Clinical trial NCT04456673
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Sanofi
Start date: 2020-07-06; Completion date: 2024-05-27
Enrollment: 935 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of dupilumab administered every 2 weeks in patients with moderate or severe Chronic Obstructive Pulmonary Disease (COPD) as measured by

* Annualized rate of acute moderate or severe COPD exacerbation (AECOPD)

Secondary Objectives:

To evaluate the effect of dupilumab administered every 2 weeks on

* Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared to placebo
* Health related quality of life, assessed by the change from baseline to Week 52 in the St. George's Respiratory Questionnaire (SGRQ)
* Pre-bronchodilator FEV1 over 52 weeks compared to placebo
* Lung function assessments
* Moderate and severe COPD exacerbations
* To evaluate safety and tolerability
* To evaluate dupilumab systemic exposure and incidence of antidrug antibodies (ADA)

Detailed description:
Approximately 68 weeks including a 4-week screening period, a 52-week treatment period, and 12 weeks of follow-up

Arms: arm 1: Participants received dupilumab 300 mg subcutaneous (SC) injection every 2 weeks (q2w) up to 52 weeks arm 2: Participants received placebo matched to dupilumab 300 mg SC injection q2w up to 52 weeks
Interventions: intervention 1: Dupilumab SAR231893 intervention 2: Inhaled Corticosteroid intervention 3: Inhaled Long-Acting Beta Agonist intervention 4: Inhaled Long-Acting Muscarinic Antagonist intervention 5: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection

Route of administration: Subcutaneous intervention 2: Pharmaceutical form: Inhaled Powder

Route of administration: Oral inhalation intervention 3: Pharmaceutical form: Inhaled Powder

Route of administration: Oral inhalation intervention 4: Pharmaceutical form: Inhaled Powder

Route of administration: Oral inhalation intervention 5: Pharmaceutical form: Solution for injection

Route of administration: Subcutaneous

Protocol documents:
Prot_000.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03  
Protocol title: 
A Randomized, Double-blind, Placebo-controlled, 
Parallel-group, 52-week Pivotal Study to Assess the 
Efficacy, Safety, and Tolerability of Dupilumab in 
Patients with Moderate-to-severe Chronic Obstructive 
Pulmonary Disease (COPD) with Type 2 inflammation 
Protocol number: 
EFC15805 (NOTUS) 
Amendment number: 
03  
Compound number 
(INN/Trademark): 
SAR231893/REGN668 (dupilumab) 
 
Study phase: 
Phase 3 
Short title: 
Pivotal study to assess the efficacy, safety and 
tolerability of dupilumab in patients with moderate-to-
severe COPD with Type 2 inflammation (NOTUS)  
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: 
105379 
EudraCT: 
2018-001954-91 
NCT: 
NCT04456673 
WHO: 
U1111-1211-8837 
Other: 
Not applicable 
 
 
Approval Date: 
28-Oct-2023 
Total number of pages: 115 


Amended Clinical Trial Protocol 03 
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28-Oct-2023 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
28-Oct-2023, Version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
All 
16-Dec-2021, Version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
29-Sep-2020, Version 1 (electronic 1.0) 
Original Protocol 
 
06-Dec-2019, Version 1 (electronic 1.0) 
Amended protocol 03 (28-October-2023) 
This amended protocol 03 (amendment 3) is considered to be non substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The overall rationale for the changes implemented in the protocol amendment is to add an interim 
analysis to determine if efficacy in the primary endpoint of annualized rate of moderate or severe 
chronic obstructive pulmonary disease (COPD) exacerbations is met at the time of the interim 
analysis, as COPD is a disease with a high unmet medical need. The interim analysis will be 
performed when ≥92% of the information fraction for the primary endpoint is available, but prior 
to all patients completing the 52-week treatment period. 
 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Added a bullet on an interim analysis. 
Interim analysis is planned for 
efficacy as COPD is a disease 
with high unmet medical need. 
 
Update of the data monitoring committee activities. 
Update 
Section 8.3.8 Disease-
related events and/or 
disease-related 
outcomes not qualifying 
as AEs or SAEs 
Deletion of “and thus will not be considered unexpected 
condition” and “Any other AE not listed as an expected event in 
the IB or in this protocol will be considered unexpected”. 
For accuracy and to clarify the 
current process. 
Section 9.2 Sample 
Size Determination 
Added details on alpha value at final analysis. 
Interim analysis is planned for 
efficacy. 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 9.4 Statistical 
Analyses 
Clarified the statistical analysis plan (SAP) will be finalized before 
the interim analysis.  
Interim analysis is planned for 
efficacy. 
Section 9.4.1 Efficacy 
analysis 
Added details that if the primary endpoint is positive at the interim 
analysis, Week 52 endpoints will be analyzed using participants 
who had the opportunity to reach Week 52 at the time of the IA 
cut-off date. 
Interim analysis is planned for 
efficacy. 
 
Update of the Statistical Analysis Methods wording for 
exploratory endpoints. 
Clarification 
Section 9.4.1.1 
Multiplicity 
Considerations 
Added details on the Kim-DeMets spending function for the 
interim analysis and hierarchical procedure for multiple 
endpoints. 
Interim analysis is planned for 
efficacy. 
Section 9.5 Interim 
Analyses 
Updated text from “No interim analysis is planned” to add details 
of an interim analysis. 
Interim analysis is planned for 
efficacy. 
Section 10.1.4 
Committees structure 
Update of the data monitoring committee activities. 
Update 
Section 10.1.5 
Dissemination of clinical 
study data 
Update of the web address for the clinical study data sharing 
“vivli.org”” replaces “clinicalstudydatarequest.com”. 
Update 
Throughout 
Minor editorial and document formatting revisions are made. 
Correction 


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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 15 
1.3.1 
Schedule of activities for patients who complete the planned treatment ....................................... 16 
1.3.2 
Reduced schedule of events for patients after early treatment discontinuation ............................ 20 
2 
INTRODUCTION ............................................................................................................................ 22 
2.1 
STUDY RATIONALE...................................................................................................................... 22 
2.2 
BACKGROUND ............................................................................................................................. 22 
2.2.1 
Dupilumab anti-IL4Rα monoclonal antibody .................................................................................. 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 27 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 28 
4 
STUDY DESIGN ............................................................................................................................ 29 
4.1 
OVERALL DESIGN ........................................................................................................................ 29 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 30 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 30 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 31 
5 
STUDY POPULATION .................................................................................................................. 32 
5.1 
INCLUSION CRITERIA .................................................................................................................. 32 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 33 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 36 


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5.4 
SCREEN FAILURES...................................................................................................................... 36 
6 
STUDY INTERVENTION ............................................................................................................... 38 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 38 
6.1.1 
Investigational Medicinal Product(s) .............................................................................................. 38 
6.1.2 
Non-investigational Medicinal Product(s) ...................................................................................... 39 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...................................................... 41 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 42 
6.3.1 
Methods of assigning patients to treatment group ......................................................................... 42 
6.3.2 
Methods of blinding ........................................................................................................................ 43 
6.3.3 
Randomization code breaking during the study ............................................................................. 43 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 43 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 44 
6.6 
DOSE MODIFICATION .................................................................................................................. 44 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 44 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 45 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 45 
7.1.1 
Permanent discontinuation ............................................................................................................ 45 
7.1.2 
Temporary discontinuation of study intervention  .......................................................................... 47 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 47 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 49 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 49 
8.1.1 
Disease-specific efficacy measures ............................................................................................... 49 
8.1.1.1 
Severity of COPD exacerbations as defined by the protocol ......................................................... 49 
8.1.1.2 
Spirometry ...................................................................................................................................... 50 
8.1.2 
Clinical outcome assessments ....................................................................................................... 51 
8.1.2.1 
Patient reported outcome questionnaires ...................................................................................... 51 
8.1.2.2 
Other clinical outcome assessments ............................................................................................. 52 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 53 
8.2.1 
Physical examinations ................................................................................................................... 53 
8.2.2 
Vital signs ....................................................................................................................................... 53 
8.2.3 
Electrocardiograms ........................................................................................................................ 53 


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8.2.4 
Clinical safety laboratory assessments .......................................................................................... 54 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 54 
8.3.1 
Adverse event of special interest ................................................................................................... 55 
8.3.2 
Time period and frequency for collecting AE and SAE information ............................................... 56 
8.3.3 
Method of detecting AEs and SAEs ............................................................................................... 56 
8.3.4 
Follow-up of AEs and SAEs ........................................................................................................... 57 
8.3.5 
Regulatory reporting requirements for SAEs ................................................................................. 57 
8.3.6 
Pregnancy ...................................................................................................................................... 57 
8.3.7 
Adjudication Committee ................................................................................................................. 57 
8.3.8 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 58 
8.3.9 
Guidelines for reporting product complaints / medical device incidents (including 
malfunctions) .................................................................................................................................. 58 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 58 
8.5 
PHARMACOKINETICS .................................................................................................................. 58 
8.5.1 
Sampling time ................................................................................................................................ 58 
8.5.2 
Handling procedures ...................................................................................................................... 59 
8.5.3 
Bioanalytic method ......................................................................................................................... 59 
8.6 
PHARMACODYNAMICS ............................................................................................................... 60 
8.6.1 
Pharmacodynamic variables/biomarkers ....................................................................................... 60 
8.7 
PHARMACOGENOMICS ............................................................................................................... 61 
8.8 
BIOMARKERS ............................................................................................................................... 61 
8.9 
HEALTH CARE RESOURCE UTILIZATION ................................................................................. 61 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 62 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 62 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 62 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 63 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 63 
9.4.1 
Efficacy analyses ........................................................................................................................... 64 
9.4.1.1 
Multiplicity considerations .............................................................................................................. 65 
9.4.2 
Safety analyses .............................................................................................................................. 66 
9.4.3 
Other analyses ............................................................................................................................... 67 
9.5 
INTERIM ANALYSES  ................................................................................................................... 68 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 70 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 70 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 70 
10.1.2 
Informed consent process .............................................................................................................. 70 
10.1.3 
Data protection ............................................................................................................................... 71 
10.1.4 
Committees structure ..................................................................................................................... 71 
10.1.4.1  Data Monitoring Committee (DMC) ................................................................................................ 71 
10.1.4.2  Adjudication committee .................................................................................................................. 72 
10.1.5 
Dissemination of clinical study data ............................................................................................... 72 
10.1.6 
Data quality assurance .................................................................................................................. 72 
10.1.7 
Source documents ......................................................................................................................... 73 
10.1.8 
Study and site closure .................................................................................................................... 73 
10.1.9 
Publication policy ........................................................................................................................... 74 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 74 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 75 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 80 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 82 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND  FOLLOW-UP 
ASSESSMENTS  ........................................................................................................................... 83 
10.7 
APPENDIX 7: LIST OF PROHIBITED LIVE ATTENUATED VACCINES ...................................... 85 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 85 
10.9 
APPENDIX 9: ABBREVIATIONS ................................................................................................... 85 
10.10 
APPENDIX 10: ST. GEORGE’S RESPIRATORY QUESTIONNAIRE .......................................... 89 
10.11 
APPENDIX 11: THE EXACT AS FORMATTED FOR PERSONAL DIGITAL ASSISTANT 
(PDA) ............................................................................................................................................. 95 
10.12 
APPENDIX 12: EXACT QUESTIONNAIRE ................................................................................... 98 
10.13 
APPENDIX 13: BODE .................................................................................................................. 101 
10.14 
APPENDIX 14:  EQ-5D-5L ........................................................................................................... 102 
10.15 
APPENDIX 15: DEFINITION OF ANAPHYLAXIS ....................................................................... 105 
10.16 
APPENDIX 16: LIST OF OPPORTUNISTIC INFECTIONS ......................................................... 105 
10.17 
APPENDIX 17: FUTURE USE OF SAMPLES ............................................................................. 106 


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10.18 
APPENDIX 18: HIGH DOSE OF INHALED CORTICOSTEROIDS: ADULTS ............................ 106 
10.19 
APPENDIX 19: PROTOCOL AMENDMENT HISTORY .............................................................. 107 
10.19.1  Amended protocol 01 (Amendment 01) (29-September-2020) ................................................... 107 
10.19.2  Amended protocol 02 (Amendment 02) (16-December-2021) .................................................... 111 
11 
REFERENCES ............................................................................................................................. 113 
 


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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 27 
Table 2 - Overview of study interventions administered ............................................................................... 38 
Table 3 - Reliever medication - Salbutamol/Albuterol nebulizer solution ...................................................... 40 
Table 4 - Reliever medication - Levosalbutamol/Levalbuterol nebulizer solution ......................................... 40 
Table 5 - Reliever medication - Ipratropium or Ipratropium/short-acting β agonists [SABA] nebulizer 
solutions ........................................................................................................................................................ 41 
Table 6 - Summary of handling procedures for dupilumab ........................................................................... 59 
Table 7 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibodies ........................ 59 
Table 8 - Populations for analyses ................................................................................................................ 63 
Table 9 - Efficacy analyses ........................................................................................................................... 64 
Table 10 - Safety analyses ............................................................................................................................ 66 
Table 11 - Other analyses ............................................................................................................................. 67 
Table 12 - Kim-DeMets alpha spending function to control the overall alpha at 0.05 ................................... 68 
Table 13 - Protocol-required safety laboratory assessments ........................................................................ 75 
Table 14 - Highly effective contraceptive methods ....................................................................................... 80 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
 


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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal Study to 
Assess the Efficacy, Safety, and Tolerability of Dupilumab in Patients with Moderate-to-severe 
Chronic Obstructive Pulmonary Disease (COPD) with Type 2 inflammation 
Short title: 
Pivotal study to assess the efficacy, safety and tolerability of dupilumab in patients with 
moderate-to-severe COPD with Type 2 inflammation (NOTUS)  
Rationale: 
Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease worldwide, 
associated with significant economic burden, and for which available standard-of-care therapy 
shows insufficient treatment effect on symptoms, lung function, exacerbations and long-term 
evolution of the disease. Though the inflammatory component in COPD is typically thought to be 
neutrophilic, there has been an identified subgroup of COPD which is characterized by a 
concomitant elevation in blood eosinophils which suggests a Type 2 inflammatory component of 
the disease in these patients. This study is designed to investigate the efficacy and safety of 
dupilumab over one year in patients with COPD with Type 2 inflammation who are in need of an 
additional treatment added to their current management. The presence of a placebo arm is 
appropriate for the objectives of this study, since it will provide the most robust assessment of the 
efficacy and safety of dupilumab. All patients will receive standard of care background 
medication throughout the study. The proposed study design provides the opportunity to assess 
the efficacy of dupilumab on multiple COPD domains including lung function, prevention of 
moderate and severe exacerbations, and symptom control. The effect on lung function and 
symptom control will be evaluated over both the short and long term. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of dupilumab 300 mg 
q2w in patients with moderate or severe 
COPD as measured by 
 
Annualized rate of acute moderate 
or severe COPD exacerbation 
(AECOPD). 
 
Annualized rate of moderate* or severe** COPD exacerbations over 
the 52-week treatment period compared to placebo. 
*Moderate exacerbations are recorded by the Investigator and 
defined as AECOPD that require either systemic corticosteroids 
(such as intramuscular, intravenous or oral) and/or antibiotics.  
**Severe exacerbations are recorded by the Investigator and 
defined as AECOPD requiring hospitalization, or observation 
for >24 hours in an emergency department/urgent care facility or 
resulting in death. 
For both moderate and severe events to be counted as separate 
events, they must be separated by at least 14 days. 


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Objectives 
Endpoints 
Key secondary 
To evaluate the effect of dupilumab 300 mg 
q2w on 
 
Pre-bronchodilator forced 
expiratory volume in 1 second 
(FEV1) over 12 weeks compared to 
placebo. 
 
Health related quality of life, 
assessed by the change from 
baseline to Week 52 in the St. 
George’s Respiratory 
Questionnaire (SGRQ). 
 
Pre-bronchodilator FEV1 over 
52 weeks compared to placebo. 
 
Change in pre-bronchodilator FEV1 from baseline to Week 12 
compared to placebo. 
 
Change from baseline to Week 52 in SGRQ total score compared to 
placebo. 
 
Proportion of patients with SGRQ improvement ≥4 points at 
Week 52. 
 
Change in pre-bronchodilator FEV1 from baseline to Week 52 
compared to placebo. 
Overall design: 
Multinational, randomized, double-blind, placebo-controlled, parallel group (2 groups), 52-week, 
pivotal Phase 3 study to assess the efficacy, safety, and tolerability of dupilumab in patients with 
moderate-or-severe COPD with Type 2 inflammation such as that driven by activation of IL-4, 
IL-5, and IL-13 on an established long acting beta-agonist (LABA), long acting muscarinic 
antagonist (LAMA) and/or inhaled corticosteroid (ICS) background therapy (triple therapy unless 
ICS contraindicated). Study treatments are dupilumab 300 mg q2w or placebo q2w administered 
during the 52-week randomized treatment period. The study includes 3 study periods. 
 Screening (4 weeks ±1 week). 
 Randomized investigational medicinal product (IMP) treatment period  
(52 weeks ±3 days). 
 Post IMP treatment period (12 weeks ±5 days). 
Patients who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following IMP treatment groups to be administered for 52 weeks. 
 Dupilumab 300 mg, administered as 1 subcutaneous (SC) injection q2w. 
 Placebo, administered as 1 SC injection of placebo matching dupilumab. 
Randomization will be stratified by country, ICS dose (high dose ICS [yes/no]) at baseline, and 
smoking status at screening (current smokers or not). Enrollment will be capped at 30% current 
smokers (as defined by smoking status at screening visit). 
Treatment discontinuation follow-up: 
Patients who discontinue the study treatment prematurely (prior to completing the 52-week 
treatment period) will perform, as soon as possible, the early treatment discontinuation (ETD) 
visit with all assessments normally planned for the end of treatment (EOT) visit, to assure a 
complete clinical assessment in close temporal proximity to the premature termination of study 
treatment is available. In addition, to allow assessment of patient outcomes over the stipulated 


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study period, patients will be asked and encouraged to complete all remaining study visits, and 
participate in all safety follow-up assessments according to the visit schedule. For these patients 
the assessment schedule will be reduced (see Section 1.3.2) and visits during the planned 
treatment period may be conducted by phone (except for planned EOT) if patient is unable to 
come in for a site visit. Assessments not completed via phone should be performed at the next 
scheduled visit. For further details please see Section 7.1.1. 
Post-IMP treatment follow-up 
Upon completing the 52-weeks randomized IMP treatment period, patients will continue their 
background ICS/LABA/LAMA therapy and enter the 12-week safety follow-up period. 
Adjustment of background medication is allowed at the discretion of the Investigator as clinically 
indicated during the post-treatment period (see Section 6.1.2 for further details). 
Disclosure Statement: This is a Parallel Treatment study with 2 arms that is blinded for patients 
and the Investigator. 
Number of participants: 
Approximately 924 patients are planned to be randomly assigned to study intervention for an 
estimated total of 462 evaluable patients per intervention group (see Section 9.2). 
Intervention groups and duration: 
Study participation for each patient will be a total of approximately 69 weeks including up to 
5 weeks for screening, 52 weeks of IMP treatment period and 12 weeks of follow-up. 
Study intervention(s) 
Investigational medicinal products. 
 Dupilumab 300 mg. 
- 
Formulation: Dupilumab 300 mg for SC administration is supplied as 150 mg/mL 
solution in 2.25 mL prefilled glass syringes to deliver 300 mg in 2 mL. 
- 
Route of administration: subcutaneous injection. All IMP applications will be done as 
separate injections into different injection sites. 
- 
Dose regimen: dupilumab 300 mg q2w administered as 1 SC injection. 
 Matching Placebo for dupilumab. 
- 
Formulation: Placebo matching dupilumab will be supplied as an identical formulation 
to the active formulation but without dupilumab. 
- 
Route of administration: subcutaneous injection. All IMP applications will be done as 
separate injections into different injection sites. 
- 
Dose regimen: Placebo administered as 1 SC injection of placebo matching dupilumab 
300 mg (2 mL). 


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Noninvestigational medicinal products(s) 
Background therapy 
Patients should continue the regular administration of their previous standard of care background 
therapy for COPD throughout the study, including: 
Triple therapy: ICS + LABA + LAMA (Double therapy: LABA + LAMA allowed if ICS is 
contraindicated) 
 Formulation: dry powder inhaler (DPI), metered dose inhaler (MDI) or pocket nebulizer. 
 Route(s) of administration: Oral inhalation. 
 Dose regimen: As prescribed. 
 Background medication should not be adjusted during Screening. Patients are strongly 
encouraged to maintain their background therapy for the entire duration of their treatment 
therapy. After 1 severe or 2 moderate exacerbations of COPD, dose adjustments in 
background therapy, if required will be permitted for symptom control and as needed for 
the remainder of the trial period. 
Reliever medication 
 Patients may use albuterol/salbutamol or levalbuterol/levosalbutamol (including 
ipratropium or ipratropium/short acting β-agonist [SABA] combinations or terbutaline) as 
reliever medications as needed during the study. 
 Formulation: MDI, nebulizer solutions or DPI. 
 Route of administration: oral inhalation. 
 Dose regimen: as prescribed. 
Statistical considerations: 
 Analysis populations 
- 
The efficacy population will be the intention-to-treat (ITT) population, defined as all 
randomized patients analyzed according to the treatment group allocated by 
randomization. 
- 
The safety population will include all patients who actually received at least one dose 
or a partial dose of the IMP, analyzed according to the treatment actually received. 
 Primary analysis: The annualized rate of moderate or severe COPD exacerbation events 
will be analyzed using a negative binomial regression model. The model will include the 
total number of events occurring during the 52-week treatment period as the response 
variable, with the treatment group, region (pooled country), ICS dose (high dose ICS 
[yes/no]), smoking status at screening (current smokers or not), baseline disease severity 
(as % predicted post-bronchodilator FEV1), and number of moderate or severe COPD 
exacerbation events within one year prior to the study (≤2, 3, or ≥4) as covariates. 
Log-transformed observation duration will be used as offset variable. Patients who 
permanently discontinue the study treatment will be encouraged to complete the study as 
planned and the additional off-treatment exacerbation events up to Week 52 will be 


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included in the primary analysis. Sensitivity analyses for handling missing data may 
include pattern mixture model by multiple imputation and tipping point analyses. 
 Analysis of key secondary endpoints: 
The change from baseline in pre-bronchodilator FEV1 at Week 12 will be analyzed using 
mixed-effect model with repeated measures (MMRM). The model will include change 
from baseline in FEV1 values up to Week 12 as response variables, and factors for 
treatment group, age, sex, baseline height, region (pooled country), ICS dose (high dose 
ICS dose [yes/no]), smoking status at screening (current smokers or not), visit, 
treatment-by-visit interaction, baseline pre-bronchodilator FEV1, and FEV1 
baseline-by-visit interaction as covariates. An unstructured correlation matrix will be used 
to model the within-patient errors. Parameters will be estimated using restricted maximum 
likelihood method using the Newton-Raphson algorithm. For patients discontinued the 
study treatment, off-treatment FEV1 values will be included in the analysis. Sensitivity 
analyses for handling missing data may include pattern mixture model by multiple 
imputation and tipping point analyses. 
The change from baseline in pre-bronchodilator FEV1 at Week 52 will be analyzed in a 
similar way as change from baseline in pre-bronchodilator FEV1 at Week 12 and the 
model will include values up to Week 52 as response variables. 
The change from baseline in SGRQ total score at Week 52 will also be analyzed in a 
similar way except that the MMRM model will include the following covariates: treatment 
group, region (pooled country), ICS dose (high dose ICS [yes/no]), smoking status at 
screening (current smokers or not), visit, treatment-by-visit interaction, baseline SGRQ 
total score, and SGRQ baseline-by-visit interaction. 
The proportion of patients with SGRQ improvement ≥4 points at Week 52 will be 
analyzed using a logistic regression model. The model will include treatment group, region 
(pooled country), ICS dose (high dose ICS [yes/no]), smoking status at screening (current 
smokers or not), and baseline SGRQ total score as covariates. Patients with missing SGRQ 
total score at Week 52 will be considered as non-responders. 
 Multiplicity considerations: Multiplicity is considered for testing multiple endpoints. 
The overall type-I error rate will be controlled at the two-sided 0.05 level. Details will be 
provided in Section 9.4.1.1. 
 Safety analyses: The safety variables, including adverse events (AEs), laboratory 
parameters, vital signs, electrocardiography, and physical examinations will be 
summarized using descriptive statistics. 
 An interim analysis will be performed during the study. See Section 9.5 for further details. 
Data Monitoring Committee: Yes 
 A data monitoring committee (DMC), independent from Sponsor, will be established for 
this study. This committee is comprised of externally-based individuals with expertise in 
the diseases under study, biostatistics, or clinical research. The primary responsibilities of 
the DMC are to review and evaluate the safety and efficacy data during the course of the 
trial, review interim analysis results and make appropriate recommendations regarding the 
conduct of the clinical trial to the Sponsor. 


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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
1.3 
SCHEDULE OF ACTIVITIES (SOA)  
The schedule of activities (SoA) for patients who complete the planned treatment is described in 
Section 1.3.1. Patients who withdraw from treatment prematurely must complete the ETD visit 
and follow the assessment in Section 1.3.2 for the remaining visits. 








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g Electronic diary is used for recording of patient’s answers to the EQ-5D-5L, EXACT and SGRQ questionnaires. This handheld device is dispensed at Screening Visit 1 (including instructions for use) and recorded 
information is reviewed on the other indicated days. At EOT visit the electronic diary is downloaded from the device and returned to the site. 
h Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
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 screening, baseline and every subsequent on-site 
visit. Height (cm) will be measured at screening (Visit 1) only. Body weight (kg) will be measured at screening (Visit 1) and at EOT/EOS visits. 
j 
Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry will include creatinine, blood urea nitrogen, glucose, 
lactate dehydrogenase, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), 
bicarbonate, and creatine phosphokinase. Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen and bilirubin. If any parameter on the dipstick is 
abnormal, a urine sample should be sent to the central laboratory for quantitative measurement. If positive for protein and/or red blood cells, microscopic analysis will be performed by the central laboratory.  
Clinical laboratory testing at Screening Visit 1 will include hepatitis screen covering hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C virus 
antibodies (HCV Ab), Human Immunodeficiency Virus (HIV) screen (Anti-HIV-1 and HIV-2 antibodies) and anti-nuclear antibody (ANA). In case of results showing HBs Ag (negative), and HBc Ab (positive), an 
HBV DNA testing will be performed prior to randomization to rule out a false positivity if the Investigator believes the patient is a false positive, or to clarify the serological status if the Investigator finds it unclear to 
interpret in absence of known HBV infection. In case of results showing HCV Ab (positive), an HCV RNA testing may be performed to rule out a false positivity, if the Investigator believes the patient is a false 
positive. Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer).  
k Refer to central lab manual for collection details. 
l 
Only for women of childbearing potential. Pregnancy will lead to definitive treatment discontinuation in all cases. In case of positive urinary test, a serum pregnancy test should be performed as soon as possible to 
confirm the pregnancy. Pregnancy testing should be done monthly, female participants will be supplied with dipsticks for between on-site visits. 
m Spirometry will be done locally according to European Respiratory Society (ERS)/American Thoracic Society (ATS) 2005 guidance but measured by a central laboratory. Spirometry will be performed during a 
trough 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 
ipratropium for at least 8 hours, withholding the last dose of LABA for at least 12 hours (ultra-long acting LABA like vilanterol should be withheld for at least 24 hours) and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the measurements. Note: When both pre- and post-bronchodilator spirometry is assessed, the post-bronchodilator spirometry should be performed consistent 
with the mechanism of action of reliever (ie, 30 minutes for albuterol or other SABA). See Section 8.1.1.2 for details. 
n Following randomization and during the treatment period - if spirometry is not performed at the scheduled visit it should be performed at the following on-site visit for all visits prior to Week 12. If not performed at 
Week 12 or at subsequent scheduled on-site visits, an unscheduled assessment is required within 3 weeks of the missed scheduled. 
o PK and ADA samples to be collected prior to the administration of the drug. 
p If collection is not completed at randomization, sample can be taken at a following visit.  
q Includes collection of sick days, lost usual activities, and additional physician visits or other health care utilization. 
r 
To be completed prior to IMP administration. 
s Telephone visit. 






