIONALE
Chronic airway inflammation is a characteristic feature of asthma (1). Chronic inflammation is 
associated with mucus production, airway smooth muscle contraction and hypertrophy, airway
hyperresponsiveness, and structural airway remodeling (2).
Although the pathophysiology of airway remodeling in asthma remains to be fully elucidated, key 
type 2 cytokines are believed to be involved in this process: IL-13 upregulate levels of fractional 
exhaled nitric oxide (FeNO) (3), which also affects airway smooth muscle function and mucus 
production, and may influence subepithelial fibrosis by secretion of periostin and other 
pro-fibrotic mediators. These effects may contribute to airway remodeling and obstruction (4).
IL-13 is implicated in tissue effects on goblet cells and airways smooth muscle cells, which 
impact on mucus secretion, smooth muscle contractility, and basement membrane thickening (5).
Airway remodeling in established asthma is poorly responsive to current therapies, such as 
inhalation of corticosteroids and administration of β2-agonists, anti-leukotrienes, theophylline,
and biologics (6, 7). It is plausible that some potentially meaningful airway responses/changes 
involved in airway remodeling could fail to be detected or demonstrated due to the poor
sensitivity of the conventional parameters utilized in these previously clinical studies. 
Patients with normal forced expiratory volume in 1 second (FEV1) can have regional airway 
structure changes. Functional imaging is a useful tool for sensitive assessment of structural and 
functional changes in the lungs after asthma treatment (8). According to previous studies (8, 9, 10,
11) functional respiratory imaging (FRI) technology has demonstrated a higher sensitivity to
detect the effect of treatment on lung function than conventional assessments like FEV1.
Type 2 biomarkers such as peripheral blood eosinophils and FeNO have been shown to identify 
different aspects of type-2 airway inflammation. Fractional exhaled nitric oxide is a simple, 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 23
non-invasive biomarker that identifies IL-4/13 mediated airway inflammation at the level of the 
respiratory epithelium, leading to increased production of NO, which can be measured as FeNO, 
and is associated with pro-inflammatory effects, including excess mucus production, airway 
remodeling, and increased bronchoconstriction (12, 13, 14). This inflammatory cascade could be 
identified via imaging including reduced airflow and increased airway wall thickness, as well as 
IL-13-mediated goblet cell production. Therefore, airway structural changes and FeNO levels 
could represent different biomarker components of IL-4 and IL-13 driven inflammation. FeNO 
has been shown to be a possible predictor of exacerbation risk and accelerated lung function 
decline and may indicate ongoing damage, although further investigations into this process are 
warranted (15, 16, 17, 18, 19, 20).
It is hypothesized that the changes in FEV1 observed with dupilumab treatment are potentially 
related to reduction in airway inflammation and changes in airway volumes detectable by 
functional respiratory imaging.
The goal of this study is to gain further insight into the effect of dupilumab on lung inflammation, 
and also explore the effect on airway changes, biomarkers, and gain preliminary understanding of 
the potential interrelationships between these parameters.
A combination of classical lung function, patient-reported outcome parameters, and FI methods
has the potential to enhance the description of the mode of action of new compounds (8). In 
addition, results from the recently published ATLANTIS study suggest that a combination of 
biomarkers (FeNO), physiological testing (FEV1), and imaging approaches provides a 
comprehensive assessment of small airway dysfunction (SAD) in asthma (21).
The QUEST study (22) has shown significant and clinically meaningful effect of dupilumab on
FEV1 improvement, particularly in the high blood eosinophil count (≥300 cells/mm3) population 
at baseline, as early as Week 2 and was sustained throughout 52 weeks.
Dupilumab also has the potential to exert an unplugging effect on the airways by reducing mucus 
production, due to the anti-inflammatory effect via direct inhibition of IL-4 and IL-13 signaling 
(3, 4, 5).
Therefore by utilizing imaging results, coupled with clinical outcomes (FEV1), biomarkers 
(FeNO), and patient-reported outcomes [ACQ, and AQLQ(S)], the study is expected to further 
characterize dupilumab’s unique mechanism of action (MoA).
2.2
BACKGROUND
Dupilumab is a fully human monoclonal antibody produced by recombinant deoxyribonucleic 
acid (DNA) technology in Chinese Hamster Ovary cell suspension culture. It inhibits IL-4 and 
IL-13 signaling by specifically binding to the IL-4Rα subunit of the IL-4 and IL-13 receptor 
complexes. 
The results of the conducted studies of dupilumab have demonstrated clinically meaningful and
statistically significant improvements, with treatment compared to placebo, in lung function 
parameters such as FEV1.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 24
Forced expiratory volume in 1 second has been used as the primary endpoint of lung function in 
the majority of asthma clinical trials over the last 3 decades (24). However, FRI emerges as a 
novel technique that can simulate different outcomes such as ventilation, lung deposition, and 
perfusion of airway blood vessels (10).
Functional respiratory imaging can assess the airway wall volume not only at the respiratory 
bronchi 1 level such as in the Haldar study but also at all central and distal airways down to the 
7th to 10th generation. In addition to changes in the airway wall volume, FRI can describe changes 
in airway lumen volume and airway resistance (8, 25, 26).
Although not yet demonstrated, dupilumab has the potential to act as mucolytic with a positive 
effect on mucus plugging. Functional respiratory imaging has been used to assess effects of 
mucolytic agents such as n-acetyl cysteine (27).
In addition to a reduction in inflammation in the larger airways, dupilumab most likely also 
reduces the inflammation in the small airways. Previous studies have suggested that regional 
hyperinflation appears to be a sensitive marker for small airways inflammation (9, 11, 28).
Functional respiratory imaging can yield regional (lobar) levels of hyperinflation by visualizing 
and quantifying trapped air and by expressing the lobe volume as percent predicted (where values 
>115% are judged to be hyper inflated compared to a reference level).
Another parameter that can be derived from FRI is the image-based ventilation/perfusion ratio 
(iV/Q) (29). As the main function of the lung is to transfer oxygen, anti-inflammatory properties 
of dupilumab could potentially result in a reduction of inflammation in the larger airways of 
asthmatics as well as the small airways from the atmosphere into the blood; therefore, the iV/Q 
parameter is highly relevant from a pathophysiological and clinical perspective.
Previous studies did demonstrate that both FEV1 and FRI based biomarkers of airway volume 
(iVaw) and resistance (iRaw) can evaluate the effects of treatment in asthma and chronic 
obstructive pulmonary disease (COPD). This study is designed to assess the effect of dupilumab
on lung function, airway inflammation and the relationship between imaging dynamics and FeNO.
2.3
BENEFIT/RISK ASSESSMENT
Dupilumab solution for injection is approved for asthma in adults and adolescents (≥12 years) in
over 60 countries worldwide and review for this indication is ongoing in several other countries 
worldwide. In the US, dupilumab is authorized for use as an add-on maintenance treatment of 
adults and pediatric patients aged 6 years and older with moderate-to-severe asthma characterized 
by an eosinophilic phenotype or with oral corticosteroids (OCS) dependent asthma; in the EU as 
an add-on maintenance treatment for adult and adolescent (12 years and older) patients as well as 
in children 6 to 11 years old with severe asthma with type 2 inflammation characterized by raised 
blood eosinophils and/or raised FeNO who are inadequately controlled with appropriate 
combination therapy (high-dose ICS over 12 years or age, medium-to-high dose ICS in those 
younger) plus another medicinal product for maintenance treatment. In Japan, dupilumab is 
authorized for use in adults and adolescents (aged ≥12 years) with severe or refractory bronchial 
asthma.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 25
Dupilumab is also approved in more than 60 countries worldwide, including US, EU, and Japan, 
for the treatment of adults with AD, in over 60 countries for use in adolescent patients (≥12 years) 
with atopic dermatitis (AD) and in over 50 countries for use in pediatric patients (age 6-11 years) 
with AD. In the US and Europe dupilumab is also approved for AD pediatric patients of 6 months 
to 5 years of age.
In addition, dupilumab is approved in over 50 countries worldwide, as an add-on maintenance 
treatment for the treatment of adults in chronic rhinosinusitis with nasal polyposis (CRSwNP).
Dupilumab is also approved in the US and Europe for the treatment of adult and pediatric patients, 
aged 12 years and older, with eosinophilic esophagitis (EoE), and for the treatment of adult 
patients with prurigo nodularis (PN).
This study in patients with asthma aims to gain insight into the effect of dupilumab on airway 
changes and on lung function improvement. The combination of clinical outcomes (FEV1),
Asthma Control Questionnaire (ACQ), forced oscillometry (FOT), biomarkers (FeNO) and 
functional imaging will provide further characterization of dupilumab’s unique mechanism of 
action (MoA). The study is medically and scientifically justified. The imaging study is designed to 
fulfill an unmet need by providing further insights into how dupilumab may improve lung 
function and reduce airway inflammation, and if the aims are achieved, it will help HCPs 
understanding dupilumab's MoA, therefore supporting optimal therapeutic management.
The functional imaging will be performed using HRCTs which will provide scientifically useful 
information on bronchodynamics and hyperinflation, airway resistance, airway wall thickness, 
ventilation defects, mucus plugging that cannot be obtained with another method. 
The protocol entails that each participant will receive 3 HRCT scans (at D1, W4 and W24), each 
comprised by 2 acquisitions, respectively on full inspiration (total lung capacity) and end 
expiration (functional residual capacity) utilizing respiratory gating. Therefore, each participant
will be exposed to a total of 6 HRCT acquisitions.
The effective radiation dose estimated from each research HRCT, assuming an average 
acquisition protocol in a modern CT scanner (at least 64 slices with radiation reduction options) is 
approximately 1.8 mSv. Assuming 6 HRCT acquisitions per participant, the average cumulative 
dose per participant will be approximately 10.8 mSv (30, 31, 32, 33).
The natural background radiation exposure form natural sources is approximately 3.0 mSv. 
Hence, total radiation from the CT scans in this study is approximately equal to less than 3.5 years 
of exposure to natural background radiation. 
The Health Physics Society recommends against quantitative estimation of health risks below an 
individual dose 50 mSv in one year, given that the risks of health effects are either too small to be 
observed or are nonexistent.   
Radiation-related risks due to HRCT are exclusively stochastic effects, primarily cancer
induction, given that current diagnostic doses of less than 10 mSv are well below the threshold for 
deterministic effects, which generally start at 2000 mSv (2 Gy) (2, 3).
The estimated additional relative risk of all cancers from the International Commission of 
Radiologic Protection published in 2007 (2) is 0.005% per each mSv of radiation dose. This is a 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 26
very small number in comparison with the baseline incidence of all cancers, which is orders of 
magnitude higher (it is estimated that the lifetime risk of developing any cancer can be as high as 
30%). Therefore, the radiation risk of a single chest CT performed with dose-reduction techniques 
is considered negligible.
Based on the UK Health Protection Agency classification of health risks related to radiation 
exposure, the proposed study falls into the “low risk” category, which implies 1 in 10 000–1 in 
1000 risk. 
In summary, the risks associated with the total cumulative radiation doses of HRCTs performed as 
part of this study are either too small to be observed or nonexistent. Therefore, the low risks of 
radiation-induced carcinogenesis associated with 6 HRCT acquisition in this research protocol do 
not outweigh the benefits of dupilumab treatment.
For further information on radiation exposure, please refer to Appendix 9 (Section 10.9).
Dupilumab is being administrated as per already studied dose regimen (loading dose of 600 mg of 
dupilumab (2x 300 mg dupilumab SC) on Day 1, followed by 300 mg every 2 weeks (Q2W) which 
demonstrated positive benefit/risk (22, 34, 35).
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies.
As of 28 September 2022, overall approximately, 14 056 participants were enrolled in the 
development program for dupilumab and are included in the safety population: 564 as healthy 
volunteers, 5009 from AD studies (including hand and foot dermatitis), 468 from eosinophilic 
esophagitis studies, 275 from allergy (grass and peanut) studies, 59 from the bullous pemphigoid 
study, 51 from the allergic bronchopulmonary aspergillosis study and 7630 from asthma, 
CRSwNP, chronic rhinosinusitis without nasal polyposis, allergic fungal rhinosinusitis, COPD,
PN, chronic spontaneous urticaria, chronic inducible cold urticaria and chronic pruritis of 
unknown origin studies.
Based on the available sales figures and World Health Organization defined daily dose of 21.4 mg 
for parenteral formulations, the cumulative patient exposure in marketed experience is estimated 
to be 926 369 patient years from 01 March 2017 through 30 September 2022, including 
220 161 patient years during the interval period from 01 April 2022 through 30 September 2022.
The adverse drug reactions identified to date for dupilumab include injection site reactions, 
conjunctivitis (including allergic and bacterial), oral herpes, herpes simplex, blepharitis, dry eye, 
eye pruritus, keratitis, ulcerative keratitis, eosinophilia, enterobiasis and anaphylactic reaction, 
angioedema, serum sickness and arthralgia. These adverse drug reactions occur with relatively 
low frequency with dupilumab treatment, and were generally mild or moderate, transient, and 
manageable. More significant serious allergic reactions were very rare. Importantly, no increased 
overall infection risk was observed in patients treated with dupilumab. 
Systemic hypersensitivity has been established as an important identified risk with dupilumab. As 
protein therapeutics, all monoclonal antibodies are potentially immunogenic. Rare serious and 
systemic hypersensitivity reactions have been observed in the dupilumab program including 
serum sickness/serum sickness-like reaction in the adult AD program and anaphylaxis related to 
dupilumab in the adult asthma clinical trials.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 27
An important potential risk for dupilumab is “eosinophilia associated with clinical symptoms in 
asthma patients”. The observed increase in eosinophil count is transient, which is consistent with 
the current understanding of the mechanism of action of dupilumab. In dupilumab asthma studies, 
a small number of patients with asthma experienced serious systemic eosinophilia presenting with 
clinical features of eosinophilic pneumonia or vasculitis consistent with eosinophilic 
granulomatosis with polyangiitis, conditions which are often treated with systemic corticosteroid 
therapy. These events have been seen in other drug development programs for severe asthma and 
usually, but not always, have been associated with the reduction of OCS therapy suggesting 
possible unmasking of these conditions with tapering of corticosteroids during dupilumab therapy. 
The association of dupilumab treatment and these events has not been established. Health care 
providers should be alert to eosinophilia associated with vasculitic rash, worsening of pulmonary 
symptoms, pulmonary infiltrate, cardiac complications, and/or neuropathy presenting in their 
patients, especially upon reduction of systemic corticosteroids.
