Clinical trial NCT04400318
Conditions: Asthma
Sponsor: Sanofi
Start date: 2020-06-20; Completion date: 2023-08-21
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

• To assess the effect of dupilumab on lung inflammation and related changes in airway volumes detectable by functional respiratory imaging

Secondary Objective:

* 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.
* To evaluate safety of dupilumab

Detailed description:
The study duration for each participant was a total of minimum 29 weeks and up to 41 weeks. This included 4 weeks +/-1 week screening period, 24 weeks of treatment period and a follow-up period up to 12 weeks or until the participants switched to commercialized dupilumab (or other biologic products), whatever came first.

Arms: arm 1: Participants received a loading dose of dupilumab 600 mg as 2 subcutaneous (SC) injections on Day 1, followed by a single dupilumab 300 mg SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller. arm 2: Participants received placebo matched to dupilumab as 2 x 2 mL SC injections on Day 1, followed by a single SC injection Q2W for 24 weeks along with a stable dose of medium to high ICS dose in combination with a second controller medication +/- a third controller.
Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: solution for injection subcutaneous intervention 2: Solution for injection subcutaneous

Protocol documents:
Prot_000.pdf: 


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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. 
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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. 
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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. 
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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 
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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 
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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 
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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 
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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 
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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 
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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).
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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) 
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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.
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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.
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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. 
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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
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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  
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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. 
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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. 
 
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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, 
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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.
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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.
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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 
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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.
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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.
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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) 
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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.
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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.
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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.
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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.
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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.
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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.
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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. 
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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.
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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.
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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).
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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.
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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 
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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).
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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.
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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.
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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.
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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).
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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.
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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).
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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 
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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 
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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 
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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
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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.
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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. 
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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).
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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.
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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.
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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.
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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).
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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.
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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).
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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).
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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,
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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.
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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.  
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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. 
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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.
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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 
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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).
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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.
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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.
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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.
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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 
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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,
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-
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. 
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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.
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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.
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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.
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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.
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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.
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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.
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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. 
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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. 
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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.
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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.
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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.
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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.
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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.
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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).
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10.10
APPENDIX 10: RADIATION EXPOSURE
Radiation Expert Affidavit
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Health Physics Society-Radiation Exposure Risk-revision 2010.
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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
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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
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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 
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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 
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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 
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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 
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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. 
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11
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9. Vos W, Hajian B, De Backer J, Van Holsbeke C, Vinchurkar S, Claes R, et al. Functional 
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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 
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of roflumilast in addition to LABA/LAMA/ICS treatment in COPD patients.Eur Respir J. 
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12. Sugiura H, Komaki Y, Koarai A, Ichinose M. Nitrative stress in refractory asthma. J Allergy 
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13. Voraphani N, Gladwin MT, Contreras AU, Kaminski N, Tedrow JR, Milosevic J, et al. An 
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stress in human severe asthma. Mucosal immunol. 2014;7(5):1175-85.
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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. 
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decline in lung function in adult-onset asthma. Eur Respir J. 2018;51(2):1701785. 
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16. Sears MR. Lung function decline in asthma. Eur Respir J. 2007;30(3):411-413.
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asthma exacerbation rates. Respir Med. 2013;107(7):943-952.
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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. 
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in difficult-to-treat asthma. Eur Respir J. 2008;32(2):344-349.
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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): 
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22. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. dupilumab Efficacy and 
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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.
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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-
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asthma and chronic obstructive pulmonary disease (AirPROM). Interface Focus. 
2013;3(2):20120057.
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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. 
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30. Biological Effects of Ionizing Radiation (BEIR) series - BEIR V.National Academy of 
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31. The 2007 Recommendations of the International Commission on Radiological Protection. 
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32. United Nations Scientific Committee on the Effects of Atomic Radiation. Summary of low-
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33. Araoz PA, Haramati LB, Mayo JR, Barbosa EJ Jr, Rybicki FJ, Colletti PM. Panel discussion: 
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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.
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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.
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SAP_001.pdf: 


Sanofi group
Final Statistical Analysis Plan, Version 2.0
Dupilumab - LPS15834
Date Issued: 25JUL2023
Page 2
TABLE OF CONTENTS
FINAL STATISTICAL ANALYSIS PLAN................................................................................1 
TABLE OF CONTENTS..............................................................................................................2 
LIST OF ABBREVIATIONS.......................................................................................................6 
DOCUMENT HISTORY-CHANGES COMPARED TO PREVIOUS VERSION OF SAP .9 
1. 
INTRODUCTION ...........................................................................................................10 
2. 
STUDY OBJECTIVES, ENDPOINTS AND ESTIMANDS .......................................11 
3. 
INVESTIGATIONAL PLAN.........................................................................................16 
3.1. OVERALL STUDY DESIGN AND PLAN....................................................................................16 
3.2. STUDY ENDPOINTS ..............................................................................................................17 
3.3. STUDY INTERVENTIONS.......................................................................................................17 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ...................................................................................18 
4. 
GENERAL STATISTICAL CONSIDERATIONS......................................................19 
4.1. SAMPLE SIZE .......................................................................................................................19 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING............................................................19 
4.3. ANALYSIS SET.....................................................................................................................19 
4.3.1. 
Screened analysis set...................................................................................................20 
4.3.2. 
Intent-to-Treat (ITT) analysis set ................................................................................20 
4.3.3. 
Safety set......................................................................................................................20 
4.4. REPORTING CONVENTIONS ..................................................................................................20 
4.4.1. 
Study intervention labels .............................................................................................20 
4.4.2. 
Visit naming conventions.............................................................................................20 
4.4.3. 
Visit windows...............................................................................................................21 
4.4.4. 
Unscheduled visits.......................................................................................................21 
4.4.5. 
Display of data summary and analysis........................................................................21 
4.4.6. 
Baseline, study day and duration derivations .............................................................22 
4.4.7. 
Change from baseline and percent change from baseline ..........................................23 
4.5. INTERCURRENT EVENT TYPES..............................................................................................23 
5. 
PARTICIPANT DISPOSITION....................................................................................24 
5.1. DISPOSITION........................................................................................................................24 
5.2. PROTOCOL DEVIATIONS.......................................................................................................25 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS...................................27 
6.1. DEMOGRAPHICS ..................................................................................................................27 
6.2. BASELINE DISEASE CHARACTERISTICS ................................................................................27 
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6.2.1. 
Respiratory characteristics at baseline.......................................................................27 
6.2.2. 
Asthma questionnaires at baseline..............................................................................29 
6.2.3. 
Asthma and associated disease characteristics at baseline ........................................29 
6.2.4. 
Biomarkers at baseline................................................................................................30 
6.3. TOBACCO USAGE.................................................................................................................30 
6.4. MEDICAL HISTORY ..............................................................................................................30 
6.4.1. 
General medical history ..............................................................................................30 
6.4.2. 
Disease-specific history...............................................................................................31 
6.5. INCLUSION AND EXCLUSION CRITERIA.................................................................................31 
6.6. OTHER BACKGROUND INFORMATION ..................................................................................31 
7. 
STUDY INTERVENTIONS AND MEDICATIONS ...................................................32 
7.1. PRIOR AND CONCOMITANT MEDICATIONS ...........................................................................32 
7.1.1. 
Prior medications........................................................................................................32 
7.1.2. 
Concomitant medications............................................................................................33 
7.1.3. 
Post-treatment medications.........................................................................................33 
7.2. STUDY INTERVENTIONS.......................................................................................................33 
7.2.1. 
Extent of exposure .......................................................................................................33 
7.2.2. 
Study intervention compliance and modifications.......................................................34 
8. 
EFFICACY ANALYSIS .................................................................................................36 
8.1. PRIMARY EFFICACY ENDPOINT ............................................................................................37 
8.1.1. 
Primary analysis..........................................................................................................37 
8.1.2. 
Assumption testing.......................................................................................................38 
8.1.3. 
Missing data handling.................................................................................................38 
8.1.4. 
Subgroup analysis .......................................................................................................38 
8.1.5. 
Sensitivity analysis.......................................................................................................39 
8.1.6. 
Supplementary analysis...............................................................................................40 
8.1.7. 
Impact of Covid-19 pandemic .....................................................................................40 
8.2. SECONDARY EFFICACY ENDPOINTS .....................................................................................40 
8.2.1. 
Lung function measured by spirometry .......................................................................40 
8.2.2. 
Fractional Exhaled Nitric Oxide (FeNO)....................................................................41 
8.2.3. 
Functional Respiratory Imaging (FRI) .......................................................................41 
8.2.4. 
Asthma Control Questionnaire (ACQ-7).....................................................................42 
8.2.5. 
Multiplicity issues........................................................................................................42 
8.2.6. 
Supplementary analysis...............................................................................................43 
 
 
 
 
 
 
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9. 
SAFETY ANALYSIS ......................................................................................................49 
9.1. ADVERSE EVENTS................................................................................................................49 
9.1.1. 
Incidence of adverse events.........................................................................................51 
9.1.2. 
Relationship of adverse events to study intervention ..................................................51 
9.1.3. 
Severity of adverse event .............................................................................................51 
9.1.4. 
Serious adverse events.................................................................................................52 
9.1.5. 
Adverse events leading to permanent study intervention discontinuation ..................52 
9.1.6. 
Adverse events leading to study discontinuation.........................................................52 
9.1.7. 
Adverse events of special interest (AESI)....................................................................52 
9.1.8. 
Adverse events leading to death ..................................................................................53 
9.1.9. 
Death ...........................................................................................................................53 
9.2. CLINICAL LABORATORY EVALUATIONS...............................................................................53 
9.3. VITAL SIGN MEASUREMENTS...............................................................................................54 
9.4. PHYSICAL EXAMINATION.....................................................................................................55 
9.5. ELECTROCARDIOGRAM .......................................................................................................55 
9.6. OTHER SAFETY DATA ..........................................................................................................55 
10. 
PHARMACOKINETICS................................................................................................56 
11. 
PHARMACODYNAMICS .............................................................................................57 
12. 
INTERIM ANALYSIS....................................................................................................58 
13. 
CHANGES IN THE PLANNED ANALYSIS...............................................................59 
14. 
REFERENCES ................................................................................................................60 
15. 
APPENDICES..................................................................................................................64 
15.1. 
SUMMARY OF STATISTICAL ANALYSES.............................................................................64 
15.2. 
SCHEDULE OF STUDY PROCEDURES..................................................................................66 
15.3. 
MISSING EFFICACY DATA.................................................................................................69 
15.4. 
MISSING SAFETY DATA ....................................................................................................69 
15.4.1. 
Handling of missing age...........................................................................................69 
15.4.2. 
Handling of computation of study intervention duration if investigational medicinal 
product end of treatment date is missing..................................................................................69 
15.4.3. 
Handling of medication missing/partial dates.........................................................70 
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15.4.4. 
Handling of adverse events with missing or partial date/time of onset ...................70 
15.4.5. 
Handling of adverse events when date and time of first investigational medicinal 
product administration is missing ............................................................................................70 
15.4.6. 
Handling of missing assessment of relationship of adverse events to investigational 
medicinal product .....................................................................................................................70 
15.4.7. 
Handling of missing severity/grades of adverse events ...........................................70 
15.4.8. 
Handling of potentially clinically significant abnormalities ...................................70 
15.5. 
VISIT WINDOWS ...............................................................................................................70 
15.6. 
SEARCH CRITERIA FOR AESI ...........................................................................................71 
15.7. 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA ................73 
15.8. 
PARTICIPANT-REPORTED OUTCOMES (PROS) .................................................................73 
15.9. 
SPIROMETRY....................................................................................................................76 
15.10. 
FUNCTIONAL RESPIRATORY IMAGING (FRI).................................................................77 
15.11. 
FORCED OSCILLOMETRY (FOT) ...................................................................................80 
15.12. 
BIOMARKERS................................................................................................................80 
15.13. 
RESCUE AND PROHIBITED MEDICATIONS. ....................................................................80 
16. 