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2 
INTRODUCTION  
Dupilumab is a systemic targeted immunomodulatory agent, inhibiting the Th2 pathway. It is a 
fully human monoclonal antibody (mAB) directed against the interleukin 4 receptor alpha 
(IL-4Rα) subunit, a component of IL-4 receptors Type I and Type II, which mediate signaling by 
IL-4 (both receptors) and by IL-13 (Type II receptor). The IL-4R alpha receptor is present on 
multiple cell types known to be involved in the Type 2 inflammatory process. Dupilumab is being 
studied as a potential novel treatment for COPD in those patients with evidence of Type 2 
inflammation as identified by the biomarker of blood eosinophils. 
2.1 
STUDY RATIONALE  
Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease, associated with 
significant economic burden, and for which available standard-of-care therapies show insufficient 
treatment effect on symptoms, lung function, exacerbations and long-term progression of the 
disease. This study is designed to investigate the efficacy and safety profile of dupilumab over one 
year in patients with COPD who are in need of an additional treatment added to their current 
management. The presence of a placebo arm is appropriate for the objectives of this study, since it 
will provide the most robust assessment of the efficacy and safety of dupilumab. All patients will 
receive standard of care background medication throughout the study. The proposed study design 
provides the opportunity to investigate the efficacy of dupilumab on multiple COPD domains 
including lung function, prevention of moderate and severe exacerbations and symptom control. 
The effect on lung function and symptom control will be evaluated over short term and long term. 
2.2 
BACKGROUND  
Chronic obstructive pulmonary disease (COPD) is a common, heterogeneous disease associated 
with an abnormal inflammatory immune response of the lung to noxious particles and gases (1). 
It results in progressive airflow obstruction that is mainly irreversible or only partially reversible 
and in many cases loss of alveolar tissue and emphysema. The disease typically starts in small 
airways, where the chronic inflammation causes structural changes including narrowing of the 
small airways, and destruction of the lung parenchyma that leads to the loss of alveolar 
attachments to the small airways and decreases lung elastic recoil. The inflammation component 
of COPD is thought to involve many cell types including structural cells, T lymphocytes, 
neutrophils, macrophages, and their biological products. Though the inflammatory component in 
COPD is typically thought to be neutrophilic, there has been an identified subgroup of COPD 
which is characterized by a concomitant elevation in blood eosinophils which suggests a Type 2 
inflammatory component of their disease. COPD is most commonly caused by smoking tobacco, 
but may also be caused by particulate and noxious gas inhalation through outdoor or indoor air 
pollution including occupational exposures to vapors, gas, dust (including silica) and fumes. 
The most common clinical symptoms include chronic dyspnea, cough and/or sputum production. 
COPD exacerbations are important contributors to the disease burden, particularly in severe 
COPD. Exacerbations are often triggered by viral and/or bacterial infections, but tend to occur 


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also more frequently in patients with COPD with Type 2 inflammatory signature, where they may 
be preceded by increases in sputum eosinophils. Exacerbations may trigger a major inflammatory 
response followed by tissue destruction and frequent exacerbations which are associated with 
forced expiratory volume in 1 second (FEV1) decline, more rapid disease progression and 
increased risk of mortality. 
In particular, current smokers with COPD have an accelerated decline in lung function, which is 
heterogeneous, exhibits considerable inter- and intra-individual variability and FEV1 decline can 
reach more than 100 ml/year in some patients with COPD. Smoking cessation attenuates the 
accelerated loss of lung function, but neither smoking cessation nor current therapies result in a 
substantial recovery of lung function lost at the time of smoking cessation (2). 
“Type 2 inflammation” exists across a spectrum of diseases. This inflammatory cascade is 
regulated by T-helper Type 2 cells and is driven by activation of IL-4, IL-5, and IL-13 cytokines. 
(3). Peripheral and airway eosinophils are present in asthmatics with Type 2 inflammation (4). 
Markers of Type 2 inflammation, including sputum IL-4 and IL-5 have been identified in 
subgroups of patients with COPD and are linked to peripheral eosinophils (5, 6).  In addition, 
peripheral eosinophilia (>300), as a marker of Type 2 inflammation,  appears to identify a 
subgroup of COPD patients with distinct clinical features (6, 7) including more frequent 
respiratory exacerbations (8) as well as worse overall mortality. At the same time, this group, 
similar to asthmatics with Type 2 inflammation (9), also appears to be more responsive to ICS (6). 
Additional biomarkers for Type 2 inflammation have been identified in asthma populations, 
including IgE, FeNO, and Periostin, but to date they have been less well studied in COPD. 
Dupilumab blocks the IL4Ra, leading to inhibition of the Type 2 cytokines IL-4 and IL-13. 
In addition, IL-13 has been shown to block mucus secretion. We hypothesize that blocking key 
mediators of Type 2 inflammation as well as reducing mucus production in COPD will lead to a 
reduction in inflammatory exacerbations as well as an improvement in lung function. We will use 
peripheral eosinophilia to identify COPD patients with Type 2 inflammation. 
Chronic obstructive pulmonary disease is a highly prevalent, serious, and progressive disease 
resulting in significant morbidity, mortality, and economic burden (10, 11). Based on the BOLD 
and other large scale epidemiological studies, it is estimated that the number of COPD cases in the 
world was 384 million in 2010, with a global prevalence of 11.7% (95% confidence interval: 
8.4%-15.0%) (10). In the US alone there are more than 12 million diagnosed patients and the 
incidence of COPD is expected to grow rapidly with an aging population. COPD is a progressive 
and irreversible inflammatory lung disease that is periodically punctuated by disease 
exacerbations that result in long-term disability and mortality, in the US, COPD is the third most 
common cause of death. In Europe the number of cases is estimated to be  66.4 million in 2010 
among people aged 30 years or more, with a prevalence of 13.7% (13.5% - 13.9%) (10). 
Globally there are around 3 million deaths attributed to COPD annually. With the increasing 
prevalence of smoking in developing countries, and aging populations in high-income countries, 
the prevalence is expected to rise and the number of deaths to reach 4.5 million by 2030. Medical 
comorbidities such as cardiovascular disease, diabetes, lung cancer, skeletal muscle dysfunction, 
osteoporosis, psychological disturbances, and metabolic syndrome are common among COPD 
patients and occur across the spectrum of disease severity. 


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The Standard of Care for moderate COPD starts with daily use of bronchodilators, mostly 
long-acting muscarinic antagonists (LAMA) and/or long-acting β2-agonists (LABA). As disease 
progresses, in particular in patients with frequent exacerbations, bronchodilators are combined 
with anti-inflammatory drugs such as inhaled corticosteroids (ICS), and phosphodiesterase Type 4 
(PDE-4) inhibitors (roflumilast) (12, 13, 14). The major limitations of the existing agents for 
COPD include modest efficacy and for inhaled corticosteroids an increased risk of respiratory 
infections including pneumonia, in particular at high doses of potent molecules and in patients 
with severe COPD. While inhaled corticosteroids have a consistent effect in reducing the risk of 
moderate COPD exacerbations defined by a COPD deterioration requiring the use of systemic 
corticosteroids and/or antibiotics, there is no consistent benefit on severe exacerbations requiring 
hospitalizations. There is increasing evidence that this treatment effect is primarily driven by 
patients with more that 2% blood eosinophils (15). 
Systemic, mostly oral corticosteroids are largely reserved for the treatment of exacerbations given 
their unacceptable safety profile with heightened concerns for a COPD population. No approved 
therapeutic agent blocks the decline in FEV1 over time or modifies the progressive disease course 
of COPD. Thus there is a high unmet need for more effective treatment of this disease. 
Currently, no targeted biological treatments addressing the immunological underpinnings of 
COPD are approved. In Phase 3 trials, the anti-interleukin (IL-5) mAb mepolizumab showed a 
modest 18%-20% reduction of exacerbations in COPD patients with high blood eosinophils (16). 
The anti-IL-5 receptor mAb benralizumab recently announced results from its Phase 3 studies and 
both studies did not meet the primary endpoint of statistically significant reduction of COPD 
exacerbations. Details on factors that may have contributed to these results are not publicly 
available. Data from the Phase 2a trial with benralizumab suggest that the FEV1 improvement 
versus placebo averaging 150 mL over time is mainly driven by the subgroup of patients with 
high blood eosinophils. In this study, no reduction of exacerbations was seen in the per-protocol 
population, and a numerical, but not statistically significant, reduction of exacerbation was seen in 
the subgroup of patients with high blood eosinophils (17). 
Thus, significant unmet medical needs continue to exist in the growing population of patients with 
COPD. The main objective for new treatments is to further improve COPD symptoms, lung 
function, and prevent exacerbations, while optimizing adherence to the treatment. 
2.2.1 Dupilumab anti-IL4Rα monoclonal antibody  
Candidate gene studies and GWAS have identified IL-4 and IL-13 variants that occur more 
frequently in COPD patients than in controls (18), and Type 2 gene expression score has been 
identified in ~20% of COPD patients (19, 20). It is known that dupilumab decreases tissue 
eosinophils and therefore may improve COPD control in patients with COPD and eosinophilia. 
Eosinophilic airway inflammation is evident in 20%-40% of COPD patients (21, 7) with increased 
levels of eosinophils in blood, sputum, and bronchial biopsies reported during acute exacerbations 
(21, 12). Additionally, through dupilumab’s blockade of the IL-13 pathway, it is postulated that 
dupilumab may play a unique role in treating the mucous hypersecretion and goblet cell 
hyperplasia which is evident in chronic bronchitis subtype of COPD. 


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Dupilumab by binding to the IL-4Rα subunit blocks signaling of the signature Type 2 cytokines 
(IL-4 and IL-13) has a broader impact on Type 2 inflammation and therefore may have an 
improved potential to treat aspects of COPD inflammation which are driven by Type 2 
inflammatory tone. 
Dupilumab is currently approved for the treatment of atopic dermatitis (AD), asthma, and chronic 
rhinosinusitis with nasal polyposis (CRSwNP), and is in late stage development for eosinophilic 
esophagitis. At the time of protocol finalization, dupilumab has been submitted for regulatory 
approval for asthma in the US and in Europe. In asthma, it has demonstrated satisfactory safety 
and excellent efficacy in a broad spectrum of asthma patients, including severe asthma patients 
and previous smokers. The planned Phase 3 program including this study will provide evidence 
on the efficacy and safety of dupilumab in COPD patients with evidence of Type 2 inflammation 
as reflected by blood eosinophil counts (≥0.3 Giga/L) at screening. 
2.3 
BENEFIT/RISK ASSESSMENT  
Dupixent® (dupilumab) 150 mg/mL solution for injection is authorized for marketing in over  
40 countries worldwide including the United States (US), European Union (EU) (Centralized 
Procedure), and Japan for the adult moderate-to-severe AD indication. The marketing 
authorization for treatment of adult AD in the US was approved on 28 March 2017. The European 
Commission (EC) granted marketing authorization for dupilumab on 26 September 2017 for use 
in adults with moderate-to-severe AD who are candidates for systemic therapy. Dupilumab was 
also authorized in the US on 11 March 2019 for use in adolescent patients (≥12 years) with 
inadequately controlled moderate-to-severe AD. It was also approved as an add-on maintenance 
treatment for CRSwNP in the US on 26 June 2019 and in the EU on 29 October 2019. Approval 
was received for dupilumab from the US Food and Drug Administration (FDA) on 19 October 
2018 for use in adults and adolescents (≥12 years) with moderate-to-severe asthma. In the EU, the 
EC issued a positive decision on 07 May 2019 for use in adults and adolescents (≥12 years) with 
severe asthma with type 2 inflammation. In Japan, dupilumab received Pharmaceuticals and 
Medical Devices Agency (PMDA) approval on 26 March 2019 for use in adults and adolescents 
(≥12 years) with severe or refractory bronchial asthma. 
Dupilumab has shown clinically relevant benefit in several Type 2 mediated immune disorders 
including AD, bronchial asthma, CRSwNP, and eosinophilic esophagitis. In patients with 
moderate to severe uncontrolled asthma, dupilumab reduced the risk of severe exacerbations 
compared to placebo by 46 to 70%, and consistently improved lung function (FEV1), including in 
oral corticosteroid dependent patients with severe asthma, in whom despite a reduction in oral 
corticosteroid use, an improvement of 220 ml compared to placebo was observed. A subgroup 
analysis of “COPD-like” patients (eg, patients with age of onset asthma >40, prior smoking 
history, and post-bronchodilator FEV1/forced vital capacity [FVC]<0.7) included in the Phase 3 
asthma study (Study EFC13579; QUEST) showed similar treatment effects in this subpopulation 
compared to the overall population. 
For dupilumab, the safety data observed so far in completed and currently ongoing studies in AD, 
CRSwNP, and asthma patients (at the same or higher doses than that proposed for this study) have 
demonstrated a satisfactory safety profile. Considering the high mortality of COPD patients, all 


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deaths will be adjudicated. Considering that cardiovascular disease is a frequent and important 
comorbidity of COPD, cardiac events will also be adjudicated throughout the study. The program 
will have an Adjudication Committee for the aforementioned events and a Data Monitoring 
Committee (DMC), which will review the benefit risk including the cardiac safety on a regular 
basis. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of dupilumab may be found in the Investigator’s Brochure, Participant 
Information Leaflet, Package Insert, Development Safety Update Report or Summary of Product 
Characteristics. 
The Sponsor also recognizes that the “Coronavirus Disease 2019” (COVID-19) pandemic may 
have an impact on the conduct of clinical trials.  The Sponsor will monitor the situation closely 
and ensure the integrity of the trial conduct and data (see Section 8). 


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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of dupilumab 300 mg 
q2w in patients with moderate or severe 
COPD as measured by 
 
Annualized rate of acute moderate 
or severe COPD exacerbation 
(AECOPD). 
 
Annualized rate of moderate* or severe** COPD exacerbations over 
the 52-week treatment period compared to placebo. 
*Moderate exacerbations are recorded by the Investigator and 
defined as AECOPD that require either systemic corticosteroids 
(such as intramuscular, intravenous or oral) and/or antibiotics.  
**Severe exacerbations are recorded by the Investigator and 
defined as AECOPD requiring hospitalization, or observation 
for >24 hours in an emergency department/urgent care facility or 
resulting in death. 
For both moderate and severe events to be counted as separate 
events, they must be separated by at least 14 days. 
Key Secondary 
To evaluate the effect of dupilumab 300 mg 
q2w on 
 
Pre-bronchodilator forced 
expiratory volume in 1 second 
(FEV1) over 12 weeks compared to 
placebo. 
 
Health related quality of life, 
assessed by the change from 
baseline to Week 52 in the 
St. George’s Respiratory 
Questionnaire (SGRQ). 
 
Pre-bronchodilator FEV1 over 52 
weeks compared to placebo. 
 
Change in pre-bronchodilator FEV1 from baseline to Week 12 
compared to placebo. 
 
Change from baseline to Week 52 in SGRQ total score compared to 
placebo. 
 
Proportion of patients with SGRQ improvement ≥4 points at Week 
52. 
 
Change in pre-bronchodilator FEV1 from baseline to Week 52 
compared to placebo. 
Other Secondary 
Evaluate the effects of dupilumab 300 mg 
q2w on lung function assessments. 
 
Change in pre-bronchodilator FEV1 from baseline to weeks other 
than 12 and 52 (ie, Weeks 2, 4, 8, 24, 36, and 44) compared to 
placebo. 
 
Change in post-bronchodilator FEV1 from baseline to Week 2, 4, 8, 
12, 24, 36 and 52 compared to placebo. 
 
Change in forced expiratory flow (FEF) 25-75% from baseline to 
Weeks 2, 4, 8, 12, 24, 36, 44, and 52. 
Evaluate the effect of dupilumab on moderate 
and severe COPD exacerbations. 
 
Annualized rate of severe COPD exacerbations compared to 
placebo over the 52-week treatment period. 
 
Time to first moderate or severe COPD exacerbation compared with 
placebo during the 52-week treatment period. 
Safety and Immunogenicity 
 
To evaluate safety and tolerability. 
 
To evaluate dupilumab systemic 
exposure and incidence of antidrug 
antibodies (ADA). 
 
Adverse events (AEs)/treatment-emergent adverse events (TEAEs). 
 
Potentially clinically significant laboratory abnormalities in 
hematology, biochemistry and urinalysis. 
 
ADA against dupilumab. 


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Objectives 
Endpoints 
Tertiary/exploratory 
To evaluate the drug concentration of 
dupilumab in serum over time. 
Serum functional dupilumab concentrations and PK profile. 
To explore the association of biomarkers with 
treatment response. 
 
Pharmacodynamic response of selected biomarkers. 
- 
Pulmonary and activation-regulated chemokine (PARC). 
- 
Eotaxin-3. 
- 
Fractional exhaled nitric oxide( FeNO; postbronchodilator). 
- 
Total IgE. 
 
Fibrinogen. 
 
Optional: Messenger ribonucleic acid (mRNA) sequencing or whole 
transcriptome analysis from blood. 
 
Optional: Deoxyribonucleic acid (DNA) for assessment of 
pharmacogenomic effects. 
Predictive effects of selected biomarkers on treatment response. 
To evaluate the effects of dupilumab 
compared with placebo on FEV1 and FVC. 
 
Annualized loss of lung function as assessed by a FEV1 slope 
analysis. 
 
Change from baseline in FVC (% predicted and absolute values in 
mL) from baseline to Week 12, Week 24 and Week 52. 
To evaluate the effects of dupilumab 
compared to placebo on annualized rate of 
moderate to severe COPD exacerbation 
utilizing the Exacerbations of Chronic 
Pulmonary Disease Tool (EXACT). 
 
Evaluation of clinical respiratory symptoms of COPD using the 
Evaluating Respiratory Symptoms in COPD (E-RS: COPD)  
comprised in the EXACT tool. 
 
Annualized rate of COPD exacerbations assessed by the EXACT 
over 52 week. 
To evaluate the effects of dupilumab 
compared to placebo on treatment failure 
requiring background medication change. 
 
Increase in number of controller medication after exacerbation. 
 
Increase in patient total daily dose of controller medication after 
exacerbation. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The efficacy and safety assessments used in this study are standard for the evaluation of therapy in 
patients with COPD. 


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
Multinational, randomized, double-blind, placebo-controlled, parallel groups (2 groups), 52-week 
Phase 3 study to assess the efficacy, safety, and tolerability of dupilumab in patients with 
moderate-to-severe Type 2 inflammatory COPD such as that driven by activation of IL-4, IL-5, 
and IL-13 on an established LABA, LAMA and/or ICS background therapy (triple therapy unless 
ICS contraindicated). Study treatments are dupilumab 300 mg q2w or placebo q2w administered 
during the 52-week treatment period. The study includes 3 study periods. 
 Screening period (4 weeks ±1 week). 
 Randomized investigational medicinal product (IMP) treatment period (52 weeks 
±3 days). 
 Post IMP treatment period (12 weeks ±5 days). 
Patients who satisfy the inclusion and exclusion criteria will be randomized (1:1) to one of the 
following IMP treatment period groups to be administered for 52 weeks: 
 Dupilumab 300 mg, administered as 1 SC injection q2w. 
 Placebo administered as 1 SC injection of placebo matching dupilumab 300 mg. 
Randomization will be stratified by country, ICS dose (high dose ICS [yes/no]) at baseline, and 
smoking status at screening (current smokers or not). As an example, the adult high dose of ICS 
for fluticasone propionate is >500 mcg (DPI or HFA) or 401-800 mcg (HFA) for Japanese 
population (please refer to Section 10.18 for definition of high dose for the most common ICS). 
Alerts will be built into the interactive voice/web response system (IVRS/IWRS) to limit enrolling 
patients who are current smokers (as defined by smoking status at screening) to less than or equal 
to 30% or 278 patients out of the total enrolled patients. 
Study intervention discontinuation follow-up 
Patients who discontinue the study intervention prematurely (prior to completing the 52-week 
treatment period) will perform, as soon as possible, the early treatment discontinuation (ETD) 
visit with all assessments normally planned for the end of treatment (EOT) visit, to assure a 
complete clinical assessment in close temporal proximity to the premature termination of study 
treatment is available. In addition, to allow assessment of patient outcomes over the stipulated 
study period, patients will be asked and encouraged to complete all remaining study visits, and 
participate in all safety follow-up assessments according to the visit schedule. For these patients 
the assessment schedule will be reduced (see Section 1.3.2) and visits during the planned 
treatment period may be conducted by phone (except for planned EOT) if patient is unable to 
come in for a site visit. Assessments not completed via phone should be performed at the next 
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Post IMP-treatment follow-up: 
Upon completing the 52-weeks randomized IMP treatment period, patients will continue their 
triple background ICS/LABA/LAMA therapy (unless ICS is contraindicated) and enter 12-week 
safety follow-up period. Adjustment of background medication will be allowed at the discretion of 
the Investigator as clinically indicated during the post-treatment period. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
A randomized, placebo-controlled study design where the effects of the IMP are assessed on top 
of optimized background therapy is considered to be the most appropriate design to explore the 
efficacy and safety of a novel biologic therapy in COPD. Similar study designs and endpoints 
have been employed for recent studies with other biologics and are considered “state-of-the-art” 
for studies in COPD (16, 17). The selection of the dose of IMP and duration of study treatment are 
explained in Section 4.3 and Section 9.2, respectively. 
4.3 
JUSTIFICATION FOR DOSE  
The proposed dose for this study is dupilumab 300 mg administered SC every other week. 
This dose has proven to be effective and to have an acceptable safety profile in various Type 2 
inflammatory diseases. The 300 mg q2w dose is the approved dose for AD, is an approved dose 
for asthma in the US, and is the only selected Phase 3 dose for the CRSwNP program, currently 
ongoing. Efficacy results from the completed pivotal studies in patients with moderate-to-severe 
asthma demonstrated that the 300 mg q2w dose had a clinically meaningful and statistically 
significant effect in reducing exacerbations, improving lung function, asthma control and quality 
of life with a satisfactory safety profile. In addition, dupilumab 300 mg q2w showed a significant 
steroid-sparing effect while significantly reducing exacerbations and improving lung function in a 
population of severe corticosteroid-dependent asthmatics. 
In the dupilumab asthma program, doses of 200 mg q2w and 300 mg q2w demonstrated 
comparable efficacy and safety in reducing exacerbations and improving FEV1 in patients with 
moderate-to-severe asthma not chronically using concomitant oral corticosteroids (OCS). 
However, analysis of the exposure-response relationships using descriptive exposure quartile and 
model-based analyses for these two efficacy endpoints showed that increasing dupilumab 
exposure resulted in a greater effect for both efficacy endpoints in patients with uncontrolled 
moderate-to-severe asthma. The lung function improvement and severe exacerbation rate 
reduction approached a maximum at the exposure of 200 mg and 300 mg q2w, with a 5 to 9% 
greater reduction in exacerbations for 300 mg q2w. FEV1 response was also predicted to be better 
maintained over the dosing interval for 300 mg q2w. In severe OCS-dependent asthma patients, 
an exposure response relationship was noted at 300 mg q2w, with more patients achieving 
OCS-free asthma control at the exposure range at 300 mg q2w (mean Ctrough approximately 
70 mg/L) than that at 200 mg q2w (mean Ctrough approximately 39 mg/L). Furthermore, the  
300 mg q2w dose is expected to saturate the target receptor in the vast majority of patients and 
therefore a higher regimen is not expected to provide additional efficacy. 


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Considering that the proposed COPD population to be enrolled in this study has the potential for 
significant risk for morbidity and mortality associated with impairment of their lung function, 
similar to the patients in the OCS-sparing Phase 3 asthma study (Study EFC13691), the Sponsor is 
including the 300 mg q2w dose regimen to achieve the optimal benefit/risk ratio in this difficult to 
treat COPD patient population. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the end of study visit. 
The end of the study is defined as completion of the last patient last visit (the End of Study Visit) 
which will occur at the end of a 12-week safety follow-up period for those patients who complete 
the study as per protocol. 
For patients who permanently discontinue the planned treatment, the recommended follow-up is 
described in Section 4.1. 


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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 ≥40 to ≤85 years of age, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Participants with a physician diagnosis of COPD who meet the following criteria at 
screening: 
 Current or former smokers with a smoking history of ≥10 pack-years. 
- 
Current smokers are defined as those patients who are active smokers with 
≥10 pack-years of smoking (active smoking includes cigarettes, e-cigarettes, cigars, 
pipes, etc). 
- 
Former smokers are defined as those patients who were active smokers with 
≥10 pack-years of smoking (active smoking includes cigarettes, e-cigarettes, cigars, 
pipes, etc) and who have stopped smoking for at least 6 months prior to Visit 1. 
 Moderate to severe COPD (post-bronchodilator FEV1/FVC ratio <0.70 and 
post-bronchodilator FEV1 % predicted >30% and ≤70%). 
 Medical Research Council (MRC) Dyspnea Scale Grade ≥2. 
 Patient-reported history of signs and symptoms of chronic bronchitis (chronic productive 
cough) for 3 months in the year up to screening in the absence of other known causes of 
chronic cough. 
 Documented history of high exacerbation risk defined as exacerbation history of 
≥2 moderate* or ≥1 severe** within the year prior to inclusion. 
At least one exacerbation should have occurred while the patient was taking 
ICS/LAMA/LABA (or LAMA/LABA if ICS is contradicted). 
* Moderate exacerbations are recorded by the Investigator and defined as AECOPD that require 
either systemic corticosteroids (intramuscular (IM), intravenous, or oral) and/or antibiotics. 
One of the two required moderate exacerbations has to require the use of systemic 
corticosteroids. 
** Severe exacerbations are recorded by the Investigator and defined as AECOPD requiring 
hospitalization or observation >24 hours in emergency department/urgent care facility. 
 Background triple therapy (ICS + LABA + LAMA) for 3 months prior to randomization 
with a stable dose of medication for ≥1 month prior to Visit 1: (Double therapy: LABA + 
LAMA allowed if ICS is contraindicated). 
I 03. Evidence of Type 2 inflammation: Patients with blood eosinophils ≥300 cells/microliter at 
Visit 1 (Screening). 


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Weight 
I 04. Body mass index (BMI) ≥16 kg/m2. 
Sex 
I 05. Male or Female. 
Contraceptive use by women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.   
a) Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 4 [Section 10.4], not breastfeeding, and at least one of the following 
conditions applies: 
- 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4), 
OR 
- 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the intervention period and for at least 12 weeks after the 
last dose of study intervention. 
Informed Consent 
I 06. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Study methodology 
E 01. COPD diagnosis for less than 12 months prior to randomization. 
E 02. A patient with current diagnosis of asthma or history of asthma according to the Global 
Initiative for Asthma (GINA) guidelines, or other accepted guidelines. 
E 03. Significant pulmonary disease other than COPD (eg, lung fibrosis, sarcoidosis, interstitial 
lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome, etc) or 
another diagnosed pulmonary or systemic disease associated with elevated peripheral 
eosinophil counts. 
E 04. Cor pulmonale, evidence of right cardiac failure. 
E 05. Long-term treatment with oxygen >4.0 L/min OR if a participant requires more than 
2.0 L/min in order to maintain oxygen saturation >88%. 
E 06. Hypercapnia requiring BiPAP. 
E 07. Acute exacerbation of COPD (AECOPD, as defined above in I 02) within 4 weeks prior to 
or during the screening period. 