Patients with known helminth infections were excluded from participation in clinical studies, 
therefore it is not known if dupilumab will influence the immune response against helminth 
infections. Consequently, patients with pre-existing helminth infections should be treated for their 
helminth infection before initiating therapy with dupilumab.
The safety data available to date, in conjunction with the risk monitoring and mitigation strategies 
in the study protocol, and the clinical benefit of dupilumab demonstrated in multiple Type 2
approved indications (AD, asthma, CRSwNP) support a favorable benefit-risk profile for 
dupilumab.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of dupilumab may be found in the in the Investigator’s Brochure (IB) and 
its updates.
Benefit/risk assessment related to COVID-19
The Sponsor recognizes that the coronavirus disease 2019 (COVID-19) pandemic is having an 
impact on the conduct of clinical trials. The Sponsor is monitoring the situation closely and may 
suspend study screening activities until the impact of the COVID-19 pandemic is deemed 
manageable and no longer interfering with the conduct of trials at individual sites, and patients 
can safely participate in this study. The continuity of clinical study conduct and oversight may 
require implementation of temporary or alternative mechanisms. Thus, a mitigation plan has been 
put in place at study level, all the contingency measures are described in Appendix 9
(Section 10.9). The participants will be properly informed on all these options by the investigators 
before the implementation of the contingency measures, as mentioned in the Informed Consent 
Form. Implementation of such mechanisms may differ country by country, depending on country 
regulations and local business continuity plans.
Based on the aforementioned potential benefits to patients participating in LPS15834, and the
appropriate precautions and mitigations instituted to manage any potential impact of COVID-19
on the conduct of the trial and the safety of the patients, the Sponsor assesses that the overall
benefit-risk balance is positive for the conduct of and patient participation in this trial.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 28
3
OBJECTIVES AND ENDPOINTS
Table 1 - Objectives and endpoints
Objectives
Endpoints
Primary
x
To assess the effect of dupilumab on 
lung inflammation and related changes in 
airway volumes detectable by functional 
respiratory imaging.  
x
Proportion of participants achieving FeNO <25 parts per billion 
(ppb) at Week 24 
x
Percent change from baseline to Week 24 in untrimmed distal 
airway volumes corrected for lung volume ([s]iVaw) at total 
lung capacity (TLC) 
 
Secondary
x
To evaluate the effect of dupilumab at 
Week 24 on bronchodynamics, 
hyperinflation, airway resistance, airway 
wall thickness, ventilation defects and 
mucus plugging derived from high-
resolution computed tomography (HRCT) 
scans, patient-reported outcomes, FeNO 
and spirometry.  
Efficacy endpoints: 
x
Percent change from baseline to Week 24 in untrimmed distal 
airway volumes corrected for lung volume ([s]iVaw) at 
functional residual capacity (FRC) 
x
Percent change from baseline to Week 24 in trimmed distal 
airway resistance corrected for lung volume ([s]iRaw) at TLC 
x
Percent change from baseline to Week 24 in trimmed distal 
airway resistance corrected for lung volume ([s]iRaw) at FRC 
x
Change from baseline to Week 24 in global lung lobar 
volumes (iVlobes) at TLC 
x
Change from baseline to Week 24 in HRCT-based internal 
airflow distribution (IAD) for each lung zone 
x
Change from baseline to Week 24 in image-based 
ventilation/perfusion (iV/Q) at TLC for each lung zone 
x
Change from baseline to Week 24 in global lung mucus 
scoring (UCSF mucus scoring) 
x
Change from baseline to Week 24 in FeNO 
x
Change from baseline to Week 24 in pre-bronchodilator FEV1 
x
Change from baseline to Week 24 in post-bronchodilator FEV1 
x
Change from baseline to Week 24 in ACQ-7 
x
To evaluate safety of dupilumab 
Safety:  
x
Incidence of treatment emergent adverse events (TEAE) and 
serious adverse events (SAE) including clinically significant 
changes in vital signs and laboratory abnormalities  
x
Incidence of adverse events of special interest (AESI) 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 29
Objectives
Endpoints
3.1
APPROPRIATENESS OF MEASUREMENTS
The efficacy and exploratory assessments will be done using imaging results (HRCT), coupled 
with clinical outcomes (FEV1), patient-reported outcomes [ACQ and AQLQ(S)], biomarkers 
(FeNO) and forced oscillation technique (FOT). The HRCT scans, spirometry, and FOT 
assessments will be performed using central reading.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 30
4
STUDY DESIGN
4.1
OVERALL DESIGN
This is a Phase 4 randomized, multinational study with a 24-week double-blind 
placebo-controlled period to explore the effect of dupilumab on airway inflammation through 
assessments of biomarkers, mucus plugging, and other lung imaging parameters in participants
with asthma.
Study participation for each participant will be a total of minimum 29 weeks and up to 41 weeks.
The study includes 3 study periods:
x
Screening period: 4 weeks (±1 week), from signed informed consent to randomization.
x
Randomized, placebo-controlled treatment period: 24 weeks from baseline (Day 1).
x
Post treatment follow-up period: up to 12 weeks or until the participants switch to 
commercialized dupilumab (or other biologic products), whatever comes first.
Participants who fulfill the inclusion criteria and do not meet any of the exclusion criteria will be 
randomized (2:1) to one of the following investigational medicinal products (IMP).
x
Dupilumab: participants will receive a loading dose of 600 mg of dupilumab (2 x 300 mg 
dupilumab SC on Day 1, followed by 300 mg every 2 weeks (Q2W) for 24 weeks.
x
Placebo: participants will receive 2 x 2 mL placebo injections SC on Day 1, then 1 placebo 
injection Q2W for 24 weeks.
Randomization will be stratified by ICS dose level (medium/high- no less than 40% in ‘high ICS’ 
stratum) and region (Eastern Europe/ROW). In total, no more than 40% participants should be in 
"Eastern Europe" strata.
Study intervention discontinuation follow-up
Participants who prematurely discontinue the study intervention (prior to completing the 24-week
treatment period) should attend an Early Treatment Discontinuation (ETD) visit at the earliest 
convenience with all the assessments planned for the End of Treatment (EOT) visit (V5), except 
HRCT and IMP. In particular cases when the ETD visit is close to a regular study visit, ETD 
could be merged and will replace the regular visit (See Section 7.1.1).
In addition, the participants will be asked and encouraged to complete all the remaining study 
visits according to the visit schedule until and including the EOT visit (V5).
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
A randomized, placebo-controlled study design where the effects of the IMP is assessed over the 
stable dose of maintenance therapy is considered to be the most appropriate design to investigate 
the objectives of this study. A randomization ratio of 2:1 for the active treatment versus placebo 
was incorporated into the study design in order to limit the number of participants exposed to 
placebo.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 31
4.3
JUSTIFICATION FOR DOSE
The dose regimen of SC dupilumab selected for this study is 300 mg Q2W. Participants will 
receive an initial loading dose of 600 mg (2 x 300 mg) dupilumab on Day 1, and Q2W dosing will 
commence 2 weeks after the loading dose. The administration of the loading dose of dupilumab 
will allow systemic concentrations to reach target saturation, potentially reducing the time to onset 
of clinical effect.  
Proof of concept has been established in the ACT11457 study (34) with 300 mg weekly dosing.
One hundred and 4 participants with persistent, moderate-to-severe asthma and a blood eosinophil 
count of at least 300 cells/μL or a sputum eosinophil level of at least 3%, partially controlled or 
uncontrolled by medium-to-high doses of ICS plus long-acting β2 agonists (LABA
(fluticasone/salmeterol, budesonide/formoterol, or mometasone/formoterol) were randomized to 
the study. The study showed significant efficacy in a population of mostly severe asthmatics with 
poor asthma control and decreased lung function with mostly high doses of ICS in combination 
with a LABA.
The results from the Phase 2b dose ranging study (DRI12544) (35) showed that 300 mg Q2W and 
200 mg Q2W treatment with dupilumab provided a significant improvement on FEV1 at Week 12 
and a statistically significant reduction in the annualized rate of severe exacerbations when 
compared to placebo. Both dose regimens provided comparable efficacy on most of the efficacy 
endpoints. Both doses were safe and well tolerated with a profile comparable to that seen with 
placebo except for an increased number of injection site reactions. To further characterize the 
optimal regimen for patients, both regimens were assessed in the Phase 3 study (QUEST) (22),
which confirmed the findings from previous studies, showing comparable efficacy and safety
profile in both 200 mg Q2W and 300 mg Q2W dose regimens, with an overall positive 
benefit-risk profile for dupilumab in comparison to placebo.
The focus of this study is to characterize the anti-inflammatory effect of dupilumab, which will be 
mainly evaluated using FRI analyses. In order to ensure maximum anti-inflammatory effect of 
dupilumab, the highest approved dose (300 mg) has been selected.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the post treatment follow-up visit (V6).
The end of the study is defined as the date of the last visit of the last participant in the study.
For the participants who permanently discontinue the planned treatment, the recommended 
follow-up is described in Section 4.1.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 32
5
STUDY POPULATION
Selection criteria are in line with the approved indication and refer to labeling information. 
Contraindications, precautions of use and warnings were considered.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
I 01.
18 to 70 years of age inclusive with the diagnosis of asthma based on Global Strategy for 
Asthma Management and Prevention (GINA) 2019 (1) at the time of signing the informed 
consent.
Type of participant and disease characteristics
I 02.
History of ≥1 exacerbation(s) in the previous year before V1.
Exacerbation is defined as deterioration of asthma that results in emergency treatment, 
hospitalization due to asthma, or treatment with systemic steroids.
I 03.
Uncontrolled moderate-to-severe asthma (ACQ-5 ≥1.5) at V1 and V2, prior to
randomization.
I 04.
Pre-bronchodilator FEV1 ≤80% of predicted normal at V1 and V2, prior to randomization.
I 05.
Exhibit bronchodilator reversibility (≥12% and 200 mL improvement in FEV1 post SABA 
administration) during screening, prior to randomization.
I 06.
Blood eosinophil ≥300 cells /μL and FeNO ≥25 ppb during screening and prior to 
randomization.
NOTES:
-
Historical values of blood eosinophil count meeting the eligibility criterion measured 
within 6 months prior to SV1 in the absence of OCS treatment are allowed.
-
FeNO value to be checked for eligibility at V2 as well.
I 07.
Existing treatment with medium to high dose ICS in combination with a second controller 
(eg, LABA, LTRA) ± a third controller. The dose regimen should be stable ≥1 month prior 
V1 and during screening.
I 08.
Willing and able to comply with all clinic visits and study related procedures.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 33
Weight
Not applicable.
Sex
I 09.
Male and Female
Contraceptive used by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly during the intervention period 
and up to 12 weeks after last dose of study intervention or until the participants switch to 
commercialized dupilumab (or other biologic products), whatever comes first, as described in 
Section 10.4 (Appendix 4).
Male participants are eligible to participate if they agree to contraception conditions described in
Section 10.4 (Appendix 4) during the intervention period and up to 12 weeks after last dose of 
study intervention or until the participants switch to commercialized dupilumab (or other biologic 
products), whatever comes first.
Informed Consent
I 10.
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1)
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
Medical conditions 
E 01. Current smoker (cigarette or e-cigarette) or cessation of smoking within 1 year prior to
randomization.
E 02. Previous smoker with a smoking history >10 pack-years.
E 03. Known hypersensitivity to dupilumab or any of its excipients.
E 04. A subject who experiences an asthma exacerbation (defined as a deterioration of asthma 
that results in emergency treatment, hospitalization due to asthma, or treatment with 
systemic steroids) during screening.
E 05. Current acute bronchospasm or status asthmaticus.
E 06. Diagnosed pulmonary (other than asthma) or systemic disease associated with elevated 
peripheral eosinophil counts.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 34
E 07. Active tuberculosis, latent untreated tuberculosis or a history of incompletely treated 
tuberculosis or non-tuberculous mycobacterial infection unless it is well documented by a 
specialist that the participant has been adequately treated and the treatment with a biologic 
agent can be initiated, in the medical judgment of the Investigator and/or infectious disease 
specialist. Tuberculosis testing would only be performed on a country by country basis 
according to the routine clinical practice and the local guidelines if required by Regulatory 
Authorities or Ethics Committees.
E 08. History or clinical evidence of COPD including Asthma-COPD Overlap Syndrome 
(ACOS) or any other significant lung disease (eg, lung fibrosis, sarcoidosis, interstitial 
lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome).
E 09. History or current evidence of clinically significant disease in any non-respiratory system 
(eg, cardiovascular, hepatic, nervous system, gastrointestinal, endocrinological, 
rheumatological, dermatological), which, in the judgment of the Investigator, could 
interfere with the study or require treatment that might interfere with the study.
E 10. Current evidence of clinically significant oncological disease, which in the opinion of the 
investigator may interfere with the objectives of the study or put the subject at undue risk.
E 11. Participants with any of the following results at V1:
-
Positive (or indeterminate) hepatitis B surface antigen (HBsAg) or,
-
Positive IgM hepatitis B core antibody (HBcAb) or,
-
Positive total HBcAb confirmed by positive HBV DNA or,
-
Positive hepatitis C virus antibody (HCVAb) confirmed by positive HCV RNA.
E 12. History of human immunodeficiency virus (HIV) infection or positive HIV serology at V1.
Prior/concomitant therapy 
E 13. Any biologic therapy (including experimental treatments and dupilumab) or any other 
biologic therapy/immunosuppressant within 3 months prior to V1.
E 14. Treatment with live (attenuated) vaccine within 4 weeks before V1.
For participants who have vaccination with live, attenuated vaccines planned during the 
course of the study (based on national vaccination schedule/local guidelines), it will be 
determined, after consultation with a physician, whether the administration of vaccine can 
be postponed until after the end of the study, or preponed to before the start of the study 
without compromising the health of the participant:
-
Participants for whom administration of live (attenuated) vaccine can be safely 
postponed would be eligible to enroll into the study.
-
Participants who have their vaccination preponed can enroll in the study only after a 
gap of 4 weeks following administration of the vaccine.
E 15. Treatment with oral corticosteroids (OCS) within 2 weeks prior to V1.
E 16. Enrolled in other ongoing studies regardless of the investigational product.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 35
E 17. Treatment with an investigational drug within 1 month or within 5 half-lives (if known), 
whichever is longer, prior to V1.
Diagnostic assessments 
E 18. Suspected or high risk of parasitic infection (helminthic infection), unless clinical and (if 
necessary) laboratory assessments have ruled out active infection prior to randomization.