SIGNATURE PAGE .......................................................................................................82 
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LIST OF ABBREVIATIONS
[s]iVaw
Specific airway volume
[s]iRaw
Specific airway resistance
ACQ
Asthma Control Questionnaire
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AQLQ(S)
Asthma Quality of Life Questionnaire with Standardized Activities
AR(1)
First-Order Autoregressive
RNA
Ribonucleic Acid
ATC
Anatomical Therapeutic Chemical
ATS
American Thoracic Society
BCP
Business Continuity Plan
BD
Bronchodilator
BMI
Body Mass Index
CI
Confidence Interval
CFD
Computational Fluid Dynamics
CMH
Cochran-Mantel-Haenszel
CS
Compound Symmetry
CSR
Clinical Study Report
CT
Computed Tomography
DBP
Diastolic Blood Pressure
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EE
Eastern Europe
ERS
European Respiratory Society
FEF25-75%
Forced Expiratory Flow at 25 and 75% of the Pulmonary Volume
FeNO
Fractional exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FOT
Forced Oscillation Technique
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
FVC
Forced Vital Capacity
GLMM
Generalized Linear Mixed Model
HBcAb
Hepatitis B core Antibody
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HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HCVAb
Hepatitis C Virus Antibodies
HIV
Human Immunodeficiency Virus
HLT
High Level Term
HLGT
High Level Group Term
HR
Heart Rate
HRCT
High-Resolution Computed Tomography
IAD
Internal Airflow Distribution
IcEv
Intercurrent Event
ICS
Inhaled Corticosteroids
IgM
Immunoglobulines M
IMP
Investigational Medicinal Product
ITT
Intent-To-Treat
iV/Q
Image-based ventilation/perfusion
iVaww
Airway wall volume
iVlobes
Lobar volumes
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-Acting Beta-Agonists
LAMA
Long-Acting Muscarinic Antagonist
LLT
Lowest Level Term
LTRA
Leukotriene Receptor Antagonists
LS
Least Square
MAR
Missing At Random
MCID
Minimal Clinically Important Difference
MCMC
Markov Chain Monte Carlo
MDCT
Multi-detector Computed Tomography
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
MMRM
Mixed Model for Repeated Measures
MNAR
Missing Not At Random
NIMP
Non-Investigational Medicinal Product
PCSA
Potentially Clinically Significant Abnormalities
ppb
Parts Per Billion
PRO
Patient-Reported Outcomes
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PT
Preferred Term
Q1
First Quartile
Q2W
Every 2 Weeks
Q3
Third Quartile
QoL
Quality of Life
ROW
Rest of World
SABA
Short-Acting Beta Agonists
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Standard Deviation
SE
Standard Error
SOC
System Organ Class
TEAE
Treatment-Emergent Adverse Events
TLC
Total Lung Capacity
TLFs
Tables, Listings, Figures
TOEP
Homogeneous Toeplitz
TOEPH
Heterogeneous Toeplitz
UCSF
University of California, San Francisco
ULN
Upper Limit of Normal
UN
Unstructured
US
United States
WHO-DD
World Health Organization-Drug Dictionary
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DOCUMENT HISTORY-CHANGES COMPARED TO PREVIOUS 
VERSION OF SAP
Version
Date
Changes
Draft 1.0
04OCT2021
Initiation
Draft 2.0
25FEB2022
Updates following Sanofi’s comments
-
Updated MMRM model for [s]iVaw
-
Removed supplementary analysis
-
Updated model for FRI secondary endpoints
Draft 3.0
11JUL2023
-
Updated model for FeNO <25 ppb achievement and moved 
to primary endpoint
-
Pre-BD FEV1 has been downgraded from primary to 
secondary endpoint
-
Post-BD FEV1 is still a secondary endpoint but will be 
removed from hierarchical testing order
-
Mucus score was upgraded from tertiary to secondary 
endpoint
-
Added tertiary endpoints change from baseline in PI10, 
Airway Wall Area, Wall Area Percentage, Airway Radius, 
Mucus volume, Reactance Area, pre- and post-BD 
FEV1/FVC, pre- and post-BD FEF25-75%
-
Added composite endpoints
-
Added supplementary analyses
-
Updated baseline and reference day definitions
-
Added deviations related to Ukrainian crisis
Final 1.0
20JUL2023
-
Changed criteria on supplementary analyses
-
Added supplementary analysis removing data with technical 
issues
Final 2.0
25JUL2023
-
Added tertiary endpoints change from baseline in airway 
resistance R5 and R20 measured by forced oscillometry
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1. INTRODUCTION
This document provides the detailed statistical methodology for the analysis of data from the 
Sanofi Group study LPS15834. The table, listing and figure shells supporting the statistical 
analysis plan (SAP) can be found in a separate SAP shell document.
The analyses described herein are based on the Amended Clinical Trial protocol, Version 3.0,
dated on 13th April 2023. Any changes or revisions to the planned analysis described in this 
document will be made prior to database lock.
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2. STUDY OBJECTIVES, ENDPOINTS AND ESTIMANDS
The study objectives and corresponding endpoints are shown in the Table 2-1;
Table 2-1 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 fractional exhaled 
nitric oxide (FeNO) <25 parts per billion (ppb) at Week 24
x
Percent change from baseline to Week 24 in untrimmed 
distal specific airway 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 
volume, ventilation defects and 
mucus plugging derived from high-
resolution computed tomography 
(HRCT) scans, patient-reported 
outcomes (PRO), FeNO and 
spirometry.
x
Percent change from baseline to Week 24 in untrimmed 
distal specific airway volume ([s]iVaw) at functional 
residual capacity (FRC)
x
Percent change from baseline to Week 24 in trimmed 
distal specific airway resistance ([s]iRaw) at TLC
x
Percent change from baseline to Week 24 in trimmed 
distal specific airway resistance ([s]iRaw) at FRC
x
Percent 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 
score (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 7 item Asthma 
Control Questionnaire (ACQ-7)
x
To evaluate safety of dupilumab
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)
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Objectives
Endpoints
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Objectives
Endpoints
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Table 2-2 Summary of primary estimands for main objectives
Endpoint Category
(estimand)
Estimands
Endpoint(s)
Population
Intercurrent event(s) handling strategy
Population-level summary
(Analysis and missing data handling)
Primary objective: To assess the effect of dupilumab on lung inflammation and related changes in airway volumes detectable by functional respiratory imaging.
Primary endpoints
Proportion of 
participants achieving 
FeNO <25 ppb at 
Week 24
ITT
x
Discontinuation of study intervention due to 
Covid-19 pandemica (IcEv1), off-study intervention 
data will be set as missing (hypothetical strategy).
x
Discontinuation of study intervention not due to 
Covid-19 pandemic (IcEv2), all data collected 
following schedule after the study intervention 
discontinuation will be used in the analysis 
(treatment policy strategy).
Achievement of FeNO <25 ppb at Week 24
will be analyzed using a Cochran-Mantal-
Haenszel (CMH) test adjusted by 
stratification factors (region and ICS dose 
level). Corresponding odds ratios and 
95% CI with p-value will be reported.
Missing data at Week 24 will be considered 
as non-responders.
Percent change from 
baseline to Week 24 in 
untrimmed distal 
specific airway volume 
([s]iVaw) at total lung 
capacity (TLC)
ITT
x
Discontinuation of study intervention due to 
Covid-19 pandemica (IcEv1), off-study intervention 
data will be set as missing (hypothetical strategy).
x
Discontinuation of study intervention not due to 
Covid-19 pandemic (IcEv2), all data collected 
following schedule after the study intervention 
discontinuation will be used in the analysis 
(treatment policy strategy). 
A mixed effect model for repeated measures 
(MMRM) under the missing at random 
(MAR) framework will be used. The MMRM 
will use percent change from baseline in 
untrimmed distal [s]iVaw at TLC up to 
Week 24 as the response variable, and will 
include study intervention, baseline value, 
region, ICS dose level, visits, study 
intervention by visit interaction, and baseline 
by visit interaction terms all as fixed effects. 
Region, ICS, study intervention and visits 
will be considered as categorical parameters. 
No explicit imputation will be done for 
missing data. Baseline values corresponding 
to the outcome variables should be used.
Secondary objective: To evaluate the effect of dupilumab at Week 24 on bronchodynamics, hyperinflation, airway resistance, airway wall volume, ventilation defects and 
mucus plugging derived from high-resolution computed tomography (HRCT) scans, patient-reported outcomes, FeNO and spirometry. 
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Endpoint Category
(estimand)
Estimands
Endpoint(s)
Population
Intercurrent event(s) handling strategy
Population-level summary
(Analysis and missing data handling)
Secondary endpoint
Change or percent 
change from baseline in 
respiratory related 
outcomes
ITT
x
Discontinuation of study intervention due to 
Covid-19 pandemica (IcEv1), off-study intervention 
data will be set as missing (hypothetical strategy). 
x
Discontinuation of study intervention not due to 
Covid-19 pandemic (IcEv2), all data collected 
following schedule after the study intervention 
discontinuation will be used in the analysis 
(treatment policy strategy). 
For spirometry and biomarker parameters, 
a mixed effect model for repeated measures 
(MMRM) under the missing at random 
(MAR) framework based on change from 
baseline up to Week 24 will be used. The 
MMRM will include study intervention, 
baseline value, region, Inhaled 
Corticosteroids (ICS) dose level, visits, age, 
height, gender, study intervention by visit 
interaction, and baseline by visit interaction 
terms all as fixed effects. Region, ICS, 
gender, study intervention and visits will be 
considered as categorical parameters. No 
explicit imputation will be done for missing 
data. Baseline values corresponding to the 
outcome variables should be used.
For Functional Respiratory (FRI) parameters, 
the same MMRM model as for untrimmed 
distal [s]iVaw at TLC primary endpoint will 
be used. Baseline values corresponding to the 
outcome variables should be used.
For Asthma Control Questionnaire (ACQ-7), 
a mixed effect model for repeated measures 
(MMRM) under the missing at random 
(MAR) framework based on change from 
baseline up to Week 24 will be used. The 
MMRM will include study intervention, 
baseline value, region, Inhaled 
Corticosteroids (ICS) dose level, visits, study 
intervention by visit interaction, and baseline 
by visit interaction terms all as fixed effects
a
The Covid-19 pandemic is unexpected and will eventually be over. The objective of the present study is to evaluate the treatment effect in absence of the pandemic and 
therefore the data collected after study intervention discontinuation due to pandemic will be set to missing.
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3. INVESTIGATIONAL PLAN
3.1. Overall study design and plan
This is a Phase IV, 2:1 randomized, parallel, multinational, multicenter study, with a 24-week 
double-blind placebo-controlled treatment period to assess the effect of dupilumab on airway 
inflammation through assessments of lung function, mucus plugging, and other lung imaging 
parameters in participants with asthma.
Approximately 97 participants will be randomly assigned to study intervention, in a 2:1 dupilumab to
placebo ratio, such that approximately 87 evaluable participants complete the study, assuming 
a 10% dropout rate (approximately 58 in the active group and 29 in the placebo group).
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 (EE)/Rest of the World
(ROW)). In total, no more than 40% participants should be in EE strata.
The study will comprise of:
x
Screening period: 4 weeks (±1 week), from signed informed consent to randomization
(Day [-35, -21] to Day -1).
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 participant switches to
commercialized dupilumab (or other biologic product), whichever comes first.
Study duration for each participant will be a total of minimum 29 weeks and up to 41 weeks. 
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.
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Figure 3-1 Study plan
3.2. Study endpoints
The study objectives and corresponding endpoints are shown in the Table 2-1.
3.3. Study interventions
The highest approved dose regimen of SC dupilumab has been selected for this study (300 mg 
Q2W).
Participants will receive;
x
Dupilumab 600 mg (2 x 300 mg dupilumab subcutaneous injections) on Day 1 (ie, the 
loading dose), followed by 1 dupilumab injection of 300 mg every two weeks (Q2W) until 
Week 24.
x
Matching placebo for dupilumab (2 x 2 mL placebo subcutaneous injections) on Day 1 
(loading dose), then 1 placebo injection Q2W until Week 24.
A home dosing diary will be provided to collect information related to at home injections.
Non-investigational medical products (NIMP)
Participants should be treated with medium to high dose of inhaled corticosteroids (ICS) in
combination with a second controller (ie, Long-Acting Beta-Agonists (LABA), Leukotriene 
Receptor Antagonists (LTRA), theophylline). A third controller is allowed but not mandatory. 
The dose regimen should be stable for ≥1 month before V1, during the screening and treatment 
period. Short-acting β2 agonists may be used as rescue medication during the study if needed. 
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In case of severe asthma exacerbations, the systemic corticosteroids are allowed as rescue 
medication as well. An asthma background therapy diary will be provided to collect information 
related to NIMP use.
3.4. Dose adjustment/modifications
Not applicable.
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4. GENERAL STATISTICAL CONSIDERATIONS
4.1. Sample size
In order to preserve the type I error at 0.05 level for the two primary endpoints, a hierarchical 
testing procedure will be applied at a 2-sided 5% significance 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
After the significance has been achieved for 2 primary endpoints, the other selected secondary 
endpoints will be tested following a hierarchical testing procedure at a 2-sided 5% significance 
level. The whole list of secondary endpoints to be tested in the hierarchical order will be specified 
in Section 8.2.5.
4.2. Randomization, stratification, and blinding
Randomization will be stratified by ICS dose level (medium/high- no less than 40% in ‘high ICS’ 
stratum) and region (EE/ROW - no more than 40% participants in EE stratum).
A randomized participant is defined as a participant who is registered and assigned with a study 
intervention kit number from the centralized treatment allocation system regardless of whether the 
intervention kit was used, as documented from its log file. A participant cannot be randomized 
more than once in the study.
4.3. Analysis set
Participants exposed to Investigational Medicinal Product (IMP) before or without being 
randomized will not be considered randomized, will not be included in any analysis set and will 
be reported in listings under a study intervention group named “not randomized but treated”. 
However, if these participants experienced any safety event, they would be documented separately 
in the Clinical Study Report (CSR).
Participants randomized but not treated will be included in all efficacy analyses. These 
participants will be analyzed for efficacy analyses according to the study intervention group to 
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which they are allocated by the Interactive Voice Response System/Interactive Web Response 
System (IVRS/IWRS).