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E 08. Respiratory tract infection within 4 weeks prior to screening, or during the screening 
period. 
E 09. History of, or planned pneumonectomy or lung volume reduction surgery. Patients who are 
participating in the acute phase of a pulmonary rehabilitation program, ie, who started 
rehabilitation <4 weeks prior to screening (Note: patients in the maintenance phase of a 
rehabilitation program can be included). 
E 10. Diagnosis of α-1 anti-trypsin deficiency. 
E 11. Inability to follow the procedures of the study (eg, due to language problems, 
psychological disorders) or unable to read, understand and fill out a questionnaire or use an 
e-Diary without any help. 
E 12. Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to Visit 1 or 
any other biologic therapy (including anti-IL5 mAb) or immunosuppressant to treat 
inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory 
bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, 
etc.) as well as other diseases within 2 months or 5 half-lives prior to Visit 1, whichever is 
longer. 
E 13. Exposure to another investigative drug (small molecules as well as monoclonal antibodies) 
within a time period prior to Visit 1 that is less than 6 months. The minimum interval since 
exposure to any other (non-antibody) investigative study medication is 30 days prior to 
Visit 1. 
E 14. History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including any 
excipients. 
E 15. Patients receiving medication or therapy that are prohibited as concomitant therapy 
(see Section 6.5). 
E 16. Patient is the Investigator, or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study. 
E 17. Clinically significant abnormal electrocardiogram (ECG) at randomization that may affect 
the conduct of the study in the judgment of the Investigator, eg, prolonged QTc interval 
[male >450 msec, female >470 msec, Fredericia correction]. 
E 18. A patient with a history of clinically significant renal, hepatic, cardiovascular, metabolic, 
neurologic, hematologic, ophthalmologic, respiratory (other than COPD), gastrointestinal, 
cerebrovascular disease/condition, substance and/or alcohol abuse disorder, or history of or 
current other significant medical illness or disorder which, in the judgment of the 
Investigator, could interfere with the study or require treatment that might interfere with 
the study. Specific examples include but are not limited to poorly controlled 
insulin-dependent diabetes, uncontrolled hypertension. 
Prior history of malignancy or active malignancy, including lymphoproliferative diseases 
(except successfully treated carcinoma in-situ of the cervix, non-metastatic squamous cell 
or basal cell carcinoma of the skin) within 5 years prior to baseline. 
E 19. Active tuberculosis or non-tuberculous mycobacterial infection, latent untreated 
tuberculosis or a history of incompletely treated tuberculosis will be excluded from the 


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study unless it is well documented by a specialist that the patient has been adequately 
treated and can now start treatment with a biologic agent, in the medical judgment of the 
Investigator and/or infectious disease specialist. Tuberculosis testing will be performed on 
a country-by-country basis, according to local guidelines if required by regulatory 
authorities or ethics boards. 
E 20. Acute myocardial infarction <6 months from screening visit. 
E 21. TIA or stroke <6 months from screening visit. 
E 22. Hospitalization for any CV or cerebrovascular event <6 months from screening visit. 
E 23. Heart failure NYHA Class III or IV. 
E 24. Patients on cardiac medications not on a stable dose during the last 6 months,  
eg, antiarrythmics, antihypertensives, and antidiuretics, etc. Dose modification of 
cholesterol-modifying agents and anticoagulants is allowed. 
E 25. Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation are excluded. 
Patients with persistent atrial fibrillation as defined by continuous atrial fibrillation for at 
least 6 months and controlled with a rate control strategy (ie, selective beta blocker, 
calcium channel blocker, pacemaker placement, digoxin or ablation therapy) and stable 
appropriate level of anticoagulation for at least 6 months may be considered for inclusion. 
E 26. Unstable ischemic heart disease or other relevant cardiovascular disorder such as 
pulmonary embolism, deep vein thrombosis within ≤6 months from enrollment that in 
Investigator's judgment may put the patient at risk or negatively affect the study outcome. 
E 27. Patients who are <80% compliant with controller therapy during screening. 
E 28. Previous use of dupilumab. 
E 29. Females who are lactating, breastfeeding or who are pregnant. 
E 30. Women of childbearing potential (pre-menopausal female biologically capable of 
becoming pregnant) who (also see Appendix 4, Section 10.4): 
- 
Do not have a confirmed negative serum beta-hCG test at Visit 1 or negative urine 
pregnancy test at Visit 2. 
- 
Who are not willing to use one of the acceptable forms of effective contraception for 
the duration of the study as per Table 14 (Appendix 4). 
- 
Postmenopausal women (defined as at least 12 consecutive months without menses) 
are not required to use additional contraception. 
E 31. Diagnosed active parasitic infection (helminthes), suspected or high risk of parasitic 
infection, unless clinical and (if necessary) laboratory assessments have ruled out active 
infection before randomization. 
E 32. History of HIV infection or positive HIV 1/2 serology at Visit 1. 
E 33. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per Investigator’s judgment. 


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E 34. Evidence of acute or chronic infection requiring treatment with antibacterials, antivirals, 
antifungals, antiparasitics, or antiprotozoals within 4 weeks before Visit 1, significant viral 
infections within 4 weeks before Visit 1 that may not have received antiviral treatment  
(eg, influenza receiving only symptomatic treatment).  
E 35. Live, attenuated vaccinations within 4 weeks prior to Visit 1 or planned live, attenuated 
vaccinations during the study; see Section 10.7 (Appendix 7) for list of prohibited live, 
attenuated vaccines. 
E 36. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, inflammatory bowel disease, primary biliary cirrhosis, systemic 
lupus erythematosus, multiple sclerosis, etc). 
E 37. Patients with any of the following result at screening: 
- 
Positive (or indeterminate) HBsAg or 
- 
Positive IgM HBc Ab or 
- 
Positive total HBc Ab confirmed by positive HBV DNA or 
- 
Positive HCV Ab confirmed by positive HCV RNA. 
E 38. Clinically significant laboratory tests at screening: 
- 
Alanine transaminase (ALT) >3 times upper limit of normal range (ULN). 
- 
Hemoglobin <10 g/100 mL for male and <9 g/100 mL for female. 
- 
Platelets <100 000/mm3. 
- 
Creatinine ≥150 μmol/L. 
E 39. Patients on macrolide (eg, azithromycin) therapy, unless on stable therapy for >12 months. 
E 40. Patient who has withdrawn consent before enrollment/randomization. 
E 41. Despite screening of the patient, enrollment/randomization is stopped at the study level. 
5.3 
LIFESTYLE CONSIDERATIONS  
The use of e-cigarettes or vaping is not permitted during the conduct of this study. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to IMP. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Patients who are eligible for rescreening may be rescreened once during the open screening period 
of the study for the following reasons only: 
 In the case of technical malfunction of equipment. 
 Previously did not meet the criteria for participation in the study. 


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Retesting of eosinophil values is allowed up to three times during the screening period to meet 
inclusion criteria for showing eosinophil count ≥300 cells/microliter (I 03) before randomization. 
A patient who is unable to complete a successful spirometry effort as defined by ATS criteria can 
be retested one additional time during the screening period of the study. 
There is no requirement for a waiting period between the screen-failure date and the rescreening 
date. The IVRS/IWRS report will flag rescreened patients. Patients that are rescreened must sign a 
new consent form.  If subject is rescreened, a different patient identification number will be 
issued, and all Visit 1 procedures must be repeated.   


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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
Study intervention name 
Dupilumab 300 mg q2w 
Placebo q2w 
Dosage formulation 
Dupilumab 300 mg for SC administration is 
supplied as 150 mg/mL solution in 2.25 mL 
prefilled glass syringes to deliver 300 mg in 
2.0 mL. 
Placebo for dupilumab will be provided in 
identically matched glass pre-filled syringe 
to deliver 2 mL which will match dupilumab 
300 mg. 
Unit dose strength(s)/Dosage 
level(s) 
300 mg 
Not applicable 
Route of administration 
Subcutaneous injection sites should 
alternate between the upper thighs, 
4 quadrants of the abdomen or the upper 
arms, so that the same site is not injected 
twice during consecutive injections. 
Subcutaneous injection sites should 
alternate between the upper thighs, 
4 quadrants of the abdomen or the upper 
arms, so that the same site is not injected 
twice during consecutive injections. 
Dosing instructions 
Every 14 ±3 days 
Every 14 ±3days 
Packaging and labeling 
Dupilumab will be supplied as one glass 
pre-filled syringe packed in a patient kit 
box.  Both glass pre-filled syringe and box 
will be labeled as required per country 
requirement. 
Placebo will be supplied as one glass 
pre-filled syringe packed in a patient kit 
box.  Both glass pre-filled syringe and box 
will be labeled as required per country 
requirement. 
6.1.1 Investigational Medicinal Product(s)  
The investigational medicinal product (IMP) is administered every 14 ±3 days (q2w) during the 
52-week treatment period (Table 2). 
Investigational medicinal product (IMP) will be administered by the Investigator/health care 
professional or designee following clinic procedures and blood collection. Patients should be 
monitored for at least 30 minutes after administration of all IMP injections. The monitoring period 
may be extended as per country specific or local site-specific requirements. 
Subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the 
abdomen or the upper arms, so that the same site is not injected twice during consecutive 
administrations. 
The first IMP administration will be done by the Investigator or delegate. The patients are allowed 
to self-inject IMP at home after at least 1 injection at investigational site, supervised by the 
Investigator or delegate.  To train patients how to prepare and inject IMP the Investigator will 


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first train the patient at the on-site visit during the treatment period.  At this visit the patient will 
perform the injection under the supervision of the Investigator or delegate. This training must be 
documented in the patient’s study file. Patient injection should only be performed in the abdomen 
or upper thighs. Patient should also be instructed to monitor for any reaction for at least 
30 minutes (or longer per country specific or local site-specific requirements) following injection. 
If the patient cannot take all the allocated IMP kits at home (eg. due to a storage issue), the DTP 
(Direct to Patient) service can be used or the patient may come to the site to pick-up the IMP kits. 
For doses not given at the study site, diaries will be provided to record information related to the 
injections. The diary will be kept as source data in the patient’s study file. 
If the patient is unable or unwilling to administer IMP at home, injections can be performed at the 
site; or arrangements can be made for qualified site personnel and/or health care professionals 
(eg, visiting nurse service) to administer IMP for the doses that are not scheduled to be given at 
the study site. 
6.1.2 Non-investigational Medicinal Product(s)  
Background therapy 
At Screening Visit 1, all patients must be on triple background therapy, for 3 months prior to  
Visit 2/Randomization and at a stable dose of medication for at least 1 month prior to the 
Screening/Visit 1, including triple therapy: LABA + LAMA + ICS (Double 
therapy: LABA + LAMA allowed if ICS is contraindicated). 
Formulation: dry powder inhaler (DPI), metered dose inhaler (MDI) or pocket nebulizer. 
Route(s) of administration: Oral inhalation. 
Dose regimen: As prescribed. 
Throughout the study, patients should continue their established background therapy for COPD, 
including dose and regimen. 
Patients must be willing to stay on their established background medication for COPD throughout 
the duration of the treatment period. After successful management of an acute exacerbation of 
COPD (eg, with oral corticosteroids and/or antibiotics), all efforts should be made to resume the 
initial background COPD treatment regimen if in the Investigator’s opinion this is medically 
acceptable. Background medications should not be adjusted during Screening. After 1 severe or  
2 moderate exacerbations of COPD, dose adjustments in background therapy will be permitted for 
symptom control and as needed for the remainder of the trial period. 
Adjustment of background medication is allowed at the discretion of the Investigator as clinically 
indicated during the post-treatment period. 
Background therapy will be supplied from the time of randomization on by Sponsor’s local 
affiliate as locally required or by sites. Reimbursement will be provided when deemed necessary 
and as per country regulation. 


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Reliever Medication 
Reliever medications will be supplied by sites and reimbursed as per country regulation or by 
Sponsor’s local affiliate as locally required. 
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol or ipratropium or 
ipratropium/short-acting β agonists [SABA] combinations or terbutaline as needed during the 
study. Nebulizer solutions may be used as an alternative delivery method. 
Formulation: MDI, nebulizer solutions or DPI. 
Route of administration: oral inhalation. 
Dose regimen: as prescribed. 
Study personnel will convert salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol 
nebulizer use as shown on the following tables: 
Table 3 - Reliever medication - Salbutamol/Albuterol nebulizer solution  
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: Patient received 
3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. 
Total daily =7.5 mg or 12 puffs. 
Table 4 - Reliever medication - Levosalbutamol/Levalbuterol nebulizer solution  
Levosalbutamol/Levalbuterol Nebulizer Solution -Total Daily Dose (mg) 
Number of Puffs* 
0.63 
2 
1.25 
4 
2.5 
8 
3.75 
12 
5 
16 
*Conversion factor:  levosalbutamol/levalbuterol nebulizer solution (1.25 mg) corresponds to 4 puffs. 
 Example of levosalbutamol/levalbuterol nebulizer-to-puff conversion: Patient received 
3 levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 and 
11 AM. Total daily =3.75 mg or 12 puffs.  


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Table 5 - Reliever medication - Ipratropium or Ipratropium/short-acting β agonists [SABA] nebulizer 
solutions  
Total Daily Dose of Ipratropium (mg) in Ipratropium or Ipratropium/SABA 
Nebulizer Solutions  
Number of Puffs* 
0.5 
4 
1.0 
8 
1.5 
12 
2.0 
16 
*Conversion factor: ipratropium or ipratropium/short-acting β agonists (SABA) nebulizer solution (with 0.5 mg Ipratropium) corresponds to 
4 puffs. 
 Example of ipratropium or ipratropium/SABA nebulizer-to-puff conversion: Patient 
received 3 ipratropium or ipratropium/SABA nebulizer treatments (0.5 mg 
Ipratropium/treatment) between 7 and 11 AM. Total daily =1.5 mg or 12 puffs. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
Storage and handling 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/noninvestigational medicinal product (NIMP) in a secure and safe place in accordance with 
local regulations, labeling specifications, policies, and procedures. 
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound must be 
managed according to the rules provided by the Sponsor in the pharmacy manual. 
The expiry date is mentioned on the IMP labels (when required by country regulation), and 
storage conditions are written on the IMP labels. 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention and NIMP received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention and NIMP 
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 and NIMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of used and unused study 
interventions are provided in a Pharmacy manual. 
Preparation of IMP 
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Responsibilities 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP/NIMP will be responsible for ensuring that the IMP/NIMP used in the clinical trial is 
securely maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. 
All IMP/NIMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP/NIMP issued and returned is 
maintained. For doses not given at study site, the home dosing diary will be used to record 
injections. 
Any quality issue noticed with the receipt or use of an IMP/NIMP (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/NIMP 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/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor, the local regulation 
may apply as well as the participant approval), allow the IMP/NIMP/device to be used other than 
as directed by this clinical trial protocol, or dispose of IMP/NIMP/device in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
6.3.1 Methods of assigning patients to treatment group  
A randomized treatment kit number list will be generated centrally by Sanofi for the IMPs. The 
IMPs (dupilumab or matching placebo) will be packaged in accordance with the list. The Sanofi 
Clinical Supply Chain team will provide the randomized treatment kit number list and the Study 
Biostatistician will provide the randomization scheme to the centralized treatment allocation 
system (IVRS/IWRS). This centralized treatment allocation system will generate the patient 
randomization list according to which it will allocate the IMPs to the patients. The Investigator 
obtains treatment kit number at randomization and subsequent scheduled visits via an 
IVRS/IWRS that will be available 24 hours a day. Patients will be randomized in a 1:1 ratio to 
receive SC administrations of either: 
 Dupilumab 300 mg q2w. 
 Matching placebo for dupilumab q2w. 
Randomization will be stratified by country, ICS dose (high dose ICS [yes/no]) at baseline, and 
smoking status at screening (current smokers or not). As an example, the adult high dose of ICS 
for fluticasone propionate is >500 mcg (DPI or HFA) or 401-800 mcg (HFA) for Japanese 
population (see Section 10.18 for definition of high dose for the most common ICS). Alerts will 
be built into the IVRS/IWRS to limit enrolling patients who are current smokers (as defined by 


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smoking status at screening) to less than or equal to 30% or 278 patients out of the total enrolled 
patients. 
Investigational medicinal products will be dispensed at the study visits summarized in SoA 
(Section 1.3). 
Returned IMP from the patient’s home should not be re-dispensed to the participants. 
6.3.2 Methods of blinding  
Dupilumab and placebo will be provided in identically matched 2 mL pre-filled syringes. 
To protect the blind, each treatment kit of 2 mL (dupilumab / placebo) glass pre-filled syringes 
will be prepared such that the treatments (dupilumab and its matching placebo) are identical and 
indistinguishable and will be labeled with a treatment kit number. 
In accordance with the double-blind design, study patients, Investigators, and study site personnel 
will remain blinded to study treatment and will not have access to the randomization arm or to the 
IMP content (dupilumab or placebo) except under circumstances described in Section 6.3.3. 
6.3.3 Randomization code breaking during the study  
In case of an AE, the code must only be broken in circumstances when knowledge of the IMP is 
required for treating the patient. 
Code breaking can be performed at any time by using the proper module of the IVRS/IWRS 
and/or by calling any other phone number provided by the Sponsor for that purpose. If the blind is 
broken, the Investigator must document the date, time of day, and reason for code breaking. 
Patient withdrawal will only occur when the code break call is made at the site level, not the study 
level. This means that if the Emergency Unblinding transaction is performed by the Investigator 
(ie, at the site level), then the patient will be withdrawn from treatment. However, if the 
Emergency Unblinding transaction is performed by the Global Safety Officer (GSO) (ie, at the 
study level, as the GSO is not site based), then the patient will not be withdrawn from treatment. 
Patients who are withdrawn from treatment should be encouraged to remain in the study and the 
Investigator should discuss with them the key visits to attend (see Section 7.2). 
6.4 
STUDY INTERVENTION COMPLIANCE  
The Investigator or pharmacist will also keep accurate records of the quantities of the IMP/NIMP 
received, dispensed, used, unused and returned/destroyed. The product accountability and 
inventory form/system is to be updated each time IMP/NIMP is dispensed. It must be established 
with the Investigator or other personnel designated by the Investigator and countersigned by the 
Investigator and the monitoring team. The study monitor will periodically check the supplies of 
the IMP held by the Investigator or pharmacist to verify accountability and inventory. 
Treatment kit number has to be recorded on the appropriate page of the electronic Case Report 
Form (eCRF) and also on the product accountability and inventory form/system. 


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All used, partially used, or unused treatments will be destroyed at each respective site, after 
accountability and reconciliation have been performed. The site must not destroy the unused 
IMP/NIMP unless the Sponsor provides written authorization. Confirmation of destruction will be 
provided to the Sponsor. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 Reason for use. 
 Dates of administration including start and end dates. 
 Dosage information including dose and frequency. 
The following concomitant medications are not permitted during the study from screening 
onwards: 
 Use of any biologic agent within 5 half-lives of that compound before study entry 
(6 months if half-life is not known) and during the course of the study. 
 Use of PDE4 inhibitors (roflumilast) and of theophylline during the course of the study 
unless stable >6 months prior to screening visit. 
 New chronic use of macrolide antibiotics (eg, azithromycin) with the exception of 
AECOPD, in which case macrolides may be used up to 28 days.  
 Systemic immunosuppressants (eg, methotrexate, any anti-TNF mAbs, B and/or T-cell 
targeted immunosuppressive therapies) including chronic use of systemic corticosteroids. 
 Intravenous immunoglobulin (IVIG) therapy. 
 Live attenuated vaccines, refer to Appendix 7 (Section 10.7). 
 Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor 
blocker used with dose stable 1 month prior to Visit 1). 
 Other investigational drugs. 
Note: The following is a list of permitted concomitant medications during the study, refer to 
Section 6.1.2 for expected background therapy and allowed reliever medications. 
 Maintenance treatment of COPD with ICS, LABA, LAMA, at a stable dosage. 
 Systemic corticosteroids in case of acute exacerbation up to a maximum of 6 weeks. 
 Rescue medication with SABA or short acting antimuscarinics (eg, atrovent). 
6.6 
DOSE MODIFICATION  
Not applicable. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
Upon completion of the treatment period (52 weeks), or after early termination, study drug will no 
longer be provided to participants. 


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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Withdrawal of consent for treatment (ie, treatment discontinuation at patient request) should be 
distinguished from (additional) withdrawal of consent for follow-up visits and from withdrawal of 
consent for non-patient contact follow-up (eg, medical record checks). The site should document 
any case of withdrawal of consent. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
The IMP should be continued whenever possible. 
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
permanent IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. 
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a patient to permanently discontinue study intervention. 
If study intervention is permanently discontinued, the participant remains in the study to be 
evaluated for as per Section 1.3.2 (see the SOA for data to be collected at the time of 
discontinuation of study intervention). 
Permanent intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP at any time during 
the study, or from the patient not to be re-exposed to the IMP whatever the reason. 
List of criteria for permanent discontinuation of study intervention 
All efforts should be made to document the reason(s) for discontinuation of study intervention and 
this should be documented in the eCRF. 
Patients must be withdrawn from the study intervention for the following reasons: 
 At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient's participation in 
the procedure(s) involved in the research). 
 If, in the Investigator's opinion, continuation on the study intervention would be 
detrimental to the patient'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. 
 Any code broken requested by the Investigator will lead to permanent discontinuation of 
study intervention. 
 Pregnancy. 


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 Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment. 
 Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
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 (see Section 10.16, Appendix 16). 
 Serum ALT >3 ULN and Total Bilirubin >2ULN (see Section 10.6, Appendix 6). 
 Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(see Section 10.6, Appendix 6). 
 If the patient misses more than 3 consecutive doses, the patient will be permanently 
discontinued from the study intervention. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient. 
See the SoA (Section 1.3.2) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Handling of participants after permanent study intervention discontinuation 
Patients who discontinue the study intervention prematurely (prior to completing the 52-week 
treatment period) will perform, as soon as possible, the ETD visit with all assessments normally 
planned for the EOT visit (Visit 16), to assure a complete clinical assessment in close temporal 
proximity to the premature termination of study treatment is available. In addition, to allow 
assessment of patient outcomes over the stipulated study period, patients will be asked and 
encouraged to complete all remaining study visits, and participate in all safety follow-up 
assessments according to the visit schedule with a ±5-day window. For these patients the 
assessment schedule will be reduced (see Section 1.3.2) and visits during the planned treatment 
period may be conducted by phone (except for planned EOT) if patient is unable to come in for a 
site visit. Assessments not completed via phone should be performed at the next scheduled visit. 
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion (ie, EOS, see Section 1.3), or up to recovery or stabilization of 
any AE to be followed-up as specified in this protocol, whichever comes last. 
Patients who discontinue early from treatment may be asked to return to the clinic to have 
additional antidrug antibody (ADA) samples collected for analysis based on the overall 
assessment of antibody titers and/or clinical presentation at the time of discontinuation. 
All cases of permanent discontinuation of study intervention should be recorded by the 
Investigator in the appropriate pages of the eCRF when considered as confirmed. 


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7.1.2 Temporary discontinuation of study intervention   
Temporary discontinuation of study intervention may be considered by the Investigator because of 
AEs. Reinitiation of treatment 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 AE is sufficiently resolved and unlikely to recur after resuming therapy 
with IMP. 
In addition, the following conditions(s) will be causes for temporary discontinuation of study 
intervention: 
 Infections or infestations that do not respond to medical treatment. 
 Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Appendix 6 (Section 10.6). 
If a patient is unable to return to clinic for a given visit within the specified visit window, patient 
should follow-up with all visit follow-up procedures planned for the subsequent visit (excluding 
randomization and EOT). If more than 12 weeks since last on-site scheduled visit, then 
unscheduled visit is required within 3 weeks of missed scheduled visit (eg, if missed scheduled 
visit at Week 24, then unscheduled visit must be performed by Week 27; if missed scheduled visit 
at Week 36, then unscheduled must be performed by Week 39). All the assessments of the missed 
scheduled on-site visit will need to be carried out at the unscheduled visit. 
For all temporary discontinuations of study intervention, duration must be recorded by the 
Investigator in the eCRF. Following a temporary interruption or missed dose, the IMP treatment 
should be reinitiated at the next scheduled dose, maintaining the original dose. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
 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.  
 See SoA (Section 1.3.2) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
Patients who withdraw from study treatment (prior to completing the planned duration of IMP 
treatment) will perform the ETD visit and will be asked and encouraged to complete all remaining 
study visits. Patients who withdraw from the study during the post-treatment phase should be 
encouraged to return for the EOS visit (for details see Section 1.3.2 and Section 7.1.1). The value 
of all their study data collected during their continued involvement will be emphasized as 
important to the public health value of the study. 


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All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF, IVRS/IWRS and in the patient’s medical records. In the medical record, at least the date 
of the withdrawal and the reason should be documented. 
In addition, a patient may withdraw his/her consent to participate 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-patient 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. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit including a systemic drug concentration sample, if appropriate, and the Post treatment Period 
Visits. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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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. 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 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) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the time 
frame defined in the SoA (Section 1.3). 
In light of the public health emergency related to COVID-19 (or in case of any other pandemic 
requiring public health emergency), the continuity of clinical study conduct and oversight may 
require implementation of temporary or alternative mechanisms, eg, phone contact, virtual visits, 
online meetings, use of local clinic or laboratory locations, and home visits by skilled staff. 
Implementation of such mechanisms may differ country by country, depending on country 
regulations and local business continuity plans. Additionally, no waivers to deviate from protocol 
enrollment criteria due to COVID-19 (or any other pandemic) will be granted. All temporary 
mechanisms utilized, and deviations from planned study procedures in response to COVID-19 are 
to be documented as being related to COVID-19 and will remain in effect only for the duration of 
the public health emergency. 
8.1 
EFFICACY ASSESSMENTS   
8.1.1 Disease-specific efficacy measures  
8.1.1.1 Severity of COPD exacerbations as defined by the protocol  
“Moderate exacerbations” are recorded by the Investigator and defined as AECOPD that require 
either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics. 
“Severe exacerbations” are recorded by the Investigator and defined as AECOPD requiring 
hospitalization, or observation for >24 hours in emergency department/urgent care facility or 
resulting in death. 
All other exacerbations will be classified as “mild”. 
For both moderate and severe events to be counted as separate events, they must be separated by 
at least 14 days. 


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Clinical symptoms of exacerbations of COPD 
In addition to the protocol-defined exacerbations of COPD listed above, clinical signs and 
symptoms of exacerbations of COPD will be captured in the eCRF (including, but not limited to 
increase in dyspnea, increase in wheezing, increase in cough, increase in sputum volume and/or 
increase in sputum purulence). 
Management of exacerbations of COPD 
Exacerbations of COPD should be treated as deemed necessary by the Investigator. 
After successful management of an acute exacerbation of COPD (eg, with oral corticosteroids 
and/or antibiotics), all efforts should be made to resume the initial background COPD treatment 
regimen if in the Investigator’s opinion this is medically acceptable. After 1 severe or 2 moderate 
exacerbations of COPD, dose adjustments in background therapy will be permitted for symptom 
control and as needed for the remainder of the trial period. 
Protocol defined COPD exacerbation events are collected as efficacy endpoints via the 
exacerbation eCRF. These events should not be reported as AEs unless they fulfill a seriousness 
criterion. 
8.1.1.2 Spirometry  
Spirometry at clinical site visits should be performed in accordance with the European 
Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines (22) and prior to 
administration of investigational product. 
For pre-bronchodilator measured parameters, including FEV1, FVC and forced expiratory flow 
(FEF) 25%-75%, 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 
12 hours (ultra-long acting LABA like vilanterol should be withheld for at least 24 hours), 
withholding the last dose of ipratropium for at least 8 hours and withholding the last dose of 
LAMA for at least 24 hours. This will be verified before performing the measurements. 
Note: When both pre- and post-bronchodilator spirometry is assessed, the post-bronchodilator 
spirometry should be performed consistent with the mechanism of action of reliever  
(ie, 30 minutes for albuterol or another SABA). 
At all visits, spirometry will be performed preferably in the morning; afternoon/evening is 
allowable in the exceptional circumstance when morning spirometry cannot be performed; 
spirometry should be done at approximately the same time at each visit throughout the study. 
Current smokers need to be reminded not to smoke for at least 1 hour before spirometry. 
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 visit, if possible. 


