A Randomized, Double-blind, Placebo-controlled, Parallel-group, Dose Ranging Study to Assess the Efficacy, Safety, and Tolerability of Subcutaneous Amlitelimab in Adult Participants With Moderate-to-severe Asthma
Phase: PHASE2
Conditions: Asthma
Sponsor: Sanofi

 
 
 
 
 
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According to Template: Sanofi OneDocument Version 6.0, dated 25-JUN-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A randomized, double-blind, placebo-controlled, 
parallel-group, dose ranging study to assess the efficacy, 
safety, and tolerability of subcutaneous amlitelimab in adult 
participants with moderate-to-severe asthma  
Protocol number: 
DRI17509 
Amendment number: 
04 
Compound number 
(INN/Trademark): 
SAR445229 
amlitelimab/Not applicable 
Brief title: 
Dose ranging study of amlitelimab in adult participants with 
moderate-to-severe asthma  
Acronym: 
TIDE-asthma 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
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: 
EudraCT: 
2022-000065-41 
NCT: 
NCT05421598 
WHO: 
U1111-1272-2612 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
Date: 
14-Dec-2023 
Total number of pages: 144 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 04 
All 
14 December 2023, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
South Korea 
03 April 2023, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
23 November 2022, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
17 June 2022, version 1 (electronic 1.0) 
Original Protocol 
 
09 March 2022, version 1 (electronic 3.0) 
Amended protocol 04 (14 December 2023) 
This amended protocol (amendment 04) 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 because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The protocol is amended to modify the type of interim analysis. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
2.3.1 Risk assessment 
Risk assessment description of this 
case in the context of the study.  
1.1 Synopsis 
4.1 Overall design 
6.1 Study intervention(s) 
administered 
Sentence added for non-IMPs: “The class of reliever 
medication should not change during the study.” 
Background therapy should remain 
stable throughout the study, 
clarification added for reliever 
medications. 
6.8.4 Prohibited concomitant 
medication 
Systemic steroids use allowed for up to 7 consecutive 
days. 
Systemic steroids for treatment of 
conditions other than asthma are 
allowed for up to 7 consecutive 
days.  
7.2 Participant 
discontinuation/withdrawal 
from the study 
A note has been added: “Safety follow-up (EOS, end-
of-study) visit should be performed after 
 after the last IMP.” 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and 9.2.2 
Primary endpoint(s) analysis 
Primary endpoint supplementary analysis of 
intercurrent events was detailed. 
Clarification. 
1.1 Synopsis and 9.2.3 
Secondary endpoint(s) 
analysis 
Modification of “supportive” analyses of intercurrent 
events to “supplementary” analysis. 
Harmonization. 
10.2 Appendix 2: Clinical 
Laboratory tests 
Addition of the following tests to the list: uric acid, total 
cholesterol, albumin, lactate dehydrogenase, chloride, 
bicarbonate. 
List of the study central laboratory 
tests was incomplete. 
10.6 Appendix 6: Liver and 
other safety: suggested 
actions and follow-up 
assessments  
Update of the management of increase in ALT as per 
Sanofi standard. 
 
 
Clarification. 
 
Section 10.12 Appendix 12: 
Protocol amendment history 
The text of summary of changes for Protocol 
amendment 03 is added. 
Appendix 12 is updated to reflect 
the document history of previous 
amendment. 
Throughout the document 
Small changes (editorial) have been made. 
Clarification. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 20 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 21 
2 
INTRODUCTION............................................................................................................................ 27 
2.1 
STUDY RATIONALE ..................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 32 
2.3.1 
Risk assessment ............................................................................................................................ 32 
2.3.2 
Benefit assessment ........................................................................................................................ 36 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 36 
3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ......................................................................... 38 
3.1 
APPROPRIATENESS OF MEASUREMENTS  ............................................................................. 41 
4 
STUDY DESIGN ............................................................................................................................ 42 
4.1 
OVERALL DESIGN ........................................................................................................................ 42 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 43 
4.2.1 
Participant input into design ........................................................................................................... 44 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 44 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 45 
5 
STUDY POPULATION .................................................................................................................. 46 
5.1 
INCLUSION CRITERIA .................................................................................................................. 46 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 48 
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5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 52 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 52 
5.3.2 
Caffeine, alcohol, and tobacco....................................................................................................... 52 
5.3.3 
Activity ............................................................................................................................................ 52 
5.4 
SCREEN FAILURES ..................................................................................................................... 52 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 54 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 55 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 55 
6.1.1 
Devices .......................................................................................................................................... 57 
6.2 
PREPARATION, HANDLING, STORAGE, AND ACCOUNTABILITY ........................................... 57 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 59 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 61 
6.5 
DOSE MODIFICATION .................................................................................................................. 61 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 61 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 62 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 62 
6.8.1 
ICS in combination with one or two other controllers..................................................................... 63 
6.8.1.1 
Screening period ............................................................................................................................ 63 
6.8.1.2 
Randomized treatment period ........................................................................................................ 63 
6.8.1.3 
Follow-up period............................................................................................................................. 63 
6.8.2 
Reliever medication ....................................................................................................................... 63 
6.8.3 
Allowed concomitant medication.................................................................................................... 64 
6.8.4 
Prohibited concomitant medication ................................................................................................ 65 
6.8.5 
Prohibited rescue medication and procedures .............................................................................. 66 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 67 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 67 
7.1.1 
Permanent discontinuation ............................................................................................................ 67 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 68 
7.1.3 
Temporary discontinuation ............................................................................................................. 69 
7.1.4 
Rechallenge ................................................................................................................................... 69 
7.1.4.1 
Study intervention restart or rechallenge after liver stopping criteria are met ............................... 69 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 69 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 70 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 71 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 72 
8.1.1 
Primary endpoint ............................................................................................................................ 72 
8.1.1.1 
Severe asthma exacerbation events ............................................................................................. 72 
8.1.2 
Secondary endpoints ..................................................................................................................... 72 
8.1.2.1 
Key secondary endpoints ............................................................................................................... 72 
8.1.2.2 
Efficacy endpoints .......................................................................................................................... 72 
8.1.3 
Disease-specific efficacy measures ............................................................................................... 73 
8.1.3.1 
Spirometry ...................................................................................................................................... 73 
8.1.3.2 
Asthma Control Questionnaire, versions 5, 6, and 7 ..................................................................... 74 
8.1.3.3 
Fractional Exhaled Nitric Oxide ...................................................................................................... 75 
8.1.3.4 
Electronic diary............................................................................................................................... 75 
8.1.3.5 
Loss of asthma control events ....................................................................................................... 75 
8.1.3.6 
Asthma Daytime Symptom Diary and Asthma Nighttime Symptom Diary..................................... 76 
8.1.3.7 
Asthma Quality of Life Questionnaire with Standardized Activities Self-administered Score ....... 76 
8.1.3.8 
St. George's Respiratory Questionnaire ........................................................................................ 76 
8.1.3.9 
Remote spirometry ......................................................................................................................... 77 
8.1.3.10 
.......................................................................................... 77 
8.1.3.11 
............................................................................................................ 78 
8.1.3.12 Digital inhaler to measure the use of bronchodilator therapy ........................................................ 79 
8.1.3.13
...................................................... 79 
8.1.3.14 
.............................................................................................................. 79 
8.1.3.15 
........................ 79 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 80 
8.2.1 
Physical examinations ................................................................................................................... 80 
8.2.2 
Vital signs ....................................................................................................................................... 81 
8.2.3 
Electrocardiograms ........................................................................................................................ 81 
8.2.4 
Clinical safety laboratory tests ....................................................................................................... 81 
8.2.5 
Pregnancy testing .......................................................................................................................... 82 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 83 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 83 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 83 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 83 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 84 
8.3.5 
Pregnancy ...................................................................................................................................... 84 
8.3.6 
Cardiovascular and death events .................................................................................................. 85 
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8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 85 
8.3.8 
Adverse events of special interest ................................................................................................. 85 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 86 
8.4 
PHARMACOKINETICS .................................................................................................................. 86 
8.5 
.................................................................................................................................... 87 
8.6 
............................................................................................................................... 87 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 88 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 88 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 88 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 90 
9.1 
POPULATIONS FOR ANALYSES ................................................................................................. 90 
9.2 
STATISTICAL ANALYSES ............................................................................................................ 91 
9.2.1 
General considerations .................................................................................................................. 91 
9.2.2 
Primary endpoint(s) analyses ........................................................................................................ 92 
9.2.3 
Secondary endpoint(s) analyses .................................................................................................... 94 
9.2.3.1 
Key secondary endpoints ............................................................................................................... 94 
9.2.3.2 
Other secondary endpoints ............................................................................................................ 96 
9.2.4 
Tertiary/exploratory endpoint(s) analyses ...................................................................................... 97 
9.2.5 
Multiplicity adjustment .................................................................................................................... 98 
9.2.6 
Safety analyses .............................................................................................................................. 98 
9.2.6.1 
Adverse events .............................................................................................................................. 98 
9.2.6.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 99 
9.2.7 
Other analyses ............................................................................................................................. 101 
9.3 
INTERIM ANALYSES  ................................................................................................................. 101 
9.4 
SAMPLE SIZE DETERMINATION............................................................................................... 101 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 103 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 103 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 103 
10.1.2 
Financial disclosure ..................................................................................................................... 104 
10.1.3 
Informed consent process ............................................................................................................ 104 
10.1.4 
Data protection ............................................................................................................................. 105 
10.1.5 
Committees structure ................................................................................................................... 108 
10.1.5.1 Data Monitoring Committee ......................................................................................................... 108 
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10.1.5.2 Adjudication Committee ............................................................................................................... 108 
10.1.6 
Dissemination of clinical study data ............................................................................................. 108 
10.1.7 
Data quality assurance ................................................................................................................ 109 
10.1.8 
Source documents ....................................................................................................................... 109 
10.1.9 
Study and site start and closure ................................................................................................... 110 
10.1.10 Publication policy ......................................................................................................................... 111 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 111 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ....................................................................... 114 
10.3.1 
Definition of AE ............................................................................................................................ 114 
10.3.2 
Definition of SAE .......................................................................................................................... 116 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 117 
10.3.4 
Reporting of SAEs ....................................................................................................................... 119 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 119 
10.4.1 
Definitions .................................................................................................................................... 119 
10.4.2 
Contraception guidance ............................................................................................................... 120 
10.5 
APPENDIX 5: 
........................................................................................................... 122 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS  ......................................................................................................................... 123 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................. 125 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 126 
10.8.1 
Japan-specific requirements ........................................................................................................ 126 
10.8.2 
South Korea specific requirements .............................................................................................. 126 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 126 
10.10 
APPENDIX 10: ADDITIONAL APPENDICES .............................................................................. 128 
10.10.1 Low, medium, and high ICS doses: adults/adolescents .............................................................. 128 
10.10.2 Comparison of systemic glucocorticoid preparations .................................................................. 128 
10.10.3 Examples of commonly used asthma controller therapies and reliver medications .................... 129 
10.10.4 Non-exhaustive list of live-attenuated vaccines ........................................................................... 130 
10.10.5 Definition of anaphylaxis .............................................................................................................. 131 
10.10.6 List of opportunistic infections ...................................................................................................... 131 
10.11 
APPENDIX 11: ABBREVIATIONS AND DEFINITIONS .............................................................. 132 
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10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY .............................................................. 134 
11 
REFERENCES............................................................................................................................. 140 
 
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LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 34 
Table 2 - Objectives and endpoints ............................................................................................................... 38 
Table 3 - Study intervention(s) administered ................................................................................................ 55 
Table 4 - Study arm(s) ................................................................................................................................... 56 
Table 5 - Conversion of salbutamol/albuterol nebulizer solution dose to number of puffs ........................... 64 
Table 6 - Conversion of levosalbutamol/levalbuterol nebulizer solution dose to number of puffs ................ 64 
Table 7 - Hepatitis serology testing ............................................................................................................... 82 
Table 8 -
................................................................................................................ 90 
Table 9 - 
.......................................................... 96 
Table 10 - Tertiary/exploratory endpoints...................................................................................................... 98 
Table 11 - 
 ................................... 98 
Table 12 - 
 ....................................................................................................... 100 
Table 13 - Protocol-required laboratory tests .............................................................................................. 113 
Table 14 - Examples of commonly used asthma controller therapies ........................................................ 129 
Table 15 - List of commonly used asthma reliever medications ................................................................. 130 
Table 16 - List of live (attenuated) vaccines ................................................................................................ 130 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 20 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A randomized, double-blind, placebo-controlled, parallel-group, dose ranging study to assess the 
efficacy, safety, and tolerability of subcutaneous amlitelimab in adult participants with 
moderate-to-severe asthma  
Brief title: 
 
Dose ranging study of amlitelimab in adult participants with moderate-to-severe asthma  
Rationale: 
Amlitelimab (also known as SAR445229 or KY1005), a human anti-OX40 ligand (OX40L, 
CD252) monoclonal antibody (mAb) (subclass IgG4PE kappa) that binds OX40L to block the 
interaction with its receptor, OX40 (CD134), is an investigational drug being developed for the 
treatment of immune-mediated diseases. This study will explore the efficacy and safety of 
amlitelimab in adult participants with moderate-to-severe asthma. 
Objectives and endpoints: 
  
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of different doses of 
amlitelimab compared to placebo in participants 
with moderate-to-severe, uncontrolled asthma. 
• 
Annualized rate of severe exacerbation events over 
48 weeks, defined as: 
- 
Worsening of asthma requiring the use of 
systemic corticosteroids for ≥3 days or, in the 
case of a stable maintenance regimen of oral 
corticosteroids (OCS) for the treatment of 
asthma, a doubling of the dose for 3 or more 
days; or  
- 
Hospitalization or emergency room visit 
because of asthma, requiring systemic 
corticosteroids 
Secondary 
 
• 
To evaluate the effects of amlitelimab compared to 
placebo on lung function as measured by forced 
expiratory volume in 1 second (FEV1) 
• 
Change from baseline in pre-bronchodilator (BD) 
FEV1 at Week 48 (key secondary endpoint) 
• 
Change from baseline in post-BD FEV1 at Week 48  
• 
The absolute change in the percent predicted FEV1 
from baseline to Week 48 (pre-BD and post-BD) 
• 
To evaluate the effects of amlitelimab on Asthma 
Control Questionnaire 5 (ACQ-5)  
• 
Change from baseline in ACQ-5 score at Week 48 
(key secondary endpoint) 
• 
Change from baseline in ACQ-5 score at Weeks 2, 
4, 8, 12, 24, 36, and 60  
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Objectives 
Endpoints 
• 
To evaluate the effects of amlitelimab on time to first 
severe exacerbation event 
• 
Time to first severe exacerbation event 
• 
To evaluate the effects of amlitelimab on other 
spirometry assessments  
• 
Change from baseline in pre-BD and post-BD FEV1 
and other lung function measurements (peak 
expiratory flow [PEF], forced vital capacity [FVC], 
and forced expiratory flow [FEF] 25-75%) at each 
spirometry endpoint 
• 
To evaluate the effects of amlitelimab on fraction of 
exhaled nitric oxide (FeNO) 
• 
Change from baseline in FeNO at Weeks 2, 4, 8, 
12, 16, 24, 36, 48 and 60 
• 
To evaluate the effects of amlitelimab compared to 
placebo on reducing the incidence of “loss of 
asthma control” (LOAC) events  
• 
Annualized rate of LOAC events, during 48 weeks 
of treatment, defined by one or several of the 
following criteria: 
- 
A 30% or greater reduction from baseline in 
morning PEF on 2 consecutive days. 
- 
≥6 additional reliever puffs of short-acting beta 
2-agonists (SABA) OR ≥4 additional puffs of 
low-dose ICS/formoterol in a 24-hour period 
(compared to baseline) on 2 consecutive days  
- 
Increase in ICS ≥4 times than the Visit 2 dose 
- 
Worsening of asthma requiring the use of 
systemic corticosteroids for ≥3 days or, in the 
case of a stable maintenance regimen of OCS 
for the treatment of asthma, a doubling of the 
dose for 3 or more days  
- 
Hospitalization or emergency room visit 
because of asthma, requiring systemic 
corticosteroids severe exacerbation event 
• 
To evaluate the effects of amlitelimab on time to first 
LOAC event 
• 
Time to first LOAC event 
• 
To evaluate the effects of amlitelimab on asthma 
symptoms  
• 
Change from baseline in the Asthma Daytime 
Symptom Diary (ADSD) 6-item daily morning score 
and in the Asthma Nighttime Symptom Diary 
(ANSD) 6-item daily evening scores at Weeks 2, 4, 
8, 12, 24, 36, 48, and 60 
• 
To evaluate the effects of amlitelimab on reducing 
the incidence of severe asthma exacerbations 
requiring hospitalization or emergency room or 
urgent care visit 
• 
Annualized rate of severe asthma exacerbations 
requiring hospitalization or emergency room or 
urgent care visit during 48 weeks of treatment  
• 
Assess the effect of amlitelimab on BD therapy 
• 
Change from baseline in the numbers of 
inhalations/day of SABA or low-dose ICS/formoterol 
for symptom relief at Weeks 2, 4, 8, 12, 24, 36, 48, 
and 60 
• 
To evaluate the pharmacokinetics (PK) of 
amlitelimab and anti-drug antibodies to amlitelimab 
in participants with asthma 
• 
Serum amlitelimab concentrations measured 
throughout the study 
• 
Incidence of anti-amlitelimab antibody positive 
response 
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Objectives 
Endpoints 
• 
To evaluate the safety of amlitelimab in participants 
with asthma  
• 
Percentage of participants with treatment-emergent 
adverse events (TEAEs), including local reactions, 
adverse events of special interest (AESIs), serious 
adverse events (SAEs)  
• 
Incidence of potentially clinically significant 
laboratory test, vital signs, and ECG abnormalities 
in the treatment period 
• 
To evaluate the effects of amlitelimab on participant 
reported outcomes (PROs)  
• 
Change from baseline in Asthma Quality of Life 
Questionnaire with Standardized Activities (AQLQ 
(S)) Self-Administered Score at Week 48 (key 
secondary endpoint) 
• 
AQLQ (S) Self-Administered Score at Weeks 2, 4, 
8, 12, 24, 36, and 60 
• 
Change from baseline in St. George’s Respiratory 
Questionnaire (SGRQ) at Weeks 2, 4, 8, 12, 24, 36, 
48, and 60 
• 
Proportion of participants with a decrease from 
baseline of at least 4 points in SGRQ total score at 
Week 48 
• 
To evaluate the effects of amlitelimab on ACQ-6 
and ACQ-7  
• 
Change from baseline in ACQ-6 score and ACQ-7 
at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 
 
 
 
 
 