4.3.1. Screened analysis set
The Screened analysis set includes all participants who sign the Informed Consent Form (ICF).
4.3.2. Intent-to-Treat (ITT) analysis set
The Intent-to-Treat (ITT) analysis set consists of randomized participant (participant with a study 
intervention kit number allocated and recorded in the IVRS/IWRS database, regardless of whether 
the study intervention kit was used or not). Participants in the ITT analysis set will be analyzed 
according to the study intervention group allocated by randomization. This analysis population 
will be applied to all efficacy analyses.
4.3.3. Safety set
The Safety set includes all randomized participants who received at least 1 injection of IMP. 
Participants will be analyzed according to the study intervention they actually received. 
Randomized participants for whom it is unclear whether the study medication was taken will be 
included in the safety set as randomized. For participants receiving more than one IMP during the 
study (ie, placebo and dupilumab), the actual study intervention group for as treated analysis will 
be the dupilumab group.
4.4. Reporting conventions
Statistical analysis will be performed using SAS® Version 9.4 or higher.
Standardized and validated SAS macros will be used to set-up table, listing, figure (TLF) formats 
(headers/footers and tabulation format) and tabulate the summaries. All tables and listings will be 
independently validated using double programming; all figures will be independently validated 
manually.
4.4.1.Study intervention labels
The following study intervention labels will be used in the Tables, Figures and Listings:
Table 4-1 Study intervention labels
Study intervention order
Study intervention group
Study intervention label
1
Placebo
Placebo
2
Dupilumab 300 mg q2w
Dupilumab 300 mg q2w
3
Total
Total
4.4.2.Visit naming conventions
The electronic Case Report Form (eCRF) visit label will be used to classify the assessments.
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4.4.3.Visit windows
The visit windows as defined in Section 15.5 will be applied to all endpoints.
4.4.4.Unscheduled visits
Unscheduled visit measurements will be used in the analysis on efficacy variables and will be 
included in the by-visit summaries for the safety variables if they are re-allocated to scheduled 
visits according to the visit window definitions in Section 15.5.
4.4.5.Display of data summary and analysis
Continuous variables will be summarized using descriptive statistics, including the following: 
sample size (n), mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), 
minimum and maximum for each study intervention group.
All mean, Q1, Q3 and median values will be formatted to one more decimal place than the 
measured value. SD values will be formatted to two more decimal places than the measured value. 
Minimum and maximum will be formatted to the same number of decimal places as the measured 
value.
95% confidence intervals (CI) will be two-sided and displayed to the same level of precision as 
the statistic they relate to. If an estimate or a CI is not estimable, it will be presented as ‘NE’. 
If neither an estimate, nor its CI are estimable, it will be presented as simply ‘NE’, not displaying 
‘NE’ twice.
The p-values will be two-sided and will be rounded to three decimal places. If a p-value is less 
than 0.001 it will be reported as ‘<0.001’. If a p-value is greater than 0.999 it will be reported as 
‘>0.999’.
Categorical and ordinal data will be summarized using the counts and percentages. When count 
data are presented, the percent will be suppressed when the count is zero in order to draw attention 
to the non-zero counts. A row denoted ‘Missing” will be included in count tabulations for 
demographics, baseline characteristics and compliance to account for missing values. 
No percentages will be displayed on the ‘Missing’ rows and the percentages on the other rows 
will be based on the number of non-missing observations. Unless otherwise specified, the 
denominator for all other percentages will be the number of participants in that study intervention
within the specific analysis set of interest. All percentages will be rounded to one decimal place. 
The number and percentage of responses will be presented in the form xx (xx.x), where the 
percentage is in the parentheses. When the numerator is equal to the denominator, the percentage 
should be presented as (100) instead of (100.0), unless otherwise specified.
All listings will be sorted for presentation in order of assigned study intervention arm, study 
center number, participant number and date of procedure or event.
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4.4.6.Baseline, study day and duration derivations
For efficacy parameters, the baseline value is defined as the last available valid (non-missing) 
value up to and including the date of first dose of IMP. For participants randomized but not 
treated, the baseline value is defined as the last available value up to and including the day of 
randomization.
For safety parameters, the baseline value is defined as the last available valid (non-missing) value 
up to and including the date of first dose of IMP.
If multiple valid values of a variable (efficacy or safety) exist within a same day (and the recorded 
times of measurement do not enable to identify which of them is the last assessment), the value 
measured during the scheduled visit will be used as Baseline in the analysis. If none of those 
values were assessed during a scheduled visit, then all these measurements will be used for the 
analysis and the average will be calculated to derive the baseline value.
Baseline safety and baseline efficacy results are presented in the safety and efficacy analyses.
The reference day (denoted as Day 1) for the calculation of extent of exposure and study day for 
AE listings will be the day of the first administration of IMP:
x
Extent of exposure (see Section 7.2.1)
x
Study day for AE listing: AE onset date – first administration date of IMP +1
The reference day (denoted as Day 1) for the calculation of study day of efficacy assessments will 
also be the day of the first administration of IMP (except for participants randomized but not 
exposed). 
x
For visit prior to the first administration of IMP, study day = assessment date – the first 
administration of IMP.
x
For visit at or after the first administration of IMP, study day = assessment date – the first 
administration of IMP +1.
Note: For participants randomized but not treated, the reference day will be the randomization 
date.
Intervals that are listed and/or tabulated in weeks will be transformed from days to weeks by using 
(without rounding) the following conversion formula:
WEEKS = DAYS /7
Intervals that are listed and/or tabulated in months will be transformed from days to months by 
using (without rounding) the following conversion formula:
MONTHS = DAYS /30.4375
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4.4.7.Change from baseline and percent change from baseline
Change from baseline is defined as:
Change from baseline = Value at specific time point – Baseline value
Percent change from baseline is defined as: 
Percent change from baseline(%) = Value at specific timepoint −Baseline value 
Baseline value
× 100%
4.5. Intercurrent event types
Table 4-2 specifies the types of Intercurrent events (IcEvs), and associated labels, used to define 
the estimands.
Table 4-2 Intercurrent event types
Label
Intercurrent Event Type
IcEv1 (discontinuation of study intervention due to 
Covid-19)
Premature study intervention discontinuation due to 
Covid-19 pandemic before Week 24
IcEv2 (discontinuation of study intervention not due to 
Covid-19)
Premature study intervention discontinuation not due 
to Covid-19 pandemic before Week 24
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5. PARTICIPANT DISPOSITION
5.1. Disposition
The participant disposition will be summarized for the ITT analysis set by study intervention
group and overall using number and percentage. This section describes participant disposition for 
both participant study status and the participant analysis sets.
For participant study status, the number and percentage of participants in the following categories 
will be presented:
x
Screened participants
x
Screen failure participants
x
Participants treated without being randomized
x
Randomized participants
x
Randomized but not treated participants
x
Randomized and treated participants
x
Participants who have completed the study intervention period
x
Participants who discontinued the study intervention period and the main reason for study 
intervention discontinuation. Relationship with COVID-19 will be reported for “Adverse 
Event” and “Other” reasons.
x
Participants who completed the study
x
Participants who discontinued the study and the main reason for study discontinuation. 
Relationship with COVID-19 will be reported for “Other” reasons
x
Participants who discontinued the study before Week 24
x
Participants who discontinued the study after Week 24 (ie, during post-study intervention
follow-up period)
x
Participants who had rescue medications during the study intervention period:
o
Participants who have completed the study intervention period and had rescue 
medications
o
Participants who did not complete the study intervention period and had rescue 
medications
x
Final Study Status
For screened, screen failure, and participants treated without being randomized, percentages will 
be calculated using the number of screened participants as the denominator for overall only. 
All other categories of participants will be presented by randomized study intervention group and 
for overall whilst the percentages will be calculated using the number of randomized participants,
within each study intervention group and overall, as denominator. Reasons for study intervention
and study discontinuation will be supplied in the disposition table showing number and 
percentage by study intervention group.
A summary of all the analysis sets for safety and efficacy (ITT) will be summarized for the ITT 
analysis set by study intervention group and overall using number and percentage.
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Participants with permanent study intervention and study discontinuation (early withdrawals) will 
be identified and described in separate listings (with the reason of discontinuation and the 
specification in case of other reason).
Additionally, trial impact (disruption) due to COVID-19 will be summarized for the ITT analysis 
set by study intervention group and overall using number and percentage. Participants for whom
at least one of the following events occur during the study will be presented:
x
Permanent end of study intervention due to COVID-19 pandemic
x
Premature end of study due to COVID-19 pandemic
x
Permanent end of study intervention due to AE related to COVID-19 infection
x
Critical or major protocol deviation due to COVID-19 pandemic
Some safety (adverse events) analyses will also be repeated on the subgroup of safety participants 
according to trial impact (disruption) due to COVID-19 pandemic (see Section 9.1).
The disposition of screened participants by country and site will be summarized for the screened 
analysis set using number and percentage.
A summary table to show participant disposition by visit according to trial impact (disruption) due 
to COVID-19 pandemic (visit not done, visit partially done on site, visit partially done by phone 
and visit done but delayed) will be provided overall and by country for the ITT analysis set.
5.2. Protocol deviations
All critical or major protocol deviations potentially impacting efficacy analyses (including
randomization and drug-dispensing irregularities; see Table 5-1), and other major or critical 
deviations will be summarized overall and according to COVID-19 impact (i.e. deviations related 
to COVID-19 pandemic) for the ITT analysis set by study intervention group and overall using 
number and percentage. Deviations related to Ukrainian crisis will be assessed as “Exceptional 
situation”.
A listing of participants with at least one critical or major protocol deviations will be provided 
with comprehensive information related to each deviation identified.
Randomization and drug-dispensing irregularities occur whenever:
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible participant is randomized, b) a participant is randomized based on 
an incorrect stratum, c) a participant is randomized twice, or d) in a dynamic 
randomization scheme the study intervention assignment is, in fact, not random, due to 
a computer program error.
OR
2. A participant is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a participant at any time in the study is dispensed a different study intervention
kit than as randomized (which may or may not contain the correct-as-randomized IMP), 
or b) a non-randomized participant is treated with IMP reserved for randomized 
participants.
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Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis. 
All randomization and drug-dispensing irregularities will be documented in the CSR. If the 
number of irregularities is large enough to make a tabular summary useful, the critical or major 
irregularities will be categorized and summarized for the ITT analysis set by study intervention
group and overall using number and percentage.
Non-randomized, treated participants will be described separately.
Randomization and drug-dispensing irregularities to be prospectively identified include but are not 
limited to:
Table 5-1 Randomization and drug dispensing irregularities
Randomization and drug allocation irregularities
x
Kit dispensation without IRT transaction
x
Erroneous kit dispensation
x
Kit not available
x
Randomization by error
x
Participant randomized twice
x
Forced randomization
x
Stratification error
x
Participant switched to another site
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6. DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics, participant characteristics and baseline disease characteristics will be 
summarized using the ITT analysis set by study intervention group and overall using descriptive 
statistics or using number and percentage. P-values on the study intervention difference for the
demographic and baseline characteristics data will not be calculated. In general, no specific 
description of the safety parameters will be provided at baseline. If relevant, the baseline values 
will be described along with each safety/efficacy analysis.
6.1. Demographics
The following demographics and participant characteristics will be summarized by treatment 
group and overall:
x
Age (years)
x
Age categories (≥18 to <40, ≥40 to <70, ≥70)
x
Gender (Male, Female)
x
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown)
x
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Multiple, Not Reported, Unknown)
x
Baseline body weight (kg)
x
Baseline body weight categories (<70, ≥70 to <100, ≥100)
x
Baseline height (cm)
x
Baseline body mass index (BMI) (kg/m²) derived as: (Weight in kg)/(Height in meters)²
x
Baseline BMI categories (<15, ≥15 to <25, ≥25 to <30, ≥30)
x
Region (EE/ROW)
6.2. Baseline disease characteristics
The following baseline disease characteristics will be summarized by study intervention group and 
overall:
6.2.1. Respiratory characteristics at baseline
x
Spirometry (see Section 15.9):
o
Pre-BD FEV1 (L)
o
Post-BD FEV1 (L)
o
% predicted pre-BD FEV1 (%)
o
% predicted post-BD FEV1 (%)
o
Pre-BD FVC (L)
o
Post-BD FVC (L)
o
% predicted Pre-BD FVC (%)
o
% predicted Post-BD FVC (%)
o
Pre-BD FEV1/FVC
o
Post-BD FEV1/FVC
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o
Pre-BD FEF 25-75% (L/s)
o
Post-BD FEF 25-75% (L/s)
x
The following Functional Respiratory Imaging (FRI) parameters (see Section 15.10),
based on low-dose inspiratory-expiratory multi-slice computed tomography images and 
computational fluid dynamics flow simulations will be presented:
o
Untrimmed distal airway volume ([s]iVaw) (in mL) at total lung capacity (TLC)
o
Untrimmed distal [s]iVaw (in mL) at functional residual capacity (FRC)
o
Trimmed distal airway resistance ([s]iRaw) (in KPA*S/L) at TLC
o
Trimmed distal [s]iRaw (in KPA*S/L) at FRC
o
UCSF mucus score, global and for each lung zone (RUL, RML, RLL, LUL, LLL)
o
Untrimmed distal airway wall volume (iVaww) (in mL) at TLC
o
Global lung lobar volumes (iVlobes) (in L) at TLC
o
Global lung iVlobes (in L) at FRC
o
Ventilation/perfusion ratio (iV/Q) at TLC for each lung zone (RUL, RML, RUL+RML, 
RLL, LUL, LLL)
o
Blood vessel density at TLC (mL) (overall lung)
o
HRCT based Internal lobar airflow distribution (IAD) (%) for each lung zone (RUL, 
RML, RUL+RML, RLL, LUL, LLL)
o
HRCT based airway occlusions at FRC (in %) for each lung zone (RUL, RML, 
RUL+RML, RLL, LUL, LLL)
o
Mucus volume (mL), global and for each lung zone (RUL, RML, RLL, LUL, LLL)
o
PI10 (mm)
o
Airway wall area (mm²)
o
Wall area percentage (%)
o
Airway radius (mm)
x
Forced oscillometry (see Section 15.11):
o
Airway resistance from R5 to R20 (in KPA*S/L)
o
Reactance area (kPa/L)
o
Airway resistance R5 (in KPA*S/L)
o
Airway resistance R20 (in KPA*S/L)
Notes for FRI parameters:
For each parameter, the zone to be presented and whether trimmed or untrimmed data should be 
presented are listed in the list of parameters above.
