Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 202
Healthy volunteers: no

Brief summary:
Primary Objective:

To assess the effect of dupilumab on sleep

Secondary Objectives:

* To evaluate the effect of dupilumab on additional participant reported sleep outcomes
* To evaluate the effect of dupilumab on objective sleep assessment
* To evaluate the effect of dupilumab on asthma symptoms
* To evaluate the effect of dupilumab on lung function
* To evaluate the safety of dupilumab

Detailed description:
Study duration per participant was approximately 16 weeks and up to 29 weeks including up to 5 weeks screening period, a 12-week treatment period and up to 12 weeks post-treatment follow-up period or until the participant switched to commercialized dupilumab (or other biologic product), whichever came first.

Arms:
arm 1: Participants received a loading dose of 400 mg of dupilumab (2 injections × 200 mg) SC on Day 1, followed by 200 mg Q2W for 12 weeks. arm 2: Participants received an initial loading dose of matching placebo (2 injections of placebo) SC on Day 1, followed by 1 injection of placebo Q2W for 12 weeks.

Interventions: intervention 1: SAR231893 intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous intervention 2: Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous

Protocol document:
Prot_000.pdf: 
Sanofi 
Dupilumab 
Protocol: LPS16677 
Clinical study report 
16.1.1 Protocol and Protocol Amendments 
This section includes the following: 
Amended Clinical Trial Protocol 02, dated 22 Sept 2022 
Page 1


Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 
Protocol title: 
A Phase 4, randomized, double-blind, placebo-controlled, 
multicenter, parallel-group study of the effect of 
dupilumab on sleep disturbance in patients with 
uncontrolled persistent asthma 
Protocol number: 
LPS16677 
Amendment number: 02 
Compound number 
(INN/Trademark): 
SAR231893 
dupilumab/Dupixent® 
Study phase: 
Phase 4 
Short title: 
Dupilumab asthma sleep study 
MORPHEO 
Sponsor name: 
Sanofi-Aventis Recherche & Développement (SARD) 
Legal registered 
address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin 
France 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
Regulatory agency identifier number(s): 
IND: 
105379 
EudraCT: 
2020-001217-20 
NCT: 
NCT04502862 
WHO: 
U1111-1249-6054 
EUDAMED 
Not applicable 
Other: 
Not applicable 
Date: 
22-Sep-2022
Total number of pages: 106 
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NCT04502862


Amended Clinical Trial Protocol 02  
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Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial protocol 02 
All 
22 September 2022, version 1 (electronic 2.0) 
Amended Clinical Trial protocol 01 
All 
17 September 2020, version 1 (electronic 1.0) 
Original Protocol 
 
24 April 2020, version 1 (electronic 1.0) 
Amended protocol 02 (22 September 2022) 
This amended protocol (amendment 02) is considered to be non-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 rationale for the Amendment is for the addition of a virtual site (Metasite) that will 
enroll approximately 10 participants from the United States. The Metasite will be managed by 
Science37 (external vendor), using telemedicine (TM), mobile study nurses, and an electronic 
application (Science37 Platform). These 10 participants will undergo the same procedures and 
provide the same data as other trial participants and will be conducted at participants’ homes. The 
Investigational Medicinal Product (IMP) supply process for the participants enrolled by the 
Metasite via direct to participant (DTP) has been detailed. Additionally, minor clarifications and 
updates were included in the statistical sections, as per statistical analysis plan (SAP), and minor 
clarifications and corrections have been implemented across the document (see summary of 
changes table). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis (Overall 
Design) 
4.1 Overall design 
Added details on Science37 Metasite. 
A Metasite has been added to support 
recruitment and decrease patient burden. 
Approximately 10 participants from the US will 
be enrolled by Science37 Metasite. 
1.1 Synopsis (overall design) 
4.1 Overall design 
Appendix 6: 
Polysomnography substudy 
Added the information that the participants 
in the
 will be enrolled in the 
US. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis ((Statistical 
considerations; primary 
endpoint) 
9.4.2 Primary endpoint(s) 
The text has been added to emphasize that 
the sleep disturbance score at Week 12 will 
be evaluated/measured in participants who 
discontinued the study intervention not due 
to COVID-19 pandemic while the data for 
those who discontinued the study 
intervention due to COVID-19 pandemic will 
not be evaluated and assumed missing. 
The COVID-19 pandemic is unexpected and 
will eventually be over. The objective of the 
present study is to evaluate the study 
intervention effect in absence of the pandemic 
and therefore the data collected after study 
intervention discontinuation due to pandemic 
will be set to missing. 
1.3 Schedule of activities 
Added a footnote on Science37 Metasite. 
Deleted the row on device deficiencies. 
In the Science37 Metasite all the study 
procedures detailed in Schedule of Activities 
will be performed by the participants at home. 
2.3.1 Risk assessment  
 
Updated the section as per new IB version 
16.0 dated 22 June 2022. 
Provided the most recent data on exposure to 
Dupilumab. 
2.3.2 Benefit assessment 
Update the regulatory information. 
Provided the updated data on regulatory 
information. 
5.1 Inclusion criteria (I 03) 
The inclusion criterion was not changed; the 
initial definition of asthma exacerbation 
(deterioration of asthma that results in 
emergency treatment, hospitalization due to 
asthma, or treatment with systemic steroids) 
remains the same and refers to severe 
asthma exacerbation. Therefore a 
clarification has been included. 
Clarification of I03 
5.2 Exclusion criteria (E 03) 
The exclusion criterion was not changed; the 
same clarification as for the I03 applies to 
E03. 
Clarification of E03 
6.1 Study intervention(s) 
administered 
6.2 Preparation/handling/ 
storage/accountability 
Added the text on procedure of IMP supply, 
preparation, handling and administration for 
the participants enrolled through Metasite. 
Clarification on the IMP supply, handling and 
administration for the participants in Science37 
Metasite. 
6.1 Study intervention(s) 
administered 
6.5.1 Rescue medicine 
Added the information that the systemic 
corticosteroids are allowed in case of severe 
asthma exacerbation, to be aligned with 
standard asthma care for the treatment of 
severe exacerbations 
Consistency of the information related to 
systemic corticosteroids across Section 6.5 
Concomitant therapy  
6.3 Measures to minimize 
bias: randomization and 
blinding 
Added the procedure for obtaining the 
intervention kit numbers at randomization 
and subsequent visits via IVRS/IWRS calls 
considering the transportation lead time for 
Science37 Metasite. 
To facilitate the participants by Science37 
Metasite to perform the study procedures at’ 
home. 
6.4 Study intervention 
compliance 
Added text regarding IMP/intervention 
accountability by Science37 for Science37 
Metasite. 
To facilitate the participants enrolled by 
Science37 Metasite to perform the study 
procedures at home. 
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Section # and Name 
Description of Change 
Brief Rationale 
8 Study assessments and 
procedures 
8.1.1 Actigraphy 
8.1.5 Asthma sleep 
disturbance questionnaire 
8.1.6 Asthma daytime 
symptom diary Asthma 
nighttime symptom diary 
8.1.7 Sleep diary 
Added the procedures for completion of the 
baseline assessments by Science37 
Metasite.  
To facilitate the participants enrolled by 
Science37 Metasite to perform the study 
procedures at home. 
8.1.3 Spirometry 
Clarification added for the retest of pre-BD 
FEV1. 
To highlight that pre-BD FEV1 can be retested 
one additional time during screening period in 
case of unsuccessful spirometry effort as 
defined by ATS criteria or evaluated by the 
investigator or did not meet the eligibility 
criterion at SV1. 
8.1.9 Asthma control 
questionnaire 7-question 
version 
7-point scale for FEV1% prediction was 
added. 
Clarification of text. 
8.1.10 Asthma quality of life 
questionnaire with 
standardized activities (self-
administered) (≥12 years) 
Clarification added on the overall score.  
Clarification of text. 
8.3.5 Pregnancy 
Updated details of study intervention 
discontinuation, pregnancy follow up and 
reporting.  
To keep consistent information related to study 
intervention discontinuation and pregnancy 
follow-up across the protocol 
8.4 Treatment overdose 
Update the definition of treatment overdose. 
Clarification of text. 
9.3 Populations for analyses 
Revised the definition of the safety 
population to include only the randomized 
participants. Further information has also 
been provided for the participants for whom 
it is unclear whether the study intervention 
was taken or for those having taken more 
than one IMP. 
This is the most common approach, and this is 
aligned with Sanofi standards. 
9.4.3 Secondary endpoint(s) 
Deleted the word “weekly average” from the 
first secondary endpoint. 
This was a typo and edited to correct the 
description of the timeline to monthly average, 
which is how the endpoint is correctly 
presented throughout the rest of the document. 
10.1.3 Informed consent 
process 
Added details on eConsent process for the 
participants enrolled by in Science37 
Metasite. 
 
Updated the details of source data and 
verification by study monitors.  
A Metasite has been added to facilitate conduct 
of study procedures remotely. 
 
To clarify the process for the Science 37 
Metasite. 
10.1.5 Dissemination of 
clinical study data 
clinicalstudydatarequest.com updated with 
www.vivli.org 
Updated site for the dissemination of clinical 
study data 
10.1.7 Source documents 
Added details of eConsent process for 
Science37 Metasite. 
A Metasite has been added to facilitate conduct 
of study procedures remotely. 
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Section # and Name 
Description of Change 
Brief Rationale 
10.2 Appendix 2: Clinical 
laboratory tests 
Added text regarding blood sample 
collection and pregnancy tests (if applicable) 
by Science37 for Science37 Metasite. 
To facilitate the participants enrolled by 
Science37 Metasite to perform the study 
procedures at home. 
10.3.1 Definition of AE 
Added the definition of unsolicited and 
solicited AE 
Information added based on new protocol 
template 
10.7 Appendix 7: Virtual 
Metasite 
Additional appendix (Appendix 7) on 
Science37 Metasite added. Subsequent 
appendices were re-numbered. 
A Metasite has been added to facilitate conduct 
of study procedures remotely. Approximately 
10 participants from the US will be enrolled by 
Science37 Metasite. 
Whole document 
The word patients modified to participant 
wherever applicable. 
To maintain consistency throughout the 
protocol. 
Whole document 
The word “treatment” modified to “study 
intervention”/ “intervention” wherever 
applicable. 
To maintain consistency throughout the 
protocol. 
Whole document 
Minor formatting, typo corrections, 
consistency, and clarification changes. 
Consistency. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 18 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
2.3.1 
Risk assessment ............................................................................................................................ 25 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
2.3.3 
Benefit/risk assessment related to COVID-19 ............................................................................... 28 
2.3.4 
Overall benefit: risk conclusion ...................................................................................................... 28 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 30 
4 
STUDY DESIGN ............................................................................................................................ 31 
4.1 
OVERALL DESIGN ........................................................................................................................ 31 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 32 
4.2.1 
Participant input into design ........................................................................................................... 33 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 33 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 33 
5 
STUDY POPULATION .................................................................................................................. 34 
5.1 
INCLUSION CRITERIA .................................................................................................................. 34 
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5.2 
EXCLUSION CRITERIA ................................................................................................................ 36 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 38 
5.4 
SCREEN FAILURES...................................................................................................................... 39 
5.5 
CRITERIA FOR TEMPORARILY DELAYING SCREENING, RANDOMIZATION, OR 
STUDY INTERVENTION ADMINISTRATION ............................................................................... 40 
6 
STUDY INTERVENTION ............................................................................................................... 41 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 41 
6.1.1 
Devices .......................................................................................................................................... 44 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 44 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 44 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 46 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 47 
6.5.1 
Rescue medicine ............................................................................................................................ 47 
6.6 
DOSE MODIFICATION .................................................................................................................. 48 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 48 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 49 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 49 
7.1.1 
Definitive discontinuation ............................................................................................................... 49 
7.1.2 
Temporary discontinuation ............................................................................................................. 50 
7.1.2.1 
Rechallenge ................................................................................................................................... 51 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 51 
7.3 
LOST TO FOLLOW-UP ................................................................................................................. 52 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 53 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 53 
8.1.1 
Actigraphy ...................................................................................................................................... 53 
8.1.2 
Fractional exhaled nitric oxide ....................................................................................................... 54 
8.1.3 
Spirometry ...................................................................................................................................... 54 
8.1.4 
Reversibility test ............................................................................................................................. 56 
8.1.5 
Asthma sleep disturbance questionnaire ....................................................................................... 56 
8.1.6 
Asthma daytime symptom diary - Asthma nighttime symptom diary ............................................. 57 
8.1.7 
Sleep diary ..................................................................................................................................... 57 
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9.4 
STATISTICAL ANALYSES ............................................................................................................ 69 
9.4.1 
General considerations .................................................................................................................. 69 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 70 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 70 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 71 
9.4.5 
Other safety analyse(s) .................................................................................................................. 71 
9.4.6 
Other analyse(s) ............................................................................................................................. 71 
9.5 
INTERIM ANALYSES .................................................................................................................... 72 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 73 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 73 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 73 
10.1.2 
Financial disclosure........................................................................................................................ 74 
10.1.3 
Informed consent process .............................................................................................................. 74 
10.1.4 
Data protection ............................................................................................................................... 75 
10.1.5 
Dissemination of clinical study data ............................................................................................... 77 
10.1.6 
Data quality assurance .................................................................................................................. 78 
10.1.7 
Source documents ......................................................................................................................... 78 
10.1.8 
Study and site start and closure ..................................................................................................... 79 
10.1.9 
Publication policy ........................................................................................................................... 80 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 80 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 81 
10.3.1 
Definition of AE .............................................................................................................................. 81 
10.3.2 
Definition of SAE ............................................................................................................................ 83 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 84 
10.3.4 
Reporting of SAEs.......................................................................................................................... 86 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 86 
10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 90 
10.6 
APPENDIX 6: POLYSOMNOGRAPHY SUBSTUDY ..................................................................... 91 
10.7 
APPENDIX 7: SCIENCE37 METASITE ......................................................................................... 93 
10.8 
APPENDIX 8: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 95 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A Phase 4, randomized, double-blind, placebo-controlled, multicenter, parallel-
group study of the effect of dupilumab on sleep disturbance in patients with 
uncontrolled persistent asthma 
Short title: 
Dupilumab asthma sleep study 
Rationale: 
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. 
The inflammatory component of asthma involves many cell types, including mast cells, 
eosinophils, T-lymphocytes, neutrophils, and epithelial cells and their biological products. For 
most asthma patients, a regimen of controller therapy and reliever therapy provides adequate 
long-term control.  
The prevalence of any sleep disturbance is higher in participants with uncontrolled asthma than 
with controlled or partially controlled asthma (32.2% versus 19.9% and 20.1% respectively, 
p <0.001). Poorer sleep quality in severe and non-severe asthma was suggested by the data 
obtained from participants enrolled in the Severe Asthma Research Program (SARP). Poor sleep 
quality was associated with worse asthma control and quality of life in patients with both severe 
and non-severe asthma (1). Poor asthma control is more common in the presence of any sleep 
disturbance (22.7 versus 13.7%, p <0.001) (2). Sleep disturbances and inability to consolidate 
sleep often result in excessive daytime sleepiness and may contribute to poor daytime functioning, 
asthma control, quality of life, and cognitive impairment, which may lead to social and 
neurobehavioral problems (3, 4, 5, 6, 7). In addition, the nighttime asthma symptom exacerbations 
are likely due to increased lower airway resistance and decreased nocturnal expiratory flow (8, 9, 
10). Since sleep disturbances adversely affect overall patient quality of life, accurate detection and 
monitoring of their manifestation is important to the management of asthma (11). Therefore, one 
of the asthma treatment goals is to eliminate asthma symptoms at night and decrease awakenings 
due to asthma symptoms. Better control of nocturnal asthma symptoms could lead to improved 
sleep quality and a decrease in daytime sleep-related symptoms (12). 
Dupilumab is a human monoclonal antibody (mAb) directed against the interleukin-4 receptor 
alpha (IL-4Rα) subunit, a component of interleukin (IL)-4 receptors Type I and Type II. The 
IL-4 receptors mediate the IL-4 signaling (both Type I and Type II) and IL-13 signaling (Type II). 
Both IL-4 and IL-13 signaling pathways are thought to play key roles in the pathophysiology of 
Type 2 inflammatory diseases. Dupilumab is approved for the treatment of patients with 
moderate-to-severe asthma in the United States (US), and for the treatment of patients with severe 
asthma in Europe and Japan. 
In dupilumab pivotal studies, around 60% of patients had sleep disturbances based on the number 
of nocturnal awakenings reported at baseline. 
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Dupilumab has shown significant improvements in nighttime symptoms in the 
study, 
especially in patients with uncontrolled asthma and evidence of Type 2 inflammation and at least 
one nocturnal awakening at baseline. 
Given the importance of disturbed sleep as an outcome in patients with asthma and considering 
the efficacy of dupilumab in reducing nocturnal awakenings and nighttime symptoms, this study 
aims at providing further evidence of the effect of dupilumab in improving sleep and reducing 
asthma symptoms, leading to better asthma control and overall improved quality of life. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To assess the effect of dupilumab on sleep 
• 
Change from baseline to Week 12 in sleep disturbance score 
using the Asthma Sleep Disturbance Questionnaire 
Secondary 
• 
To evaluate the effect of dupilumab on 
additional participant reported sleep 
outcomes 
• 
Change from baseline to Week 12 on the number of 
nocturnal awakenings (Sleep Diary) 
• 
Change from baseline to Week 12 in Patient Reported 
Outcomes Measurement Information System (PROMIS) 
Sleep-Related Impairment 8a scale 
• 
Change from baseline to Week 12 in sleep quality (Sleep 
Diary) 
• 
Change from baseline to Week 12 in restorative sleep (Sleep 
Diary) 
• 
Change from baseline to Week 12 in wake after sleep onset 
(WASO) (Sleep Diary) 
• 
To evaluate the effect of dupilumab on 
objective sleep assessment 
• 
Change from baseline to Week 12 in WASO based on 
actigraphy data 
• 
To evaluate the effect of dupilumab on 
asthma symptoms 
• 
Change from baseline to Week 12 in Asthma Daytime 
Symptom Diary (ADSD) and Asthma Nighttime Symptom 
Diary (ANSD) 
• 
To evaluate the effect of dupilumab on lung 
function 
• 
Change from baseline to Week 12 in prebronchodilator 
forced expiratory volume (pre-BD FEV1) 
• 
To evaluate the safety of dupilumab 
• 
Incidence of treatment-emergent adverse events (TEAEs) 
and serious adverse events (SAEs) including clinically 
significant changes in vital signs 
• 
Incidence of adverse events of special interest (AESI) 
Overall design: 
This is a Phase 4, randomized 1:1, multicenter study with 12-week double-blind, parallel-group, 
placebo-controlled treatment period to assess the effect of dupilumab in improving sleep 
outcomes, asthma control, and health-related quality of life (HRQoL), and in reducing daytime 
and nighttime asthma symptoms. 
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Intervention groups and duration: 
Study intervention groups: 
Participants who satisfy the inclusion and exclusion criteria will be randomized centrally (1:1) to 
one of the following investigational medicinal product (IMP) treatment groups: 
• Dupilumab 200 mg every 2 weeks (Q2W). 
• Matching placebo. 
Duration of study period (per participant): 
Study duration per participant will be approximately 16 weeks and up to 29 weeks. 
The study includes 3 study periods: 
• Screening period:  
- 
Screening Period 1: Day -35 to Day -12, from signed informed consent. 
- 
Screening Period 2 (Pre-baseline assessments): participants eligible to continue will 
complete the assessments specified in the schedule of activities (SoA) from Day -11 to 
Day -1 (right before Day 1).  
- 
If preferred by the participant and the investigator for logistic reasons, screening visit 1 
(SV1) and screening visit 2 (SV2) can be merged into a single on-site visit. 
Importantly, this single screening visit will have to be done on Day -11 at the latest. 
• Randomized, placebo-controlled treatment period: 12 weeks from baseline (Day 1). 
• 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 intervention(s) 
Investigational medicinal product(s) 
Dupilumab 200 mg and placebo matching dupilumab 200 mg supplied in visually 
indistinguishable prefilled syringes. 
Dupilumab 
• Formulation: Dupilumab 200 mg: a 175 mg/mL dupilumab solution in a prefilled syringe 
to deliver 200 mg in a 1.14 mL injection. 
• Route(s) of administration: subcutaneous (SC) injection. 
• Dose regimen: one injection of 200 mg Q2W after an initial loading dose of 400 mg 
(2 injections of 200 mg) on Day 1. 
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Placebo 
• Formulation: Placebo matching dupilumab 200 mg: identical formulation to the active 
200 mg formulation without dupilumab, in a prefilled syringe to deliver placebo in a 
1.14 mL injection. 
• Route(s) of administration: SC injection. 
• Dose regimen: one injection of placebo matching dupilumab 200 mg Q2W after an initial 
matching placebo loading dose of 400 mg (2 injections of placebo matching dupilumab 
200 mg) on Day 1. 
Noninvestigational medicinal products(s) 
Background asthma therapy with medium to high dose of ICS in combination with a second 
controller medication (eg, long-acting β2 agonist [LABA], leukotriene receptor antagonist 
[LTRA) at a stable dose ≥1 month prior to SV1 and during the screening period (Table 3). 
Participants requiring a third controller for their asthma will be considered eligible for this study, 
also at a stable dose ≥1 month prior to SV1 and during the screening period. Theophylline is not 
allowed because it can interfere with sleep and may confound the study assessments. 
• Formulation and route(s) of administration: refer to label. 
• Dose regimen: as prescribed. 
The asthma background therapy should be maintained at a stable dose during the study treatment 
period. 
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: 
• Primary endpoint: The primary endpoint will be analyzed using a mixed-effect model 
with repeated measurement (MMRM) approach. The model will include change from 
baseline in sleep disturbance score up to Week 12 as response variables, and treatment, 
age, body mass index (BMI), stratification factors, visit, treatment-by-visit interaction, 
baseline Asthma Control Questionnaire-5 (ACQ-5), baseline sleep disturbance score and 
baseline-by-visit interaction as covariates. An unstructured correlation matrix will be used 
to model the within-participant errors. Parameters will be estimated using restricted 
maximum likelihood method with the Newton-Raphson algorithm. No imputations for 
missing values will be carried out. To mitigate the risk of potential different responses 
based on the Sleep Disturbance Questionnaire before and after amendment 01, the primary 
analysis of change from baseline in sleep disturbance score will exclude the participants 
who use the original questionnaire at baseline and/or post-baseline. 
Statistical inferences on treatment comparisons for the change from baseline in sleep 
disturbance score at Week 12 will be derived from the mixed-effect model. The least 
squares (LS) mean of each treatment group, difference in the LS mean between the 
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dupilumab group and placebo, and the corresponding 95% confidence interval (CI) of the 
differences and p-values will be provided. For participants discontinuing the study 
intervention before Week 12 unrelated to the COVID-19 pandemic, the sleep disturbance 
scores measured off-study intervention will be included in the primary analysis. In 
contrast, for any participants discontinuing the study intervention due to the COVID-19 
pandemic, off-treatment data will not be included (i.e., set to missing) but will be assumed 
missing at random. 
• Main secondary endpoints: The change from baseline in the continuous endpoints to 
Week 12 will analyzed using the MMRM model in the same fashion as for the primary 
endpoints based on the intent-to-treat (ITT) population. For the spirometry endpoints, the 
model will also include sex and baseline height as the covariates. 
Data Monitoring Committee: No  
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
* An interim analysis will be performed to re-estimate sample size when 50% of participants (approximately 130) reach Week 12 visit or discontinue the study. 
D1: Day 1; ICF: informed consent form; Q2W: every 2 weeks; R: randomization; SV: screening visit; V: visit. 
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g Serum pregnancy test at screening visit (SV1) and urine pregnancy tests at the other visits using dipstick. A WOCBP must have a negative highly sensitive pregnancy test at SV1 (serum pregnancy test) and on 
Day 1 before the first dose of study intervention (urine or serum, if required by local regulations). If a urine test on Day 1 cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. 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 follow-up visit. 
h Hepatitis screening covering hepatitis B surface antigen (HBs Ag), total hepatitis B core antibody (total 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 screening (Anti-HIV-1 and HIV-2 antibodies). Tuberculosis testing will be performed 
only on a country by country basis according to the routine clinical practice and the local guidelines if required by Regulatory Authorities or Ethics Committees. 
i 
Retesting of eosinophil count is allowed up to three times during the screening period to meet inclusion criteria for showing eosinophil count ≥150 cells/microliter cells/mL (I 04) before randomization. This is only 
required if the participant doesn’t have the blood eosinophil count measured within 6 months prior to SV1 in the absence of OCS treatment. 
j 
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. On Day 1, loading dose as follows: 400 mg dupilumab for the dupilumab arm (200 mg x 2 syringes injections) and 2 placebo syringes for the 
placebo arm. Science37 Metasite: Investigational product (IMP) administrations will be done at participant's home by Science37 home nursing service. 
k Should be completed by participants regularly to record investigational (home dosing diary) and non-investigational (asthma background therapy diary) product information. Recorded data will be collected by the 
investigator at each on-site visit. 
l 
Retesting of 
can be performed one additional time during screening if the eligibility criterion for 
was not met at SV1. 
 will be rechecked at randomization visit (V2) for eligibility. It will be performed 
after a wash-out period of bronchodilators according to their action duration. Further details on the procedure will be provided in a separate instruction manual. 
m Spirometry test should be performed before IMP administration, in the morning if possible. 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. This will be verified before performing the measurements. A 
participant who is unable to complete a successful spirometry effort as defined by 2005 ATS criteria or evaluated by the investigator or did not meet the eligibility criterion for pre-BD FEV1 at SV1 can be retested 
one additional time during the screening period of the study. For spirometry the investigator will assess the eligibility based on the FEV1 local values from SV1 and Visit 2 before randomization (the results from 
central reading will not be available on the same day). Further details on the procedure will be provided in a separate instruction manual.  
n 3 attempts may be performed during the screening period to meet the eligibility criteria for reversibility before randomization. 
o Actigraphy: The participants will complete baseline assessments from Day -11 to Day -1 (right before Day 1); daily assessment thereafter until Week 4; then only the week before a clinical visit until EOT. Baseline 
value will be calculated using the data from Day -7 to Day -1. Science37 Metasite: For the completion of the baseline and postbaseline assessments, refer to Appendix 7 (Section 10.7). 
p 
 