Overall design: 
This is a Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, dose-ranging study to assess the efficacy, safety, and tolerability of add-on therapy with 
subcutaneous (SC) amlitelimab in adult participants (aged 18-75 years, inclusive) with moderate-
to-severe asthma. All eligible participants will be randomized into (2:2:1:2) ratio and treated for 
60 weeks, receiving a SC administration of amlitelimab every 4 weeks (Q4W) for the first 6 doses 
and every 12 weeks (Q12W) thereafter or matching placebo according to one of the following 
doses: 
• 
Amlitelimab 250 mg with 500 mg loading dose on Day 1 
• 
Amlitelimab 125 mg with 250 mg loading dose on Day 1 
• 
Amlitelimab 62.5 mg with 125 mg loading dose on Day 1 
• 
Matching placebo 
Randomization will be stratified by Screening Visit 1 eosinophil count (<300 cells/μL and 
≥300 cells/μL), number of severe asthma exacerbations (as defined above in the ‘objectives and 
endpoints’ table) in the previous 12 months (=1 exacerbation or >1 exacerbations) and by region. 
To avoid recruiting a skewed population due to competing studies, alerts will be built into the 
interactive voice/web response system (IVRS/IWRS) to limit enrolling participants in the 
following 2 stratification groups: 
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• 
Only 1 severe asthma exacerbation in the previous 12 months: not more than 
approximately 50% of participants (210 participants).  
• 
Eosinophils <300 eosinophils/μL: not more than approximately 50% of participants 
(210 participants). 
Amlitelimab will be administered as add-on therapy to inhaled corticosteroid (ICS) in 
combination with a second controller medication (eg, long-acting beta agonist [LABA], 
leukotriene receptor antagonist [LTRA], methylxanthines, long-acting muscarinic antagonist 
[LAMA]) with or without oral prednisone for the maintenance treatment of asthma. Participants 
requiring a third controller are allowed to participate in this study (please see Section 5.1), which 
consists of three periods: 
• 
Screening period (up to 4 weeks) to determine whether participants meet entry criteria and 
to establish the level of asthma control before randomization 
• 
Randomized treatment period (approximately 60 weeks) 
• 
Follow-up period (approximately 12 weeks) to monitor participants after treatment 
- 
Eligible participants who complete the treatment period will be offered the opportunity 
to participate in the long term safety (LTS) study with amlitelimab. Participants 
subsequently enrolled in the LTS study will not participate in the follow-up period of 
this trial but will have a follow up period after the LTS study. 
Brief summary:  
This is a parallel, Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, 
dose-ranging, four-arms study for treatment. 
The purpose of this study is to assess the efficacy, safety, and tolerability of add-on therapy with 
amlitelimab in adult participants with moderate-to-severe asthma. 
Study details include: 
• 
The study duration (per participant) will be up to approximately 76 weeks for participants 
not going into LTS study and will be up to approximately 64 weeks for participants going 
into LTS study. 
• 
The randomized treatment duration will be up to approximately 60 weeks. 
• 
The scheduled number of visits will be 13. 
Number of participants: 
Approximately 420 participants will be randomized to study intervention. 
Note: Randomized participants are all participants from screened participants who have been 
allocated to an intervention by IVRS/IWRS regardless of whether the intervention was received or 
not.  
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Intervention groups and duration: 
All participants will receive SC administration of amlitelimab 250 mg with 500 mg loading dose 
on Day 1, or 125 mg with 250 mg loading dose on Day 1, or 62.5 mg with 125 mg loading dose 
on Day 1 or matching placebo, Q4W for the first 6 doses and Q12W thereafter until Week 48 for 
all arms.  
Study intervention(s) 
Amlitelimab and placebo matching amlitelimab are supplied as solutions in vials that are visually 
indistinguishable.  
Investigational medicinal product(s) 
• 
Formulation: 
- 
Amlitelimab: a 125 mg/mL amlitelimab solution in a vial to deliver up to 125 mg of 
amlitelimab in a 1 mL injection.  
- 
Placebo matching amlitelimab: identical formulation to the active amlitelimab 
formulation without amlitelimab, in a vial to deliver placebo in a up to 1 mL injection.  
• 
Route(s) of administration: SC injection, to abdomen or outer thigh. IMP should not be 
administered at the exact site of a recent injection or in areas which in the Investigator's 
opinion are not suitable (eg, tender, bruised, red or hard). 
• 
Dose regimen: 
- 
Amlitelimab 250 mg with 500 mg loading dose treatment group: one initial loading 
dose of 500 mg of amlitelimab (two 2 mL injections of 250 mg of amlitelimab) on 
Day 1, followed by one 2 mL injection of 250 mg of amlitelimab Q4W until Week 20 
(inclusive) and Q12W starting from Week 24 and thereafter until Week 48.  
- 
Amlitelimab 125 mg with 250 mg loading dose treatment group: one initial loading 
dose of 250 mg of amlitelimab (two 2 mL injection of 125 mg of amlitelimab) on 
Day 1, followed by one 2 mL injection of 125 mg of amlitelimab Q4W until Week 20 
(inclusive) and Q12W starting from Week 24 and thereafter until Week 48. 
- 
Amlitelimab 62.5 mg with 125 mg loading dose treatment group: one initial loading 
dose of 125 mg of amlitelimab (two 2 mL injections of 62.5 mg of amlitelimab) on 
Day 1, followed by one 2 mL injection of 62.5 mg of amlitelimab Q4W until Week 20 
(inclusive) and Q12W starting from Week 24 and thereafter until Week 48.  
- 
Placebo treatment group: one initial dummy loading dose of only placebo (two 2 mL 
injections of placebo matching amlitelimab) on Day 1, followed by one 2 mL injection 
of placebo matching amlitelimab Q4W until Week 20 (inclusive) and Q12W starting 
from Week 24 and thereafter until Week 48.  
Noninvestigational medicinal products 
On a daily basis throughout the study, the participant will use an electronic diary (eDiary) to 
record daily use of ICS in combination or administered concurrently with other controllers as used 
just prior to screening.  
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The recognized asthma controllers for the study will include the following 5 classes: ICS, LABA, 
LAMA, anti-leukotrienes and methylxanthines. Please refer to Section 10.10.3 for a list of 
commonly used asthma controller medication. 
• 
Screening period:    
Prior to screening, participants must be on a stable background therapy for at least 
3 months, composed of medium to high dose ICS (≥500 μg fluticasone propionate daily or 
comparable ICS dosage up to a maximum of 2000 μg/day of fluticasone propionate or 
clinically comparable ([1], see Section 10.10.1) in combination with a second controller 
medication (eg, LABA, LTRA, LAMA, methylxanthines) with stable doses ≥1 month 
prior to Visit 1. Participants requiring a third controller are allowed to participate in this 
study. The third controller should also be used for at least 3 months with a stable dose 
≥1 month prior to Visit 1. For Japan, please see Section 10.8 for details. 
Route of administration: Oral inhalation 
If on chronic oral corticosteroid (OCS) treatment for the maintenance treatment of asthma, 
up to a maximum of 15 mg prednisone or equivalent daily or 30 mg every other day, must 
be on stable dose for ≥1 month prior to Visit 1 (see Section 10.10.2 for comparison of 
systemic glucocorticoid preparations). 
Route of administration: Oral tablets. 
• 
Randomized treatment period:  
During this period, participants will continue to take their controller medication(s) used 
during the screening period and will use an eDiary to record daily use. The dose and 
regimen should not be changed, except for the OCS, for which the dose could be changed 
per Investigator medical judgement.  
• 
Follow-up period:  
Upon completing the randomized treatment period, participants will proceed to be treated 
with the controller medication regimen and dose used during the randomized treatment 
period, which could be adjusted based on the medical judgment of the Investigator of the 
participants’ asthma control status. 
Reliever Medication 
Participants may administer SABA metered dose inhaler (MDI) and dry powder inhaler (DPI) as 
reliever medication as needed during the study. Nebulizer solutions may be used as an alternative 
delivery method, if previously used by the patient. Alternatively, low-dose ICS/formoterol may be 
used as reliever medication, per Global Initiative for Asthma (GINA) 2021 recommendation (2) 
and Investigator discretion. The class of reliever medication should not change during the study. 
Reliever medication use will be recorded in the eDiary. Please refer to Section 6.8.2 for a list of 
commonly used asthma reliever medications. 
Route of administration: Oral inhalation  
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Devices:  
Sanofi or a designee will provide standard study supplies to the sites for the execution of trial-
related activities. These supplies include the following: 
• 
Electronic Diaries 
• 
Spirometry devices 
• 
Electronic Spirometry devices for remote spirometry and PEF measurement 
• 
Digital inhalers to measure the reliever use (in certain countries, optional) 
• 
Impulse oscillometry devices 
• 
FeNO measurement devices 
• 
Laboratory kits including tubes, needles, dipsticks 
• 
IMP transportation material as described in the Pharmacy Manual 
Instructions on material supply, tracking, return and destruction will be provided in vendor 
manuals. 
  
Duration of study intervention 
Eligible participants who complete the treatment period will be offered the opportunity to 
participate in the LTS study with amlitelimab. Participants subsequently enrolled in the LTS study 
will not participate in the follow-up period of this trial but will have a follow up period after the 
LTS study. 
Total duration would be approximately 76 weeks for participants not going into LTS study, 
including up to 4 weeks for screening period, approximately 60 weeks for randomized treatment 
period, and approximately 12 weeks for follow up period.  
Total duration would be approximately 64 weeks for participants going into LTS study, including 
up to 4 weeks for screening period and approximately 60 weeks for randomized treatment period, 
then enrollment into LTS study. 
Statistical considerations: 
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Data Monitoring/Other committee: Yes 
A Data Monitoring Committee (DMC) has been appointed for this study. The DMC (board) is a 
group of independent physician and scientist experts who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to the 
Sponsor regarding the stopping of a study for efficacy, for harms, or for futility. The composition 
of the committee is dependent upon the scientific skills and knowledge required for monitoring 
the particular study.  
The DMC procedures and safety data to be reviewed by the DMC are described in the DMC 
charter. In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible 
for promptly reviewing and for taking into account in a timely manner the recommendations of 
the DMC in terms of trial continuation with or without alterations or of potential trial termination. 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
Procedure 
Screening 
(Week -4 to -2)aa 
Randomized treatment period (60 weeks) 
Follow-up 
(12 weeks 
after EOT) 
Early treatment 
discontinuation 
Visit 
Visit Days 
Visit window (days) 
Visit Weeks 
Informed consenta 
Inclusion and exclusion 
criteria 
Demography 
Previous medical and 
surgical history 
Qualifying Spirometry and 
Reversibilityb 
Prior & concomitant 
medications 
IVRS/IWRS 
Randomization 
Study intervention 
IMP administrationc 
NIMP administration 
Safety 
Full physical examinationd 
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Procedure 
Screening 
(Week -4 to -2)aa 
Randomized treatment period (60 weeks) 
Follow-up 
(12 weeks 
after EOT) 
Early treatment 
discontinuation 
Visit 
Visit Days 
Visit window (days) 
Visit Weeks 
Pregnancy test (WOCBP 
only, serum at Screening, 
urine thereafter)e 
HIV, Hepatitis B and C 
screeningf 
Laboratory tests (include 
clinical chemistries)g 
12-lead ECGh 
Vital signsi 
TB assessmentj 
COVID-19 testingk 
AE reporting, including SAEs 
Pharmacokinetics 
PK samplingo 
Anti-drug antibodies (serum)o 
Electronic Diary and digital devicesz 
eDiary dispensation  
eDiary review 
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Procedure 
Screening 
(Week -4 to -2)aa 
Randomized treatment period (60 weeks) 
Follow-up 
(12 weeks 
after EOT) 
Early treatment 
discontinuation 
Visit 
Visit Days 
Visit window (days) 
Visit Weeks 
e-Spirometer dispensationm 
Digital inhaler dispensation 
and instruction (in certain 
countries)l 
Exhaled nitric oxide (FeNO)n  
Efficacy 
Spirometry (pre-BD) t, n 
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Procedure 
Screening 
(Week -4 to -2)aa 
Randomized treatment period (60 weeks) 
Follow-up 
(12 weeks 
after EOT) 
Early treatment 
discontinuation 
Visit 
Visit Days 
Visit window (days) 
Visit Weeks 
Spirometry (post-BD)t, n 
Remote spirometry (pre-BD) 
training/instructionsu 
Remote spirometry (pre-BD)v  
ACQ-7w 
ANSD (AM)x  
ADSD (PM)x  
PROs 
AQLQ(S) 
SGRQ 
 
Abbreviations: EOT=End of Treatment; EOS=End of Study; IMP=investigational medicinal product; NIMP=Non investigational medicinal product; WOCBP=women of childbearing potential; IVRS/IWRS=interactive 
voice/web response system; HIV=human immunodeficiency virus; ECG=electrocardiogram; TB=tuberculosis; AE=adverse event; SAE=serious adverse event; PK=pharmacokinetics; PEF=peak expiratory flow; 
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eDiary=electronic Diary; e-Spirometer=electronic Spirometer; ADSD=Asthma Daytime Symptom Diary; ANSD=Asthma Nighttime Symptom Diary; FeNO=fraction of exhaled nitric oxide; IgE=Immunoglobulin E; 
DNA=deoxyribonucleic acid; BD=bronchodilator; ACQ-7=asthma control questionnaire-7; PRO=participant-reported outcome; SGRQ=St. George’s Respiratory Questionnaire; AQLQ (S)=Asthma Quality Of Life 
Questionnaire with Standardized Activities; 
 
a Informed consent will cover study consent to all mandatory tests as per SoA. Optional consent will cover pharmacogenetics analysis and use of data and samples for future research. 
b Participants with reversibility of at least 12% and 200 mL in FEV1 after administration of 2 to 4 puffs (200-400 μg) of albuterol/salbutamol or levalbuterol/levosalbutamol during screening or documented history of a 
reversibility test that meets these criteria within 12 months prior to Visit 1 is considered acceptable to meet this inclusion criteria (I 07). Alternatively, a Severe Asthma Research Program (SARP) method could be 
used: maximal change in FEV1 after the administration of 4, 6, and 8 puffs of albuterol (360, 540, 720 μg albuterol). If the participant does not meet the qualifying criteria for reversibility at Visit 1/Screening, up to 
2 additional attempts during the screening period, each on a different day prior to Visit 2/Baseline, may be performed. When reversibility assessment is repeated during the screening period, the prebronchodilator 
FEV1 should again meet the inclusion criteria (I 05) of >40% and <80% of predicted normal. 
c All eligible participants will be treated for 60 weeks, receiving a subcutaneous (SC) administration of IMP every 4 weeks (Q4W) for the first 6 doses and every 12 weeks (Q12W) thereafter with a loading dose 
(two SC injections) on Day 1. 
d Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
e If urine pregnancy test is positive, a serum control must be done before IMP administration. Urine pregnancy testing should continue every 4 weeks after switching to Q12W regimen. Follow-up pregnancy test will 
be performed until 
 after the last administration of study intervention. 
f 
Clinical laboratory testing at Screening (Visit 1) will include a hepatitis screen covering hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), total hepatitis B core antibody (HBc Ab), IgM 
antibody to hepatitis B core antigen (IgM HBc Ab), hepatitis C virus antibodies (HCV Ab), HIV screen (anti-HIV-1 and HIV-2 antibodies). In case of results showing HBs Ag (negative), and HBc Ab Total (positive), 
HBV DNA testing will be performed prior to randomization to rule out a false positivity to clarify the serological status. In case of results showing HCV Ab (positive), HCV RNA testing will be performed to rule out a 
false positivity. Please refer to Table 7 in Section 8.2.4. 
g Hematology: hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with five-part differential count, and total red blood cell count. Serum chemistry: creatinine, blood urea nitrogen, glucose, uric 
acid, total cholesterol, total protein, albumin, total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, lactate dehydrogenase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. The blood sample for serum chemistry must be taken with 
the participant in fasting state which means no intake of any food or drink except for water for at least 8 hours (if the visit can only be done at a different time of the day and the participant is not fasting, then he/she 
should be advised to eat light food and the site should document that serum chemistry was not obtained under fasting conditions). Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrite, 
leukocyte esterase, urobilinogen, and bilirubin. If any urinalysis parameter on the dipstick is abnormal, a urine sample should be sent to the central laboratory for quantitative measurement. If urinalysis sample is 
abnormal for protein and/or red blood cells, microscopic analysis will be performed by the central laboratory. 
h The ECGs will be obtained prior to laboratory assessments and prior to spirometry. 
i 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured at every visit. Height (cm) will be measured at 
screening (Visit 1) only. Body weight (kg) will be measured at Visit 1/Screening, Visit 2/Baseline, Visit 9, Visit 11, Visit 12/EOT, and Visit 13/EOS or early discontinuation. Vital sign should be done before IMP 
administration. 
j 
TB assessment per local guidelines or, if not available, in central laboratory using a Quantiferon® test.  
k COVID-19 test will be performed at screening, randomization and prior to each IMP administration (no administration if positive). Tests should be performed no more than 5 days prior to IMP administration. 
Method of testing as required per local guidelines. 
l 
Further details will be available in a separate operational manual provided to the sites. 
m Electronic spirometer (eSpirometer) will be dispensed at Visit 1. Further details on remote spirometry will be available in a separate operational manual provided to the sites. 
n When FeNO, impulse oscillometry, and spirometry are scheduled at the same time, sequence of measurements will be in the following order: 1) FeNO; 2) impulse oscillometry; 3) spirometry. 
o Samples will be collected prior to administration of IMP during the randomized treatment period. Additionally, serum samples should also be collected at the final visit from participants who discontinued study 
intervention or were withdrawn from the study. 
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t 
Spirometry (pre-BD FEV1, post-BD FEV1, and PEF, FVC, FEF) should be performed in the morning if possible, but if it could only be done at a different time of the day, the spirometry should be done at 
approximately the same time of the day at each visit throughout the study. Spirometry will be performed after a wash out period of bronchodilators according to their action duration, for example, withholding the 
last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at least 24 hours, and finally the last dose of ultralong-acting LABA (like vilanterol) or the 
last dose of LAMA should be withheld for at least 36 hours), and prior to administration of investigational product. The post-BD spirometry may be repeated several times within 30 minutes after administration of 
bronchodilator. 
u Remote spirometry training/instructions to be done during the screening period and at regular intervals throughout the study. Additional instructions will be provided and available to participants. 
v Electronic spirometer (eSpirometer) will be used for FEV1 and PEF measurements to be performed daily in the AM and PM (see Section 8.1.3.9 for further instructions).  
w To calculate ACQ-7, the ACQ-6 is completed in the participant’s eDiary during clinic visits. ACQ-6 score will be used to follow up evaluations in all participants. ACQ-5 (the first 5 items of the ACQ-6) score is used 
for eligibility evaluation at Visit 1 and Visit 2 for all participants. 
x ADSD and ANSD captured daily via eDiary; ANSD captures nocturnal asthma symptoms is to be completed upon awakening; ADSD captures daytime asthma symptoms is to be completed at end of day (before 
retiring for sleep). 
z Electronic diary (eDiary) is a handheld device used for daily recording of reliever use, asthma controller drug use, ADSD and ANSD, and recording of participant’s answers to the ACQ-5, ACQ-6, AQLQ(S), and 
other PROs questionnaires during the scheduled visits. This handheld device is dispensed at Visit 1 (including instructions for use) and recorded information is downloaded from this device on the other indicated 
days. For each site visit, the participants will bring their electronic devices and will complete the questionnaire on site. Electronic handheld devices will be returned to the vendor at EOS at the latest. 
aa A maximum of 14 days is required to get IMP on site. Randomization of the participant must take this constraint into consideration. In case of severe asthma exacerbation during screening, screening period can be 
extended to up to 3 months. Please see Screen Failures section for instructions and for South Korea, please see Section 10.8.2 for details. 
 