All FRI parameters are assessed in the following different zones of the respiratory system:
x
Overall lung (except for HRCT based IAD)
x
Right upper lobe (RUL)
x
Right middle lobe (RML)
x
Right lower lobe (RLL)
x
Left upper lobe (LUL)
x
Left lower lobe (LLL)
[s]iVaw, [s]iRaw and iVaww are also assessed in the following zones of the respiratory system:
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x
Distal lung
However, the possibility exists that for some participants no distinction can be made between the 
different lung lobes. In this case, the following zones can also be identified, but will be excluded 
from tables, figures and models (only listed):
x
Right upper and middle lobe (RUL+RML)
x
Right middle and lower lobe (RML+RLL)
x
Right upper and lower lobe (RUL+RLL)
x
Right upper, middle and lower lobe (RUL+RML+RLL)
x
Left upper and lower lobe (LUL+LLL)
Trimmed and untrimmed results (see Section 15.10) are available for [s]iVaw, [s]iRaw and 
iVaww.
6.2.2. Asthma questionnaires at baseline
The following asthma questionnaires (see Section 15.8) will be summarized at baseline:
x
7-item Asthma Control Questionnaire (ACQ-7) score
x
ACQ-6 score
x
ACQ-5 score
x
Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ(S)) global
score
6.2.3. Asthma and associated disease characteristics at baseline
Asthma history will be summarized by study intervention group and overall:
x
Dose level of inhaled corticosteroid (ICS) (Medium, High)
x
Age at asthma diagnosis (years),
x
Age at asthma diagnosis categories (<18, ≥18 to <40, ≥40 to <70, ≥70),
x
Number of severe asthma exacerbation events (identified using LLT) within 1 year prior to 
the study,
x
Number of severe asthma exacerbation events (identified using LLT) within 1 year prior to 
the study (1, 2, >2),
x
Time since last severe asthma exacerbation (months),
x
Number of controller medications at study entry (2 or 3)
x
Atopic comorbid condition (yes/no)
The age at asthma diagnosis is defined as the date of asthma diagnosis minus the year of birth and 
June 30th divided by 365.25, keeping the integer part of the result.
The time since last severe asthma exacerbation in months is defined as the informed consent date 
minus the date of the last severe asthma exacerbation divided by 30.4375.
Exacerbation is defined as deterioration of asthma that results in emergency treatment, 
hospitalization due to asthma, or treatment with systemic steroids.
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6.2.4. Biomarkers at baseline
The following biomarkers (see Section 15.12) will be summarized at baseline:
x
FeNO (ppb)
x
FeNO in class (<25, ≥25 to <50, >=50 ppb)
x
Blood Eosinophil count (cells/μL)
x
Eosinophils counts in class (≥300 to <500, ≥500 cells/μL)
Blood Eosinophils counts collected in 10^9/L will be converted to cells/μL using the following 
formula:
1 10^9/L *1000 = cells/μL
6.3. Tobacco usage
The following smoking habits at screening will be summarized by study intervention group and 
overall:
x
Tobacco consumption: status (never, current, former) and amount (cigarette) per day
x
Electronic cigarette consumption: status (never, current, former) and amount (mg) per day
6.4. Medical history
6.4.1. General medical history
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the participant.
Medical and surgical history will be coded to “lowest level term (LLT)”, “preferred term (PT)”, 
“high level term (HLT)”, “high level group term (HLGT)”, and associated primary “system organ 
class (SOC)” using the version of Medical Dictionary for Regulatory Activities (MedDRA) in 
effect at Sanofi at the time of each database lock.
The number and percentage of participants with any medical history will be summarized by study 
intervention group and overall and for each primary SOC, HLT and PT. SOC will be sorted by
internationally agreed order of primary SOC, and HLT and PT will be sorted by alphabetical 
order. Participants experiencing severe asthma exacerbations will be further summarized using the 
LLT level as appropriate within medical history summaries.
Additionally, a separate table will present atopic comorbidities captured in the past and current 
medical conditions eCRF page by primary SOC, HLT and PT based on the ITT set. Atopic
comorbidities will be identified via a file provided by Sanofi containing the following CMQ 
codes: CMQ10646, CMQ10540, CMQ10541, CMQ10537, CMQ10076, CMQ10799, 
CMQ10800.
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6.4.2. Disease-specific history
Not applicable.
6.5. Inclusion and exclusion criteria
Inclusion and exclusion criteria will be presented for the screened analysis set using number and 
percentage.
6.6. Other background information
Not applicable.
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7.
STUDY INTERVENTIONS AND MEDICATIONS
7.1. Prior and concomitant medications
The prior and concomitant medications will be presented for the ITT analysis set for each study 
intervention group (and overall for prior medications) using number and percentage. No statistical 
test for the between-group difference will be performed.
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version in effect at Sanofi at the time of each database lock.
Medications will be summarized by study intervention group according to the WHO-DD, 
considering the first digit of the anatomic category (ATC) class (anatomic category – Level 1) and 
the first 3 digits of the ATC class (therapeutic category – Level 2), unless otherwise specified. All 
ATC codes corresponding to a medication will be summarized, and participants will be counted 
once in each ATC category (anatomic or therapeutic) linked to the medication. Therefore, 
participants may be counted several times for the same medication.
The summaries for prior and concomitant medications will be sorted by decreasing frequency of 
ATC followed by all other therapeutic classes based on the incidence in the Dupilumab study 
intervention group. In case of equal frequency regarding ATCs, alphabetical order will be used.
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete medication 
start and stop dates will be imputed as described in Section 15.4.3.
A given medication can be classified as a prior medication as well as a concomitant medication.
7.1.1. Prior medications
Prior medications are those the participant began prior to first IMP intake. Prior medications can 
be discontinued before first study intervention administration or can be ongoing during the study 
intervention phase.
The following prior medication summaries will be generated separately by study intervention
group and overall:
x
Inhaled corticosteroids, in combination with other controllers summarized by medication 
type (ICS, LABA, Long-Acting Muscarinic Antagonist (LAMA), LTRA, Other) and 
standardized medication name.
Note: These medications are recorded in the Asthma controller medication eCRF page and 
ATC codes will be used to categorize them into ICS (ATC class R03BA), LABA (ATC 
class R03AC), LAMA (ATC class R03BB), LTRA (ATC class R03DC) or Other.
x
Reliever medications summarized by medication type (Short-Acting Beta Agonists 
(SABA), systemic corticosteroids, other) and standardized medication name 
(see Section 15.13).
Note: These medications are recorded in the Asthma reliever medication eCRF page.
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x
Other prior medications.
Note: These medications are recorded in the Other medications eCRF page.
The prior prohibited medications will also be presented by prohibited medication category as 
defined in deviation and standardized medication name (see Section 15.13).
7.1.2. Concomitant medications
Concomitant medications are any treatments received by the participant concomitantly to the 
IMP, starting from the 1st administration of IMP to the date of last administration +98 days.
The following concomitant medications summaries will be generated separately by study 
intervention group:
x
Inhaled corticosteroids in combination with other controllers summarized by medication 
type (ICS, LABA, LAMA, LTRA, Other) and standardized medication name.
Note: These medications are recorded in the asthma controller medication eCRF page and 
ATC codes will be used to categorize them into ICS (ATC class R03BA), 
LABA (ATC class R03AC), LAMA (ATC class R03BB), LTRA (ATC class R03DC) 
or Other.
x
Reliever (rescue) medications summarized by medication type (SABA, systemic 
corticosteroids, other) and standardized medication name (see Section 15.13).
Note: These medications are recorded in the asthma reliever medication eCRF page.
x
Other concomitant medications.
Note: These medications are recorded in the other medications eCRF page.
The concomitant prohibited medications will also be presented by prohibited medication category 
as defined in deviation and standardized medication name (see Section 15.9).
7.1.3. Post-treatment medications
Post-treatment medications are those the participant took (continued or initiated) in the period 
running from the 99th day after the last administration of IMP up to the end of the study. 
Post-treatment medications will not be summarized or presented in the CSR.
7.2. Study interventions
The extent of IMP exposure and compliance will be assessed and summarized by actual study 
intervention group for the safety set.
7.2.1.Extent of exposure
The extent of IMP exposure will be assessed by the duration of IMP exposure.
Duration of IMP exposure is defined as last IMP administration dose date – first IMP 
administration dose date +14 days, regardless of unplanned intermittent discontinuations.
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Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, Q1, Q3, minimum and maximum). In addition, duration of IMP exposure will 
also be summarized categorically by numbers and percentages for each of the following 
categories:
x
>0 and ≤2 weeks
x
>2 and ≤4 weeks
x
>4 and ≤8 weeks
x
>8 and ≤12 weeks
x
>12 and ≤16 weeks
x
>16 and ≤20 weeks
x
>20 and ≤24 weeks
x
>24 and ≤26 weeks
x
>26 weeks
and cumulatively according to the following categories:
x
≥1 day
x
>2 weeks
x
>4 weeks
x
>8 weeks
x
>12 weeks
x
>16 weeks
x
>20 weeks
x
>24 weeks
x
>26 weeks
Additionally, the sum of the duration of IMP (total) exposure for all participants will be 
summarized by study intervention group and will be expressed in participant years.
7.2.2.Study intervention compliance and modifications
A given administration will be considered non-compliant if the participant did not take the 
planned dose of study intervention as required by protocol (i.e., a syringe not fully injected is 
considered as a non-compliant administration). No imputation will be made for missing or 
incomplete data.
Percentage of compliance for a participant will be defined as the number of administrations that 
the participant was compliant (planned dose fully injected) divided by the total number of 
administrations that the participant was planned to take during the study intervention period.
Percentage of compliance (%) = ቂ
Total number of compliant administrations during the study intervention period
Number of planned administrations during the study intervention period
ቃ× 100%
Loading doses for the same participant will be counted as 1 dose.
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Percentage of injections with compliance for a participant will be defined as the number of 
injections that the participant was compliant divided by the total number of injections that the 
participant was planned to take during the study intervention period.
Percentage of injections with compliance (%) = ቂ
Total number of compliant injections during the study intervention period
Number of planned injections during the study intervention period
ቃ× 100%
Loading doses for the same participant will be counted as 2.
Percentage of compliance and percentage of injections with compliance to the IMP administration 
will be summarized descriptively as quantitative variables (number, mean, SD, median, Q1, Q3, 
minimum and maximum). In addition, the percentage of compliance will be presented by the 
specific ranges:
x
<80%
x
≥80 %
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. Cases of symptomatic overdoses will constitute AESIs and will be 
listed as such. More generally, dosing irregularities will be listed in Section 5.2.
Dose modification of IMP for an individual participant is not allowed and therefore no summary of 
dose modifications will be provided.
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8. EFFICACY ANALYSIS
Efficacy analyses will be performed on the ITT analysis set.
Participants will be analyzed for efficacy according to the study intervention group to which they 
are allocated by the IRT according to the randomization schedule at the randomization visit 
(as randomized), irrespective of the study intervention actually received.
For all efficacy analyses, time window will be used to assign the visit (see Section 15.5).
For the analysis of primary objective in the study intervention period, 
x
The null statistical hypothesis tested is that 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.
x
The alternative statistical hypothesis tested is that 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.
In order to preserve the type I error at 0.05 level for the two primary endpoints, a hierarchical 
testing procedure will be adopted. The tests will be performed in this order:
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
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation, except if study intervention discontinuation was due to 
the COVID-19 pandemic. Refer to Table 2-2 for more details.
For efficacy endpoints where a change from baseline or percent change from baseline is assessed, 
only the participants with a baseline and at least one post-baseline value available will be included 
in the analysis model (number of participants included in the analysis model reported in the table).