 
 
q Each participant in this substudy will have a total of two overnight 
: 1 overnight 
 using Type II home devices on Day -1 to collect baseline data and 1 more at Week 12. If the sleep recording is inadequate 
as judged by the central reading site, the at-home sleep assessment will be repeated within 1 week of the original assessment. 
r 
Science37 Metasite: participant randomization in IVRS/IWRS will occur on Day 1, with first loading dose occurring up to 5 days post randomization to account for the lag between IVRS/IWRS randomization trigger 
for IMP DTP shipment and IMP availability to participant/mobile study nurse. 
s Science37 Metasite: the windows for subsequent at home dosing visits (week 4, week 8, week 12), up to 3 days (maximum visit window) to account for the lag between IWRS trigger for IMP DTP shipment and 
IMP availability to participant/mobile study nurse. 
ACQ-5: Asthma Control Questionnaire-5; 
 AD: atopic dermatitis; ADSD: Asthma Daytime Symptoms Diary; AE: adverse event; AESI: adverse event of special interest; ALT: 
alanine transaminase; ANSD: Asthma Nighttime Symptoms Diary; 
 ATS: American Thoracic Society; BD: bronchodilator; 
CRSw/sNP; chronic rhinosinusitis with/without nasal polyps; D: day; E/D: early discontinuation; ECG: electrocardiogram; EOS: end of study; EOT: end of treatment; ESD: early study discontinuation; ETD: early 
treatment discontinuation; 
e; FEV1: forced expiratory volume; HBcAB: hepatitis B core antibody; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; 
HCVAb: hepatitis C virus antibody; HIV: human immunodeficiency virus; IMP: investigational medicinal product; IVRS: interactive voice response system; IWRS: interactive web response system; OCS: oral 
corticosteroid; 
 PRO: patient-reported outcome; PROMIS: patient-reported outcome measurement information system; 
 
RNA: ribonucleic acid; SAE: serious adverse event; TB: tuberculosis; W: week; WOCBP: woman of childbearing potential; 
.
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2 
INTRODUCTION  
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. 
The inflammatory component of asthma involves many cell types, including mast cells, 
eosinophils, T-lymphocytes, neutrophils, and epithelial cells and their biological products. For 
most asthma patients, a regimen of controller therapy and reliever therapy provides adequate long-
term control.  
Respiratory disturbances during sleep are recognized as extremely common disorders with 
important clinical consequences in patients with asthma. Difficulties inducing sleep, sleep 
fragmentation, early morning awakenings, and daytime sleepiness are more common in subjects 
with asthma compared with subjects without asthma (13). 
Dupilumab, a fully human monoclonal antibody, is directed against the IL-4Rα subunit, which is a 
component of IL-4 heterodimeric receptors Type I (IL4-ligand only) and Type II (both IL-4 and 
IL-13 ligands). The binding of dupilumab to IL-4Rα results in blockade of downstream signaling 
initiated by both IL-4 and IL-13. These cytokines play key roles in the pathogenesis of various 
allergic diseases including asthma (14). 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 (15), reducing oral 
glucocorticoid use (16) as well as decreasing disturbance measured by evening symptom score 
and nocturnal awakening. 
Dupilumab is approved in the US for use in adults and adolescents (≥12 years) with moderate-to-
severe eosinophilic asthma and in the European Union (EU) for use in adults and adolescents 
(≥12 years) with severe asthma with Type 2 inflammation. In Japan, dupilumab received 
Pharmaceuticals and Medical Devices Agency (PMDA) approval for use in adults and adolescents 
(≥12 years) with severe or refractory bronchial asthma. 
2.1 
STUDY RATIONALE  
Sleep is a significant dimension of a patient’s life and the long-term interruption of normal 
sleeping patterns adversely affects physical, emotional functioning and quality of life (17, 18, 19, 
20) as well as increases the risk for poor health outcomes and psychological distress (21, 22). 
In addition, poorer sleep quality in severe and non-severe asthma was suggested by the data 
obtained from participants enrolled in the SARP. Poor sleep quality was associated with worse 
asthma control and quality of life in patients with both severe and non-severe asthma (1). Sleep 
disturbances and inability to consolidate sleep often result in excessive daytime sleepiness and 
may contribute to poor daytime functioning, asthma control, quality of life, and to cognitive 
impairment, which may lead to social and neurobehavioral problems (3, 4, 5, 6, 7).  
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The prevalence of any sleep disturbance is higher in participants with uncontrolled asthma than 
with controlled or partially controlled asthma (32.2% versus 19.9% and 20.1% respectively, 
p <0.001). There is no significant difference in prevalence of sleep disturbances between subjects 
with controlled asthma and subjects without asthma. Poor asthma control is more common in the 
presence of any sleep disturbance (22.7% versus 13.7%, p <0.001) (2). The nighttime asthma 
symptom exacerbations are likely due to increased lower airway resistance and decreased 
nocturnal expiratory flow (8, 9, 10). 
Since sleep disturbances adversely affect overall patient quality of life, accurate detection and 
monitoring of their manifestation is important to the management of asthma (11). 
One of the asthma treatment goals is to eliminate asthma symptoms at night and decrease 
awakenings due to asthma symptoms. Better control of nocturnal asthma symptoms could lead to 
improved sleep quality and a decrease in daytime sleep-related symptoms (12). 
A recently published observational study assessing sleep quality in patients with asthma (N=1150) 
showed that 58% of the patients had impaired sleep quality (Pittsburgh Sleep Quality Index 
[PSQI] >5), while sleep quality was significantly associated with HRQoL (23). 
In dupilumab pivotal studies, around 60% of patients had sleep disturbances based on the number 
of nocturnal awakenings and the nighttime symptoms reported at baseline. 
Dupilumab has shown significant improvements in nighttime symptoms in the 
 study, 
especially in patients with uncontrolled asthma and evidence of Type 2 inflammation and at least 
one nocturnal awakening at baseline. 
There is no published evidence showing a beneficial effect of asthma medication on sleep quality 
thus far. In fact, the existing literature on this topic is scant. 
Therefore, there is a data gap to generate evidence that can potentiate dupilumab therapeutic 
benefit on sleep quality and disturbances in patients with asthma. 
Given the importance of disturbed sleep as an outcome in patients with asthma and considering 
the efficacy of dupilumab in reducing nocturnal awakenings and night-time symptoms, this study 
aims at providing further evidence of the effect of dupilumab in improving sleep and reducing 
asthma symptoms, leading to better asthma control and overall improved quality of life. 
2.2 
BACKGROUND  
Dupilumab is a human mAb directed against the IL-4Rα subunit, a component of IL-4 receptors 
Type I and Type II. The IL-4 receptors mediate the IL-4 signaling (both Type I and Type II) and 
IL-13 signaling (Type II). Both IL-4 and IL-13 signaling pathways are thought to play key roles in 
the pathophysiology of Type 2 inflammatory diseases.  
The results of the conducted studies of dupilumab have demonstrated significant improvements, 
with treatment compared to placebo in some sleep outcomes, such as nocturnal awakenings or 
nighttime symptoms. 
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There are several subjective measures to assess sleep quality and disturbances, however the 
majority of them are not specific to patients with asthma (ie, PSQI) or are not completely 
dedicated to assessing sleep (ie, ACQ, Asthma Control Test [ACT], AQLQ). 
Food and Drug Administration (FDA)-validated questionnaire to assess asthma symptoms at night 
includes the ADSD, which evaluates the impact of nighttime symptoms due to asthma. 
Actigraphy is one of the most common objective measures of sleep disturbances. It is a procedure 
that records and integrates the occurrence and degree of limb movement activity over time. In 
addition to providing a graphical summary of wakefulness and sleep patterns over time, 
actigraphy generates estimates of certain sleep parameters (24). 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupilumab has shown clinically relevant benefit in several Type 2-driven immunological 
disorders such as AD, bronchial asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), and 
eosinophilic esophagitis (EoE). A satisfactory safety profile has been observed so far in completed 
and currently ongoing studies. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of dupilumab may be found in the Investigator’s Brochure. 
This study aims at evaluating the effect of dupilumab on sleep disturbances due to asthma 
symptoms, using a combination of participant-reported outcomes and objective measures of sleep 
quality (actigraphy) in patients with moderate-to-severe asthma and high disease burden. The 
study is medically and scientifically justified. 
The selected dose regimen has been evaluated in dupilumab pivotal trials (loading dose of 400 mg 
of dupilumab [2 x 200 mg dupilumab SC] on Day 1, followed by 200 mg Q2W) and approved by 
regulatory authorities, demonstrating a positive benefit/risk. 
2.3.1 Risk assessment  
No tissue targets or specific hazards to humans were identified in nonclinical general and 
reproductive toxicology studies. 
Dupilumab has an extensive safety database. 
As of 28 March 2022 (data cut-off date), approximately 13 577 subjects were enrolled into the 
development program for dupilumab and are included in the safety population: 564 as healthy 
volunteers; 4998 from AD studies (including atopic hand and foot dermatitis); 4195 from asthma 
studies; 880 from the rhinosinusitis (CRSwNP, CRSsNP, and AFRS) studies; 468 from EoE 
studies; 275 from the allergy (grass and peanut); 1495 from COPD studies; 309 from PN studies; 
311 from the urticaria studies (CSU and CICU); 45 from the BP study; and 37 from the ABPA 
study. 
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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 could be 
estimated to be 706 212 patient years from 01 March 2017 through 31 March 2022, including 
332 123 patient years during the interval period from 01 April 2021 through 31 March 2022.  
Dupilumab has been generally well tolerated in all populations tested in clinical development 
programs consistent with a positive benefit/risk profile. The adverse drug reactions (ADRs) 
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, anaphylactic reaction, angioedema, serum sickness and arthralgia . These 
ADRs were not consistently observed in all indications (see Investigator’s Brochure [IB] for 
greater details). 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.  
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. 
Other potential risks based on the safety profile in particular indications are discussed in the IB. It 
is anticipated that dupilumab in patients with uncontrolled persistent asthma will have a favorable 
safety profile as observed across other Type 2-driven immunological disorders. 
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2.3.2 Benefit assessment  
Dupilumab solution for injection is currently authorized: 
• In over 60 countries worldwide for asthma indication, including the US, for use as an add-
on maintenance treatment of adults and pediatric patients aged 6 years and older with 
moderate-severe asthma characterized by an eosinophilic phenotype or with OCS 
dependent asthma; 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 appropriate combination therapy (high-dose ICS over 
12 years or age, medium-to-high dose in those younger, taken by inhalation) plus another 
medicinal product for maintenance treatment, and in Japan, for use in adults and 
adolescents (aged ≥12 years) with severe or refractory bronchial asthma. 
• In over 60 countries worldwide, including the US, EU, and Japan for the treatment of 
adults with inadequately controlled moderate-to-severe AD. In over 50 countries, 
including the US and EU, it has also been authorized for use in adolescent patients 
(≥12 years) with inadequately controlled moderate-to-severe AD. Additionally, dupilumab 
has been approved in over 50 countries for the treatment of inadequately controlled 
pediatric patients (age 6-11 years) with moderate to severe AD or of pediatric patients with 
severe AD who are candidates for systemic therapy. In the US, dupilumab is also approved 
for use in pediatric patients of 6 months to 5 years of age. 
• Dupilumab is approved for the CRSwNP indication in more than 50 countries worldwide; 
including the US for the use as an add-on maintenance treatment for adults with 
inadequately controlled CRSwNP; in EU for use as an add-on therapy with intranasal 
corticosteroids (INCs) in adults with severe CRSwNP for whom therapy with systemic 
corticosteroids (SCSs) and/or surgery do not provide adequate disease control and in 
Japan, for use in adults with CRSwNP (only patients not adequately controlled with 
existing therapies). 
One of the asthma treatment goals is to eliminate asthma symptoms at night and decrease 
awakenings due to asthma symptoms, which could lead to improved quality of life (12). 
Dupilumab has shown significant improvements in nighttime symptoms and nocturnal 
awakenings in the pivotal clinical studies, especially in patient with uncontrolled asthma and 
evidence of Type 2 inflammation. Data generated from the present study might provide further 
evidence of the effect of dupilumab in improving sleep and reducing asthma symptoms, leading to 
better asthma control and overall improved quality of life. 
The participants with moderate-severe asthma uncontrolled by medium to high dose ICS and a 
second controller +/- a third controller might benefit by the treatment with dupilumab 
(double-blind, randomized 1:1 study). The asthma background therapy with ICS and a second 
controller (eg, LABA or LTRA) +/- a third controller will be maintained at a stable dose during 
the treatment period. The participants will be closely followed-up according to SoA (Section 1.3). 
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2.3.3 Benefit/risk assessment related to COVID-19  
The Sponsor recognizes that the 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 7 (Section 10.7). 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 LPS16677, 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. 
2.3.4 Overall benefit: risk conclusion  
Taking into account the measures taken to minimize risk to participants participating in this study, 
the potential risks identified in association with dupilumab are justified by the anticipated benefits 
that may be afforded to participants with uncontrolled persistent asthma. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To assess the effect of dupilumab on sleep 
• 
Change from baseline to Week 12 in sleep disturbance score 
using the Asthma Sleep Disturbance Questionnaire 
Secondary 
• 
To evaluate the effect of dupilumab on 
additional participant reported sleep 
outcomes 
• 
Change from baseline to Week 12 on the number of nocturnal 
awakenings (Sleep Diary) 
• 
Change from baseline to Week 12 in Patient-Reported 
Outcomes Measurement Information System (PROMIS) Sleep-
Related Impairment 8a scale 
• 
Change from baseline to Week 12 in sleep quality (Sleep Diary) 
• 
Change from baseline to Week 12 in restorative sleep (Sleep 
Diary) 
• 
Change from baseline to Week 12 in wake after sleep onset 
(WASO) (Sleep Diary) 
• 
To evaluate the effect of dupilumab on 
objective sleep assessment 
• 
Change from baseline to Week 12 in WASO based on actigraphy 
data 
• 
To evaluate the effect of dupilumab on 
asthma symptoms 
• 
Change from baseline to Week 12 in Asthma Daytime Symptom 
Diary (ADSD) and Asthma Nighttime Symptom Diary (ANSD) 
• 
To evaluate the effect of dupilumab on lung 
function 
• 
Change from baseline to Week 12 in prebronchodilator forced 
expiratory volume (pre-BD FEV1) 
• 
To evaluate the safety of dupilumab 
• 
Incidence of treatment-emergent adverse events (TEAEs) and 
serious adverse events (SAEs) including clinically significant 
changes in vital signs 
• 
Incidence of adverse events of special interest (AESI) 
Tertiary/exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Science37 Metasite: A virtual site (Metasite) will enroll approximately 10 participants from the 
US. The Metasite will be managed by Science37, using telemedicine (TM), mobile study nurses, 
and an electronic application (Science37 Platform). These 10 participants will undergo the same 
procedures and provide the same data as other trial participants but this will be done at home. As 
part of this study, Science37 participants will interact with their study doctors by using a 
telemedicine (TM) model during the study. The goal of TM is to decrease the participants’ burden 
to take part in the study. The participants enrolled by Science 37 Metasite will not participate in 
. Further details can be found in Section 10.7. 
Randomization will be stratified according to 5 strata: one stratum for all participants included in 
the 
 (regardless of dose level of ICS, regardless of region) and 4 strata for 
participants not included in 
, according to region and ICS dose (Eastern Europe with 
high ICS dose, Eastern Europe with medium ICS dose, ROW with high ICS dose, and ROW with 
medium ICS dose). In total, no less than 40% participants need to be in “high ICS” strata, and no 
more than 25% participants need to be in ‘Eastern Europe’ strata. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Given the importance of disturbed sleep as an outcome in patients with asthma and considering 
the efficacy of dupilumab in reducing nocturnal awakenings and night-time symptoms, this study 
aims at providing further evidence of the effect of dupilumab in improving sleep and reducing 
asthma symptoms, leading to better asthma control and overall improved quality of life.  
The primary endpoint will be assessed based on the sleep disturbance score using the Asthma 
Sleep Disturbance Questionnaire.  
Secondary and the tertiary endpoints will be based on the data collected in the PROs coupled with 
key objective assessments such as actigraphy, knowing that this procedure is one of the most 
common objective measures of sleep disturbance (24), clinical outcomes (pre-BD FEV1), 
 