Other exclusions 
E 19. Females who are lactating, breastfeeding, or who are pregnant.
E 20. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized.
E 21. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the International Council for Harmonisation [ICH] Good Clinical Practice [GCP]
Ordinance E6).
E 22. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals.
E 23. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study.
E 24. Any country-related specific regulation that would prevent the subject from entering the
study.
5.3
LIFESTYLE CONSIDERATIONS
No restrictions are required.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently eligible to be randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.
Reasons for screen failure may be unfulfilled eligibility criteria and withdrawal of consent during 
screening period, between screening and randomization.
Participants who do not meet the eligibility criteria for participation in this study and for whom 
resolution of the screen failure reason may not be expected within a reasonable time frame, will 
be deemed as screen failure. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 36
Rescreening: The participants may be rescreened once during the open screening period and all 
the screening procedures will be repeated; a different participant identification number will be 
issued.
There is no requirement for a waiting period between the screen failure date and the rescreening
date. The Interactive voice recognition system (IVRS)/ Interactive web response system (IWRS)
report will flag rescreened participants. Participants that are rescreened must sign a new consent 
form and all Visit 1 procedures must be repeated.
Retesting: If certain dynamic laboratory tests do not meet the eligibility criteria, these laboratory 
assessments may be repeated, at the discretion of the Investigator, if it is judged that they are
likely to return to acceptable range for study inclusion within the screening visit window (21 to 
35 days) prior to Day 1. These participants do not need to sign a new ICF and a new participant
number will not be allocated.
Retesting of eosinophil values is allowed up to 3 times during the screening period to meet
inclusion criteria for showing eosinophil count ≥300 cells/μL (I 06) before randomization. This is 
only required if the participant does not have the blood eosinophils measured within 6 months 
prior to V1 in the absence of OCS treatment.
A participant who is unable to complete a successful spirometry effort as defined by American 
Thoracic Society (ATS) criteria or assessed by the Investigator or did not meet the eligibility 
criterion for pre-BD FEV1 at V1 can be retested 1 additional time during the screening period.
Up to three attempts may be performed for the reversibility test during the screening period to 
meet the eligibility criterion. This is only required if a reversibility test meeting the eligibility 
criterion was not performed within 6 months prior to V1.
FeNO can be assessed one additional time during screening period if FeNO value measured at V1 
does not meet the eligibility criterion.
5.5
CRITERIA FOR TEMPORARILY DELAYING SCREENING, RANDOMIZATION, OR 
STUDY INTERVENTION ADMINISTRATION
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix 9 (Section 10.9) should be considered for the screening, randomization, or 
administration of study intervention.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 37
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
6.1
STUDY INTERVENTION(S) ADMINISTERED
Table 2 - Overview of study interventions administered
Intervention name
Dupilumab
Placebo
Type
Biological/Vaccine 
Other 
Dose formulation
solution 
solution 
Unit dose strength(s)
150 mg/mL 
Not applicable 
Dosage level(s)
Loading dose of 600 mg at Day 1a 
following 300 mg Q2W injections 
2 x 2 mL placebo injections at Day 1 following 
Q2W injections 
Route of administrationb
SC injection 
SC injection 
IMP and NIMP
IMP 
IMP 
Packaging and labeling 
One glass prefilled syringe packed in a 
participant kit box. Both glass prefilled 
syringe and box will be labeled as 
required per country requirement.  
One glass prefilled syringe packed in a 
participant kit box. Both glass prefilled 
syringe and box will be labeled as required 
per country requirement.
aIf HRCT scan cannot be performed at D1 due to logistic reasons, it can be scheduled the next day. In this particular situation the investigator 
should ensure that the IMP loading dose is administered after the HRCT scan, at D1+1 day. 
bA subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the abdomen or the upper arms, so that the same site 
is not injected twice during consecutive administrations. Injection in the upper arms can only be done by a trained person (caregiver) trained by 
Investigator or delegate or health care professional but not the participants themselves. 
Investigational medicinal product(s)
Dupilumab and matching placebo will be supplied in prefilled syringes that are visually 
indistinguishable.
The IMP is administered every 14±3 days (Q2W) during the 24-week treatment period.
Dupilumab 300 mg
x
Formulation: a 150 mg/mL dupilumab solution in a prefilled glass syringe to deliver 
300 mg in a 2 mL injection.
x
Route of administration: SC injection.
x
Dose regimen: Q2W after an initial loading dose of 600 mg (2 injections of 300 mg) on 
Day 1.
Matching Placebo 
x
Formulation: matching placebo will be supplied as an identical formulation to the active 
formulation without dupilumab, in a prefilled syringe to deliver placebo in a 2 mL
injection.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 38
x
Route of administration: SC injection.
x
Dose regimen: Q2W after an initial loading dose (2 injections) on Day 1.
In specific situations, between the protocol-scheduled on-site visits, interim visits may be required 
for IMP dispensing. As an alternative to the on-site IMP dispensing, IMP may be supplied from 
the site to the participant via a Sponsor-approved courier company where allowed by local 
regulations and approved by the participant.
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9 (Section 10.9).
Investigational medicinal product will be administered by the Investigator/health care professional 
or designee following clinical procedures and blood collection. Participants should be monitored 
for at least 30 minutes after administration of all IMP injections at site. The monitoring period 
may be extended as per country-specific or local site-specific requirements.
Subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the 
abdomen or the upper arms, so that the same site is not injected twice during consecutive 
administrations. Injection in the upper arms can only be done by a trained person (caregiver) or
health care professional but not by the participants themselves.
The Investigator or delegate will train the participant (or caregiver) how to prepare and inject IMP 
at Visit 2 and retrain if needed during the treatment period. The site staff will inject the first dose 
of the 2 injections at D1. The participant (or caregiver) will perform the second injection under 
the supervision of the Investigator or delegate. This training must be documented in the 
participant’s study file. Participant or caregiver should be trained by the site staff to recognize 
potential signs and symptoms of hypersensitivity reaction and to self-monitor/monitor at home for 
at least 30 minutes (or longer per country specific or local site-specific requirements) following 
injection. In case of hypersensitivity symptoms, the participant should contact healthcare
provider/emergency.
Participants should be instructed to avoid missing any dose of medication during the study. Any 
participant who misses one dose should be reminded to be diligent, in order to avoid further 
missing doses thereafter. In case of missed dose(s), no loading dose of 2 injections will be 
administered when restarting the treatment, whatever the number of missed doses. The 
participants should continue their scheduled IMP treatment and visits, even if more than
2 consecutive doses were missed.
Between the protocol-scheduled on-site visits, the investigational product (dupilumab or placebo) 
will be administrated at home by the participant himself/herself or by a caregiver or by a nurse or 
at the study site. A home dosing diary for collecting information related to at home injections will 
be provided. The home dosing diary will be kept as source data in the participant’s study file. 
Non-investigational medicinal product(s)
Participants should be on a stable dose of medium to high dose ICS in combination with a second 
controller medication (eg, LABA, LTRA, theophylline) ≥1 month prior to V1 and during the 
Screening Period (Table 3).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 39
Participants requiring a third controller for their asthma will be considered eligible for this study,
also at a stable dose ≥1 month prior to V1 and during the Screening Period.
x
Formulation and route(s) of administration: refer to label.
x
Dose regimen: As prescribed.
The asthma background therapy should be maintained on a stable dose during the study treatment 
period.
Short-acting β2 agonists (SABA) may be used as rescue medication during the study if needed.
Systemic corticosteroids are allowed for the treatment of severe asthma exacerbations.
Table 3 - Low, medium and high daily doses of inhaled corticosteroids (mcg)
Inhaled corticosteroid
Low
Medium
High
Beclometasone dipropionate (CFC) 
200-500 
>500-1000 
>1000 
Beclometasone dipropionate (HFA) 
100-200 
>200-400 
>400 
Budesonide (DPI) 
200-400 
>400-800 
>800 
Ciclesonide (HFA) 
80-160 
>160-320 
>320 
Fluticasone furoate (DPI) 
100 
n.a. 
200 
Fluticasone propionate (DPI) 
100-250 
>250-500 
>500 
Fluticasone propionate (HFA) 
100-250 
>250-500 
>500 
Mometasone furoate 
110-220 
>220-440 
>440 
Triamcinolone acetonide 
400-1000 
>1000-2000 
>2000 
CFC= Chlorofluorocarbon propellant; DPI=Dry powder inhaler; HFA= Hydrofluoroalkane propellant 
The GINA table above refers to metered doses. This is not a table of equivalence, but an
estimated clinical comparability, based on available studies and product information. Categories 
of “low”, “medium” and “high’ doses are based on published information and available studies, 
including direct comparisons where available. Doses may be country-specific depending on 
labeling requirements. For new preparations, manufacturer’s information should be reviewed 
carefully, products containing the same molecule may not be clinical equivalent (1). The list 
presents examples of ICS and might support future changes.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound must be 
managed according to the rules provided by the Sponsor in the Pharmacy manual.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 40
The expiry date is mentioned on the IMP labels (when required by country regulation), and 
storage conditions are written on the IMP labels.
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator
and authorized site staff.
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of used and unused study
interventions are provided in a Pharmacy manual.
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor.
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.6).
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards.
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
Randomization
A randomized treatment kit number list will be generated centrally by Sanofi. The IMP
(dupilumab or placebo) will be packaged in accordance with this list. 
The Sanofi Clinical Supplies team will provide the randomized treatment kit number list and the 
Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system. This centralized treatment allocation system will generate the participant
randomization list according to which it will allocate the treatments to the participants.
The Investigator obtains treatment kit numbers at randomization (V2) and subsequent scheduled 
visits via an Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) 
that will be available 24 hours a day.  
Participants who meet the entry criteria will be randomized to receive either dupilumab or 
placebo. Participants will be randomized using a 2:1 randomization ratio for dupilumab 300 mg 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 41
Q2W and placebo Q2W. Randomization will be stratified by ICS dose level (medium and high-
no less than 40% in ‘high ICS’ stratum) and region (Eastern Europe/ROW). In total, no more than 
40% participants should be in "Eastern Europe" strata.
A randomized participant is defined as a participant who is registered and assigned with a 
treatment kit number from the centralized treatment allocation system, as documented from its log 
file. A participant cannot be randomized more than once in the study.
Returned IMP from the participant’s home should not be re-dispensed to the participants.
Blinding
Dupilumab and placebo will be provided in identically matched 2 mL prefilled syringes. To 
protect the blind, each treatment kit of 2 mL (dupilumab/placebo) glass prefilled syringes will be 
prepared such that the treatments (dupilumab and its matching placebo) are identical and 
indistinguishable and will be labeled with a treatment kit number. The randomized treatment kit 
number list will be generated by Sanofi.
Both the participant and Investigator will be blinded to assigned active drug or placebo. Study 
participants, investigators, and study site personnel will not have access to the randomization 
(treatment codes).
Randomization code breaking during the study
In case of an AE, the code must only be broken in circumstances when knowledge of the IMP is 
required for treating the participant.
Code breaking can be performed at any time by using the proper module of the IVRS/IWRS 
and/or by calling any other phone number provided by the Sponsor for that purpose. If the blind is 
broken, the Investigator must document the date, time of day, and reason for code breaking.
Participant withdrawal will only occur when the code break call is made at the site level, not the
study level. This means that if the Emergency Unblinding transaction is performed by the 
Investigator (ie, at the site level), then the participant will be withdrawn from treatment. However, 
if the Emergency Unblinding transaction is performed by the Global Safety Officer (ie, at the 
study level, as the Global Safety Officer is not site based), then the participant will not be 
withdrawn from treatment. Sponsor safety staff may unblind the intervention assignment for any 
participant with an SAE for the purpose of expedited regulatory reporting (see Section 8.3.2).
Sponsor staff involved in the conduct of the study will remain blinded to the participant 
intervention assignment.
Participants who are withdrawn from treatment should be encouraged to remain in the study and 
the Investigator should discuss with them the key visits to attend (see Section 7.1.1).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 42
6.4
STUDY INTERVENTION COMPLIANCE
Measures taken to ensure and document treatment compliance and IMP accountability include:
x
Proper recording of treatment kit number as required on appropriate electronic case report 
form (e-CRF page for accounting purposes.
x
All medication treatment kits (whether empty or unused) are returned by the participant at 
each visit when a treatment dispensing is planned:
-
The completed home dosing diary (returned to the site at each visit), returned treatment 
kit boxes and any unused prefilled syringes will be used for drug accountability 
purposes. 
x
The Investigator or designee tracks treatment accountability/compliance, either by home
dosing diary, or by counting the number of used treatment kits and fills in the appropriate 
page of the participant treatment log. 
The monitor in charge of the study then checks the data entered on the IMP administration page 
by comparing them with the IMP that has been retrieved and the participant treatment log form. 
The Investigator or pharmacist will also keep accurate records of the quantities of the IMP
received, dispensed, used, unused, and returned/destroyed. The product accountability and
inventory form/system are to be updated each time IMP is dispensed.
All used, partially used, or unused treatments will be destroyed at each respective site, after
accountability and reconciliation have been performed. The site must not destroy the unused IMP 
unless the Sponsor provides written authorization. Confirmation of destruction will be provided 
to the Sponsor.
6.5
CONCOMITANT THERAPY
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with:
x
Reason for use.
x
Dates of administration including start and end dates.
x
Dosage information including dose and frequency.
Prohibited concomitant therapy: 
x
Any biologic therapy (including experimental treatments and dupilumab) or any other 
biologic therapy/immunosuppressant.
x
Treatment with live (attenuated) vaccine.
x
Treatment with systemic corticosteroids (systemic corticosteroids can only be used to treat 
an asthma exacerbation, and are not allowed to be used for other conditions)
During the FU period the asthma treatment will be administered based on Investigator's medical 
judgment and normal clinical practice.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 43
6.6
RESCUE MEDICINE
The SABA rescue medications may be used. The rescue medication will be administered as 
prescribed by the physician. Systemic corticosteroids are allowed for the treatment of asthma 
exacerbations. Although the use of rescue medications is allowed at any time during the study, 
every attempt should be made to perform all necessary measurements prior to the use of rescue 
medications. If SABA rescue medications are given prior to any measurements, including HRCT,
the measurements should be performed after a wash-out time mentioned in Table 4 (Section 8.1).