All available results will be included in the descriptive statistics.
Line plots for change and percent change from baseline will be presented by study intervention 
group, displaying the LS mean and SE at each visit. These plots will be provided for the primary 
and all secondary continuous endpoints.
Bar plots for percentage of participants having achieved FeNO <25 parts per billion (ppb) at 
Week 24 will be presented by study intervention group, displaying the percentage of achievers 
participants at each visit.
When applicable, inferential tests will be performed at all scheduled visits: The adjusted least 
square (LS) mean in change from baseline of each study intervention group, the LS mean 
difference between the dupilumab and placebo groups, and the corresponding SEs and 95% CIs 
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will be provided. The p-value corresponding to the LS mean difference will be provided at 
Week 24 only.
8.1. Primary efficacy endpoint
The two primary endpoints are:
x
Proportion of participants achieving response of FeNO <25 ppb at Week 24
x
Percent change from baseline to week 24 in untrimmed distal specific airway volume
([s]iVaw) at total lung capacity (TLC) (see Section 15.10)
8.1.1.Primary analysis
Proportion of participants achieving FeNO <25 ppb at week 24 will be analyzed with a 
Cochran-Mantel-Haenszel (CMH) test adjusted by stratification factors (ICS dose level at baseline 
and region). 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 COVID-19 pandemic, off-
treatment data will be used to determine the responder/non-responder status. For any participants 
who discontinued 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.
Percent change from baseline in untrimmed distal [s]iVaw at TLC will be analyzed with a 
MMRM model under the MAR framework. The MMRM model will use percent change from 
baseline in untrimmed distal [s]iVaw up to week 24 as response variable and include study 
intervention (dupilumab, placebo), baseline value of untrimmed distal [s]iVaw at TLC, region 
(EE/ROW), ICS dose level (medium/high), visits (up to week 24), study intervention by visit 
interaction, and baseline untrimmed distal [s]iVaw at TLC by visit interaction terms all as fixed 
effects. An unstructured correlation matrix will be used to model the within-participant errors.
The Kenward-Roger approximation (ddfm=kr) will be used to estimate the denominator of 
degrees of freedom. Parameters will be estimated using restricted maximum likelihood method 
with the Newton-Raphson algorithm. The adjusted LS mean in percent change from baseline of 
each study intervention group, the LS mean difference between the dupilumab and placebo
groups, and the corresponding SEs and 95% CIs will be provided at all scheduled visits. The 
p-value corresponding to the LS mean difference will be provided at Week 24 only.
For participants who discontinued the study intervention before Week 24 not due to the 
COVID-19 pandemic, off-study intervention imaging data measured up to Week 24 will be 
included in the analysis. In contrast, for any participants discontinuing the study intervention due 
to the COVID-19 pandemic, off-study intervention data will not be included (ie, set to missing) 
but will be assumed missing at random.
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.
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Data may be logarithmically transformed prior to analysis if extreme skewness was observed 
based on blinded data review.
If the MMRM model under unstructured correlation matrix fails to achieve convergence due to 
complexity of model specification, different covariance structures will be used according to the 
following order till convergence is achieved:
1. Heterogeneous Toeplitz (TOEPH)
2. Homogeneous Toeplitz (TOEP)
3. First-Order Autoregressive [AR(1)]
4. Compound Symmetry (CS)
8.1.2.Assumption testing
No assumption testing will be performed.
8.1.3.Missing data handling
No imputation will be made for the missing values for the primary analysis, unless specified 
differently in the estimand strategy (see Table 2-2, Table 2-1).
8.1.4.Subgroup analysis
Primary analysis will be replicated for the following subgroups:
x
Age category (≥18 to <40, ≥40 years)
x
Gender (Male, Female)
x
Race (Not-White, White)
x
Baseline body weight (<70, ≥70 kg)
x
Baseline BMI (<25, ≥25 to <30, ≥30)
x
Region (EE/ROW)
x
Baseline ICS dose level (Medium, High)
x
Age of asthma diagnosis (<18, ≥18 to <40, ≥40 years)
x
Number of severe asthma exacerbation events within 1 year prior to the study (1, >1)
x
Number of controller medications at study entry (2, 3)
x
Smoking history (Former, Never)
x
Baseline FeNO (≥25 to <50, >=50 ppb)
x
Baseline Eosinophils (<500, ≥500 cells/μL)
x
Baseline ACQ-5
o
(≤3, >3)
o
(≤3.5, >3.5)
x
Baseline Global Lung Mucus Score
o
Low (0-3.5)
o
High (4-20)
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Subgroups might be combined in case the sample size is too small.
In these subgroup analyses, nominal p-value will be provided for descriptive purpose only.
Results will also be illustrated with forest plots.
8.1.5.Sensitivity analysis
A sensitivity analysis on the two primary endpoints of achievement of FeNO <25 ppb at Week 24
and percent change from baseline to week 24 in untrimmed distal [s]iVaw at TLC will be carried 
out. For the latter, an analysis of covariance model (ANCOVA) with data from multiple 
imputation (MI) on missing results under an assumption of missing at random (MAR) will be 
used. For response of FeNO <25 ppb at week 24, a CMH testing procedure with data from 
multiple imputation (MI) on missing results under an assumption of missing at random (MAR) 
will be performed. Under this assumption, each missing score will be imputed 100 times and 
incorporated with non-missing data form 100 complete datasets. Each dataset will include FeNO /
untrimmed distal [s]iVaw at baseline, week 4, week 12 (only for FeNO), and week 24, as well as 
relevant covariates specified below to support the analysis. Following steps will be conducted for 
this analysis. The number of imputations (100) will be informally verified by replicating sets of 
100 imputations and checking whether the combined results are stable. If not stable, the number 
of imputations will be increased and informally checked as above, until stable estimates are 
obtained.
x
Use the Markov chain Monte Carlo (MCMC) method to impute for intermittent missing 
values by study intervention group and to create 100 datasets with monotone missing 
pattern. According to the nature of the endpoint, minimum and maximum values will be 
specified in this imputation.
x
For each of 100 datasets with monotone missing pattern created from MCMC imputation, 
use monotone regression method to impute remaining missing value by study intervention 
group up to week 24. In the imputation regression model, the following covariates will be 
included:
o
region (EE/ROW) and ICS dose level (medium/high)
Percent change from baseline at week 24 and achievement of FeNO <25 ppb can be 
calculated with non-missing score or imputed score for every single participant in all 
datasets. All 100 datasets with full imputation for missing values will be input to the
following models.
x
Repeatedly perform ANCOVA modeling for each of 100 datasets with full imputation for 
missing values. Percent change from baseline of untrimmed distal [s]iVaw at TLC at week 
24 will be analyzed on the ITT population in this ANCOVA model, and study intervention
(Dupilumab, Placebo), baseline of the analyzed endpoint and respective above covariates, 
will be included as covariates.
x
The adjusted LS means in change or percent change from baseline of each study 
intervention group, the LS mean difference between the dupilumab and placebo groups, 
and the corresponding SEs and 95% CIs of the differences generated from the 
100 ANCOVA models will be combined using Rubin’s formula and presented in a 
statistical table for the ITT population.
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x
Repeatedly perform CMH testing on each of 100 datasets with full imputation for missing 
values. Achievement of response of FeNO <25 ppb at week 24 will be analyzed on the 
ITT population, adjusted on stratification factors.
x
The Wilson-Hilferty transformation will be used to perform a combined CMH test and 
odds-ratios will be combined using a log transformation and Rubin’s formula. The 
combined p-value, odds-ratio and corresponding CIs will be presented in a statistical table 
for the ITT population.
8.1.6.Supplementary analysis
A supplementary subgroup analysis will be performed on primary endpoints, for the following 
subgroups:
x
Participants who had concomitant SCS rescue medications (identified with file provided 
by Sanofi containing CDGsn00010 medications) (Yes, No)
x
Participants who have respected SABA washout period (only for untrimmed distal 
[s]iVaw)
x
Removing data with technical issues (only for untrimmed distal [s]iVaw)
In these subgroup analyses, nominal p-value will be provided for descriptive purpose only.
Results will also be illustrated with forest plots.
8.1.7.Impact of Covid-19 pandemic
During the Covid-19 pandemic, a business continuity plan (BCP) was put in place to minimize the 
impact of the clinic visit interruption, ensure IMP treatment continuity and data collection. 
Direct to participant delivery of IMP from the site(s) and home injection(s) done by qualified site 
personnel and/or health care professionals for study drug administration were made available, 
where allowed by local regulations and approved by the participant, as planned per protocol. 
IMP permanent discontinuation due to Covid-19 pandemic is therefore expected to be minimum. 
Site(s) can update/correct the schedule of completion if visit is rescheduled/delayed – unless site 
staff cannot access vendor platform to update scheduled dates.
Missing data due to Covid-19 pandemic is likely to be missing at random. Therefore, the primary 
analysis using MMRM can adequately address this type of missing data. Participant disposition 
summaries by visit according to trial impact (disruption) due to COVID-19 overall and by country 
are already mentioned in Section 5.1 of this SAP.
8.2. Secondary efficacy endpoints
8.2.1.Lung function measured by spirometry
Pre-BD FEV1 and Post-BD FEV1 (see Section 15.9) will be summarized in terms of actual value 
and change from baseline at baseline and at week 24.
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In addition, at each post-baseline visit, the change from baseline will be modelled using an 
MMRM model under the missing at random framework. The MMRM model will include study 
intervention (dupilumab, placebo), baseline value of the parameter, region (EE/ROW), ICS dose 
level (medium/high), visits (up to week 24), age (years), height (cm), gender (male/female), study 
intervention by visit interaction, and baseline value of the parameter by visit interaction terms all 
as fixed effects. An unstructured (UN) correlation matrix will be used to model the within-
participant errors.
The same strategy as for MMRM model for primary endpoint untrimmed distal [s]iVaw will be 
used for the selection of the covariance structure if MMRM under unstructured correlation matrix 
fails to achieve convergence.
8.2.2.Fractional Exhaled Nitric Oxide (FeNO)
FeNO (see Section 15.12) will be summarized in terms of actual value and change from baseline 
at Week 24).
In addition, at each post-baseline visit, the change from baseline will be modelled using the same 
MMRM model as the one used for the secondary endpoint relating to pre-BD and post-BD FEV1.
LS mean of each study intervention group, LS mean difference between the dupilumab and 
placebo groups, and the corresponding SEs and 95% CIs will be provided at all scheduled visits. 
The p-value corresponding to the LS mean difference will be provided at Week 24 only. FeNO 
data may be logarithmically transformed prior to analysis if extreme skewness was observed 
based on blinded data review.
The same strategy as for MMRM model for primary endpoint untrimmed distal [s]iVaw will be 
used for the selection of the covariance structure if MMRM under unstructured correlation matrix 
fails to achieve convergence.
8.2.3.Functional Respiratory Imaging (FRI)
FRI secondary endpoints (see Section 15.10) will be summarized in terms of actual value and 
change from baseline or percent change from baseline to each post-baseline visit (Week 4 and 
Week 24).
In addition, at each post-baseline visit, the change from baseline or percent change from baseline 
will be modelled using the same MMRM model as the one used for the primary end point relating 
to untrimmed distal [s]iVaw at TLC. Baseline value will be the one of the variable being analyzed 
and, in case of variables in the percentage scale, it will be the baseline value on the raw scale. 
LS mean of each study intervention group, LS mean difference between the dupilumab and 
placebo groups, and the corresponding SEs and 95% CIs will be provided at all scheduled visits. 
The p-value corresponding to the LS mean difference will be provided at Week 24 only.
The same strategy as for MMRM model for primary endpoint untrimmed distal [s]iVaw will be 
used for the selection of the covariance structure if MMRM under unstructured correlation matrix 
fails to achieve convergence.
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FRI secondary endpoints are the following:
x
Untrimmed distal [s]iVaw at FRC (percentage change from baseline)
x
Trimmed distal [s]iRaw at TLC (percentage change from baseline)
x
Trimmed distal [s]iRaw at FRC (percentage change from baseline)
x
Global lung iVlobes at TLC (percentage change from baseline)
x
iV/Q at TLC (change from baseline) for lower and upper lung
x
HRCT based IAD (change from baseline) for lower and upper lung
x
Global lung UCSF mucus scoring (change from baseline)
* Data may be logarithmically transformed prior to analysis if extreme skewness was observed 
based on blinded data review.
8.2.4.Asthma Control Questionnaire (ACQ-7)
ACQ-7 score (see Section 15.8) will be summarized in terms of actual value and change from 
baseline at baseline and at each post-baseline visit (Week 4 and Week 24).
In addition, at each post-baseline visit, the change from baseline will be modelled using MMRM 
model including study intervention (dupilumab, placebo), baseline value of the score, region 
(EE/ROW), ICS dose level (medium/high), visits (up to Week 24), study intervention by visit 
interaction, and baseline score by visit interaction terms all as fixed effects. An unstructured 
correlation matrix will be used to model the within-participant errors. LS mean of each study 
intervention group, LS mean difference between the dupilumab and placebo groups, and the 
corresponding SEs and 95% CIs will be provided at all scheduled visits. The p-value 
corresponding to the LS mean difference will be provided at Week 24 only.