  
The randomized double-blind treatment period of 12 weeks was considered relevant for the 
efficacy assessments.  
The aim of this study is to provide further evidence of the effect of dupilumab in improving sleep 
and reducing asthma symptoms, leading to a better asthma control and overall improved quality of 
life. A control arm is needed so that the effect of dupilumab on the study endpoints can be 
distinguished from an effect due to other reasons, such as natural improvement over time or better 
adherence to treatment as a result of being in a clinical trial. Therefore, the presence of a placebo 
arm is appropriate for the objectives of this study, since it will provide the most robust assessment 
of the efficacy and safety of dupilumab. The participants will be appropriately informed of and 
will provide written consent to the eventuality of receiving placebo during the randomized 
double-blind treatment period. They may withdraw from the study intervention or from the study 
at any time and receive the conventional treatment as prescribed by the physician. 
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The safety follow-up period will be up to 12 weeks or until the participant switches to biologics 
(including commercialized dupilumab), considering that after the last steady-state dose, the 
median time for dupilumab concentrations to decrease below the lower limit of detection, 
estimated by population PK analyses was 9 weeks for the 200 mg Q2W (see the Investigator’s 
Brochure).  
4.2.1 Participant input into design  
Not applicable. 
4.3 
JUSTIFICATION FOR DOSE  
The dose regimen of SC dupilumab selected for this study is 200 mg Q2W. Participants will 
receive an initial loading dose of 400 mg (2 x 200 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. 
The results from the Phase 2b dose ranging study (DRI12544) (25) showed that 300 mg Q2W and 
200 mg Q2W treatment with dupilumab 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 (
) (15), 
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. 
As evidenced by dupilumab’s clinical development program, clinical efficacy and safety data for 
the 200 mg dose is similar to 300 mg, however selecting 300 mg dose would imply potential 
inclusion of OCS dependent patients, in alignment with approved regulatory labels in some 
countries. Patients on OCS treatment commonly experience sleep disturbances as AEs (26), 
therefore OCS use can be a confounding variable in the evaluation of sleep outcomes, given that 
improvements in sleep outcomes could be seen due to OCS reduction or complete withdrawal that 
patients experience on dupilumab treatment. This supports the selection of the 200 mg dose for 
the study purpose. 
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. 
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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. Participant must be 18 to 65 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 02. Participants with a physician diagnosis of asthma based on the Global Initiative for 
Asthma (GINA) 2020 (27) for ≥12 months treated with medium to high dose ICS and a 
second controller (ie, LABA, LTRA). A third controller is allowed but not mandatory. The 
dose regimen should be stable for at least 1 month before SV1 and during the screening 
period. 
I 03. History of at least one severe asthma exacerbation within 1 year prior to SV1. 
Severe exacerbation is defined as deterioration of asthma that results in emergency 
treatment, hospitalization due to asthma, or treatment with systemic steroids (oral or 
injectable). 
I 04. Participants with eosinophils ≥150 cells/μL and FeNO ≥25 ppb during screening, 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 05. ACQ-5 ≥2.5 at SV1 and Visit 2, prior to randomization. 
I 06. Pre-BD FEV1 ≤80% of predicted normal during screening and at V2, prior to 
randomization. 
I 07. Exhibit bronchodilator reversibility (≥12% and 200 mL improvement in FEV1 post SABA 
administration) during screening period, prior to randomization, unless reversibility test 
meeting the inclusion criteria was done within 6 months prior to SV1. 
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I 08. Weekly average nocturnal awakenings due to asthma symptoms in the week prior to SV1 
is ≥1. 
I 09. Willing and able to comply with all clinic visits and study-related procedures. 
Sex 
I 10. Male or female. 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a) Female participants 
- 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
- 
Is not a WOCBP.  
OR 
- 
Is a WOCBP and agrees to use a contraceptive method that is highly effective, with 
a failure rate of <1%, as described in Appendix 4 (Section 10.4) of the protocol 
during the study, ie, at a minimum until 12 weeks after the last dose of study 
intervention or until the participant switches to commercialized dupilumab (or 
other biologic product), whichever comes first. 
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) on Day 1 before the first dose of study intervention. 
- 
If a urine test on Day 1 cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
- 
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2 (Section 10.2). 
- 
The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
I 11. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. In countries where legal age of majority is above 18 years, a specific ICF 
must also be signed by the participant’s legally authorized representative. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Current smoker. 
E 02. Former smoker for 10 years with a smoking history of >10 pack-years. 
E 03. Severe asthma exacerbation during screening, prior to randomization. 
E 04. 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 05. History of or current evidence of clinically significant non-respiratory diseases 
(eg, cardiovascular, hepatic, nervous system, gastrointestinal, endocrinological, 
rheumatological, dermatological), that in the opinion of the investigator may interfere with 
the aims of the study or put the participant at undue risk. 
E 06. Participants with active TB or non-tuberculous mycobacterial infection, or a history of 
incompletely treated TB will be excluded from the study unless it is well documented by a 
specialist that the participant has been adequately treated and can now start treatment with 
a biologic agent, in the medical judgment of the Investigator and/or infectious disease 
specialist. Tuberculosis testing would be performed on a country-by-country basis, 
according to local guidelines if required by Regulatory Authorities or ethics boards. 
E 07. Diagnosed active endoparasitic infection; suspected or high risk of endoparasitic infection, 
unless clinical and (if necessary) laboratory assessment have ruled out active infection 
before randomization. 
E 08. History of HIV infection or positive HIV 1/2 serology at SV1. 
E 09. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, 
antiprotozoals, or antifungals within 2 weeks before SV1. 
E 10. Known or suspected immunodeficiency, including history of invasive opportunistic 
infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, and 
aspergillosis) despite infection resolution, or otherwise recurrent infections of abnormal 
frequency or prolonged duration suggesting an immune-compromised status, as judged by 
the Investigator. 
E 11. 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 participant at undue 
risk. 
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E 12. History of systemic hypersensitivity or anaphylaxis to any biologic therapy (including 
dupilumab or any of its excipients; see Section 10.9 ). 
E 13. Participant with severe uncontrolled depression. 
E 14. Sleep disturbances not related to asthma, including sleep apnea, hypersomnia, or insomnia 
secondary to chronic pain, AD, COPD, etc, as determined by the Investigator. 
E 15. Participants who work night shifts (ie, any work between 8 PM and 6 AM). 
E 16. Participants with erratic sleep habits, as determined by the Investigator. 
E 17. Evidence of restless leg syndrome or periodic limb movement disorder. 
Prior/concomitant therapy 
E 18. Chronic treatment with OCS within 2 weeks prior to SV1. 
E 19. Participants taking sedative, anxiolytic, or hypnotic treatments, including melatonin, 
within 3 months before randomization. 
E 20. Participants taking systemic sedative antihistamines (this does not include the newer 
generations of antihistamines) or theophylline.  
E 21. Current treatment with antidepressants, lipophilic beta blockers, clonidine, opioids, or 
other medications known to interfere with sleep and may confound the study assessments, 
as determined by the Investigator.  
Note: In most cases, chronic treatments administered regularly and at stable dosing should 
be acceptable. Investigators should assess the degree to which an individual medication 
may cause changes in sleep pattern or sleep quality during the study, compared to the pre-
baseline state. 
E 22. Participant who has taken biologic therapy (including dupilumab)/systemic 
immunosuppressant to treat inflammatory disease or autoimmune disease (eg, rheumatoid 
arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus 
erythematosus, multiple sclerosis, etc) within 2 months or 5 half-lives before SV1, 
whichever is longer. 
E 23. Treatment with live (attenuated) vaccine within 4 weeks before SV1. 
NOTE: 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 (ie, after the 12-week follow-up 
period off-treatment or until the participant switches to commercialized dupilumab or other 
biologic product, whichever comes first), or preponed to before the start of the study 
without compromising the health of the participant: 
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- 
Participant 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 24. Planned or anticipated use of any prohibited medications (Section 6.5) and procedures 
during screening and study treatment period. 
Prior/concurrent clinical study experience 
E 25. Enrolled in other ongoing studies regardless of the investigational product.  
E 26. Treatment with an investigational drug within 1 month or within 5 half-lives (if known), 
whichever is longer, prior to SV1. 
Diagnostic assessments 
E 27. Participants with any of the following results at SV1: 
• Positive (or indeterminate) HBsAg or, 
• Positive total HBcAb confirmed by positive HBV DNA or, 
• Positive HCVAb confirmed by positive HCV RNA.  
Other exclusions 
E 28. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 29. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 30. 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 (in 
conjunction with section 1.61 of the ICH-GCP Ordinance E6). 
E 31. Any specific situation during study implementation/course that may rise ethics 
considerations. 
E 32. 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.  
5.3 
LIFESTYLE CONSIDERATIONS  
No restrictions are required. 
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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. 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 
reasons, 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 a screen failure.  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. The participants may be rescreened once during the open screening period. There is 
no requirement for a waiting period between the screen failure date and the rescreening date. 
Participants who are rescreened must sign a new consent form and all SV1 procedures must be 
repeated. A different participant identification number will be issued. The interactive voice 
recognition system (IVRS)/ interactive web response system (IWRS) report will flag rescreened 
participants.  
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 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 ≥150 cells/µL (I 04) before randomization. This is 
only required if the participant doesn’t have the blood eosinophils measured within 6 months prior 
to SV1 in the absence of OCS treatment. 
A participant who is unable to complete a successful spirometry effort as defined by ATS criteria 
or assessed by the Investigator or did not meet the eligibility criterion for pre-BD FEV1 at SV1 
can be retested one additional time during the screening period of the study. 
Three attempts may be performed during the screening period to meet the eligibility criteria for 
reversibility before randomization. This is only required if a reversibility test meeting the 
eligibility criterion was not performed within 6 months prior to SV1. 
FeNO can be assessed one additional time during the screening if the FeNO value measured at 
SV1 doesn’t meet the eligibility criterion. 
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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 8 (Section 10.8) 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  
ARM name 
Dupilumab 200 mg 
Placebo 
Intervention name 
Dupilumab 200 mg 
Placebo matching dupilumab 200 mg 
Type  
Biological 
Other 
Dose formulation 
Dupilumab 200 mg: a 175 mg/mL 
dupilumab solution in a prefilled syringe 
to deliver 200 mg in 1.14 mL 
Placebo matching dupilumab 200 mg 
will be supplied as an identical 
formulation to the active 200 mg 
formulation without dupilumab, in a 
prefilled syringe to deliver placebo in 
1.14 mL 
Unit dose strength(s) 
200 mg  
0 mg 
Dosage level(s) 
200 mg every 14 ±3 days after an initial 
loading dose of 400 mg 
0 mg every 14 ±3 days after an initial 
loading dose of 0 mg  
Route of administration 
SC injectiona 
SC injectiona 
Use 
experimental 
placebo- comparator 
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.  
Current/Former name(s) or 
alias(es) 
Dupixent 
 