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2 
INTRODUCTION  
Amlitelimab (also known as KY1005 or SAR445229) is a novel human anti-OX40L mAb 
(subclass IgG4PE kappa) that is being developed to modulate the persistent inflammation caused 
by autoreactive memory T cell (Tmem) populations and may provide a means of inducing 
immune tolerance to exogenous or autoantigens (eg, in immune mediated/autoimmune disease) or 
alloantigens (eg, following transplants). 
2.1 
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 inflammation component of asthma is thought to involve many cell types including epithelial 
cells, T lymphocytes, eosinophils, mast cells, neutrophils, innate lymphoid cells type 2 (ILC2) and 
their biological products. Patients with asthma most often present with symptoms of wheezing, 
shortness of breath, cough, and chest tightness (3).  
Despite current treatment options, uncontrolled asthma continues to carry a significant burden, 
with more than 1 million moderate-to-severe asthmatic adolescents and adults in the U.S. having 
uncontrolled symptoms on ICS combined with bronchodilator drug(s) or systemic corticosteroid 
therapy (4). These patients are prone to severe exacerbations and contribute disproportionately to 
the overall morbidity in this condition, including more hospital days, emergency room visits, and 
lost work/school days than matched controls with good asthma control. Additionally, they are 
likely to experience co-morbidities such as anxiety, depression, and insomnia (5, 6). Furthermore, 
systemic corticosteroids, while modestly effective, are associated with significant side effects, 
such as fluid retention and swelling, weight gain, glaucoma, increased blood pressure, increased 
risk of infections, diabetes, osteoporosis, and impaired growth in children (7). 
For severe uncontrolled asthma patients, there are several currently approved biologics (8). In the 
severe, corticosteroid-refractory allergy-induced asthma population, the anti-immunoglobulin E 
(IgE) agent omalizumab (Xolair®) has shown efficacy. In the severe population with an 
eosinophilic phenotype, the two currently approved anti interleukin (IL)-5 agents, mepolizumab 
(Nucala®) and reslizumab (Cinqair®), and the anti-IL5 receptor benralizumab (Fasenra®) have 
shown efficacy as well. These anti-IL5 agents now provide additional therapeutic options with 
important limitations. Even in the high eosinophilic group, 36% of patients on mepolizumab had 
no decrease in OCS dose or had a lack of asthma control (9), suggesting that targeting a single 
cytokine in a heterogenous disease such as asthma is not sufficient. To address these limitations, 
dupilumab, an anti-IL4-Rα antibody that blocks the biologic activities of both IL-4 and IL-13 was 
more recently developed and approved (10). Most recently, Tezepelumab (Tezspire®), a thymic 
stromal lymphopoietin (TSLP) blocker, was approved in December 2021 for the treatment of 
severe asthma (11). However, even when using currently available biologics, substantial 
proportions of patients continue to experience exacerbations and may benefit from agents that 
target different molecular pathways (12, 13, 14). Therefore, despite these additional therapeutic 
options, there is still a clear unmet medical need among patients with severe asthma, both within 
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the eosinophilic (“Type 2-high”) subset of asthmatics specifically targeted by most of the 
currently available biologics, and in the non-eosinophilic (“Type 2-low”) subset which currently 
benefits from few if any effective asthma therapies. Furthermore, treatment with currently 
approved biologics is associated with certain adverse events (AE), including infections, eye 
disorders, headache, injection site reactions. Xolair and Cinqair are associated with a black box 
warning of potential for anaphylaxis (15, 16). The main objectives for new therapies are to further 
improve asthma symptoms, lung function, quality of life and prevent exacerbations, while 
optimizing safety and tolerability of treatment.  
Amlitelimab (also known as KY1005 or SAR445229) binds OX40L and blocks interaction with 
its receptor, OX40. The engagement between OX40 and OX40L occurs during the T-cell-antigen-
presenting cell (APC) interaction, after antigen recognition, and provides essential signals for the 
generation and survival of Tmem, the enhancement of the T helper (Th) cell (such as Th1, Th2, 
Th17 and Th22) response and the prolongation of inflammatory responses (17). Asthma is a 
heterogeneous disease, with approximately half of asthma patients showing evidence of Type 2 
inflammation, elevated Th2 cytokines (IL-5, IL-13, and IL-4) and eosinophilic infiltration, the 
target of current biologics. Few effective therapies are currently in place for asthma patients 
showing evidence of non-eosinophilic, Type 2-low inflammation (18). 
Amlitelimab data collected to this stage of development in two healthy volunteer studies and a 
single Phase 2a study in participants with moderate-to-severe atopic dermatitis (AD) suggest an 
unremarkable safety profile with no specific identified risk from nonclinical/clinical programs so 
far. 
The objective of this DRI17509 study is to assess the efficacy and safety of amlitelimab, a human 
anti OX40L mAb, in participants with moderate-to-severe asthma which is not well controlled on 
ICS in combination with other controller medication(s) with or without OCS therapy. 
2.2 
BACKGROUND  
Overview of amlitelimab 
Amlitelimab binds OX40L to block the interaction with its receptor, OX40 (CD134). The Fc 
regions were modified to the IgG4PE variant to reduce Fc receptor binding and stabilize the 
antibody hinge region. The resulting molecule is therefore expected to have null effector function 
(known not to deplete target cells) and would not undergo fragment antigen binding arm exchange 
as has been reported for natural IgG4. 
OX40L is inducibly expressed on professional antigen presenting cells, such as B cells, dendritic 
cells (DC) and macrophages upon activation (19). Other cells such as endothelial cells, smooth 
muscle cells, mast cells and natural killer cells can also be induced to express OX40L (20). 
OX40L interacts “monogamously” with OX40, which is expressed on activated T cells (21), CD4 
and CD8 T cells, inducing differentiation towards Th2, Th1, Th17, and Th22. The OX40/OX40L 
axis has also been shown to enhance the proliferation and activation of Tmem and abrogate 
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forkhead box P3 positive regulatory T cells (Treg) function (22). OX40-OX40L interaction is also 
necessary for the differentiation of activated B cells into highly Ig-producing cells. 
The interaction between OX40 and OX40L occurs during the T cell DC interaction, following 
inducible expression of OX40L on DCs between hours and days after antigen recognition. After 
disengaging from DCs, the OX40 expressing T cell may then interact with other OX40L 
expressing cells, which in turn provide essential signals for the generation of Tmem with a drive 
to Th2 polarization and the prolongation of the inflammatory responses. OX40 signals render 
T cells resistant to Treg cell mediated suppression and furthermore, OX40 signaling in Treg cells 
directly inhibits their suppressive function. 
Expression of OX40 and OX40L is reportedly increased in the lungs (lamina propria) of mild 
asthma patients and serum OX40L is elevated in pediatric asthma patients (23, 24). In a Phase 2 
trial, oxelumab, an OX40L antagonist depleting mAb given to mild atopic asthma participants, 
resulted in a 17% reduction in total IgE levels and 75% reduction in sputum eosinophils, however 
ultimately oxelumab did not attenuate early- or late-phase asthmatic responses upon an allergen 
challenge and did not have an effect on airway hyper-responsiveness or blood eosinophils 
compared to placebo (25). The reasons for an OX40L antagonist not improving clinical outcomes 
in allergic airway disease are unknown. 
 
Allergic asthma is one subset of the Type 2-high asthma endotype. Production of alarmins IL-25, 
TSLP and IL-33 by the respiratory epithelium downstream of viral infections, allergens and 
pollutants plays a major role in initiating Type 2 inflammation. OX40L expression on ILC2 cells 
is regulated by IL-33 and is considered a checkpoint of type 2 inflammation (26), while TSLP is 
thought to partly exert its effects via OX40L expression on DCs to modulate type 2 inflammation 
(27). 
Non-clinical Data 
In Vitro Characterization 
Amlitelimab has high affinity for human OX40L and blocks its interaction with OX40 in 
biochemical assays in vitro. 
Demonstration of poor or no binding to human Fc receptors indicates that amlitelimab is unlikely 
to cause Fc receptor mediated OX40L superclustering and consequent activation of target 
downstream pathway(s). 
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In Vivo Characterization 
Treatment of cynomolgus monkeys with amlitelimab resulted in inhibition of the T-dependent 
antibody response (TDAR). 
Pharmacokinetics and Non-clinical Safety 
Amlitelimab has been evaluated in multiple toxicity studies in cynomolgus monkeys, including 
Good Laboratory Practice (GLP)-compliant, 13-week and 26-week repeat dose studies.  
No local or systemic toxicity was observed in the 13-week and 26-week IV repeated dose toxicity 
studies in monkeys and there was no effect on safety pharmacology parameters. There was no 
evidence of infection in either study. 
 
The potential for local toxicity of amlitelimab in the formulation intended for SC administration in 
humans was evaluated in a GLP-compliant local tolerance and PK study in cynomolgus monkeys. 
 Details of these and 
additional non-clinical studies can be found in the amlitelimab (KY1005) Investigator’s Brochure 
(IB). 
Clinical Data 
Amlitelimab has been administered to healthy volunteers (studies KY1005-CT01 and KY1005-
CT04) and to participants with moderate-to-severe AD (study KY1005-CT02, study KY1005-
CT05). These studies are summarized below. Further information can be found in the amlitelimab 
(KY1005) IB.  
Study KY1005-CT01 
Study KY1005-CT01 was the first-in-human (FIH) study of amlitelimab that explored the safety 
and tolerability of single and repeat doses of amlitelimab in healthy volunteers.  
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This study was conducted at a single investigative site, in line with a typical FIH dose escalation 
design. Eight cohorts were studied, 
 All cohorts comprised 8 healthy volunteers 
allocated at random to either active (6 participants) or matching placebo (2 participants).  
Overall, this study identified no meaningful safety or tolerability concerns and provided PK and 
pharmacodynamics (PD) data to support the dose selection for the Phase 2a KY1005-CT02 study.  
Regarding immunization whilst not causing complete suppression it was noted that the response 
to the neo-antigen KLH was blunted by the administration of amlitelimab in HVs. For the recall 
antigen tetanus toxin (TT), no observable effect of amlitelimab was noted for anti-TT IgG, 
although anti-TT IgM suppression was numerically greater than placebo, but not dose dependent. 
Further information can be found in the IB. 
Study KY1005-CT02 
The Phase 2a (KY1005-CT02; NCT03754309), randomized, double blind, placebo controlled, 
parallel group, multicenter study was designed to explore the efficacy and safety of monotherapy 
amlitelimab in adult participants with moderate-to-severe AD who have a documented history, 
within 6 months prior to baseline, of either inadequate response to topical treatments or 
inadvisability of topical treatments.  
Participants (n=89) were randomized in a 1:1:1 ratio to receive either an IV lower dose (200 mg 
loading/100 mg maintenance) or higher dose (500 mg loading/250 mg maintenance) of 
amlitelimab, or matching placebo. Participants received amlitelimab or placebo Q4W from 
baseline to Day 85/Week 12 when the last dose was received. 
Meaningful efficacy differences in the key endpoints (Eczema Area and Severity Index [EASI] 
and SCORing of atopic dermatitis [SCORAD]) between those receiving amlitelimab and placebo 
were observed from Day 15 and maintained to the primary endpoint (Day 113). Supporting 
efficacy, an improvement in pruritis was also observed. No meaningful difference between the 
amlitelimab treatment arms was noted. In those participants achieving a Investigator Global 
Assessment (IGA) of 0/1 at Day 113, additional efficacy assessments through the safety follow-up 
demonstrated a maintenance of response in the majority of participants of up to 5.5 months (end 
of study [EOS]) following the last dose of amlitelimab. 
The most common AEs in the study were exacerbation of AD and nasopharyngitis, the incidence 
of which were numerically higher in the placebo group compared to those receiving KY1005. 
Overall, no meaningful differences were observed when considering TEAEs.  
Further detailed information regarding the safety outcomes from the Phase 2a study can be found 
in the IB. 
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Study KY1005 CT04 
KY1005-CT04 (NCT04449939) was a Phase 1, open label study to assess the PK, safety and 
tolerability of KY1005 after single dose administration by the SC and IV routes in male healthy 
volunteers. The purpose of this study was to assess the PK of KY1005 after SC administration and 
to compare the safety and tolerability of KY1005 when given via SC injection and IV infusion, to 
support SC administration. Intravenous KY1005 was included as a reference treatment. Twenty-
four healthy volunteers were enrolled as 3 treatment groups of 8 healthy male participants (250 
mg IV, 125 mg SC, 250 mg SC). 
The primary endpoint was the characterization of the PK of SC and IV administered KY1005 
after a single dose. Key secondary endpoints included safety and tolerability.  
There were no clinically meaningful trends noted in the incidence or nature of the AEs or 
abnormal laboratory results and KY1005 was well tolerated when given SC with low incidence of 
injection site pain/reactions. 
A full description of the KY1005-CT04 study together with the results can be found in the IB. 
Study KY1005-CT05 
The Phase 2b (KY1005-CT05; NCT05131477), randomized, double blind, placebo controlled, 
parallel group, multicenter dose ranging study designed to explore the efficacy (including 
dose/exposure response) and safety of KY1005/SAR445229 across a range of doses/exposures 
(500 mg loading dose followed 28 days later and thereafter with 250 mg Q4W, or 250 mg Q4W, 
or 125 mg Q4W, or 62.5 mg Q4W, or Placebo Q4W) for a maximum duration of 52 weeks in 
adult participants with moderate-to-severe AD who have had an inadequate response to topical 
therapies or where topical therapies are not advised. The study is ongoing.  
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of amlitelimab may be found in the amlitelimab IB and participant information 
leaflet. 
2.3.1 Risk assessment  
Amlitelimab specific risks, including any associated with SC administration, have not been 
identified to date from the non-clinical or clinical program. Potential risks include hypersensitivity 
and/or anaphylactic reactions, serious and opportunistic infections (including helminthic 
infections), decreased antibody response to neoantigens and/or new vaccinations, injection site 
reactions, malignancy (discussed further in the IB). These potential risks are in common with 
other immunomodulatory drugs and there is no evidence to date to suggest these will be 
exaggerated in the specific case of OX40/OX40L blockade. One participant in the prior healthy 
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In the Phase 2a KY1005-CT02 study, no meaningful differences in TEAEs were observed 
between the amlitelimab groups or between the amlitelimab and placebo groups. The most 
common AEs in the study were exacerbation of AD and nasopharyngitis, the incidence of which 
were numerically higher in the placebo group compared to those receiving amlitelimab. Fourteen 
events of headache were reported, 12 of which were in 3 participants in the high dose amlitelimab 
group. Of note, 3 participants reported an event of conjunctivitis: 1 event of infectious 
conjunctivitis (low dose amlitelimab mild intensity, not deemed related), 1 allergic conjunctivitis 
(high dose amlitelimab, moderate intensity, not related), and 1 haemorrhagic conjunctivitis (high 
dose amlitelimab, mild intensity, not related). In all 3 cases, participants received management, 
and all completed the study. 
 
There are no available data with the use of amlitelimab in pregnancy to evaluate a drug-associated 
risk of birth defects, miscarriage, or adverse maternal or fetal outcomes. Women of childbearing 
potential (WOCBP) who are not taking adequate birth control measures will not be included in the 
study. Pregnancy is an adverse event of special interest in this study. Testing and adequate 
contraceptive precautions are included for study participation. 
No meaningful clinical events were reported in the KY1005-CT04 SC healthy volunteer study. 
Injection site reactions/pain are a known risk with SC administration. Three out of 16 participants 
receiving SC amlitelimab reported local injection site pain/tenderness. All were mild in severity 
and resolved without sequelae.  
In the KY1005-CT05 AD study, one participant with moderate-to-severe AD was hospitalized for 
bullous and pustular dermatitis following 2.5 months of amlitelimab (125 mg Q4W) treatment. 
While some clinical features at initial presentation raised the possibility of a hypersensitivity 
reaction or Stevens-Johnson syndrome/toxic epidermal necrolysis, the final diagnostic workup 
and clinical course did not support either of these diagnoses, and the final etiology remains 
unclear. The skin biopsy showed features more suggestive of acute generalized exanthematous 
pustulosis, although pustular psoriasis was also in the differential diagnosis, as well as possible 
infectious etiology (infectious work-up was not performed). The patient recovered on 
hospitalization Day 12, after treatment with ceftriaxone and methylprednisolone, and amlitelimab 
was discontinued. 
Further details can be found in the IB. 
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Table 1 - Risk assessment  
Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Hypersensitivity 
and/ or anaphylactic 
reactions 
Class effect with monoclonal antibodies. 
Large protein molecules, despite humanization, 
can be immunogenic. Amlitelimab is a biologic 
therapeutic protein and hypersensitivity risk is 
considered as a class effect with monoclonal 
antibodies. 
 
Exclude participants with or history of 
hypersensitivity or allergy to any of the excipients or 
IMP or other allergy that, in the opinion of the 
Investigator, contraindicates participation in the 
study.  
Evaluate for severe allergies and atopy prior to 
initiating treatment with the IMP. Stop IMP 
if reaction develops and manage according to 
standard of care. 
Study centers are required to have procedures and 
personnel trained and experienced in the 
management of emergencies such as systemic and 
localized allergic reactions and cytokine release 
syndrome. 
To further characterize this potential risk, allergic 
reaction is an adverse event of special interest 
(AESI) for amlitelimab. 
Serious and 
opportunistic 
infections (including 
Helminthic 
infections) 
Serious infections are common to 
immunomodulatory drugs and there is no 
evidence to suggest these will be exaggerated 
in the specific case of OX40/OX40L blockade. 
Since the physiological role of T cells is host 
defense against infections, treatment with an 
OX40L blocker may be associated with a risk of 
reduced control of infections 
l
in the clinical program to date, including 
KY1005-CT01 (Phase 1, healthy volunteers) 
and KY1005-CT02 (Phase 2, participants with 
moderate-to-severe atopic dermatitis [AD]). 
More detailed information is available in the IB. 
Evaluation for serious infection prior to initiating 
treatment with the IMP is recommended. 
Routine monitoring of serious infection via indicative 
clinical signs and symptoms. If signs or symptoms of 
clinically important acute infection occur, IMP will be 
withheld, and the infection managed according to 
standard of care.  
Helminthic Infections: Exclusion of participants with 
chronic or active helminth infections. All such 
infections should be treated before initiating therapy 
with the IMP. If participants become infected while 
receiving the IMP, the IMP should be discontinued 
until infection is resolved. 
The following are considered exclusion criteria from 
study participation: 
• 
Known history of or suspected significant 
current immunosuppression, including 
history of invasive opportunistic or 
helminthic infections despite infection 
resolution or otherwise recurrent infections 
of abnormal frequency or prolonged 
duration. 
• 
Any active or chronic infection requiring 
systemic treatment within 2 weeks prior to 
baseline (1 week in the event of superficial 
skin infections). 
• 
Active or latent TB infection  
• 
Active/chronic infections including 
helminthic infection. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
In the event of any infection, Investigators will 
determine whether temporary or permanent 
discontinuation of IMP is necessary.  
To further characterize this potential risk, any severe 
or opportunistic viral, bacterial, or fungal infection 
and/or any uncommon, unanticipated or persistent 
infection (viral, parasitic, bacterial, or fungal) are 
considered an AESI for amlitelimab.  
Decreased antibody 
response to 
neoantigens and/or 
new vaccinations 
Clinical observation  
In phase I study in healthy volunteers, 
SAR445229 appeared to have a 
pharmacodynamic effect from doses of 
0.45 mg/kg and above based on the attenuation 
of the neoantigen (anti-KLH IgG and anti-KLH 
IgM) response. Potential impact on new vaccine 
response should be considered. 
Assure that all pending and necessary vaccination 
(especially live/attenuated as well as for COVID-19) 
occurs per local recommendations and well in 
advance of dosing. 
• 
Exclusion of vaccination with a live 
(attenuated) immunization within 12 weeks 
prior to Baseline; completion of required 
administrations of COVID-19 vaccine 
within 14 days prior to Baseline. 
• 
In cases where booster vaccinations are 
recommended per local regulations it is 
not recommended that participants receive 
their COVID-19 vaccinations/boosters 
within less than 14 days immediately prior 
to or following the IMP administration. 
Injection site 
reactions 
l
Routine monitoring for all events of injection site 
reactions. 
On IMP administration days, local skin reactions 
around the site of injection will be assessed by the 
Investigator or other appropriately trained site 
personnel 30 minutes after the injection. 
Light pressure will be applied at the injection site 
and any pain, itchiness, tenderness, erythema, and 
induration will be recorded in the eCRF. Pain and 
tenderness will be assessed according to the 
following scale: 
Definitions of pain and tenderness: 
• 
None: nothing. 
• 
Mild: easily tolerated. 
• 
Moderate: interferes with daily activities. 
• 
Severe: prevents normal everyday 
activities or sleep. 
Erythema and induration will be measured using a 
ruler, or a template supplied by the Sponsor.  
Severe injection site reactions that last longer than 
24 hours are considered AESI. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Malignancy 
The OX40/OX40L axis modulates the 
antineoplastic T cell response, which is involved 
in tumor surveillance and defense. 
Inhibition of OX40L may therefore lead to 
impaired immune surveillance and control of 
established tumors (growth, metastasis, and re-
emergence).  
Evaluation for malignancy will be made prior to IMP 
initiation and participants with known existing/prior 
history of neoplasm will be excluded based on the 
following criteria: 
• 
Participants with a history of any type of 
malignancy to be excluded, with the 
exception of basal and squamous cell skin 
cancer or in situ cervical carcinoma that 
has been excised and cured in >3 years 
prior to baseline. 
Based on routine monitoring for clinical signs and 
symptoms, IMP will be held in case of suspected 
diagnosis of a malignancy during the study and 
permanently discontinued immediately upon 
confirmed diagnosis. 
To further characterize the risk, routine monitoring 
will be performed. Malignancy is considered an 
AESI, and all cases of malignancy will be reviewed 
periodically by an Independent Data Monitoring 
Committee (IDMC). 
2.3.2 Benefit assessment  
In the KY1005-CT02 study in participants with moderate-to-severe AD, amlitelimab provided 
meaningful improvements in the signs and symptoms of AD and no safety or tolerability issues 
were noted with 12 weeks of treatment. 
2.3.3 Overall benefit/risk conclusion  
Overall, blockade of OX40/OX40L in humans is precedented without acute severe adverse 
consequences. These findings suggest that OX40L mediated clearance is not relevant at 
pharmacological doses and that such binding, in disease states in which OX40L is upregulated, 
does not lead to common adverse reactions. Mitigation of the theoretical risks is possible through 
selection of appropriate study populations and monitoring in clinical trials.   
The design of the present study (DRI17509) including selection criteria of the study population, 
risk mitigation strategy, and monitoring of safety variables, should maintain the positive balance 
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regarding the expected efficacy/safety ratio for amlitelimab in the treatment of participants with 
asthma. 
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3 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the efficacy of different doses of 
amlitelimab compared to placebo in participants 
with moderate-to-severe, uncontrolled asthma. 
• 
Annualized rate of severe exacerbation events over 
48 weeks, defined as: 
- 
Worsening of asthma requiring the use of 
systemic corticosteroids for ≥3 days or, in the 
case of a stable maintenance regimen of oral 
corticosteroids (OCS) for the treatment of 
asthma, a doubling of the dose for 3 or more 
days; or  
- 
Hospitalization or emergency room visit 
because of asthma, requiring systemic 
corticosteroids 
Secondary 
 