The same strategy as for MMRM model for primary endpoint untrimmed distal [s]iVaw will be 
used for the selection of the covariance structure if MMRM under unstructured correlation matrix 
fails to achieve convergence.
8.2.5.Multiplicity issues
The overall type-I error rate will be controlled at the two-sided 0.05 level using a hierarchical 
testing procedure. The primary endpoints will be tested sequentially in the order described in 
Section 8. The secondary endpoints will be tested following the hierarchical testing procedure 
with a pre-specified order, that is, inferential conclusions about successive secondary endpoints 
require statistical significance at 0.05 significance level of the previous one.
The following secondary endpoints will be included in the multiplicity adjustment scheme and 
tested in the following order:
x
Change from baseline to Week 24 in global lung UCSF Mucus Scoring
x
Percent change from baseline to week 24 in trimmed distal [s]iRaw at TLC
Each endpoint will be tested at 0.05 (two-sided) level of significance. If at any step the null 
statistical hypothesis of no study intervention difference is not rejected, the endpoints listed after 
that step will be reported at nominal level, otherwise will be technically eligible for being declared 
significant.
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8.2.6.Supplementary analysis
Change from baseline to week 24 in pre-BD FEV1 will be analyzed as a supplementary analysis in 
the following ways:
x
Removing potential outliers using z-score method
Records with change from baseline value more than 3 standard deviations away from the mean 
change from baseline for each visit and treatment group will be considered as potential outliers.
Change from baseline will be modelled using an MMRM model under the missing at random 
framework. The MMRM model will include study intervention (dupilumab, placebo), baseline 
value of pre-BD FEV1, region (EE/ROW), ICS dose level (medium/high), visits (up to Week 24), 
age (years), height (cm), gender (male/female), study intervention by visit interaction, and 
baseline pre-BD FEV1 by visit interaction terms all as fixed effects. An unstructured (UN) 
correlation matrix will be used to model the within-participant errors.
The same strategy as for MMRM model for primary endpoint untrimmed distal [s]iVaw will be 
used for the selection of the covariance structure if MMRM under unstructured correlation matrix 
fails to achieve convergence.
x
Using data borrowing approach
The Dupilumab Phase III ‘LIBERTY ASTHMA QUEST’ study will be used as the source of 
historical data, and the propensity score matching method will be implemented first to select 
appropriate participants, then the Bayesian dynamic borrowing approach will be implemented to 
evaluate the change from baseline to Week 24 in pre-BD FEV1. The adjusted LS means in each 
study intervention group, the LS mean difference between the dupilumab and placebo groups, and 
the corresponding SE and 95% CI will be provided, and the nominal p-value corresponding to the 
LS mean difference will be provided for descriptive purpose only.
Untrimmed distal [s]iVaw at FRC, trimmed distal [s]iRaw at TLC and trimmed distal [s]iRaw at 
FRC will be analyzed as a supplementary analysis in the following way:
x
Removing FRI data with technical issues
Percent change from baseline will be modelled using an MMRM model under the missing at 
random framework. The MMRM model will include study intervention (dupilumab, placebo), 
baseline value of the parameter, region (EE/ROW), ICS dose level (medium/high), visits (up to
Week 24), study intervention by visit interaction, and baseline value by visit interaction terms all 
as fixed effects. An unstructured (UN) correlation matrix will be used to model the within-
participant errors.
The same strategy as for MMRM model for primary endpoint untrimmed distal [s]iVaw will be 
used for the selection of the covariance structure if MMRM under unstructured correlation matrix 
fails to achieve convergence.
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9. SAFETY ANALYSIS
All safety results will be summarized using the safety set by actual study intervention group.
The observation periods include:
x
The pre-treatment period is defined as the time from the signed informed consent date up 
to first administration of the IMP.
x
The treatment-emergent adverse event (TEAE) period is defined as the time from the 
first administration of the IMP (on Day 1) to the last administration of the IMP +98 days 
and up to the end of the study follow-up.
x
The post-treatment period is defined as the time starting 1 day after the end of the TEAE 
period up to the end of the study follow-up.
9.1. Adverse events
The adverse event types include:
x
Pre-treatment adverse events are adverse events that developed or worsened or became 
serious during the pre-treatment period.
x
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the TEAE period.
x
Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period. AEs categorized as post-treatment AEs 
(following the rules specified below) will not be summarized. 
The primary focus of adverse event reporting will be on TEAEs. Pre-treatment adverse events will 
be summarized separately.
All AEs will be coded by LLT, PT, HLT, HLGT, and associated primary SOC using the version 
of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the 
time of each database lock.
Adverse events will be recorded from the time of signed informed consent until the end of the 
study or the resolution/stabilization of all SAE and AESI.
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pre-treatment, treatment-
emergent, or post-treatment. The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment-emergent unless there is definitive information to 
determine it is pre-treatment or post-treatment. Details on classification of adverse events with 
missing or partial onset dates are provided in Section 15.4.5.
Adverse events will be summarized by primary SOC, HLGT, HLT, and PT, sorted by 
internationally agreed order of primary SOC and then alphabetically for the other levels, for each 
study intervention group using number and percentage of participants experiencing an adverse 
event. Multiple occurrences of the same event in the same participant will be counted only once in 
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the tables within an observation period (pre-treatment period or TEAE period). The denominator 
for computation of percentages will be the safety analysis set within each study intervention
group. Participants experiencing asthma exacerbations will be further summarized using the LLT 
level as appropriate within adverse event summaries.
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent). For that purpose, the table of all 
treatment-emergent adverse events presented by primary SOC and PT (sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs in the dupilumab 
group) will define the presentation order for all other summaries unless otherwise specified. 
In case of equal frequency regarding PTs, alphabetical order will be used.
On top of the analysis planned below, all TEAEs, all treatment emergent SAEs, TEAEs leading to 
permanent study intervention discontinuation and TEAEs leading to death will be summarized by 
study intervention group and repeated on the subgroups of safety participants according to trial 
impact (disruption) due to COVID-19 pandemic.
Overview summary of the number and percentages of participants within the following categories 
will be provided by study intervention group:
x
Any TEAE
x
Any study intervention related TEAE
x
Any severe TEAE
x
Any serious TEAE
x
Any TEAE leading to permanent study intervention discontinuation
x
Any TEAE of special interest
x
Any serious TEAE of special interest
x
Any TEAE leading to death
The overview summary for TEAEs will be provided on the safety set and will be repeated on the 
subgroups of safety participants according to trial impact (disruption) due to COVID-19
pandemic.
Additionally, an overview of pre-treatment AEs will be presented using similar categories 
including:
x
Any AE
x
Any Severe AE
x
Any Serious AE
x
Any AESI
x
Any Serious AESI
x
Any AE leading to death
Individual listings (AEs, SAEs, TEAEs leading to permanent study intervention discontinuation, 
AEs leading to death, AESI and all AEs in treated but not randomized participants (where such 
participants are recorded in the study)) will be provided to support the summary tables based on 
the safety set.
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Additionally, any defect in the IMP will 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 (e.g., 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 the quality issue must be reported together with an AE or SAE.
No analysis of these data is foreseen. Reporting of these information falls beyond the scope of this 
SAP. 
9.1.1. Incidence of adverse events
The following TEAE summaries will be generated for the safety analysis set, for each study 
intervention group.
x
All TEAEs presented by primary SOC, HLGT, HLT, and PT, showing the number and 
percentage of participants with at least 1 TEAE
x
All TEAEs presented by primary SOC, showing number and percentage of participants 
with at least 1 TEAE, sorted by the internationally agreed primary SOC order
x
All TEAEs presented by PT, showing number and percentage of participants with at least 
1 TEAE, sorted by decreasing incidence of PT in the Dupilumab group
x
All pre-treatment AE presented by primary SOC and PT, showing number and percentage 
of participants with at least 1 pre-treatment AE
x
All TEAEs presented by primary SOC and PT, showing number and percentage of patients 
with at least 1 TEAE
x
All treatment-emergent COVID-19 related adverse events presented by primary SOC and 
PT, showing number and percentage of participants with at least 1 treatment-emergent 
COVID-19 related AE
x
Common TEAEs (PTs with an incidence ≥5% in any study intervention group) by primary 
SOC, HLGT, HLT, and PT
Search criteria for COVID-19 related AE will be provided by SANOFI.
9.1.2. Relationship of adverse events to study intervention
The following TEAE summary will be generated.
x
All TEAEs by relationship, presented by primary SOC, HLGT, HLT and PT, showing the 
number and percentage of participants with at least 1 TEAE
9.1.3. Severity of adverse event
The following TEAE summary will be generated.
x
All TEAEs by maximal severity, presented by primary SOC and PT, showing the number 
and percentage of participants with at least 1 TEAE by severity (ie, mild, moderate, 
severe).
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9.1.4. Serious adverse events
The following TEAE summaries will be generated.
x
All serious TEAEs presented by primary SOC, HLGT, HLT and PT, showing the number 
and percentage of participants with at least 1 serious TEAE.
x
All serious TEAEs by relationship, presented by primary SOC, HLGT, HLT and PT, 
showing the number and percentage of participants with at least 1 serious TEAE.
9.1.5. Adverse events leading to permanent study intervention discontinuation
The following TEAE summary will be generated.
x
All TEAEs leading to permanent study intervention discontinuation, presented by primary 
SOC, HLGT, HLT and PT, showing the number and percentage of participants with at 
least 1 TEAE leading to permanent study intervention discontinuation.
9.1.6. Adverse events leading to study discontinuation
Not applicable.
9.1.7. Adverse events of special interest (AESI)
As defined in Appendix 15.6, Adverse Events of Special Interest (AESI) include:
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 Alanine Aminotransferase (ALT) elevation:
o
ALT >5 x ULN in participants with baseline ALT ≤2 x ULN;
or
o
ALT >8 x ULN if baseline ALT >2 x ULN.
x
Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP;
o
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,
o
In the event of pregnancy in a female participant, IMP should be discontinued,
o
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,
o
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE
o
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
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x
Symptomatic overdose (serious or nonserious) with IMP/NIMP.
o
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.
o
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 following TEAE summaries will be generated.
x
All TEAEs of Special Interest, presented by primary SOC, HLGT, HLT and PT, showing 
the number and percentage of participants with at least 1 TEAE of Special Interest.
x
All serious TEAEs of Special Interest, presented by primary SOC, HLGT, HLT and PT, 
showing the number and percentage of participants with at least 1 serious TEAE of Special 
Interest.
9.1.8. Adverse events leading to death
The following TEAE summary will be generated.
x
All TEAEs leading to death (death as an outcome on the eCRF form “Adverse Event” as 
reported by Investigator), presented by primary SOC, HLGT, HLT and PT, showing the 
number and percentage of participants with at least 1 TEAE leading to death.
9.1.9. Death
The following summaries of deaths will be generated.
x
Number and percentage of participants who died during the trial by study period (ie, on
study, pre-treatment period, TEAE period and post-treatment period).
x
Number and percentage of participants who died during the trial by cause of death.
x
Number and percentage of non-randomized but treated participants or randomized but not 
treated participants who died (where such participants are recorded in the study).
A listing of all participants who died during the study will be provided.
9.2. Clinical laboratory evaluations
The laboratory tests will be performed by the local laboratories according to routine clinical 
practice at site and country level. The Investigator will review the laboratory report, document this 
review, and record any clinically relevant findings/changes occurring during the study in the AE 
section of the CRF.
The following laboratory tests will be performed:
x
Hematology: blood eosinophil count
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x
Highly sensitive (Serum at screening and urine at the other visits) human chorionic 
gonadotropin (hCG) pregnancy test (as needed for women of childbearing potential)
x
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 HBsAg (negative), and HBcAb (positive), an hepatitis B virus 
(HBV) deoxyribonucleic acid (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 hepatitis C virus (HCV)
ribonucleic acid (RNA) testing may be performed to rule out a false positivity, if the 
Investigator believes the participant is a false positive.
x
Human Immunodeficiency Virus (HIV) screening (Anti-HIV-1 and HIV-2 antibodies).
x
Tuberculosis testing would only be performed on a country by country basis according to 
the routine clinical practice and the local guidelines or if required by Regulatory 
Authorities or Ethics Committees.
Additional laboratory tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations; any clinically significant abnormal 
lab values will be included in the adverse event analyses. These additional laboratory tests will be 
displayed in a separate listing.
Eosinophil counts (in cells/μL) will be summarized for the safety analysis set by study 
intervention group using descriptive statistics of actual values and change from baseline for each 
visit or study assessment (baseline, Week 4, Week 12 and Week 24).
9.3. Vital sign measurements
Vital signs including weight, heart rate (HR), sitting systolic (SBP) and diastolic blood pressure 
(DBP), temperature and respiratory rate, will be collected at screening visit, at baseline visit 
(Day 1) before receiving the IMP and then at all subsequent visits.
The vital sign results will be summarized using descriptive statistics for each visit or study 
assessment (baseline, each-post-baseline time point).