In case of severe asthma exacerbations treated with systemic corticosteroids, the visits can be 
postponed up to 1 week to ensure the wash-out period (Table 4) is completed before performing 
HRCT scan, FeNO, FOT, and spirometry. In case this is not possible (eg, a participant
experiences an exacerbation shortly before the scheduled visit), the procedures can be performed 
as planned, but it should be recorded that the participant had recently taken systemic 
corticosteroids. The date and time of rescue medication administration as well as the name and 
dosage regimen of the rescue medication must be recorded.
6.7
DOSE MODIFICATION
Not applicable.
6.8
INTERVENTION AFTER THE END OF THE STUDY
Not applicable.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 44
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Withdrawal of consent for treatment (ie, treatment discontinuation at participant request) should 
be distinguished from (additional) withdrawal of consent for follow-up visits. The site should 
document any case of withdrawal of consent.
7.1
DISCONTINUATION OF STUDY INTERVENTION
7.1.1
Definitive discontinuation
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety and efficacy. See the schedule of activities (SoA) for data to be 
collected at the time of discontinuation of study intervention (Section 1.3).
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in the algorithm Increased in
alanine aminotransferase (ALT) (Section 10.5) or if the Investigator believes that it is in best 
interest of the participant.
List of criteria for permanent discontinuation of study intervention
Every effort should be made to document the reason(s) for discontinuation of study intervention 
and this should be documented in the e-CRF.
Participants may be withdrawn from the study intervention for the following reasons:
x
At their own request or at the request of their legally authorized representative (legally
authorized representative means an individual or judicial or other body authorized under
applicable law to consent on behalf of a prospective participant to the participant 's 
participation in the procedure(s) involved in the research).
x
If, in the Investigator's opinion, continuation in the study would be detrimental to the
participant 's well-being.
x
At the specific request of the Sponsor.
x
If the Emergency Unblinding transaction is performed by the Investigator (ie, at the site 
level).
x
Pregnancy.
x
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment.
x
Any opportunistic infection, such as tuberculosis or other infections whose nature or 
course may suggest an immunocompromised status.
x
Serum ALT >3 upper limit of normal (ULN) and Total Bilirubin >2 ULN 
(see Section 10.5, Appendix 5).
x
Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(see Section 10.5, Appendix 5). “Baseline” refers to ALT sampled at baseline visit or, if 
baseline value is unavailable, to the latest ALT value before the baseline visit.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 45
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of definitive discontinuation of the IMP for the concerned participant.
Handling of participants after permanent study intervention discontinuation:
Participants who prematurely discontinue the study intervention (prior to completing the 
24-weeks treatment period) should attend an ETD visit at earliest convenience with all procedures 
required at the EOT visit, except HRCT and IMP. In particular cases when the ETD visit is closed 
to a regular study visit, ETD could be merged and will replace the regular visit. In addition, the 
participants will be asked and encouraged to complete all the remaining study visits according to 
the visit schedule until and including the EOT visit (V5). Participants will be followed-up
according to the study procedures specified in this protocol in SoA (Section 1.3). Under 
exceptional circumstances when a participant cannot come to the site for the scheduled visit, a 
phone contact can be made after sponsor approval is given. During the phone contact, at least 
information about AEs and concomitant medication should be collected. 
All cases of permanent discontinuation of study intervention should be recorded by the 
Investigator in the appropriate pages of the e-CRF when considered as confirmed.
7.1.2
Temporary discontinuation
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency. For a regional or national emergency declared by a governmental 
agency, contingency measures are included in Appendix 9 (Section 10.9). For all temporary 
intervention discontinuations, duration should be recorded by the Investigator in the appropriate 
pages of the e-CRF.
In addition, the following conditions will be causes for temporary discontinuation of study 
intervention:
x
Infections or infestations that do not respond to medical treatment.
x
Treatment with a live (attenuated) vaccine.
x
Treatment with immunomodulating biologics (including experimental treatments).
x
Treatment with systemic corticosteroids (except systemic corticosteroids used to treat an
asthma exacerbation) or systemic immunosuppressive drugs.
x
Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Appendix 5 (Section 10.5).
7.1.2.1
Rechallenge
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned event was unlikely 
and if the selection criteria for the study are still met (refer to Section 5.1 and Section 5.2).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 46
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9).
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
x
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.
x
Participants who prematurely discontinue the study, should attend an Early Study 
Discontinuation (ESD) visit at the earliest convenience with all the procedures planned for 
the End of Treatment Visit (Visit 5) except IMP, as shown in the SoA (Section 1.3). See 
SoA for data to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed. If the Investigator considers that the time 
from the last HRCT scan exposure is not acceptable, the investigation will not be done.
x
The participant will be permanently discontinued both from the study intervention and 
from the study at that time.
x
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
x
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records.
If participants no longer wish to take the IMP, they will be encouraged to remain in the study.
The investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study.
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any adverse event (AE) information elicited 
must be documented.
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up,
eg, medical record checks. The site should document any case of withdrawal of consent.
Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 47
7.3
LOST TO FOLLOW UP
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
x
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
x
Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
x
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1
(Section 10.1.9).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 48
8
STUDY ASSESSMENTS AND PROCEDURES
x
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed.
x
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
x
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
x
Procedures conducted as part of the participant’s routine clinical management (eg, blood
eosinophil count, reversibility test) and obtained before signing of the ICF may be utilized 
for screening purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
x
The lab tests will be done by the local laboratories, the maximum amount of blood 
collected from each participant over the duration of the study will be according to the 
routine clinical practice in each country and site. As the blood analysis will be performed 
by the local laboratories, any leftover blood sample will not be used for any other research 
purposes related to the study (re-analyses) or for future exploratory use (secondary use).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
x
For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 9 (Section 10.9).
8.1
EFFICACY ASSESSMENTS
Disease-specific efficacy measures
Spirometry
A spirometer that meets the American Thoracic Society(ATS)/European Respiratory Society 
(ERS) recommendations will be used. Spirometry should be performed in accordance with these 
recommendations (36).
For pre-bronchodilator measured parameters, including FEV1 and FVC spirometry will be 
performed after withholding the standard of care asthma treatment as follows:
Table 4 - Wash out period of asthma controllers and rescue medication before HRCT scan and lung 
function assessments
Oral Xanthine derivatives 
Long-acting beta agonists (LABA) (eg, salmeterol) 
72 hours 
24 hours 
Long-acting muscarinic antagonist(LAMA) (eg, Tiotropium) 
48 hours 
Inhaled ICS 
12 hours 
Inhaled ICS/LABA  
24 hours 
Inhaled Ultralong ICS/LABA combinations     
48 hours 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 49
Inhaled and/or nebulized SABAs (eg, salbutamol) 
6 hours 
Inhaled and/or nebulized SAMAs (eg, ipratropium)  
8 hours 
SABA/SAMA combination 
8 hours 
Inhaled and/or nebulized corticosteroid (ICS) 
12 hours 
Long-acting beta agonists (LABA)   
24 hours 
Long-acting muscarinic antagonist (LAMA)  
48 hours 
Inhaled ICS/LABA 
24 hours 
Systemic corticosteroids (oral, IM, IV) 
4 weeks 
This will be verified before performing the measurements.
In case of asthma exacerbations treated with systemic corticosteroids, the visits can be postponed 
up to 1 week to ensure the wash-out period before performing HRCT scan, FeNO, FOT and 
spirometry. In case this is not possible (eg, a participant experiences an exacerbation shortly 
before the scheduled visit), the procedures can be performed as planned, but it should be recorded
that the participant had recently taken systemic corticosteroids.  
For post-bronchodilator FEV1, the measurement should follow the steps as that at screening test 
for reversibility validation. 
At all visits, spirometry should be performed before IMP administration, in the morning, if
possible. The same spirometer and standard spirometric techniques, including calibration, will be 
used to perform spirometry at all visits and, whenever possible, the same person should perform 
the measurements; afternoon/evening is allowable in the exceptional circumstance when morning 
spirometry cannot be performed; spirometry should be done at approximately the same time at 
each visit throughout the study.
Pulmonary function tests will be measured in the sitting position; however, if necessary to 
undertake the testing with the subject standing or in another position, this should be noted on the 
spirometry report. For any subject, the position should be consistent throughout the study. 
Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained 
at every visit. The acceptability criteria must be applied before the repeatability criteria. 
Unacceptable maneuvers must be discarded before applying the repeatability criteria. At least 
2 acceptable curves must be obtained. 
The largest FEV1 and largest FVC should be recorded after the data are examined from all of the 
acceptable curves, even if they do not come from the same curve.
The spirometer must be calibrated following the principles of the ATS/ERS guidelines every day 
that a study subject is seen, and spirometry is carried out. The calibration records should be kept 
in a reviewable log. It is preferred that the calibration equipment (ie, 3-liter syringe) that is used to 
calibrate the spirometer be subjected to a validated calibration according to the manufacturer’s 
specifications. A participant who is unable to complete a successful spirometry effort as defined 
by ATS criteria or evaluated by the investigator or did not meet the eligibility criterion for pre-BD 
FEV1 at V1 can be retested one additional time during the screening period of the study. The 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 50
spirometry will be centrally read. The locally read values of FEV1 will be considered for the 
participant qualification into the study at V1 and V2. For the statistical analysis we will use 
centrally read values. Further details on the procedure will be provided in a separate instructions 
manual.
Reversibility
A reversibility test will be administered following pulmonary function testing after asthma 
medications have been withheld for the appropriate intervals. Subjects will receive 2 to up to 
4 puffs of albuterol/salbutamol from a primed metered dose inhaler (MDI). Alternatively, and 
only if it is consistent with usual office practice (to be documented), reversibility may be 
performed using inhalation of nebulized albuterol/salbutamol. Spirometry may be repeated several 
times within 30 minutes after administration of bronchodilator. Reversibility, which is defined as 
an increase in absolute FEV1 of 12% over the baseline value, with an absolute increase of at least 
200 mL, must be demonstrated within 30 minutes of bronchodilator administration. If the 
participant does not meet the eligibility criterion for reversibility at V1, up to 3 attempts may be 
performed during the screening period. This is only required if a reversibility test meeting 
eligibility criterion was not performed within 6 months prior to V1.
Asthma Control Questionnaire 7-question version
The ACQ-7 is comprised of 7 items: the first 5 items assess the most common asthma symptoms: 
1. frequency in past week awoken by asthma during the night; 2. severity of asthma symptoms in 
the morning; 3. limitation of daily activities due to asthma; 4. shortness of breath due to asthma;
and 5. wheeze; plus question 6. short-acting bronchodilator use; and 7. FEV1 (% predicted).
Participants are asked to recall how their asthma has been during the previous week and to 
respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum 
impairment).
Clinic staff score for FEV1% is predicted on a 7-point scale. The details are given in Table 5.
Table 5 - Clinic staff score for FEV1%
FEV1% predicted
Score
>95% predicted 
0 
95%-90% 
1 
89%-80% 
2 
79%-70% 
3 
69%-60% 
4 
59%-50% 
5 
<50% 
6 
Abbreviation: FEV1 = forced expiratory volume in 1 second 
A global score is calculated: the questions are equally weighted and the ACQ-7 score is the mean 
of the 7 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). 
Higher score indicates lower asthma control. Participants with a score below 1.0 reflect 
adequately controlled asthma and participants with scores above 1.0 reflect inadequately 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 51
controlled asthma. On the 7-point scale of the ACQ-7, a change or difference in score of 0.5 is the 
smallest change that can be considered clinically important, corresponding to the Minimal 
Clinically Important Difference (MCID) defined by the developer.
The participants will complete the ACQ-7 on paper.
Asthma Control Questionnaire items 1 to 6 should be completed by the participant, independently 
from their physician, the study nurse or any other medical personnel and without any help from 
friends or relatives. The questionnaire should be completed by the participants before the 
consultation and clinical tests, including spirometry, in a quiet place.
The ACQ-5 (Mean of the responses to the first 5 questions) and ACQ-6 (Mean of the responses to 
the first 6 questions) will be derived from ACQ-7. For the ACQ-7 scores will be considered the 
local values of FEV1 For the statistical analysis we will use the centrally read values.
Asthma Quality of Life Questionnaire with Standardized Activities (Self-Administered)
Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) was designed as a 
self-administered patient-reported outcome to measure the functional impairments that are most 
troublesome to adolescents ≥12 years of age and adults as a result of their asthma. The instrument 
is comprised of 32 items, each rated on a 7-point Likert scales from 1 to 7. The AQLQ(S) has 
4 domains. The domains and the number of items in each domain are as follows:
x
Symptoms (12 items).
x
Activity limitation (11 items).
x
Emotional function (5 items).
x
Environmental Stimuli (4 items).
Individual items are equally weighted. The overall score is the mean of response to each of the 
32 questions (ranging from 1 to 7). Higher scores indicate better quality of life. The instrument 
has been used in many clinical trials, and it has been shown to be reliable, valid (participant
interviews), and sensitive to change. The MCID for AQLQ(S) is 0.5 (37).
The participants will complete the AQLQ(S) on paper.
Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) should be 
completed by the participant, independently from their physician, the study nurse or any other 
medical personnel and without any help from friends or relatives. The questionnaire should be 
completed by the participants before the consultation and clinical tests, including spirometry, in a 
quiet place.
Forced Oscillometry
Asthma is an inflammatory airway disease affecting the entire bronchial tree, including the small 
airways, defined as those with an internal diameter of 2 mm or less. Multiple lines of evidence 
suggest that, within subjects with asthma, the small airways are dysfunctional (38), inflamed (39),
and damaged (40), therefore playing an important role in asthma. Forced oscillation technique 
(FOT) R5 - R20 is a direct measure of anatomical narrowing in the small airways (41). The FOT
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 52
determines breathing mechanics by superimposing small external pressure signals on the 
spontaneous breathing of the subject. It is indicated as a diagnostic method to obtain reliable 
differentiated tidal breathing analysis. As FOT is performed without closure of a valve connected 
to the mouthpiece, and without maximal or forced respiratory maneuvers, it is unlikely that FOT 
itself will alter airways smooth muscle tone.
Forced oscillation technique utilizes the external applied pressure signals and their resultant flows 
to determine lung mechanical parameters. These pressure-flow relationships are largely distinct 
from the natural pattern of individual respiratory flows, so that measured FOT results are, for the 
most part, independent of the underlying respiratory pattern. Therefore, oscillometry minimizes
demands on the participant and requires only passive cooperation of the subject: maintenance of 
an airtight seal of the lips around a mouthpiece and breathing normally through the measuring 
system with a nose-clip occluding the nares. FOT should be conducted prior to spirometry. The 
assessment will be done by central reading. Further details on the procedure will be provided in a 
separate instruction manual.