• 
To evaluate the effects of amlitelimab compared to 
placebo on lung function as measured by forced 
expiratory volume in 1 second (FEV1) 
• 
Change from baseline in pre-bronchodilator (BD) 
FEV1 at Week 48 (key secondary endpoint) 
• 
Change from baseline in post-BD FEV1 at Week 48  
• 
The absolute change in the percent predicted FEV1 
from baseline to Week 48 (pre-BD and post-BD) 
• 
To evaluate the effects of amlitelimab on Asthma 
Control Questionnaire 5 (ACQ-5)  
• 
Change from baseline in ACQ-5 score at Week 48 
(key secondary endpoint) 
• 
Change from baseline in ACQ-5 score at Weeks 2, 
4, 8, 12, 24, 36, and 60  
• 
To evaluate the effects of amlitelimab on time to first 
severe exacerbation event 
• 
Time to first severe exacerbation event 
• 
To evaluate the effects of amlitelimab on other 
spirometry assessments  
• 
Change from baseline in pre-BD and post-BD FEV1 
and other lung function measurements (peak 
expiratory flow [PEF], forced vital capacity [FVC], 
and forced expiratory flow [FEF] 25-75%) at each 
spirometry endpoint 
• 
To evaluate the effects of amlitelimab on fraction of 
exhaled nitric oxide (FeNO) 
• 
Change from baseline in FeNO at Weeks 2, 4, 8, 
12, 16, 24, 36, 48 and 60 
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Objectives 
Endpoints 
• 
To evaluate the effects of amlitelimab compared to 
placebo on reducing the incidence of “loss of 
asthma control” (LOAC) events  
• 
Annualized rate of LOAC events, during 48 weeks 
of treatment, defined by one or several of the 
following criteria: 
- 
A 30% or greater reduction from baseline in 
morning PEF on 2 consecutive days. 
- 
≥6 additional reliever puffs of short-acting beta 
2-agonists (SABA) OR ≥4 additional puffs of 
low-dose ICS/formoterol in a 24-hour period 
(compared to baseline) on 2 consecutive days  
- 
Increase in ICS ≥4 times than the Visit 2 dose 
- 
Worsening of asthma requiring the use of 
systemic corticosteroids for ≥3 days or, in the 
case of a stable maintenance regimen of OCS 
for the treatment of asthma, a doubling of the 
dose for 3 or more days  
- 
Hospitalization or emergency room visit 
because of asthma, requiring systemic 
corticosteroids severe exacerbation event 
• 
To evaluate the effects of amlitelimab on time to first 
LOAC event 
• 
Time to first LOAC event 
• 
To evaluate the effects of amlitelimab on asthma 
symptoms  
• 
Change from baseline in the Asthma Daytime 
Symptom Diary (ADSD) 6-item daily morning score 
and in the Asthma Nighttime Symptom Diary 
(ANSD) 6-item daily evening scores at Weeks 2, 4, 
8, 12, 24, 36, 48, and 60 
• 
To evaluate the effects of amlitelimab on reducing 
the incidence of severe asthma exacerbations 
requiring hospitalization or emergency room or 
urgent care visit 
• 
Annualized rate of severe asthma exacerbations 
requiring hospitalization or emergency room or 
urgent care visit during 48 weeks of treatment  
• 
Assess the effect of amlitelimab on BD therapy 
• 
Change from baseline in the numbers of 
inhalations/day of SABA or low-dose ICS/formoterol 
for symptom relief at Weeks 2, 4, 8, 12, 24, 36, 48, 
and 60 
• 
To evaluate the pharmacokinetics (PK) of 
amlitelimab and anti-drug antibodies to amlitelimab 
in participants with asthma 
• 
Serum amlitelimab concentrations measured 
throughout the study 
• 
Incidence of anti-amlitelimab antibody positive 
response 
• 
To evaluate the safety of amlitelimab in participants 
with asthma  
• 
Percentage of participants with treatment-emergent 
adverse events (TEAEs), including local reactions, 
adverse events of special interest (AESIs), serious 
adverse events (SAEs)  
• 
Incidence of potentially clinically significant 
laboratory test, vital signs, and ECG abnormalities 
in the treatment period 
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Objectives 
Endpoints 
• 
To evaluate the effects of amlitelimab on participant 
reported outcomes (PROs)  
• 
Change from baseline in Asthma Quality of Life 
Questionnaire with Standardized Activities (AQLQ 
(S)) Self-Administered Score at Week 48 (key 
secondary endpoint) 
• 
AQLQ (S) Self-Administered Score at Weeks 2, 4, 
8, 12, 24, 36, and 60 
• 
Change from baseline in St. George’s Respiratory 
Questionnaire (SGRQ) at Weeks 2, 4, 8, 12, 24, 36, 
48, and 60 
• 
Proportion of participants with a decrease from 
baseline of at least 4 points in SGRQ total score at 
Week 48 
• 
To evaluate the effects of amlitelimab on ACQ-6 
and ACQ-7  
• 
Change from baseline in ACQ-6 score and ACQ-7 
at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 
Tertiary/Exploratory 
 
i
l
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Objectives 
Endpoints 
i
 
 
 
 
 
 
Primary estimands defined for primary and key secondary efficacy endpoints are provided in 
Section 9.2. 
3.1 
APPROPRIATENESS OF MEASUREMENTS   
The primary and key secondary efficacy and safety assessments used in this study are standard for 
the evaluation of therapy in participants with moderate-to-severe asthma, which have been used or 
are being used in similar designed Phase 2 and 3 studies using dupilumab (Liberty Asthma 
QUEST, Phase 3, NCT02414854,) and tezepelumab (PATHWAY, Phase 2, NCT02054130, and 
NAVIGATOR, Phase 3, NCT03347279). 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 2, global, multicenter, randomized, double-blind, placebo-controlled, parallel-
group, dose-ranging study to assess the efficacy, safety, and tolerability of add-on therapy with 
amlitelimab in adult participants (aged 18-75 years, inclusive) with moderate-to-severe asthma 
who are not well controlled on ICS plus a second controller medication (eg, LABA, LTRA, 
methylxanthines, LAMA) with or without oral prednisone for the maintenance treatment of 
asthma. Participants requiring a third controller are allowed to participate in this study (please see 
Section 5.1). Study treatments are amlitelimab 250 mg with 500 mg loading dose on Day 1, 
amlitelimab 125 mg with 250 mg loading dose on Day 1, amlitelimab 62.5 mg with 125 mg 
loading dose on Day 1, or matching placebo, administered during the 60 weeks treatment period. 
The primary endpoint is the annualized rate of severe asthma exacerbation events over 48 weeks 
(28). Maintenance of effect will be evaluated at Week 60. Severe exacerbations will be recorded 
by the Investigator and are defined as either worsening of asthma requiring the use of systemic 
corticosteroids for ≥3 days or, in the case of a stable maintenance regimen of OCS for the 
treatment of asthma, a doubling of the dose for 3 or more days; or hospitalization or emergency 
room visit because of asthma, requiring systemic corticosteroids. For exacerbation events to be 
counted as 2 separate events, they must be separated by at least 7 days between courses of 
systemic corticosteroids or doubling of the dose of stable background OCS.  
For efficacy endpoint analysis, the primary population will be the intent-to-treat (ITT) population 
(Section 9). The efficacy analysis of subgroups will be detailed in the statistical analysis plan 
(SAP). 
Randomization will be stratified by region, screening blood eosinophil count (<300 cells/μL and 
≥300 cells/μL), and number of severe asthma exacerbations in the previous 12 months 
(=1 exacerbation or >1 exacerbations). During the randomization procedure, the eosinophil count 
at Screening (Visit 1) must be entered in the IVRS/IWRS system. To ensure enrollment according 
to intended distribution of exacerbation history and eosinophil count, the number of participants 
enrolled into each stratification group will be controlled and monitored as follows: 
• 
Only 1 severe asthma exacerbation in the previous 12 months: not more than 
approximately 50% of participants (210 participants).  
• 
Eosinophils <300 eosinophils/μL: not more than approximately 50% of participants 
(210 participants). 
The clinical trial consists of three periods, as outlined below:  
• 
Screening period (up to 4 weeks) to determine whether participants meet entry criteria and 
to establish level of asthma control before randomization.  
- 
The screening of a participant triggers the IMP shipment to site in IVRS/IWRS 
system. A maximum of 2 weeks is required to get IMP on site. Randomization of the 
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participant must take this constraint into consideration (up to 2 weeks will need to be 
allowed for IMP shipment between screening and randomization). 
• 
Randomized treatment period (60 weeks) 
• 
Follow-up period (12 weeks) to monitor participants after treatment 
- 
Eligible participants who complete the treatment period will be offered the opportunity 
to participate in the LTS study with amlitelimab. Participants subsequently enrolled in 
the LTS study will not participate in the follow-up period of this trial but will have a 
follow up period after the LTS study. 
Participants must have been on existing treatment with medium-to-high doses of ICS therapy 
(≥500 μg of fluticasone propionate daily or comparable ICS dosage up to a maximum of 
2000 μg/day of fluticasone propionate or clinically comparable) in combination with a second 
controller (eg, LABA, LTRA, LAMA, methylxanthines) for at least 3 months with a stable 
dose≥1 month prior to Screening (Visit 1) and must stay on their established controller medication 
for asthma throughout the duration of the study, with the exception of OCS used for maintenance 
treatment of asthma. The class of reliever medication should not change during the study. For 
Japan, please see Section 10.8 for details. 
All eligible participants will be randomized (2:2:1:2) to one of the following IMP treatment 
groups to be administered for 60 weeks by SC administrations Q4W for the first 6 doses and 
Q12W thereafter until Week 48: 
• 
Amlitelimab 250 mg with 500 mg loading dose on Day 1 
• 
Amlitelimab 125 mg with 250 mg loading dose on Day 1  
• 
Amlitelimab 62.5 mg with 125 mg loading dose on Day 1 
• 
Matching placebo 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
A randomized, placebo-controlled study design where the effect of the IMP is assessed on top of 
standard of care background therapy (medium-to-high doses of ICS in combination with a second 
controller) is considered to be the most appropriate design to examine the efficacy and safety of a 
novel biologic therapy in asthma. Annualized rate of severe asthma exacerbations was selected as 
the primary endpoint as it is generally considered to be the most clinically relevant outcome in 
asthma. Asthma exacerbations constitute the greatest risk to patients, increase the risk of asthma 
mortality, are a cause of anxiety to patients and their families, result in the greatest stress on 
health care providers, and generate the greatest cost to the health care system (28). The 60-week 
duration of this study allows for assessment of the broad range of short-term and mid-term effects 
amlitelimab may have on annualized asthma exacerbation rate, lung function, health-related 
quality of life  (HRQoL), and symptom control, while reducing the impact of seasonal variations 
observed in exacerbations. 
The study is dose-ranging to gather information for the selection of the ultimate dose for future 
clinical development. A total of 3 dosing groups plus placebo will be tested in this study.   
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Based on the inclusion criteria for this study, all study participants will meet criteria for GINA 
definition of moderate-to-severe asthma step 4 and 5 (3). The GINA Guidelines recommend the 
following maintenance regimens for management of step 4 and 5 participants: medium-to-high 
dose of ICS-LABA with consideration of additional controllers (LAMA, LTRA, etc) and referral 
for phenotypic assessment for biologics (anti-IgE, anti-IL5/5R, anti-IL4/4R). Therefore, the study 
will allow for the use of double or triple controller therapy.  
4.2.1 Participant input into design  
A report of participant insights was provided in November of 2021 for the DRI17509 protocol. 
Feedback was obtained from various past participant insights collected by Sanofi, including 
participant panels. Feedback related to at-home spirometry, PROs/questionnaires, visit schedule, 
recruitment and retention was taken in consideration while developing the current protocol.   
4.3 
JUSTIFICATION FOR DOSE  
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4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the EOS Visit of the last participant in the study.  
A participant is considered to have completed the study if he/she has completed all periods of the 
study. 
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5 
STUDY POPULATION  
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 75 years of age inclusive, at the time of signing the informed 
consent.  
Type of participant and disease characteristics 
I 02. A physician-diagnosed moderate-to-severe asthma for ≥ 12 months based on GINA 
definition step 4 and 5 (3) (Section 10.10.1).  
I 03. Participants with existing treatment with medium-to-high doses of ICS therapy (≥500 μg 
of fluticasone propionate daily or comparable ICS dosage up to a maximum of 2000 
μg/day of fluticasone propionate or clinically comparable) in combination with a second 
controller (eg, LABA, LTRA, LAMA, methylxanthines) for at least 3 months with a stable 
dose ≥1 month prior to Visit 1.  
Note: Participants requiring a third controller for their asthma will be considered eligible 
for this study, and it should also be used for at least 3 months with a stable dose ≥1 month 
prior to Visit 1. 
Note for Japan: participants must be on ≥400 μg of fluticasone propionate daily or 
equivalent. 
I 04. ≥1 severe asthma exacerbation in the past year, with at least one exacerbation occurring 
while on treatment with medium to high doses of ICS therapy (≥500 μg of fluticasone 
propionate daily or comparable ICS dosage), and defined as: 
• 
Treatment with systemic corticosteroids (oral or parenteral) for ≥3 days for worsening 
asthma; in case of a stable maintenance regimen of OCS, a doubling of the dose for 3 
or more days, OR 
• 
Hospitalization or emergency medical care visit for worsening asthma, requiring 
systemic corticosteroids. 
Note for Japan: at least one severe exacerbation occurring while on treatment with ≥400 μg 
of fluticasone propionate daily or equivalent. 
I 05. Participants with pre-BD FEV1>40% and <80% of predicted normal (29, 30) at 
Visit 1/Screening. 
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I 06. 5-item ACQ-5 score >1.5 at screening and randomization. 
I 07. Participants with reversibility of at least 12% and 200 mL in FEV1 after administration of 
2 to 4 puffs (200-400 μg) of albuterol/salbutamol or levalbuterol/levosalbutamol during 
screening or documented history of a reversibility test that meets these criteria within 
12 months prior to Visit 1 is considered acceptable to meet this inclusion criterion. 
- 
Alternatively, a Severe Asthma Research Program (SARP) method could be used: 
maximal change in FEV1 after the administration of 4, 6, and 8 puffs of albuterol 
(360, 540, 720 μg albuterol) (31) 
I 08. If on chronic OCS treatment for the maintenance treatment of asthma, up to a maximum of 
15 mg prednisone or equivalent daily or 30 mg every other day is allowed, must be on 
stable dose for ≥1 month prior to Visit 1. 
Weight 
I 09. Weight ≥40 kg and ≤150 kg at Baseline. 
Sex, contraceptive/barrier method and pregnancy testing requirements/breastfeeding 
I 10. All    
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants with partners of childbearing potential and who are eligible to participate if they 
agree to the following during the study intervention period and until 5 months after the last 
administration of study intervention or the early termination visit:  
• 
Refrain from donating or cryopreserving sperm 
Plus either:  
 
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b) Female participants 
A female participant is eligible to participate if she is incapable of becoming pregnant, not 
pregnant or breastfeeding, and one of the following conditions applies: 
Informed Consent 
I 11. Capable of giving signed informed consent as described in Section 10.1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (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. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Chronic lung disease other than asthma. 
E 02. Current smoker or former smoker with cessation within 6 months of screening or history of 
>10 pack-years. Active vaping of any products and/or marijuana smoking within 6 months 
of screening.  
E 03. Participants who experience a deterioration of asthma that results in emergency treatment 
or hospitalization, or treatment with systemic steroids within 1 month prior to the 
Screening Visit.  
Note: counting from the date of completion of treatment for asthma exacerbation. 
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E 04. Participants who have experienced an upper or lower respiratory tract infection within the 
4 weeks prior to screening. 
E 05. Suspicion of, or confirmed, coronavirus disease 2019 (COVID-19) infection or in contact 
with known exposure to COVID-19 at Screening or during the screening period; known 
history of COVID-19 infection within 4 weeks prior to Screening; history of requiring 
mechanical ventilation or extracorporeal membrane oxygenation (ECMO) secondary to 
COVID-19 within 3 months prior to Screening; participants who have had a COVID-19 
infection prior to Screening who have not yet sufficiently recovered to participate in the 
procedures of a clinical trial. 
E 06. Known history of, or suspected, significant current immunosuppression, including history 
of invasive opportunistic or helminthic infections despite infection resolution or otherwise 
recurrent infections of abnormal frequency or prolonged duration. 
E 07. Active/chronic infections including helminthic infection. 
E 08. Any active or chronic infection requiring systemic treatment within 2 weeks prior to 
Baseline (1 week in the event of superficial skin infections). 
E 09. For participants on chronic OCS use for the maintenance treatment of asthma: history of a 
serious infection requiring hospitalization. 
E 10. Participants with active tuberculosis (TB), latent TB, a history of incompletely treated TB, 
suspected extrapulmonary TB infection, or who are at high risk of contracting TB (such as 
close contact with individuals with active or latent TB) or received Bacillus Calmette-
Guérin (BCG)-vaccination within 12 weeks prior to Screening. 
Note: TB testing is mandatory to rule out active/latent TB and should be performed, 
assessed and documented according to local guidelines. If no local guidelines are available 
or are not able to be performed at the site, a blood sample for Quantiferon testing should be 
sent to the central laboratory. Participants with confirmed positive TB test are excluded 
from the study unless all of the following conditions are met: 
a) have a history of prior documented completed chemoprophylaxis for latent TB 
infection (with a treatment regimen as per local guidelines), OR treated for active TB 
infection,  
AND 
b) have obtained consultation with a specialist to rule out or treat active TB infection, 
AND 
c) for whom review and approval from Sponsor have been granted are eligible. 
E 11. A history of malignancy of any type (excluding basal and squamous cell skin cancer and in 
situ cervical carcinoma that has been excised and cured >3 years prior to baseline).  
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E 12. History of solid organ transplant.  
E 13. Participants positive for human immunodeficiency virus; participants with any of the 
following result at Screening (Visit 1): Positive (or indeterminate) hepatitis B surface 
antigen (HBs Ag) or positive IgM antibody to hepatitis B core antigen (IgM HBc Ab)  or 
positive total hepatitis B core antibody (HBc Ab) confirmed by positive hepatitis B virus 
(HBV) DNA or positive hepatitis C virus total antibody (HCV Ab) confirmed by positive 
hepatitis C virus (HCV) RNA. Guidance on hepatitis serology eligibility interpretation is 
provided in Table 7 in Section 8.2.4.  
Note for Japan: For Japan, the presence of HBsAg with/without positive HBV-DNA test 
result or the presence of HBc Ab or the presence of HBs Ab with positive HBV-DNA test 
result at screening or within 3 months prior to the screening visit is an exclusion criterion.  
E 14. Clinically significant laboratory abnormalities at Screening (Visit 1): 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 times upper 
limit of normal range (ULN). 
- 
Serum total bilirubin >1.5 × ULN (participants with Gilbert’s syndrome can be 
included with total bilirubin >1.5 × ULN as long as direct bilirubin is <1.5 × ULN). 
- 
Hemoglobin <10 g/100 mL for male and <9 g/100 mL for female. 
- 
Neutrophils <1500/μL (<1000/μL for those of African descent). 
- 
Platelets <100 000/μL. 
- 
Creatinine ≥150 μmol/L. 
E 15. Severe concomitant illness that would in the Investigator's opinion inhibit the participant's 
participation in the study, including for example, but not limited to, hypertension, renal 
disease, neurological conditions, heart failure and pulmonary disease. 
E 16. History (within last 2 years prior to Baseline) of prescription drug or substance abuse, 
including alcohol, considered significant by the Investigator. 
E 17. Elective surgery planned to be scheduled for any time in the period up to 3 months 
following the last dose of IMP. 
Prior/concomitant therapy 
E 18. Anti-IgE mAb therapy (eg, omalizumab [Xolair]) within 130 days prior to Visit 1 or any 
other biologic therapy (including anti-IL4/4R, IL-5/5R, or anti-TSLP mAb) or systemic 
immunosuppressant (eg, methotrexate) to treat inflammatory disease or autoimmune 
disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, 
systemic lupus erythematosus, multiple sclerosis) and other diseases, within 2 months or 
5 half-lives prior to Visit 1, whichever is longer, except stable dose OCS used for the 
maintenance treatment of asthma. 
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E 19. Participants who have received bronchial thermoplasty within 2 years prior to Visit 1 or 
plan to begin therapy during the screening period or the randomized treatment period. 
E 20. Treatment with a live (attenuated) immunization within 12 weeks prior to Baseline; 
completion of required administration of COVID-19 vaccine within 14 days prior to 
Baseline.  
E 21. History of hypersensitivity or allergy to any of the excipients or IMP or other allergy that, 
in the opinion of the Investigator, contraindicates participation in the study. Known or 
suspected hypersensitivity to amlitelimab or excipients used in the presentation of 
amlitelimab or in preparation for administration.   
E 22. Any prior use of anti-OX40 or anti-OX40L mAb, including amlitelimab. 
Prior/concurrent clinical study experience 
E 23. Investigational therapy for the treatment of asthma or other conditions within 5 half-lives 
or the limit of PD effects or 3 months where the t1/2 is unknown. 
E 24. Concurrent participation in any other clinical study, including noninterventional studies. 
Diagnostic assessments 
Not applicable. 
Other exclusions 
E 25. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 26. Any country-related specific regulation that would prevent the participant from entering 
the study – see Appendix 8 (Section 10.8) of the protocol (country-specific requirements). 
E 27. 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 28. 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 29. 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. 
 