The Potentially Clinically Significant Abnormalities (PCSA) at any time during the TEAE period 
will be summarized using number and percentage. The PCSA are provided in Section 15.7.
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries. The summaries will include participants who have at 
least 1 assessment performed during the TEAE period. When a PCSA definition involves a 
change from baseline value, participants must also have a baseline value to be included in the 
summaries.
A listing of participants with at least 1 post-baseline PCSA will be provided and will display the 
participant’s full profile (all participant’s results) over time of all vital sign parameters.
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Individual data listings will include the following flags:
x
Baseline values will be flagged “B”,
x
Parameter values reaching a PCSA limit will be flagged (+, or - depending of the 
direction).
9.4. Physical examination
There will be a physical examination at screening visit, at baseline visit (Day 1) before receiving 
the IMP and then at week 24 visit to examine and assess any abnormalities that may be present, as 
indicated by the participant’s medical history. It will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Body weight will also be 
measured at screening, baseline and visit 5 whereas height will be measured at screening only. 
The weight will be summarized the same way as vital sign parameters, including PCSA 
description. Results (normal, abnormal or not done) from the assessment will be reported. 
All deviations from normal will be recorded, including those attributable to the participant’s 
disease.
Any new or worsening finding will be reported as a new adverse event.
No analysis is planned for physical examinations.
9.5. Electrocardiogram
12-lead ECG will be obtained at screening visit using an ECG machine that automatically 
calculates HR (Heart Rate) and measures PR, QRS, QT, and QTc intervals.
A summary of ECG overall interpretation at baseline (abnormal/normal) will be presented for the 
safety analysis set.
9.6. Other safety data
Not applicable.
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10.PHARMACOKINETICS
Pharmacokinetic parameters are not evaluated in this study.
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11.PHARMACODYNAMICS
Pharmacodynamic parameters are not evaluated in this study.
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12.INTERIM ANALYSIS
Not applicable.
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13.CHANGES IN THE PLANNED ANALYSIS
Not applicable.
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imaging of changes in small airways of patients treated with extrafine beclomethasone/formoterol. 
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lung deposition and analysis of the effect of fluticasone / salmeterol hydrofluoroalkane (HFA) 
pressurized metered dose inhaler (pMDI) in stable persistent asthma patients using functional 
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Sears MR. Lung function decline in asthma. Eur Respir J. 2007;30(3):411-413. 
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of lung function in controlled asthma. Allergol Int Off J Jpn Soc Allergol. 2016;65(3):266-271.
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difficultto-treat asthma. Eur Respir J. 2008;32(2):344-349. doi:10.1183/09031936.00135907
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dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018;378(26):2475-85.
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American Thoracic Society/European Respiratory Society statement: asthma control and 
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Crit Care Med. 2009;180(1):59-99.
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computational models of the airways to unravel the pathophysiological mechanisms in asthma and 
chronic obstructive pulmonary disease (AirPROM). Interface Focus. 2013;3(2):20120057.
De Backer L, Vos WG, Salgado R, De Backer JW, Devolder A, Verhulst SL, et al. 2011
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dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients.
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extrafine beclometasone/formoterol (BDP/F) on lung function, dyspnea, hyperinflation, and
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airway geometry in COPD patients: novel insight using functional respiratory imaging. J Aerosol 
Med Pulm Drug Deliv. 2015;28(2):88-99.
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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.
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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.
Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in Persistent 
Asthma with Elevated Eosinophil Levels. NEJM 2013.
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL,et al. 
Standardization of Spirometry 2019 Update. An Official American Thoracic Society and 
European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019 Oct 
15;200(8):e70-e88.
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 placebocontrolled pivotal 
phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44.
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 Jul;116:19-27.
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 Jul;100(1):44-51.
Hyde DM, Hamid Q, Irvin CG. Anatomy, pathology, and physiology of the tracheobronchial tree: 
emphasis on the distal airways. J Allergy Clin Immunol. 2009 Dec;124(6 Suppl):S72-7.
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. AJRCCM. 2019 Oct 15; Vol. 200,No.8.
Hochberg, Y. (1988). A Sharper Bonferroni Procedure for Multiple Tests of Significance. 
Biometrika, 75(4), 800–802. https://doi.org/10.2307/2336325
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Cahn A, Hamblin JN, Robertson J, et al. An Inhaled PI3Kδ Inhibitor Improves Recovery in 
Acutely Exacerbating COPD Patients: A Randomized Trial. Int J Chron Obstruct Pulmon Dis. 
2021;16:1607-1619. Published 2021 Jun 3.
De Backer W, De Backer J, Vos W, et al. A randomized study using functional respiratory 
imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by 
a metered dose inhaler using co-suspension delivery technology in patients with COPD. Int J 
Chron Obstruct Pulmon Dis. 2018;13:2673-2684. Published 2018 Aug 30.
De Backer W, De Backer J, Verlinden I, et al. Functional respiratory imaging assessment of 
glycopyrrolate and formoterol fumarate metered dose inhalers formulated using co-suspension 
delivery technology in patients with COPD. Ther Adv Respir Dis. 2020;14:1753466620916990.
van den Berge M, De Backer J, Van Holsbeke C, et al. Functional respiratory imaging assessment 
of budesonide/glycopyrrolate/formoterol fumarate and glycopyrrolate/formoterol fumarate 
metered dose inhalers in patients with COPD: the value of inhaled corticosteroids. Respir Res. 
2021;22(1):191. Published 2021 Jul 1.
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15.APPENDICES
15.1.
Summary of statistical analyses
Table 15-1 Summary of statistical analyses
Endpoint
Analysis
Set
Primary analysis
Supportive analysis
Subgroup
analysis
Estimands
Primary endpoints
Achievement of FeNO <25 ppb at 
Week 24
(Dupilumab, placebo)
ITT
CMH test, (missing 
data considered as 
non-responders)
Sensitivity analyses: Repeat of Primary 
analysis based on multiple imputation 
analysis.
Supplementary analyses: Repeat on primary 
analysis based on concomitant SCS use
Yes
Yes
Untrimmed distal [s]iVaw at TLC: 
percent change from baseline to 
week 24
(Dupilumab, placebo)
ITT
MMRM (missing data 
handled through the 
MMRM model only, no 
additional imputation 
performed)
Sensitivity analyses: Repeat of Primary 
analysis based on multiple imputation 
analysis.
Supplementary analyses: Repeat on primary 
analysis based on concomitant SCS use,
based on participants having respected 
SABA washout period, and removing FRI
data with technical issues
Yes
Yes
Secondary endpoints
Continuous variables
ITT
Same approach as 
primary endpoint
Untrimmed distal 
[s]iVaw at TLC
Supplementary analyses of pre-BD FEV1:
Removing potential outliers
Using data borrowing approach
Supplementary analyses for [s]iRaw at TLC 
and FRC and [s]iVaw at FRC removing data 
with technical issues
No
Yes (only for secondary 
endpoints included in the 
hierarchical testing 
procedure)
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Endpoint
Analysis
Set
Primary analysis
Supportive analysis
Subgroup
analysis
Estimands
Tertiary/Exploratory endpoints
Continuous variables
ITT
Same approach as 
primary endpoint 
Untrimmed distal 
[s]iVaw at TLC
No
No
No
Composite endpoints
ITT
Same approach as 
primary endpoint 
achievement of FeNO 
<25 ppb at Week 24
No
No
No
Lung function parameters (post-BD
FEV1, pre-BD FEV1), Imaging 
parameters (untrimmed distal 
[s]iVaw at TLC, untrimmed distal
[s]iVaw at FRC, trimmed distal 
[s]iRaw at TLC, trimmed distal 
[s]iRaw at FRC, iVlobes at TLC,
iVlobes at FRC, iV/Q at TLC, HRCT 
based IAD, iVaww at TLC, UCSF 
mucus scoring, HRCT based airway 
occlusions at FRC, mucus volume)
and biomarker levels (FeNO)
ITT
Correlation
No
No
No
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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 Standardised Activities [AQLQ(S)] should be completed by the patient, 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 patients before the consultation and/or clinical tests, in a quiet place.
j
FeNO should be conducted prior to spirometry and the patient 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 protocol (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 rechecked 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 protocol (Table 4 (Section 8.1)). If HRCT scan can’t 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 protocol (Table 4 (Section 8.1)). This will be verified before performing the measurements. A patient who is unable to complete a successful spirometry effort as defined by ATS 
criteria or evaluated by the investigator or didn’t 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/μL) (I 06) before 
randomization. This is only required if the patient doesn’t 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.
r
Should be completed by patients 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 
(patient, 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:
• The contingency measures for a regional or national emergency declared by a governmental agency are detailed in Appendix 9 of the protocol (Section 10.9).
• 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 (protocol Table 4) is completed before 
performing HRCT scan, FeNO, FOT, and spirometry. In case this is not possible (eg, a patient experiences an exacerbation shortly before the scheduled visit), the procedures can be performed as
planned, but it should be recorded that the patient had recently taken systemic corticosteroids.
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15.3. Missing efficacy data
Asthma Control Questionnaire (ACQ-7, ACQ-6 and ACQ-5)
x
Based on the manual of ACQ (2), any more than one missing value is not acceptable. 
If more than one of the questions have missing value, the global score is invalid and will 
be considered as missing. If only one question has missing score, it will be interpolated 
(pro-rated) using the completed questionnaires from the previous visit. For instance, 
answer to question 5 is missing at Visit 4, and all questions are completed at Visit 3. 
Then the question 5 score at Visit 4 is interpolated as: (sum of score at Visit 4/sum of 
scores excluding question 5 at Visit 3) × score of question 5 at Visit 3. If the questionnaire 
from the previous visit is not complete either, the missing value will be imputed as the 
average of the completed questions within the current visit.
Asthma Quality of Life Questionnaire (AQLQ)
x
To have a valid overall score, it is not acceptable to have more than three missing 
responses or more than one missing response per domain. For responses with more than 
acceptable amount of missing value(s), the overall score will be considered as missing. 
For responses with amount of missing value(s) within accept range, the missing score will 
be interpolated using the previous completions of the questionnaire following the similar 
algorithm used for ACQ.
15.4. Missing safety data
For categorical variables, participants with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of participants with missing 
data is presented.
15.4.1.Handling of missing age
If age is missing but year of birth is collected, then age will be derived as year of informed 
consent signed minus year of birth.
15.4.2.Handling of computation of study intervention duration if investigational medicinal 
product end of treatment date is missing
For the calculation of the study intervention duration, the date of the last dose of IMP is equal to 
the date of last administration reported on the eCRF “Treatment status” page. If this date is 
missing, the last available administration date in the “Exposure” form will be used.
The last dose intake should be clearly identified in the eCRF and should not be approximated by 
the last returned package date.
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15.4.3.Handling of medication missing/partial dates
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant and post-treatment medication.
15.4.4.Handling of adverse events with missing or partial date/time of onset
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
study intervention or after the study intervention period, the adverse event will be classified as 
treatment emergent. No imputation of adverse event end dates/times will be performed. 
These data imputations are for categorization purpose only and will not be used in listings. 
No imputation is planned for date/time of adverse event resolution.
15.4.5.Handling of adverse events when date and time of first investigational medicinal 
product administration is missing
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events. 
The exposure duration should be kept as missing.
The last dose intake should be clearly identified in the eCRF and should not be approximated by 
the last returned package date.
15.4.6.Handling of missing assessment of relationship of adverse events to investigational 
medicinal product
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of related adverse 
events, but no imputation should be done at the data level.
15.4.7.Handling of missing severity/grades of adverse events
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered. If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table.
15.4.8.Handling of potentially clinically significant abnormalities
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition.
15.5. Visit windows
The analysis window below “[in brackets]” will be applied to post-baseline measurements to 
allocate them to a scheduled visit for the parameter (see Appendix 15.2 for details of scheduled 
visits).
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Table 15-2 Analyses window definition
Scheduled visit 
post-baseline
Targeted 
study day*
Visit window
AQLQ(S)
FRI and ACQ
Biomarkers, Forced Oscillometry,
Spirometry and Vital signs
Week 4 (Visit 3)
29
[2, 98]
[2, 56]
Week 12 (Visit 4)
85
[57, 126]
Week 24 (Visit 5)
169
[2, Ğ]
[99, Ğ]
[127, Ğ]
* The reference day (denoted as Day 1) for the calculation of study day will be the day of the first administration of IMP (except 
for participants randomized but not exposed). (See Section 4.4.6). 
After applying the above time windows, if multiple assessments are associated to the same time 
point, the closest from the targeted study day will be used. In case of equality, the last measurement 
will be used. Re-allocated scheduled visits (ie, visit numbers) should be sequential if ordered by the 
date of measurement.
If there is no measurement available for a given parameter in an analysis window, data is considered 
missing for the corresponding visit.