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Further details on spirometry will be available in a separate operational manual provided to the 
sites. 
8.1.2 Clinical outcome assessments  
8.1.2.1 Patient reported outcome questionnaires  
At screening (Visit 1), patients will be issued an electronic diary. Patients will be instructed and 
trained by members of the clinical staff on the use of the device, and written instructions on the 
use of the electronic device will be provided to the patients. Recorded information is downloaded 
from this device on the other indicated days (Section 1.3). 
On a daily basis during screening and treatment, the patient will use an electronic diary to: 
 Respond to the COPD exacerbation and symptom scale questions of the EXACT tool. 
 Record use of established controller inhalation therapy. 
The electronic diary will be used for other patient related questionnaires such as SGRQ from the 
protocol. 
In the Post IMP Treatment Period, the patient's response in the electronic diary will not be 
recorded daily; electronic questionnaires will only be administered at on-site visits as outlined in 
the SoA. 
Patient-reported outcome questionnaires at a site visit should be completed prior to any other 
assessments or procedures. 
8.1.2.1.1 St. George's Respiratory Questionnaire (SGRQ)  
The St. George's Respiratory Questionnaire (SGRQ [23, 24]) is a 50-item questionnaire designed 
to measure and quantify health status in adult patients with chronic airflow limitation. A global 
score ranges from 0 to 100. Scores by dimension are calculated for three domains: Symptoms, 
Activity and Impacts (Psycho-social) as well as a total score. Lower score indicates better quality 
of life (QoL) (see Appendix 10: St. George's Respiratory Questionnaire,  
Section 10.10). 
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 recall 
period of the questionnaire is over the past 4 weeks. 
Psychometric testing has demonstrated its repeatability, reliability and validity. Sensitivity has 
been demonstrated in clinical trials. A minimum change in score of 4 units was established as 
clinically relevant after patient and clinician testing. The SGRQ has been used in a range of 
disease groups including asthma, COPD and bronchiectasis. 


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8.1.2.1.2 Exacerbations of chronic pulmonary disease tool (EXACT)  
The EXACT tool quantifies and measures exacerbations of COPD and assesses the symptomatic 
manifestations of these COPD exacerbations (see Appendix 12: Exacerbations of Chronic 
obstructive pulmonary disease tool [EXACT], Section 10.12). The instrument is a daily diary 
composed of a total of 14 items representing the following domains: 
 Breathlessness (5 items). 
 Cough and sputum (2 items). 
 Chest symptoms (3 items). 
 Difficulty bringing up sputum (1 item). 
 Tired or weak (1 item). 
 Sleep disturbance (1 item). 
 Scared or worried (1 item). 
Development and validation history of the tool is consistent with guidelines proposed by the FDA, 
EMA and well-known measurement principles. The EXACT total score assesses COPD 
exacerbations. The higher the score, the more severe are the symptoms. 
The Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD) scale is a part of the 
EXACT tool. It is a derivative instrument used to measure the effect of treatment on the severity 
of respiratory symptoms in stable COPD. The E-RS utilizes the 11 respiratory symptom items 
contained in the 14-item EXACT. The RS-Total score represents respiratory symptom severity, 
overall. Three subscales can be used that assess: 1) breathlessness (RS-Breathlessness), 2) cough 
and sputum (RS-Cough and Sputum), and 3) chest-related symptoms (RS-Chest Symptoms). 
The higher the score the more severe are the symptoms. 
8.1.2.1.3 The 5-level Euro Quality of Life-5 Dimension questionnaire (EQ-5D-5L)  
EQ-5D-5L is a standardized health-related QoL questionnaire developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. EQ 5D is 
designed for self-completion by patients. The EQ-5D consists of a descriptive system and the EQ 
Visual Analog Scale (VAS). The descriptive system comprises five dimensions: mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 
no problems, slight problems, moderate problems, severe problems and extreme problems. 
The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, 
(Appendix 14, see Section 10.14). 
8.1.2.2 Other clinical outcome assessments  
8.1.2.2.1 Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index 
(BODE Index)  
The BODE Index is a composite measure composed of a Performance Outcome Measure, a 
Patient-Reported Outcome Measure and a Biomarker. The BODE Index is a multidimensional 
grading system to assess the respiratory and systemic expressions of COPD (25). It comprises  


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4 domains: 1) Degree of pulmonary impairment (FEV1); 2) Patient’s perception of symptoms 
(mMRC); and 2 independent domains: the 6 Minute Walking Distance (6MWD) and the 
Body-Mass Index (BMI). Each domain can be scored independently; the global score ranges from 
0 to 10, with a higher score indicating a higher risk of death (see Appendix 13, Section 10.13). 
8.2 
SAFETY ASSESSMENTS   
The same safety assessments will be applied across both arms. 
Adverse events, including SAEs and adverse events of special interest (AESI), will be collected at 
every visit. The assessments for AE, SAE and AESI are described in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
A complete physical examination will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. All 
deviations from normal will be recorded, including those attributable to the patient’s disease. 
Refer to Section 1.3 for the schedule of physical examinations performed throughout this study. 
Investigators should pay special attention to clinical signs related to previous serious illnesses or 
signs of infection. 
Any new clinically significant finding or worsening of previous finding should be reported as a 
new adverse event. 
8.2.2 Vital signs  
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), 
body temperature (°C), and respiratory rate will be measured at screening, baseline and every 
subsequent on-site visit. Height (cm) will be measured at Screening (Visit 1) only. Body weight 
(kg) will be measured at Screening (Visit 1) and EOT/EOS visits. Refer to Section 1.3 for the 
schedule of vital signs performed throughout this study. 
8.2.3 Electrocardiograms  
Recording of a standard 12-lead ECG will be performed at the site. Refer to Section 1.3 for 
the schedule of ECG performed throughout this study. At the post randomization visits, ECGs will 
be performed prior to investigational product administration. A minimum of 3 complexes in an 
appropriate lead (lead II) will be averaged to determine the PR-interval, QT/QTc-interval, 
QRS-complex and heart rate will be measured for each ECG; the triplicate ECGs are required. 
Refer to ECG reading manual for more details. All ECG recordings will be centrally read 
by independent experts. 


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8.2.4 Clinical safety laboratory assessments  
The clinical laboratory tests are planned to be conducted at a central laboratory. 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 98 days after the last dose of study intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA. 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the CRF. 
The clinical laboratory parameters that will be measured are described in Appendix 2: Clinical 
laboratory tests (Section 10.2). Decision trees for the management of certain laboratory 
abnormalities by Sanofi are provided in Appendix 6: Liver and Other Safety: Suggested Actions 
and Follow-up Assessments (Section 10.6). 
For patient(s) who have consented to it, the samples that are archived, unused or left over after 
planned testing may be used for additional research purposes (Appendix 17: Future Use of 
Samples, see Section 10.17. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The definitions of an AE or SAE can be found in Appendix 3: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting (Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 


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up AEs that are serious, considered related to the IMP or study procedures, or that caused the 
participant to discontinue the IMP (Section 7). 
8.3.1 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 8.3.2, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the e-CRF.  If an SAE or any AESI of 
anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment, 
or severe injection site reactions lasting longer than 24 hours, occurs in a patient, blood samples 
should be collected for determination of functional dupilumab concentration, and ADA 
assessment at or near the onset and completion of the occurrence of the event, if possible  
(see Section 8.5.3 for details). 
 Clinically symptomatic eosinophilia (or eosinophilia associated with clinical symptoms). 
 Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Appendix 15, Section 10.15). 
 Severe injection site reactions that last longer than 24 hours. 
 Any infection meeting at least one of the following criteria: 
- 
Any serious infection (SAE). 
- 
Requires parenteral (intravenous, intramuscular, subcutaneous) antimicrobial therapy. 
- 
Requires oral antimicrobial therapy for longer than 2 weeks. 
- 
Is a parasitic infection. 
- 
Is an opportunistic infection (see Appendix 16, Section 10.16). 
Note:  antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents 
 Any severe type of conjunctivitis or blepharitis.  
 Keratitis. 
 Significant ALT elevation: 
- 
ALT >5 × the upper limit of normal (ULN) in patients with baseline ALT ≤2 × ULN, 
or 
- 
ALT >8 × ULN if baseline ALT >2 × ULN. 
 Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP. 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient 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. 


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- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Appendix 4 
[Section 10.4]). 
- 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Symptomatic overdose (serious or nonserious) with IMP/NIMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose during an interval of less than 11 days. The circumstances (ie, accidental 
or intentional) should be clearly specified in the overdose form and symptoms, if any, 
entered on separate adverse event forms. 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
maximum daily dose as specified in a drug label, within the intended therapeutic 
interval. The circumstances (ie, accidental or intentional) should be clearly specified in 
the overdose form and symptoms, if any, entered on separate adverse event forms. 
Asymptomatic overdose should also be reported on the overdose form. 
8.3.2 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 1.3), or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.3 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 


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8.3.4 Follow-up of AEs and SAEs  
After the initial AE/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 non-serious AEs 
of special interest (as defined in Section 8.3.1), will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.5 Regulatory reporting requirements for SAEs  
 Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
 The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review 
Boards (IRB)/Independent Ethics Committees (IEC), and Investigators. 
 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. 
 Adverse events that are considered expected will be specified in the reference safety 
information. 
 An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.6 Pregnancy  
See AESI (Section 8.3.1). 
8.3.7 Adjudication Committee  
Adjudication will be performed by experts independent of sponsor for the evaluation of whether 
deaths, cardiovascular SAEs and respiratory SAEs meet criteria for certain safety endpoints. 
A confirmatory adjudication will occur for AECOPD exacerbations. Adjudicators will adjudicate 
these events in a consistent and unbiased manner throughout the study. 
The goal of the adjudication is to ensure that all events reported by the site are judged uniformly, 
using pre-specified criteria by a group independent of the Sponsor. Adjudication Committee 
members will be blinded to treatment allocation. Adjudication Committee members’ 
responsibilities and the process for data review are described in the AC Charter/Manual of 
Operation. 


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8.3.8 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
In this study, some AEs are considered related to the underlying condition. Specifically, for 
patients with COPD worsening of underlying condition is not considered an AE unless it meets 
serious criteria as defined in Appendix 3 (Section 10.3). 
8.3.9 Guidelines for reporting product complaints / medical device incidents (including 
malfunctions)  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
Symptomatic overdose is an AESI (defined in Section 8.3.1). No antidote is available for 
dupilumab. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically. 
3. Obtain a serum sample for PK analysis as soon as possible from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
8.5.1 Sampling time  
Blood samples will be collected for determination of functional dupilumab and anti-dupilumab 
antibodies in serum as specified in the SoA (Section 1.3). Special procedures for collection, 
storage, and shipping of serum are described in separate operational manuals. The date and time 
of collection should be recorded in the patient e-CRF. 


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8.5.2 Handling procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and ADA is provided in Table 6. 
Table 6 - Summary of handling procedures for dupilumab  
Sample type 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Blood sample volume 
5 mL 
5 mL 
Anticoagulant 
None 
None 
Blood handling procedures 
See Operational Manual 
See Operational Manual 
Serum aliquot split 
2 aliquots 
2 aliquots 
Storage conditions 
<6 months:  below -20°C 
<24 months: below -80°C (preferred) 
<6 months:  below -20°C 
<24 months: below -80°C (preferred) 
Serum shipment condition 
In dry ice 
In dry ice 
8.5.3 Bioanalytic method  
Serum PK and ADA samples will be assayed using validated methods as described in Table 7. 
Table 7 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibodies  
Analyte 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Analytical technique 
ELISA 
Electro-chemiluminescence 
Site of bioanalysis 
Regeneron 
Regeneron 
ELISA=enzyme-linked immunosorbent assay. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
Note: In case of a suspected SAE or any AESI event like anaphylactic reactions or systemic 
hypersensitivity that may be related to IMP and require treatment, or severe and serious injection 
site reactions lasting more than 24 hours, if feasible, additional blood samples may be collected 
for the determination of functional dupilumab concentration and ADA assessment at or near the 
event. The exact date and time of sample collection must be recorded and entered into the 
database by the central laboratory. An unscheduled systemic drug concentration page in the eCRF 
must be completed as well. If necessary for safety monitoring, additional ADA samples may be 
collected after the EOS visit until resolution of SAE or AESI. 
Specifically for PK, any changes in the timing or addition of time points for any planned study 
assessments must be documented and approved by the relevant study team member and then 
archived in the Sponsor and site study files, but will not constitute a protocol amendment. 
The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring 
scheme or amendment of the ICF. 


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8.6 
PHARMACODYNAMICS  
8.6.1 Pharmacodynamic variables/biomarkers  
 Pharmacodynamic response of selected biomarkers. 
- 
PARC. 
- 
Eotaxin-3. 
- 
FeNO (postbronchodilator). 
- 
Total IgE. 
- 
Fibrinogen. 
 Serum/plasma for archival purposes.  
For timing of PD sample collection refer to SoA (Section 1.3). 
Assay methodologies are briefly summarized below. More detailed information on the collection, 
handling, transport, and preservation of samples (eg, minimum volumes required for blood 
collection and for aliquots for each biomarker assay) will be provided in a separate laboratory 
manual. 
Specific procedures for collection, storage and shipping of samples collected for 
pharmcodynamics will be provided in a lab manual. 
Whole blood biomarkers 
Blood eosinophil and neutrophil counts will be measured as part of the standard 5-part WBC 
differential cell count on a hematology auto analyzer. Blood eosinophil and neutrophil counts will 
be measured at timepoints additional to hematology (Section 1.3). 
Plasma/serum biomarkers 
PARC will be assayed using a validated enzyme immunoassay. 
Fibrinogen assay: (development of immunoassay method ongoing). 
Eotaxin-3 will be measured in heparinized plasma with a validated enzyme immunoassay. 
Total IgE will be measured with a quantitative method (eg, Phadia ImmunoCAP) approved for 
diagnostic testing. 
Exhaled nitric oxide 
FeNO will be analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden), or similar 
analyzer using a flow rate of 50 mL/s, and reported in parts per billion (ppb). This assessment 
should be done after pre-bronchodilator spirometry and before post bronchodilator spirometry. 
Further details on the procedure for measuring exhaled nitric oxide with NIOX will be provided in 
a separate instruction manual. 


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8.7 
PHARMACOGENOMICS  
Pharmacogenetic/Pharmacogenomic testing is optional and voluntary. Written informed consent 
must be obtained before sampling. 
For those patients who consent to the optional pharmacogenetic/pharmacogenomic sample 
collection section of the informed consent form (ICF), blood samples for exploratory genetic 
analysis of DNA or RNA will be collected at the study visit as specified in the SoA (Section 1.3), 
and these samples will be stored for future analysis. Specific procedures for collection, storage 
and shipping of pharmacogenetic/pharmacogenomic samples will be provided in a lab manual. 
For patient(s) who have consented to it, the samples that are archived, unused or left over after 
planned testing may be used for additional research purposes (Appendix 17: Future use of 
samples, see Section 10.17). 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. 
8.8 
BIOMARKERS  
Pharmacodynamic and pharmacogenetics biomarkers are described in Section 8.6.1 and 
Section 8.7, respectively. 
8.9 
HEALTH CARE RESOURCE UTILIZATION  
A questionnaire of health care resource utilization (reliever medication, physician visit, 
hospitalization, emergency or urgent medical care facility visit, sick leaves including loss of usual 
activity days) will be collected by the Investigator for all participants throughout the study. 


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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The statistical hypotheses used to test dupilumab 300 mg q2w against placebo on the primary 
endpoint of annualized rate of moderate-to-severe COPD exacerbations over the 52-week 
treatment period are as follows: 
 Null hypothesis: 𝑟ௗ௨௣௜௟௨௠௔௕𝑟௣௟௔௖௘௕௢
ൗ
ൌ1. 
 Alternative hypothesis: 𝑟ௗ௨௣௜௟௨௠௔௕𝑟௣௟௔௖௘௕௢
ൗ
്1. 
Where 𝑟ௗ௨௣௜௟௨௠௔௕ and 𝑟௣௟௔௖௘௕௢ represent exacerbation rate in the dupilumab and placebo groups, 
respectively. 
The statistical hypotheses used to test dupilumab 300 mg q2w against placebo on the key 
secondary endpoint of pre-bronchodilator FEV1 from baseline to Week 12 are as follows: 
 Null hypothesis: 𝑐ௗ௨௣௜௟௨௠௔௕ൌ𝑐௣௟௔௖௘௕௢. 
 Alternative hypothesis: 𝑐ௗ௨௣௜௟௨௠௔௕്𝑐௣௟௔௖௘௕௢. 
Where 𝑐ௗ௨௣௜௟௨௠௔௕ and 𝑐௣௟௔௖௘௕௢ represent change in pre-bronchodilator FEV1 in the dupilumab and 
placebo groups, respectively. 
The statistical hypotheses to be tested on other key secondary endpoints, change in 
pre-bronchodilator FEV1 from baseline to Week 12 and change from baseline to Week 52 in the 
SGRQ total score compared to placebo, can be specified similarly as those on the change in FEV1 
at Week 12. For the proportion of patients with SGRQ improvement ≥4 points at Week 52, the 
null hypothesis is the odds ratio of response between the dupilumab and placebo group is equal 
to 1, while the alternative hypothesis is the odds ratio is unequal to 1. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size of the study is determined based on power calculations for the primary endpoint 
of annualized rate of moderate or severe COPD exacerbations over the 52-week treatment period. 
Assuming the number of exacerbations following a negative binomial distribution with a 
dispersion parameter of 1, a placebo annualized rate of  exacerbations being 1.5, an average 
treatment duration of 0.95 year (to account for an average of 5% of the planned treatment period 
with missing data), and a randomization ratio of 1:1 to the two treatment arms, with  
924 randomized patients (462 for each treatment arm), the study will have 90% power to detect a 
25% relative risk reduction (ie, annualized rate of 1.125 for the dupilumab group) in the 
annualized rate of moderate or severe COPD exacerbations at the 2-tailed significance level of 
α =0.05. With the addition of an interim analysis, the final alpha may be reduced to 0.049, which 
maintains approximately 90% power (see Section 9.5 for further details). 
Patients will be randomized using a 1:1 randomization ratio to dupilumab 300 mg q2w or placebo. 
Randomization will be stratified by country, ICS dose (high dose ICS [yes/no]) at baseline, and 


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smoking status at screening (current smokers or not). As an example, the adult high dose of ICS 
for fluticasone propionate is >500 mcg (DPI or HFA) or 401-800 mcg (HFA) for Japanese 
population (please refer to Section 10.18 for the most common ICS). Alerts will be built into the 
IVRS/IWRS to limit enrolling patients who are current smokers (as defined by smoking status at 
screening) to less than or equal to 30% or 278 patients out of the total enrolled patients. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 8): 
Table 8 - Populations for analyses  
Population 
Description 
Screened 
All patients who signed the ICF. 
Randomized 
The randomized population includes all patients with a treatment kit number allocated and recorded 
in the IRT database, and regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population, but will be included in the safety population. 
Intent-to-treat (ITT) 
All randomized patients analyzed according to the treatment group allocated by randomization. 
Efficacy 
The ITT population. 
Safety 
The safety population includes all patients who actually received at least one dose or partial of a 
dose of the IMP, analyzed according to the treatment actually received. 
Randomized patients for whom it is unclear whether they took the study medication will be included 
in the safety population as randomized.  
For patients on dupilumab but accidentally receive different treatment from the planned, the actual 
treatment group allocation for as-treated analysis will be the dupilumab group. 
The pharmacodynamic (PD) analyses will be performed on the safety population. 
Pharmacokinetic (PK) 
The PK population includes all patients in the safety population with at least one non-missing result for 
functional dupilumab concentration in serum after first dose of the study treatment. Patients will be 
analyzed according to the treatment actually received. 
Antidrug antibody (ADA) 
ADA population includes all patients in the safety population who have at least one non-missing ADA 
result after first dose of the study treatment.  Patients will be analyzed according to the treatment actually 
received. 
 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock for the interim 
analysis (see Section 9.5) and will describe the participant populations to be included in the 
analyses, and procedures for accounting for missing, unused, and spurious data. This section is a 
summary of the planned statistical analyses of the primary and secondary endpoints. 


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9.4.1 Efficacy analyses  
Table 9 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
Annualized rate of moderate 
and severe COPD 
exacerbations over 52-week 
treatment period. 
The annualized rate of moderate and severe COPD exacerbation events will be analyzed 
using a negative binomial regression model. The model will include the total number of 
events occurring during the 52-week treatment period as the response variable, with the 
treatment group, region (pooled country), ICS dose (high dose ICS [yes/no]), smoking status 
at screening (current smokers or not), baseline disease severity (as % predicted post-
bronchodilator FEV1), and number of moderate or severe COPD exacerbation events within 
one year prior to the study (≤2, 3, or ≥4) as covariates. Log-transformed observation 
duration will be used as offset variable. The estimated annualized event rate for each 
treatment group and its two-sided 95% confidence intervals will be derived. The event rate 
ratio of the dupilumab group against placebo, its two-sided 95% confidence interval and 
p-value will be provided. Patients who permanently discontinue the study treatment will be 
encouraged to complete the study as planned and the additional off-treatment exacerbation 
events up to Week 52 will be included in the primary analysis. Sensitivity analyses for 
handling missing data may include pattern mixture model by multiple imputation and tipping 
point analyses. 
Subgroup analysis 
To assess the consistency in treatment effects across different subgroup levels, subgroup 
analyses will be performed for the primary efficacy endpoints with respect to age, gender, 
region, race, weight, BMI, smoking status, ICS dose (high dose ICS [yes/no]), disease 
severity (as % predicted post-bronchodilator FEV1), number of moderate-or-severe COPD 
exacerbation events within one year prior to the study, pre-bronchodilator FEV1, and other 
factors that will be specified in SAP.  
Baseline biomarker-by-treatment interaction on the efficacy endpoints will be analyzed to 
evaluate the potential predictive effect of baseline biomarkers on the treatment response. 
Key secondary 
Change in pre-bronchodilator 
FEV1 from baseline to Week 12. 
The change from baseline in pre-bronchodilator FEV1 at Week 12 will be analyzed using 
mixed-effect model with repeated measures (MMRM). The model will include change from 
baseline in FEV1 values up to Week 12 as response variables, and factors for treatment 
group, age, sex, baseline height, region (pooled country), ICS dose (high dose ICS 
[yes/no]), smoking status at screening (current smokers or not), visit, treatment-by-visit 
interaction, baseline pre-bronchodilator FEV1, and FEV1 baseline-by-visit interaction as 
covariates. An unstructured correlation matrix will be used to model the within-patient errors. 
Parameters will be estimated using restricted maximum likelihood method using the 
Newton-Raphson algorithm. The least square (LS) mean of the change in 
pre-bronchodilator FEV1 of each treatment group, difference in the LS mean changes 
between the dupilumab group and placebo, the corresponding 95% CI of the differences 
and p-values will be provided. For patients who discontinued the study treatment, 
off-treatment FEV1 values will be included in the analysis. Sensitivity analyses for handling 
missing data may include pattern mixture model by multiple imputation and tipping point 
analyses. 
Change in pre-bronchodilator 
FEV1 from baseline to Week 52. 
The change from baseline in pre-bronchodilator FEV1 at Week 52 will be analyzed in a 
similar way as change from baseline in pre-bronchodilator FEV1 at Week 12 and the model 
will include values up to Week 52 as response variables. 
Change in the SGRQ total 
score from baseline to week 52. 
The change from baseline in SGRQ total score at Week 52 will be analyzed in a similar way 
as change in pre-bronchodilator FEV1 at Week 52 except that the MMRM model will include 
the following covariates: treatment group, region (pooled country), ICS dose (high dose ICS 
[yes/no]), smoking status at screening (current smokers or not), visit, treatment-by-visit 
interaction, baseline SGRQ total score, and SGRQ baseline-by-visit interaction. 


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Endpoint 
Statistical Analysis Methods 
Proportion of patients with 
SGRQ improvement  
≥4 points at Week 52. 
The proportion of patients with SGRQ improvement ≥4 points at Week 52 will be analyzed 
using a logistic regression model. The model will include treatment group, region (pooled 
country), ICS dose (high dose ICS [yes/no]), smoking status at screening (current smokers 
or not), and baseline SGRQ total score as covariates. Patients with missing SGRQ total 
score at Week 52 will be considered as non-responders. 
Other secondary 
Change in pre-bronchodilator 
FEV1 from baseline to Weeks 
other than 12 & 52. 
The change in pre-bronchodilator FEV1 from baseline at other time points will be analyzed in 
the same way as the change from baseline in pre-bronchodilator FEV1 at Week 52. 
Change in post-bronchodilator 
FEV1, change in forced 
expiratory flow (FEF) 25-75%. 
The change in the spirometry parameters from baseline will be analyzed similarly as the 
change in pre-bronchodilator FEV1 except that the corresponding baseline of the parameter 
will replace baseline pre-bronchodilator FEV1 to be adjusted for in the MMRM model. 
Time to first moderate or severe 
COPD exacerbation compared 
to placebo during the 52-week 
treatment period. 
The time to first moderate or severe COPD exacerbation will be analyzed using a Cox 
regression model. The model will include the time to the first event as the dependent 
variable, and treatment group, region (pooled country), ICS dose (high dose ICS [yes/no]), 
smoking status at screening (current smokers or not), baseline disease severity (as % 
predicted post-bronchodilator FEV1), and number of moderate or severe COPD 
exacerbation events within one year prior to the study (≤2, 3, or ≥4) as covariates. 
The Kaplan-Meier method will be used to derive the probabilities that a patient would 
experience event up to specific timepoints for each treatment group. 
Annualized rate of severe 
COPD exacerbations over the 
52-week treatment period. 
The annualized event rate of severe COPD exacerbations will be analyzed in the same way 
as the primary analysis for the annualized rate of moderate or severe COPD exacerbation 
events. 
Exploratory 
Analysis of Exploratory endpoints will be described in the SAP finalized before database 
lock for the interim analysis. 
 
If the primary endpoint is statistically significant at the interim analysis then for the continuous 
and proportion type endpoints at Week 52, only participants who have the opportunity to reach 
Week 52 assessments at the time of the interim analysis cut-off date (ie, completed the Week 52 
study period or would have completed had they not discontinued) will contribute to the inferential 
analyses. 
9.4.1.1 Multiplicity considerations  
Multiplicity is considered for performing an interim analysis and for testing multiple endpoints. 
The overall Type-I error rate will be controlled at the two-sided 0.05 level. 
An interim analysis will be performed using the Kim-DeMets spending function (26) when the 
information fraction for the primary endpoint is ≥0.92 (see Section 9.5). A hierarchical testing 
procedure will be used for the testing primary, key secondary and other endpoints. The annualized 
rate of moderate and severe COPD exacerbations over the 52-week treatment period will be first 
tested with an alpha as determined in Table 12. Only upon rejection of the null hypothesis for the 
annualized rate of moderate and severe COPD exacerbations can the key secondary endpoint, 
change in pre-bronchodilator FEV1 from baseline to Week 12 be tested. 
Multiplicity adjustment for the other efficacy endpoints will be described in the study SAP. 


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9.4.2 Safety analyses  
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the Safety Population. The baseline value is defined generally as the last available 
value before randomization. The treatment emergent adverse event (TEAE) period is defined as 
the time between the first administration of study medication to the last administration of the  
IMP +98 days. 
Table 10 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
AE, SAE, AE 
leading to 
death, AE 
leading to 
permanent 
treatment 
discontinuation. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by internationally agreed 
order), high-level group term (HLGT), high level term (HLT) and preferred term (PT) sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an AE. Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a treatment 
phase. The denominator for computation of percentages is the safety population within each treatment 
group. 
Proportion of patients with at least one TEAE, treatment emergent SAE, TEAE leading to death, and TEAE 
leading to permanent treatment discontinuation will be tabulated by treatment group. In addition TEAEs will 
be described according to maximum intensity and relation to the study drug. AEs that occur outside the 
treatment-emergent period will be summarized separately. 
Major 
Cardiovascular 
Adverse 
Events (MACE) 
The number and percentage (%) of patients with any treatment-emergent event selected for adjudication will 
be summarized by primary SOC and PT. 
All events submitted for adjudication will be listed, including the final adjudicated result. 
The number and percentage (%) of patients experiencing a treatment-emergent adjudicated event will be 
summarized within each treatment group. 
The risk difference (asymptotic 95% CI with continuity correction) will be computed for the dupilumab dose 
versus placebo. Kaplan-Meier plots to depict the course of onset over time will also be provided. 
AESI and other 
AE groupings 
Incidence of each type of AESI and other AE groupings will be tabulated by treatment group. For each type 
of AESI, the following analysis will be generated. 
 