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5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
No meals and dietary restrictions are required, except for the FeNO test and blood sample for 
serum chemistry.  
Participants should not eat or drink 1 hour prior to having the FeNO test, as this may affect the 
results.  
The blood sample for serum chemistry must be taken with the participant in fasting state which 
means no intake of any food or drink except for water for at least 8 hours (if the visit can only be 
done at a different time of the day and the participant is not fasting, then he/she should be advised 
to eat light food and the site should document that serum chemistry was not obtained under fasting 
conditions).   
5.3.2 Caffeine, alcohol, and tobacco  
Smoking and/or vaping and/or smoking marijuana will not be allowed from 6 months prior to 
Screening (Visit 1) until after the final follow-up visit.   
Use of alcohol and caffeine is allowed. However, 8 hours prior to spirometry, no alcohol should 
be consumed (for details, refer Section 8.1.3.1).  
5.3.3 Activity  
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung 
function assessments at the center. 
5.4 
SCREEN FAILURES  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any SAE. 
Participants who are eligible for rescreening may be rescreened once for any reason, except for 
PRO criteria (ie, ACQ-5<1.5), which will lead to screen failure without an option for rescreening. 
Please note exceptions for South Korea, please refer to Section 10.8.2.  Participants who fail any 
of the other inclusion or meet any exclusion criteria may be rescreened during the open screening 
period of the study; a different participant identification number will be issued. There is no 
requirement for a waiting period between the screen-failure date and the rescreen. Participants 
who are rescreened are required to sign a new ICF. 
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In the case of technical malfunction of equipment during spirometry, the participant may be 
retested. A participant who is unable to complete a successful spirometry effort as defined by 
American Thoracic Society/European Respiratory Society (ATS/ERS) criteria can be retested one 
additional time during the screening period of the study. If a participant is unable to perform an 
attempt of adequate quality 2 times in a row, it needs to be assessed if the participant is good 
candidate for the study.  
If the participant does not meet the qualifying criteria for reversibility at Visit 1/Screening (I 07), 
up to 2 additional attempts during the screening period, each on a different day prior to Visit 
2/Baseline, may be performed. When reversibility assessment is repeated during the screening 
period, the prebronchodilator FEV1 should again meet the inclusion criteria (I 05) of >40% and 
<80% of predicted normal. 
Participants with an upper or lower respiratory tract infection during the screening period may be 
rescreened after 4 weeks or 14 days after recovery, ie, completion of the therapy, whichever is 
longer. 
Participants who experience an asthma exacerbation that results in emergency treatment or 
hospitalization, or treatment with systemic steroids during the screening period may remain in 
screening and proceed with randomization 1 month after they have completed their course of OCS 
or returned to their maintenance dose of OCS. Screening period in this case can be extended to up 
to 3 months. Note: extension of screening is not allowed in South Korea, please refer to 
Section 10.8.2. 
If certain dynamic laboratory tests do not meet the inclusion criteria at Screening (Visit 1), these 
laboratory assessments may be repeated, at the discretion of the Investigator, if the parameter 
result is judged to be likely to return to acceptable range for study inclusion within the screening 
period prior to Baseline/Randomization (Visit 2). There is no need to screen fail such participants 
if the test finally meets the inclusion criteria. 
It is intended to include approximately 50% of participants with blood eosinophils<300 cells/μL 
and 50% of participants with blood eosinophils ≥300 cells/μL. By including up to approximately 
50% of participants with high blood eosinophils, it is expected to have adequate power to evaluate 
treatment effects in these important subgroups of asthma participants. If one of the stratification 
groups is filled, the IVRS/IWRS will close enrollment in this group. As other studies are 
recruiting participants with blood eosinophils ≥300 cells/μL, there will be increased competition 
for this subset of participants. Having this control measure in place, this should guarantee 
sufficient number of participants in both blood eosinophil count subgroups. New participants 
should be prescreened based on their historical eosinophil value that needs to be confirmed at 
Screening (Visit 1). Retesting of the eosinophil count is allowed up to 3 times during the 
screening period if needed. If a participant does not finally meet the required eosinophil count 
before randomization the participant should be screen failed. 
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5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Appendix 9 (Section 10.9): Contingency measures for a regional or national emergency that is 
declared by a governmental agency should be considered. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
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  
The IMP is to be administered every 28±3 days (Q4W) for the first 6 doses and every 84±3 days 
(Q12W) thereafter during the 60 weeks treatment period (Table 4).  
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 
Section 10.9: Contingency measures for a regional or national emergency that is declared by a 
governmental agency. 
Table 3 - Study intervention(s) administered  
Intervention label 
Amlitelimab 
Amlitelimab matching placebo 
Intervention name 
Amlitelimab 
Placebo 
Intervention description 
One initial loading dose of amlitelimab 
(two 2 mL injections) on Day 1, followed 
by one 2 mL injection of amlitelimab 
Q4W until Week 20 (inclusive) and 
Q12W starting from Week 24 and 
thereafter until Week 48 
One initial loading dose of amlitelimab 
matching placebo (two 2 mL injections) 
on Day 1, followed by one 2 mL injection 
of amlitelimab matching placebo Q4W 
until Week 20 (inclusive) and Q12W 
starting from Week 24 and thereafter 
until Week 48. 
Type 
Drug 
Drug 
Dose formulation 
Vial 
Vial 
Unit dose strength(s) 
125 mg/mL 
Dummy dose of placebo, to match 
amlitelimab 
Dosage level(s) 
Amlitelimab 250 mg with 500 mg loading 
dose, Amlitelimab 125 mg with 250 mg 
loading dose or Amlitelimab 62.5 mg with 
125 mg loading dose 
Dummy dose of placebo, to match 
amlitelimab 
Route of administration 
Subcutaneous injection 
Subcutaneous injection 
Use 
Experimental 
Placebo 
IMP and NIMP 
IMP 
IMP 
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Packaging and labeling 
IMP will be provided in 2 mL Type 1 clear 
glass vial. Each vial will be labeled as 
required per country requirement. 
IMP will be provided in 2 mL Type 1 clear 
glass vial. Each vial will be labeled as 
required per country requirement. 
[Current/former name(s) or 
alias(es)] 
KY1005 
NA 
Table 4 - Study arm(s)  
Arm title 
Amlitelimab 250 mg 
with 500 mg loading 
dose 
Amlitelimab 125 mg 
with 250 mg loading 
dose 
Amlitelimab 62.5 mg 
with 125 mg loading 
dose 
Placebo 
Arm type 
Experimental 
Experimental 
Experimental 
Placebo 
Arm description 
Participants will 
receive one initial 
loading dose of 500 
mg of amlitelimab on 
Day 1, followed by 
one injection of 250 
mg of amlitelimab 
Q4W until Week 20 
(inclusive) and Q12W 
starting from Week 
24 and thereafter 
until Week 48. 
Participants will 
receive one initial 
loading dose of 250 
mg of amlitelimab on 
Day 1, followed by 
one injection of 125 
mg of amlitelimab 
Q4W until Week 20 
(inclusive) and Q12W 
starting from Week 
24 and thereafter 
until Week 48. 
Participants will 
receive one initial 
loading dose of 125 
mg of amlitelimab on 
Day 1, followed by 
one injection of 62.5 
mg of amlitelimab 
Q4W until Week 20 
(inclusive) and Q12W 
starting from Week 
24 and thereafter 
until Week 48. 
Participants will 
receive one initial 
dummy loading dose 
of only placebo 
matching amlitelimab 
on Day 1, followed by 
one injection of 
placebo matching 
amlitelimab Q4W 
until Week 20 
(inclusive) and Q12W 
starting from Week 
24 and thereafter 
until Week 48. 
Associated 
intervention labels 
Amlitelimab  
Amlitelimab  
Amlitelimab  
Placebo 
Amlitelimab 
 
A complete description of amlitelimab and its proper preparation and handling will be provided in 
the Pharmacy Manual available to the clinical site. 
Non-investigational medicinal products(s) 
Participants must continue their established controller and reliever therapy. 
Participants must continue the controller therapy regimen and continue to use the same dose, 
except for the OCS (see Section 6.8). 
• 
Formulation: DPI, MDI, nebulizer 
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• 
Route of administration: oral inhalation for LABA, ICS, LAMA, ICS+LABA, 
LAMA+LABA, or LAMA+LABA+ICS 
• 
Dose regimen: as per prescribed 
If on maintenance treatment with OCS, the dose could be changed per Investigator medical 
judgement. 
• 
Formulation: tablets 
• 
Route of administration: oral 
• 
Dose regimen: as per prescribed 
Participants may administer SABA or low-dose ICS/formoterol (per GINA 2021 recommendation 
[3]) as reliever medication. The class of reliever medication should not change during the study. 
• Formulation: DPI, MDI, nebulizer 
• 
Route of administration: oral inhalation 
• 
Dose regimen: as per prescribed 
For other information related to asthma controllers including safety precautions please consult the 
prescription labels. 
6.1.1 Devices  
Sanofi or a designee will provide standard study supplies to the sites for the execution of trial-
related activities. These supplies include the following: 
• 
Electronic Diaries 
• 
Spirometry devices 
• 
Electronic Spirometry devices for remote spirometry (FEV1) and PEF measurement 
• 
Digital inhalers to measure the reliever use (in certain countries, optional) 
• 
Impulse oscillometry devices 
• 
FeNO measurement devices 
• 
Laboratory kits including tubes, needles, dipsticks 
• 
IMP transportation material as described in the Pharmacy Manual 
Instructions on material supply, tracking, return and destruction will be provided in vendor manuals. 
6.2 
PREPARATION, HANDLING, STORAGE, AND 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. 
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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). 
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 8.3.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
Packaging, Labelling and storage conditions 
All packaging, labeling, and production of IMP will be in compliance with current Good 
Manufacturing Practices, or local applicable regulations, where necessary. The IMP labels and 
external packaging will include all appropriate information as per local labeling requirements. 
Storage conditions and use-by-end date (when required by country regulations) are part of the 
label text.  
Additional details regarding packaging, labelling and storage conditions will be available in the 
Pharmacy Manual. 
Allocation of IMP 
This is a double-blind study, the IMPs to be administered to a participant will be assigned 
centrally using an IVRS/IWRS.  
The study visits for IMP allocation are summarized in the SoA (Section 1.3). The IVRS/IWRS 
will allocate for each participant the kit numbers corresponding to the visit.  
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Before the study is initiated, the login information and the instructions for the IVRS/IWRS 
management will be provided to each site. 
The site will contact the IVRS/IWRS prior to the start of study IMP administration for each 
participant at each visit where IMP is administered. The site will record the IMP assignment on 
the applicable case report form, if required.  
Study Treatment Administration 
Amlitelimab will be administered as a SC injection Q4W until Week 20 (inclusive) and Q12W 
IMP should not be administered at the site of a recent injection or in areas which in the 
Investigator's opinion are not suitable eg, tender, bruised, red or hard.  
Details of administration will be documented in the study specific Pharmacy Manual. 
Additional information regarding treatment allocation, preparation and administration are 
available in the Pharmacy Manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
The randomized intervention kit number list is generated centrally by Sanofi. The IMPs 
(amlitelimab or placebo) are packaged in accordance with this list. 
All participants will be centrally assigned to randomized study intervention using an IVRS/IWRS. 
Before the study is initiated, the log in information and directions for the IVRS/IWRS will be 
provided to each site. Study intervention will be dispensed at the study visits summarized in the 
SoA. Details of the IVRS/IWRS procedure will be provided in the IVRS/IWRS Site Manual. 
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Returned study intervention should not be re-dispensed to the participants. 
Randomized participants are defined as all participants from screened population who have been 
allocated to a randomized intervention by IVRS/IWRS regardless of whether the intervention was 
received. Participants exposed to study intervention before or without being randomized will not 
be considered randomized and will not be included in any analysis population. The safety 
experience of these participants will be reported separately. Randomized participants for whom it 
is unclear whether they took the study intervention will be considered as exposed and will be 
included in the safety population as randomized.  
Randomization will be stratified by region, screening blood eosinophil count (<300 cells/μL and 
≥300 cells/μL), and number of asthma exacerbations in the previous 12 months (=1 exacerbation 
or >1 exacerbations). During the randomization procedure, the eosinophil count at Screening 
(Visit 1) must be entered in the IVRS/IWRS system. To ensure enrollment according to intended 
distribution of exacerbation history and eosinophil count, the number of participants enrolled into 
each stratification group will be controlled and monitored as follows: 
• 
Only 1 severe asthma exacerbation in the previous 12 months: not more than 
approximately 50% of participants (210 participants).  
• 
Eosinophils <300 eosinophils/μL: not more than approximately 50% of participants 
(210 participants). 
A participant cannot be randomized more than once in the study.  
On Day 1 participants will be assigned a unique number (randomization number) in ascending 
numerical order at each study site. The randomization number encodes the participant’s 
assignment to one of the 4 arms of the study, according to the randomization schedule generated 
prior to the study by the Statistics Department at Sponsor. Each participant will be dispensed 
blinded study intervention, labeled with his/her unique randomization number, throughout the 
study. 
Blind break  
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of an emergency, 
the Investigator has the sole responsibility for determining if unblinding of a participant’s 
intervention assignment is warranted (eg, in case of available antidote). In case of an AE/SAE, the 
code can be broken only in circumstances when knowledge of the study IMP is required essential 
for treating the study participant. Participant safety must always be the first consideration in 
making such a determination. If the Investigator decides that unblinding is warranted, he/she may, 
at his/her discretion, contact the Sponsor to discuss the situation prior to unblinding a participant’s 
intervention assignment unless this could delay emergency treatment of the participant. If a 
participant’s intervention assignment is unblinded, the Sponsor must be notified within 24 hours 
after breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable. If the code is broken, the participant 
must withdraw from IMP administration. 
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Sponsor safety staff may unblind the intervention assignment for any participant with an SAE. If 
the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a 
copy of the report, identifying the participant’s intervention assignment, may be sent to 
Investigators in accordance with local regulations and/or Sponsor policy.  
Methods of blinding 
Amlitelimab and placebo will be provided in identically matched 1 mL vials. To protect the blind, 
each treatment kit of 1 mL (amlitelimab/placebo) glass vials will be identical and 
indistinguishable and labeled with a treatment kit number. A specific volume in each vial will be 
collected in order to prepare syringes such that the treatments (amlitelimab and its matching 
placebo) are identical and indistinguishable. 
In accordance with the double-blind design, study participants, Investigators, and study site 
personnel will remain blinded to study treatment and will not have access to the randomization 
scheme or to the IMP content (amlitelimab or placebo) except under circumstances described in 
Section 6.3. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Participants will receive study intervention directly from the Investigator or designee at the site, 
under medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention.  
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 
Section 10.9: Contingency measures for a regional or national emergency that is declared by a 
governmental agency.  
6.5 
DOSE MODIFICATION  
Not applicable. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Eligible participants who complete the treatment period will be offered the opportunity to 
participate in the LTS study with amlitelimab. Participants subsequently enrolled in the LTS study 
will not participate in the follow-up period of this trial but will have a follow up period after the 
LTS study. 
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6.7 
TREATMENT OF OVERDOSE  
For this study, any administration of 
will be considered an overdose. No antidote is available for 
amlitelimab.   
Amlitelimab has a 
  If 
severe adverse reactions occur after an overdose of amlitelimab, then plasmapheresis (or infusion 
of albumin) to reduce the drug exposure may be considered. 
NIMP overdose: any dose in excess of the maximum dose recommended in the respective 
medication labeling. 
In the event of an overdose (symptomatic or asymptomatic), the Investigator/treating physician 
should: 
• 
Contact the Sponsor immediately. 
• 
Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or whether the dose should be reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
• 
Obtain a serum sample for PK analysis within 7 days from the date of the last dose of IMP 
if requested by the Sponsor (determined on a case-by-case basis). 
• 
Document appropriately in the eCRF and report the overdose as an AESI (if symptomatic) 
within 24 hours of learning of the event. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest 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 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the Investigator and 
Sponsor, the medication will not interfere with the study. 
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Paracetamol/acetaminophen, at doses of ≤2 g/day, is permitted for use any time during the study.  
6.8.1 ICS in combination with one or two other controllers  
On a daily basis throughout the study, the participant will use an eDiary to record daily use of ICS 
in combination with one or two other controllers as used just prior to screening.  
The recognized asthma controllers for the study will include the following 5 classes: ICS, LABA, 
LAMA, anti-leukotrienes and methylxanthines. Please refer to Section 10.10.3 for a list of 
commonly used asthma controller medication. 
6.8.1.1 Screening period  
Prior to screening, participants must be on a stable background therapy for at least 3 months, 
composed of medium to high dose of ICS (≥500 μg of fluticasone propionate daily or comparable 
ICS dosage to a maximum of 2000 μg/day of fluticasone propionate or clinically comparable [1]) 
in combination with a second controller medication (eg, LABA, LTRA, LAMA, 
methylxanthines), with or without third asthma controller medication. The second and third 
controller both should be used for at least 3 months with a stable dose ≥1 month prior to Visit 1. 
Participants requiring a third controller for their asthma will be considered eligible for this study, 
and it should also be used for at least 3 months with a stable dose ≥1 month prior to Visit 1. For 
Japan, please see Section 10.8 for details. 
If on chronic OCS treatment for the maintenance treatment of asthma, up to a maximum of 15 mg 
prednisone or equivalent daily or 30 mg every other day, must be on stable dose for ≥1 month 
prior to Visit 1 (see Section 10.10.2 for comparison of systemic glucocorticoid preparations). 
6.8.1.2 Randomized treatment period  
During this period, participants will continue to take their controller medication(s) used during the 
screening period and will use an eDiary to record daily use. The dose and regimen should not be 
changed, except for the OCS, for which the dose could be changed per Investigator medical 
judgement.  
6.8.1.3 Follow-up period  
Upon completing the randomized treatment period, participants will proceed to be treated with the 
controller medication regimen and dose used during the randomized treatment period, which 
could be adjusted based on the medical judgment of the Investigator of the participants’ asthma 
control status. 
6.8.2 Reliever medication  
Please refer to Table 15 for a list of commonly used asthma reliever medications in 
Section 10.10.3. Participants may administer SABA MDI and DPI as reliever medication as 
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needed during the study. Nebulizer solutions may be used as an alternative delivery method. 
Alternatively, low-dose ICS/formoterol may be used as reliever medication, per GINA 2021 
recommendation (2) and Investigator’s discretion. Reliever medication use will be reported by 
participants in the eDiary.  
If a nebulizer is used, the dose administered via nebulizer must be converted to puffs using the 
nebulizer-to-puff conversion factor (Table 5, Table 6) (32) and entered in the eDiary. 
Table 5 - Conversion of salbutamol/albuterol nebulizer solution dose to number of puffs  
Salbutamol/albuterol nebulizer solution - total daily dose (mg) 
Number of puffs* 
2.5 
4 
5.0 
8 
7.5 
12 
10 
16 
*Conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs. 
Example of salbutamol/albuterol nebulizer-to-puff conversion: Participant received 
3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 AM and 11 AM. Total 
daily=7.5 mg or 12 puffs. 
Table 6 - Conversion of levosalbutamol/levalbuterol nebulizer solution dose to number of puffs  
Levosalbutamol/levalbuterol nebulizer solution - total daily dose (mg) 
Number of puffs* 
0.63 
2 
1.25/1.26 
4 
1.89 
6 
2.5/2.52 
8 
3.15 
10 
3.75/3.78 
12 
5/5.04 
16 
 