Fractional Exhaled Nitric Oxide
Fractional exhaled nitric oxide will be analyzed using a NIOX instrument using a flow rate of 
50 mL/s and reported in ppb. This assessment should be conducted prior to spirometry and the
participant should refrain from eating and drinking for at least 1 hour prior to the procedure. The 
test will be performed after a wash out period of bronchodilators according to their action duration 
as detailed in Table 4 (Section 8.1). Retesting of FeNO can be done one additional time during 
screening if the eligibility criterion for FeNO was not met at V1. FeNO will be re-checked at 
randomization visit (V2) for eligibility. Further details on the procedure for measuring exhaled 
nitric oxide with NIOX will be provided in a separate instruction manual. FeNO assessment will 
be performed by local reading. The recommendation is to perform the investigations in the 
following order: FeNO, FOT, spirometry.
Functional Respiratory Imaging
Functional Respiratory Imaging is a non-invasive measurement of the participant specific 
respiratory system. A set of distinct imaging parameters analyzes exposure, structure and function 
of the lungs and airways in asthma. 
The process starts with the acquisition of low dose, pre-bronchodilator HRCT scans of the 
participant.
The measurements are performed on the segmented 3-dimensional geometries from these scans. 
Computational fluid dynamics (CFD) is used to quantify airflow and exposure.
Airway Volume ([s]iVaw)
(s)iVaw is the change of volume of the airways (in mL), taking into account the lung volume 
changes (in L) as well. 
With anti-inflammatory compounds, often the lung volumes reduce (they become less inflamed), 
while the airway volumes increase, since lower volume increase airway resistance showing a 
better picture of the true dynamics of the airways versus the lung volumes.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 53
The anti-inflammatory effect of dupilumab can be described in terms of changes in airway caliber 
such as airway volumes ([s]iVaw).
Airway caliber changes are more sensitive compared to FEV1 hence can provide additional 
insights into potential remodeling and additional improvements not described by FEV1
(eg, between Weeks 4 and 24).
A study to evaluate the use of FI to visualize and quantify airways involvement in asthma and 
COPD evaluated the correlation between FEV1 and FRI-based airway volumes, showing that a 
10% change in FEV1 corresponds to a change of 21% in airway volumes (Figure 2) (Lanclus et al. 
Respiration in revision), indicating that FRI is a more sensitive tool to detect therapeutic effects 
compared to FEV1.
Figure 2 - Correlation between FEV1 and FRI-based airway volumes
Airway Resistance ([s]iRaw)
(s)iRaw is defined as the pressure drop over the flow rate of the fluid. The unit is [kPa/(L/s)]) or
[kPa*s/L]. 
Asthmatic lungs have higher regional resistances due to presence of mucus or airway 
inflammation.
When the pressure drop over the airways stays the same (force exerted to inhale stays equal) but 
the airways become smaller (because of eg, obstructions or inflammation), the flow rate will 
become smaller (there will be less liters of air flowing through these smaller airways in 1 second 
than when airways are bigger), leading to a higher resistance. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 54
If the lung wants to compensate the higher resistance encountered in the lung, it will need to exert 
a higher pressure drop. Specific image-based resistance (siRaw) is similar to the image-based 
resistance (iRaw), but it takes the changes of the lung volume into account.
A study to evaluate the use of functional imaging to visualize and quantify airway involvement in 
asthma and COPD evaluated the correlation between FEV1 and FRI-based airway volumes. 
Evaluated the correlation between FEV1 and FRI-based airway resistance, in which a 10% change 
in FEV1 corresponded to a change of 25% in airway resistance (Figure 3) (Lanclus et al. 
Respiration in revision).
Figure 3 - Correlation between FEV1 and FRI-based airway resistance
Mucus score
University of California, San Francisco (UCSF researchers (John Fahy’s research group) have 
developed a new method to measure the burden of intraluminal mucus using Multi-detector 
Computed Tomography (MDCT) by quantifying the number of bronchopulmonary segments that 
are completely occluded with mucus. This technology has been validated in participants with
asthma using CT scans with normal dose radiation protocols (39).
A high mucus score (plugs in ≥4 segments) occurred in 67% of subjects with asthma with FEV1
of less than 60% of predicted volume, 19% with FEV1 of 60% to 80%, and 6% with FEV1 greater 
than 80% (P< 0.001). N=146, among those 96 were severe asthma participants (65%) (39).
Functional Respiratory Imaging can accurately assess the regional airway closures induces by 
mucus plugs and the re-opening of airways due to intrapulmonary percussive ventilation in COPD 
participants (40).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 55
Airway wall thickness
Asthmatics have increased airway wall volumes due to inflammation compared to healthy 
individuals. 
The airway wall volume/airway lumen ratio parameter can be derived from the FRI parameters 
airway wall volume and airway volume. Airway wall thickness can be derived from this as well 
(and can be shown in discreet locations).
After a treatment with ICS in asthma an increase in airway lumen volume (iVaw) and a reduction
in airway wall volume (iVaww) can be observed. The effect size of iVaw is larger than effect size 
iVaww due to the better resolution of iVaw in HRCT. Similar findings were observed by Haldar 
et al when studying Mepolizumab (41).
Lobar volumes
By identifying and grouping the 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. 
Therefore, not only the total lung volume is determined, but also the volume of each lobe 
individually, which allows to pick up substantial regional physiological changes of the airways 
and the lobe volumes.
The HRCT scans assessment will be performed by central reading. Further details on the 
procedure will be provided in a separate instructions manual. The wash out period of asthma 
controllers and rescue medication before HRCT scan is detailed in the Table 4 (Section 8.1).
If HRCT scan cannot be performed at D1 due to logistic reasons, it can be scheduled the next day. 
In this particular situation the investigator should ensure that the IMP loading dose is administered 
after the HRCT scan, at D1+1 day.
At visits, the HRCT scan can be done before spirometry or before post-BD FEV1 or after 
spirometry (in the latter case the wash-out period of SABA should be ensured), as per 
Investigator's decision.
8.2
SAFETY ASSESSMENTS 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical examinations
x
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height and weight 
will also be measured and recorded. Height (cm) will be measured only at the screening 
visit (V1).
x
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
x
Any new finding or worsening of previous finding should be reported as a new AE.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 56
8.2.2
Vital signs
x
Temperature (degrees Celsius), heart rate (beats per minute), respiratory rate (breaths per 
minute), and blood pressure (mmHg) will be assessed.
x
Blood pressure and pulse measurements will be assessed in semi-supine or sitting position
using the same arm at each visit with a completely automated device. Manual techniques 
will be used only if an automated device is not available. Blood pressure and pulse will be 
measured prior to receiving investigational product at the clinic visits.
x
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones).
x
Refer to Section 1.3 for the schedule of vital signs performed throughout this study.
8.2.3
Electrocardiograms
x
Single 12-lead electrocardiogram (ECG ) will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.
8.2.4
Clinical safety laboratory assessments
x
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency.
x
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes meeting the AE definition (Section 10.3) occurring during the 
study in the AE section of the e-CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the Investigator to be more severe 
than expected for the participant's condition.
x
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or medical monitor.
-
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor
notified.
-
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2),
must be conducted in accordance with the SoA (Section 1.3).
-
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the e-CRF.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 57
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Adverse event of special interest
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment.
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 8.3.4, even if not fulfilling a seriousness criterion, using the
screens in the e-CRF.
x
Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms).
x
Anaphylactic reactions.
x
Systemic hypersensitivity reactions.
x
Helminthic infections.
x
Keratitis
x
Any severe type of conjunctivitis or blepharitis
x
Significant ALT elevation:
-
ALT >5 x ULN in participants with baseline ALT ≤2 x ULN; 
or
-
ALT >8 x ULN if baseline ALT >2 x ULN.
“Baseline” refers to ALT sampled at baseline visit or, if baseline value is unavailable, 
to the latest ALT value before the baseline visit
x
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP;
-
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria,
-
In the event of pregnancy in a female participant, IMP should be discontinued,
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.
-
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE.
-
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
x
Symptomatic overdose (serious or nonserious) with IMP/NIMP.
x
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice the 
intended dose during an interval of less than 11 days. The circumstances (ie, accidental or 
intentional) should be clearly specified in the verbatim and symptoms, if any, entered on 
separate adverse event forms.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 58
An overdose (accidental or intentional) with any NIMP is an event suspected by the Investigator 
or spontaneously notified by the participant and defined according to the drug label. The 
circumstances (ie, accidental or intentional) should be clearly specified in the overdose form.
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that
caused the participant to discontinue the IMP (see Section 7).
8.3.1
Time period and frequency for collecting AE and SAE information
All SAEs will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3).
All AE will be collected from the signing of the ICF at the time points specified in the SoA 
(Section 1.3).
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3).
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor.
8.3.2
Method of detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and
nonserious AESIs (as defined in Section 8.3) will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
Further information on follow-up procedures is given in Appendix 3 (Section 10.3).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 59
8.3.4
Regulatory reporting requirements for SAEs
x
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
x
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
x
Serious adverse events that are considered expected will be specified in the reference 
safety information (IB).
x
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.
x
An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities.
8.3.5
Pregnancy
x
Details of all pregnancies in female participants and female partners of male participants
will be collected after the start of study intervention and until the outcome has been 
determined.
x
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4).
x
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
x
The participant /pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant /pregnant 
female partner and the neonate and the information will be forwarded to the Sponsor.
x
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor. While the Investigator is 
not obligated to actively seek this information in former study participants /pregnant 
female partner, he or she may learn of an SAE through spontaneous reporting.
x
Any female participant who becomes pregnant while participating in the study will 
discontinue the study intervention.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 60
8.3.6
Guidelines for reporting product complaints
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines.
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator
will assess whether or not the quality issue has to be reported together with an AE or SAE.
8.4
TREATMENT OF OVERDOSE
For this study, the overdose of dupilumab is defined as at least twice the intended dose during an 
interval of less than 11 days.
Symptomatic overdose (serious or nonserious) is an AESI (defined in Section 8.3). No antidote is 
available for dupilumab.
In the event of an overdose, the Investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
dupilumab can no longer be detected systemically.
3. Obtain a plasma sample for pharmacokinetic analysis as soon as possible from the date of 
the last dose of study intervention if requested by the Medical Monitor (determined on a 
case-by-case basis).
4. Document appropriately in the e-CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5
PHARMACOKINETICS
Pharmacokinetic parameters are not evaluated in this study.
8.6
PHARMACODYNAMICS
Pharmacodynamic variables/biomarkers:
x
Fractional exhaled nitric oxide (FeNO) levels.
Fractional exhaled nitric oxide should be conducted prior to spirometry and following a fast of
≥1 hour. Further details on the procedure for measuring FeNO will be provided in a separate 
instruction manual. Fractional exhaled nitric oxide levels will be measured at the time points 
mentioned in the SoA (Section 1.3).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 61
8.7
GENETICS
Pharmacogenetic/pharmacogenomic testing is not performed in this study.
8.8
BIOMARKERS
x
Whole blood biomarkers: blood eosinophil count.
Eosinophil counts will be measured at the time points requested mentioned in the SoA 
(Section 1.3).
8.9
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS
Medical resource utilization and health economics data are not collected in this study.
8.10
USE OF DATA FOR FUTURE RESEARCH
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data will be stored and used for future 
research when consented to by participants (see Section 10.1.3) unless prohibited by local laws or 
IRBs/IECs.
For participants who consent to the storage and use of their data, data may be used after the study 
ends for future research related either to the drug, the mechanism of action, and the disease or its 
associated conditions.
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects.
Data will be used in compliance with the information provided to participants in the ICF Part 2 
(future research).
All study participant data will be coded such that no participant direct identifiers will be linked to 
them. Coded data may be transferred to a Sponsor site (or a subcontractor site), which may be 
located outside of the country where the study is conducted. The Sponsor adopts safeguards for 
protecting participant confidentiality and personal data (see Section 10.1.4).
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws.
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 62
9
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES
For comparison of dupilumab treatment group to placebo, the following hypotheses of the 
2 primary endpoints will be tested.
1. Null hypothesis: 1) the proportion of participants achieving response of FeNo <25 ppb at 
Week 24 is the same between dupilumab and placebo group; 2) the percentage change 
from baseline in untrimmed distal [s]iVaw is the same between dupilumab and placebo 
group.
2. Alternative hypothesis: 1) the proportion of participants achieving response of 
FeNo <25 ppb at Week 24 is different between dupilumab and placebo group; 2) the 
percentage change from baseline in untrimmed distal [s]iVaw is different between 
dupilumab and placebo group.
9.2
SAMPLE SIZE DETERMINATION AND PRESERVATION OF TYPE I ERROR FOR THE
PRIMARY ENDPOINTS
To control the type-I error rate for the 2 primary endpoints, a hierarchical testing procedure will 
be applied at a 2-sided 5% significance level, ie, each hypothesis will be formally tested only if 
the preceding one is significant at 5% level. The hierarchy of the tests for primary endpoints will 
be:
1. Proportion of participants achieving response of FeNO <25 ppb at Week 24
2. Percentage change from baseline to Week 24 in untrimmed distal [s]iVaw at TLC
Assumptions for the [s]iVaw parameter were based on extrapolating the limited available data in 
asthma looking at associations between FEV1 and lung imaging parameters. Clinically meaningful 
differences for the imaging parameters have not yet been established. However, expert opinion
and literature suggest that they are more sensitive than the lung function parameters, such as 
pre-BD FEV1 mentioned above. 
By replacing FEV1 change from baseline at Week 24 with proportion of participants achieving 
response of FeNO <25 ppb at Week 24 as one of the primary endpoints,
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 63
With the original assumptions for [s]iVaw, 87 evaluable participants will provide approximately 
64% power with two-sample t-test at 2-sided 0.05 significance level.
9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined (Table 6):
Table 6 - Populations for analyses
Population
Description
Screened 
All participants who sign the informed consent form 
Randomized 
Randomized participants consist of all participants with a treatment kit number allocated and recorded in 
the IVRS database, regardless of whether the treatment kit was used or not.  
Participants treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. Data from these participants will be summarized separately.  
Intent-to-treat (ITT) 
The analysis population for the efficacy endpoints will be the intent-to-treat population: all randomized 
participants will be included in the ITT population, and analyzed according to the treatment group 
allocated by randomization.  
Safety 
The safety population will include all randomized participants who received at least 1 injection of IMP.  
For safety analyses, participants will be analyzed according to the treatment actually received. 