A summary of the number (%) of patients with 
- 
Any TEAE. 
- 
Any SAE (regardless of treatment-emergent status). 
- 
Any treatment-emergent SAE. 
- 
Any AE leading to death. 
- 
Any TEAE leading to death. 
- 
Any TEAE leading permanent treatment discontinuation. 
- 
Any TEAE related to IMP reported by Investigator. 
- 
Number of patients with the TEAE per 100 patient-years. 
- 
Any TEAE by maximum intensity, corrective treatment, and final outcome. 
 
Kaplan-Meier (K-M) estimates of probability of having at least one TEAE at specific time points, 
and K-M curve to depict the course of event onset over time. 
The method to identify AESIs and other AE groupings will be specified in the SAP. 
Death 
The following deaths summaries will be generated: 
 
Number (%) of patients who died by study period (TEAE, on-study) summarized on the safety 
population by treatment received. 
 
Death in nonrandomized patients or randomized and not treated patients. 
Treatment-emergent AE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (%) of patients sorted by internationally 
agreed order of SOC and alphabetic order of HLGT, HLT, and PT. 


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Endpoint 
Statistical Analysis Methods 
Laboratory 
parameters 
Results and change from baseline for the parameters will be summarized by treatment group for baseline 
and each post baseline time point, endpoint, minimum and maximum value. Summary statistics will include 
number of patients, mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
The following definitions will be applied to laboratory parameters. 
 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review and defined by the Sponsor for clinical laboratory tests. 
 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment period, 
taking into account all evaluations performed during the on-treatment period, including 
unscheduled or repeated evaluations. The number of all such patients will be the numerator for the 
on-treatment PCSA percentage. 
The proportion of patients who had at least one incidence of PCSA at any time during the TEAE period will 
be summarized by treatment group. Shift tables showing changes with respect to the baseline status will be 
provided. 
9.4.3  Other analyses   
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalized before database lock. The population PK analysis and pharmacodynamic 
analyses will be presented separately from the main clinical study report (CSR). 
Table 11 provides a summary of the planned statistical analyses of the other endpoints. 
Table 11 - Other analyses  
Endpoint 
Statistical Analysis Methods 
PK 
Serum concentrations of SAR231893 (REGN668) will be summarized for the dupilumab treatment group using 
arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation (CV), minimum, 
median and maximum per sampling time. 
ADA 
The incidence of treatment-emergent ADA response for SAR231893 (REGN668) will be provided by treatment 
groups, including characterization of the response with titers and neutralizing antibody status. Association of 
ADA with impact on drug concentration profile, efficacy and safety may be explored. ADA analysis will be 
detailed in the SAP. 
PD 
For all PD parameters, raw data at each visit, absolute changes from baseline, and percent changes from 
baseline will be summarized in descriptive statistics by treatment group and time point.  
Summary plots (mean ± standard error of the mean) on raw data, absolute changes from baseline and percent 
changes from baseline will be provided by treatment groups. 
 
Data collected regarding the impact of the COVID-19 or other pandemics on the participants will 
be summarized (eg, discontinuation due to COVID-19). Any additional analyses and methods 
required to investigate the impact of COVID-19 or other events requiring public health emergency 
on the efficacy (eg, missing data due to COVID-19) and safety will be detailed in the SAP. 


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9.5 
INTERIM ANALYSES   
An interim analysis is planned when the information fraction is ≥0.92 based on follow-up time for 
the primary endpoint of annualized rate of moderate or severe COPD exacerbations over a 52-
week treatment period. All participants will have complete follow-up for the key secondary 
endpoint of change from baseline in FEV1 at Week 12. The purpose of this interim analysis is to 
potentially demonstrate efficacy when ≥92% of the information fraction for the primary endpoint 
is available, but prior to all patients completing the 52-week treatment period, as COPD is a 
disease with a high unmet medical need.  
To control the overall type I error at α=0.05, the Kim-DeMets approach (26) will be used with the 
power parameter rho (ρ) determined based on the information fraction observed at the time of the 
interim analysis and to maintain an α=0.049 at the final analysis (Table 12). 
Table 12 - Kim-DeMets alpha spending function to control the overall alpha at 0.05  
Information fraction 
Rho (ρ) 
α at interim analysis 
α at final analysis 
0.92 to <0.93 
12 
0.018 
0.049 
0.93 to <0.94 
12 
0.020 
0.049 
0.94 to <0.95 
13 
0.022 
0.049 
0.95 to <0.96 
14 
0.024 
0.049 
0.96 to <0.97 
15 
0.027 
0.049 
If the primary endpoint does not demonstrate efficacy at this interim analysis then the study will 
remain blinded and the primary endpoint will be retested at the final analysis with an α=0.049. 
If the primary endpoint demonstrates efficacy at this interim analysis then the rest of the 
multiplicity-controlled endpoints will be tested with α=0.05. Further details will be provided in 
the study SAP. 
This interim analysis will be performed by independent statisticians that support the DMC and are 
separated from personnel involved in the trial conduct. The DMC will review the unblinded result 
of the primary endpoint and will communicate if the criterion for efficacy is met as prespecified in 
the SAP. The DMC is established and will continue the regular review of unblinded safety data as 
described in the DMC charter. In the event that statistical significance is demonstrated on the 
primary endpoint the additional analyses will be performed by the unblinded Sponsor team. To 
maintain study integrity with respect to the subsequent visits, follow-up and analyses after this 
interim analysis, a dissemination plan will be written. This plan will clearly identify two 
independent study teams (blinded team and unblinded team) and provide further details on the 
unblinding plan. People involved in the conduct of the study (patients, Investigators, Site Staff, 
and the blinded Study and Project Team) will have no access to unblinded patient level data, 
individual patient treatment codes, or unblinded tables or figures (see the Dissemination plan for 
details). 
If efficacy at the interim analysis is not demonstrated the database lock for primary analysis is 
planned based on the date when the last patient completes the Week 52 visit or discontinues from 


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the study before Week 52. Analyses will be based on all data collected up to this database lock 
and will be considered as the final analysis of the CSR. Additional data between this database 
lock and last patient completing last visit will be summarized in a CSR addendum. 
If efficacy at the interim analysis is demonstrated, then the interim analysis database lock will be 
considered the primary analysis for all endpoints. The database lock for final analysis is planned 
when all patients complete the Week 52 visit or discontinue from the study before Week 52, but 
may occur when all patients complete the Week 64 visit or discontinue from the study. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and Ethical Considerations  
 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 Good Clinical Practice (GCP) Guidelines. 
- 
Applicable laws and regulations. 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted, as required by local regulation, to an 
IRB/IEC and to the Health Authorities (competent regulatory authority) by the 
Investigator or Sponsor and, where further required by regulation, reviewed and approved 
by the IRB/IEC and Health Authorities before the study is initiated. 
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
 The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
- 
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), and all other applicable local regulations. 
10.1.2 Informed consent process  
 The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
 Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of  
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 


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 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. 
 Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.3 Data protection  
 All personal data collected related to participants, Investigators, or any person involved in 
the study, which may be included in the Sponsor’s databases, shall be treated in 
compliance with all applicable laws and regulations including the GDPR (Global Data 
Protection Regulation). 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 these data are required 
by regulatory agencies (eg, on African American population for the FDA or on Japanese 
population for the PMDA in Japan). 
 Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
 The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
 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. 
 When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.4 Committees structure  
Study committees 
The study data will be reviewed by a DMC and adjudication committee. 
10.1.4.1 Data Monitoring Committee (DMC)  
A DMC, independent from sponsor will be established for this study. This committee is 
comprised of externally-based individuals with expertise in the diseases under study, biostatistics, 
or clinical research. The primary responsibilities of the DMC are to review and evaluate the safety 


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data during the course of the trial, review interim analysis results and make appropriate 
recommendations regarding the conduct of the clinical trial to the Sponsor. 
The DMC procedures and safety and efficacy 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. 
10.1.4.2 Adjudication committee  
Adjudication will be performed by experts independent of sponsor for the evaluation of whether 
deaths, cardiovascular SAEs and respiratory SAEs meet criteria for certain safety endpoints. 
A confirmatory adjudication will occur for AECOPD exacerbations. Adjudicators will adjudicate 
these events in a consistent and unbiased manner throughout the study. 
The goal of the adjudication is to ensure that all events reported by the site are judged uniformly, 
using pre-specified criteria by a group independent of the Sponsor. Adjudication Committee 
members will be blinded to treatment allocation. Adjudication Committee members’ 
responsibilities and the process for data review are described in the AC Charter/Manual of 
Operation. 
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. 
These websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well 
as some national registries. 
In addition, results from clinical trials in patients 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. 
10.1.6 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. 


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 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
 The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.7 Source documents  
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
 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. 
 Definition of what constitutes source data can be found in the Study Reference Manual. 
10.1.8 Study and site closure  
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. 


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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. 
10.1.9 Publication policy  
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
 The tests detailed in Table 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. 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 CRF. 
 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. 


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Table 13 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
To include hemoglobin, hematocrit, platelet count, total white blood cell count with five-part differential 
count and total red blood cell count. 
Clinical 
chemistry 
To include 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 (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate 
dehydrogenase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. 
Routine 
urinalysis 
To include urine dipstick analysis including specific gravity, pH, glucose, ketones, blood, protein, nitrite, 
leukocyte esterase, urobilinogen and bilirubin (by dipstick).  If any assessment on the dipstick is abnormal, 
a urine sample should be sent to the central laboratory for testing. If positive for proteins, microscopic 
analysis is performed by central laboratory. 
Other tests 
Clinical laboratory testing at Screening Visit 1 will include hepatitis screen covering hepatitis B surface 
antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C 
virus antibodies (HCV Ab), Human Immunodeficiency Virus (HIV) screen (Anti-HIV-1 and HIV-2 antibodies) 
and anti-nuclear antibody (ANA). In case of results showing HBs Ag (negative), HBs Ab (negative) and 
HBc Ab (positive), an HBV DNA testing may be performed prior to randomization to rule out a false 
positivity if the Investigator believes the patient is a false positive, or to clarify the serological status if the 
Investigator finds it unclear to interpret in absence of known HBV infection. In case of results showing HCV 
Ab (positive), an HCV RNA testing may be performed to rule out a false positivity, if the Investigator 
believes the patient is a false positive. 
Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer). 
Investigators must document their review of each laboratory safety report. 
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. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
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. 
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). 


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 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
 "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 fulfil the definition of an AE or SAE. 
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
 AECOPD unless it meets the criteria for SAE. 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE. 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) Is life-threatening. 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 


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c) Requires inpatient hospitalization or prolongation of existing hospitalization. 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d) Results in persistent disability/incapacity. 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect. 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the CRF. 
 It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF page. 
 There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’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. 


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 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
 The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 The Investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
 The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 


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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. 
 New or updated information will be recorded in the originally completed CRF. 
The Investigator will submit any updated SAE data to the Sponsor/Sponsor’s representative 
within 24 hours of receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor’s representative 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 for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section). 
 The site will enter the SAE data into the electronic system as soon as it becomes available. 
 After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
 Contacts for SAE reporting can be found in the Protocol. 
SAE reporting to the Sponsor’s representative via paper CRF (if eCRF is not available) 
 Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
 In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
 Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in the Protocol.  


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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal. 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy. 
- 
Documented bilateral salpingectomy. 
- 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
- 
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. 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 14. 
Table 14 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 
 
Oral 
 
Intravaginal 
 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oral 
 
Injectable 


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Highly effective methods that are user independenta 
 
Progestin only Implants 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral Tubal Ligation 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
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. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
PREGNANCY TESTING: 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test (at Screening). Urine pregnancy tests will be performed 
monthly subsequently. 
Additional pregnancy testing as shown in the SoA (Section 1.3) and as follows. 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
COLLECTION OF PREGNANCY INFORMATION: 
Female participants who become pregnant 
 The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
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Male participants with partners who become pregnant 
The Investigator will attempt to collect pregnancy information on any male participant’s female 
partner who becomes pregnant while the male participant is in this study. This applies only to 
male participants who receive study treatment. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the Investigator will record pregnancy information on the appropriate form and submit it to the 
Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to  
8 weeks following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
10.5 
APPENDIX 5: GENETICS  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to drug, other COPD clinical outcome measures and possible AEs. In 
addition, associations between genomic variants and prognosis or progression of COPD as well 
as related allergic/atopic diseases may also be studied. These data may be used or combined with 
data collected from other studies to identify and validate genomic markers related to the study 
drug or COPD and related diseases. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. Results from the genomic analyses will not be 
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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. 
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 for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
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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 
is met. 
 


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10.7 
APPENDIX 7: LIST OF PROHIBITED LIVE ATTENUATED VACCINES  
 Bacillus Calmette-Guérin (BCG) antituberculosis vaccine. 
 Chickenpox (Varicella). 
 Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection 
is permitted. 
 Measles (Rubeola). 
 Measles-mumps-rubella (MMR) combination. 
 Measles-mumps-rubella-varicella (MMRV) combination. 
 Mumps. 
 Oral polio (Sabin). 
 Oral typhoid. 
 Rotavirus. 
 Rubella. 
 Smallpox (Vaccinia). 
 Varicella Zoster (shingles). 
 Yellow fever. 
This list is indicative and not exhaustive. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.9 
APPENDIX 9: ABBREVIATIONS  
 
AC: 
Audit Committee 
AD: 
atopic dermatitis 
ADA: 
antidrug antibody 
AE: 
adverse event 
AECOPD: 
acute exacerbation of chronic obstructive pulmonary disease 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase  
ANA: 
anti-nuclear antibody 
AST: 
aspartate aminotransferase 
ATS: 
American Thoracic Society 
BCG: 
Bacillus Calmette-Guérin 
BD: 
bronchodilator 
BID: 
twice daily assessments 
BiPAP: 
bi‐level positive airway pressure 
BMI: 
Body‑Mass Index 


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BODE: 
Body-mass index, airflow Obstruction, Dyspnea, and Exercise 
CAT: 
COPD assessment test 
CFR: 
Code of Federal Regulations 
CI: 
confidence interval 
CIOMS: 
Council for International Organizations of Medical Sciences 
CONSORT: 
Consolidated Standards of Reporting Trials 
COPD: 
chronic obstructive pulmonary disease 
CRF: 
Case Report Form 
CRSwNP: 
chronic rhinosinusitis with nasal polyposis 
CSR: 
clinical study report 
CT: 
computed tomography 
CV: 
cardiovascular 
DMC: 
Data monitoring Committee 
DNA: 
deoxyribonucleic acid 
DPI: 
dry powder inhaler 
DTP: 
Direct to Patient 
EC: 
European Commission 
ECG: 
electrocardiogram 
eCRF: 
electronic Case Report Form 
ELISA: 
enzyme-linked immunosorbent assay 
EOS: 
End of Study 
EOT: 
end of treatment 
EQ-5D-5L: 
Euro Quality of Life-5 Dimension 5-Level questionnaire 
E-RS: 
Evaluating Respiratory Symptoms 
ETD: 
early treatment discontinuation 
EU: 
European Union 
EudraCT: 
European Union Drug Regulating Authorities Clinical Trials 
EXACT: 
Exacerbations of Chronic Pulmonary Disease Tool 
FDA: 
US Food and Drug Administration 
FEF: 
forced expiratory flow 
FeNO: 
fractional exhaled nitric oxide 
FEV1: 
forced expiratory volume in first second 
FSH: 
follicle stimulating hormone 
FVC: 
forced vital capacity 
GCP: 
Good Clinical Practices 
GDPR: 
Global Data Protection Regulation 
GINA: 
Global Initiative for Asthma 
GSO: 
Global Safety Officer 
GWAS: 
genome-wide association study 
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
HFA: 
hydrofluoroalkane 
HIPAA: 
Health Insurance Portability and Accountability Act 
HIV: 
Human Immunodeficiency Virus 
HLGT: 
high-level group term 
HLT: 
high level term 


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HRT: 
hormonal replacement therapy 
IB: 
Investigator’s Brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICS: 
inhaled corticosteroid 
IEC: 
Independent Ethics Committee 
IgE: 
Immunoglobulin E 
IL-13: 
Interleukin 13 
IL-4: 
interleukin 4 
IL-4Rα: 
Interleukin-4 receptor alpha 
IL-5: 
Interleukin-5 
IMP: 
investigational medicinal product 
INN: 
International Nonproprietary Names 
IRB: 
Institutional Review Board 
IRT: 
Interactive Response Technology 
ITT: 
intent-to-treat 
IUD: 
Intrauterine device 
IUS: 
Intrauterine hormone-releasing system 
IVIG: 
intravenous immunoglobulin 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LABA: 
long acting beta agonist 
LAMA: 
long acting muscarinic antagonist 
LS: 
least square 
mAbs: 
monoclonal antibodies 
MDI: 
metered dose inhaler 
MMR: 
Measles-mumps-rubella 
mMRC: 
Modified Medical Research Council Dyspnea Scale 
MMRM: 
mixed-effect model with repeated measures 
MMRV: 
Measles-mumps-rubella-varicella 
MRI: 
magnetic resonance imaging 
NIMP: 
noninvestigational medicinal product 
NYHA: 
New York Heart Association Functional Classification 
OCS: 
oral corticosteroids 
PARC: 
pulmonary and activation-regulated chemokine 
PCSA: 
potentially clinically significant abnormality 
PMDA: 
Pharmaceuticals and Medical Devices Agency 
PT: 
preferred term 
SABA: 
short-acting β agonists 
SAP: 
statistical analysis plan 
SGRQ: 
St. George's Respiratory Questionnaire 
SoA: 
schedule of activities 
SOC: 
system organ class 
SOP: 
standard operating procedure 
SUSAR: 
suspected unexpected serious adverse reactions 


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TEAE: 
treatment emergent adverse event 
TIA: 
transient ischemic attack 
TNF: 
tumour necrosis factor 
ULN: 
upper limit of normal 
US: 
United States 
VAS: 
Visual Analog Scale 
WBC: 
white blood cells 
WHO: 
World Health Organization 
WOCBP: 
woman of childbearing potential 
β-hCG: 
Human chorionic gonadotropin-beta 
 


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10.10 APPENDIX 10: ST. GEORGE’S RESPIRATORY QUESTIONNAIRE  


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10.11 APPENDIX 11: THE EXACT AS FORMATTED FOR PERSONAL DIGITAL ASSISTANT 
(PDA)  


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10.12 APPENDIX 12: EXACT QUESTIONNAIRE  


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10.13 APPENDIX 13: BODE  




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10.15 APPENDIX 15: DEFINITION OF ANAPHYLAXIS  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death (27)." 
Clinical criteria for diagnosing anaphylaxis 
 
10.16 APPENDIX 16: LIST OF OPPORTUNISTIC INFECTIONS  
 Aspergillosis. 
 Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers). 
 Candidiasis - only systemic or extensive mucosal or cutaneous candidiasis.  
 Coccidioides immitis (endemic south-western US and Central and South America). 
 Cryptococcus. 
 Cytomegalovirus. 
 Herpes Simplex (disseminated). 
 Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes). 
 Histoplasmosis (pulmonary or disseminated; most common tropical areas 
Tennessee-Ohio-Mississippi river basins). 
 Listeriosis. 
 Mycobacterium tuberculosis. 
 Mycobacterium avium. 
 Nontuberculosis mycobacteria. 
 Pneumocystis pneumonia (PCP). 
This list is indicative and not exhaustive. 
 


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10.17 APPENDIX 17: FUTURE USE OF SAMPLES  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patient(s) who have consented to it, the samples that are archived, unused or left 
over after planned testing may be used for additional research purposes (any genetic analysis 
subject to additional consent per Section 8.7). For patients who have consented to it, archival 
blood samples will be collected at the visits specified in the study flow chart (see Section 1.3). 
Additional details will be provided in the laboratory manual. 
These archived serum and plasma samples, and any residual or leftover serum, plasma or blood 
remaining from planned laboratory work, may be used for research purposes related to COPD or 
other respiratory diseases such as asthma or inflammatory diseases (eg, exploratory biomarkers of 
disease or drug effect), pathway biology, additional drug safety assessments or development and 
validation of bioassay methods beyond those defined in the present protocol. These samples will 
remain labelled with the same identifiers as the ones used during the study (ie, Subject ID, sample 
ID). They will be transferred to a Sanofi site (or a subcontractor site) which can be located outside 
of the country where the study is conducted. The Sponsor has included safeguards for protecting 
subject confidentiality and personal data (Section 10.1.3). 
10.18 APPENDIX 18: HIGH DOSE OF INHALED CORTICOSTEROIDS: ADULTS  
The following list of high dose of ICS is not a comprehensive list; the ICS that are not part of the 
list should be discussed with the Sponsor to confirm high vs. lower dose prior to randomization. 
Note: The reported ICS doses in the Tables below refer to METERED dose. 
 
Inhaled corticosteroid 
Daily dose (mcg) 
 
High 
Lower doses 
Beclometasone dipropionate (CFC) 
>1000 
≤1000 
Beclometasone dipropionate (HFA) 
>400 
≤400 
Budesonide (DPI) 
>800 
≤800 
Ciclesonide (HFA) 
>320 
≤320 
Fluticasone propionate (DPI or HFA) 
>500 
≤500 
Mometasone furoate  
>440 
≤440 
Triamcinolone acetonide 
>2000 
≤2000 
(Adapted from GINA 2014 Guidance). 
High dose of inhaled corticosteroids:  Adults (Japan) 
 
Inhaled corticosteroid 
Daily dose (mcg) 
 
High dose 
Lower doses 
Beclometasone dipropionate (HFA) 
401-800 
≤400 
Fluticasone propionate (HFA) 
401-800 
≤400 
Ciclesonide (HFA) 
401-800 
≤400 
Fluticasone propionate (DPI) 
401-800 
≤400 


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Inhaled corticosteroid 
Daily dose (mcg) 
 
High dose 
Lower doses 
Budesonide (DPI) 
801-1600 
≤800 
Budesonide inhalation suspension  
1<x<=2 
≤1.0 
(Adapted from Japanese Asthma Prevention and Management Guideline 2018).  
CFC - chlorofluorocarbon; HFA - hydrofluoroalkane; DPI - dry powder inhaler. 
10.19 APPENDIX 19: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.19.1 Amended protocol 01 (Amendment 01) (29-September-2020)  
This amended protocol 01 (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the changes implemented in the protocol amendment is to decrease the 
study burden on patients, to minimize COVID-19 pandemic-related risks in this vulnerable and 
elderly population of COPD patients, and to update the AESIs with the updated Sponsor safety 
information related to eye disorders. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Added the NCT number 
Addition of NCT number 
1.3.1 Schedule of 
activities for patients who 
complete the planned 
treatment 
And 
1.3.2 Reduced schedule 
of events for patients after 
early treatment 
discontinuation 
Replaced the following on-site visits with telephone visits:V7 (w16), 
V8 (w20), V10 (w28), V11 (W32), V13 (w40), V15 (w48), V17 (w56), 
V18 (w60). 
Footnotes added and updated to reflect this change. The 
assessments were adjusted accordingly. 
To decrease the burden 
of on-site visits for 
patients while maintaining 
patient safety and data 
quality; to minimize 
COVID-19 pandemic-
related risks in vulnerable 
and elderly population of 
COPD patients. 
BODE score added at EOT/ETD  
Omission corrected 
1.3.1 Schedule of 
activities for patients who 
complete the planned 
treatment 
Added EQ-5D-5L assessment at w24 and w52. 
To develop the economic 
model 
Clarifying in table and footnote ‘l’ that the urine pregnancy test can 
be performed monthly at home using ‘urine dipsticks’, in between 
on-site visits. 
Update 
Updated footnote ‘a’ to clarifiy in case of missed scheduled on-site 
visits. 
Update 
Updated footnote ‘m’ to explain in case of missed spirometry 
assessments during on-site visits. 
Update 


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Section # and Name 
Description of Change 
Brief Rationale 
1.3.1 Schedule of 
activities for patients who 
complete the planned 
treatment 
And 
6.1.1 Investigational 
Medicinal Product(s) 
Updated text/footnote ‘f’ to reflect that after at least 1 injection 
supervised by the Investigator or delegate and after the training has 
been completed and documented, the patient can be allowed to self-
inject the IMP. 
Dupilumab is currently 
marketed and self 
administration after 
proper training in 
subcutaneous injection 
technique aligns with 
approved label. 
Added below text: 
If the patient is unable or unwilling to administer IMP at home, 
injections can be performed at the site; or arrangements can be 
made for qualified site personnel and/or health care professionals 
(eg, visiting nurse service) to administer IMP for the doses that are 
not scheduled to be given at the study site. 
Provided further clarity for 
administration of IMP 
1.3.2 Reduced schedule 
of events for patients after 
early treatment 
discontinuation 
Added urine pregnancy test to be performed on w4, w8, w16, w20, 
w28, w32, w40, w44, and w48. Updated footnote ‘g’ to clarify  that 
the urine pregnancy test can be performed monthly at home using 
‘urine dipsticks’, in between on-site visits. 
 
Update 
Removed pharmacokinetic assessments in case of ETD (early 
treatment discontinuation) at End of Study. 
Correction 
Whole blood RNA (optional) sampling added at ETD 
Correction 
EQ-5D-5L questionnaire added at ETD and updated footnote ‘i’. 
To develop the economic 
model. 
2.3 Benefit/Risk 
Assessment,  
8 Study Assessments 
And Procedures 
9.4.3 Other analyses 
Statement regarding study conduct in Emergency situation like 
Covid-19 is added. 
To align with recent 
regulatory requests 
seeking to understand 
the Sponsor's risk 
mitigations during the 
COVID-19 pandemic. 
3 Objectives and 
Endpoints 
Updated a ‘tertiary/exploratory' endpoint wording from (“removed 
moderate to severe”): 
 
Annualized rate of moderate to severe COPD 
exacerbations assessed by the EXACT over 52 week. 
To: 
 
Annualized rate of COPD exacerbations assessed by the 
EXACT over 52 week. 
Correction on type of 
COPD exacerbations 
assessed by the EXACT. 
Updated the endpoints of “Other Secondary Objective” to reflect the 
deletion of pre-bronchodilator forced expiratory volume in first 
second (FEV1) at w16, w20, w28 and w48; and deletion of forced 
expiratory flow (FEF) at w16, w28. 
Update based on deleted 
assessments for FEV1 
and FEF because of 
replacement of on-site 
visits to telephone visits. 
5.1 Inclusion Criteria 
Updated I 02 to:  Participants with a physician diagnosis of COPD 
who meet the following criteria at screening. 
“at screening” was added. 
Clarity 
5.2 Exclusion Criteria 
E 33: removed “tuberculosis” from examples of invasive opportunistic 
infections. 
Clarity 
 
E38: deleted the phrase “randomization (Visit 1)”. Revised text: 
Clinically significant laboratory tests at screening:… 
Correction 


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Section # and Name 
Description of Change 
Brief Rationale 
5.4 Screen Failures 
Updated the bullet point for rescreening criteria from: 
 
Fail to meet exclusion criteria. 
To: 
 
Previously did not meet the criteria for participation in the 
study. 
To allow more flexibility 
for rescreening of 
patients. 
Moved the following sentence to another paragraph under same 
heading: 
If subject is rescreened, a different patient identification number will 
be issued. 
Clarity 
6.1.1 Investigational 
Medicinal Product(s) 
Added below text: 
If the patient cannot take all the allocated IMP kits at home (eg. due 
to a storage issue), the DTP (Direct to Patient) service can be used 
or the patient may come to the site to pick-up the IMP kits. For doses 
not given at the study site, diaries will be provided to record 
information related to the injections. The diary will be kept as source 
data in the patient’s study file. 
Provided further clarity for 
supply of IMP. 
6.2 Preparation/ Handling/ 
Storage/ Accountability 
- Responsibilities 
Added provision for local regulation application for DTP (Direct to 
Patient) shipment. 
Clarity 
6.5 Concomitant Therapy 
Added reference to Section 6.1.2 for expected background therapy 
and allowed reliever medications. 
Clarity 
 
The phrase " are allowed during the study " was removed from the 
sentence and updated as below (under permitted concomitant 
medications list): 
 
Maintenance treatment of COPD with ICS, LABA, LAMA, 
at a stable dosage. 
Clarity 
7.1.1 Permanent 
discontinuation 
In the list of criteria for permanent discontinuation of study 
intervention, replaced the phrase “in the study” by “on the study 
intervention” and updated the point as below: 
 
If, in the Investigator's opinion, continuation on the study 
intervention would be detrimental to the patient's well-
being. 
Updated the below sentence from: 
''Patients must be withdrawn from the study for the following reasons:  
To: 
''Patients must be withdrawn from the study intervention for the 
following reasons:  
Typographical correction 
 
Moved the following point from temporary study intervention 
discontinuation to permanent discontinuation of study intervention: 
 
If the patient misses more than 3 consecutive doses, the 
patient will be permanently discontinued from the study 
intervention. 
Clarity 
7.1.2 Temporary 
discontinuation of study 
intervention 
Created subheading 7.1.2 Temporary discontinuation of study 
intervention under 7.1 Discontinuation of Study Intervention. 
Clarity 
Added text to clarifiy in case of missed scheduled on-site visits. 
Update 
8.2.3 Electrocardiograms 
Updated the wording to clarify that the triplicate ECGs are required. 
Clarity 


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Section # and Name 
Description of Change 
Brief Rationale 
8.3.1 Adverse event of 
special interest 
Added following AESIs: 
 
Any severe type of conjunctivitis or blepharitis. 
 