a SC 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. 
IMP: investigational medicinal product; SC: subcutaneous. 
In specific situation, 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 participants enrolled through virtual site (Metasite), IMP will be supplied from the virtual site 
to the participant via DTP service which will be handled and under the responsibility of 
Science37. 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 8 (Section 10.8). 
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The Investigator or delegate will train the participant (or caregiver) how to prepare and inject IMP 
at Visit 2. The site staff will inject the first dose of the two injections. 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. At subsequent administrations, 
participants are allowed to self-inject IMP at home.  
For participants enrolled through Science37 Metasite, IMP will be administered by a mobile study 
nurse at the randomization dosing visit. As described above, the participants/caregivers will be 
instructed how to prepare and self-inject/inject the IMP at the first dosing visit and will be allowed 
to self-administer/administer for the remainder of the treatment period. If the participant is not 
comfortable with self-administration, the mobile study nurse will perform the administrations at 
home visits at every 2 weeks, according to the scheduled IMP administrations. The mobile study 
nursing management with all related activities will be under the responsibility of Science37. 
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 two 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 two 
consecutive doses were missed. 
When the participant has a study visit, the IMP will be administered following clinical procedures 
and blood collection. Participants should be monitored for at least 30 minutes. The monitoring 
period may be extended as per country-specific or local site-specific requirements. 
If the participant (or caregiver) is unable or unwilling to administer IMP, injections can be 
performed at the site by way of unscheduled visits; or arrangements can be made for qualified site 
personnel and/or health care professionals (eg, visiting nurse service) to administer IMP for the 
doses that are not scheduled to be given at the study site or if the participant can’t attend the on-
site visit.  
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 
delegate) or health care professional but not the participants themselves.  
Participant or caregiver should be trained by the site staff to recognize potential signs and 
symptoms of hypersensitivity reaction in order 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. 
A home dosing diary will be provided to collect information related to at home injections. The 
diary will be kept as source data in the participant’s study file.  
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Noninvestigational 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) ≥1 month prior to SV1 and during the Screening 
Period (Table 3).  
Participants requiring a third controller for their asthma will be considered eligible for this study, 
also at a stable dose ≥1 month prior to SV1 and during the Screening Period. Theophylline is not 
allowed knowing that it can interfere with sleep and may confound the study assessments. 
• Formulation and route(s) of administration: refer to label. 
• Dose regimen: as prescribed. 
The asthma background therapy should be maintained on a stable dose during the study treatment 
period. 
Short-acting β2 agonists may be used as rescue medication during the study if needed. 
Systemic corticosteroids are allowed for the treatment of severe asthma exacerbations. 
Table 3 - Medium and high daily doses of inhaled corticosteroids (mcg)  
Inhaled corticosteroid 
Medium 
High 
Beclometasone dipropionate (pMDIa, HFA) 
>500-1000 
>1000 
Beclometasone dipropionate (pMDI, extrafine particle, HFA) 
>200-400 
>400 
Budesonide (DPI) 
>400-800 
>800 
Ciclesonide (pMDI, extrafine particle, HFA) 
>160-320 
>320 
Fluticasone furoate (DPI) 
100. 
200 
Fluticasone propionate (DPI) 
>250-500 
>500 
Fluticasone propionate (pMDIa, HFA) 
>250-500 
>500 
Mometasone furoate (DPI) 
200 
440 
Mometasone furoate (pMDIa, HFA) 
200-400 
400 
DPI = Dry powder inhaler; HFA = Hydrofluoroalkane propellant (non-CFC), pMDI = pressurized metered dose inhaler. 
a standard (non-fine) particles.  
The GINA table above refers to metered doses. This is not a table of equivalence but suggested 
total daily ICS doses for the “medium” and “high” dose options. It is based on available studies 
and product information. Doses may be country-specific depending on local availability, 
regulatory labelling, and clinical guidelines. For new preparations, the manufacturer’s product 
information should be reviewed carefully, as products containing the same molecule may not be 
clinically equivalent (27). The list presents examples of ICS and might support future changes.  
An asthma background therapy diary will be provided to collect information related to 
noninvestigational medicinal product (NIMP) use. The diary will be kept as source data in the 
participant’s study file. 
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6.1.1 Devices  
Not applicable. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
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. Science 37 Metasite: For the preparation, handling, storage and accountability of study 
intervention, refer to Appendix 7 (Section 10.7). 
Responsibilities 
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 8.3.7). 
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 DTP shipment, unless 
the courier company has been approved by the Sponsor (or Science37 for the virtual site), or 
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 intervention 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 intervention kit number list and 
the Study Biostatistician will provide the randomization scheme to the centralized intervention 
allocation system. This centralized intervention allocation system will generate the participant 
randomization list according to which it will allocate the intervention to the participants.  
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The Investigator obtains intervention kit numbers at randomization (Visit 2) and subsequent 
scheduled visits via an IVRS/IWRS that will be available 24 hours a day.  
Science37 Metasite: The investigator of Metasite obtains intervention kit numbers at 
randomization (Visit 2) and subsequent scheduled visits via IVRS/IWRS. Science37 participant 
randomization in IVRS/IWRS will occur on Day 1, with first loading dose occurring up to 5 days 
post randomization to account for the lag between IVRS/IWRS randomization trigger for IMP 
DTP shipment and IMP availability to participant/mobile study nurse. 
Science37 participant windows increased up to 3 days (the maximum visit window) for the 
subsequent at home dosing visits (week 4, week 8, week 12), to account for the lag between 
IVRS/IWRS trigger for IMP DTP shipment and IMP availability to participant/mobile study 
nurse. 
Participants who meet the entry criteria will be randomized to receive either dupilumab or 
placebo. Participants will be randomized centrally using a 1:1 randomization ratio for dupilumab 
200 mg Q2W and placebo Q2W. Randomization will be stratified according to 5 strata: 
one stratum for all participants included in the 
 (regardless of dose level of ICS, 
regardless of region) and 4 strata for participants not included in 
, according to 
region and ICS dose (Eastern Europe with high ICS dose, Eastern Europe with medium ICS dose, 
ROW with high ICS dose, and ROW with medium ICS dose). In total, no less than 
40% participants need to be in “high ICS” strata, and no more than 25% participants need to be in 
“Eastern Europe” strata. 
A randomized participant is defined as a participant who is registered and assigned with an 
intervention kit number from the centralized intervention allocation system, as documented from 
its log file, regardless whether the intervention kit was used or not. 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. 
Methods of blinding 
Dupilumab and placebo will be provided in identically matched 1.14 mL prefilled syringes. To 
protect the blind, each intervention kit of 1.14 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. 
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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. 
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). 
6.4 
STUDY INTERVENTION COMPLIANCE  
Measures taken to ensure and document intervention compliance and IMP accountability include: 
• Proper recording of intervention kit number as required on appropriate electronic case 
report form (e-CRF) page for accounting purposes. 
• All intervention kits (whether empty or unused) are returned by the participant at each visit 
when an intervention dispensing is planned: 
• Science37 Metasite: All intervention kits accountability and return (whether empty or 
unused) will be managed and under the responsibility of Science37. 
- 
The completed participant home dosing diary (returned to the site at each visit), 
returned intervention kits and any unused prefilled syringes will be used for drug 
accountability purposes.  
• The Investigator or designee tracks intervention accountability/compliance, either by 
diary, or by counting the number of used intervention 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, pharmacist, or qualified nurse 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 interventions 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. 
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6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrollment or receives during the study must be recorded 
along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
During the FU period the asthma treatment will be administered based on Investigator's medical 
judgment and normal clinical practice. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Prohibited concomitant therapy:  
• Any biologic therapy (including experimental treatments) or systemic immunosuppressive 
drugs. 
• Treatment with systemic corticosteroids (systemic corticosteroids can only be used to treat 
a severe asthma exacerbation and are not allowed to be used for other conditions). 
• Treatment with live (attenuated) vaccine.  
• Sedative, anxiolytic, or hypnotic treatments including melatonin.  
• Antihistamines, except the newer generations of antihistamines (eg, cetirizine, loratadine 
and fexofenadine). 
• Theophylline. 
• Lipophilic beta blockers, opioids, clonidine, antidepressants or other medications known 
to interfere with sleep, as determined by the Investigators. 
Note: In most cases, chronic treatments administered regularly and at stable dosing are acceptable. 
Investigators should assess the degree to which an individual medication may cause changes in 
sleep pattern or sleep quality during the study, compared to the prebaseline state. 
6.5.1 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 severe 
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 
 or spirometry, the measurements should be 
performed after a wash-out time mentioned in Table 4 (Section 8.1.3). The date and time of rescue 
medication administration as well as the name and dosage regimen of the rescue medication must 
be recorded. 
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6.6 
DOSE MODIFICATION  
Not applicable. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
No intervention is planned after the end of the study. 
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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 (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for efficacy and safety. See the SoA 
(Section 1.3) for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
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 “Increase in 
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: 
• 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). 
• If, in the Investigator's opinion, continuation in the study would be detrimental to the 
participant’s well-being. 
• At the specific request of the Sponsor. 
• If the Emergency Unblinding transaction is performed by the Investigator (ie, at the site 
level).  
• Pregnancy. 
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Section 10.9). 
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin.  
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• Any opportunistic infection, such as tuberculosis or other infections whose nature or 
course may suggest an immunocompromised status. 
• Serum ALT >3 upper limit of normal (ULN) and Total Bilirubin > 2 ULN (see 
Section 10.5, Appendix 5). 
• 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. 
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 definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of EOT visit (Visit 5), or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
Participants who prematurely discontinue the study intervention (prior to completing the 12-week 
treatment period) should attend an ETD visit at earliest convenience with all procedures required 
at the EOT visit, except 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 (Visit 5). 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 8 (Section 10.8). For all temporary 
intervention discontinuations, duration should be recorded by the Investigator in the appropriate 
pages of the e-CRF.  
The following definition can be considered: temporary intervention discontinuation decided by 
the Investigator corresponds to more than one dose not administered to the participant. 
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In addition, the following conditions will be causes for temporary discontinuation of study 
intervention: 
• Infections or infestations that do not respond to medical treatment. 
• Treatment with a live (attenuated) vaccine. 
• Treatment with immunomodulating biologics (including experimental treatments). 
• Treatment with systemic corticosteroids (except systemic corticosteroids used to treat a 
severe asthma exacerbation) or systemic immunosuppressive drugs. 
• 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(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (Section 5.1 and Section 5.2). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 8 (Section 10.8). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• 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. 
• A participant who prematurely discontinues the study should attend an 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.  
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• 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. 
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. 
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Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any 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.  
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: 
• 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. 
• 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. 
• 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 10.1.8). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• 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.  
• 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 or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA. 
• The laboratory tests will be done locally, 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.  
• Patient-reported outcome measures completed at the clinical site should be completed by 
the participants before the consultation and/or clinical tests, in a quiet place when 
completed at study visits. The questionnaires should be completed by the participants 
themselves, independently from their physician, the study nurse or any other medical 
personnel and without any help from friends or relatives. 
• Science37 Metasite: For the study procedures performed by the participants enrolled by 
the Metasite, refer to Appendix 7 (Section 10.7) 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 8 (Section 10.8). 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Actigraphy  
Actigraphy is a procedure that records and integrates the occurrence and degree of limb 
movement activity over time. For sleep applications, the devices are typically worn on the wrist or 
ankle. Mathematical algorithms are then applied to these data to estimate wakefulness and sleep. 
In addition to providing a graphical summary of wakefulness and sleep patterns over time, 
actigraphy generates estimates of certain sleep parameters (24). 
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For prebronchodilator measured parameters, including FEV1 and forced vital capacity (FVC), 
spirometry will be performed before IMP administration and after withholding the standard of 
care asthma treatment as follows: 
Table 4 - Wash-out period of asthma controllers and rescue medication before 
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/LABA 
24 hours 
Inhaled Ultralong ICS/LABA combinations  
48 hours 
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 corticosteroids (ICS) 
12 hours 
Systemic corticosteroids (oral, IM, IV) 
4 weeks 
ICS: inhaled corticosteroid; IM: intramuscular; IV: intravenous; LABA: long-acting beta agonist; LAMA: long-acting muscarinic antagonist; 
SABA: short-acting beta2 agonist; SAMA: short-acting muscarinic antagonist  
This will be verified before performing the measurements. 
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 spirometer provided by the service provider should be used 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 if possible. If the testing was 
made with the participant 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 each visit. The acceptability criteria must be applied before the repeatability criteria. 
Unacceptable maneuvers must be discarded before applying the repeatability criteria. If a 
participant fails to provide repeatable maneuvers, an explanation should be recorded in the e-CRF. 
At least two acceptable curves must be obtained.  
The largest FEV1 and largest FVC should be recorded after the data from all of the acceptable 
curves have been examined, even if they do not come from the same curve. 
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The spirometer must be calibrated following the principles of the ATS/ERS guidelines every day 
that a participant is seen and subjected to spirometry. The calibration records should be kept in a 
reviewable log. It is preferred that the equipment that is used to calibrate the spirometer (ie, 3-liter 
syringe) 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 SV1 can 
be retested one additional time during the screening period of the study. The spirometry will be 
centrally read. Further details on the procedure will be provided in a separate instruction manual. 
8.1.4 Reversibility test  
A reversibility test will be administered following pulmonary function testing after asthma 
medications have been withheld for the appropriate intervals mentioned in Table 4. Participants 
will receive 2 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 reversibility at SV1, up to 
3 repeat attempts can be performed at any time (ie, unscheduled visits) prior to the randomization 
visit (Visit 2). This is only required if a reversibility test meeting eligibility criterion was not 
performed within 6 months prior to SV1. 
8.1.5 Asthma sleep disturbance questionnaire  
The Asthma Sleep Disturbance Questionnaire is a PRO measure designed to assess the impact of 
asthma on participants’ sleep. Scores range between 0 to 4 with 0 indicating no impact of asthma 
on sleep and 4 indicating higher impact of asthma on sleep.  
Participants will be instructed to record the severity of the disturbance of their sleep due to asthma 
as follows:  
• 0 = Slept through the night, no asthma symptoms, 
• 1 = Slept well, no nighttime awakenings because of asthma, but some asthma symptoms in 
the morning, 
• 2 = Woke up once because of asthma (may or may not include early awakening), 
• 3 = Woke up several times because of asthma (may or may not include early awakening), 
• 4 = Bad night, awake most of the night because of asthma. 
The participants will record their sleep disturbance in an electronic diary, once a day upon 
awakening. The participants will complete Asthma Sleep Disturbance Questionnaire as per SoA 
(see Section 1.3). 
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Science37 Metasite: For the completion of the baseline and postbaseline assessments, refer to 
Appendix 7 (Section 10.7). 
8.1.6 Asthma daytime symptom diary - Asthma nighttime symptom diary  
The ADSD and ANSD are PRO measures developed by the PRO Consortium’ Asthma Working 
Group. Both instruments have been designed to measure asthma symptoms in adult and 
adolescent (12 years of age and older) participants diagnosed with mild to severe asthma. ADSD 
and ANSD assess asthma severity based on patient self-report of asthma core symptoms, ie, 
difficulty breathing; wheezing; shortness of breath; chest tightness; chest pain; and cough. 
Participants are asked to complete the ADSD every night before they go to bed, thinking about 
their asthma symptoms today, from when they got up this morning until now; the ANSD when 
getting up, thinking about their asthma symptoms last night from when they went to bed until 
now. 
They have demonstrated adequate evidence of content validity and cross-sectional measurement 
properties (ie, internal consistency reliability, test-retest reliability, convergent validity, and 
known-groups validity) to measure symptoms of asthma. Both the ADSD and ANSD are 
composed of 6 items rated using an 11-point NRS that ranges from 0 = None to 10 = As bad as 
you can imagine (29).  
The participants will complete the ADSD and the ANSD as per SoA (see Section 1.3). 
Science37 Metasite: For the completion of the baseline and postbaseline assessments, refer to 
Appendix 7 (Section 10.7). 
8.1.7 Sleep diary  
The Sleep Diary is composed of seven generic, patient-reported questions that assess sleep 
concepts of relevance and importance to adults who report sleep disturbance due to asthma. 
The Sleep Diary features two subjective, patient-rated items that use a 0-to-10 NRS to assess sleep 
quality and feeling rested upon awakening (ie, restorative sleep). Additional items include the 
patient-estimated initial sleep attempt time and sleep onset time, number of nighttime awakenings 
after sleep onset, total time spent awake after sleep onset, and wake time the next day. Participants 
are instructed to complete all questions upon awakening each day. All questions except the one 
about restorative sleep ask participants to recall “last night”; question about restorative sleep asks 
participants to recall “when they got up for the day today”. Items about sleep quality and 
restorative sleep are scored; the other items are reported/described separately, as appropriate for 
each item. 
The participants will complete the items of the Sleep Diary daily, as per SoA (see Section 1.3). 
Science37 Metasite: For the completion of the baseline and postbaseline assessments, refer to 
Appendix 7 (Section 10.7). 
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8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• 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 SV1. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
• Temperature (degrees Celsius), heart rate (beats per minute), respiratory rate (breaths per 
minute), and blood pressure (mmHg) will be assessed. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• 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) and 
will consist of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the 3 blood 
pressure readings will be recorded in the e-CRF. 
8.2.3 Electrocardiograms  
• 12-lead ECG will be obtained at SV1 as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT 
intervals. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for the timing and frequency.  
• The laboratory tests will be performed by the local laboratories according to routine 
clinical practice at site and country level. Considering this, 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).  
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the 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. 
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• 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.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse events 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 study intervention (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 EOS Visit (Visit 6) at the time 
points specified in the SoA (Section 1.3). 
All AEs will be collected from the signing of the ICF until the EOS Visit (Visit 6) 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. 
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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 prespecified study end-date, all SAEs, and AESI 
as defined in Section 8.3.6), 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 provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• 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.  
• 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. 
• Adverse events that are considered expected will be specified in the reference safety 
information (the IB and its updates).  
• 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. 
• An Investigator who receives an Investigator safety report describing a 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  
• The pregnancy information for female participants or female partners of male participants 
will be collected after the start of study intervention and until the outcome has been 
determined. Generally, the follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. 
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• 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). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
• 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.   
• 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. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue the study intervention. 
8.3.6 Adverse event of special interest  
An 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 10.3.4, even if not fulfilling a seriousness criterion, using the 
screens in the e-CRF. 
• Anaphylactic reactions (see Section 10.9). 
• Systemic hypersensitivity reactions. 
• Helminthic infections. 
• Keratitis. 
• Any severe type of conjunctivitis or blepharitis. 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms). 
• Significant ALT elevation  
- 
ALT >5 × the ULN in participants with baseline ALT ≤2 × ULN; “Baseline” refers to 
ALT sampled at baseline visit or, if baseline value is unavailable, to the latest ALT 
value before the baseline visit, 
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.  
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- 
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 (see Appendix 3 [Section 10.3]). 
- 
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 (See Appendix 4 
[Section 10.4]) 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
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. 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the maximum prescribed daily dose, within the intended therapeutic interval. 
8.3.7 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  
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 8.3.6). 
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. 
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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 two 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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9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 5): 
Table 5 - 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. 
ITT 
The analysis population for the efficacy endpoints (except the primary endpoint) 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. 
ITT for primary 
endpoint (ITTp) 
All ITT participants excluding those who used the original version of sleep disturbance questionnaire at 
baseline and/or post-baseline. This analysis population is only applied to primary endpoint analysis. 
Safety (As-treated) 
All randomized participants who take at least 1 dose of study intervention will be the safety population. 
Participants will be analyzed according to the intervention they actually received. Randomized 
participants for whom it is unclear whether the study medication or intervention was taken will be 
included in the safety population as randomized. For participants receiving more than one IMP during 
the study (i.e., placebo and dupilumab), the actual study intervention group for as treated analysis will 
be the dupilumab group. 
ITT: intent-to-treat; ITTp: intent-to-treat for primary endpoint; IVRS: interactive voice recognition system 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be developed and finalized prior to database lock and it 
will include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. 
9.4.1 General considerations  
The multiplicity procedure is proposed to control the overall Type I error rate for testing the 
primary and selected secondary endpoints assessed for dupilumab 200 mg Q2W versus placebo. 
The overall alpha is 0.05. The list of secondary endpoints to be tested in the hierarchical order will 
be specified in the SAP. 
The baseline value is defined generally as the last available value before randomization. 
The primary analysis will be performed on the ITTp population, and all other efficacy analyses 
will be performed on the ITT population, unless otherwise noted. All safety analyses will be 
performed on the Safety Population. 
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9.4.2 Primary endpoint(s)  
The primary endpoint is change from baseline in sleep disturbance score at Week 12 assessed 
using the Asthma Sleep Disturbance Questionnaire for dupilumab 200 mg Q2W versus placebo. 
The primary endpoint will be analyzed on the ITTp population using an MMRM approach. The 
model will include change form baseline in sleep disturbance score up to Week 12 as response 
variables, and treatment, age, BMI, stratification factors, visit, treatment-by-visit interaction, 
baseline ACQ-5, baseline sleep disturbance score and baseline-by-visit interaction as covariates. 
An unstructured correlation matrix will be used to model the within-participant errors. Parameters 
will be estimated using restricted maximum likelihood method with the Newton-Raphson 
algorithm. No imputations for missing values will be carried out. Statistical inferences on 
treatment comparisons for the change from baseline in sleep disturbance score at Week 12 will be 
derived from the mixed-effect model. The least square (LS) mean of each treatment group, 
difference in the LS mean between the dupilumab group and placebo, and the corresponding 
95% CI of the differences and p-values will be provided. For participants discontinuing the study 
intervention before Week 12 unrelated to the COVID-19 pandemic, the sleep disturbance scores 
measured off-study intervention will be included in the primary analysis. In contrast, for any 
participants discontinuing the study intervention due to the COVID-19 pandemic, off-study 
intervention data will not be included (i.e., set to missing) but will be assumed missing at random. 
The sensitivity analysis will be conducted using the ITT population. 
9.4.3 Secondary endpoint(s)  
Differences will be assessed between dupilumab and placebo in the following secondary efficacy 
endpoints: 
• Change from baseline to Week 12 on the number of nocturnal awakenings (Sleep Diary). 
• Change from baseline to Week 12 in prebronchodilator FEV1. 
• Change from baseline to Week 12 in ADSD and ANSD. 
• Change from baseline to Week 12 in PROMIS Sleep-Related Impairment 8a scale. 
• Change from baseline to Week 12 in Sleep Diary Questions: sleep quality, restorative 
sleep, and WASO. 
• Change from baseline to Week 12 in WASO from actigraphy data. 
The change from baseline in the above continuous endpoints to Week 12 will be analyzed using 
the MMRM model in the same fashion as for the primary endpoint, based on the ITT population.  
For the spirometry endpoints, the model will also include sex and baseline height as the 
covariates. 
The details for the analysis for actigraphy will be provided in the SAP. 
The incidence of TEAEs, SAEs including clinically significant changes in vital signs, and AESI 
will be used to evaluate the safety of dupilumab. 
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9.5 
INTERIM ANALYSES  
An interim analysis (IA) in the study is planned for the purpose of 
 when 
approximately 50% of participants (approximately 130 participants from the ITTp population) 
would have completed Week 12 visit or discontinued the study. The sample size re-estimation is 
planned to mitigate risk of power loss, given the large variability of placebo effects observed in 
 Interim analysis will be performed as follows: 
• The sample size re-estimation will be performed based on the observed treatment effects at 
the time of IA. Sample size may be increased if conditional power falls into the promising 
zone. No additional IA will be performed in the case of sample size increase. The test 
statistic at the final analysis may be adjusted as appropriate and details will be specified in 
the SAP. 
• There is no plan to stop trial early for superiority at the time of IA. In order to preserve the 
overall Type I error rate of 0.05 (2-sided), gamma family alpha spending function will be 
utilized.  
The IA will be performed by an internal independent statistical team, who are separate from 
personnel involved in the trial conduct. An independent Interim Analysis Committee (IAC) 
consisting of two clinicians and one statistician will review the results and make decision if the 
sample size needs to be adjusted based on prespecified criteria. A detailed plan will be defined in 
the SAP, including the plan to describe the processes intended to control access to comparative 
interim results to preserve trial integrity. People involved in the conduct of the study (participants, 
Investigators, Study Team, and Project Team) will have no access to the IA results. 
At the time of IA, the primary efficacy endpoint will be analyzed using the same method 
described in the primary endpoint section (Section 9.4.2). The analysis population for the IA will 
be approximately 130 randomized participants from the ITTp population. The analysis of the 
endpoints will use all the data collected for the analysis population up to the IA cut-off time. 
The database lock for final analysis is planned based on the date when the last participant 
completes the Week 12 visit or discontinues from the study before Week 12. Analyses will be 
based on all data collected up to this database lock and will be considered as the final analysis in 
the CSR. 
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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  
• 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 International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• 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.  
• 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.  
• 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 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  
• 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).  
• 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.  
• Science37 Metasite participants will complete the consent process remotely with 
Science37 study staff and sign the eConsent in the Science37 platform, accessible via an 
App on a smartphone or tablet, or on a computer desktop browser. 
• 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. 
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• 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).  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• Science37 Metasite participants will be informed that they may download and print a copy 
of the eICF, or a copy may be emailed to them upon the participant’s request. 
• Participants who are rescreened are required to sign a new ICF. 
The ICF contains two 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. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 8 (Section 10.8).  
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. 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 because they are expected to modify 
the drug response/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. 
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• 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 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.  
• 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.  
• 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. 
• 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  
• 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. 
• 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).  
• 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. 
• 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 
• 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:  
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- 
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.  
• 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. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• 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 phamaceutical 
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.  
• 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 Dissemination of clinical study data  
Study participants 
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. 
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 www.vivli.org. 
Individual participant data and supporting clinical documents are available for request at 
www.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: www.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”. 
10.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on electronic 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 
electronically signing the CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 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. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations [CRO]) 
• 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.  
• 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.  
10.1.7 Source documents  
• 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. 
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• 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 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
• 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, home dosing diary, asthma background 
therapy diary, recorded data from automated instruments etc. Data downloaded from the 
local laboratories, spirometry, actigraphy, 
, ECG, patient diaries, 
electronic PROs will be considered source data. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 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. 
• For the Science37 Metasite, the Science37 platform is the repository for all source 
documents and participant information. 
10.1.8 Study and site start and closure  
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 site open and will be the study start date. 
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: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
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• 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. 
- 
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 shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
10.1.9 Publication policy  
• 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.  
• 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. 
• 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  
• The tests detailed in Table 6 will be performed by the local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted as 
mentioned in the SoA (Section 1.3). 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
the end of relevant systemic exposure corresponding with the time frame for female 
participant contraception in Section 5.1, Inclusion Criteria. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant's participation in the study. 
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• In exceptional situations when the participants cannot attend the on-site visits, 
arrangements can be made for qualified site personnel and/or health care professionals 
(eg, visiting nurse service) for blood sample collection, if allowed by local regulations and 
approved by the participant. 
• Science37 Metasite: the blood sample collection and pregnancy tests (if applicable) will be 
done at participants’ home by the Science37 home nursing service. The processing, 
shipment, analysis of the blood samples are under Science37 responsibility.  
Table 6 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Eosinophils 
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); 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. 
Human Immunodeficiency Virus screening (Anti-HIV-1 and HIV-2 antibodies). 
Tuberculosis test performed only 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 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 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  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• 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. 
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Definition of unsolicited and solicited AE 
• 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. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, 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. 
• 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. 
• 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. 
Events meeting the AE definition 
• 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. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
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Events NOT meeting the AE definition 
• 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. 
• 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. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 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. 
10.3.2 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 untoward medical occurrence 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. 
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- 
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. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• 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. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• 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 CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. 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. 
• 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 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
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• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 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 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• 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. 
• The Investigator will use clinical judgment to determine the relationship. 
• 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. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• 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. 
• 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 representative. 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. 
• 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. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor’s 
representative 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. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.  
• New or updated information will be recorded in the originally completed CRF. 
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• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• 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. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 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. 
• 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 representative by telephone. 
• Contacts for SAE reporting can be found in the protocol. 
SAE reporting to the Sponsor via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
• 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. 
• 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. 
• Contacts for SAE reporting can be found in the protocol. 
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 postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
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Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 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), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with more than one FSH measurement is 
required. 
- 
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. 
CONTRACEPTION GUIDANCE: 
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. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
Vasectomized partner 
(Vasectomized partner 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. Spermatogenesis cycle is approximately 90 days.) 
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Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
Sexual abstinence 
(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. 
c If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be used 
together (due to risk of failure with friction). 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• 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. 
• 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.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
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• 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. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) 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. 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.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
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10.7 
APPENDIX 7: SCIENCE37 METASITE  
One study center will be managed by Sponsor designee Science37, using TM, mobile study 
nurses, and an electronic application called the Science37 Platform.  
Study participants will undergo the same procedures and provide the same data as other trial 
participants as outlined in the protocol. The difference is that Science37 will interact with their 
participants using an innovative model, an electronic application and/or mobile nurses. 
As part of this study, Science37 participants will see their study doctors by using a TM model 
during the study. The goal of TM is to make it easier for the participants to take part in the study. 
Telemedicine will use secure video conferences, phone calls, and a web portal and/or mobile 
application as a way of communicating with and monitoring participants. Science37 will provide 
mobile study nurses to the participant’s home or location for study procedures, rather than a 
traditional investigative site. As part of this process, an electronic application called the Science37 
Platform will be utilized for data collection. 
The Science37 Platform is an electronic application developed by Science37. The Science37 
Platform is password protected and only the study participant can access their own login. No one 
other than the participant and the study staff is able to view personal identifiable (e.g. 
photographs) and/or trial data in the Science37 Platform. As a function of the platform, 
information and/or photographs are transmitted to the research staff securely via the platform. 
Data submitted by the participant via the Science37 mobile application (whether trial related 
information and/or photographs) are never saved locally on the device (tablet/phone). All 
information and/or photographs received by the study personnel via the Science37 Platform will 
be stored securely and confidentially within the platform. A participant’s personal use of 
information stored on the device will not be monitored. Participants will still be able to visit all 
local doctors as they normally would, but the Science37 study doctors and nurses will also 
communicate with the participant’s doctor to explain the study and coordinate participant care 
during the study. Participants will also be provided and requested to sign an informed consent 
document (e-ICF) which explains rights as a participant in the study. Science37 Metasite 
participants will complete the consent process remotely with Science37 study staff and sign the 
eConsent in the platform, accessible via an App on a smartphone or tablet, or on a computer 
desktop browser. The participants will be informed that they may download and print a copy of 
the e-ICF, or a copy may be emailed to them upon the participant’s request. 
For participants enrolled through virtual site (Metasite), IMP (and some other study materials, if 
needed) will be supplied from the virtual site to the participant via DTP service which will be 
handled and under the responsibility of Science37. 
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The IMP will be administered by a mobile study nurse at the randomization dosing visit. 
Participants/caregivers will be instructed as per Section 6.1 how to prepare and self-inject/inject 
the IMP at the first dosing visit and will be allowed to self-administer for the remainder of the 
treatment period. This training must be documented in the participant’s study file. If the 
participant is not comfortable with self-administration, the mobile study nurse will perform the 
administrations at home visits at every 2 weeks, according to the scheduled IMP administrations.  
The mobile study nursing management with all related activities will be under the responsibility 
of Science37. The investigator of Metasite obtains intervention kit numbers at randomization 
(Day 1) and subsequent scheduled visits via IVRS/IWRS. 
Science37 participant randomization in IVRS/IWRS will occur on Day 1, with first loading dose 
occurring up to 5 days after randomization to account for the lag between IVRS/IWRS 
randomization trigger for IMP DTP shipment and IMP availability to participant/mobile study 
nurse. 
For the subsequent at home dosing visits (week 4, week 8, week 12) the window may increase up 
to 3 days (maximum visit window) to account for the lag between IVRS/IWRS trigger for IMP 
DTP shipment and IMP availability to participant/mobile study nurse.  
All intervention kits accountability and return (whether used or empty or unused) of participants 
enrolled through Metasite will be managed and under the responsibility of Science37. 
Study procedures: 
Asthma Sleep Disturbance Questionnaire, sleep diary: the completion of the daily questionnaires 
for the baseline and for postbaseline assessments will be done as per SoA and will continue until 
the IMP dose administrations, considering the lag between IVRS/IWRS trigger for IMP DTP 
shipment and IMP availability to participant/mobile study nurse.  
Actigraphy: the participants will perform the baseline and postbaseline assessments as per SoA 
and will continue until the day prior to IMP dose administrations.  
ADSD: will be completed by the participants until the day prior to IMP dose administrations, 
every 4 weeks.  
ANSD: will be completed by the participants until and including the day of IMP administrations, 
every 4 weeks.  
All the other study assessments will be done as per SoA, (see Section 1.3). 
Approximately 10 participants will be enrolled to the Decentralized Clinical Trial Site (DCTS), a 
clinical trial operating model that enables remote participation in clinical trials. One DCTS in the 
US will be included in the study. The DCTS is a remote study model that integrates TM 
technology into the clinical research process and supports management of research activities, 
including data collection. As part of this model, study visits are completed using the DCTS 
technology platform. This 21 CFR Part 11 compliant software interface facilitates recruitment, 
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enrollment, and study data collection within a single cloud-based technology. It connects 
participants to their investigators and study team through a study-issued smartphone. 
Decentralizing research studies from traditional site-based centers, making them “site-less,” aims 
to eliminate participation barriers, such as inaccessibility due to geography and the inconvenience 
of traveling to site visits. A DCTS complies with all regulatory requirements applicable to study 
investigators, as delineated in 21 CFR 312 and ICH E6 (R2). As such, it does not assume any 
Sponsor or CRO obligations. 
The participants enrolled by Science37 Metasite will not participate in 
. 
10.8 
APPENDIX 8: 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: 
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 2.3.3, Section 5.5, 
Section 6.1, Section 7.1.2, Section 7.1.2.1, Section 8, Section 9.4.6, 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: 
• If onsite visits are not possible during the intervention period, the visit can be performed 
remotely ensuring at least the procedures that can be done at home: PROs completion, 
actigraphy, home 
(if applicable), IMP administration, blood samples collection, 
pregnancy test if applicable, safety reporting, and concomitant medications. 
• If on-site visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely (eg, spirometry, 
 on-site 
PROs, vital signs). 
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• Use of local laboratory locations may be allowed.  
• 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 two 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 two consecutive doses were 
missed.  
Contingencies implemented due to emergency will be documented.  
Statistical analysis: a sensitivity analysis may be conducted; details will be specified in the SAP. 
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). 
10.9 
APPENDIX 9: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (36)”. 
 