9.4
STATISTICAL ANALYSES
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints.
9.4.1
Efficacy analyses
All efficacy analyses will be performed on the Intent-to-treat (ITT) population, unless otherwise 
noted.
Note that at each scan, images will be taken from each zone of the lung, thus there will be 
multiple observations per visit for each imaging parameter. Data may be logarithmically 
transformed prior to analysis if extreme skewness was observed based on blinded data review.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 64
Table 7 - Efficacy analyses
Endpoint
Statistical Analysis Methods
Primary
x
Proportion of participants achieving FeNO 
<25 ppb at Week 24 
 
 
x
 The primary analysis will be conducted by Cochran-Mantel-
Haenszel (CMH) test adjusted by stratification factors. 
Comparison of the proportions of responders between 
dupilumab and placebo will be derived, and corresponding 
odds ratios and 95% CI along with the p-value will be 
reported. For participants who discontinued the study 
treatment not due to COVD-19 pandemic, off-treatment data 
will be used to determine the responder/non-responder 
status. For any participants discontinue the study treatment 
due to COVID-19 pandemic, off-treatment data will be set to 
missing. Missing data at Week 24 will be considered as non-
responders. 
x
Percent change from baseline to Week 24 
in untrimmed distal airway volumes 
corrected for lung volume ((s)iVaw) at total 
lung capacity (TLC) 
x
 Percent change from baseline to Week 24 in distal [s]iVaw at 
TLC will be analyzed using a mixed model repeated 
measures model (MMRM). The model will include percent 
change from baseline values up to Week 24 as the response 
variable, and factors for treatment group, region (Eastern 
Europe/ROW), ICS dose level (medium/high), visit, 
treatment-by-visit interaction, baseline value, and baseline-
by-visit interaction. An unstructured covariance matrix will be 
used to model the within participant errors. No imputations 
for missing values will be carried out. The least square (LS) 
mean of each treatment group, the LS mean difference 
between the dupilumab group and placebo, and the 
corresponding 95% CI of the differences and p-values will be 
provided. For participants who discontinued the study 
treatment not due to COVID-19 pandemic, off-treatment 
imaging data, as available, will be included in the analysis. 
For any participants who discontinued study treatment due 
to COVID-19, off-treatment data will be set to missing. Note: 
baseline value corresponds to the baseline value of the 
variable being analyzed. In case of variables in the 
percentage scale, this will be the baseline value on the raw 
scale. 
Secondary
x
Percent change from baseline to Week 24 
in untrimmed distal airway volumes 
corrected for lung volume ((s)iVaw) at 
functional residual capacity (FRC) 
x
Same as the primary imaging parameter. 
x
Percent change from baseline to Week 24 
in trimmed distal airway resistance 
corrected for lung volume ((s)iRaw) at TLC 
x
Same as above 
x
Percent change from baseline to Week 24 
in trimmed distal airway resistance 
corrected for lung volume ((s)iRaw) at FRC 
x
Same as above 
x
Change from baseline to Week 24 in global 
lung lobar volumes (iVlobes) at TLC 
x
Same as above.  
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 65
Endpoint
Statistical Analysis Methods
x
Change from baseline to Week 24 in 
HRCT-based internal airflow distribution 
(IAD) for each lung zone 
x
Same as above. 
x
Change from baseline to Week 24 in 
image-based ventilation/perfusion (iV/Q) at 
TLC for each lung zone 
x
Same as above.  
x
Change from baseline to Week 24 in FeNO 
x
Same as above.  
x
Change from baseline to Week 24 in pre-
bronchodilator FEV1 
x
Same as above.  
x
Change from baseline to Week 24 in 
post-bronchodilator FEV1 
x
Same as above. 
x
Change from baseline to Week 24 in ACQ-
7 
x
Same as above. 
x
Change from baseline to Week 24 in global 
lung mucus scoring (UCSF mucus scoring) 
x
Same as above. 
Exploratory
x
Will be described in the statistical analysis plan finalized 
before database lock. These will include investigating the 
relationship between key lung function parameters, imaging 
parameters and biomarker levels. 
9.4.2
Safety analyses
All safety analyses will be performed on the safety population and will be presented by treatment 
group.
The treatment-emergent is defined as the period of time from the date and time of the first dose of 
IMP through the date of last dose + 12 weeks (or the day before switch to commercialized 
dupilumab or other biologic treatment, whichever occurs first).
Table 8 - Safety analyses
Endpoint
Statistical Analysis Methods
Secondary
x
Incidence of TEAEs, TESAEs, 
TEAE leading to study 
intervention discontinuation and 
AESI 
 
x
Adverse event incidence tables will be presented by system organ 
class (SOC) (sorted by internationally agreed order), high-level group 
term (HLGT), high level term (HLT) and preferred term (PT), the 
number (n) and percentage (%) of participants experiencing an AE. 
Multiple occurrences of the same event in the same participant will be 
counted only once in the tables. The denominator for computation of 
percentages is the safety population within each treatment group. 
x
Proportion of participants with at least one TEAE, serious TEAE, 
AESI, and TEAE leading to discontinuation of the study intervention 
will be tabulated by treatment group. In addition, TEAEs will be 
described according to maximum intensity and relation to the study 
drug. Serious AEs and AEs leading to study discontinuation that occur 
outside the treatment-emergent period will be summarized separately. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 66
Multiplicity Considerations for the secondary endpoints
A multiplicity control procedure and the selected list of secondary endpoints to be tested in the 
hierarchical order will be specified in the Statistical Analysis Plan. Regardless of eligibility to be 
declared significant, results for all comparisons will be presented. Descriptive statistics including 
number of participants, mean, standard deviation, and LS means will also be provided.
9.4.3
Other analyses
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). The sensitivity analysis may be conducted, and details 
will be specified in the Statistical Analysis Plan.
9.5
INTERIM ANALYSES 
Not applicable.
9.5.1
Data Monitoring Committee (DMC)
A DMC is not planned for this study.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 67
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT
CONSIDERATIONS
10.1.1 Regulatory and ethical considerations
x
This study will be conducted in accordance with the protocol and with the following:
-
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines,
-
Applicable ICH GCP Guidelines,
-
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation [GDPR]).
x
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
x
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
x
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants.
x
The Investigator will be responsible for the following:
-
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC,
-
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding:
-
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and
-
The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity. 
-
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out 
of being notified and the finding has consequences for other individuals, eg, the 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 68
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps.
-
In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures,
-
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation.
10.1.2 Financial disclosure
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
10.1.3 Informed consent process
x
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study including what happens to the participant when his/her participation ends 
(posttrial access strategy for the study).
x
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Privacy and 
Data Protection requirements including those of the GDPR and of the French law, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.
x
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
x
In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 69
x
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
x
Participants who are rescreened are required to sign a new ICF.
x
The ICF contains 2 separate sections that addresses the use for research of participants’ 
data. Optional exploratory research must be detailed in the section “Optional 
tests/procedures” and future research is to be defined in Core Study Informed Consent 
Form (CSICF) Part 2. Each option is subject to an independent consent and must be 
confirmed by ticking a checkbox in CSICF Part 3. The Investigator or authorized designee 
will explain to each participant the objectives of the exploratory research and why data are 
important for future research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the 
storage period.
x
For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 9 (Section 10.9).
10.1.4 Data protection
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party.
Protection of participant data
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective.
Participant race and ethnicity will be collected in this study be /because they are required by 
regulatory agencies (eg, on African American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation.
x
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers, when applicable, will 
be identifiable only by the unique identifier; participant names or any information which 
would make the participant identifiable will not be transferred to the Sponsor.
x
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 70
x
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
x
Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results.
Protection of data related to professionals involved in the study 
x
Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed.
x
Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
x
In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list.
x
Personal data can be communicated to the following recipients: 
-
Personnel within Sanofi or partners or service providers involved in the study 
-
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency
x
Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably: 
-
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers,
-
Sanofi’s Binding Corporate Rules for intra-group transfers. 
x
Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority.
x
Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 71
x
In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project. 
x
Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact).
10.1.5 Committees structure
Study committees: Not applicable
10.1.6 Dissemination of clinical study data and results
Study participants
At the end of the clinical study, the Sponsor may publish the study results in scientific journal(s). 
As part of the review for publication, independent scientists may need to use “coded” data of all 
the study participants to independently verify the study’s results.
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include ClinicalTrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. For pediatric and adult trials, the results will generally be 
submitted/released 6 and 12 months, respectively, after the end of the clinical trial worldwide 
(ie, the last active, participating country).
In addition, results from clinical trials in participants are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance and 
intellectual property. For those journals that request sharing of the analyzable data sets that are 
reported in the publication, interested researchers are directed to submit their request to vivli.org.
Individual participant data and supporting clinical documents are available for request at vivli.org.
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 72
Professionals involved in the study or in the drug development program
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”.
10.1.7 Data quality assurance
x
All participant data relating to the study will be recorded on e-CRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The Investigator is
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the e-CRF.
x
Guidance on completion of CRFs will be provided in the CRF Completion Instructions.
x
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
x
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents.
x
The Sponsor or designee is responsible for the data management of this study including
quality checking of the data.
x
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations).
x
Study monitors will perform ongoing source data verification to confirm that data entered 
into the e-CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
x
Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8 Source documents
x
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site.
x
Data entered in the e-CRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 73
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
x
Definition of what constitutes source data: Source data is all information in original 
records and certified copies of original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.
Source data are contained in source documents. Source documents are original documents, 
data and records such as hospital records, clinic and office charts, laboratory reports, 
notes, memoranda, pharmacy dispensing records, recorded data from automated 
instruments etc. Data downloaded from the laboratories, spirometry, FeNO measurement, 
ECG, forced oscillometry, HRCT scans, home dosing diary and asthma background 
therapy diary, paper questionnaires (ACQ-7, AQLQ[S]) will be considered source data.
x
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
x
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
10.1.9 Study and site closure
First act of recruitment
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first participant screened and will be the study start date.
Study/Site termination
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to:
x
For study termination:
-
Information on the product leads to doubt as to the benefit/risk ratio,
-
Discontinuation of further study intervention development.
x
For site termination:
-
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines,
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 74
-
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator,
-
Total number of participants included earlier than expected.
If the study is prematurely terminated or suspended, the Sponsor should promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigators shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
10.1.10 Publication policy
x
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.
x
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement.
x
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS
x
The tests detailed in Table 9 will be performed by the local laboratories.
x
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
x
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
x
Pregnancy testing as mentioned in the SoA (Section 1.3).
Table 9 - Protocol-required laboratory assessments
Laboratory assessments
Parameters
Hematology 
Eosinophil count 
Other screening tests 
Highly sensitive (Serum at screening and urine at the other visits) human chorionic 
gonadotropin (hCG) pregnancy test (as needed for women of childbearing potential). 
 
Hepatitis screening covering hepatitis B surface antigen (HBsAg), total hepatitis B core 
antibody (total HBcAb) including IgM HBcAb; hepatitis C virus antibodies (HCVAb). In 
case of results showing HBs Ag (negative), and HBcAb (positive), an HBV DNA testing 
will be performed to rule out a false positivity if the Investigator believes the participant is a 
false positive, or to clarify the serological status if the Investigator finds it unclear to 
interpret in absence of known HBV infection. In case of results showing HCVAb (positive), 
an HCV RNA testing may be performed to rule out a false positivity, if the Investigator 
believes the participant is a false positive. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 75
Laboratory assessments
Parameters
 
Human Immunodeficiency Virus (HIV) screening (Anti-HIV-1 and HIV-2 antibodies). 
 
Tuberculosis testing would only be performed on a country by country basis according to 
the routine clinical practice and the local guidelines if required by Regulatory Authorities or 
Ethics Committees. 
 
The results of each test must be entered into the e-CRF 
NOTES : 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are given in 
Section 7.1.1 and Appendix 5 (Section 10.5). Although the liver function tests are not requested in the protocol, the routinely done lab tests 
might identify increased values of ALT, bilirubin. All events related to ALT, bilirubin which may indicate severe liver injury (possible Hy’s Law) 
must be reported as an SAE.  
Investigators must document their review of each laboratory safety report. 
10.3
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
DEFINITION OF AE
AE definition
x
An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention.
x
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Definition of unsolicited and solicited AE
x
An unsolicited adverse event is an adverse event that was not solicited using a home 
dosing diary and that is communicated by a participant who has signed the informed 
consent. Unsolicited AEs include serious and non-serious AEs.
x
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalisation, or emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records.
x
Unsolicited AEs that are not medically attended nor perceived as a concern by participant
will be collected during interview with the participants and by review of available medical 
records at the next visit.
x
Solicited AEs are predefined local and systemic events for which the participant is 
specifically questioned, and which are noted by the participants in their home dosing 
diary.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 76
Events meeting the AE definition
x
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:
-
Symptomatic and/or,
-
Requiring either corrective treatment or consultation, and/or,
-
Leading to IMP discontinuation or modification of dosing, and/or,
-
Fulfilling a seriousness criterion, and/or,
-
Defined as an AESI.
x
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
x
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.
x
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
x
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication.
x
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
x
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting the AE definition
x
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.
x
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.
x
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to
the procedure is the AE.
x
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
x
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 77
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A SAE is defined as any adverse event that, at any dose:
a) Results in death.
b) Is life-threatening:
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c) Requires inpatient hospitalization or prolongation of existing hospitalization:
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d) Results in persistent disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e) Is a congenital anomaly/birth defect
f)
Other situations:
-
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 78
RECORDING AND FOLLOW-UP OF AE AND/OR SAE
AE and SAE recording
x
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
x
The Investigator will then record all relevant AE/SAE information in the e-CRF.
x
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE e-CRF page.
x
There may be instances when copies of medical records for certain cases are requested by
the Sponsor’s representatives. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representatives.
x
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories:
x
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
x
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
x
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of causality
x
The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
x
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
x
The Investigator will use clinical judgment to determine the relationship.
x
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention
administration will be considered and investigated.
x
The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 79
x
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
x
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representatives. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representatives.
x
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
x
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
x
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representatives to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
x
If a participant dies during participation in the study or during a recognized follow-up
period, the Investigator will provide the Sponsor’s representatives with a copy of any post-
mortem findings including histopathology.
x
New or updated information will be recorded in the originally completed e-CRF.
x
The Investigator will submit any updated SAE data to the Sponsor’s representatives within 
24 hours of receipt of the information.