Keratitis. 
To align the AESIs with 
safety evaluation 
regarding eye related 
disorders with updated 
product information in IB 
edition 14. 
 
Replaced the word “verbatim” by “overdose form” and updated the 
IMP overdose text as below: 
 
An overdose (accidental or intentional) with the IMP is an 
event suspected by the Investigator or spontaneously 
notified by the patient and defined as at least twice the 
intended dose during an interval of less than 11 days. The 
circumstances (ie, accidental or intentional) should be 
clearly specified in the overdose form and symptoms, if 
any, entered on separate adverse event forms. 
Clarity 
 
Updated the NIMP overdose text to as below: 
 
An overdose (accidental or intentional) with any NIMP is an 
event suspected by the Investigator or spontaneously 
notified by the patient and defined as at least twice the 
maximum daily dose as specified in a drug label, within the 
intended therapeutic interval. The circumstances (ie, 
accidental or intentional) should be clearly specified in the 
overdose form and symptoms, if any, entered on separate 
adverse event forms. 
Clarity 
 
Replaced below text: 
Of note, asymptomatic overdose has to be reported as a standard 
AE. 
by: 
Asymptomatic overdose should also be reported on the overdose 
form. 
Clarity 
10.3 Appendix 3: Adverse 
Events: Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-Up, and Reporting 
Updated the text in definition of SAE from: 
If an event is not an AE per definition above, then it cannot be an 
SAE even if serious conditions are met (eg, hospitalization for 
signs/symptoms of the disease under study, death due to 
progression of disease). 
To: 
If an event is not an AE per definition above, then it cannot be an 
SAE. 
Clarity 
10.4 Appendix 4: 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Added pregnancy data collection information for male participants 
with partners who become pregnant. 
To align with Sponsor 
standard operating 
procedure (SOP). 
Clarifying that the urine pregnancy test will be performed monthly 
instead of only on site visits. 
Update 
Throughout 
Correction of small errors (eg, comma errors, duplication of words); 
slight rewordings for clarity, removal of repeated footnote markers in 
SoA table, and updation of abbreviations. 
Correction 


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10.19.2 Amended protocol 02 (Amendment 02) (16-December-2021)  
This amended protocol 02 (amendment 2) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the changes implemented in the protocol amendment is to provide 
flexibility for participant enrollment criteria while maintaining the favorable benefit risk profile 
and scientific objectives of the study. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
Criteria 
Text in Inclusion Criterion I01: “participant must be ≥40 to ≤80 
years of age” was replaced with “participant must be ≥40 to ≤85 
years of age”. 
Upper age limit is increased 
to allow participation of older 
COPD patients who could 
potentially benefit from 
dupilumab while maintaining 
favorable benefit-risk profile. 
Section 5.2 Exclusion 
Criteria 
Exclusion Criterion E02 wordings updated from: 
“A patient with current diagnosis of asthma or history of asthma 
according to the 2018 Global Initiative for Asthma (GINA) 
guidelines, or other accepted guidelines”  
To  
“A patient with current diagnosis of asthma or history of asthma 
according to the Global Initiative for Asthma (GINA) guidelines, 
or other accepted guidelines”. 
For clarification. 
 
Exclusion Criterion E05 revised from: 
“treatment with oxygen of more than 12 hours per day”  
To  
“Long-term treatment with oxygen >4.0 L/min OR if a participant 
requires more than 2.0 L/min in order to maintain oxygen 
saturation >88%”. 
To allow COPD patients on 
long-term oxygen therapy to 
participate in the study who 
could potentially benefit from 
dupilumab while maintaining 
favorable benefit-risk profile. 
 
Exclusion Criterion E17: updated wording by adding “eg,” within 
the sentence to clarify the exclusion criteria  
For clarification.  
 
Exclusion Criterion E18: Moved the following sentence to a new 
paragraph under the same exclusion criterion. 
“Prior history of malignancy or active malignancy, including 
lymphoproliferative diseases (except successfully treated 
carcinoma in-situ of the cervix, non-metastatic squamous cell or 
basal cell carcinoma of the skin) within 5 years prior to baseline”. 
For clarification. 
Section 6.1 Study 
Intervention(s) 
Administered 
The term “consecutive visits” was replaced with “consecutive 
injections” in Table 2. 
For clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.4 Treatment of 
Overdose 
A word “symptomatic” was added at the beginning of the 
following sentence: ‘Symptomatic overdose is an AESI (defined 
in Section 8.3.1). No antidote is available for dupilumab.’ 
For clarification. 
Section 10.18 
Appendix 18 
Added a note for the tables, “the reported ICS doses in the 
Tables below refer to METERED doses”. 
For clarification. 
Throughout 
Minor editorial and document formatting revisions are made. 
Correction. 
 


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11 
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1. Global strategy for the diagnosis, management, and prevention of chronic obstructive 
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5. Ghebre MA, Pang PH, Diver S, Desai D, Bafadhel M, Haldar K, et al. Biological exacerbation 
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6. Bafadhel M, Saha S, Siva R, McCormick M, Monteiro W, Rugman P, et al. Sputum IL-5 
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7. Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-Singer R. Eosinophilic 
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8. Yun JH, Lamb A, Chase R, Singh D, Parker MM, Saferali A, et al. Blood eosinophil count 
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13. Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. 
Tiotropium in Combination with Placebo, Salmeterol, or Fluticasone-Salmeterol for Treatment 
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25. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-
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Page 1 
STATISTICAL ANALYSIS PLAN      
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 52-week Pivotal 
Study to Assess the Efficacy, Safety, and Tolerability of Dupilumab in Patients 
With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD) with 
Type 2 inflammation 
SAR231893 (REGN668)-EFC15805 
STATISTICIAN:
DATE OF ISSUE: 30-Oct-2023 
Total number of pages: 
96 
NCT04456673


Statistical Analysis Plan  
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TABLE OF CONTENTS  
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 6 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 9 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 9 
1.2 
OBJECTIVES ................................................................................................................................... 9 
1.2.1 
Primary objectives ............................................................................................................................ 9 
1.2.2 
Secondary objectives ....................................................................................................................... 9 
1.2.3 
Exploratory objectives .................................................................................................................... 10 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 10 
1.4 
STUDY PLAN ................................................................................................................................. 10 
1.4.1 
Graphic study design ..................................................................................................................... 11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 11 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 12 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 12 
2.1.1 
Demographic and baseline characteristics .................................................................................... 12 
2.1.2 
Prior or concomitant medications ................................................................................................... 15 
2.1.2.1 
COPD controller medication .......................................................................................................... 15 
2.1.2.2 
Reliever medication........................................................................................................................ 16 
2.1.3 
Efficacy endpoints .......................................................................................................................... 16 
2.1.3.1 
Primary efficacy endpoint ............................................................................................................... 16 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 16 
2.1.4 
Safety endpoints ............................................................................................................................ 19 
2.1.4.1 
Adverse events variables ............................................................................................................... 20 
2.1.4.2 
Deaths ............................................................................................................................................ 23 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 23 
2.1.4.4 
Vital signs variables ....................................................................................................................... 24 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 24 
2.1.4.6 
Physical Examination ..................................................................................................................... 24 


Statistical Analysis Plan  
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2.1.5 
Pharmacokinetic variables ............................................................................................................. 24 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................ 25 
2.1.7 
Health Related Quality-of-life endpoints ........................................................................................ 26 
2.1.7.1 
The 5-level Euro Quality of Life-5 Dimension questionnaire (EQ-5D-5L) ...................................... 26 
2.1.8 
Health economic endpoints ............................................................................................................ 26 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 27 
2.2.1 
Protocol deviations ......................................................................................................................... 28 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 28 
2.3.1 
Efficacy populations ....................................................................................................................... 28 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 28 
2.3.2 
Safety population ........................................................................................................................... 29 
2.3.3 
Pharmacokinetics (PK) population ................................................................................................. 29 
2.3.4 
Anti-drug antibody population ........................................................................................................ 29 
2.4 
STATISTICAL METHODS ............................................................................................................. 29 
2.4.1 
Demographics and baseline characteristics .................................................................................. 29 
2.4.2 
Prior or concomitant medications ................................................................................................... 30 
2.4.2.1 
ICS in combination with other controllers ...................................................................................... 30 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 32 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 32 
2.4.3.2 
Compliance .................................................................................................................................... 33 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 33 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 33 
2.4.4.2 
Analyses of key secondary efficacy endpoints .............................................................................. 37 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 40 
2.4.4.4 
Additional efficacy analyses ........................................................................................................... 41 
2.4.4.5 
Analyses of exploratory efficacy endpoints .................................................................................... 42 
2.4.4.6 
Missing data handling .................................................................................................................... 44 
2.4.5 
Analyses of safety data .................................................................................................................. 44 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 45 
2.4.5.2 
Deaths ............................................................................................................................................ 48 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 49 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 49 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 50 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 50 
2.4.6.1 
Pharmacokinetic analyses ............................................................................................................. 50 
2.4.6.2 
Pharmacodynamics/genomics analyses ........................................................................................ 52 
2.4.7 
Analyses of health economics variables ........................................................................................ 52 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 52 
2.5.1 
General conventions ...................................................................................................................... 52 


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2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 53 
2.5.3 
Missing data ................................................................................................................................... 54 
2.5.4 
Windows for time points ................................................................................................................. 55 
2.5.5 
Unscheduled visits ......................................................................................................................... 59 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 59 
2.5.7 
Statistical technical issues ............................................................................................................. 59 
3 
INTERIM ANALYSIS ..................................................................................................................... 60 
4 
DATABASE LOCK ........................................................................................................................ 61 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 62 
6 
REFERENCES ............................................................................................................................... 63 
7 
LIST OF APPENDICES ................................................................................................................. 64 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 65 
APPENDIX B 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE ......................................................... 69 
APPENDIX C 
SGRQ SCORING ALGORITHM .......................................................................................... 75 
APPENDIX D 
EXACT QUESTIONNAIRE .................................................................................................. 80 
APPENDIX E 
EQ-5D .................................................................................................................................. 83 
APPENDIX F 
BODE ................................................................................................................................... 86 
APPENDIX G 
HIGH DOSE OF INHALED CORTICOSTEROIDS: ADULTS ............................................. 87 
APPENDIX H 
DEFINITION OF ANAPHYLAXIS ........................................................................................ 88 
APPENDIX I 
LIST OF OPPORTUNISTIC INFECTIONS ........................................................................... 89 
APPENDIX J 
SELECTION CRITERIA FOR AE GROUPINGS.................................................................. 90 
APPENDIX K 
HANDLING OF MISSING DATA ......................................................................................... 91 
APPENDIX L 
SUMMARY OF PRIMARY ESTIMANDS FOR MAIN ENDPOINTS .................................... 95 
 


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LIST OF TABLES  
Table 1 - Major statistical changes in protocol amendment(s) ...................................................................... 11 
Table 2 - Criteria for adverse events of special interest and other selected AE groupings .......................... 21 
Table 3 - Equivalent dose for inhaled corticosteroids for adults ................................................................... 31 
Table 4 - Equivalent dose of inhaled corticosteroid for adults (Japan) ......................................................... 31 
Table 5 - Periodical average of daily efficacy assessment ........................................................................... 53 
Table 6 - Time window for safety endpoints .................................................................................................. 55 
Table 7 - Time window for efficacy variables ................................................................................................ 57 
Table 8 - Time window for pharmacokinetics/pharmacodynamics variables ................................................ 58 
Table 9 - Kim-DeMets alpha spending function to control the overall alpha at 0.05 ..................................... 60 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
AD 
Atopic Dermatitis 
ADA 
Anti-drug Antibodies  
AE 
Adverse Event 
AECOPD 
Acute exacerbation of chronic obstructive pulmonary disease 
AESI 
Adverse Event of Special Interest  
ALT 
Alanine Aminotransferase 
AM 
Ante Meridiem 
ANA 
Antinuclear Antibodies 
ANCOVA 
Analysis of Covariance 
ATS 
American Thoracic Society 
BODE 
Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity 
CI 
Confidence Interval 
CID 
Clinically important deterioration  
COPD 
Chronic Obstructive Pulmonary Disease 
CPK 
Creatine Phosphokinase 
CRFs 
Case Report Forms 
CV 
Coefficient of Variation 
DMC 
Data Monitoring Committee  
DNA 
Deoxyribonucleic Acid 
DPI 
Dry Powder Inhaler 
ECG 
Electrocardiography  
e-CRF 
Electronic Case Report Form 
e-diary 
Electronic Diary 
EQ-5D 
European Quality of Life-5D Scale 
EOS 
End-of-Study 
EOT 
End-of-Treatment 
ERS 
European Respiratory Society  
E-RS: COPD 
Evaluating Respiratory Symptoms (E-RS) in COPD 
EXACT 
Exacerbations of Chronic Pulmonary Disease Tool 
FEF 25-75 
Forced Expiratory Flow at 25% to 75% of forced vital capacity 
FeNO 
Fractional Exhaled Nitric Oxide  
FEV1 
Forced Expiratory Volume in one second 
FVC 
Forced Vital Capacity  
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBc Ab 
Hepatitis B Core Antibody 
HBs Ab 
Hepatitis B Surface Antibody 
HBs Ag 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCV Ab 
Hepatitis C Virus Antibody 
HEVA 
Health Economics and Value Assessment  
HFA 
Hydrofluoroalkane 
HLGT 
High-Level Group Term  


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HLT 
High Level Term 
HIV 
Human Immunodeficiency Virus  
HRQoL 
Health Related Quality of Life  
ICH 
International Council for Harmonisation 
ICS 
Inhaled Corticosteroid 
ICU 
Intensive Care Unit  
IDMC 
Independent Data Monitoring Committee 
IEC 
Institutional Ethics Committee 
IgE 
Immunoglobulin E 
IMP 
Investigational Medicinal Product 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IRT 
Interactive Response Technologies 
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System  
K-M 
Kaplan-Meier 
LFT 
Liver Function Test 
LABA 
Long-Acting Beta-Agonist 
LAMA 
Long-Acting Muscarinic Antagonist 
LLOQ 
Lower Limit of Quantitation 
LS 
Least Squares 
MCID 
Minimal Clinically Important Difference 
MDI 
Metered Dose inhaler  
MI 
Multiple Imputation 
MID 
Minimal Important Difference 
MMRM 
Mixed-effect Model with Repeated Measures  
NIMP 
Noninvestigational Medicinal Product 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
PARC 
Pulmonary and Activation-regulated Chemokine  
PCSA 
Potentially Clinically Significant Abnormalities   
PD 
Pharmacodynamics 
PK 
Pharmacokinetics  
pre-BD 
pre-bronchodilator 
PROs 
Patient-Reported Outcomes  
PT 
Preferred Term 
q2w 
Every 2 weeks 
QoL 
Quality of Life 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event  
SABA 
Short-Acting Beta-Agonist 
SC 
Subcutaneously 
SD 
Standard Deviation 
SEM 
Standard Error of the Mean  
SGRQ 
SMQ 
St. George’s Respiratory Questionnaire 
Standardised MedDRA Queries 


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SOC 
System Organ Class  
TE 
Treatment-Emergent 
TEAE 
Treatment-Emergent Adverse Event 
Th2 
Type 2 T-helper cell 
ULN 
Upper Limit of Normal  
US 
United States 
V 
Visit 
VAS 
Visual Analogue Scale  
WBC 
White Blood Cell 
 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
Multinational, randomized, double-blind, placebo-controlled, parallel groups (2 groups), 52-week 
Phase 3 study to assess the efficacy, safety, and tolerability of dupilumab in patients with 
moderate-to-severe type 2 inflammatory COPD such as that driven by activation of IL-4, IL-5, 
and IL-13 on an established LABA, LAMA and/or ICS background therapy (triple therapy unless 
ICS contraindicated). Study treatments are dupilumab 300 mg q2w or placebo q2w administered 
during the 52-week treatment period. 
After a run-in period of 4 weeks ±1 week, patients will be centrally randomized using a permuted 
block randomization schedule via Interactive Voice Response System/Interactive Web Response 
System (IVRS/IWRS) in a 1:1 randomization ratio for dupilumab 300 mg q2w and a matching 
placebo q2w for SC administration. Randomization will be stratified by country, by ICS dose 
(high dose ICS [yes/no]) at baseline, and smoking status at screening (current smokers or not). 
Enrollment will be capped at 30% current smokers (as defined by smoking status at screening 
visit). 
A total of approximately 924 patients with COPD will be randomized to two treatment arms 
(462 patients/arm).  
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to evaluate the efficacy of dupilumab 300 mg every 2 weeks 
compared to placebo in reducing annualized rate of acute moderate or severe COPD exacerbation 
(AECOPD) over the 52-week treatment period in patients with moderate or severe COPD. 
1.2.2 Secondary objectives  
To evaluate the effect of dupilumab 300 mg q2w on 
 Pre-bronchodilator forced expiratory volume in 1 second (FEV1) over 12 weeks compared 
to placebo 
 Health related quality of life, assessed by the change from baseline to Week 52 in the 
St. George’s Respiratory Questionnaire (SGRQ)  
 Pre-bronchodilator FEV1 over 52 weeks compared to placebo 
 To evaluate the effects of dupilumab 300 mg q2w on lung function assessments 
 To evaluate the effect of dupilumab on moderate and severe COPD exacerbations 
 To evaluate safety and tolerability 
 To evaluate dupilumab systemic exposure and incidence of antidrug antibodies (ADA) 


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1.2.3  Exploratory objectives   
 To evaluate the drug concentration of dupilumab in serum over time  
 To explore the association of biomarkers with treatment response  
 To evaluate the effects of dupilumab compared with placebo on FEV1 and FVC   
 To evaluate the effects of dupilumab compared to placebo on annualized rate of COPD 
exacerbation utilizing the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) 
 To evaluate the effects of dupilumab compared to placebo on treatment failure requiring 
background medication change  
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size of the study is determined based on power calculations for the primary endpoint 
of annualized rate of acute moderate or severe COPD exacerbations over the 52-week treatment 
period. Assuming the number of exacerbations follows a negative binomial distribution with a 
dispersion parameter of 1, a placebo annualized rate of exacerbations of 1.5, an average treatment 
duration of 0.95 year (to account for an average of 5% of the planned treatment period with 
missing data), and a randomization ratio of 1:1 to the two treatment arms, with 924 randomized 
patients (462 for each treatment arm), the study will have 90% power to detect a 25% relative risk 
reduction (ie, annualized rate of 1.125 for the dupilumab group) in the annualized rate of moderate 
or severe COPD exacerbations at the 2-tailed significance level of α=0.05. With the addition of an 
interim analysis, the final alpha may be reduced to 0.049, which maintains approximately 
90% power (see Section 3 for further details). 
Patients will be randomized using a 1:1 randomization ratio to dupilumab 300 mg q2w or placebo. 
Randomization will be stratified by country, ICS dose (high dose ICS [yes/no]) at baseline, and 
smoking status at screening (current smokers or not).  
1.4 
STUDY PLAN  
The clinical trial consists of three periods: 
Screening period (4 weeks ±1 week): to determine a patient’s eligibility and establish level of 
COPD control before randomization. 
Randomized investigational medicinal product (IMP) treatment period (52 weeks +/- 3 days): 
to randomize the patient into a treatment arm and treat with dupilumab or placebo dose regimen. 
Post IMP treatment period (12 weeks +/- 5 days): to continue to collect data for PK, 
immunogenicity, safety, and efficacy after the patient has completed the study drug treatment 
period. 


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1.4.1 Graphic study design  
Please refer to Section 1.2 of the study protocol for the detailed study flow chart. 
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled) and protocol amendment 3 (dated 
28 October 2023). These changes are not based on any unblinded study data. 
The modifications to the protocol statistical section are listed below. 
Table 1 - Major statistical changes in protocol amendment(s)  
Amendment 
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
3 
28-Oct-2023 
To add an interim analysis to determine if 
efficacy in the primary endpoint is met 
before all patients complete the 52-week 
treatment period 
An interim analysis was added when the 
information fraction is ≥0.92 based on follow-
up time for moderate or severe COPD 
exacerbations over 52-week treatment 
period. The Kim-Demets approach will be 
used to control the type I alpha.  
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
Not applicable. 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value of efficacy parameters is defined as the last available value up to 
randomization but prior to the first dose of study medication unless otherwise specified. The 
baseline value of the other parameters is defined as the last available value prior to the first dose 
of investigational medicinal product (IMP) if the patient is treated, or the last available value up to 
randomization if the patient is not exposed to IMP.  
The calculation of the baseline for daily ediary questionnaire scores will be specified in  
Section 2.1.3.2.2.1. 
All baseline safety and efficacy parameters (apart from those listed below) will be presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are: 
 Gender (Male, Female),  
 Race (Caucasian/White, Black/of African descent, Asian/Oriental, American Indian or 
Alaska Native, Native Hawaiian or other Pacific Island, Unknown) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
 Age in years (quantitative and qualitative variable: 40-64, 65–74, 75-80, 81-85 years) 
 Region (Latin America: Argentina, Colombia, Peru, Chile, Brazil and Mexico; East 
Europe: Russia, Ukraine, Poland, Bulgaria, Lithuania, Latvia, Czech Republic, Slovakia, 
Hungary, Romania, Serbia; Western Countries: Australia, Belgium, France, Portugal, 
Spain, Germany, Netherlands, United Kingdom, South Africa, Canada, USA, Greece)  
 Territory (North America: Canada and USA; European Union: Belgium, Poland, Bulgaria, 
Spain, France, Portugal, Germany, Netherlands, Lithuania, Latvia, Greece, United 
Kingdom, Czech Republic, Slovakia, Hungary, Romania; Rest of World: Australia, South 
Africa, Argentina, Chile, Colombia, Peru, Brazil, Mexico, Russia, Ukraine, Serbia) 
 Weight in kg (quantitative and qualitative variable: <50, 50-<100, ≥100 kg) 
 BMI in kg/m2 (quantitative and qualitative variable: <25, 25-<30, 30-<35, ≥35 kg/m2) 
Medical or surgical history 
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the patient. 


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This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
COPD-related comorbid history and type 2 disease history will be summarized separately. The 
following will be summarized from eCRF pages which were filled in by investigators based on 
patient reporting.  
 Emphysema history (Yes, Ongoing condition) 
 Chronic bronchitis history (Yes, Ongoing condition) 
 Bronchiectasis history (Yes, Ongoing condition) 
 Nasal polyps history (Yes, Ongoing condition) 
 Chronic sinusitis history (Yes, Ongoing condition) 
 Atopic dermatitis history (Yes, Ongoing condition) 
 Allergic conjunctivitis history (Yes, Ongoing condition) 
 Allergic rhinitis history (Yes, Ongoing condition) 
 Food allergy history (Yes, Ongoing condition) 
 Hives history (Yes, Ongoing condition) 
 Eosinophilic esophagitis history (Yes, Ongoing condition) 
 Hypersensitivity to aspirin history (Yes, Ongoing condition) 
 Hypersensitivity to NSAID history (Yes, Ongoing condition) 
Disease characteristics at baseline   
The following baseline disease characteristics will be summarized by treatment group: 
 High-dose ICS from medical history (Yes, No) 
 High-dose ICS from IVRS (Yes, No) 
 Spirometry data including pre- and post-bronchodilator FEV1 (L), pre- and post-
bronchodilator FEV1 percent predicted, pre- and post-bronchodilator FVC (L), pre- and 
post-bronchodilator FVC percent predicted, pre- and post-bronchodilator FEV1/FVC 
Ratio, pre- and post-bronchodilator forced expiratory flow (FEF) 25-75% (L/s), pre- and 
post-bronchodilator FEF 25-75% percent predicted, FEV1 reversibility (%), and FEV1 
reversibility >12% and change >0.2 L 
- 
FEV1 reversibility (%) is calculated as (Post-bronchodilator FEV1(L) – 
Pre-bronchodilator FEV1(L)) / Pre-bronchodilator FEV1(L) * 100 
 SGRQ total score 
 EQ-5D-5L single index score and EQ visual analog scale score 
 Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index (BODE 
Index) score 
 E-RS: COPD total scores and domain scores 


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 Time since first diagnosis of COPD (years) to be derived as 
- 
(Year of randomization – Year of first diagnosis of COPD) + (month of randomization 
– month of first diagnosis of COPD)/12 
 Age of onset of COPD (years) 
 Smoking history (former, current), smoking duration (years) and smoking quantities in 
pack-years 
 Cessation prior to screening (months) for former smokers to be derived as 
 (Year of randomization – Year of cessation) ×12 + (month of randomization – month of 
cessation) 
 Time since last COPD exacerbation (months) to be derived as  
- 
(Year of randomization – Year of last COPD exacerbation) ×12 + (month of 
randomization– month of last COPD exacerbation) 
 Number of moderate or severe COPD exacerbation experienced within 1 year before 
Visit 1 
 Number of moderate COPD exacerbations experienced within one year before Visit 1 
Among them, number of those required 
- 
systemic steroids and treatment days for systemic steroids 
- 
antibiotics and treatment days for antibiotics 
 Number of severe COPD exacerbations experienced within one year before Visit 1 
Among them, number of those required 
- 
systemic steroids and treatment days for systemic steroids 
- 
antibiotics and treatment days for antibiotics 
- 
emergency medical care visit only 
- 
hospitalization without ICU 
- 
hospitalization in ICU  
 Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity at screening and 
baseline. 
Biomarkers at baseline 
The following baseline biomarkers will be summarized by treatment group: 
 Maximum blood eosinophil at screening (giga/L) (quantitative and qualitative variable: 
<0.5, ≥0.5) 
 Baseline blood eosinophil (giga/L) (quantitative and qualitative variable: <0.3, ≥0.3) 
 Baseline fractional exhaled nitric oxide (FeNO) (ppb) (quantitative and qualitative 
variable: <20, ≥20) 
 Baseline plasma eotaxin-3 (pg/mL) 
 Baseline serum pulmonary and activation-regulated chemokine (PARC) (pg/mL) 
 Baseline serum total Immunoglobulin E (IgE) (IU/mL) 


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 Baseline fibrinogen (mg/dL). 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken within 30 days prior to screening and until end of the study, including 
COPD controller medications, systemic corticosteroids, and all other medications are to be 
reported in the case report form (CRF) pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version currently in effect at Sanofi at the time of database lock. 
Prior medications are those the patient used prior to first IMP injection.  Prior medications can be 
discontinued before first administration or can be ongoing during treatment phase.   
Concomitant medications are any treatments received by the patient concomitantly to the IMP, 
anytime from the first administration of IMP to the last administration of IMP + 98 days. A given 
medication can be classified as a prior medication, concomitant medication and posttreatment 
medication at the same time. 
Posttreatment medications are those the patient took in the period from the last administration of 
IMP + 99 days to the end of the study. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.2.1 COPD controller medication  
At Screening Visit 1, all patients must be on triple background therapy, for 3 months prior to 
Visit 2/Randomization and at a stable dose of medication for at least 1 month prior to the 
Screening/Visit 1, including triple therapy: LABA + LAMA +ICS (Double therapy: LABA + 
LAMA allowed if ICS is contraindicated).  
Throughout the study, patients should continue their established background therapy for COPD, 
including dose and regimen. 
Patients must be willing to stay on their established background medication for COPD throughout 
the duration of the treatment period. After successful management of an acute exacerbation of 
COPD (eg, with oral corticosteroids and/or antibiotics), all efforts should be made to resume the 
initial background COPD treatment regimen if in the investigator’s opinion this is medically 
acceptable. Background medications should not be adjusted during Screening. After 1 severe or 
2 moderate exacerbations of COPD, dose adjustments in background therapy will be permitted for 
symptom control and as needed for the remainder of the trial period. 
Adjustment of background medication is allowed at the discretion of the investigator as clinically 
indicated during the post-treatment period. 