Clinical criteria for diagnosing anaphylaxis 
 
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10.10 APPENDIX 10: ABBREVIATIONS  
 
ACOS: 
asthma-COPD overlap syndrome 
ACQ: 
asthma control questionnaire 
ACT: 
asthma control test 
AD: 
atopic dermatitis 
ADR: 
adverse drug reaction 
ADSD: 
asthma daytime symptom diary 
AE: 
adverse event 
AESI: 
adverse event of special interest 
 
 
ALT: 
alanine transaminase 
ANSD: 
asthma nighttime symptom diary 
 
 
ATS: 
American Thoracic Society 
BD: 
bronchodilator 
BMI: 
body mass index 
CFR: 
code of federal regulations 
CI: 
confidence interval 
CIOMS: 
Council for International Organizations of Medical Sciences 
CONSORT: 
Consolidated Standards of Reporting Trials 
CRO: 
contract research organization 
CRSwNP: 
chronic rhinosinusitis with nasal polyps 
CSICF: 
core study informed consent form 
DCTS: 
decentralized clinical trial site 
DPI: 
dry powder inhaler 
DTP: 
direct to participant 
E/D: 
early discontinuation 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
e-ICF: 
electronic informed consent form 
EoE: 
eosinophilic esophagitis 
EOS: 
end of study 
EOT: 
end of treatment 
ERS: 
European Respiratory Society 
ESD: 
early study discontinuation 
ETD: 
early treatment discontinuation 
FDA: 
Food and Drug Administration 
FeNO: 
fractional exhaled nitric oxide 
FEV1: 
forced expiratory volume 
FSH: 
follicle stimulating hormone 
FVC: 
forced vital capacity 
GCP: 
Good Clinical Practice 
GDPR: 
General Data Protections Regulation 
GINA: 
Global Initiative for Asthma 
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pMDI: 
pressurized metered dose inhaler 
pre-BD FEV1: 
prebronchodilator forced expiratory volume 
PRO: 
patient-reported outcome 
PROMIS: 
patient-reported outcome measurement information system 
 
 
PSQI: 
Pittsburgh Sleep Quality Index 
PT: 
preferred term 
Q2W: 
every 2 weeks 
RNA: 
ribonucleic acid 
ROW: 
rest of world 
SABA: 
short-acting beta2 agonist 
SAE: 
serious adverse event 
SAMA: 
short-acting muscarinic antagonist 
SAP: 
statistical analysis plan 
SARP: 
severe asthma research program 
SC: 
subcutaneous 
SD: 
standard deviation 
 
 
SoA: 
schedule of activities 
SOC: 
system organ class 
 
 
SUSAR: 
suspected unexpected serious adverse reaction 
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse event 
 
 
ULN: 
upper limit of normal 
WASO: 
Wake after sleep onset 
WOCBP: 
women of childbearing potential 
 
 
 
10.11 APPENDIX 11: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents. 
10.11.1 
Amended protocol 01 (17 September 2020)  
This amended protocol (amendment 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. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for the Amendment is the decision to perform the 
 
assessments in the substudy at patient’s home using Type II 
devices instead of on-site 
overnight assessments as initially planned. This decision was taken considering that the patients' 
safety is of outmost importance in the context of the coronavirus disease 2019 (COVID-19) 
pandemic with unpredictable evolution. In addition, an updated version of the sleep disturbance 
questionnaire has been implemented based on patient feedback to improve its understanding. 
Further updates have been done in adverse events of special interest (AESI) listing and 
Benefit/Risk assessment chapter based on the new SAR231893 Investigator's Brochure (IB) dated 
19-Jun-2020. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 1.3 Schedule 
of Activities (SoA); 
4.1 Overall design; 
 
 
 
 
 
The 
parameters will be assessed using 
Type II home 
devices instead of on-site 
 assessments. 
Patients' safety is of outmost importance in the 
context of COVID-19 pandemic and its 
unpredictable evolution, thus it was decided to 
perform the 
assessment at home using 
Type II devices, instead of on-site overnight 
 as initially planned.  
1.1 Synopsis; 1.3 Schedule 
of Activities (SoA); 
4.1 Overall design; 
 
 
 
 
 
The 
 assessments will be done at home 
at two timepoints (on Day -1 and at End of 
Treatment [EOT] visit); the assessment on 
Day -2 for the control of “first night effect” 
has been removed. 
The 
 assessment on Day -2 for the control 
of any “first night effect” is not needed in case 
of home 
 
1.1 Synopsis; 1.3 Schedule 
of Activities (SoA); 
4.1 Overall design; 
10.6 Appendix 6: 
Polysomnography substudy 
If the sleep recording is inadequate as 
judged by the central reading site, the at-
home sleep assessment will be repeated 
within 1 week of the original assessment. 
To mitigate the risk of missing data due to 
inadequate recording 
3 Objectives and Endpoints 
Exploratory endpoint: 
 
 
 
 
 
 
Parameters added 
 
  
1.3 Schedule of Activities 
(SoA); 5.1 Inclusion criteria; 
8.1.2 Fractional exhaled 
nitric oxide;  
FeNO will be rechecked at randomization. 
Ensure eligibility. 
8.3.6 Adverse event of 
special interest 
Any severe type of conjunctivitis or 
blepharitis has been added to the AESI list. 
In agreement with latest IB. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Inclusion criteria 
I04. Historical values of blood eosinophil 
count meeting the eligibility criterion I04 
measured within 6 months prior to SV1 in 
the absence of OCS treatment are allowed. 
To clarify in the inclusion criterion I04 that the 
historical values of blood eosinophil count 
measured within 6 months prior to SV1 in the 
absence of OCS treatment are allowed. 
5.2 Exclusion criteria 
E18. Chronic treatment with oral 
corticosteroids (OCS) is forbidden within 
2 weeks prior to Screening Visit 1 (SV1). 
To clarify timeframe for chronic OCS treatment 
and to avoid confounding effects on sleep 
quality assessment. 
5.2 Exclusion criteria 
E23. Clarifications regarding the vaccination 
prohibition until the end of the study. 
Clarification based on the comment raised by 
the Medicines and Healthcare products 
Regulatory Agency (MHRA) (Health Authorities 
from the United Kingdom). 
5.2 Exclusion criteria 
E.26. Treatment with an investigational drug 
is not allowed within 1 month or within 5 
half-lives (if known), whichever is longer, 
prior to SV1. 
An interdiction of non-antibody investigational 
drugs for 2 months before SV1 is unnecessary. 
2.3.1 Risk assessment; 
2.3.2 Benefit assessment;  
Updated regulatory information and safety 
information based on recent Investigator’s 
Brochure update. 
Provide most recent safety data in the protocol. 
2.3.3 Benefit/risk 
assessment related to 
COVID-19; 5.5 Criteria for 
temporarily delaying 
screening, randomization, or 
study intervention 
administration; 6.1 Study 
intervention(s) administered; 
7.1.2 Temporary 
discontinuation; 
7.1.2.1 Rechallenge; 8 Study 
assessments and 
procedures; 9.4.6 Other 
analyse(s); 10.1.3 Informed 
consent process; 
10.7 Appendix 7 
Contingency measures for a 
regional or national 
emergency that is declared 
by a governmental agency 
Contingency measures to apply during a 
regional or national emergency declared by 
a governmental agency are described. 
To ensure trial continuity in case of regional or 
national emergency declared by a 
governmental agency. 
1.3 Schedule of Activities 
(SoA) 
Complete physical examinations will be 
performed at SV1, V2, and V5. 
The number of complete physical examinations 
has been reassessed in order to decrease the 
participants’ burden. 
1.3 Schedule of Activities  
 
 
 will be provided to participants at 
SV2. 
Devices must be provided to participants at 
SV2 so that they can start using them for 7 
days before V2. 
1.3 Schedule of Activities 
(SoA) 
ACQ-5 score is the mean of the responses 
to the first 5 questions. 
Correction related to the calculation of ACQ-5 
score. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.1 Study intervention(s) 
administered; 7.1.1 
Definitive discontinuation; 
10.7 Appendix 7 
Contingency measures for a 
regional or national 
emergency that is declared 
by a governmental agency 
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 
 
8.1.1 Actigraphy 
No training on actigraphy diary completion 
will be provided. 
There are no actigraphy diaries. 
8.1.5 Asthma sleep 
disturbance questionnaire 
Updated questionnaire. 
Wording changes in the questionnaire have 
been implemented following the feedback 
received from asthma patients to enhance its 
understanding 
 8.1.6 Asthma daytime 
symptom diary - Asthma 
nighttime symptom diary 
Details of asthma symptoms recording have 
been removed 
Clarification: the sentence was confusing. 
1.1 Synopsis; 9.2 Sample 
Size Determination; 
9.3 Populations for analyses; 
9.4.1 General 
considerations; 9.4.2 
Primary endpoint(s); 9.4.3 
Secondary endpoint(s); 9.4.4 
Tertiary/exploratory 
endpoint(s); 9.5 Interim 
analysis  
In order to mitigate the risk of potential 
different responses based on the Sleep 
Disturbance Questionnaire before and after 
amendment 01, the primary analysis of 
change from baseline in sleep disturbance 
score will exclude the participants who use 
the original questionnaire at baseline. The 
number of participants randomized up to the 
implementation of this protocol amendment 
is limited (ie, ≤10), therefore the study 
power can be preserved at ≥89% and 
therefore no participant replacement is 
planned.  
The Sleep Disturbance Questionnaire 
(assessment of primary endpoint) has been 
updated. The participants already enrolled in 
the study completed the initial version of the 
questionnaire. These participants will be 
excluded from the primary analysis to mitigate 
the risk of potential different responses before 
and after this amendment.  
8.3.4 Regulatory reporting 
requirements for SAEs 
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 
Correction of the instructions for the 
preparation of Investigators safety reports in 
case of SUSARs  
 
8.11 Use of data for future 
research; 10.1.3 Informed 
consent process 
Details on retention and use of data for 
future research. 
In agreement with current legal requirements 
and Sponsor’s policy. 
10.1.4 Data protection; 
10.1.5 Dissemination of 
clinical study data 
Description of data measures for 
professionals involved in the study. 
In agreement with current legal requirements 
and Sponsor’s policy. 
5.2 Exclusion criteria; 
7.1.1 Definitive 
discontinuation; 
8.3.6 Adverse event of 
special interest; 
10.8 Appendix 8: Definition 
of anaphylaxis 
Definition of anaphylaxis was added as an 
appendix. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.1 Definitive 
discontinuation; 
8.3.6 Adverse event of 
special interest 
Definition of baseline alanine transaminase 
(ALT) has been added. 
Clarification. 
Whole document 
Minor formatting, typo corrections, and 
consistency changes. 
Consistency. 
 
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productivity loss and activity impairment in severe or difficult-to-treat asthma. Value Health. 
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33. Turner-Warwick, M. Epidemiology of nocturnal asthma. Am J Med. 1988;85(1B):6-8. 
34. Catterall JR, Douglas NJ, Calverley PM, Brash HM, Brezinova V, Shapiro CM, et al. Irregular 
breathing and hypoxaemia during sleep in chronic stable asthma. Lancet. 1982;1(8267):301-4. 
35. Montplaisir J, Walsh J, Malo JL. Nocturnal asthma: features of attacks, sleep and breathing 
patterns. Am Rev Respir Dis. 1982;125(1):18-22. 
36. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report - 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.  
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SAP_001.pdf: 
Sanofi 
Dupilumab 
Protocol: LPS16677 
Clinical study report 
16.1.9 Documentation of statistical methods 
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Sanofi 
Dupilumab 
Protocol: LPS16677 
Clinical study report 
16.1.9.1 Final statistical analysis plan (and amendments)  
This section contains the following document: 
Statistical Analysis Plan version 2.0, dated 24 Feb 2022  
Addendum to Statistical Analysis Plan for LPS16677 version 1.0, dated 09 Oct 2023 
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Statistical Analysis Plan, Version 2.0 
 
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Date Issued: 24FEB2022 
 
  
 
 
 2
TABLE OF CONTENTS 
LIST OF TABLES ........................................................................................................................ 5 
LIST OF FIGURES ...................................................................................................................... 5 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1. 
INTRODUCTION............................................................................................................. 7 
2. 
STUDY OBJECTIVES, ENDPOINTS AND ESTIMANDS ......................................... 7 
3. 
INVESTIGATIONAL PLAN ........................................................................................ 11 
3.1. OVERALL STUDY DESIGN AND PLAN ................................................................................ 11 
3.2. STUDY ENDPOINTS ........................................................................................................... 12 
3.3. STUDY INTERVENTIONS .................................................................................................... 12 
3.4. DOSE ADJUSTMENT/MODIFICATIONS ............................................................................... 13 
4. 
GENERAL STATISTICAL CONSIDERATIONS ..................................................... 13 
4.1. SAMPLE SIZE .................................................................................................................... 13 
4.2. RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 13 
4.3. ANALYSIS SETS ................................................................................................................ 14 
4.3.1. 
Screened Analysis Set ............................................................................................... 14 
4.3.2. 
Intent-to-Treat (ITT) Analysis Set ............................................................................. 14 
4.3.3. 
Intent-to-Treat for primary endpoint (ITTp) Analysis Set ........................................ 14 
4.3.4. 
Analysis Set ....................................................................................................... 14 
4.3.5. 
Safety Analysis Set .................................................................................................... 14 
4.4. REPORTING CONVENTIONS ............................................................................................... 14 
4.4.1. 
Study Intervention labels........................................................................................... 15 
4.4.2. 
Visit naming Conventions ......................................................................................... 15 
4.4.3. 
Visit Windows............................................................................................................ 15 
4.4.4. 
Unscheduled Visits .................................................................................................... 15 
4.4.5. 
Display of Data Summary and Analysis ................................................................... 15 
4.4.6. 
Baseline, study day and duration derivations ........................................................... 16 
4.4.7. 
Change from baseline ............................................................................................... 17 
4.5. INTERCURRENT EVENT TYPES .......................................................................................... 17 
5. 
PARTICIPANT DISPOSITION ................................................................................... 17 
5.1. DISPOSITION ..................................................................................................................... 17 
5.2. PROTOCOL DEVIATIONS ................................................................................................... 18 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................. 19 
6.1. DEMOGRAPHICS AND PARTICIPANT CHARACTERISTICS ..................................................... 19 
6.2. BASELINE DISEASE CHARACTERISTICS ............................................................................. 20 
6.2.1. 
Sleep characteristics and sleep related impairment at baseline ............................... 20 
6.2.2. 
Asthma and associated disease characteristics at baseline ...................................... 20 
6.2.3. 
Biomarkers ................................................................................................................ 21 
6.3. ALCOHOL, TOBACCO AND CAFFEINE USAGE .................................................................... 21 
6.4. MEDICAL HISTORY ........................................................................................................... 21 
6.4.1. 
General Medical History .......................................................................................... 21 
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9.1.7. 
Adverse Events of Special Interest (AESI) ................................................................ 34 
9.1.8. 
Adverse Events Leading to Death ............................................................................. 35 
9.1.9. 
Death ......................................................................................................................... 35 
9.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 36 
9.3. VITAL SIGN MEASUREMENTS ........................................................................................... 36 
9.4. PHYSICAL EXAMINATION ................................................................................................. 37 
9.5. ELECTROCARDIOGRAM ..................................................................................................... 37 
9.6. OTHER SAFETY DATA ....................................................................................................... 37 
10. 
PHARMACOKINETICS ............................................................................................... 37 
11. 
PHARMACODYNAMICS............................................................................................. 37 
12. 
INTERIM ANALYSIS ................................................................................................... 37 
13. 
CHANGES IN THE PLANNED ANALYSIS .............................................................. 39 
13.1. NOCTURNAL AWAKENINGS AVERAGE ............................................................................... 39 
13.2. STUDY INTERVENTION DISCONTINUATION DUE TO COVID-19 HANDLING IN PRIMARY 
ANALYSIS ................................................................................................................................... 39 
13.3. SAFETY ANALYSIS SET ...................................................................................................... 39 
14. 
REFERENCES ................................................................................................................ 40 
15. 
APPENDICES ................................................................................................................. 43 
15.1. 
SUMMARY OF STATISTICAL ANALYSES ......................................................................... 43 
15.2. 
SCHEDULE OF STUDY PROCEDURES .............................................................................. 44 
15.3. 
MISSING EFFICACY DATA ............................................................................................. 50 
15.4. 
MISSING SAFETY DATA ................................................................................................. 50 
15.4.1. 
Handling of missing age ........................................................................................ 51 
15.4.2. 
Handling of computation of study intervention duration if investigational 
medicinal product end of treatment date is missing ............................................................... 51 
15.4.3. 
Handling of medication missing/partial dates....................................................... 51 
15.4.4. 
Handling of adverse events with missing or partial date/time of onset................. 51 
15.4.5. 
Handling of adverse events when date and time of first investigational medicinal 
product administration is missing .......................................................................................... 51 
15.4.6. 
Handling of missing assessment of relationship of adverse events to 
investigational medicinal product .......................................................................................... 51 
15.4.7. 
Handling of missing severity/grades of adverse events ......................................... 51 
15.4.8. 
Handling of potentially clinically significant abnormalities ................................. 51 
15.5. 
VISIT WINDOWS ............................................................................................................ 52 
15.6. 
SEARCH CRITERIA FOR AESI ........................................................................................ 52 
15.7. 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES (PCSA) CRITERIA .............. 55 
15.8. 
PARTICIPANT-REPORTED OUTCOMES (PROS) ............................................................... 55 
15.9. 
CLINICIAN-REPORTED OUTCOMES (CLINROS) ............................................................ 60 
15.9.1. 
Clinician Assessments............................................................................................ 60 
15.9.2. 
Center Assisted Assessments ................................................................................. 62 
15.9.3. 
Actigraphy data ..................................................................................................... 62 
15.10. 
RESCUE AND PROHIBITED MEDICATIONS. .................................................................. 62 
16. 
SIGNATURE PAGE ....................................................................................................... 64 
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LIST OF TABLES 
Table 2-1 Objectives and endpoints ................................................................................................ 7 
Table 2-2 Summary of primary estimands for main objectives ...................................................... 9 
Table 4-1 Study Intervention labels .............................................................................................. 15 
Table 4-2 Intercurrent Event Types .............................................................................................. 17 
Table 5-1 Randomization and drug dispensing irregularities ....................................................... 19 
Table 15-1 Analyses window definition ....................................................................................... 52 
Table 15-2 Search Criteria for AESI ............................................................................................ 52 
Table 15-3 Potentially Clinically Significant Abnormalities Criteria .......................................... 55 
Table 15.8.1 PROMIS Sleep-Related Impairment conversion table ............................................ 57 
LIST OF FIGURES 
Figure 3-1 Study Plan ................................................................................................................... 12 
LIST OF ABBREVIATIONS 
ACQ 
Asthma Control Questionnaire 
ADSD 
Asthma Daytime Symptom Diary 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
 