REPORTING OF SAEs
Serious adverse event reporting to the Sponsor’s representatives via an electronic data 
collection tool
x
The primary mechanism for reporting an SAE to the Sponsor’s representatives will be the 
electronic data collection tool.
x
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours.
x
The site will enter the SAE data into the electronic system as soon as it becomes available.
x
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.
x
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representatives by telephone.
x
Contacts for SAE reporting can be found in the CTP.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 80
Serious adverse event reporting to the Sponsor’s representatives via paper CRF
x
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representatives.
x
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service.
x
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
x
Contacts for SAE reporting can be found in the CTP.
10.4
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION
DEFINITIONS:
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
x
A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause.
x
A high follicle-stimulating hormone level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT).
x
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
Permanent sterilization methods include:
x
Documented hysterectomy
x
Documented bilateral salpingectomy
x
Documented bilateral oophorectomy
x
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry eligibility.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 81
Women in the following categories are considered WONCBP:
1. Any female with permanent infertility due to one of the following:
-
Documented hysterectomy,
-
Documented bilateral salpingectomy,
-
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry.
2. Postmenopausal female
A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause.
-
A high follicle-stimulating hormone level in the postmenopausal range 
[may/should/must] be used to confirm a postmenopausal state in women not using 
hormonal contraception or HRT. 
-
Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
CONTRACEPTION GUIDANCE
If locally required, acceptable contraceptive methods are limited to those which inhibit ovulation 
as the primary mode of action.
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly.
x
Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
x
Intrauterine device (IUD) 
x
Intrauterine hormone-releasing system (IUS) 
x
Bilateral tubal occlusion 
x
Azoospermic partner (vasectomized or due to a medical cause) 
x
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.  
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 82
Highly effective methodsb that are user dependent Failure rate of <1% per year when used 
consistently and correctly.
x
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
-
oral 
-
intravaginal 
-
transdermal 
-
injectable 
x
Progestogen-only hormone contraception associated with inhibition of ovulation 
-
oral 
-
injectable 
x
Sexual abstinence 
x
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 intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. 
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b
Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should 
not be used together (due to risk of failure from friction). 
PREGNANCY TESTING:
x
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test.
x
Additional urine pregnancy testing should be performed at each visit during the 
intervention period. In case of positive urinary test during the study, a serum pregnancy 
test should be performed as soon as possible to confirm the pregnancy. A urine pregnancy 
test will be performed at home at the end of study visit.
x
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
x
Pregnancy testing, with a sensitivity of ≥5 mIU/mL will be performed 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
x
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention.
x
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 83
Female participants who become pregnant 
x
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure.
x
Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4 of the protocol. While the Investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
x
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 84
10.5
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Although the liver function tests are not requested in the protocol, the routinely done lab tests might identify increased values of ALT, bilirubin.
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.
Note:
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening.
See Section 8.3.1 for guidance on safety reporting.
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 85
10.6
APPENDIX 6: LIST OF PROHIBITED LIVE ATTENTUATED VACCINES
x
Bacillus Calmette-Guérin (BCG) antituberculosis vaccine.
x
Chickenpox (Varicella).
x
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection 
is permitted.
x
Measles (Rubeola).
x
Measles-mumps-rubella (MMR) combination.
x
Measles-mumps-rubella-varicella (MMRV) combination.
x
Mumps.
x
Oral polio (Sabin).
x
Oral typhoid.
x
Rotavirus.
x
Rubella.
x
Smallpox (Vaccinia).
x
Varicella Zoster (shingles).
x
Yellow fever.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 90
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 91
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 92
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 93
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 94
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 95
10.8
APPENDIX 8: COUNTRY SPECIFIC REQUIREMENTS
Guidance on Contraceptive Methods
Highly effective contraceptive method of birth control may be defined according to the local
medical practice and regulations.
For Denmark:
Highly effective contraceptive methods of birth control for participants enrolled in Denmark 
include:
x
Intra-uterine devices (IUD).
x
Hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal 
vaginal devices or injections with prolonged release).
x
Subjects using a double-barrier contraceptive method (condom used with a diaphragm for 
example). However, this is limited to exceptional cases or conditions where the participant
cannot use other contraceptive methods (ie, hormonal contraceptives or IUD).
x
Subject having a sterilized permanent partner may be allowed to participate in the study.
The allowed methods of contraception can be also described in the participant’s information 
(subject information leaflet).
The above methods of contraception must be used in this study by women of childbearing 
potential throughout the entire trial period and for at least 3 months after the last injection of study 
medication, covering more than 5 times the terminal half-life of IMP.
Sterilized or infertile subjects (defined as having undergone surgical sterilization ie, 
vasectomy/bilateral tubectomy, hysterectomy and bilateral ovariectomy or as being 
postmenopausal defined as at least 12 months of amenorrhea prior enrolment) will be exempted 
from the requirements to use contraception in this study.
For UK:
Adequate contraceptive measures include:
x
Placement of an IUD or intrauterine system (IUS).
x
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. The use of barrier contraceptives 
should always be supplemented with the use of a spermicide.
x
Male sterilization (with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate).
x
True abstinence: When this is in line with the preferred and usual lifestyle of the subject.
[Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception].
Age of Majority 
For Taiwan: The age of majority is in accordance to the most updated local regulation.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 96
10.9
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY
Continuation of the study in the event of a regional or national emergency declared by a
governmental agency:
For European countries contingency measures are currently only applicable for the COVID-19
pandemic.
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site.
Contingency procedures are suggested below and in sections (Section 2.3, Section 5.5, Section 
6.1, Section 7.1.2, Section 7.1.2.1, Section 8, Section 9.4.3, Section 10.1.3) for an emergency that 
prevents access to the study site, to ensure the safety of the participants, to consider continuity of 
the clinical study conduct, protect trial integrity, and assist in maintaining compliance with Good 
Clinical Practice in Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained 
prior to the implementation of these procedures for the duration of the emergency.
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, screening may be temporarily delayed/halted (see also Section 5.5).
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study.
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency:
x
If onsite visits are not possible visit windows may be extended for the assessment of safety 
and/or efficacy data that cannot be obtained remotely (eg, spirometry, FeNO, FOT, HRCT
scan, vital signs).
x
Use of local laboratory locations may be allowed.
x
Arrangements can be made for qualified site personnel and/or health care professionals
(eg, visiting nurse service) for blood sample collection and study drug administration, if
allowed by local regulations and approved by the participant.
As an alternative to the on-site IMP dispensing, IMP may be supplied from the site to the
participant via a Sponsor-approved courier company where allowed by local regulations and
approved by the participant.
Rechallenge: In case of missed dose(s), no loading dose of 2 injections will be administered when
restarting the treatment, whatever the number of missed doses. The participants should continue
their scheduled IMP treatment and visits, even if more than 2 consecutive doses were missed.
Contingencies implemented due to emergency will be documented.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 97
Statistical analysis: a sensitivity analysis may be conducted; details will be specified in the 
Statistical Analysis Plan.
For a regional or national emergency declared by a governmental agency, contingency procedures
may be implemented for the duration of the emergency. The participants or their legally
authorized representative should be verbally informed prior to initiating any changes that are to be
implemented for the duration of the emergency (eg, study visit delays/treatment extension, use of
local labs).
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 98
10.10
APPENDIX 10: RADIATION EXPOSURE
Radiation Expert Affidavit
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 99
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 100
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 101
Health Physics Society-Radiation Exposure Risk-revision 2010.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 102
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 103
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 104
10.11 APPENDIX 11: ABBREVIATIONS
ACQ:
Asthma Control Questionnaire 
AD:
atopic dermatitis
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase
AQLQ(S):
Asthma Quality of Life Questionnaire with Standardized Activities
ATS:
American Thoracic Society
CFR:
Code of Federal Regulations
COPD:
chronic obstructive pulmonary disease
COVID-19:
coronavirus disease 2019
CRSwNP:
chronic rhinosinusitis with nasal polyposis
CT:
computed tomography
ECG:
electrocardiogram
e-CRF:
electronic case report form
EoE:
eosinophilic esophagitis
EOT:
end of treatment
ERS:
European Respiratory Society 
ETD:
early treatment discontinuation
FeNO:
fractional exhaled nitric oxide
FEV1:
forced expiratory volume in 1 second
FI:
functional imaging
FOT:
forced oscillation technique
FRC:
functional residual capacity
FRI:
functional respiratory imaging 
GCP:
Good Clinical Practice
GDPR:
General Data Protection Regulation
HBcAb:
hepatitis B core antibody 
HBsAg:
hepatitis B surface antigen 
HCVAb:
hepatitis C virus antibody 
HIV:
human immunodeficiency virus
HRCT:
high-resolution computed tomography
HRT:
hormonal replacement therapy
IB:
Investigator’s Brochure 
ICF:
informed consent form
ICH:
International Council for Harmonisation
ICS:
inhaled corticosteroids
IEC:
Independent Ethics Committees
IMP:
investigational medicinal product
IRB:
Institutional Review Boards
IUD:
Intra-uterine device
IVRS:
interactive voice recognition system
IWRS:
interactive web response system
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 105
LABA:
long-acting β2 agonists 
LTRA:
leukotriene receptor antagonist
MCID:
minimal clinically important difference
MMRM:
mixed model repeated measures model 
MoA:
mechanism of action 
OCS:
oral corticosteroids
PN:
prurigo nodularis
SABA:
short-acting β2 agonists 
SAD:
small airway dysfunction
SAE:
serious adverse event
SoA:
schedule of activities 
TB:
tuberculosis
TEAE:
treatment emergent adverse event
UCSF:
University of California, San Francisco 
ULN:
upper limit of normal
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 106
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC).
10.12.1 Amended protocol 02 (15 March 2021)
This amended protocol 02 is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
The main reasons for the amended protocol 02 are to introduce some clarifications in the 
eligibility criteria, to decrease the patient burden and to allow more flexibility for some of the 
study procedures (eg, FeNO assessment, complete clinical examination, the sequence of the study 
procedures). We are also taking this opportunity to align the safety reporting (AESI) with the 
updated IB and to incorporate contingency measures in case of a regional or national emergency. 
The stratification factor related to regions has been changed to Eastern Europe/ROW. In total, no
more than 40% participants should be in "Eastern Europe" strata.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis; 4.1 Overall design; 
6.3 Measures to minimize bias: 
randomization and blinding; 
9.4.1 Efficacy analyses 
The stratification factor related to regions has 
been changed to Eastern Europe/ROW. In total, 
no more than 40% participants should be in 
"Eastern Europe" strata. 
Differences in treatment effect of 
dupilumab 300 mg seen in pivotal 
Phase 3 study QUEST in EE vs ROW 
1.3 Schedule of Activities 
(SoA); 5.1 Inclusion criteria; 
8.1 Efficacy Assessments; 
FeNO will be rechecked at randomization. 
Ensure FeNO eligibility at V2 
 
Section 1.3 Schedule of Activities 
(SoA) 
Complete physical examinations will be 
performed at V1, V2, and V5. 
The number of complete physical 
examinations has been reassessed in 
order to decrease the participants’ 
burden. 
Retesting of FeNO one additional time during 
screening if the eligibility criterion for FeNO was 
not met at V1. FeNO will be re-checked at 
randomization visit (V2) for eligibility. 
To allow more flexibility for FeNO 
assessment during screening; to 
ensure that the FeNO eligibility criterion 
should be met at V2 as well. 
ACQ-5 score is the mean of the responses 
to the first 5 questions. 
Correction related to the calculation of 
ACQ-5 score 
ACQ-6 score is the mean of the responses 
to the first 6 questions. 
Correction related to the calculation of 
ACQ-6 score 
Clarifications related to HRCT scan at V2  
Clarifications related to HRCT scan 
Added provision for retesting of spirometry for 
patients who did not meet eligibility criterion for 
pre-BD FEV1 at V1 
Clarifications related to the retesting of 
pre-BD FEV1 during screening 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 107
Section # and Name
Description of Change
Brief Rationale
Updated recommendation related to the 
sequence of the procedures and HRCT scan 
Clarifications related to the sequence 
of the procedures 
Added provision of administration of IMP 
loading dose at D1+1 day when HRCT scan is 
performed the day after D1  
Clarifications related to the 
administration of IMP loading dose, in 
case that HRCT scan can’t be 
performed at V2 
Added note for contingency measures for a 
regional or national emergency and reference to 
the Appendix 9 
Contingency measures in case of 
regional and national emergency 
Clarification added in footnote “r” regarding 
home dosing diary and asthma background 
therapy diary 
Clarification 
Section 2.3 Benefit/Risk 
Assessment 
Updated text related to dupilumab worldwide 
marketing authorization approval status for all 
indications 
Updated numbers of patients exposed to 
dupilumab in various clinical studies and post-
marketing exposure 
Updated the ADRs list for dupilumab 
Also updated text on eosinophilia as important 
potential risk 
Added benefit/risk assessment related to 
COVID-19 
Regulatory and safety updates related 
to dupilumab 
Section 5.1 Inclusion Criteria 
I.06. Added provision for consideration of 
historical blood eosinophil count, and FeNO 
assessment at V2 as well. 
To clarify in the inclusion criterion I06 
that the historical values of blood 
eosinophil count measured within 
6 months prior to V1 in the absence of 
OCS treatment are allowed; FeNO to 
be assessed for eligibility at V2 as well 
I.09. Added provision for male contraception 
duration  
Correction related to male 
contraception duration 
Section 5.2 Exclusion Criteria 
E.04. Added clarifications related to asthma 
exacerbation 
Clarifications on asthma exacerbation 
E09. Added exclusion provision for hepatic 
clinically significant disease, as judged by the 
investigators 
Minor update of the criterion 
E14. Updated exclusion criterion for treatment 
with live (attenuated) vaccine 
Clarification of the criterion related to 
vaccination with live (attenuated) 
vaccine  
E15. Updated exclusion criterion regarding the 
treatment with oral corticosteroids (OCS) within 
2 weeks prior to V1 
To clarify timeframe for OCS treatment 
E18. Updated exclusion criterion regarding the 
treatment with an investigational drug within 1 
month or within 5 half-lives (if known), 
whichever is longer, prior to V1. 
An interdiction of non-antibody 
investigational drugs for 2 months 
before V1 is unnecessary. 