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2.1.2.2 Reliever medication  
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol or ipratropium or 
ipratropium/short-acting β agonists [SABA] combinations or terbutaline as needed during the 
study. Nebulizer solutions may be used as an alternative delivery method. 
2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint  
The primary endpoint for this study is the annualized rate of moderate or severe COPD 
exacerbation (as defined below) over the 52-week treatment period compared to placebo. 
Moderate exacerbations are recorded by the Investigator and defined as AECOPD that require 
either systemic corticosteroids (such as intramuscular, intravenous or oral) and/or antibiotics.  
Severe exacerbations are recorded by the Investigator and defined as AECOPD requiring 
hospitalization, or treatment for >24 hours in emergency department/urgent care facility or result 
in death. 
For both moderate and severe events to be counted as separate events, they must be separated by 
at least 14 days. 
The number of moderate or severe exacerbation events during the 52-week treatment period is 
defined as the number of moderate or severe exacerbation events with onset during the 52-week 
treatment period per patient-year. Patients who permanently discontinue the study medication will 
be asked and encouraged to return to the clinic for all remaining study visits and their additional 
off-treatment moderate or severe exacerbation events up to Visit 16 (Week 52) will be included. 
AECOPD recorded in eCRF will go through a confirmatory adjudication by experts independent 
of sponsor for the evaluation. Details of the adjudication process are described in the AC 
Charter/Manual of Operation. Only the adjudicated confirmed AECOPD will be used for analysis. 
2.1.3.2 Secondary efficacy endpoint(s)  
The key secondary endpoints of this study include: 
 Change in pre-bronchodilator FEV1 from baseline to Week 12  
 Change in pre-bronchodilator FEV1 from baseline to Week 52 
 Change in pre-bronchodilator FEV1 from baseline to Week 12 in the subgroup of patients 
with baseline FeNO ≥20 ppb 
 Change in pre-bronchodilator FEV1 from baseline to Week 52 in the subgroup of patients 
with baseline FeNO ≥20 ppb  
 Change from baseline to Week 52 in SGRQ total score  
 Proportion of patients with SGRQ improvement ≥4 points at Week 52  
 Annualized rate of moderate or severe COPD exacerbation compared to placebo over the 
52-week treatment period in the subgroup of patients with baseline FeNO ≥20 ppb 


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Other secondary efficacy endpoints include: 
 Change in pre-bronchodilator FEV1 from baseline through weeks other than 12 and 52 
(ie, Weeks 2, 4, 8, 24, 36, and 44 compared to placebo)  
 Change in post-bronchodilator FEV1 from baseline to Weeks 2, 4, 8, 12, 24, 36 and 52  
 Change in forced expiratory flow (FEF) 25-75% from baseline to Weeks 2, 4, 8, 12, 24, 
36, 44, and 52 
 Annualized rate of severe COPD exacerbations compared to placebo over the 52-week 
treatment period  
 Time to first moderate or severe COPD exacerbation compared with placebo during the 
52-week treatment period. 
2.1.3.2.1 Key secondary endpoint  
2.1.3.2.1.1 Spirometry  
Spirometry at clinical site visits should be performed in accordance with the European 
Respiratory Society (ERS)/American Thoracic Society (ATS) guidelines (1) and prior to 
administration of investigational product.  
For pre-bronchodilator measured parameters, including FEV1, FVC and forced expiratory flow 
(FEF) 25%-75%, 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 
12 hours (ultra-long acting LABA like vilanterol should be withheld for at least 24 hours), 
withholding the last dose of ipratropium for at least 8 hours and withholding the last dose of 
LAMA for at least 24 hours. This will be verified before performing the measurements.  
Note: When both pre- and post-bronchodilator spirometry is assessed, the post-bronchodilator 
spirometry should be performed consistent with the mechanism of action of reliever 
(ie, 30 minutes for albuterol or another SABA). 
At all visits, spirometry will be performed preferably in the morning; afternoon/evening is 
allowable in the exceptional circumstance when morning spirometry cannot be performed; 
spirometry should be done at approximately the same time at each visit throughout the study. 
Current smokers need to be reminded not to smoke for at least 1 hour before spirometry. 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 visit, if possible. 
2.1.3.2.1.2 St. George's Respiratory Questionnaire (SGRQ)  
The St. George's Respiratory Questionnaire (SGRQ) (2, 3) is a 50-item questionnaire designed to 
measure and quantify health status in adult patients with chronic airflow limitation (see Appendix B). 


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Scores by dimension are calculated for three domains: Symptoms, Activity and Impacts (Psycho-
social) as well as a total score. Global and domain scores range from 0 to 100, with 100 representing 
the worst possible health status and 0 indicating the best possible health status. See St. George's 
Respiratory Questionnaire manual Version 2.3 page 8-13 (Appendix C) for the scoring algorithm. 
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 recall period of the 
questionnaire is over the past 4 weeks.  
Psychometric testing has demonstrated its repeatability, reliability and validity. Sensitivity has 
been demonstrated in clinical trials. A minimum change in score of 4 units was established as 
clinically relevant after patient and clinician testing (4, 5). The SGRQ has been used in a range of 
disease groups including asthma, COPD and bronchiectasis. 
SGRQ is assessed at Visit 2 (Week 0), Visit 4 (Week 4), Visit 6 (Week 12), Visit 9 (Week 24), 
Visit 12 (Week 36), Visit 16 (Week 52), and Visit 19 (Week 64). 
2.1.3.2.2 Exploratory/Tertiary efficacy endpoints  
2.1.3.2.2.1 Exacerbations of chronic pulmonary disease tool (EXACT)  
The EXACT tool quantifies and measures exacerbations of COPD and assesses the symptomatic 
manifestations of these COPD exacerbations (see Appendix D). The instrument is a daily diary 
composed of a total of 14 items representing the following domains: 
 Breathlessness (5 items), 
 Cough and sputum (2 items), 
 Chest symptoms (3 items), 
 Difficulty bringing up sputum (1 item), 
 Tired or weak (1 item), 
 Sleep disturbance (1 item), and 
 Scared or worried (1 item). 
The EXACT total score assesses COPD exacerbations. The higher the score, the more severe are 
the symptoms.  
The EXACT questionnaire is assessed daily from screening to Visit 16 (Week 52). Baseline 
EXACT score as well as the post-baseline weekly scores will be calculated as the mean within-
patient score over the prior 7 days, with data present for a minimum of 4 of the 7 days.  If fewer 
than 4 days of data are available in the 7-day window, the EXACT score cannot be calculated and 
will be considered as missing. For the exacerbation analysis, the baseline would be reset during 


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the study. Additional information related to computing scores and frequency, severity, and 
duration of events can be found in the user manual (6). 
The Evaluating Respiratory Symptoms (E-RS) in COPD (E-RS: COPD) scale is a part of the 
EXACT tool. It is a derivative instrument used to measure the effect of treatment on the severity 
of respiratory symptoms in stable COPD. The E-RS utilizes the 11 respiratory symptom items 
contained in the 14-item EXACT.  
The daily COPD RS-Total score is computed by taking the sum of the 11 items comprising the 
instrument. It has a range of 0 to 40, with higher values indicating more severe respiratory 
symptoms. 
The same summation procedure is used to derive the three daily domain scores: 
 COPD RS-Breathlessness (sum of items 7, 8, 9, 10, and 11; score range 0–17) 
 COPD RS-Cough and Sputum (sum of items 2, 3, 4; score range 0–11) 
 COPD RS-Chest Symptoms (sum of items 1, 5, 6; score range 0–12) 
Like for EXACT, the baseline RS score as well as the post-baseline weekly domain and total 
scores are calculated as the mean within-patient score over the prior 7 days, with data present for a 
minimum of 4 of the 7 days. If fewer than 4 days of data are available in the 7-day window, the 
RS scores cannot be calculated and will be considered as missing. 
2.1.3.2.2.2 Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index 
(BODE Index)   
The BODE Index is a composite measure composed of a Performance Outcome Measure, a 
Patient-Reported Outcome Measure and a Biomarker. The BODE Index is a multidimensional 
grading system to assess the respiratory and systemic expressions of COPD (7). It comprises 
4 domains: 1) Degree of pulmonary impairment (FEV1 percent predicted); 2) Patient’s perception 
of symptoms (mMRC); and 2 independent domains: the 6 Minute Walking Distance (6MWD) and 
the Body-Mass Index (BMI). Each domain can be scored independently; the global score ranges 
from 0 to 10, with a higher score indicating a higher risk of death (see Appendix F for scoring 
algorithm details) 
The BODE index will be assessed at Visit 2 (Week 0) and Visit 16 (Week 52). 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events and other safety information, 
such as clinical laboratory data, vital signs, ECG and physical examination. 
Observation period  
The observation period will be divided into 4 epochs: 
 The screening epoch is defined as the time from the signed informed consent date up to 
the time prior to first administration of the IMP. 


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 The treatment epoch is defined as the time from the first administration of the IMP to the 
last administration of the IMP + 14 days.  
 The residual treatment epoch is defined as the time from the last administration of the 
IMP +15 days to the last administration of the IMP + 98 days. 
The treatment-emergent adverse event period will include both treatment and residual 
treatment epochs. 
 The posttreatment epoch is defined as the period of time starting the day after the end of 
the treatment-emergent adverse event period up to the end of the study (defined as last 
protocol planned visit or the resolution/stabilization of all serious adverse events and 
adverse events with pre-specified monitoring). 
 The on-study observation period is defined as the time from start of treatment until the end 
of the study (defined as last protocol planned visit or lost to follow-up or the 
resolution/stabilization of all serious adverse events and adverse events with pre-specified 
monitoring).  
Safety events adjudication 
Adjudication will be performed by experts independent of sponsor for the evaluation of whether 
deaths, cardiovascular SAEs and respiratory SAEs meet criteria for cardiovascular assessment 
endpoints. A confirmatory adjudication will occur for AECOPD exacerbations.  Adjudicators will 
adjudicate these events in a consistent and unbiased manner throughout the study. 
The goal of the adjudication is to ensure that all events reported by the site are judged uniformly, 
using pre-specified criteria by a group independent of the Sponsor.  Adjudication Committee 
members will be blinded to treatment allocation.  Adjudication Committee members’ 
responsibilities and the process for data review are described in the AC Charter/Manual of 
Operation. 
2.1.4.1 Adverse events variables  
Adverse event observation period  
 Pretreatment adverse events are adverse events that developed or worsened or became 
serious during the screening epoch 
 Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period 
 Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment epoch. 
All adverse events (including serious adverse events and adverse events with pre-specified 
monitoring/of special interests) will be coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the version of Medical Dictionary for Regulatory Activities (MedDRA) currently in 
effect at Sanofi at the time of database lock. 


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The occurrence of adverse events (including serious adverse events and adverse events with 
prespecified monitoring) will be recorded from the time of signed informed consent until the end 
of the study.  
Cardiovascular assessment 
All events submitted for cardiovascular adjudication will be listed and summarized, including the 
final classification results. A swimmer plot including all events classified as cardiovascular, 
including cardiovascular death, will also be provided. 
Furthermore, events classified as cardiovascular will be evaluated according to the following 
composite endpoints: 
 Major Cardiovascular Adverse Events (MACE): cardiovascular death, non-fatal 
myocardial infarction, or non-fatal stroke 
 MACE + hospitalization for unstable angina  
 Cardiovascular death: death resulting from myocardial infarction, stroke, pulmonary 
embolism, heart failure, procedure-related death or other cardiovascular cause. 
 Hospitalization: for unstable angina, for atrial fibrillation/flutter, for other symptomatic 
arrhythmias, for transient ischemic attack. 
 Other cardio/cerebrovascular events: non-fatal heart failure, peripheral arterial event, 
pulmonary embolism, non-acute coronary syndrome/myocardial ischemia, others. 
Adverse events of special interest (AESI) and other selected AE groupings will be searched 
based on the criteria in Table 2. 
Table 2 - Criteria for adverse events of special interest and other selected AE groupings  
AE Grouping 
Criteria 
AESI 
 
Anaphylactic reaction 
Anaphylactic reaction algorithmic approach (Introductory Guide for Standardised 
MedDRA Queries (SMQs) Version 18.1): includes anaphylactic reaction narrow SMQ 
(20000021) terms and programmatic identification of cases based on occurrence of at 
least two preferred terms meeting the algorithm criteria occurring within 24 hours of 
each other. The latter cases identified using the algorithm will undergo blinded 
medical review taking into account the timing of events relative to each other and to 
IMP administration for final determination of an anaphylactic reaction or not. 
Hypersensitivity (medically reviewed) 
SMQ hypersensitivity (20000214) narrow search and [AE corrective 
treatment/therapy=’Y’ or Action taken with IMP=’Drug withdrawn’ or Action taken with 
IMP=’Drug interrupted’] followed by blinded medical review (documented process) for 
selection of relevant systemic hypersensitivity events  
Severe injection site reactions that last 
longer than 24 hours  
HLT = ‘Injection site reactions’ and with severe status and (AE end date/time - AE 
start date/time) ≥eg, 24 hours or ongoing 
Serious infection 
Primary SOC = ‘Infections and infestations’ and with serious status 
Parasitic infection 
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AE Grouping 
Criteria 
Infection requires parenteral 
(intravenous, intramuscular, 
subcutaneous) antimicrobial therapy 
“Have any parenteral treatment (IV, Intramuscular, SC) been given for this event?” 
was answered Yes on eCRF page “Infection Event Form” 
Infection requires oral antimicrobial 
therapy for longer than 2 weeks 
“Did this event require Prolonged Medication (greater than 14 Days)?” was answered 
Yes on eCRF page “Infection Event Form” 
Opportunistic infection 
The Infection Type ‘Opportunistic’ was checked on eCRF page “Infection Event Form” 
Pregnancy of a female patient entered in 
a study as well as pregnancy occurring in 
a female partner of a male patient 
entered in a study with IMP/NIMP 
“Pregnancy” or “Partner Pregnancy” checked on the Pregnancy eCRF page as 
reported by the investigator 
Symptomatic overdose with IMP 
Symptomatic Overdose is answered Yes, with Overdose of IMP answered Yes on AE 
eCRF.  
Symptomatic overdose with NIMP 
Symptomatic Overdose is answered Yes, with Overdose of NIMP answered Yes on 
AE eCRF.  
Clinically symptomatic eosinophilia (or 
eosinophilia associated with clinical 
symptoms) 
HLT = ‘Eosinophilic disorders’ or PT = ‘Eosinophil count increased’ followed by 
blinded medical review for selection of relevant events 
Any severe type of conjunctivitis 
Based on PTs in (Appendix J) and “Severe” ticked in Adverse Events eCRF page 
Any severe type of blepharitis 
HLT as “Lid, lash and lacrimal infections, irritations and inflammations” and “Severe” 
ticked in Adverse Events eCRF page 
Keratitis 
PT in (keratitis, allergic keratitis, ulcerative keratitis, atopic keratoconjunctivitis, herpes 
ophthalmic, ophthalmic herpes simplex, corneal infection) 
Significant ALT elevation 
“ALT increase” was checked and “Is the event an AESI” was answered Yes on AE 
eCRF as reported by the investigator (ALT >5 × ULN in participants with baseline 
ALT ≤2 × ULN;OR ALT >8 × ULN if baseline ALT >2 × ULN) 
Other selected AE grouping 
 
Injection site reactions  
HLT = ‘Injection site reactions’  
Malignancy 
Sub-SMQ (20000091)– Malignant or unspecified tumors 
Conjunctivitis (narrow) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis 
viral, Atopic keratoconjunctivitis) 
Conjunctivitis (broad) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis 
viral, Atopic keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye pruritus, 
Lacrimation increased, Eye discharge, Foreign body sensation in eyes, Photophobia, 
Xerophthalmia, Ocular hyperaemia, Conjunctival hyperaemia) 
Conjunctivitis (FDA) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis 
viral, Eye irritation, Eye inflammation, Giant papillary conjunctivitis) 
Helminthic infections 
HLGT= “Helminthic disorder” 
AEs related to COVID-19 illness 
SMQ [20000237] – COVID-19 narrow 


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2.1.4.2 Deaths  
The deaths observation period is per the observation periods defined above.  
 Death on-study: deaths occurring during the on-study observation period 
 Death on-treatment: deaths occurring during the treatment-emergent adverse event period  
 Death poststudy: deaths occurring after the end of the study  
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis including cotinine.  Clinical laboratory values after conversion will be analyzed into 
standard international units and international units will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken at Visit 1 (Week -4±1), Visit 2 (Week 0), 
Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 (Week 12), Visit 9 (Week 24), Visit 12 (Week 36), 
Visit 16 (Week 52), Visit 19 (Week 64) and early termination unless otherwise specified.  The 
laboratory parameters will be classified as follows:   
 Hematology  
- 
Red blood cells and platelets and coagulation:  hemoglobin, hematocrit, red blood 
cell count, platelet count 
- 
White blood cells:  white blood cell count, differential count 
 Clinical chemistry  
- 
Metabolism:  glucose, total cholesterol, total protein, creatine phosphokinase 
- 
Electrolytes:  sodium, potassium, chloride, bicarbonate 
- 
Renal function:  creatinine, blood urea nitrogen, uric acid 
- 
Liver function:  alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin (in case of values above the normal 
range, differentiation in conjugated and non-conjugated bilirubin), albumin 
- 
Pregnancy test:  Serum β-human chorionic gonadotropin (all female patients) will be 
performed at screening (V1) in women of childbearing potential, and a urine 
pregnancy test will be performed at V2 prior to randomization and every 4 weeks 
thereafter. A negative result must be obtained at V1 and V2 prior to randomization. In 
case of positive urinary test the study treatment will be withheld and a serum 
pregnancy test to confirm the pregnancy should be performed as soon as possible. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
- 
Hepatitis screen: hepatitis B surface antigen (HBs Ag), hepatitis B Surface antibody 
(HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C virus antibodies (HCV Ab) 
will be tested at screening (V1). In case of results showing HBs Ag (negative), HBs 
Ab (negative) and HBc Ab (positive), an HBV DNA testing will be performed prior to 
randomization to rule out a false positivity if the investigator believes the patient is a 
false positive, or to clarify the serological status if the investigator finds it unclear to 
interpret in absence of known HBV infection. In case of results showing HCV Ab 
(positive), an HCV RNA testing may be performed to rule out a false positivity, if the 
investigator believes the patient is a false positive. 


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- 
HIV screen: Anti-HIV-1 and HIV-2 antibodies will be tested at Visit 1  
- 
Anti-nuclear antibody (ANA) will be tested at Visit 1  
- 
Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer).  
 Urinalysis  
Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, 
leukocyte esterase, urobilinogen and bilirubin. If any parameter on the dipstick is 
abnormal, a urine sample should be sent to the central laboratory for quantitative 
measurement. If positive for protein and/or red blood cells, microscopic analysis will be 
performed by the central laboratory. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables  
Vital signs, including blood pressure (mmHg), pulse rate (beats per minute), respiratory rate 
(breaths per minute), body temperature (degrees Celsius) will be measured at Visit 1 (Week -4±1), 
Visit 2 (Week 0), Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 (Week 12), Visit 9 
(Week 24), Visit 12 (Week 36), Visit 14 (Week 44), Visit 16 (Week 52), and Visit 19 (Week 64). 
Height (cm) will be measured at screening (Visit 1) only. Body weight (kg) will be measured at 
screening (Visit 1) and at EOT/EOS visits. Vital signs will be measured in the sitting position 
using the same arm (preferably) at each visit and will be measured prior to receiving IMP at the 
clinic visits. 
2.1.4.5 Electrocardiogram variables  
A standard 12-lead electrocardiogram (ECG) will be performed centrally at Visit 1 (Week -4±1), 
Visit 2 (Week 0), Visit 6 (Week 12), Visit 9 (Week 24), Visit 12 (Week 36), Visit 16 (Week 52), 
and Visit 19 (Week 64). At the post randomization visits, ECGs will be performed prior to 
investigational product administration. A minimum of 3 complexes in an appropriate lead (lead II) 
will be averaged to determine the PR-interval, QT/QTc-interval, QRS-complex and heart rate will 
be measured for each ECG. All ECG recordings will be centrally read by independent experts. 
2.1.4.6 Physical Examination  
Physical examinations will be performed at Visit 1 (Week -4±1), Visit 2 (Week 0), Visit 9 
(Week 24), Visit 16 (Week 52), and Visit 19 (Week 64) including an assessment of skin, nasal 
cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and 
musculoskeletal systems. All deviations from normal will be recorded, including those 
attributable to the patient’s disease. 
2.1.5 Pharmacokinetic variables  
Predose serum dupilumab concentrations at Visit 2 (Day 1), dupilumab trough levels at Week 2, 
Week 4, Week 8, Week 12, Week 24, Week 36, Week 52/EOT Visit and posttreatment serum 
dupilumab at Week 64/EOS Visit will be provided. 


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Anti-dupilumab antibody (ADA) status (negative or titer value, if positive in the ADA assay) at 
Visit 2 (Day 1), Week 12, Week 24, Week 52 and follow up at Week 64 will be provided. Patients 
who discontinue early from treatment may be asked to return to the clinic to have additional ADA 
samples collected for analysis based on the overall clinical presentation at that time.  
ADA incidence will be classified as the following: 
Pre-existing immunoreactivities are defined as:  
An ADA positive response in the assay at baseline with all post treatment ADA results negative, 
OR an ADA positive response at baseline with all post treatment ADA responses less than 4-fold 
over baseline titer levels. 
Treatment-emergent anti-drug antibodies are defined as:  
A positive response in the ADA assay post first dose, when baseline results are negative or 
missing. 
Treatment-emergent ADA responses are further classified as Persistent, Indeterminate or Transient 
a) Persistent Response- defined as a treatment-emergent ADA response with two or more 
consecutive ADA positive sampling time points, separated by greater than (>) 12-week 
period (84 days), with no ADA negative samples in between. 
b) Indeterminate Response- defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay  
c) Transient Response - defined as a treatment-emergent response that is not considered 
persistent OR indeterminate 
Treatment-boosted response is defined as:   
An ADA positive response in the assay post first dose that is greater-than or equal to 4-fold over 
baseline titer levels, when baseline results are positive. 
Titer values (Titer value category) 
 Low (Titer <1000) 
 Moderate (1000 ≤ Titer ≤10 000) 
 High (Titer >10 000)  
On-treatment ADA incidence will also be derived in the same way except that only on-treatment 
measurements (measurements during the treatment epoch) are considered post first dose.   
2.1.6 Pharmacodynamic/genomics endpoints  
Whole blood biomarkers blood eosinophil and neutrophil counts will be measured as part of the 
standard 5-part WBC differential cell count on a hematology auto analyzer. 


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For plasma/serum biomarkers, Eotaxin-3 will be assayed at Visit 2 (Week 0), Visit 4 (Week 4), 
Visit 6 (Week 12), Visit 9 (Week 24), Visit 16 (Week 52) and Visit 19 (Week 64); total IgE will 
be assayed at Visit 2 (Week 0), Visit 6 (Week 12), Visit 16 (Week 52) and Visit 19 (Week 64); 
Pulmonary and Activation-Regulated Chemokine [PARC] will be assayed at Visit 2 (Week 0), 
Visit 16 (Week 52) and Visit 19 (Week 64); Fibrinogen will be assayed at Visit 2 (Week 0), 
Visit 9 (Week 24), Visit 16 (Week 52) and Visit 19 (Week 64). 
Fractional exhaled nitric oxide (FeNO; postbronchodilator) will be analyzed using a NIOX 
instrument (Aerocrine AB, Solna, Sweden), or similar analyzer using a flow rate of 50 mL/s, and 
reported in parts per billion (ppb). This assessment should be conducted prior to spirometry and 
following a fast of at least 1 hour at Visit 2 (Week 0), Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 
(Week 12), Visit 9 (Week 24), Visit 12 (Week 36), Visit 16 (Week 52) and Visit 19 (Week 64).  
Pharmacogenetic testing is optional and voluntary. A separate written informed consent form 
must be signed before sampling. For those patients who signed the optional pharmacogenetic 
informed consent form, blood samples for exploratory genetic analysis of DNA or RNA will be 
collected at the study visit as specified in the study flow chart, and these samples will be stored 
for future analysis. 
2.1.7 Health Related Quality-of-life endpoints  
2.1.7.1 The 5-level Euro Quality of Life-5 Dimension questionnaire (EQ-5D-5L)  
The 5-level Euro Quality of Life-5 Dimension questionnaire (EQ-5D-5L) (Appendix E) is a 
standardized HRQoL questionnaire developed by the EuroQol Group in order to provide a simple, 
generic measure of health for clinical and economic appraisal (8). EQ-5D is designed for self-
completion by patients. 
The EQ-5D essentially consists of 2 pages: the EQ-5D descriptive system and the EQ VAS. The 
EQ-5D comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. EQ-5D-5L health status will be converted into 
a single index value by using EQ-5D-5L value sets based on UK population. The EQ VAS 
records the respondent’s self-rated health on a vertical VAS. The EQ VAS ‘thermometer’ has 
endpoints of 100 (best imaginable health state) at the top and 0 (worst imaginable health state) at 
the bottom. EQ-5D self-reported VAS data generates information on the self-perceived overall 
health-related quality of life.  
EQ-5D will be assessed at Visit 2 (Week 0), Visit 9 (Week 24), and Visit 16 (Week 52). 
2.1.8 Health economic endpoints  
A questionnaire of health care resource utilization (collection of sick days, lost usual activities, 
and additional physician visits or other health care utilization) will be administered at Visit 2 
(Week 0), Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 (Week 12), Visit 7 (Week 16), Visit 8 
(Week 20), Visit 9 (Week 24), Visit 10 (Week 28), Visit 11 (Week 32), Visit 12 (Week 36), 


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Visit 13 (Week 40), Visit 14 (Week 44), Visit 15 (Week 48), Visit 16 (Week 52) and Visit 19 
(Week 64). 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
 Screened patients 
 Screen failure patients and reasons for screen failure 
 Nonrandomized but treated patients 
 Randomized patients 
 Randomized but not treated patients 
 Randomized and treated patients 
 Patients who did not complete treatment as per protocol 
 Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation including due to the COVID-19 pandemic 
 Patients who withdraw from study 
 Patients who withdraw from study prior to Week 52 
 Patients who withdraw from study prior to Week 52 by main reason for study 
discontinuation including due to the COVID-19 pandemic 
 Patients who withdraw from study by main reason for study discontinuation including due 
to the COVID-19 pandemic 
 Vital status at last study contact 
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group. This summary will be provided by treatment group.  
All critical or major deviations related to randomization procedures will be summarized in tables 
giving numbers and percentages of deviations by treatment group. 
Additionally, efficacy populations will be summarized by number of patients on the randomized 
population. 


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 Efficacy population: intent-to-treat (ITT) population defined in Section 2.3 
The analysis populations for safety defined in Section 2.3 pharmacokinetics/pharmacodynamics 
(PK/PD) will be summarized by number of patents on the safety population. 
 Safety population 
 PK population 
 ADA population 
2.2.1 Protocol deviations  
The number and percentage of patients with a critical or major protocol deviation will be 
summarized by deviation and overall within treatment group, and according to COVID-19 impact 
(ie, deviations related to the COVID-19 pandemic and deviations not related to the COVID-19 
pandemic).  Specific deviations related to randomization may be summarized separately.  A 
listing of patients with at least one critical or major deviation will be provided.  
2.3 
ANALYSIS POPULATIONS  
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
If >10% participants are impacted by the COVID-19 pandemic, additional summaries by 
COVID-19 subgroups will be provided. Participants impacted by the COVID-19 pandemic are 
defined as randomized participants with any critical or major deviation related to the COVID-19 
pandemic or who permanently discontinued study intervention or study due to the COVID-19 
pandemic or a COVID-19 related AE. 
2.3.1 Efficacy populations  
The primary efficacy analysis population will be the ITT population as defined in Section 2.3.1.1. 
2.3.1.1 Intent–to-treat population  
The intent-to-treat (ITT) population is the randomized population analyzed according to the 
treatment group allocated by randomization.  
Patients will be analyzed in the treatment group to which they are randomized. 