 
ALT 
Alanine Transaminase 
ANSD 
Asthma Nighttime Symptom Diary 
 
 
ATC 
ATS 
Anatomical Therapeutic Chemical 
American Thoracic Society 
BCP 
Business Continuity Plan 
BD 
Bronchodilator 
CI 
Confidence Interval 
CLINRO 
Clinician-Reported Outcome 
CP 
Conditional Power 
CRSwNP 
Chronic rhinosinusitis with nasal polyps 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
ERS 
European Respiratory Society 
FeNO 
Fractional exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume 
FVC 
Forced Vital Capacity 
HLT 
High Level Term 
HLGT 
High Level Group Term 
HR 
Heart Rate 
IA 
Interim Analysis 
IcEv 
Intercurrent Event 
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1. Introduction 
This document provides the detailed statistical methodology for the analysis of data from the Sanofi-
Aventis Recherche & Développement (SARD) study LPS16677. 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 Protocol 1, Version 1.0, dated on 17th September 
2020. Any changes or revisions to the planned analysis described in this document will be made prior to 
database lock. 
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 
• 
To assess the effect of 
dupilumab on sleep in 
participants with moderate-to-
severe asthma 
• 
Change from baseline to Week 12 in sleep disturbance 
score using the Asthma Sleep Disturbance 
Questionnaire 
Secondary 
• 
To evaluate the effect of 
dupilumab on additional 
participant reported sleep 
outcome 
• 
Change from baseline to Week 12 on the number of 
nocturnal awakenings (Sleep Diary) 
• 
Change from baseline to Week 12 in Patient-Reported 
Outcomes Measurement Information System 
(PROMIS) sleep-related impairment Short Form 8a 
scale 
• 
Change from baseline to Week 12 in sleep quality 
(Sleep Diary) 
• 
Change from baseline to Week 12 in restorative sleep 
(Sleep Diary) 
• 
Change from baseline to Week 12 in wake after sleep 
onset (WASO) (Sleep Diary) 
 
 
• 
To evaluate the effect of 
dupilumab on objective sleep 
assessment 
• 
To evaluate the effect of 
dupilumab on asthma 
symptoms 
• 
To evaluate the effect of 
dupilumab on lung function 
 
• 
To evaluate the safety of 
dupilumab 
• 
Change from baseline to Week 12 in WASO based on 
actigraphy data 
 
• 
Change from baseline to Week 12 in Asthma Daytime 
Symptom Diary (ADSD) and Asthma Nighttime 
Symptom Diary (ANSD) 
• 
Change from baseline to Week 12 in 
prebronchodilator forced expiratory volume (pre-BD 
FEV1) 
• 
Incidences of treatment-emergent adverse events 
(TEAEs) and serious adverse events (SAEs) including 
clinically significant changes in vital signs 
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• 
Incidences of adverse events of special interest 
(AESI) 
 
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Table 2-2 Summary of primary estimands for main objectives 
Endpoint 
Category 
(estimand) 
Estimands 
 
Endpointa 
Population 
Intercurrent event handling strategy 
Population-level summary 
(Analysis and missing data 
handling) 
 
Primary objective: To assess the effect of dupilumab on sleep 
 
Primary endpoint 
Change from 
baseline to 
Week 12 in 
sleep 
disturbance 
score using 
the Asthma 
Sleep 
Disturbance 
Questionnaire 
ITTp 
• 
Discontinuation of study intervention due to Covid-19 
pandemicb (IcEv1), off-study intervention data will be set as 
missing (hypothetical strategy).  
• 
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) assumption will be 
used. The MMRM will 
include study intervention, 
age, BMI, stratum (Eastern 
Europe with high ICS dose, 
Eastern Europe with medium 
ICS dose, rest of world 
[ROW] with high ICS dose 
and ROW with medium ICS 
dose), inclusion in
 visit, study 
intervention-by-visit 
interaction, baseline ACQ-5, 
baseline sleep disturbance 
score and baseline sleep 
disturbance score-by-visit 
interaction all as covariates. 
Stratification factors, study 
intervention and visit will be 
included as categorical 
parameters. 
 
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Endpoint 
Category 
(estimand) 
Estimands 
 
Endpointa 
Population 
Intercurrent event handling strategy 
Population-level summary 
(Analysis and missing data 
handling) 
 
Secondary objective: To evaluate the effect of dupilumab on additional participant reported sleep outcome. 
 
 
Secondary endpoint  
Change from 
baseline to 
Week 12 in 
number of 
nocturnal 
awakenings 
(Sleep Diary) 
ITT 
Same as the primary endpoint 
The same MMRM as for the 
primary estimand (primary 
objective), with the baseline 
values corresponding to the 
outcome variables. 
 
 
 
 
 
 
 
a Additional endpoints (secondary or tertiary) that are not included in this table will be handled with a similar analysis according to the endpoint type 
(i.e., continuous, binary, time-to-event) but without formal testing (i.e., nominal p-value provided for descriptive purpose only). The other 
secondary/tertiary endpoints are listed in Section 8.2.  
b 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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  11 
3. Investigational Plan 
3.1. Overall Study Design and Plan 
This is a Phase IV, 1:1 randomized, parallel, multicenter study, with a 12-week double-blind placebo-
controlled treatment period to assess the effect of dupilumab in improving sleep outcomes, asthma control, 
and health related quality of life, and in reducing daytime and nighttime asthma symptoms. 
 
Approximately 260 participants will be randomly assigned to study intervention in a 1:1 Dupilumab to 
placebo ratio to achieve 234 evaluable participants for an estimated total of 117 evaluable participants per 
study intervention group.  
 
The study will comprise of: 
• 
Screening Period 1 (Day -35 to -12 from signed informed consent): Participants will be evaluated 
according to inclusion and exclusion criteria 
• 
Screening Period 2 (Day -11 to -1; pre-baseline assessments): eligible participants will complete 
the assessments specified in the schedule of activities (SoA).  
If preferred by the participant and the investigator for logistical reasons, screening visit 1 and 
screening visit 2 can be merged into a single on-site visit which will have to be done on Day -11 
at the latest 
• 
Baseline (Day 1): Participants who remain eligible will be randomized 
• 
Randomized double-blind placebo-controlled treatment period (12 weeks from baseline): 
Participants will be randomized to receive either Dupilumab or placebo 
• 
Post-treatment follow-up period: up to 12 weeks after last dose of IMP or until the participant 
switches to commercialized dupilumab (or other biologic product), whichever comes first.  
 
Study duration for each participant will be approximately 16 weeks and up to 29 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. 
 
The end of the study is defined as the date of the last visit of the last participant in the study. 
 
The study analysis will be conducted in two steps. A primary database lock will be performed when all 
randomized participants will have completed the Week 12 visit or will have discontinued the study. The 
database will be updated at the end of the study for all participants to include the post-treatment follow-up 
information and updates for the events previously ongoing at the time of the primary lock. The CSR will 
include analyses from both the primary database lock and the final database lock. 
  
Analysis methods and conventions described in the other sections of this SAP will be applied for all 
analyses as applicable. 
 
The Sleep Disturbance Questionnaire (assessment of primary endpoint) has been updated in the Amended 
Protocol 01. The participants already enrolled in the study who completed the initial version of the 
questionnaire will be excluded from the primary analysis to mitigate the risk of potential different responses 
before and after the protocol amendment.  
 
 
 
 
 
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  15 
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 200 mg q2w 
Dupilumab 200 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. Where 
applicable, visit name will be formatted as “Week X” in summaries.  
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 (CIs) 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’. 
 
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. 
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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. 
4.4.6. Baseline, study day and duration derivations 
 
For assessments to be completed daily during the week prior to baseline visit (i.e., asthma sleep disturbance 
questionnaire, actigraphy parameters, sleep diary, ADSD and ANSD), the baseline value will be calculated 
by averaging the data collected/recorded from Day -6 to Day 1 (for ADSD: from Day -7 to Day -1). For 
actigraphy parameters, assessments performed at the same date as Day 1 will be taken into account for 
baseline calculation only if the end time of assessment is before 12 pm, reflecting the last night before the 
visit.  
 
If less than 4 measurements are available between Day -6 and Day 1 (for ADSD: between Day -7 and Day 
-1), the most recent 4 measurements will be used for the calculation; if finally, less than 4 measurements 
are available, it will be considered as missing. 
 
For all the other parameters, the baseline value is generally defined as the last available valid (non-missing) 
value up to and including the day 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. 
 
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 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: 
• 
Extent of exposure (see Section 7.2.1) 
• 
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). 
• 
For visit prior to the first administration of IMP, study day = assessment date – the first 
administration of IMP. 
• 
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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The last on-treatment value of safety parameters is the final measurement assessed during the treatment-
emergent adverse event period regardless of the introduction of rescue therapy and including measurements 
at unscheduled visits. 
4.4.7. Change from baseline 
Change from baseline is defined as: Change from baseline = Value at specific time point – Baseline 
value. 
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 12 
IcEv2 (discontinuation of study intervention not 
due to Covid-19) 
Premature study intervention discontinuation not 
due to Covid-19 pandemic before Week 12 
 
 
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: 
• 
Screened participants 
• 
Screen failure participants 
• 
Participants treated without being randomized 
• 
Randomized participants 
• 
Randomized but not treated participants 
• 
Randomized and treated participants 
• 
Participants who have completed the treatment period 
• 
Participants who did not complete the treatment period and the main reason for study intervention 
discontinuation. Relationship with COVID-19 will be reported for “Adverse Event” and “Other” 
reasons. 
• 
Participants who completed the study 
• 
Participants who did not complete the study and the main reason for study discontinuation. 
Relationship with COVID-19 will be reported for “Other” reasons 
• 
Participants who discontinued the study before Week 12 
• 
Participants who discontinued the study after Week 12 (i.e., during post-treatment follow-up 
period) 
• 
Participants who had rescue medications: 
o Participants who have completed the treatment period and had rescue medications 
o Participants who did not complete the treatment period and had rescue medications 
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• 
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. 
 
Participants with permanent study intervention and study discontinuation (early withdrawals) will be 
identified and described in separate listings. 
 
A summary of all the analysis sets for safety and efficacy (ITT, ITTp, and 
 will be summarized for the 
ITT analysis set by study intervention group and overall using number and percentage.  
 
Additionally, trial impact (disruption) due to COVID-19 pandemic will be presented on ITT population and 
will be considered for a participant if at least one of those events occur during the study: 
• 
Permanent end of study intervention due to COVID-19 pandemic 
• 
Premature end of study due to COVID-19 pandemic 
• 
Permanent end of study intervention due to AE related to COVID-19 infection 
• 
Critical or major protocol deviations due to COVID-19 pandemic 
 
Some safety (adverse events) analyses will also be repeated on the subgroups 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 (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. 
 
A listing of participants with at least one critical or major protocol deviation 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 
 
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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. 
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 clinical study report.  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 
• 
Kit dispensation without IRT transaction 
• 
Erroneous kit dispensation 
• 
Kit not available 
• 
Randomization by error 
• 
Participant randomized twice 
• 
Forced randomization 
• 
Stratification error 
• 
Participant switched to another site 
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 treatment 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 and participant characteristics 
The following demographics and participant characteristics will be summarized by study intervention 
group and overall, both for the ITT and 
sets: 
• 
Age (years) 
• 
Age category (≥18 to <40, ≥40 to ≤65, >65 years) 
• 
Gender (Male, Female) 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown), 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Not Reported, Unknown) 
• 
Baseline body weight (kg) 
• 
Baseline body weight category (<70, ≥70 to <100, ≥100 kg) 
• 
Baseline height (cm) 
• 
Baseline body mass index (BMI) (kg/m²) derived as: (Weight in kg)/(Height in meters)² 
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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 both for the ITT and
 analysis 
sets. The table will be sorted by internationally agreed order of primary SOC, and by alphabetical order of 
HLTs and PTs. Participants experiencing 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 analysis set. Atopic comorbidities 
will be identified via a file provided by Sanofi containing the following CMQ codes: CMQ10646, 
CMQ10440, CMQ10540, CMQ10541, CMQ10537, CMQ10076, CMQ10539, CMQ10538. 
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. 
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. 
 
A given medication can be classified as a prior medication as well as a concomitant 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. 
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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: 
• 
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. 
 
• 
Reliever medications summarized by medication type (SABA, systemic corticosteroids, other) and 
standardized medication name (see Section 15.10). 
Note: These medications are recorded in the Asthma reliever medication eCRF page. 
 
• 
Other prior medications. 
Note: These medications are recorded in the Other medication eCRF page. 
 
The prior prohibited medications will also be presented by prohibited medication category as defined in 
deviation and standardized medication name (see Section 15.10). 
 
7.1.2. Concomitant Medications 
Concomitant medications are any treatments received by the participant concomitantly to the IMP, starting 
from the date of 1st administration of IMP to the date of last administration + 14 days (boundary included).  
 
The following concomitant medications summaries will be generated separately by study intervention 
group: 
• 
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. 
 
• 
Reliever (rescue) medications summarized by medication type (SABA, systemic corticosteroids, 
other) and standardized medication name (see Section 15.10). 
Note: These medications are recorded in the Asthma reliever medication eCRF page. 
 
• 
Other concomitant medications. 
Note: These medications are recorded in the Other medication eCRF page. 
 
The concomitant prohibited medications will also be presented by prohibited medication category as 
defined in deviation and standardized medication name (see Section 15.10). 
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7.1.3. Post-treatment medications 
Post-treatment medications are those the participant took (continued or initiated) in the period running 
from the 15th day after the last administration of IMP up to the end of the study, based on Investigator’s 
decision. Post-treatment medications will not be summarized or presented in the CSR. 
7.2. Study Interventions 
The extents of IMP exposure and compliance will be assessed and summarized by actual study intervention 
group and overall using the safety analysis 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 dose administration date – first IMP dose administration 
date + 14 days, regardless of unplanned intermittent discontinuations. 
 
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: 
• 
>0 and ≤2 weeks 
• 
>2 and ≤4 weeks 
• 
>4 and ≤8 weeks 
• 
>8 and ≤12 weeks 
• 
>12 weeks 
 
and cumulatively according to the following categories: 
 
• 
≥1 day 
• 
>2 weeks 
• 
>4 weeks 
• 
>8 weeks 
• 
>12 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 for each 
study intervention group: 
• 
<80% 
• 
≥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 within the intended 
therapeutic interval (planned treatment period), adjusted according to the tested drug. 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. 
8. Efficacy Analysis 
All efficacy analyses will be performed on the ITT analysis set, except for that of the primary efficacy 
endpoint, which will employ the ITTp set. 
 
Participant will be analyzed for efficacy according to the study intervention group to which they are 
allocated by the IVRS according to the randomization schedule at the randomization visit (as randomized), 
irrespective of the study intervention actually received. 
 
For the analysis of primary objective in the treatment period,  
• 
The null statistical hypothesis tested is that there is no mean treatment difference between 
Dupilumab and placebo on sleep disturbance score in adult participants moderate-to-severe 
uncontrolled asthma and evidence of Type 2 inflammation. 
• 
The alternative statistical hypothesis tested is that there is a mean treatment difference between 
Dupilumab and placebo on sleep disturbance score in adult participants moderate-to-severe 
uncontrolled asthma and evidence of Type 2 inflammation 
 
Note that due to the small sample size of the 
, no statistical testing will be conducted for 
analyses in the
 analysis set. Summary statistics with 95% CI by study intervention group will be 
provided. 
 
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; for more details, refer to Table 2-2. 
 
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For efficacy endpoints where a change from baseline is assessed, only the participants who have a baseline 
and at least one post-baseline value available will be included in the analysis (number of participants 
included in the analysis model reported in the table). 
 
All daily assessments (i.e., asthma sleep disturbance questionnaire, sleep diary) will be analyzed as monthly 
averages, calculated from the 28 days immediately preceding (and including) the theoretical expected day 
of the study visit calculated from the day of first IMP intake (note that 28 days is a maximum and that it 
could be less, in case fewer assessments have been performed within the corresponding 28 days window). 
 
Although actigraphy parameters are assessed daily between Baseline (Day 1) and Week 4, they will be 
analyzed at each timepoint as weekly averages for the week immediately preceding the study visit, 
including the day of the visit (same approach for ADSD and ANSD as these data are collected only for each 
of the 7 days prior the visit [including the day of the visit only for ANSD]). 
 
The other efficacy parameters (spirometry, 
, PROMIS, ACQ-5, 
 
 and 
) will not use any of these approach since they are collected/measured a 
single time before or the day of the visit. 
 
Line plots for 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 
except for 
.  
 
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 will be provided. The p-value 
corresponding to the LS mean difference will be provided at Week 12 only. 
8.1. Primary Efficacy Endpoint 
The primary endpoint is change from baseline in sleep disturbance score at Week 12 assessed using the 
Asthma Sleep Disturbance Questionnaire. 
8.1.1. Primary Analysis 
 
Change from baseline in sleep disturbance score will be analyzed on the ITTp population using a MMRM 
approach under the Missing at Random (MAR) framework. The MMRM model will include study 
intervention (Dupilumab, Placebo), age, BMI, stratum (Eastern Europe with high ICS dose, Eastern Europe 
with medium ICS dose, rest of world [ROW] with high ICS dose and ROW with medium ICS dose), 
inclusion in 
, visit (up to Week 12), study intervention-by-visit interaction, baseline ACQ-
5, baseline sleep disturbance score and baseline-by-visit interaction as covariates. 
 
An unstructured correlation matrix will be used to model the within-participant errors covariances. 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 least square (LS) mean in change from baseline of each study intervention group, 
the LS means difference between the dupilumab and placebo groups, and the corresponding SEs and 95% 
CI will be provided at all scheduled visits. The p-value corresponding to the LS mean difference will be 
provided at Week 12 only. For participants discontinuing the study intervention before Week 12 not due to 
the COVID-19 pandemic, off-study intervention sleep disturbance scores measured up to Week 12 will be 
included in this analysis. In contrast, for any participants discontinuing the study intervention due to the 
COVID-19 pandemic, off-study intervention data will not be included (i.e., set to missing) but will be 
assumed missing at random.  
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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). 
8.1.4. Subgroup Analysis 
Primary analysis will be replicated for the following subgroups: 
- 
Age category (≥18 to <40, ≥40 years) 
- 
Gender (Male, Female) 
- 
Race (Not-White, White) 
- 
Baseline body weight (<70, ≥70 to <100, ≥100 kg) 
- 
Region (Eastern Europe, ROW) 
- 
Participants who had concomitant SCS rescue medications (identified with file provided by 
Sanofi containing CDGsn00010 medications)  (Yes, No) 
- 
Baseline ICS dose level (Medium, High) 
- 
Age of onset of asthma (<18, ≥18 to <40, ≥40 years)  
- 
Number of severe asthma exacerbation events (1, 2, >2) within 1 year prior to the study 
- 
Number of controller medications at study entry (2 , 3) 
- 
Smoking history (Former, Never) 
- 
Baseline 
 
 
- 
Baseline Eosinophils (<300, ≥300 cells/uL) 
- 
Baseline ACQ-5  
• 
(≤3, >3,) 
• 
(≤3.5, >3.5) 
- 
Participants with > 2 weekly average nocturnal awakenings at baseline (Yes, No) 
- 
Participants with Chronic rhinosinusitis with nasal polyps (CRSwNP) co-morbidities (Yes, 
No) 
 
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 primary endpoint of change from baseline in average sleep disturbance score 
at Week 12 will be carried out using an analysis of covariance model (ANCOVA) with data from multiple 
imputation (MI) on missing scores under an assumption of missing at random (MAR). Under this 
assumption, each missing score will be imputed 100 times and incorporated with non-missing data to 
form 100 complete datasets.  Each dataset will include average sleep disturbance score at Baseline, Week 
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4, Week 8, and Week 12, 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. 
 