15.6. Search criteria for AESI
Table 15-3 Search criteria for AESI
AESI
Search Criteria
Anaphylactic reactions
Anaphylactic reactions: includes anaphylactic reaction 
narrow SMQ (20000021) terms and programmatic 
identification of cases based on occurrence of at least 
two preferred terms meeting the algorithm criteria 
occurring within 2 consecutive days of each other
Systemic hypersensitivity reactions
SMQ: Hypersensitivity [Narrow]
Helminthic infections
HLTs of “Helminthic infections NEC”
Keratitis
PTs of
x
Keratitis, Allergic keratitis
x
Corneal infection
x
Ulcerative keratitis
x
Atopic keratoconjunctivitis
x
Herpes ophthalmic
x
Ophthalmic herpes simplex
Any severe type of conjunctivitis or blepharitis
1. Conjunctivitis is defined as the following PTs with 
intensity “severe” in eCRF AE page:
x
Adenoviral conjunctivitis
x
Conjunctival irritation
x
Conjunctival oedema
x
Conjunctival ulcer
x
Conjunctivitis
x
Conjunctivitis allergic
x
Conjunctivitis chlamydial
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AESI
Search Criteria
x
Conjunctivitis gonococcal neonatal
x
Conjunctivitis tuberculous
x
Conjunctivitis viral
x
Giant papillary conjunctivitis
x
Inclusion conjunctivitis
x
Ophthalmia neonatorum
x
Seasonal allergy
x
Herpes simplex virus conjunctivitis neonatal
x
Conjunctival hyperaemia
x
Inclusion conjunctivitis neonatal
x
Conjunctivitis bacterial
x
PingueculitisPhotoelectric conjunctivitis
x
Oculorespiratory syndrome
x
Acute haemorrhagic conjunctivitis
x
Blebitis
x
Ligneous conjunctivitisNoninfective 
conjunctivitis
x
Oculoglandular syndrome
x
Conjunctivitis fungal
x
Conjunctival suffusion
x
Giant fornix syndrome
2. Blepharitis is defined as the following PTs with 
intensity “severe” in eCRF AE page:
x
Abscess of eyelidBlepharitis
x
Blepharitis allergic
x
Blepharochalasis
x
Chalazion
x
Dacryoadenitis acquired
x
Dacryocanaliculitis
x
Dacryocystitis
x
Eczema eyelids
x
Erythema of eyelid
x
Eyelid boil
x
Eyelid infection
x
Eyelid oedema
x
Hordeolum
x
Lacrimal sac cellulitis
x
Meibomianitis
x
Swelling of eyelid
x
Swollen tear duct
x
Lid margin discharge
x
Meibomian gland discharge
x
Eyelid margin crusting
x
Bacterial dacryocystitis
x
Eyelid folliculitis
x
Eyelid irritation
x
Eyelid cyst
x
Meibomian gland dysfunction
x
Inflammation of lacrimal passage
x
Eyelid rash
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Search Criteria
x
Staphylococcal blepharitis
x
Bacterial blepharitis
x
Lacrimal gland abscess
x
Demodex blepharitis
Clinically symptomatic eosinophilia (or eosinophilia 
associated with clinical symptoms)
CMQ10641 based on HLT=Eosinophilic disorders or 
PT=Eosinophil count increased followed by blinded 
medical review for selection of relative events
Significant ALT elevation
- ALT >5 × the ULN in participants with baseline 
ALT ≤2 × ULN
or
- ALT >8 × ULN if baseline ALT >2 × ULN
Pregnancy of a female participant entered in a study as 
well as pregnancy occurring in a female partner of 
a male participant entered in a study with IMP
“Pregnancy” or “Partner Pregnancy” checked in eCRF 
form “Pregnancy”
Symptomatic overdose (serious or nonserious) with 
IMP/NIMP
“Overdose of Study Treatment” or “Overdose of 
NIMP” checked and “Symptomatic overdose” checked 
in eCRF form “Overdose”
15.7. Potentially Clinically Significant Abnormalities (PCSA) Criteria
Table 15-4 Potentially Clinically Significant Abnormalities Criteria
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES
(From BTD-009536 May 21, 2014)
Parameter
PCSA
Comments
HR
≤50 bpm and decrease from baseline ≥20 bpm
≥120 bpm and increase from baseline≥20 bpm
To be applied for all positions 
(including missing) except 
STANDING.
SBP
≤95 mmHg and decrease from baseline 
≥20mmHg
≥160 mmHg and increase from baseline ≥20 
mmHg
To be applied for all positions 
(including missing) except 
STANDING.
DBP
≤45 mmHg and decrease from baseline ≥10 
mmHg
≥110 mmHg and increase from baseline ≥10 
mmHg
To be applied for all positions 
(including missing) except 
STANDING.
Weight
≥5% increase from baseline
≥5% decrease from baseline
FDA Feb 2007
15.8. Participant-Reported Outcomes (PROs)
Asthma Control Questionnaire (ACQ-7, ACQ-6 and ACQ-5)
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Asthma Control Questionnaire-7 (ACQ-7) collects participants assessment of their asthma during 
the previous week based on 6 questions on a 7-point scale (0 = no impairment to 6 = maximum 
impairment) and a scoring of the FEV1% predicted by clinic staff, also on a 7-point scale.
The ACQ was designed to measure both the adequacy of asthma control and change in asthma 
control which occurs either spontaneously or as a result of study intervention.
The ACQ-7 has 7 questions with the first 5 items assessing the most common asthma symptoms 
(corresponding to ACQ-5),
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
5. wheeze
6. short-acting bronchodilator use
7. FEV1 % predicted
The first 6 items will be used directly according to the result recorded on the 7-point scale (0 = no 
impairment to 6 = maximum impairment).
For Item 7, the Percent predicted FEV1 value will be used and converted into the same 7-point scale, 
according to the following table:
FEV1% predicted
Score
>95% predicted
0
95-90%
1
89-80%
2
79-70%
3
69-60%
4
59-50%
5
<50% predicted
6
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 
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 
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should be completed by the participants before the consultation and clinical tests, including 
spirometry, in a quiet place.
The local values of FEV1 will be considered for the ACQ-7 scores. For the statistical analysis we 
will use centrally read values.
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.
Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S])
AQLQ[S] was designed as a self-administered participant 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)
6 - Chest Tightness
8 - Short of Breath
10 - Wheeze
12 - Coughing
14 - Chest Heaviness
16 - Clear Your Throat
18 - Difficulty Breathing Out
20 - Wake Up with Asthma Symptoms
22 - Heavy Breathing
24 - Woken at Night
29 - Interference with a Good Night
30 - Fighting for Air
x
Activity limitation (11 items)
1 - Strenuous Activities
2 - Moderate Activities
3 - Social Activities
4 - Work/School-Related Activities
5 - Sleeping
11 - Avoid Cigarette Smoke
19 - Avoid Dust
25 - Avoid Weather Pollution Outside
28 - Avoid Strong Smells or Perfume
31 - Overall Range of Activities
32 - All the Activities
x
Emotional function (5 items)
7 - Having Asthma
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13 - Frustrated
15 - The Need to Use Medication
21 - Asthma Medication Not Available
27 - Getting Out of Breath
x
Environmental Stimuli (4 items)
9 - Exposure to Cigarette Smoke
17 - Exposure to Dust
23 - Weather or Air Pollution Outside
26 - Exposure to Strong Smells
The overall AQLQ[S] score is the mean of all 32 responses and the individual domain scores are 
the means of the items in those domains. 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 (28).
The participants will complete the AQLQ(S) on paper. 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.
15.9. Spirometry
A spirometer that meets the 2019 ATS/European Respiratory Society (ERS) recommendations 
will be used.
For pre-BD measured parameters, including FEV1 and FVC spirometry will be performed before 
IMP administration and after withholding the standard of care asthma treatment.
For post-BD 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 participant standing or in another position, this should be noted on 
the spirometry report. For any participant, 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. If a 
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participant fails to provide repeatable maneuvers, an explanation should be recorded in the e-CRF. 
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 participant 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 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 centrally read values will be used.
15.10. Functional Respiratory Imaging (FRI)
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-BD 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.
HRCT scans will be used to generate FRI measurements allowing for an evaluation of regional 
asthma disease manifestation and treatment effect. These CT images are taken during breath hold 
at two distinct lung levels: at the end of a normal exhalation (functional residual capacity; FRC) 
and at the maximal inspiration (total lung capacity; TLC).
The following FRI parameters, based on low-dose inspiratory-expiratory multi-slice computed 
tomography images and computational fluid dynamics flow simulations will be analyzed:
x
Lobar volumes at FRC and TLC
x
(specific) airway volumes at FRC and TLC
x
(specific) airway resistance at FRC and TLC
x
(percent predicted) internal lobar airflow distribution
x
Blood vessel density at TLC
x
(specific) airway wall volume at TLC
x
Air trapping at FRC
x
Ventilation/perfusion ratio
x
UCSF mucus scoring
x
Mucus volume
x
PI10 (change from baseline)
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x
Airway wall area (change from baseline)
x
Wall area percentage (change from baseline)
x
Airway radius (change from baseline)
FRI parameters are assessed in the following different zones of the respiratory system:
x
Overall lung (except for HRCT based IAD)
x
Distal lung (only for [s]iVaw, [s]iRaw and iVaww)
x
Central lung (only for [s]iVaw, [s]iRaw and iVaww)
x
Right upper lobe (RUL)
x
Right middle lobe (RML)
x
Right lower lobe (RLL)
x
Left upper lobe (LUL)
x
Left lower lobe (LLL)
However, the possibility exists that for some participants no distinction can be made between the 
different lung lobes. In this case, the following zones can also be identified:
x
Right upper and middle lobe (RUL+RML)
x
Right middle and lower lobe (RML+RLL)
x
Right upper and lower lobe (RUL+RLL)
x
Right upper, middle and lower lobe (RUL+RML+RLL)
x
Left upper and lower lobe (LUL+LLL)
As the visible area on the scanner can vary from one visit to another, the results can be trimmed
(use only generations of airways that are visible in all the scans for each segment) in order to keep 
only the area common to the different visits, or untrimmed (use all the generations visible at the 
particular study visit scan for each segment). Trimmed and untrimmed data will be available.
Specific 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. It corresponds to the ratio between the airway volume (iVaw) and the lobar 
volume.
Specific 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].
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.
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Airway wall volume:
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 discrete locations).
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.
Airway dilation:
Airway dilation is defined as the difference between the trimmed airway volume at week 24 and 
the trimmed airway volume at baseline.
Airway recruitment:
Airway recruitment is defined as the difference between the untrimmed airway volume at week 24 
and the untrimmed airway volume at baseline and the airway dilation.
Pi10:
Pi10 represents the average airway wall thickness normalized to a ‘theoretical’ airway lumen of
10-mm inner perimeter. This endpoint is calculated from a segmental level (distal airway zone).
Airway wall percentage:
Airway wall percentage represents the wall area as a percentage of the sum of wall area and the 
airway lumen area. This endpoint will be calculated for central, distal and for each of the 5 lobes.
Airway wall area:
The airway wall area represents the average area per zone of the airway wall, and will be 
calculated for central, distal and for each of the 5 lobes.
Airway radius:
Airway radius represents the average per zone of the airway radius from centerline to airway wall. 
This endpoint will be calculated for central, distal and for each of the 5 lobes.
Mucus volume:
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Mucus volume is the total volume of all detectable mucus plugs, which are defined as a complete 
occlusion of the airway, at TLC.
15.11. Forced Oscillometry (FOT)
The FOT determines breathing mechanics by superimposing small external pressure signals on the
spontaneous breathing of the participant. It is indicated as a diagnostic method to obtain reliable 
differentiated tidal breathing analysis. R5 represents the total resistance of the airways. R20 
represents resistance of the large, or proximal, airways. R5 − R20 is an indirect measure of the 
resistance in the small airways, which refers to freq dependence of resistance 5-20Hz.
FOT should be conducted prior to spirometry and HRCT scan. The assessment will be done by 
local reading.
Area of Reactance:
Area of reactance (AX) is the integrated low frequency respiratory reactance magnitude between 
5 Hz and Fres (Resonant frequency). Resonant frequency (Fres) indicates the frequency at which 
the inertial properties of the airways and capacitance of lung periphery are equal. Total reactance 
at this point is zero. Normal Fres is 6–11 Hz. Fres increases in peripheral airway obstruction and 
fibrosis.
AX relates to respiratory compliance, small airway patency and correlates with R5–R20.
15.12. Biomarkers
Fractional exhaled nitric oxide (FeNO) 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,
FOT and HRCT scan and the participant should refrain from eating and drinking for at least 
1 hour prior to the procedure.
15.13. Rescue and Prohibited Medications.
Rescue medications (ie, reliever medications) will be identified from the "Asthma Reliever 
Medication" eCRF page.
In the table summary, rescue medications will be categorized into SABA (ATC class R03AC), 
systemic corticosteroids (ATC class H02AB) or Other.
Treatment with the following medications is considered as prohibited:
x
Immunosuppressants and biologic therapy within 3 months prior to V1 until EOT (V5)
x
Treatment with live (attenuated) vaccine within 4 weeks before V1 until the end of study
x
Treatment with systemic corticosteroids within 2 weeks prior to V1, during screening and 
randomized study intervention period. Systemic corticosteroids can only be used to treat 
an asthma exacerbation during the randomized study intervention period and are not 
allowed to be used for other conditions.
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