*Conversion factor: levosalbutamol/levalbuterol nebulizer solution (1.25 mg) corresponds to 4 puffs 
Example of levosalbutamol/levalbuterol nebulizer-to-puff Conversion: Participant received 
3 levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 AM and 
11 AM. Total daily=3.75 mg or 12 puffs. 
6.8.3 Allowed concomitant medication  
Medications that have not been listed as exclusion criteria are permitted for use during the trial. 
These include the following: 
• 
Oral contraceptives 
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• 
Intranasal, ocular or topical corticosteroids 
• 
Previously initiated immunotherapy will be allowed to continue during the study.  
• 
Antihistamines  
• 
Paracetamol/acetaminophen 
• 
COVID-19 vaccination: 
- 
To allow for an optimal immune response as well as protection against COVID-19, it 
is strongly recommended that participants complete their COVID-19 vaccination 
schedule (per local requirements) a minimum of 14 days prior to Baseline. The safety 
profile and effectiveness of COVID-19 vaccines in people with compromised immune 
systems or therapies (such as amlitelimab) that modify or that suppress their immune 
response is not yet established. 
- 
While vaccination with an approved COVID-19 vaccine (including booster dose) is 
widely recommended (33), a participant’s decision to have a COVID-19 booster 
during the study should only be made after discussing with his/her physician and the 
Investigator to assess the benefits/risks of receiving a COVID-19 vaccination during 
this study. In this instance, if the vaccine is authorized, available, and recommended by 
the local regulatory health authority, it should be administered according to the label or 
local health authority recommendations. The vaccine should not be administered 
within less than 14 days immediately prior to or following the IMP administration. 
Details of the COVID-19 vaccine should be recorded in the eCRF. 
6.8.4 Prohibited concomitant medication  
The following concomitant treatments are not permitted during the screening or treatment phases: 
• 
Systemic steroids for more than 7 consecutive days (except systemic steroids to treat 
asthma exacerbations and for maintenance treatment of asthma within allowed doses 
initiated before participation in the study) 
• 
Systemic immunosuppressant within 2 months or 5 half-lives prior to Visit 1, whichever is 
longer (eg, methotrexate, any anti-TNF mAbs, B and/or T cell targeted 
immunosuppressive therapies)  
• 
Intravenous Ig (IVIG) therapy  
• 
Anti-IgE therapy (eg, omalizumab [Xolair]) within 130 days prior to Visit 1 or any other 
biologic therapy within 2 months or 5 half-lives prior to Visit 1, whichever is longer 
• 
Live Attenuated Vaccines within 12 weeks prior to baseline (see Section 10.10.4) 
• 
Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor 
blocker used with stable dose at least 1 month prior to Visit 1)  
• 
Asthma relievers other than SABA and low-dose ICS/formoterol: their use is not 
recommended during the study period. In case of use in exceptional circumstances 
(eg, prescribed by a physician not participating in the study), their use will be documented 
in the participant's file and reported in the eCRF.  
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• 
Initiation of immunotherapy  
• 
Other investigational drugs  
6.8.5 Prohibited rescue medication and procedures  
Rescue medications and procedures could be used per Investigator’s medical judgement. The 
following rescue medications and procedures constitute a treatment failure: 
• 
Anti-IL4R mAb (eg, dupilumab [Dupixent®])  
• 
Anti-IL5 or IL-5R mAb (eg, benralizumab [Fasenra], mepolizumab [Nucala], or 
reslizumab [Cinqair])  
• 
Anti-IgE mAb (eg, omalizumab [Xolair])  
• 
Anti-TSLP mAb (eg, Tezepelumab [Tezspire®])  
• 
Bronchial thermoplasty 
• 
Initiation of continuous oral corticosteroid treatment during the study beyond 14 days 
consecutively 
The date and time of rescue medication administration as well as the name, route of 
administration, reason for starting and dosage regimen of the rescue medication must be recorded.  
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Discontinuation of specific sites or of the study as a whole are detailed in Appendix 1 
(Section 10.1.9). 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will have an early 
treatment discontinuation visit with all assessments planned for the EOT Visit. See the SoA 
(Section 1.3) for data to be collected at the time of early discontinuation of study intervention.  
Definitive (permanent) discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP whatever the reason. 
The participants may withdraw from treatment with the IMP if they decide to do so, at any time 
and irrespective of the reason, or this may be the Investigator’s decision. All efforts should be 
made to document the reason(s) for treatment discontinuation and this should be documented in 
the eCRF.  
Participants must be permanently withdrawn from the study treatment 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 
• 
In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor 
• 
Pregnancy 
• 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Appendix 10 [Section 10.10.5]) 
• 
Severe intercurrent illness 
• 
Diagnosis of a malignancy during study, excluding squamous or basal cell carcinoma of 
the skin 
• 
Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (Appendix 10 [Section 10.10.6]) 
• 
Severe laboratory abnormalities: 
- 
Absolute neutrophil count ≤0.5×109/L 
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- 
Platelet count ≤50×109/L 
- 
Serum ALT >3 ULN and total bilirubin >2 ULN 
- 
Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT 
>2 ULN 
- 
Note: Any clinically significant abnormal laboratory value will be immediately 
rechecked for confirmation after 24 hours before making a decision of permanent 
discontinuation of the IMP for the concerned participant. If the laboratory abnormality 
is considered causally related to the IMP, the IMP will be permanently discontinued. 
In cases where a causal relationship to the IMP can be reasonably excluded (ie, an 
alternative cause is evident), the IMP will be discontinued but it may be resumed when 
the laboratory abnormality is sufficiently normalized.  
• 
Occurrence of AEs, that, in the opinion of Investigator/Sponsor, may jeopardize 
participant's safety or data integrity 
• 
Treatment with any prohibited systemic concomitant medication or procedure (see 
Section 6.8.4) 
• 
Treatment with any prohibited rescue medication or procedure (see Section 6.8.5) 
See the SoA (Section 1.3) for data to be collected at the time of definitive intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. Any 
abnormal laboratory value or ECG parameter will be immediately rechecked for confirmation 
(within 48 hours) before making a decision of definitive discontinuation of the IMP for the 
concerned participant. 
Handling of participants after permanent intervention discontinuation 
Participants will be encouraged to remain in the study visits and to participate in all assessments 
according to schedule, up to the scheduled date of study completion, or up to recovery or 
stabilization of any AE to be followed-up as specified in this protocol, whichever comes last. 
Their study data collected during their continued involvement is important to the study efficacy 
analysis and study value. 
If possible, and after the permanent discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including a 
PK sample, if appropriate. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in Appendix 6 (Section 10.6) or in the presence 
of abnormal liver chemistries not meeting protocol-specified stopping rules if the Investigator 
believes that it is in best interest of the participant. 
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7.1.3 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 (Appendix 9 [Section 10.9]: Contingency measures for a regional or 
national emergency that is declared by a governmental agency). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF. Following a temporary interruption or missed dose, the IMP treatment should be reinitiated 
at the next scheduled visit, maintaining the original dose. 
For the purpose of this study, a temporary discontinuation is defined as no more than 1 missed 
IMP administration. Two or more missed IMP administrations during the study will be considered 
permanent and relevant eCRF sections should be populated. 
7.1.4 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned AE was unlikely 
and if the selection criteria for the study are still met (refer to Section 5). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 Section 10.9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
7.1.4.1 Study intervention restart or rechallenge after liver stopping criteria are met  
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study are not allowed. 
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 or 
compliance reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, 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.  
Note: Safety follow-up (EOS, end-of-study) visit should be performed 
after the last IMP. 
• 
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 a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
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If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF 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 (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, counsel the participant on the importance of maintaining the assigned visit schedule, 
and ascertain whether 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. 
• 
If a participant continues to be unreachable and has been withdrawn from the study, the 
site should continue to try to obtain a vital status update (death) via available resources, if 
possible. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.9 Study and site start and closure). 
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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 
count, urine tests) 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 timeframe defined in the SoA. 
• 
Safety/laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded. 
• 
In case a study procedure in not performed, or not performed in time due to COVID-19, it 
is important to capture this specific deviation related information in the eCRF and explain 
the basis of the missing or delayed data, including the relationship to COVID-19. 
• 
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will be within a safe limit for 
human clinical trials as recommended by the local Institutional Review Boards (IRB) and 
Independent Ethics Committees (IEC). 
• 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
It is recommended that assessments/procedures at a site visit are performed in the following order 
if applicable and possible: 
• 
PROs and other questionnaires 
• 
ECG 
• 
Procedures: 
- 
FeNO measurement 
- 
Impulse oscillometry 
- 
Spirometry 
- 
eDiary download 
- 
Safety and laboratory assessments 
- 
Administration of IMP 
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Remote spirometry (pre-BD) and PEF measurements to be performed by participants daily in the 
AM and PM.  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9: Contingency measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.9).  
8.1 
EFFICACY ASSESSMENTS   
Planned timepoints for all assessments are provided in the SoA (Section 1.3). 
8.1.1 Primary endpoint  
The primary endpoint for this study is the annualized rate of severe exacerbation events over a 
period of 48 weeks. 
8.1.1.1 Severe asthma exacerbation events  
Severe asthma exacerbation event is defined as: 
• 
Worsening of asthma requiring the use of systemic corticosteroids for ≥3 days or, in the 
case of a stable maintenance regimen of OCS for the treatment of asthma, a doubling of 
the dose for 3 or more days; or 
• 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids. 
8.1.2 Secondary endpoints  
8.1.2.1 Key secondary endpoints  
Key secondary endpoints include: 
• 
Change from baseline in pre-BD FEV1 at week 48 
• 
Change from baseline in ACQ-5 score at Week 48 
• 
Change from baseline in AQLQ (S) Self-Administered Score at Week 48 
8.1.2.2 Efficacy endpoints  
Other secondary efficacy endpoints include: 
• 
Change from baseline in post-BD FEV1 at week 48 
• 
The absolute change in the percent predicted FEV1 from baseline to week 48 (pre-BD and 
post-BD) 
• 
Change from baseline in ACQ-5 score at Weeks 2, 4, 8, 12, 24, 36, and 60 
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• 
Time to first severe exacerbation event 
• 
Change from baseline in pre-BD and post-BD FEV1 and other lung function 
measurements (PEF, FVC, and FEF 25-75%) at each spirometry endpoint 
• 
Change from baseline in FeNO at Weeks 2, 4, 8, 12, 16, 24, 36, 48, and 60 
• 
Annualized rate of LOAC events, during 48 weeks of treatment, defined by one or several 
of the following criteria: 
- 
A 30% or greater reduction from baseline in morning PEF on 2 consecutive days. 
- 
≥6 additional reliever puffs of SABA OR ≥4 additional puffs of low-dose 
ICS/formoterol in a 24-hour period (compared to baseline) on 2 consecutive days  
- 
Increase in ICS ≥4 times than the Visit 2 dose 
- 
Worsening of asthma requiring the use of systemic corticosteroids for ≥3 days or, in 
the case of a stable maintenance regimen of OCS for the treatment of asthma, a 
doubling of the dose for 3 or more days 
- 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids severe exacerbation event 
• 
Time to first LOAC event 
• 
Change from baseline in the ADSD 6-item daily morning score and in the ANSD 6-item 
daily evening scores at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 
• 
Annualized rate of severe asthma exacerbations requiring hospitalization or emergency 
room or urgent care visit during 48 weeks of treatment 
• 
Change from baseline in the numbers of inhalations/day of SABA or low-dose 
ICS/formoterol for symptom relief at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 
• 
Change from baseline in AQLQ (S) Self-Administered Score at Weeks 2, 4, 8, 12, 24, 36, 
and 60 
• 
Change from baseline in SGRQ at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 
• 
Proportion of participants with a decrease from baseline of at least 4 points in SGRQ total 
score at Week 48 
• 
Change from baseline in ACQ-6 and ACQ-7 score at Weeks 2, 4, 8, 12, 24, 36, 48, and 60 
8.1.3 Disease-specific efficacy measures  
8.1.3.1 Spirometry  
Spirometry will be performed in accordance with the ATS/ERS guidelines (34) and prior to 
administration of IMP at the planned time point (Section 1.3, SoA). For pre-BD measured 
parameters, including FEV1, PEF, FVC and FEF 25%-75%, spirometry will be performed after a 
wash out period of bronchodilators according to their action duration, following the guidance of 
the ATS/ERS 2019 guidance (34). For example, withholding the last dose of salbutamol/albuterol 
or levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at least 
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24 hours, and finally the last dose of ultralong-acting LABA (like vilanterol) or the last dose of 
LAMA should be withheld for at least 36 hours). This will be verified before performing the 
measurements. In addition, participants are asked to avoid consuming alcohol 8 hours prior to 
spirometry, and to avoid engaging in strenuous exertion for at least 30 minutes prior to all lung 
function assessments. 
At all site visits, spirometry will be performed preferably in the morning, afternoon is allowable in 
the exceptional circumstance when morning spirometry cannot be performed. Spirometry will be 
done at approximately the same time at each visit throughout the study. The same spirometer and 
standard spirometric techniques, including calibration, will be used to perform spirometry at all 
visits, and whenever possible, the same person should perform the measurements. Three 
measurements fulfilling the ATS acceptability and repeatability criteria should be obtained at 
every site visit, if possible.  
Reversibility is defined as an increase of the absolute FEV1 after administration of bronchodilator 
and is measured by spirometry as post-BD increase in FEV1 in percent of the pre-BD FEV1. 
After spirometry for measuring pre-BD FEV1, participants will receive 2-4 puffs of 
albuterol/salbutamol or levalbuterol/levosalbutamol from a primed MDI. Reversibility may be 
performed using inhalation of nebulized albuterol/salbutamol or levalbuterol/levosalbutamol, if it 
is consistent with usual office practice (to be documented). The post-BD spirometry may be 
repeated several times within 30 minutes after administration of bronchodilator. 
Further details on spirometry will be available in a separate operational manual provided to the 
sites. 
8.1.3.2 Asthma Control Questionnaire, versions 5, 6, and 7  
The ACQ is a questionnaire that measures the adequacy of asthma control and any changes in 
asthma control that may occur spontaneously or as a result of treatment. The ACQ-5 has five 
questions on the asthma symptoms and patients are asked to recall how their asthma has been 
during the previous week. The ACQ-6 includes an additional item that scores the average number 
of daily puffs needed from a SABA bronchodilator during the past week and the ACQ-7 includes 
this SABA item, plus a final clinic-assessed item scoring FEV1% predicted. Each item of the 
ACQ is measured on a 7-point response scale (0=no impairment, 6=maximum impairment).  The 
ACQ score is the mean of the item responses and ranges from 0 (totally controlled) and 6 
(severely uncontrolled).  A high score indicates low asthma control. Participants with a score 
below 1.0 reflect adequately controlled asthma and participants with scores above 1.0 reflect 
inadequately controlled asthma (35). On the 7-point scale of the ACQ questionnaires, 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 
(36). 
Measurement properties such as reliability and ability to detect change have been documented in 
the literature (36). Participants will complete the questionnaires in an eDiary during on-site visits 
as described in the SoA (Section 1.3). 
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8.1.3.3 Fractional Exhaled Nitric Oxide  
Fractional Exhaled Nitric Oxide (FeNO) is a measure of nitric oxide in exhaled breath produced 
by epithelial cells in the lung and considered as a biomarker of Type-2 inflammation in asthma. 
FeNO levels (ppb) will be collected on site with a dedicated medical device (such as a 
commercially available hand worn device NIOX VERO®]). The FeNO test needs to be completed 
prior to impulse oscillometry and spirometry in order to avoid any impact on the nitric oxide 
measurement. In addition, participants should not eat or drink 1 hour prior to having the FeNO 
test, as this may affect the results. Further details on the procedure for measuring exhaled nitric 
oxide with NIOX VERO will be provided in a separate instruction manual. 
8.1.3.4 Electronic diary  
Electronic diary (eDiary) is a handheld device used for daily recording of reliever use, asthma 
controller drug use, ADSD and ANSD, and recording of participant’s answers to the ACQ-6, 
AQLQ(S), and other PROs questionnaires during the scheduled visits. This handheld device is 
dispensed at Visit 1 with including instructions for use and recorded information is downloaded 
from this device on the other indicated days. For each site visit, the participants will bring their 
electronic devices and will complete the questionnaire on site. Electronic handheld devices will be 
returned to the vendor at EOS at the latest. 
On a daily basis throughout the study, the participant uses an eDiary to:  
• 
Respond to the morning and evening asthma symptom score ADSD/ANSD questions. 
• 
Indicate the number of inhalations/day of reliever medications for symptom relief.  
• 
Record the use of controller medications per day.  
8.1.3.5 Loss of asthma control events  
Annualized rate of LOAC events, during 48 weeks of treatment, defined by one or several of the 
following criteria: 
• 
A 30% or greater reduction from baseline in morning PEF on 2 consecutive days. 
• 
≥6 additional reliever puffs of SABA OR ≥4 additional puffs of low-dose ICS/formoterol 
in a 24-hour period (compared to baseline) on 2 consecutive days  
• 
Increase in ICS ≥4 times than the Visit 2 dose 
• 
Worsening of asthma requiring the use of systemic corticosteroids for ≥3 days or, in the 
case of a stable maintenance regimen of OCS for the treatment of asthma, a doubling of 
the dose for 3 or more days  
• 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids severe exacerbation event 
Participants will measure their PEF using electronic spirometer (e-Spirometer) (Section 8.1.3.9). 
Reliever medication use will be recorded in the eDiary (Section 8.1.3.4). 
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8.1.3.6 Asthma Daytime Symptom Diary and 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) patients diagnosed with mild-to-severe asthma. ADSD and 
ANSD assess asthma severity based on patient self-report of asthma core symptoms, ie, difficulty 
of breathing; wheezing; shortness of breath; chest tightness; chest pain; and cough. Patients 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. Average scores are calculated for both 
the morning and evening diaries, referred to as the “6-Item ADSD Daily Morning Score” and 
“6-Item ANSD Daily Evening Score”, respectively, using 6 out of 6 of the ADSD items (note: no 
weighting so each item contributes equally). 
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 (37). The participants will record their daytime 
and nighttime asthma symptoms in an eDiary, once in the evening and once in the morning, 
respectively. The participants will complete the ADSD and the ANSD as per SoA (Section 1.3). 
8.1.3.7 Asthma Quality of Life Questionnaire with Standardized Activities 
Self-administered Score  
The AQLQ(S) was designed as a self-administered participant reported outcome to measure the 
functional impairments that are most troublesome to adolescents and adults ≥12 years of age as a 
result of their asthma over the past two weeks. The instrument is comprised of 32 items, each 
rated on a 7-point Likert scales from 1 to 7. The AQLQ(S) has 4 domains. The domains and the 
number of items in each domain are as follows:  
• Symptoms (11 items) 
• Activity limitation (12 items, 5 of which are individualized) 
• Emotional function (5 items) 
• Environmental Exposure (4 items) 
A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate 
better quality of life. The instrument has been used in many clinical trials, and it has been shown 
to be reliable, valid (patient interviews), and sensitive to change. The MCID for AQLQ(S) is 0.5 
(38). Participants will complete the questionnaire in an eDiary during on-site visits as described in 
the SoA. 
8.1.3.8 St. George's Respiratory Questionnaire  
The SGRQ is a 50-item questionnaire designed to measure and quantify health status in adult 
patients with chronic airflow limitation (39, 40). A global score ranges from 0 to 100. Scores by 
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dimension are calculated for three domains: Symptoms (8 items), Activity (16 items) and Impacts 
(26 items) as well as a total score. Lower score indicates better quality of life (QoL). The first part 
("Symptoms") evaluates symptomatology, including frequency and severity of cough, sputum 
production, wheeze, breathlessness and the duration and frequency of attacks of breathlessness or 
wheeze. The second part has two components: “Activity” and “Impacts”. The “Activity” section 
addresses disturbances to patients’ daily physical activities. The "Impacts" section covers a range 
of effects that chest troubles may have on patients’ daily life and psycho-social functions 
(eg, daily life activities and functioning, employment, physical functioning, emotional impact, 
stigmatization, and patients’ perceptions when treated). The MCID is 4 points for SGRQ (41). 
The recall period of the questionnaire is over the past 4 weeks. 
The following efficacy parameters will be analyzed by assessing exploratory endpoints: 
8.1.3.9 Remote spirometry   
On a daily basis throughout the study, the participant uses an e-spirometer to measure morning 
and evening FEV1, and PEF. E-spirometer will be dispensed at screening (Visit 1). Initial training 
and written instructions will be provided for participants during screening with additional 
reminder training/instructions at regular intervals throughout the study.   
The following instructions will be provided to the participant and are described in the study 
manual: 
• 
Participants will be instructed to perform expiratory flow maneuvers  
• 
AM e-spirometry is to be performed within 15 minutes after arising (between 5:30 AM 
and 12:00 PM) prior to taking any reliever medication (SABA or low-dose 
ICS/formoterol). 
• 
PM e-spirometry is to be performed in the evening (between 5:30 PM and 12 AM) prior to 
taking any reliever medication (SABA or low-dose ICS/formoterol). 
• 
Participants should try to withhold reliever medication (SABA or low-dose 
ICS/formoterol) for at least 6 hours prior to e-spirometry.  
• 
Three e-spirometry efforts will be performed by the participant; all 3 values will be 
recorded by the e-spirometer, and the highest value will be used for evaluation.  
Baseline AM e-spirometry data (FEV1 and PEF) will be the mean AM measurement recorded for 
the 7 days prior to the first dose of investigational product, and baseline PM data will be the mean 
PM measurement recorded for the 7 days prior to the first dose of investigational product. Period 
stability limit is defined as the respective mean AM or PM data obtained over the last 7 days prior 
to Day 1. There should be at least 4 days’ measurement for setting up the stability limit, and the 
first dosing visit should be rescheduled until data for 4 days are available. 
8.1.3.10 
 