• 
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 sleep disturbance score, minimum and maximum values will be specified in this 
imputation.  
• 
For each of 100 datasets with monotone missing pattern created from MCMC imputation, use 
monotone regression method to impute the remaining missing value by study intervention group 
up to Week 12. In the imputation regression model, age, BMI, stratum (Eastern Europe with high 
ICS dose, Eastern Europe with medium ICS dose, rest of world [ROW] with high ICS dose and 
ROW with medium ICS dose), inclusion in 
, baseline ACQ-5 score, and baseline 
sleep disturbance score, will be included as covariates. Change from baseline in sleep disturbance 
score at Week 12 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 
ANCOVA models. 
• 
Repeatedly perform ANCOVA modeling for each of 100 datasets with full imputation for missing 
values. Change from baseline in sleep disturbance score at Week 12 will be analyzed on the ITTp 
population in this ANCOVA model, and study intervention (Dupilumab, Placebo), age, BMI, 
stratum (Eastern Europe with high ICS dose, Eastern Europe with medium ICS dose, rest of world 
[ROW] with high ICS dose and ROW with medium ICS dose), inclusion in 
, baseline 
ACQ-5, and baseline sleep disturbance score as covariates. 
• 
The adjusted LS means 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% CI of 
the differences generated from the 100 ANCOVA models will be combined using Rubin’s 
formula and presented in a statistical table for the ITTp population. 
8.1.6. Supplementary Analyses 
As a supplementary analysis, the primary analysis will be replicated for the ITT population to investigate 
the robustness of the results. 
 
Similarly, the primary analysis will be repeated for the ITT population but excluding the first 19 
randomized participants, who were accidentally potentially unblinded to study team due to an issue with 
Interactive Response Technology (IRT), where study intervention arm was wrongly included in the IRT 
transfer to the IVRS library. 
 
The primary analysis will also be repeated for ITTp population but setting to missing any assessment 
performed the night following a prohibited medication intake (whichever the prohibited medication and 
half-life of the product).  
 
Lastly, the primary analysis will also be repeated for ITTp population but setting to missing any 
assessment performed after SCS intake. 
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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 interruptions and 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. Participant reported outcome data are not 
expected to be missing as they can be completed at the participant’s home on his/her electronic devices. 
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. 
 
Data missing due to the Covid-19 pandemic are likely to be MAR. 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 and Tertiary/Exploratory Efficacy Endpoints 
The secondary and tertiary efficacy endpoints associated with “Change from baseline” (except
, due to 
limited sample size) will be analyzed using the MMRM model in the same fashion as for the analysis of 
the primary endpoint (see Table 2-2) with the baseline values corresponding to the outcome variables. 
Adjusted LS means for each study intervention group, LS mean difference between the Dupilumab and 
placebo groups, and the corresponding SEs and 95% CIs will be provided for all endpoints (and p-value 
corresponding to the LS mean difference provided at Week 12 only). However, formal statistical testing 
will be performed only for the number of nocturnal awakenings and PROMIS t-score that will be performed 
in the frame of the hierarchical procedure considered to account for multiplicity issues (nominal two-sided 
p-value provided for descriptive purpose only for other secondary and tertiary endpoints). 
Further definitions of endpoints are included in Section 15.8 and Section 15.9. 
8.2.1. Sleep diary 
In addition to MMRM model, the number of nocturnal awakenings, sleep quality, restorative sleep, 
 
 WASO and
, all based on sleep diary data, will be summarized at baseline and each post-baseline 
visit (Week 4, Week 8, and Week 12). 
The number of nocturnal awakenings will be determined based on the answer on the question 3 from the 
sleep diary: “Approximately how many times did you wake up last night (not including when you woke up 
for the day today)?” 
8.2.2. Actigraphy data 
Duration and patterns of sleep (i.e., 
, WASO and 
) will be estimated through a device 
(Actiwatch)  worn on the wrist of the non-dominant hand of the participants, who will complete assessments 
from Day -11 to Day -1 (right before Day 1); daily assessment thereafter until Week 4; then only the week 
before a clinical visit until EOT.  
 
In addition to MMRM model, all actigraphy parameters will be summarized through descriptive statistics 
at baseline and each post-baseline visit (Week 4, Week 8, and Week 12). WASO will be summarized 
separately to other actigraphy endpoints. 
8.2.3. 
 
In addition to MMRM model, 
 will be summarized through descriptive statistics at baseline and each 
post-baseline visit (Week 4, Week 8, and Week 12). 
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9. Safety Analysis 
All safety results will be summarized using the Safety analysis set by actual study intervention group. 
 
The observation periods include: 
• 
The pre-treatment period is defined as the time from the signed informed consent date up to first 
administration of the IMP. 
• 
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 + 84 days or until the 
participant switches to commercialized dupilumab or other biologics  
• 
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: 
• 
Pre-treatment adverse events are adverse events that developed or worsened or became serious 
during the pre-treatment period. 
• 
Treatment-emergent adverse events are adverse events that developed or worsened or became 
serious during the TEAE period. 
• 
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 AE reporting will be on TEAEs.  Pre-treatment adverse events will be summarized 
separately. 
 
All AEs will be coded to a 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 15.4.4. 
 
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 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 or 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 
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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: 
• 
Any TEAE 
• 
Any study intervention related TEAE 
• 
Any Severe TEAE 
• 
Any Serious TEAE 
• 
Any TEAE leading to permanent study intervention discontinuation 
• 
Any TEAE of special interest 
• 
Any Serious TEAE of special interest 
• 
Any TEAE leading to death 
 
The overview summary for TEAEs will be provided on the safety analysis 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: 
• 
Any AE 
• 
Any Severe AE 
• 
Any Serious AE 
• 
Any AE of special interest 
• 
Any Serious AE of special interest 
• 
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 analysis set. 
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 (i.e., 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 summaries will be generated for the safety analysis set, for each study intervention group. 
• 
All TEAEs presented by primary SOC, HLGT, HLT, and PT, showing the number and 
percentage of participants with at least 1 TEAE 
• 
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 
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• 
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  
• 
All pre-treatment AEs presented by primary SOC and PT, showing number and percentage of 
participants with at least 1 pre-treatment AE 
• 
All TEAEs presented by primary SOC and PT, showing number and percentage of participants 
with at least 1 TEAE  
• 
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 
• 
Common TEAEs (PTs with an incidence ≥ 5% in any study intervention group) by primary 
SOC, HLGT, HLT, and PT 
9.1.2. Relationship of Adverse Events to Study Intervention 
The following TEAE summaries will be generated for the safety analysis set, for each study intervention 
group. 
• 
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 summaries will be generated for the safety analysis set, for each study intervention 
group. 
• 
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 (i.e., mild, moderate, severe). 
9.1.4. Serious Adverse Events 
The following TEAE summaries will be generated for the safety analysis set, for each study intervention 
group. 
• 
All serious TEAEs presented by primary SOC, HLGT, HLT and PT, showing the number and 
percentage of participants with at least 1 serious TEAE  
• 
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 summaries will be generated for the safety analysis set, for each study intervention 
group. 
• 
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: 
• 
Anaphylactic reactions 
• 
Systemic hypersensitivity reactions 
• 
Helminthic infections 
• 
Keratitis 
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• 
Any severe type of conjunctivitis or blepharitis 
• 
Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms) 
• 
Significant alanine transaminase (ALT) elevation: 
o ALT >5X the upper limit of normal (ULN) in participants with baseline ALT ≤2X ULN  
(“Baseline” refers to ALT sampled at baseline visit or, if baseline value is unavailable, to 
the latest ALT value before the baseline visit) 
or 
o ALT >8X ULN if baseline ALT >2X 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 
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 
• 
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 following TEAE summaries will be generated for the safety analysis set, for each study intervention 
group. 
• 
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. 
• 
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 summaries will be generated for the safety analysis set, for each study intervention 
group. 
• 
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 for the safety analysis set, for each study 
intervention group.  
• 
Number and percentage of participants who died during the trial by study period (i.e., on study, 
pre-treatment period, TEAE period, post-treatment period, and post-study). 
• 
Number and percentage of participants who died during the trial by cause of death. 
• 
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). 
 
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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: 
 
• 
Hematology: blood eosinophil count 
• 
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); hepatitis C virus antibodies (HCVAb). 
• 
Human Immunodeficiency Virus screening (Anti-HIV-1 and HIV-2 antibodies). 
• 
Tuberculosis test performed only 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 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 
and week 12). 
9.3. Vital Sign Measurements 
Vital signs including weight, heart rate (HR), sitting systolic (SBP) and diastolic blood pressure (DBP), 
temperature and respiration 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 for the safety analysis set by study intervention group using 
descriptive statistics and for each visit or study assessment (baseline, each-post-baseline time point, last on-
treatment value). 
 
The Potentially Clinically Significant Abnormalities (PCSA) at any time during the TEAE period will be 
summarized for the safety analysis set by study intervention group, 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 in the safety analysis set who 
have at least 1 assessment performed during the TEAE period. 
 
A listing of participants with at least 1 post-baseline PCSA will be provided and will display the 
participants’ profile over time of all vital sign parameters. 
 
Individual data listings will include the following flags: 
• 
Baseline values will be flagged “B”, 
• 
Parameter values reaching a PCSA limit will be flagged (+, or - depending on the direction). 
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13. Changes in the Planned Analysis 
13.1. Nocturnal Awakenings Average 
Protocol specifies that the analysis of the Change from Baseline on average number of nocturnal 
awakenings from Sleep Diary data is to be performed on a weekly average. In final analysis this will be 
performed on a monthly average (28 days preceding the visit).  
13.2. Study Intervention Discontinuation Due to Covid-19 Handling in Primary 
Analysis 
Protocol states that in MMRM analysis of the primary endpoint, participants discontinuing study 
intervention prior to Week 12 will have all data included as part of the model, including off study 
intervention sleep disturbance scores. In SAP it is clarified that participants who experienced study 
intervention discontinuation due to Covid-19 pandemic will have off-study intervention sleep disturbance 
data set to missing and not included in the model.  
13.3. Safety Analysis Set 
The definition of the safety analysis in the protocol has been expanded in the SAP to only include 
randomized participants. 
 
 
 
 
 
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14. References 
 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: A 
practical guide with examples. StatMed. 2010; DOI: 10.1002/sim.4102 
 
Luyster FS, Teodorescu M, Bleecker E, Busse W, Calhoun W, Castro M, et al. Sleep quality 
and asthma control and quality of life in non-severe and severe asthma. Sleep Breath. 
2012;16(4):1129-37. 
 
Sundbom F, Malinovschi A, Lindberg E, Almqvist C, Janson C. Asthma control and asthma 
severity in relation to sleep disturbances: results of the lifegene study. Eur Respir J. 
2018;52:PA5046. 
 
Aldrich M. Impact, presentation and diagnosis. In: Kryger MH, Roth T, Dement WC, editor. 
Principles and practice of sleep medicine. 3rd ed. Philadelphia (PA): W.B. Saunders Co.; 
2000. p. 521-80. 
 
Engleman HM, Kingshott RN, Martin SE, Dougles NJ. Cognitive function in the sleep 
apnea/hypopnea syndrome. Sleep. 2000;23 Suppl 4:S102-8. 
 
Kim HC, Young T, Matthews CG, Weber SM, Woodward AR, Palta M. Sleep disordered 
breathing and neuropsychological deficits: a population-based study. Am J Crit Care Med. 
1997;156(6):1813-9. 
 
Curcio G, Ferrara M, De Gennaro L. Sleep loss, learning capacity and academic performance. 
Sleep Med Rev. 2006;10(5):323-37. 
 
Smaldone A, Honig JC, Byrne MW. Sleepless in America: inadequate sleep and relationships 
to health and well-being of our nation's children. Pediatrics. 2007;119 Suppl 1:S29-37. 
Greenberg H, Cohen RI. Nocturnal asthma. Curr Opin Pulm Med. 2012;18(1):57-62. 
 
Clark TJ, Hetzel MR. Diurnal variation of asthma. Br J Dis Chest. 1977;71(2):87-92. 
 
Storms WW, Bodman SF, Nathan RA, Byer P. Nocturnal asthma symptoms may be more 
prevalent than we think. J Asthma. 1994;31(4):313-8. 
 
Sorscher AJ. How is your sleep: A neglected topic for health care screening. J Am Board Fam 
Med. 2008;21(2):141-8. 
 
Mastronarde JG, Wise RA, Shade DM, Olopade CO, Scharf SM, American Lung Association 
Asthma Clinical Research Centers. Sleep quality in asthma: results of a large prospective 
clinical trial. J Asthma. 2008;45(3):183-9. 
 
Cukic V, Lovre V, Dragisic D. Sleep disorders in patients with bronchial asthma. Mater 
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Sociomed. 2011;23(4):235-7. 
 
Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper type 2- 
driven inflammation defines major subphoenotypes of asthma. Am J Respir Crit Care Med. 
2009;180(5):388-95. 
 
Castro M, Corren J, Pavord I.D, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy 
and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018;378:2486-96. 
 
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. 
 
Morphy H, Dunn KM, Lewis M, Boardman HF, Croft PR. Epidemiology of insomnia: a 
longitudinal study in a UK population. Sleep. 2007;30(3):274-80. 
 
Fortier-Brochu E, Beaulieu-Bonneau S, Ivers H, Morin CM. Insomnia and daytime cognitive 
performance: a meta-analysis. Sleep Med Rev. 2012;16(1):83-94. 
 
Lian Y, Xiao J, Liu Y, Ning L, Guan S, Ge H, et al. Associations between insomnia, sleep 
duration and poor work ability. J Psychosom Res. 2015;78(1):45-51. 
 
Sanz de Burgoa V, Rejas J, Ojeda P, investigators of the Coste Asma study. Self-perceived 
sleep quality and quantity in adults with asthma: findings from the costeasma study. J Investig 
Allergol Clin Immunol. 2016;26(4):256-62. 
 
Stone KL, Xiao Q. Impact of Poor Sleep on Physical and Mental Health in Older Women. 
Sleep Med Clin. 2018;13(3):457-65. 
 
Scott D, Paterson JL, Happell B. Poor sleep quality in Australian adults with comorbid 
psychological distress and physical illness. Behav Sleep Med. 2014;12(4):331-41. 
Braido F, Baiardini I, Ferrando M, Scichilone N, Santus P, Petrone A, et al. The prevalence of 
sleep impairments and predictors of sleep quality among patients with asthma. J Asthma. 
2020;12:1-7. 
 
Smith MT, McCrae CS, Cheung J, Martin JL, Harrod CG, Heald JL, et al. Use of Actigraphy 
for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An 
American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE 
Assessment. J Clin Sleep Med. 2018;14(7):1209-30. 
 
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. 
 
Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C, et al. 
Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data 
from the optimum patient care research database and the British Thoracic Difficult Asthma 
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Registry. Thorax. 2016;71(4):339-46. 
 
Global Initiative for Asthma. 2020 GINA report. Global strategy for asthma management and 
prevention. 2020. 
 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005;26(2):319-38. 
 
Gater A, Nelsen L, Fleming S, Lundy J.J, Bonner N, Hall R, et al. Assessing asthma 
symptoms in adolescents and adults: qualitative research supporting development of the 
Asthma Daily Symptom Diary. Value Health. 2016;9:440-50. 
 
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. 
 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-65. 
 
Chen H, Blanc PD, Hayden ML, Bleecker ER, Chawla A, Lee JH, et al. Assessing 
productivity loss and activity impairment in severe or difficult-to-treat asthma. Value Health. 
2008;11(2):231-9. 
 
Turner-Warwick, M. Epidemiology of nocturnal asthma. Am J Med. 1988;85(1B):6-8. 
 
Catterall JR, Douglas NJ, Calverley PM, Brash HM, Brezinova V, Shapiro CM, et al. Irregular 
breathing and hypoxaemia during sleep in chronic stable asthma. Lancet. 1982;1(8267):301-4. 
 
Montplaisir J, Walsh J, Malo JL. Nocturnal asthma: features of attacks, sleep and breathing 
patterns. Am Rev Respir Dis. 1982;125(1):18-22. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report - 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7. 
 
Juniper E. Asthma control questionnaire: Background, administration and analysis. 2021; QOL 
Technologies, West Sussex, UK. 
 
PROMIS Patient-Reported Outcomes Measurement Information System. PROMIS – Sleep-
Related Impairment. 2020. 
 
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15. Appendices 
15.1. 
Summary of Statistical Analyses 
 
Endpoint 
Analysis 
Set 
Primary 
analysis 
Sensitivity and Supportive 
analysis 
Subgroup 
analysis 
 Estimands 
Primary endpoint 
 
 
 
 
 
Sleep Disturbance score: change 
from baseline to week 12 
(Dupilumab, placebo) 
ITTp 
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 of 
Primary analysis four times: one for 
ITT population and one for ITT 
population excluding first 19 
randomized participants due to IRT 
issue, one for ITTp population 
setting to missing any assessment 
performed the night following a 
prohibited medication intake, and 
one for ITTp population setting to 
missing any assessment performed 
after SCS intake. 
Yes 
Yes 
Secondary endpoints 
 
 
 
 
 
Continuous variables 
ITT 
Same approach as primary 
endpoint 
No 
No 
Yes (only for 
secondary 
endpoints 
included in the 
hierarchical 
testing 
procedure) 
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Endpoint 
Analysis 
Set 
Primary 
analysis 
Sensitivity and Supportive 
analysis 
Subgroup 
analysis 
 Estimands 
Tertiary/Exploratory endpoints 
 
 
 
 
 
15.2. 
Schedule of Study Procedures 
 
 
 
 
 
 
 
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i 
Retesting of eosinophil count is allowed up to three times during the screening period to meet inclusion criteria for showing eosinophil count ≥150 cells/microliter cells/mL (details in 
Protocol I 04) before randomization. This is only required if the participant doesn’t have the blood eosinophil count measured within 6 months prior to SV1 in the absence of OCS 
treatment.  
j 
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. On Day 1, loading dose as follows: 400 mg dupilumab for the dupilumab arm (200 mg x 2 
syringes injections) and 2 placebo syringes for the placebo arm.  
k Should be completed by participants regularly to record investigational (home dosing diary) and non-investigational (asthma background therapy diary) product information. Recorded 
data will be collected by the investigator at each on-site visit.  
l 
Retesting of 
can be performed one additional time during screening if the eligibility criterion for 
 was not met at SV1. 
 will be re-checked at randomization visit (V2) 
for eligibility. It will be performed after a wash-out period of bronchodilators according to their action duration.  Further details on the procedure will be provided in a separate instruction 
manual.  
m Spirometry test should be performed before IMP administration, in the morning if possible. 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. 
This will be verified before performing the measurements. For spirometry the investigator will assess the eligibility based on the FEV1 local values from SV1 and Visit 2 before 
randomization (the results from central reading will not be available on the same day). Further details on the procedure will be provided in a separate instruction manual.   
n A participant who is unable to complete a successful spirometry effort as defined by 2005 ATS criteria or evaluated by the investigator can be retested one additional time during the 
screening period of the study.  
o Actigraphy: The participants will complete baseline assessments from Day -11 to Day -1 (right before Day 1); daily assessment thereafter until Week 4; then only the week before a 
clinical visit until EOT. Baseline value will be calculated using the data from Day -7 to Day -1.  
p 
 
 
  
q Each participant in this substudy will have a total of 2 overnight 
 1 overnight 
 using Type II home devices on Day -1 to collect baseline data and 1 more at Week 12. If the 
sleep recording is inadequate as judged by the central reading site, the at-home sleep assessment will be repeated within 1 week of the original assessment.  
ACQ-5: Asthma Control Questionnaire-5; 
 AD: atopic dermatitis; ADSD: Asthma Daytime Symptoms Diary; AE: adverse event; AESI: adverse 
event of special interest; ALT: alanine transaminase; ANSD: Asthma Nighttime Symptoms Diary; 
 
ATS: American Thoracic Society; BD: bronchodilator; CRSw/sNP: chronic rhinosinusitis with/without nasal polyps; D: day; E/D: early discontinuation; ECG: electrocardiogram; EOS: end 
of study; EOT: end of treatment; ESD: early study discontinuation; ETD: early treatment discontinuation; 
 FEV1: forced expiratory volume; HBcAB: 
hepatitis B core antibody; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HCVAb: hepatitis C virus antibody; HIV: human immunodeficiency virus; 
IMP: investigational medicinal product; IVRS: interactive voice response system; IWRS: interactive web response system; OCS: oral corticosteroid; 
 
; PRO: patient-reported outcome; PROMIS: patient-reported outcome measurement information system; 
; 
; RNA: ribonucleic acid; SAE: serious adverse event; TB: tuberculosis; W: week; F WOCBP: woman of childbearing potential; 
 
 
 
 
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15.3. 
Missing Efficacy Data 
ADSD and ANSD 
 
Global score to be calculated if both conditions meet 
• 
There are at least 4 items (out of 6) available at each day. 
• 
There are at least 4 days available to calculate the average weekly score. For post baseline visits, if 
less than 4 measurements are available from the 7 days prior the visit [including the day of the visit 
for ANSD]), the most recent 4 measurements from the 11 days prior the visit will be used for the 
calculation; if finally, less than 4 measurements are available, it will be considered as missing. 
 