Section 5.4 Screen Failures 
Added provision for retesting of FeNO, 
spirometry, reversibility test during screening 
FeNo retesting allowed one additional 
time during screening: minor updates 
on spirometry and reversibility re-test 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 108
Section # and Name
Description of Change
Brief Rationale
Section 5.5 Criteria for 
Temporarily Delaying Screening, 
Randomization, or Study 
Intervention Administration 
Statement for provisions in case of regional or 
national emergency added with reference to 
Appendix 9 (Section 10.9) 
Contingency measures in case of 
regional or national emergency 
Section 6.1 Study Intervention(s) 
Administered 
 
Updates related to IMP administration, patients’ 
instructions on hypersensitivity reactions and 
self-monitoring after the administration of IMP at 
home are added; 
Clarifications related to the IMP 
administration and monitoring after IMP 
administration 
Process in case of missed IMP doses is detailed 
 
To clarify the process in case a 
participant misses IMP 
administration(s). The participants will 
not be prematurely discontinued from 
treatment in case they miss 
2 consecutive doses, to align with the 
pivotal study QUEST.  
Section 6.1 Study Intervention(s) 
Administered 
Section 6.5  Concomitant 
Therapy 
Section 6.6 Rescue Medicine 
Text added allowing systemic corticosteroids for 
the treatment of asthma exacerbations. 
Systemic corticosteroids are allowed 
for the treatment of asthma 
exacerbation 
Section 7.1.2 Temporary 
discontinuation 
 
Updated criteria for  temporary discontinuation: 
x treatment with a live (attenuated) vaccine 
x treatment with immunomodulating biologics 
(including experimental treatments) 
x systemic corticotherapy (except the 
administration in case of asthma 
exacerbation) 
Clarification related to criteria for 
temporary discontinuation 
Section 7.1.2.1 Rechallenge 
Section 9.4.3 Other analyses 
Updates related to regional or national 
emergency are added 
Contingency measures in case of 
regional and national emergency 
Section 7.1.1 Definitive 
discontinuation 
Added definition of baseline ALT value 
Clarifications on the definition of 
baseline ALT value 
Section 7.1.2 Temporary 
Discontinuation 
Conditions updated for temporary 
discontinuation 
Temporary intervention discontinuation 
may be considered by the Investigator 
also in case of disruption of the clinical 
trial due to a regional or national 
emergency declared by a 
governmental agency; The treatment 
with systemic corticosteroids in case of 
asthma exacerbation has been added 
Section 8.1 Efficacy 
Assessments 
 Updates based on the changes added in the 
SoA  
Clarifications on the study procedures 
(HRCT scan, FeNO, FOT, spirometry) 
according to SoA 
Section 8.3 Adverse Events and 
Serious Adverse Events 
Updated list of AESI  
Added definition of baseline ALT value 
Updated definition of overdose for NIMP 
Updated list of AESI based on the new 
Investigator’s Brochure; updated 
definition of overdose with NIMP 
Section 8.3.5 Pregnancy 
Clarified instructions related to pregnancy 
reporting 
Clarification 
Section 8.4 Treatment of 
Overdose 
Clarifications on the instructions in case of IMP 
overdose 
Clarifications on the instructions 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 109
Section # and Name
Description of Change
Brief Rationale
Section 8.10 Use of Data for 
Future Research 
Added new section for provisions and 
procedures followed in case of participant data 
use for future research 
Clarifications related to participant data 
used for future research 
Section 9.4.2 Safety analyses 
Added definition of TE period 
Clarification 
Section 10.1.1 Regulatory and 
Ethical Considerations 
Added GDPR to be followed 
Updated procedure to be followed for 
substantial protocol amendments 
Updated the Investigator’s responsibility 
Clarification 
Section 10.1.3 Informed consent 
process 
Updated the provisions and procedures of 
Informed consent process 
Clarification  
Section 10.1.4 Data protection 
Updated data protection section and added 
subsections - protection of participant data, 
protection of data related to professionals 
involved in the study 
Clarification 
Section 10.1.6 Dissemination of 
clinical study data 
Added subsection - professionals involved in the 
study or in the drug development program, and 
updated text 
Clarification 
Section 10.1.7 Data quality 
assurance 
Updated procedures to be followed for data 
quality assurance 
Clarification on the process of data 
quality assurance   
Section 10.1.8 Source 
documents 
Updated provisions for source documents 
Minor changes 
Section 10.1.9 Study and site 
closure 
Added subsection - first act of recruitment, and 
text 
Clarification 
Section 10.3 Appendix 3: 
Adverse Events: Definitions and 
Procedures for Recording, 
Evaluating, Follow-Up, and 
Reporting 
Added subsection - definition of unsolicited and 
solicited AE, and text 
Clarification 
Section 10.4 Appendix 4: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information 
Updated definition of WOCBP and WONCBP, 
and Contraception Guidance 
Updated contraceptive guidance   
Section 10.5 Appendix 5: Liver 
and Other Safety: Suggested 
Actions and Follow-Up 
Assessments 
Updated algorithm chart for increase in ALT 
Updated algorithm  
Section 10.8. Appendix 8: 
Country specific requirements 
Majority of age added for Taiwan 
Country specific requirement for 
Taiwan 
Section 10.9 Appendix 9: 
Contingency Measures for a 
Regional or National Emergency 
that is Declared by a 
Governmental Agency 
Summary of contingency measures for regional 
or national emergency declared by a 
governmental agency 
New appendix with the summary of the 
contingency measures 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 110
10.12.2 Amended protocol 01 (12 March 2020)
This amended protocol 01 is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
The main reason for the amendment is to meet requirements for Regulatory Agency.
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of activity 
5.2 Exclusion criteria 
10.2 Appendix 2: Clinical 
laboratory tests 
Addition of an exclusion criterion E07 related to 
tuberculosis and tuberculosis testing. 
Addition of tuberculosis testing and related 
footnote q. 
Table 8: Addition of tuberculosis testing 
As per Regulatory Agency review, 
patient with tuberculosis should not be 
included in the study. 
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 111
11
REFERENCES
1. Global Initiative for Asthma. Global Stratergy for Asthma Management and Prevention 
(GINA). 2019.
2. Israel E, Reddel HK. Severe and Difficult-to-Treat Asthma in Adults. N Engl J Med. 
2017;377(10):965-76.
3. Spahn JD, Malka J, Szefler SJ. Current application of exhaled nitric oxide in clinical practice. 
J Allergy Clin Immunol. 2016;138(5):1296-8.
4. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, et al. Periostin: a novel 
component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13
signals. J Allergy Clin Immunol. 2006;118(1):98-104.
5. Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key 
proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov. 2016;15(1):35-50.
6. Boulet LP, Boulay MÈ, Dérival JL, Milot J, Lepage J, Bilodeau L, et al. Asthma-COPD 
Overlap Phenotypes and Smoking: Comparative features of asthma in smoking or non-
smoking patients with an incomplete reversibility of airway obstruction. COPD. 
2018;15(2):130-8.
7. Sumi Y, Hamid Q. Airway Remodeling in Asthma. Allergol Int. 2007;56(4):341-8.
8. Vos W, De Backer J, Poli G, De Volder A, Ghys L, Van Holsbeke C, et al. Novel functional 
imaging of changes in small airways of patients treated with extrafine 
beclomethasone/formoterol. Respiration. 2013;86(5):393-401.
9. Vos W, Hajian B, De Backer J, Van Holsbeke C, Vinchurkar S, Claes R, et al. Functional 
respiratory imaging to assess the interaction between systemic roflumilast and inhaled 
ICS/LABA/LAMA. Int J Chron Obstruct Pulmon Dis. 2016;11:263-71.
10. De Backer J, Van Holsbeke C, Vos W, Vinchurkar S, Dorinsky P, Rebello J, et al. Assessment 
of lung deposition and analysis of the effect of fluticasone / salmeterol hydrofluoroalkane 
(HFA) pressurized metered dose inhaler (pMDI) in stable persistent asthma patients using 
functional respiratory imaging. Expert Rev Respir Med. 2016;10(8):927-33.
11. De Backer W, Vos W, Van Holsbeke C, Vinchurkar S, Claes R, Hufkens A, et al. The effect 
of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients.Eur Respir J. 
2014;44(2):527-9.
12. Sugiura H, Komaki Y, Koarai A, Ichinose M. Nitrative stress in refractory asthma. J Allergy 
Clin Immunol. 2008;121(2):355-60.
13. Voraphani N, Gladwin MT, Contreras AU, Kaminski N, Tedrow JR, Milosevic J, et al. An 
airway epithelial iNOS–DUOX2–thyroid peroxidase metabolome drives Th1/Th2 nitrative 
stress in human severe asthma. Mucosal immunol. 2014;7(5):1175-85.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 112
14. Semprini R, Williams M, Semprini A, et al. Type 2 Biomarkers and Prediction of Future 
Exacerbations and Lung Function Decline in Adult Asthma. J Allergy Clin Immunol Pract. 
2018;6(6):1982-1988.e1. doi:10.1016/j.jaip.2018.03.004
15. Coumou H, Westerhof GA, de Nijs SB, Zwinderman AH, Bel EH. Predictors of accelerated 
decline in lung function in adult-onset asthma. Eur Respir J. 2018;51(2):1701785. 
doi:10.1183/13993003.01785-2017
16. Sears MR. Lung function decline in asthma. Eur Respir J. 2007;30(3):411-413.
doi:10.1183/09031936.00080007
17. Donohue JF, Jain N. Exhaled nitric oxide to predict corticosteroid responsiveness and reduce 
asthma exacerbation rates. Respir Med. 2013;107(7):943-952.
doi:10.1016/j.rmed.2013.02.018
18. Matsunaga K, Hirano T, Oka A, Ito K, Edakuni N. Persistently high exhaled nitric oxide and 
loss of lung function in controlled asthma. Allergol Int Off J Jpn Soc Allergol. 
2016;65(3):266-271. doi:10.1016/j.alit.2015.12.006
19. van Veen IH, ten Brinke A, Sterk PJ, et al. Exhaled nitric oxide predicts lung function decline 
in difficult-to-treat asthma. Eur Respir J. 2008;32(2):344-349.
doi:10.1183/09031936.00135907
20. Bjermer L, Alving K, Diamant Z, et al. Current evidence and future research needs for FeNO 
measurement in respiratory diseases. Respir Med. 2014;108(6):830-841.
doi:10.1016/j.rmed.2014.02.005
21. Postma DS, Brightling C, Baldi S, Van den Berge M, Fabbri LM, Gagnatelli A, et al. 
Exploring the relevance and extent of small airways dysfunction in asthma (ATLANTIS): 
baseline data from a prospective cohort study. Lancet Respir Med. 2019;7(5):402-16.
22. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. dupilumab Efficacy and 
Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378:2486-96.
23. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of 
dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-
85.
24. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official 
American Thoracic Society/European Respiratory Society statement: asthma control and 
exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J 
Respir Crit Care Med. 2009;180(1):59-99.
25. Burrowes KS, De Backer J, Smallwood R, Sterk PJ, Gut I, Wirix-Speetjens R, et al. Multi-
scale computational models of the airways to unravel the pathophysiological mechanisms in 
asthma and chronic obstructive pulmonary disease (AirPROM). Interface Focus. 
2013;3(2):20120057.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 113
26. De Backer L, Vos WG, Salgado R, De Backer JW, Devolder A, Verhulst SL, et al. 2011 
Functional imaging using computer methods to compare the effect of salbutamol and 
ipratropium bromide in patient specific airway models of COPD. Int J Chron Obstruct Pulmon 
Dis. 2011;6:637-46.
27. De Backer J, Vos W, Van Holsbeke C, Vinchurkar S, Claes R, Parizel PM, et al. Effect of 
high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD 
patients. Int J Chron Obstruct Pulmon Dis. 2013;8:569-79.
28. De Backer J, Vos W, Vinchurkar S, Van Holsbeke C, Poli G, Claes R, et al. The effects of 
extrafine beclometasone/formoterol (BDP/F) on lung function, dyspnea, hyperinflation, and 
airway geometry in COPD patients: novel insight using functional respiratory imaging. J 
Aerosol Med Pulm Drug Deliv. 2015;28(2):88-99.
29. Hajian B, De Backer J, Sneyers C, Ferreira F, Barboza KC, Leemans G, et al. 
Pathophysiological mechanism of long-term noninvasive ventilation in stable hypercapnic 
patients with COPD using functional respiratory imaging. Int J Chron Obstruct Pulmon Dis. 
2017;12:2197-205.
30. Biological Effects of Ionizing Radiation (BEIR) series - BEIR V.National Academy of 
Sciences. 1990. 
31. The 2007 Recommendations of the International Commission on Radiological Protection. 
ICRP Publication 103. Ann ICRP. 2007;37(2-4):1-332.
32. United Nations Scientific Committee on the Effects of Atomic Radiation. Summary of low-
dose radiation effects on health. UNSCEAR Website. 2010.
33. Araoz PA, Haramati LB, Mayo JR, Barbosa EJ Jr, Rybicki FJ, Colletti PM. Panel discussion: 
pulmonary embolism imaging and outcomes. AJR Am J Roentgenol. 2012;198(6):1313-9.
34. Ivanov VK1, Kashcheev VV, Chekin SY, Menyaylo AN, Pryakhin EA, Tsyb AF, et al. 
Estimating the lifetime risk of cancer associated with multiple CT scans. J Radiol Prot. 
2014;34(4):825-41.
35. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in 
persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-66.
36. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. ATS/ERS Task 
Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-38.
37. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B et al. Dupilumab eﬃcacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-
controlled pivotal phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44.
38. Usmani OS, Singh D, Spinola M, Bizzi A3, Barnes PJ. The prevalence of small airways 
disease in adult asthma: A systematic literature review. Respir Med. 2016;116:19-27.
99&/,1

Amended Clinical Trial Protocol 03
SAR231893-LPS15834
13-Apr-2023
Version number: 1
Property of the Sanofi group - strictly confidential
Page 114
39. Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR, Hegele RG, et al. Inflammation of 
small airways in asthma. J Allergy Clin Immunol. 1997;100(1):44-51.
40. Hyde DM, Hamid Q, Irvin CG. Anatomy, pathology, and physiology of the tracheobronchial 
tree: emphasis on the distal airways. J Allergy Clin Immunol. 2009;124(6 Suppl):S72-7.
41. Foy BH, Soares M, Bordas R, Richardson M, Bel Al, Singapuri A, et al. Lung Computational 
Models and the Role of the Small Airways in Asthma. Am J Respir Crit Care Med. 
2019;200(8):982-91.
99&/,1

6LJQDWXUH3DJHIRU99&/,1Y
OSVDPHQGHGSURWRFRO
$SSURYH	H6LJQ
$SSURYH	H6LJQ
99&/,1