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8.1.3.12 Digital inhaler to measure the use of bronchodilator therapy  
Digital inhalers will be optional and will be available in certain countries to measure the reliever 
medication use (bronchodilator therapy, inhalations/day). Further details will be available in a 
separate operational manual. 
8.1.3.13 
8.1.3.14 
8.1.3.15 
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8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than AEs which are presented in Section 8.3. 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• 
A complete physical examination will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
Height and weight will also be measured and recorded at Screening (the participant is 
allowed to wear indoor, daytime clothing with no shoes). Weight will also be measured 
and recorded at the Baseline/Randomization (Visit 2), Week 24 (Visit 9), Week 48 
(Visit 11), EOT (Visit 12) and EOS (Visit 13) or early discontinuation.  
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses and pay special attention to signs or symptoms of infection or malignancy. 
• 
Any new finding or worsening of previous finding should be reported as a new AE. 
Local Skin Reactions 
On IMP administration days, local skin reactions around the site of injection will be assessed by 
the Investigator or other appropriately trained site personnel 30 minutes after the injection. Light 
pressure will be applied at the injection site and any pain, itchiness, tenderness, erythema, and 
induration will be recorded in the eCRF. Pain and tenderness will be assessed according to the 
following scale: 
• 
Definitions of pain and tenderness: 
- 
None 
 
nothing 
- 
Mild 
 
easily tolerated 
- 
Moderate 
interferes with daily activities 
- 
Severe  
prevents normal everyday activities or sleep 
Erythema and induration will be measured using a ruler, or a template supplied by the Sponsor. 
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8.2.2 Vital signs  
• 
Oral/Tympanic/Rectal/Axillary/Skin/Temporal artery temperature, pulse rate, respiratory 
rate, and blood pressure 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). 
8.2.3 Electrocardiograms  
• 
Single 12-lead electrocardiogram (ECG(s)) will be obtained as outlined in the SoA (see 
Section 1.3) using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and corrected QT (QTc) intervals. The ECGs will be obtained 
prior to laboratory assessments and prior to spirometry. A qualified Investigator or 
appropriate designee (qualified physician) should review the ECGs in a timely manner to 
determine if there are any safety concerns and for clinical management of the participant. 
In case of abnormal findings identified by the qualified Investigator or appropriate 
designee (qualified physician), the ECG should be provided to the cardiologist for further 
confirmation and description of findings. The Investigator must always date and sign the 
ECG and comment on the assessment before filing this in the medical records. In the event 
of any clinically significant abnormal finding that meet the definition of an AE 
(Section 10.3), the Investigator will continue to monitor the participant with additional 
ECGs until the ECG findings return to baseline ECG findings or the Investigator 
determines that follow-up is no longer necessary. 
• 
Any clinically significant ECG related to a preexisting condition at Screening (Visit 1) that 
does not affect the conduct of the study per the Investigator’s judgment will need to be 
well documented in the source documentation. 
8.2.4 Clinical safety laboratory tests  
• 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• 
The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• 
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. 
- 
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. 
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- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3.) 
- 
If laboratory values from non-protocol specified laboratory tests 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.  
- 
Critical values alerts are linked to extremely high or low laboratory test values which 
are considered to be potentially life threatening. In the event a critical value is 
reported, Central Laboratory will contact the site. 
- 
Special procedures for collection, storage, and shipping of serum are described in the 
Central Laboratory Manual. 
- 
At Screening, hepatitis serology testing is performed in order to rule out active or 
chronic infection. Guidance on hepatitis serology eligibility interpretation is provided 
in Table 7. 
Table 7 - Hepatitis serology testing  
Hepatitis serology result 
Protocol action 
HBs Ag: positive or indeterminate 
Excluded 
HBs Ab positive, HBsAg negative, HBc Ab: negative 
Eligible 
HBc Ab IgM: positive 
Excluded 
HBc Ab Total: positive  
(with or without HBs Ab positive) 
Test for HBV DNA 
If HBV DNA Positive: Excluded 
If HBV DNA Indeterminate: 
Eligible 
HCV antibody: positive 
Test for HCV RNA 
If HCV RNA Positive: Excluded 
If HCV RNA Indeterminate: 
Eligible 
DNA = deoxyribonucleic acid; HBc Ab = total hepatitis B core antibody; HBc Ab IgM = IgM antibody to hepatitis B core antigen; HBsAg = 
hepatitis B surface antigen; HBV = hepatitis B virus; HBs Ab = hepatitis B surface antibody; HCV = hepatitis C virus; Ig = immunoglobulin. 
8.2.5 Pregnancy testing  
• 
Refer to Section 5.1 Inclusion criteria for pregnancy testing criteria; the Investigator is 
responsible for review of medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female participant with an early undetected pregnancy. 
• 
See SoA (Section 1.3) for the timing and type of pregnancy testing to be conducted during 
the study. 
• 
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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8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of AESI is provided in Section 8.3.8. 
The definitions of unsolicited and solicited AEs can be found in Appendix 3 (Section 10.3). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant’s legally authorized representative [LAR]) that meet the definition of an AE or 
SAE and remain responsible for following up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until EOS visit at the 
timepoints 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 information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and AEs of 
special interest (as defined in Section 8.3.8), 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). 
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8.3.4 Regulatory reporting requirements for SAEs  
• 
Prompt notification by the Investigator to the Sponsor of an 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, IRB/IEC, and Investigators. 
• 
Serious adverse events that are considered expected will be specified in the reference 
safety information in the IB.  
• 
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 an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB 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  
• 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and 
after 
the last administration of study intervention. 
• 
If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy. 
• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• 
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 as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former participant/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 study intervention or be withdrawn from the study. 
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8.3.6 Cardiovascular and death events  
Not applicable. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable.  
8.3.8 Adverse events of special interest  
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. For AESI, 
the Sponsor is to be informed immediately (ie, within 24 hours), as per SAE notification 
guidelines, even if a seriousness criterion is not met, using the corresponding pages of the CRF (to 
be sent) or screens in the eCRF. 
• 
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 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 Section 8.3.5) 
• 
Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator and defined as any administration of 
- 
NIMP: any dose in excess of the maximum dose recommended in the respective 
medication labeling. 
• 
Increase in ALT>3×ULN - see the “Increase in ALT” flow chart in Appendix 6 
(Section 10.6). 
• 
Other project specific AESI(s) 
- 
Systemic or localized allergic reactions that require immediate treatment (in the event 
that a participant has a systemic allergic reaction that requires immediate treatment, 
blood samples should be withdrawn as soon as feasible [not to interfere with treatment 
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of the reaction] for the analysis of ADA, serum tryptase, C1q, C1 inhibitor, C3 and C4, 
and repeated at 4 hours and 24 hours) 
- 
Severe injection site reactions that last longer than 24 hours 
- 
Any severe or opportunistic viral, bacterial or fungal infection whose nature or course 
may suggest an immunocompromised status and/or any uncommon, unanticipated or 
persistent infection (viral, parasitic, bacterial, or fungal; for example, but not limited to 
tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, 
aspergillosis)  
- 
Diagnosis of a malignancy during the study. 
8.3.9 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 
PHARMACOKINETICS  
• 
Blood samples will be collected for measurement of serum concentrations of amlitelimab 
as specified in the SoA (Section 1.3). 
• 
Additional samples may be collected at additional timepoints during the study if warranted 
and agreed upon between the Investigator and the Sponsor. The timing of sampling may 
be altered during the course of the study based on newly available data (eg, to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
• 
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor in a separate document. The actual date and time of each sample will be recorded. 
Pharmacokinetic samples will be tested by the Sponsor or Sponsor's designee. 
• 
Samples collected for analyses of amlitelimab concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study. 
Pharmacokinetic samples could be used for testing analytical method performance such as 
comparability and incurred sample reproducibility. The exploratory data will not be included in 
the study report but will be kept on file.  
Population PK approaches will be used for amlitelimab and will be reported as stand alone. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
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8.5 
8.6 
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8.7 
IMMUNOGENICITY ASSESSMENTS  
Instructions for the collection and handling of these samples will be provided by the Sponsor in a 
separate document. Antibodies to amlitelimab will be evaluated in serum samples collected from 
all participants according to the SoA (Section 1.3). Additionally, serum samples should also be 
collected at the final visit from participants who discontinued study intervention or were 
withdrawn from the study. The actual date and time of each sample will be recorded. These 
samples will be tested by the Sponsor or Sponsor’s designee using a validated assay method. 
A 3-tiered approach will be employed to assess the immunogenicity of amlitelimab when 
applicable: Samples will be screened and then confirmed for antibodies binding to amlitelimab 
and the titer of confirmed positive samples will be reported. Other analyses may be performed to 
further characterize the immunogenicity of amlitelimab. 
All samples collected for detection of antibodies to study intervention may also be evaluated for 
study intervention serum concentration to enable interpretation of the antibody data. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Health economics OR medical resource utilization and health economics parameters are not 
evaluated in this study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, mechanism of action, or possible toxicity, and can help identify new drug targets or 
biomarkers that predict participant response to treatment. Therefore, data and biological samples 
will be stored and used for future research when consented to by participants (see Section 10.1.3) 
unless prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will 
not be included in the local ICF).  
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For participants who consent to the storage and use of their data and remaining (leftover) and/or 
extra (additional) clinical samples, data and samples may be used for future research related either 
to the drug, the mechanism of action, and the disease or its associated conditions. Such research 
may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites.  If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. Results from future 
research will not be entered into the study database and will be reported separate from the CSR. 
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 and 
samples will be used in alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These coded data 
and samples 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). 
Relating data and biological samples for future research will be stored for up to 25 years after the 
end of the study. Any samples remaining at the end of retention period will be destroyed. If a 
participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed and related coded data will be anonymized unless otherwise required by 
applicable laws. 
Participant’s coded datasets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
POPULATIONS FOR ANALYSES  
Table 8 - 
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9.2 
STATISTICAL ANALYSES  
9.2.1 General considerations  
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9.2.2 Primary endpoint(s) analyses  
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9.2.3 Secondary endpoint(s) analyses  
9.2.3.1 Key secondary endpoints  
 
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9.2.3.2 Other secondary endpoints  
Table 9 - 
 
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9.2.4 Tertiary/exploratory endpoint(s) analyses  
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Table 10 - Tertiary/exploratory endpoints  
9.2.5 Multiplicity adjustment  
  
Table 11 - 
9.2.6 Safety analyses  
9.2.6.1 Adverse events  
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9.2.6.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
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Table 12 - 
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9.2.7 Other analyses  
9.3 
INTERIM ANALYSES   
An administrative interim analysis (IA) will be performed when the last randomized participant 
has completed 24 weeks. The purpose of the IA is to support the planning of subsequent clinical 
studies of amlitelimab in asthma. The results of the administrative IA will not be made available 
to the study team, Investigators or study participants, who will all remain blinded. A small group 
of Sponsor individuals independent from the study team will be unblinded. No alpha will be spent 
on the interim analysis as the analysis results will not make an early claim on the treatment effect 
of efficacy endpoints and the study will continue unchanged irrespective of the interim analysis 
results. The statistical analysis plan will describe the planned interim analyses in greater detail. 
9.4 
SAMPLE SIZE DETERMINATION  
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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 ICH GCP guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation-GDPR) 
• 
The protocol, protocol amendments, ICF, IB, [IDFU], 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. 
• 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• 
The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her 
designated healthcare professional, if so designated by the participant) is 
consistent with all applicable national, state, or regional laws and regulations in 
the country where the study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical 
validity.  
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- 
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 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 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (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, including the 
risks and benefits, to the participants or their LAR and answer all questions regarding 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, where 
applicable, and the IRB/IEC or study center.  
• 
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 addition to “main” protocol ICF required for study participation, the participant can 
consent to the following optional assessments: 
- 
Pharmacogenetic RNA/DNA assessments 
- 
Future Use of Samples 
- 
Home nursing visits 
• 
Prior to any additional optional assessment, such as collection of blood for 
pharmacogenetics, the optional section of ICF (written) should be completed by the 
participant, and by the person who conducted the informed consent discussion. 
• 
The screening period starts on the day of ICF signature. The registration of Visit 1 in the 
IVRS/IWRS should also be performed on the day of ICF signature. 
• 
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 their legally authorized 
representative, where applicable.  
Participants who are rescreened are required to sign a new ICF. More information related to 
rescreening is included in Section 5.4.  
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
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 and samples 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 9 Section 10.9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency.  
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.  
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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. 
• 
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. 
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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:  
- 
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 pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• 
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). 
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10.1.5 Committees structure  
10.1.5.1 Data Monitoring Committee  
A DMC, independent from the Sponsor, will be established for this study. This committee is 
governed by a DMC Charter. The DMC will comprise externally based individuals with expertise 
in the diseases under study, biostatistics, or clinical research. The composition of the committee is 
dependent upon the scientific skills and knowledge required for monitoring the particular study. 
The primary responsibilities of the DMC are to review safety data, and efficacy where needed, 
during the course of the trial for evaluation of benefit/risk, review results (eg, IA), and make 
appropriate recommendations to the Sponsor regarding the stopping of a study for efficacy, for 
harms, or for futility. In the above-mentioned capacities, the DMC is advisory to the Sponsor. The 
Sponsor is responsible for promptly reviewing and for taking into account in a timely manner the 
recommendations of the DMC in terms of trial continuation with or without alterations, or of 
potential termination of a dose or trial. 
10.1.5.2 Adjudication Committee  
Adjudication will be performed by experts independent of the Sponsor for asthma exacerbations. 
Adjudicators will adjudicate and confirm these events in a consistent and unbiased manner 
throughout the study. 
10.1.6 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, ClinicalTrialRegister.eu, 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 vivli.org.  
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org. 
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 
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professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• 
All participant data relating to the study will be recorded on printed or 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 
physically or electronically signing the CRF. 
• 
Guidance on completion of CRFs will be provided in the CRF completion instructions. 
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study and important deviations from the QTLs and remedial 
actions taken will be summarized in the CSR. 
• 
Monitoring details describing strategy, including definition of study critical data items and 
processes (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). 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• 
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. 
• 
Data reported on the CRF or entered in the eCRF 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. 
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• 
Definition of what constitutes source data can be found in study manuals and monitoring 
guidelines. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• 
For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• 
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 contract research organization(s) 
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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. 
10.1.10 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 13 will be performed by the central laboratory.   
• 
Local laboratory results are only required in the event that: 
- 
the central laboratory results are not available in time for either study intervention 
administration and/or response evaluation, or 
- 
in case the participant cannot come to the clinic due to travel restrictions related to a 
pandemic and the blood sample cannot be obtained at the participant’s home using the 
central laboratory kit supplied by the vendor (after Sponsor approval). 
- 
Local regulation does not allow the transportation of (specific) samples outside of the 
country of origin (after Sponsor approval). 
- 
If a local sample is required, it is important that the sample for central analysis is 
obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be entered 
into the eCRF. 
• 
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. 
• 
TB testing must be done using local laboratory according to local guidelines. In case no 
local guidelines are available, or local TB testing is not possible, a blood sample can be 
sent to the central laboratory for a Quantiferon test.  
- 
For TB testing, see Section 5.2 exclusion criteria 11. 
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- 
In case a TB test result is positive or indeterminate, a repeat test is allowed. In case the 
repeated test is negative, or in case the first AND the second tests are indeterminate, an 
Investigator assessment should take place. If the Investigator confirms the participant 
has no signs of infection, AND the participant is not at high risk of contracting TB 
AND the participant is not from a TB endemic area, AND specialist consultation has 
ruled out active disease, the participant can be randomly assigned if eligible. 
• 
Pregnancy testing will be performed at screening with a blood test using a central 
laboratory, and at subsequent visits using Sponsor-provided urine tests. 
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Table 13 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose (fasting or random) 
 
Potassium 
 
Sodium 
 
Calcium 
Creatine phosphokinase (CPK) 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total bilirubin (case of values above the normal range, differentiation in conjugated and 
non-conjugated bilirubin) 
 
Total protein 
Uric acid 
Total cholesterol 
Albumin 
Lactate dehydrogenase 
Chloride 
Bicarbonate 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)b 
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Laboratory tests 
Parameters 
Other screening tests 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBs Ag], and hepatitis C 
virus antibody or specify other tests)  
• 
Tuberculosis testing according to local guidelines (local laboratory) or if not 
available, in central laboratory (Quantiferon test) at Screening (Visit 1) 
• 
Tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; the 
virus that causes coronavirus disease 2019 [COVID-19]) at Screening (Visit 1), 
randomization and prior to each IMP administration (no administration if positive). 
Tests should be performed no more than 5 days prior to IMP administration. 
Method of testing as required per local guidelines 
• 
All study-required laboratory tests will be performed by a central laboratory, with 
the exception of tuberculosis testing and COVID-19 testing 
 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Appendix 6 (Section 10.6). 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: 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. 
Definition of unsolicited and solicited AE 
• 
An unsolicited adverse event is an adverse event that was not solicited using a participant 
diary and that is communicated by a participant or LAR who has signed the informed 
consent. Unsolicited AEs include serious and nonserious AEs. 
• 
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, emergency room visit, or visit to/by a health care provider). The 
participants/LARs 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/LAR concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records. 
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• 
Unsolicited AEs that are not medically attended nor perceived as a concern by the 
participant/LAR will be collected during an interview with the participants/LAR and by 
review of available medical records at the next visit. 
• 
Solicited AEs are predefined local at the injection site and systemic events for which the 
participant is specifically questioned, and which are noted by the participants in their 
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 condition 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. 
• 
Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that 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. 
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• 
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  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more 
of the criteria listed: 
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 admitted (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 or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that 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 by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that 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. 
- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
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important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm   
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse  
- 
ALT >3×ULN + total bilirubin >2×ULN or asymptomatic 
ALT increase >10×ULN  
- 
Suicide attempt or any event suggestive of suicidality  
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling)  
- 
Bullous cutaneous eruptions   
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. 
• 
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 required form. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
• 
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
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• 
Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self care 
ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden 
Assessment of causality 
• 
The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The Investigator will use clinical judgment to determine 
the relationship. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• 
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 Sponsor. 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 Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send an 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 the 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 postmortem findings 
including histopathology. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
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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) 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 
offline 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 
offline, 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 site initiation training slides. 
SAE reporting to the Sponsor via paper data collection tool 
• 
Facsimile transmission of the SAE paper data collection tool 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 data collection tool within the designated reporting timeframes. 
• 
Contacts for SAE reporting can be found in the site initiation training slides. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• 
A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range should be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• 
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. 
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Permanent sterilization methods include: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
• 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
Women in the following categories are considered WONCBP: 
1. Any female with permanent infertility due to one of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
- 
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), Investigator discretion should be applied to determining study entry. 
2. Postmenopausal female 
- 
A postmenopausal state is defined as the period of time after a woman has 
experienced no menses for 12 consecutive months without an alternative medical 
cause. 
- 
A high FSH level in the postmenopausal range should be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT.  
- 
Females on HRT and whose menopausal status is in doubt must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
10.4.2 Contraception guidance  
• 
Participants should be given advice about donation and cryopreservation of germ cells 
prior to the start of the study intervention, in line with the fact that study intervention may 
affect 
after the last administration of study 
intervention or early termination visit. (See Section 5.1 inclusion criteria). 
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• 
If locally required, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.  
Note: documentation of azoospermia for a male participant can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history interview. 
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 Male condoms should be used in addition to hormonal contraception  
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should 
not be used together (due to risk of failure from friction). 
 
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10.5 
APPENDIX 5: 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS   
 
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
** Unless a protocol-defined criterion for permanent discontinuation is met 
*** See box below 
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3.4  for guidance on safety reporting. 
 
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 10.3.3 is met. 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
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10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
10.8.1 Japan-specific requirements  
Section 5.1 Inclusion criteria (see Section 5.1) 
For I 03, participants must be on ≥400 μg of fluticasone propionate daily or equivalent. 
For I 04, at least one severe exacerbation occurring while on treatment with ≥400 μg of 
fluticasone propionate daily or equivalent. 
Section 5.2 Exclusion criteria (see Section 5.2) 
For E 13, for Japan, the presence of HBs Ag with/without positive HBV-DNA test result or the 
presence of HBc Ab or the presence of HBs Ab with positive HBV-DNA test result at screening 
or within 3 months prior to the screening visit is an exclusion criterion. 
10.8.2 South Korea specific requirements  
Section 5.4 Screen failures (see Section 5.4) 
For South Korea, in case of an asthma exacerbation during the screening period that results in 
emergency treatment or hospitalization, or treatment with systemic steroids, eligible participants 
will be screen failed and can be rescreened 1 month after they have completed their course of 
OCS or returned to their maintenance dose of OCS. In those cases, participants are allowed to be 
rescreened one additional time (ie, one rescreening is allowed for any reason other than PRO 
criteria [ACQ-5<1.5], per Section 5.4, and one additional rescreening is allowed in case of an 
asthma exacerbation during screening as described above). 
When rescreening, participants will sign a new ICF and will repeat all screening procedures in 
accordance with the SoA (Section 1.3); a different participant identification number will be 
issued.    
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
• 
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 in this appendix and in Section 5.5, Section 6, 
Section 7.1, Section 8, Section 9.2.7, and 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 
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GCP 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, alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/randomization, and administration of study intervention may be 
temporarily delayed/halted. 
• 
For a regional or national emergency declared by a governmental agency, contingency 
procedures may be implemented for the duration of the emergency. The participant 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 laboratories, remote spirometry). 
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 a regional 
or national emergency, focus should be given to assessments necessary to ensure the safety of 
participants and those assessments 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 for the duration of the emergency (after Sponsor agreement is obtained): 
• 
If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor) 
may be planned for the IMP administration and collection of possible safety and/or 
efficacy data. 
Vital signs, hematology and clinical chemistry, routine urine analysis plus dipstick test 
(pregnancy) and AE reporting should have priority from a safety perspective. The asthma 
exacerbation reporting, spirometry (if remote spirometry is available/possible) and PROs 
(ACQ, AQLQ, ADSD/ANSD, SGRQ, etc) should have priority from an efficacy 
perspective. 
• 
If onsite visits are not possible, visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely (eg, spirometry visit window 
±2 weeks for the randomized IMP treatment period). 
• 
Use of local clinic or laboratory locations may be allowed for hematology and clinical 
chemistry samples. 
Contingencies implemented due to a regional or national emergency will be documented. 
If in case of unforeseen circumstances, a decision for each individual participant to remain and/or 
start in the study has to be made; this should be done on a case–by-case basis by the Investigator 
based on his/her best medical judgment. Clinical judgment of the treating physician should guide 
the management plan of each participant based on individual benefit/risk assessment. All 
applicable local laws, institutional, and IEC/IRB regulations regarding study visits should be 
followed. Local guidelines related to Personal Protective Equipment use should also be followed. 
As previously mentioned, attempts should be made to perform all assessments in accordance with 
the protocol, but only if and when possible. Investigators should closely monitor and document all 
deviations to the study protocol and share them with the Sponsor contact on a real-time basis. 
 