 
• 
A given score cannot be calculated if there is at least one response used for the calculation that is 
missing. 
• 
Responses from other assessments should not be used to impute missing data.  For example, if a 
participant indicated that he worked 40 hours at one assessment, but left that question blank on 
another assessment, the blank response should remain missing. 
• 
If the participant entered a range of hours, the midpoint should be considered for the analysis. 
 
Asthma Control Questionnaire 
 and ACQ-5) 
 
• 
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. 
 
 
 
• 
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. 
Other Participant-Reported Outcomes 
For all other questionnaires, if one or more questions are left unanswered, the questionnaire is not scored. 
No imputation will be made for the missing values. 
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. 
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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. 
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 treatment or after the 
treatment 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. 
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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). 
 
Table 15-1 Analyses window definition 
 
Scheduled 
visit  
post 
baseline 
 
Targeted  
study 
day* ** 
 
 
 
 
/Weight/ 
Eosinophil 
parameters 
 
parameter 
Diary data 
(Asthma sleep 
disturbance 
questionnaire/ 
Sleep diary) 
All other 
parameters  
Week 4 
(Visit 3) 
29 
 
[2, 56] 
[2, 29] 
[2, 42] 
Week 8 
(Visit 4) 
57 
 
 
[30, 57] 
[43, 70] 
Week 12 
(Visit 5) 
85 
[2, ∞] 
[57, ∞] 
[58, ∞] 
[71, ∞] 
* 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). 
** For actigraphy data as well as for ADSD/ANSD parameters, each post-baseline assessment will be 
allocated to a scheduled visit, taking into account the day of the corresponding actual visit on site. For 
other parameters (daily collected or collected once per visit) each post-baseline assessment will be allocated 
to a scheduled visit, taking into account the day of the assessment. 
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 (i.e., 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 15-2 Search Criteria for AESI 
AESI 
Search Criteria 
Anaphylactic reactions 
SMQ: Anaphylaxis [Narrow] 
Systemic hypersensitivity reactions 
SMQ: Hypersensitivity [Narrow] 
Helminthic infections 
HLTs of “Helminthic infections NEC” 
Keratitis 
PTs of 
• 
Keratitis, Allergic keratitis 
• 
Ulcerative keratitis 
• 
Atopic keratoconjunctivitis 
• 
Herpes ophthalmic 
• 
Ophthalmic herpes simplex 
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Any severe type of conjunctivitis or blepharitis 
1. Narrow conjunctivitis is defined as the 
following PTs 
• 
Conjunctivitis 
• 
Conjunctivitis allergic 
• 
Conjunctivitis bacterial 
• 
Conjunctivitis viral 
• 
Atopic Keratoconjunctivitis 
 
2. Broad conjunctivitis is defined as the 
following PTs 
• 
Conjunctivitis, Conjunctivitis allergic 
• 
Conjunctivitis bacterial 
• 
Conjunctivitis viral 
• 
Atopic Keratoconjunctivitis 
• 
Blepharitis 
• 
Dry eye 
• 
Eye irritation 
• 
Eye pruritus 
• 
Lacrimation increased 
• 
Eye discharge 
• 
Foreign body sensation in eyes 
• 
Photophobia, Xerophthalmia 
• 
Ocular hyperaemia 
• 
Conjunctival hyperaemia 
 
3. Conjunctivitis is defined as the following 
PTs 
• 
Conjunctivitis 
• 
Non-infective conjunctivitis 
• 
Conjunctivitis allergic 
• 
Conjunctivitis bacterial 
• 
Conjunctivitis viral 
• 
Eye irritation 
• 
Eye inflammation 
 
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” 
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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” 
 
 
 
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15.7. 
Potentially Clinically Significant Abnormalities (PCSA) Criteria 
Table 15-3 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 Sleep Disturbance Questionnaire 
The Asthma Sleep Disturbance Questionnaire is a PRO measure designed to assess the impact of asthma 
on participants’ sleep. Scores range between 0 to 4 with 0 indicating no impact of asthma on sleep and 4 
indicating higher impact of asthma on sleep. 
Participants will be instructed to record the severity of the disturbance of their sleep due to asthma as 
follows: 
• 0 = Slept through the night, no asthma symptoms, 
• 1 = Slept well, no nighttime awakenings because of asthma, but some asthma symptoms in the 
morning, 
• 2 = Woke up once because of asthma (may or may not include early awakening), 
• 3 = Woke up several times because of asthma (may or may not include early awakening), 
• 4 = Bad night, awake most of the night because of asthma. 
The participants will record their sleep disturbance in an electronic diary, once a day upon awakening. 
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standardized score with a mean of 50 and a standard deviation of 10. Therefore, a person with a T-score of 
40 is one SD below the mean. The standardized T-score is reported as the final score for each participant.  
 
Table 15.8.1 PROMIS Sleep-Related Impairment conversion table 
Raw Score 
T-score 
Raw Score 
T-score 
8 
30 
25 
60.3 
9 
35.1 
26 
61.3 
10 
38.7 
27 
62.3 
11 
41.4 
28 
63.3 
12 
43.6 
29 
64.3 
13 
45.5 
30 
65.3 
14 
47.3 
31 
66.3 
15 
48.9 
32 
67.3 
16 
50.3 
33 
68.4 
17 
51.6 
34 
69.5 
18 
52.9 
35 
70.7 
19 
54 
36 
71.9 
20 
55.1 
37 
73.3 
21 
56.1 
38 
75 
22 
57.2 
39 
76.9 
23 
58.2 
40 
80 
24 
59.3 
 
 
 
 
PROMIS score will be directly provided by CLARIO. 
Sleep diary 
Collected daily including 11 days immediately preceding the baseline visit (V2), and daily for 12 weeks 
(until end of study intervention). 
A sleep diary is designed to gather information about participant’s daily sleep pattern. Participants are 
instructed to complete all questions upon awakening each day.  
The Sleep Diary is composed of seven generic, participant-reported questions that assess sleep concepts of 
relevance and importance to adults who report sleep disturbance due to asthma. 
The Sleep Diary features two subjective, participant-rated items that use a 0-to-10 NRS to assess sleep 
quality and feeling rested upon awakening (i.e., restorative sleep). Additional items include the participant-
estimated initial sleep attempt time and sleep onset time, number of nighttime awakenings after sleep onset, 
total time spent awake after sleep onset, and wake time the next day. All questions except the one about 
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Spirometry 
 
A spirometer that meets the 2005 ATS/European Respiratory Society (ERS) recommendations will be used. 
Spirometry should be performed in accordance with these recommendations. 
For prebronchodilator measured parameters, including FEV1 and forced vital capacity (FVC), spirometry 
will be performed before IMP administration and after withholding the standard of care asthma treatment 
as detailed in the clinical trial protocol which will be verified before performing the measurements. 
 
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 
spirometer provided by the service provider should be used 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 if possible. If the testing was made with 
the participant 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 each 
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 from all of the acceptable curves have 
been examined, 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 
participant is seen and subjected to spirometry. The calibration records should be kept in a reviewable log. 
It is preferred that the equipment that is used to calibrate the spirometer (ie, 3-liter syringe) 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 who 
didn’t meet the eligibility criterion at SV1 can be retested one additional time during the screening period 
of the study. The spirometry will be centrally read. 
 
Spirometry data will be provided by CLARIO. 
 
Reversibility test 
 
A reversibility test will be administered following pulmonary function testing after asthma medications 
have been withheld for the appropriate intervals. Participants will receive 2 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 reversibility at SV1, up to 3 repeat 
attempts can be performed at any time during screening, prior to the randomization visit (Visit 2). This is 
only required if a reversibility test meeting eligibility criterion was not performed within 6 months prior to 
SV1. 
 
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• 
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)* 
• 
Live (attenuated) vaccine** 
• 
Sedative, anxiolytic, or hypnotic treatments (including melatonin) 
• 
Systemic sedative antihistamines (except the newer generations of antihistamines like cetirizine, 
loratadine and fexofenadine) 
• 
Theophylline 
• 
Lipophilic beta blockers, Opioids, Clonidine, Antidepressants or other medications known to 
interfere with sleep*** 
* For participants recruited before protocol amendment 1, systemic corticosteroids intake is considered as 
prohibited. For other participants, systemic corticosteroids used to treat an asthma exacerbation are 
allowed and recorded (i.e., considered as rescue medication, not prohibited). 
** Also considered as prohibited after the last IMP intake, up to the end of the study. 
*** Note: In most cases, chronic treatments administered regularly and at stable dosing are acceptable. 
Investigators should assess the degree to which an individual medication may cause changes in sleep pattern 
or sleep quality during the study, compared to the pre-baseline state. 
 
 
 
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ADDENDUM TO STATISTICAL ANALYSIS PLAN FOR LPS16677  
The SAP was approved in February 2022.  Due to data issues detected during the course of the study, this 
addendum provides additional data handling rules not included in the SAP approved.  
#1 In Section 15.8 of SAP: Handling rule of duplicates records for daily questionnaires  
There are many duplicate records for daily questionnaires remotely completed by phone (Asthma sleep 
disturbance questionnaire/sleep diary/ANSD/ADSD). The duplicates (same participant, question, date, 
but with different time/answer provided) will have to be managed at ADaM level. 
The rule to select the most appropriate record is as the followings: 
1. To select the most frequently recorded response for a given patient/question/day. 
2. If it does not enable to identify a unique response (eg, 2 different answers submitted 2 times), 
then the earliest submission (based on recorded time) will be selected. 
 
#2 In Section 15.8 of SAP: Handling of Sleep Diary Data 
Sleep diary is one of the PRO questionnaires in LPS16677 with the following questions: 
1: Select the number that best describes the quality of your sleep last night 
2a: Approximately what time did you start trying to fall asleep last night? 
2b: Approximately what time did you fall asleep last night? 
3. Approximately how many times did you wake up last night (not including when you woke up 
for the day today)? Record “0” if you do not remember waking up last night. 
4. Considering all the times you woke up last night, how much time were you awake in total? 
Record “0” if you do not remember waking up last night. 
5: At what time did you wake up for the day today? 
6. Select the number that best describes how rested you felt when you got up for the day today. 
 
During the ongoing blinded data review, illogical/inconsistent responses to these questions have been 
identified within the same participant and questionnaire submission. For example, time falling asleep is 
recorded to occur before trying to fall asleep, time waking up is recorded to occur before time of falling 
asleep, total sleep time is recorded as being longer than the time in bed, etc.  
In order to remove the illogical responses in the derivation of sleep related endpoints, the following rules 
will be applied:  
A. For questions related to previous night (2a and 2b), if the recorded time lies between 12:00 and 
23:59 then set the date equal to the day before the questionnaire was completed.  Otherwise set 
date equal the day questionnaire was completed.  
B. Additionally, the following conditions will be checked: 
1. “Date/Time Did You Wake Up Today” must be equal or later than “Date/Time Fall Asleep 
Last Night” 
2. “Date/Time Did You Wake Up Today” must be later than “Date/Time Try Fall Asleep Last 
Night” 
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3. “Date/Time Did You Wake Up Today” minus “Date/Time Fall Asleep Last Night” must be 
equal or greater than WASO which is “Time awake after initial sleep onset but before the 
final awakening” and is the response to Question 4. 
4. “Date/Time Fall Asleep Last Night” must be equal or later than “Date/Time Try Fall Asleep 
Last Night” 
5. WASO is equal or greater than zero. 
If any of the above conditions fail, then the data collected on that day will not be considered in the 
derivations.    
Once the above rules are applied, the following parameters will be derived (except for WASO which is 
collected directly from the questionnaire) and used for analysis: 
WASO = Wake After Sleep Onset = Time awake after initial sleep onset but before the final 
awakening 
 
 
 
 
 
#3 The team noted some typo in PROMIS conversion table (raw-score to t-score) in the section 15.8 of 
SAP for LPS16677 – Morpheo study. 
 
Please see corrections below: 
• 
Raw-score = 9 => t-score = 35.2 
• 
Raw-score = 37 => t-score = 73.4 
• 
Raw-score = 40 => t-score = 80.1 
 
#4 In section 8.1.4, it is indicated that SCS rescue medications will be identified using CDGsn00010.  The 
medical team discussed this point, and finally decided to use ATC code to identify SCS from rescue 
medication page (Asthma Reliever page) to keep consistency with section 15.10 (ie, CDGsn00010 will 
finally not be used). 
 
#5 Asthma Control Questionnaire (
 and ACQ-5) in section 15.3: 
In the final approved SAP, it is indicated that if only one question has missing score, it will be 
interpolated following the example below:  
(Sum of score at Visit 4/sum of scores excluding question 5 at Visit 3) × score of question 5 at 
Visit 3. 
This will be done, except in rare cases where the sum of scores excluding the missing question at the 
previous visit is 0. In that case, the missing question will not be imputed at the current visit. 
#6 The final SAP approved in February 2022 was developed based on Amended Protocol 1, Version 1.0  
dated September 17th, 2020. Contents of final approved SAP Section 13 reflects the changes performed in 
SAP compared to this amended protocol 1. After the SAP has been signed, a new protocol amendment 
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was performed (Amended Protocol 2, Version 2.0, dated September 26th 2022). All the changes 
mentioned in Section 13 from SAP have been implemented in this amended protocol v2.0. 
 
#7 
 If multiple records are available for a same participant at the same date, the earliest record 
(based on recorded time) will be used for the analysis. 
 
#8 No further analyses are planned for patients recruited by Metasite (Science37) mentioned in protocol 
amendment v2.0. 
 
#9 The following modifications of prohibited medications identification rules (Section 15.10) will be 
implemented based on medical team review: 
1. Any medication that started after the EOT visit is not prohibited except for the Live (attenuated) 
vaccines that are prohibited until the EOS visit. 
2. Blinded medical review will be conducted in order to confirm (or not) prohibited status for those 
medications identified as prohibited using programming rules. Only the medications confirmed as 
prohibited during the medical review will be presented in the analysis. 
In those tables (both prior and concomitant prohibited medications), “Medication type" is determined as 
per CDG (ie, 1 CDG = 1 “Medication type”).  
 
#10 The following modifications of AESI identification rules will be implemented  
1. Anaphylactic reactions: includes anaphylactic reaction using CMQ name CMQsn00021 and 
programmatic identification of cases based on occurrence of at least two events meeting the 
algorithm criteria occurring within 2 consecutive days of each other.  The latter cases identified 
using the algorithm will undergo blinded medical review taking into account the timing of events 
relative to each other and to IMP administration for final determination of an anaphylactic 
reaction or not. 
2. Systemic hypersensitivity reactions: CMQ name CMQsn00214 and [AE corrective 
treatment/therapy=’Y’ or Action taken with IMP=’Drug withdrawn’ or Action taken with 
IMP=’Drug interrupted’] followed by blinded medical review (documented process) for selection 
of relevant systemic hypersensitivity events 
3. Any severe type of conjunctivitis or blepharitis: Based on the CMQ names CMQ10498 and 
CMQ10497 with “Severe” ticked in Adverse Events eCRF page. 
4. Helminthic infections: Based on CMQ name CMQ10548. 
5. Keratitis: Based on CMQ name CMQ10642. 
6. Clinically symptomatic eosinophilia: based on CMQ name CMQ10641 followed by blinded 
medical review (documented process) for selection of relevant eosinophilia events. 
7. ALT increase: based on the CMQ names CMQ00029 with the addition of “Is the event an AESI” 
answered YES on AE eCRF as reported by the investigator. 
For AESI Anaphylactic reactions, Clinically symptomatic eosinophilia and Systemic hypersensitivity 
reactions: blinded medical review will be conducted in order to confirm (or not) AESI status for those 
AEs identified as AESI using programming rules. Only the AEs confirmed as AESI during the 
medical review will be presented in the analysis. 
 
#11 The codelist to identify Atopic comorbidities is updated, CMQs CMQ10440, CMQ10539 and 
CMQ10538 have been replaced by CMQ10799 and CMQ10800 to get more appropriate terms. 
 
#12 In accordance with the general changes made to all Dupi studies, the following changes are made: 
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1. TEAE period is defined as the time from the first administration of the IMP to the last 
administration of the IMP + 98 days (instead of 84 days in Section 9 from approved SAP); 
2. Concomitant medication is defined as any treatments received concomitantly to the IMP, starting 
from the date of first IMP administration to the date of last administration + 98 days (instead of 
14 days in Section 7.1.2 from approved SAP). 
 
#13 As stratification factors are generally used separately in modeling, both Region (Eastern Europe, rest 
of world [ROW]) and baseline ICS Dose (high, medium) variables will be included separately in all 
MMRM models to replace the single variable of stratum (Eastern Europe with high ICS dose, Eastern 
Europe with medium ICS dose, ROW with high ICS dose and ROW with medium ICS dose). 
#14 As only 1 participant has been recruited in 
, inclusion in 
 (YES/NO) is 
removed from the covariate list in all analytic models. Also, 
data will be presented as listings instead 
of being summarized through descriptive statistics. 
#15 Section 8.2, qualitative descriptive analysis by visits showing number/proportion of participants in 
each category will be displayed for 
 (“Poor”, “Fair”, “Good”, “Very good”, “Excellent”), 
 
(“very much better”, “moderately better”, “a little better”, “no change”, “a little worse”, “moderately 
worse”, “very much worse”) and 
 (adequately controlled [score <= 1.0], inadequately controlled 
[score > 1]).  
#16 Section 15.8, under Asthma Control Questionnaire (
 and ACQ-5), MCID is not an appropriate 
wording, thus the following clarifications revisions are made.  
• 
“On the 7-point scale of the 
, 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” is replaced by “On the 7-point scale of the 
 
a change or difference in score of 0.5 represents the within-patient change that can be considered 
clinically meaningful”. 
• 
“On the 7-point scale of the ACQ-5, a change or difference in score of 0.5 is the smallest change 
that can be considered clinically important, corresponding to the MCID” is replaced by “On the 
7-point scale of the ACQ-5, a change or difference in score of 0.5 represents the within-patient 
change threshold that can be considered clinically meaningful. 
#17 Section 8.1.4 Subgroup Analysis, listed subgroups may be combined due to small sample size or 
modified based on actual data collected. For instance, number of severe asthma exacerbation events (1, 
2, >2) within 1 year prior to the study will be combined into 2 subgroups (1, >=2) instead of the proposed 
3 subgroups; number of controller medications at study entry will be modified from (2, 3) to (2, >=3) to 
include participants who used more than 3 controllers.  
#18 For the Participant 
 recruited in 
, stratification factors entered into the 
IVRS system (Region = “All” / ICS dose = “All”) do not match with expectations and do not enable to 
include the participant in the analyses as appropriate.  In order to fix this issue and include this participant 
in the analyses, new specific variables will be derived for Region and ICS dose:   
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• 
For the participant 
: Based on external file provided by sponsor (in which Region 
and ICS dose level are determined according to information recorded in the database)  
• 
For all other participants: Based on values recorded in IVRS.  
 
 
#19 Section 5.2 Protocol deviations. The following modification will be made: Category “potentially 
impacting efficacy” removed and category “Impact due to war in Ukraine” added.   
The paragraph “All critical or major protocol deviations potentially impacting efficacy analyses 
(including randomization and drug-dispensing irregularities; see Table 5-1 Randomization and drug 
dispensing irregularities), 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.” is replaced by “All critical or major 
protocol deviations (including randomization and drug-dispensing irregularities; see Table 5-1 
Randomization and drug dispensing irregularities) will be summarized overall and according to COVID-
19 impact (i.e., deviations related to COVID-19 pandemic) as well as impact due to war in Ukraine for 
the ITT analysis set by study intervention group and overall using number and percentage.”  
#20 Section 7.2.1 Extent of exposure. As definition for duration of exposure is taking into account last 
IMP + 14 days, the analysis by categories will be modified to capture appropriately the participants that 
took their treatment up to the end. The category “> 12 weeks” will be replaced by “>12 and <=14 weeks” 
and “>14 weeks” (and in cumulative analysis, category “>14 weeks” will be added)  
#21 Section 5.1 Disposition. In the approved SAP, it is written: “A summary table to show participant 
disposition by visit according to trial impact (disruption) due to COVID-19 (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”. 
To avoid confusion with participants included in the subgroup [trial impact (disruption) due to 
COVID-19], it should be replaced as follows: “A summary table to reflect COVID-19 impact at each visit 
(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”. And title of the corresponding table updated 
accordingly. 
 
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16.1.9.2 Other supporting statistical documentation 
Not applicable since LPS16677 statistical documentation consists of SAP only.   
 
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