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10.10 APPENDIX 10: ADDITIONAL APPENDICES  
10.10.1 Low, medium, and high ICS doses: adults/adolescents  
Daily doses in this table are shown as metered doses. See product information for delivered doses. 
 
Source: GINA (1, 3). 
10.10.2 Comparison of systemic glucocorticoid preparations  
 
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For example, to convert a cortisone total daily dose to a prednisone equivalent total daily dose, a 
multiplication factor of 0.2 = 5/25 should be used. 
Source: (53) 
10.10.3 Examples of commonly used asthma controller therapies and reliver medications  
Table 14 - Examples of commonly used asthma controller therapies  
Controller groups 
Medications 
ICS 
Beclomethasone dipropionate CFC 
ICS 
Beclomethasone dipropionate HFA 
ICS 
Budesonide 
ICS 
Ciclesonide 
ICS 
Fluticasone propionate 
ICS 
Mometasone furoate 
ICS 
Triamcinolone acetonide 
ICS 
Fluticasone furoate  
ICS/LABA 
Fluticasone Propionate / Salmeterol 
ICS/LABA 
Fluticasone Propionate / Formoterol 
ICS/LABA 
Fluticasone Furoate / Vilanterol 
ICS/LABA 
Budesonide /Formoterol 
ICS/LABA 
Mometasone Furoate / Formoterol 
ICS/LABA 
Mometasone furoate/indacaterol 
ICS/LABA 
Beclometasone Dipropionate/ Formoterol 
LABA 
Salmeterol  
LABA 
Formoterol  
LABA 
Bambuterol  
LABA 
Clenbuterol  
LABA 
Tulobuterol 
LABA 
Vilanterol 
LABA 
Olodaterol 
LABA 
Indacaterol 
LAMA 
Tiotropium 
LAMA 
Glycopyrronium bromide 
LAMA 
Aclidinium bromide 
LAMA 
Umeclidinium 
Anti-Leukotrienes 
Montelukast  
Anti-Leukotrienes 
Pranlukast 
Anti-Leukotrienes 
Zafirlukast  
Anti-Leukotrienes 
Zileuton 
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Controller groups 
Medications 
Methylxanthines 
Aminophylline 
Methylxanthines 
Theophylline 
Methylxanthines 
Dyphylline  
Methylxanthines 
Oxtriphylline 
Methylxanthines 
Diprophylline 
Methylxanthines 
Acebrophylline 
Methylxanthines 
Bamifylline 
Methylxanthines 
Doxofylline 
Table 15 - List of commonly used asthma reliever medications  
Group 
Medication 
SABA 
Albuterol/salbutamol 
SABA 
Levalbuterol/Levosalbutamol 
SABA 
Terbutaline 
Low dose ICS-LABA* 
Budesonide-formoterol 
*LABA formoterol has an onset of action similar to albuterol (5 to 20 minutes), so combination inhalers that contain inhaled corticosteroid and 
formoterol (eg, budesonide-formoterol) can be used for relief of acute asthma symptoms in addition to long-term maintenance (3). 
10.10.4 Non-exhaustive list of live-attenuated vaccines  
Table 16 - List of live (attenuated) vaccines  
Live  (attenuated) vaccines   
Chickenpox (Varicella), Intranasal influenza, Measles (Rubeola), Measles-mumps-rubella (MMR) combination, 
Mumps, Oral polio (Sabin), Oral typhoid, Rubella, Smallpox (Vaccinia), Shingles (Herpes zoster), Bacille 
Calmette-Guerin, Yellow fever. 
 
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10.10.5 Definition of anaphylaxis  
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (54). 
Clinical criteria for diagnosing anaphylaxis 
 
10.10.6 List of opportunistic infections  
• 
Aspergillosis 
• 
Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
the Mississippi and Ohio Rivers) 
• 
Candidiasis - only systemic, extensive mucosal or cutaneous candidiasis. 
• 
Coccidioides immitis (endemic south-western US and Central and South America) 
• 
Cryptococcus 
• 
Cytomegalovirus 
• 
Herpes simplex (severe/disseminated) 
• 
Herpes zoster 
• 
Histoplasmosis (pulmonary or disseminated; most common tropical areas 
Tennessee-Ohio-Mississippi river basins) 
• 
Listeriosis 
• 
Mycobacterium avium 
• 
Nontuberculosis mycobacteria 
• 
Pneumocystis pneumonia (PCP) 
• 
Tuberculosis (TB) 
This list is indicative and not exhaustive. 
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10.11 APPENDIX 11: ABBREVIATIONS AND DEFINITIONS  
 
ACQ: 
Asthma Control Questionnaire 
AD: 
atopic dermatitis 
ADA: 
anti-drug antibody  
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase  
ANCOVA: 
analysis of covariance  
ANSD: 
asthma nighttime symptom diary 
AQLQ(S): 
Asthma Quality of Life Questionnaire with Standardized Activities 
AST: 
aspartate aminotransferase 
ATS/ERS: 
American Thoracic Society/European Respiratory Society  
AUC: 
area under the serum concentration curve 
BDR: 
bronchodilator response 
Cmax: 
maximum observed serum/plasma drug or metabolite concentration 
CSR: 
clinical study report  
DC: 
dendritic cell 
DMC: 
Data Monitoring Committee 
DPI: 
dry powder inhaler  
EASI: 
Eczema Area and Severity Index 
ECG: 
electrocardiogram  
eCRF: 
electronic case report form  
eDiary: 
electronic diary 
EOS: 
end of study 
EOT: 
end of treatment  
 
e-Spirometer: 
electronic spirometer  
FeNO: 
Fractional Exhaled Nitric Oxide 
FEV1: 
forced expiratory volume in 1 second  
FEV6: 
forced expiratory volume in 6 seconds 
FIH: 
first-in-human 
FSH: 
follicle-stimulating hormone 
FVC: 
forced vital capacity 
GCP: 
good clinical practice  
GDPR: 
General Data Protection Regulation 
GINA: 
global initiative for asthma  
GLP: 
good laboratory practice 
HBc Ab: 
hepatitis B core antibody 
HBs Ag: 
hepatitis B surface antigen 
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
HCV Ab: 
hepatitis C virus antibody 
HLGT: 
high-level group term 
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HLT: 
high level term 
HRQoL: 
health-related quality of life 
HRT: 
hormonal replacement therapy  
IA: 
interim analysis 
IB: 
Investigator’s Brochure 
IC90: 
90% inhibitory concentration  
ICF: 
informed consent form  
ICS: 
inhaled corticosteroid  
IDFU: 
investigational directions for use 
IE: 
intercurrent event 
IEC: 
Independent Ethics Committees  
IFNγ: 
Interferon-gamma 
Ig: 
immunoglobulin 
IGA: 
Investigator Global Assessment 
IgE: 
immunoglobulin E  
IL: 
interleukin  
ILC2: 
innate lymphoid cells type 2 
IRB: 
Institutional Review Boards  
ITT: 
Intent-to-treat 
IV: 
intravenous(ly) 
IVRS/IWRS: 
interactive voice/web response system 
KLH: 
keyhole limpet haemocyanin 
LABA: 
long-acting beta agonist 
LAMA: 
long-acting muscarinic antagonist  
LAR: 
legally authorized representative 
LOAC: 
loss of asthma control  
LS: 
least squares  
LTRA: 
leukotriene receptor antagonist 
LTS: 
long term safety  
mAb: 
monoclonal antibody 
MCID: 
Minimal Clinically Important Difference 
MDI: 
metered dose inhaler 
NOAEL: 
no observed adverse effect level 
OCS: 
oral corticosteroid 
OX40L: 
OX40 ligand 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamics 
PEF: 
peak expiratory flow  
PK: 
pharmacokinetics 
PRO: 
Participant-reported outcome 
PT: 
preferred term 
Q12W: 
every 12 weeks 
Q4W: 
every 4 weeks 
QoL: 
quality of life  
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QTL: 
Quality tolerance limit 
Rrs: 
Respiratory resistance 
SABA: 
short-acting beta 2-agonists 
SAE: 
serious adverse event  
SAP: 
statistical analysis plan, statistical analysis plan 
SARP: 
Severe Asthma Research Program 
SC: 
subcutaneous 
SoA: 
schedule of activities  
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
TARC: 
Thymus and Activation-Regulated Chemokine 
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse event 
Th: 
T helper 
Tmem: 
memory T cells 
TNF: 
Tumour necrosis factor 
Treg: 
Regulatory T cell 
TSLP: 
thymic stromal lymphopoietin 
ULN: 
upper limit of normal range 
VAS: 
Visual Analog Scale 
WOCBP: 
woman of childbearing potential 
WONCBP: 
woman of nonchildbearing potential 
Xrs: 
Respiratory reactance 
  
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). 
The primary reasons for first protocol amendment are summarized below. 
Amended protocol 01 (17 June 2022) 
This amended protocol (amendment 01) is considered to be nonsubstantial 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 because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reason for this amendment to Protocol DRI17509 is to fulfil requirement from the 
Medicines and Healthcare products Regulatory Agency (MHRA), UK.  
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule 
of Activities (SoA) 
“Tests should be performed no more than 5 days prior 
to IMP administration” is added and “COVID-19 
molecular test will be performed at screening (Day -1)” 
is revised to “COVID-19 test will be performed at 
screening” in footnote k. 
Clarification on COVID testing for the 
investigators. 
Section 10.2 
Appendix 2: clinical 
laboratory tests 
The text for COVID-19 testing in table 13 is revised as: 
“Tests for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2; the virus that causes 
coronavirus disease 2019 [COVID-19]) at Screening 
(Visit 1), randomization and prior to each IMP 
administration (no administration if positive). Tests 
should be performed no more than 5 days prior to IMP 
administration. Method of testing as required per local 
guidelines”. 
 
Section 5.2 Exclusion 
Criteria E14 
“Serum total bilirubin >1.5 x ULN (participants with 
Gilbert’s syndrome can be included with total bilirubin 
>1.5 x ULN as long as direct bilirubin is <1.5 x ULN)” is 
added in E14. 
To fulfil requirement from MHRA, UK. 
Section 6.8 
Concomitant Therapy 
“Other concomitant medications may be considered on 
a case-by-case basis by the Investigator in consultation 
with the medical monitor if required” is removed. 
To fulfil requirement from MHRA, UK. 
Section 7.1.1 
Permanent 
Discontinuation 
“A decision to resume the IMP will be made jointly by 
the Investigator and Medical Monitor (Medical Monitor’s 
written approval is required)” is removed. 
To fulfil requirement from MHRA, UK. 
Section 10.2 
Appendix 2: clinical 
laboratory tests 
“Creatine phosphokinase (CPK)” is added in Table 13.  
Clarification to align with the footnote g 
under the SoA. The inconsistency was 
pointed out by FDA. 
Section 10.12 
Appendix 12: 
Protocol 
Amendment 
History 
Updated 
Changes made based on Sanofi standard. 
Section 11 
References 
Reference 25 is corrected. 
Correction of the reference. 
Cover page 
“NCT05421598” is added. 
Update on ClinicalTrials.gov identifier 
number. 
Throughout the 
document 
Other minor editorial changes (eg, grammatical, 
stylistic, and minor typographical corrections). 
To increase the clarity or consistency of 
the protocol. 
 
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Amended protocol 02 (23 November 2022) 
This amended protocol (amendment 02) is considered to be nonsubstantial 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 because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reason for this amendment to DRI17509 amended protocol 01 is to remove all 
references to China, since China is removed from participation in the study. Some editorial and 
operational modifications are made. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
and Section 6.1.1 
Devices 
The text “(in certain countries)” is deleted after impulse 
oscillometry devices 
Clarification on the supply of impulse 
oscillometry devices by Sanofi or 
designees 
Section 1.1 Synopsis 
and Section 6.2 
Preparation, handling, 
storage and 
accountability  
The text for the route of administration is changed to: 
“SC injection, to abdomen or outer thigh. IMP should 
not be administered at the exact site of a recent 
injection or in areas which in the Investigator's opinion 
are not suitable (eg, tender, bruised, red or hard).” 
Clarification to align with amlitelimab 
program 
Section 1.3 Schedule 
of Activities (SoA) 
 
Remote spirometry (pre-BD) is performed daily 
throughout the study during the Screening as it is 
during the rest of the study 
Clarification of remote spirometry (pre-BD) 
measurements during the Screening 
 
ANSD (AM) and ADSD (PM) will be performed at 
screening as preformed throughout the study 
Clarification of ANSD and ADSD 
measurements schedule 
 
In footnote b, the timelines “15 to 30 minutes” is 
deleted for the reversibility of at least 12% and 200 mL 
in FEV1 after administration of 2 to 4 puffs (200-400 μg) 
of albuterol/salbutamol or levalbuterol/levosalbutamol 
during screening or documented history of a 
reversibility test that meets these criteria within 
12 months prior to Visit 1. 
The timeframe for reversibility testing is 
unnecessarily restrictive and not mandated 
by the 2019 ATS-ERS guideline 
 
Footnote w is changed to “To calculate ACQ-7, the 
ACQ-6 is completed in the participant’s eDiary during 
clinic visits. ACQ-6 score will be used to follow up 
evaluations in all participants. ACQ-5 (the first 5 items 
of the ACQ-6) score is used for eligibility evaluation at 
Visit 1 and Visit 2 for all participants.” 
To align with ACQ-7 assessment listed as 
efficacy outcome in the schedule of 
activities (SOA) table 
 
In the footnote aa, the sentence “In case of severe 
asthma exacerbation during screening, screening 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
period can be extended to up to 3 months. Please see 
Screen Failures section for instructions” is added. 
Section 5.1 Inclusion 
criteria 
Inclusion criterion I 06 is changed to “5-item ACQ-5 
score >1.5 at screening and randomization. 
5-item ACQ-5 score >1.5 is required at 
screening for eligibility which is stated in 
the SoA and in the Screen Failures 
section; I 06 language updated accordingly 
 
In inclusion criterion I 07, the timelines “15 to 
30 minutes” is deleted for the reversibility of at least 
12% and 200 mL in FEV1 after administration of 2 to 
4 puffs (200-400 μg) of albuterol/salbutamol or 
levalbuterol/levosalbutamol during screening or 
documented history of a reversibility test that meets 
these criteria within 12 months prior to Visit 1. 
The timeframe for reversibility testing is 
unnecessarily restrictive and not mandated 
by the 2019 ATS-ERS guideline 
Section 5.2 Exclusion 
criteria 
Exclusion criterion E03 is updated. Participants are 
excluded if they experience a deterioration of asthma 
within 1 month prior to the Screening Visit.” 
A clarifying note is added: “counting from the date of 
completion of treatment for asthma exacerbation” 
Clarification of exclusion of participants for 
deterioration of asthma 
Section 5.4 Screen 
failures 
The text “without an option for rescreening” is added to 
the sentence “Participants who are eligible for 
rescreening may be rescreened once for any reason, 
except for PRO criteria (ie, ACQ-5<1.5), which will lead 
to screen failure.” 
Editorial change 
 
The text for technical malfunction of equipment during 
spirometry is revised as: “In the case of technical 
malfunction of equipment during spirometry, the 
participant may be retested”. 
Operational clarification 
 
The text for the participants who experience an upper 
or lower respiratory tract infection during the screening 
period is revised as:” Participants with an upper or 
lower respiratory tract infection within the 4 weeks prior 
to screening or during the screening period may be 
rescreened (Exclusion criterion E 04) after 4 weeks or 
14 days after recovery, ie, completion of the therapy, 
whichever is longer.” 
Clarification of rescreening timelines for the 
participants who experience an upper or 
lower respiratory tract infection during the 
screening period 
 
The text for “Participants who experience an asthma 
exacerbation that results in emergency treatment or 
hospitalization, or treatment with systemic steroids 
during the screening period” is updated to “remain in 
screening and proceed with randomization 1 month 
after they have completed their course of oral 
corticosteroid (OCS) or returned to their maintenance 
dose of OCS. Screening period in this case can be 
extended to up to 3 months.” 
Clarification of extension of screening 
period for participants who experience an 
asthma exacerbation that results in 
emergency treatment or hospitalization, or 
treatment with systemic steroids during the 
screening period 
Section 8 Study 
assessments and 
procedures 
In the list of assessments/procedures performed at site, 
the text “spirometry pre-BD and spirometry post-BD” 
are simplified to “spirometry”. 
Clarification of assessments/procedures 
performed at site 
Section 8.1.3.4 
Electronic diary 
ACQ-5 is changed to ACQ-6 
Typo 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.2 
Appendix 2: Clinical 
laboratory tests: 
Table 13 
Random is added to fasting for glucose measurement. 
Clarification of glucose measurement 
 
Direct bilirubin measurement is deleted. Conjugated 
and non-conjugated bilirubin measurements are added 
when total bilirubin is above normal range. 
Clarification of bilirubin measurement 
Section 10.8.1 China-
specific requirements 
Section removed and subsequent section is re-
numbered. 
China is removed from participation in the 
study 
Section 10.9 
Appendix 9: 
Contingency 
measures for a 
regional or national 
emergency that is 
declared by a 
governmental agency 
Cotinine is deleted in the sentence: “Vital signs, 
hematology and clinical chemistry, routine urine 
analysis plus dipstick test (pregnancy) and AE 
reporting should have priority from a safety 
perspective.” 
Cotinine measurement is deleted as 
priority from a safety perspective; typo 
Section 10.10.1. Low, 
medium, and high ICS 
doses: 
adults/adolescents 
The text: “Daily doses in this table are shown as 
metered doses. See product information for delivered 
doses”, is added 
Clarification of inhaled corticosteroid 
treatments 
Section 10.12 
Appendix 12: Protocol 
amendment history 
The text of summary of changes for protocol 
amendment 01 is added 
Appendix 12 is updated to reflect the 
document history of previous amendment, 
ie, amendment 01 
Throughout the 
document 
All references to China are removed 
China is removed from participation in the 
study 
Throughout the 
document 
The text moderate-to-high doses of ICS therapy is 
changed to medium-to-high doses of ICS therapy 
Wording accuracy 
 
Amended protocol 03 (03 April 2023) 
This amended protocol (amendment 03) is considered to be nonsubstantial 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 because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
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Page 139 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the amendment is to respond to the Health Authorities (Ministry of Food 
and Drug Safety [MFDS]) requests: to implement conditions and set a limited number of two 
rescreening options during the screening period (one rescreening due to asthma exacerbation and 
one additional rescreening for any reason other than PRO criteria [ACQ-5<1.5]) in South Korea 
since 3-month extended screening period is not allowed in that country. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
(SOA) 
Under footnote aa, a reference to Section 10.8.2 was newly 
added for South Korea. 
Regulatory Authority (MFDS) 
request 
5.4 Screen failures 
The following wording was added: “Please note exceptions 
for South Korea” and “Note: extension of screening is not 
allowed in South Korea”. References to Section 10.8.2 were 
added. 
 
10.8.2 South Korea specific 
requirements 
A new subsection was added to adapt the process of 
rescreening in case of screen failures for study participants 
from South Korea. 
 
10.1.6 Dissemination of 
clinical study data and results 
The following website “clinicalstudydatarequest.com” was 
updated to “vivli.org”. 
To update due to recent 
change of website. 
 
 
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11 
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