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2.3.2 Safety population  
The safety population is defined as: All patients who actually received at least 1 dose or partial of 
a dose of the IMP, analyzed according to the treatment patients actually received. 
In addition:  
 Nonrandomized but treated patients will be part of the safety population 
 Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
 For patients on placebo but accidentally exposed to dupilumab, the treatment group 
allocation for as-treated analysis will be dupilumab group 
 For patients on dupilumab but accidentally receive placebo, the actual treatment group 
allocation for as-treated analysis will be dupilumab group 
2.3.3 Pharmacokinetics (PK) population  
The PK population will consist of all patients in the safety population with at least one evaluable 
functional dupilumab concentration result. Patients will be analyzed according to the treatment 
actually received. 
2.3.4 Anti-drug antibody population  
The anti-drug antibody (ADA) population will consist of all patients in the safety population with 
at least one reportable ADA results (either ‘ADA negative’ or ‘ADA positive’) after first dose of 
the study treatment. Patients will be analyzed according to the treatment actually received. 
2.4 
STATISTICAL METHODS  
2.4.1 Demographics and baseline characteristics  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group.  
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.  Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  
Medical and surgical history will be summarized by treatment group and by system organ class 
(SOC) and preferred term (PT) sorted by internationally agreed order of SOC and by the 


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decreasing frequency of PT within SOC based on the overall incidence across treatment groups. 
Atopic medical history will be summarized separately.  
No statistical testing on demographic and baseline characteristic data will be performed.  
No specific description of the safety parameters will be provided at baseline.  If relevant, the 
baseline values will be described along with each safety analysis. 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be presented for the randomized population.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the 
first 3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a 
medication will be summarized, and patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore patients may be counted several 
times for the same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
Concomitant medication received during first IMP to last IMP +14 days and concomitant 
medication received during first IMP to last IMP +98 days will be summarized separately. The 
tables for concomitant medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the incidence in the dupilumab 300 q2w group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
Medications will also be summarized by generic name sorted by decreasing frequency based on 
the incidence in the dupilumab group. 
In addition, inhaled corticosteroid in combination with other controllers and reliever medications 
will be summarized separately. 
2.4.2.1 ICS in combination with other controllers  
ICS and other COPD controller medications will be identified as the medications reported on the 
“Prescribed COPD Controller Medications” eCRF page. 
Prior COPD controller medications will be summarized by treatment group sorted by decreasing 
frequency of standard medication name on the incidence in the overall treatment group. 
Concomitant COPD controller medications will be summarized by treatment group sorted by 
decreasing frequency of standard medication name on the incidence in the dupilumab group. 
The total daily dose of ICS in COPD controller medication at randomization will be classified as 
high dose or lower dose according to Appendix G. If a patient takes more than one medication 


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containing ICS, the ICS dose of different products will be standardized according to equivalent 
dose specified in Table 3 and Table 4. After conversion, the total daily dose for inhaled 
corticosteroid will be calculated and classified as high dose or lower dose. 
Table 3 - Equivalent dose for inhaled corticosteroids for adults  
Inhaled corticosteroid  
Equivalent dose (mcg) to 500 mcg Fluticasone 
propionate (DPI or HFA) 
FLUTICASONE FUROATE 
200-* 
BECLOMETASONE DIPROPIONATE (CFC) 
1000 
BECLOMETASONE DIPROPIONATE (HFA) 
400 
BUDESONIDE (DPI) 
800 
CICLESONIDE (HFA) 
320 
MOMETASONE FUROATE 
440 
TRIAMCINOLONE ACETONIDE 
2000 
ADAPTED FROM GINA 2016 GUIDELINES 
HFA=hydrofluoroalkane, DPI= Dry Powder Inhaler 
* Fluticason furoate (FF) dose >=200 mcg is converted to equivalent fluticasone propionate (DPI or HFA) dose of (FF dose +1) × 2.5; FF dose 
<200 mcg is converted to equivalent fluticasone propionate (DPI or HFA) dose of FF dose × 2.5. 
Example: A patient received 400 mcg budesonide (DPI) and 440 mcg mometasone furoate. They are equivalent to 250 mcg and 500 mcg 
fluticasone propionate correspondingly. The combined total daily dose is equivalent to 750 mcg fluticasone propionate and classified as high 
dose. 
Table 4 - Equivalent dose of inhaled corticosteroid for adults (Japan)  
Inhaled corticosteroid 
Equivalent dose (mcg) to 400 Fluticasone 
propionate (DPI or HFA) 
FLUTICASONE FUROATE 
100 
BECLOMETHASONE DIPROPIONATE -HFA 
400 
CICLESONIDE -HFA 
400 
BUDESONIDE-DPI 
800 
BUDESONIDE INHALATION SUSPENSION 
1.0 mg 
BUDESONIDE INHALATION SOLUTION 
1000 
MOMETASONE FUROATE-DPI 
400 
Adapted from Japanese Guideline for Adult Asthma 2014  
Example: A patient received 400 mcg Beclomethasone dipropionate -HFA and 400 mcg Ciclesonide-HFA. They are both equivalent to 400 
fluticasone propionate. The combined total daily dose is equivalent to 800 fluticasone propionate. 
Number and percentage of patients on ICS, ICS/LABA, LABA, LAMA, LTRA, Anti-
Leukotriene, Methylxanthine and other controller medications at baseline will also be 
summarized. 


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2.4.2.1.1 Compliance  
During the study, the daily intake of each prescribed COPD controller medication will be 
recorded on the electronic diary every evening. Compliance for the controller medications with 
ICS component and overall compliance to all prescribed controller medications will be calculated 
for each patient. For each day, a patient is considered as compliant with the prescribed controller 
medication with ICS component if the actual dose of each controller medication with ICS 
component is same as or greater than the prescribed dose. Similarly, a patient is considered as 
compliant with all controller medication if the actual dose of each controller medication is same 
as or greater than the prescribed dose. 
Compliance for controller medication(s) with ICS component is defined as the number of days 
when the patient is compliant with the prescribed controller medication(s) with ICS component 
divided by the number of days the patient stays in the treatment period (from first dose to last dose 
+ 14 days). 
Overall controller medication(s) compliance is defined as the number of days when the patient 
is compliant with all prescribed controller medication divided by the number of days the patient 
stays in the treatment period. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data). Duration of IMP exposure will be summarized descriptively as a quantitative 
variable (number, mean, SD, median, minimum, and maximum).  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories:  
 >0 and ≤2 weeks 
 >2 and ≤4 weeks 
 >4 and ≤8 weeks 
 >8 and ≤12 weeks 
 >12 and ≤16 weeks 
 … 
 … 
 >48 and ≤52 weeks 
 >52 weeks and ≤52 weeks + 3 days 
 >52 weeks + 3 days 


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Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data. 
Percentage of compliance for a patient will be defined as the number of administrations that the 
patient was compliant divided by the total number of administrations that the patient was planned 
to take during the treatment epoch defined in Section 2.1.3.2.2.1. 
Treatment compliance percentages will be summarized descriptively as quantitative variables 
(number, mean, SD, median, minimum, and maximum). The percentage of patients whose 
compliance is <80% will be summarized in Section 2.4.4.5.  
Cases of overdose (defined as at least twice the intended dose during an interval of less than 
11 days) will be specified in the overdose form and symptoms, if any, entered on separate adverse 
event forms. 
2.4.4 Analyses of efficacy endpoints  
If efficacy at the interim analysis is demonstrated for the primary endpoint of annualized rate of 
moderate and severe COPD exacerbations over the 52-week treatment period with an alpha as 
determined in Table 9 (see Section 3): 
 All data up to the time of the interim analysis cut-off date will be used in the inferential 
analyses for the event type endpoints including the primary endpoint and time to event 
endpoints (up to the cut-off date), and the change from baseline in pre-BD FEV1 at 
Week 12 endpoints (both the ITT population and the baseline FeNO ≥20 ppb subgroup). 
 For Week 52 endpoints, only participants who have the opportunity to reach Week 52 
assessments at the time of the IA cut-off date (ie, completed the Week 52 study period or 
would have completed had they not discontinued) will contribute to the inferential 
analyses for the continuous and proportion type endpoints at Week 52 and by visit.   
2.4.4.1 Analysis of primary efficacy endpoint(s)  
Primary efficacy variable 
The primary efficacy variable is annualized rate of moderate or severe COPD exacerbations over 
the 52-week treatment period compared to placebo.  


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The following null hypothesis and alternative will be tested for dupilumab arm against placebo:  
 H0: No treatment difference between the dupilumab dose regimen and placebo in 
annualized rate of COPD exacerbation. 
 H1: There is a treatment difference between the dupilumab dose regimen and placebo in 
annualized rate of COPD exacerbation. 
Primary statistical model (ITT analysis)  
The primary analysis of the annualized rate of moderate or severe exacerbation events during the 
52-week placebo-controlled treatment period is to assess the efficacy of dupilumab in an 
intention-to-treat setting. Adjudicated COPD exacerbation events data will be used. Patients who 
permanently discontinue the study medication will be encouraged to return to the clinic for all 
remaining study visits. If a patient stays in study until the end of 52-week treatment period, all 
moderate or severe exacerbation events that happen up to Visit 16 will be included in the primary 
analysis, regardless of if the patient is on treatment or not. And the observation duration is defined 
as from randomization to Visit 16 (Week 52). If a patient withdraws from study prior to the end of 
52-week treatment period, all observed moderate or severe exacerbation events up to the last 
contact date or the end date of the planned 52-week treatment period (whichever is earlier) will be 
included in the analysis, and the observation duration is defined as from randomization to the last 
contact date or the end date of the planned 52-week treatment period whichever is earlier. 
No imputation will be performed for the unobserved events that may happen after study 
discontinuation and up to Week 52. This estimand compares the rates of moderate or severe 
exacerbation for the patients randomized to the dupilumab and placebo arms, regardless of what 
treatment patients actually received. It assesses the benefits of the treatment policy or strategy 
relative to placebo. 
The annualized rate of moderate or severe COPD exacerbation events will be analyzed using a 
negative binomial regression model. The model will include the total number of events that 
occurred during the 52-week planned treatment period as the response variable, with the treatment 
group, region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking status at 
screening (current smokers or not), baseline disease severity (as % predicted post-bronchodilator 
FEV1), and number of moderate or severe COPD exacerbation events within one year prior to the 
study (≤2, 3, or ≥4) as covariates. Log-transformed observation duration will be used as offset 
variable. The estimated annualized event rate for each treatment group and its two-sided 
95% confidence intervals will be derived. The event rate ratio of the dupilumab group against 
placebo, its two-sided 95% confidence interval and p-value will be provided.  
The rate difference between dupilumab and placebo, two-sided 95% confidence intervals of the 
rate difference and its p-value derived using delta method will also be provided as supportive 
information. 
The analysis model will be built with the following sample SAS code: 
 
proc glimmix data=event; 
class  ics trt01pn cntygr1n smoking copdnum; 
model numevents=trt01pn cntygr1n ics smoking FEV1bl copdnum 
/offset=logdur dist=negbin link=log solution; 
run; 


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If the model fails to achieve convergence, different estimation algorithms will be applied 
following the order: default→LAPLACE→QUAD. If the issue still exists, other handling may be 
considered. The adjustment will be added to the footnote of the corresponding outputs. 
The gross estimated annualized event rate will also be presented by treatment group. 
Mean cumulative function plot will be provided for descriptive purpose. 
Primary estimand for the primary efficacy endpoint is summarized in Appendix L. 
Sensitivity analysis 
If patients withdraw from the study before Visit 16 (Week 52), moderate or severe exacerbation 
events that may occur after study discontinuation will not be observed. These patients are 
considered as patients with missing data on moderate or severe exacerbation. Number of patients 
with missing data, reasons and timing for patient withdrawals will be summarized by treatment 
groups. Summary statistics of selected demographic and baseline disease characteristics will be 
provided for patients with missing data and patients with complete data separately. In addition, the 
following sensitivity analyses will be conducted to assess the robustness of the conclusion based 
on the primary analysis. 
Pattern mixture model - multiple imputation (PMM-MI) 
For each patient with missing data of moderate or severe exacerbation events, individual 
bi-weekly event probability will be estimated using observed data with adjustment of the planned 
treatment group, region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking 
status at screening (current smokers or not), baseline disease severity (as % predicted post-
bronchodilator FEV1), and number of moderate or severe COPD exacerbation events within 
one year prior to the study (≤2, 3, or ≥4). The total number of AECOPD moderate or severe 
events (on bi-weekly basis) will be calculated based on data imputed using multiple imputation. 
Control-based PMM-MI 
For each patient with missing data of moderate or severe exacerbation events, individual 
bi-weekly event probability will be estimated using observation in the placebo arms only, with 
adjustment of region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking 
status at screening (current smokers or not), baseline disease severity (as % predicted post-
bronchodilator FEV1), and number of moderate or severe COPD exacerbation events within one 
year prior to the study (≤2, 3, or ≥4). The total number of AECOPD moderate or severe events 
(on bi-weekly basis) will be calculated based on data imputed using multiple imputation. 
Tipping point analysis 
For each patient with missing data of moderate or severe exacerbation events, the bi-weekly event 
will be imputed in a similar fashion as PMM-MI based on various odds values. If the patient is on 
dupilumab, the predicted odds will be increased; if the patient is on Placebo, the predicted odds 
value will be decreased. The adjusted rate will then be used to impute the number of events that 


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would occur during the missing observation period. A sequence of increasing/decreasing ratio will 
be used to generate different imputed datasets. 
For each of the above methods, a negative binomial model will be fitted using each of the 
complete datasets composed of observed and imputed data, including the total number of 
observed and imputed events during the 52 weeks as the response variable, with the treatment 
group, region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking status at 
screening (current smokers or not), baseline disease severity (as % predicted post-bronchodilator 
FEV1), and number of moderate or severe COPD exacerbation events within one year prior to the 
study (≤2, 3, or ≥4) as covariates. Log transformed observation duration will be the offset variable 
for patients who complete the 52-Week treatment/study period, and log transformed 52 weeks will 
be the offset variable for patients who discontinue the study before Visit 16 (Week 52). SAS 
MIANALYZE procedure will be used to generate statistical inferences by combining results from 
the analysis with each dataset using Rubin’s formula. 
More details of the imputation and analyses methods are provided in Appendix K: 
Subgroup analyses 
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be conducted for the primary efficacy endpoint with respect to:  
 Age group (<65, ≥65 years; 40-64, 65-74, 75-85) 
 Gender (Male, Female) 
 Region  
 Territory  
 Race (White, Non-white) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Baseline weight (<70, ≥70- <90, ≥90 kg; <60, ≥60 kg) 
 Baseline BMI (<25, ≥25- <30, ≥30 kg/m2)  
 ICS high dose level at baseline (High-dose ICS, Non-high-dose ICS, No ICS) 
 ICS dose level at baseline (< median, ≥ median) 
 Smoking status at screening (current smokers, former smokers) 
 Number of moderate-or-severe COPD exacerbation events within one year prior to V1 
(≤2, 3, or ≥4) 
 Number of severe COPD exacerbation events within one year prior to V1 (0, 1, ≥2; 0, ≥1) 
 Baseline predicted post-bronchodilator FEV1% (<50%, ≥50%) 
 Baseline pre-bronchodilator FEV1 (< median, ≥ median) 
 Baseline FEV1 reversibility (<12%, ≥12%; < median, ≥ median) 
 Baseline fractional exhaled nitric oxide (FeNO) (<20, ≥20 ppb) 
 Baseline eotaxin-3 (< median, ≥ median) 
 Baseline IgE (<100, ≥100 IU/ml) 


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 Baseline PARC (< median, ≥ median) 
 Baseline Fibrinogen (<350, ≥350 mg/dL) 
 Maximum eosinophils count during screening (<0.5, ≥0.5 Giga/L) 
 Emphysema ongoing at baseline (Yes, No) 
 Baseline BODE (≤4, >4) 
Treatment by subgroup interaction and its p-value will be derived from a negative binomial 
model. This model will include the total number of events occurring during the observation period 
as the response variable, with the two treatment groups, region (pooled country), ICS dose at 
baseline (high dose ICS [yes/no]), smoking status at screening (current smokers or not), baseline 
disease severity (as % predicted post-bronchodilator FEV1), and number of moderate or severe 
COPD exacerbation events within one year prior to the study (≤2, 3, or ≥4), subgroup (if different 
than the aforementioned covariates) and treatment by subgroup interaction as covariates. 
Log transformed observation duration will be the offset variable. Summary statistics of moderate 
or severe exacerbations will be provided within each subgroup. Forest plot of relative risks and 
corresponding CIs and forest plot of risk differences and corresponding CIs comparing dupilumab 
dose group vs. placebo for the subgroups will be provided.  
2.4.4.2 Analyses of key secondary efficacy endpoints  
2.4.4.2.1 Analysis of the change from baseline in pre-bronchodilator(pre-BD) FEV1 at Week 12 
for dupilumab versus placebo  
The change from baseline in pre-bronchodilator FEV1 at Week 12 will be analyzed using mixed-
effect model with repeated measures (MMRM). The analysis will be performed in the full ITT 
population and also in the baseline FeNO ≥20 ppb subgroup. The model will include change from 
baseline in FEV1 values up to Week 12 as response variables, and factors for treatment group, 
age, sex, height, region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking 
status at screening (current smokers or not), visit, treatment-by-visit interaction, baseline pre-
bronchodilator FEV1, and FEV1 baseline-by-visit interaction as covariates. An unstructured 
correlation matrix will be used to model the within-patient errors. Parameters will be estimated 
using restricted maximum likelihood method using the Newton-Raphson algorithm. The least 
square (LS) mean of the change in pre-bronchodilator FEV1 of each treatment group, difference in 
the LS mean changes between the dupilumab group and placebo, the corresponding 95% CI of the 
differences and p-values will be provided. For patients who discontinued the study treatment, 
off-treatment FEV1 values will be included in the analysis.  
Primary estimand for the key secondary efficacy endpoints is summarized in Appendix L. 
Subgroup analyses 
To assess the consistency treatment effects across the subgroup levels, subgroup analyses will be 
conducted for the change from baseline in pre-BD FEV1 at Week 12 with the same set of subgroups 
as defined for the annualized rate of moderate or severe AECOPD events in Section 2.4.4.1. 


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Treatment-by-subgroup interaction at Week 12 and its p-value will be derived from a MMRM 
model. The model will include change from baseline in pre-BD FEV1 values up to Week 12 as 
response variables, and treatment, age, sex, height, region (pooled country), ICS dose at baseline 
(high dose ICS [yes/no]), smoking status at screening (current smokers or not), visit, treatment-
by-visit interaction, baseline pre-bronchodilator FEV1, and FEV1 baseline-by-visit interaction, 
subgroup (if different than the aforementioned covariates), subgroup-by-treatment interaction and 
subgroup-by-treatment-by-visit interaction as covariates. Summary statistics of change from 
baseline in pre-bronchodilator FEV1 will be provided within each subgroup. Forest plot of LS 
mean difference and corresponding CIs for the subgroups will be provided.  
Sensitivity analysis 
Patients who discontinue the treatment are encouraged to follow the planned clinical visits, and all 
data collected after treatment discontinuation will be used in the analysis. Descriptive statistics of 
pre-BD FEV1 by visit up to Week 12 will be summarized for patients with some missing data and 
patients with complete data up to Week 12 separately. Number of patients with missing pre-BD 
FEV1, reasons and timing for missing pre-BD FEV1 will be summarized by treatment groups. In 
addition, following sensitivity analyses will be conducted to assess the robustness of the 
conclusion of the main model using the full ITT population: 
Pattern mixture model-multiple imputation (PMM-MI) 
Missing pre-BD FEV1 values will be imputed multiple times with adjustment for covariates 
including treatment groups, age, sex, height, region (pooled country), ICS dose at baseline (high 
dose ICS [yes/no]), smoking status at screening (current smokers or not), and baseline pre-BD 
FEV1. Each of the complete datasets will be analyzed using the ANCOVA model with change 
from baseline in pre-BD FEV1 at Week 12 as the response variable, treatment, age, sex, height, 
region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking status at 
screening (current smokers or not), and baseline pre-BD FEV1 value as covariates. Then the SAS 
MIANALYZE procedure will be used to generate statistical inference by combining results using 
Rubin’s formula. 
Tipping point analysis 
First, missing values will be imputed by PMM-MI as illustrated above. The imputed values in 
placebo group will then be shifted by adding a sequence of positive values and the imputed values 
in dupilumab group will be shifted by subtracting a sequence of positive values. For each 
combination of the shift parameters, each of the imputed and shifted datasets will be analyzed 
with the ANCOVA model and their results will be combined using Rubin’s formula to generate 
statistical inference. LS mean difference between dupilumab and placebo in change from baseline 
in pre-BD FEV1 at Week 12 and the corresponding p-values will be provided for each 
combination of shift parameters. 
More details of the imputation and analyses methods are included in Appendix K. 


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2.4.4.2.2 Analysis of the change from baseline in pre-bronchodilator FEV1 and SGRQ total score 
and domain scores at Week 52 for dupilumab versus placebo  
The change from baseline in pre-bronchodilator FEV1 at Week 52 will be analyzed in a similar 
way as change from baseline in pre-bronchodilator FEV1 at Week 12 and the model will include 
values up to Week 52 as response variables. The analysis will be performed in the full ITT 
population and also in the baseline FeNO ≥20 ppb subgroup. 
The change from baseline in SGRQ total score and domain scores at Week 52 will be analyzed in 
a similar way as change in pre-bronchodilator FEV1 at Week 52 except that the MMRM model 
will include the following covariates: treatment group, region (pooled country), ICS dose at 
baseline (high dose ICS [yes/no]), smoking status at screening (current smokers or not), visit, 
treatment-by-visit interaction, baseline SGRQ total score, and SGRQ baseline-by-visit interaction.  
Descriptive statistics including number of patients, mean, standard error, and least squares (LS) 
means will be provided. In addition, difference in LS means and the corresponding 95% 
confidence intervals (CI) will be provided along with the p-values. 
2.4.4.2.3 Analysis of proportion of patients with SGRQ improvement ≥4 points at Week 52 
dupilumab versus placebo  
The proportion of patients with SGRQ improvement ≥4 points at Week 52 will be analyzed using 
a logistic regression model. The model will include treatment group, region (pooled country), ICS 
dose at baseline (high dose ICS [yes/no]), smoking status at screening (current smokers or not), 
and baseline SGRQ total score as covariates. For patients who discontinue treatment early, data 
collected during the off- treatment period will be used to determine the responder/non- responder 
status. Patients with missing SGRQ total score at Week 52 will be considered as non-responders.  
Odds ratio of being a responder comparing dupilumab to placebo will be provided along with the 
corresponding 95% CI and p-value. Descriptive statistics including number and percentage of 
responders will also be provided. 
Cumulative distribution function (CDF) of change from baseline in SGRQ at Week 52 will be 
presented by treatment group. 
2.4.4.2.4 Analysis of annualized rate of moderate or severe COPD exacerbation compared to 
placebo over the 52-week treatment period in the subgroup of patients with baseline 
FeNO ≥20 ppb  
The annualized rate of moderate or severe COPD exacerbation compared to placebo over the 52-week 
treatment period in the subgroup of patients with baseline FeNO ≥20 ppb will be performed in the 
same approach as that for the primary efficacy endpoint except that the analyzed population is not the 
full ITT population but the subgroup of patients with baseline FeNO ≥20 ppb. 
The estimated annualized event rate for each treatment group and its two-sided 95% confidence 
intervals will be derived. The event rate ratio of the dupilumab group against placebo, its two-
sided 95% confidence interval and p-value will be provided.  


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The rate difference between dupilumab and placebo, two-sided 95% confidence intervals of the 
rate difference and its p-value derived using delta method will also be provided as supportive 
information. 
Mean cumulative function plot will be provided for descriptive purpose. 
2.4.4.3 Multiplicity issues  
Multiplicity is considered for performing an interim analysis and for testing multiple endpoints. 
The overall Type-I error rate will be controlled at the two-sided 0.05 level. 
An interim analysis will be performed using the Kim-DeMets (9) spending function when the 
information fraction is ≥0.92 based on follow-up time for the primary endpoint of annualized rate 
of moderate or severe COPD exacerbations over 52-week treatment period (see Section 3). 
A hierarchical testing procedure will be used for testing primary, key secondary and other 
endpoints. If the primary endpoint does not demonstrate efficacy at this interim analysis then the 
study will remain blinded and the primary endpoint will be retested at the 52-week final analysis 
time point with an α=0.049. If the primary endpoint demonstrates efficacy at this interim analysis 
based on the alpha allocated, then the rest of the multiplicity-controlled endpoints will be tested 
with α=0.05. The comparisons will be tested based on the hierarchical order below.  
1) Primary efficacy endpoints: 
 Annualized rate of moderate or severe COPD exacerbations over the 52-week treatment 
period compared to placebo. 
2) Secondary/exploratory efficacy endpoints:  
 Change in pre-bronchodilator FEV1 from baseline to Week 12 compared to placebo 
 Change in pre-bronchodilator FEV1 from baseline to Week 52 compared to placebo   
 Change in pre-bronchodilator FEV1 from baseline to Week 12 compared to placebo in the 
subgroup of patients with baseline FeNO ≥20 ppb 
 Change in pre-bronchodilator FEV1 from baseline to Week 52 compared to placebo in the 
subgroup of patients with baseline FeNO ≥20 ppb 
 Change from baseline to Week 52 in SGRQ total score compared to placebo 
 Proportion of patients with SGRQ improvement ≥4 points at Week 52 compared to 
placebo 
 Change in E-RS COPD total score from baseline to Week 52 compared to placebo  
 Annualized rate of moderate or severe COPD exacerbation compared to placebo over the 
52-week treatment period in the subgroup of patients with baseline FeNO ≥20 ppb 
The study is considered positive when the primary endpoint achieves statistical significance. 
 


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2.4.4.4 Additional efficacy analyses  
2.4.4.4.1 Comparisons for other secondary efficacy endpoints  
 Change in pre-bronchodilator FEV1 from baseline to Weeks other than 12 and 52 
 Change in post-bronchodilator FEV1, forced expiratory flow (FEF) 25-75%, FEV1/FVC 
from baseline to Weeks up to Week 52 
 Time to first moderate or severe COPD exacerbation compared to placebo during the 
52-week treatment period 
 Annualized rate of severe COPD exacerbations over the 52-week treatment period 
2.4.4.4.2 Analyses of other efficacy endpoints for dupilumab versus placebo up to Week 52  
Change from baseline in continuous endpoint (pre-bronchodilator FEV1, post-bronchodilator 
FEV1, FEF25-75%, SGRQ total scores) at all time-points will be analyzed in a similar way as 
change from baseline in pre-bronchodilator FEV1 at Week 52. Age, sex and height will be 
included as covariates only in the models for spirometry parameters. Descriptive statistics 
including number of patients, mean, standard error, and least squares (LS) means will be provided 
for all visits. In addition, difference in LS means and the corresponding 95% confidence intervals 
(CI) will be provided along with the p-values. 
Proportion type efficacy endpoints (SGRQ improvement from baseline ≥4 points) during the 
treatment period will be analyzed in a similar way as proportion of patients with SGRQ 
improvement ≥4 points at Week 52, except that the response variable will be the responder status 
at the corresponding visit instead of at Week 52. Odds ratio of being a responder comparing 
dupilumab to placebo will be provided along with the corresponding 95% CI and p-value at each 
visit. Descriptive statistics including number and percentage of responders will also be provided. 
Primary estimand for other secondary efficacy endpoints is summarized in Appendix L. 
2.4.4.4.3 Analyses of time to first moderate or severe COPD exacerbation compared to placebo 
during the 52-week treatment period  
The time to first moderate or severe COPD exacerbation will be analyzed using a Cox regression 
model. The model will include the time to the first event as the dependent variable, and treatment 
group, region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking status at 
screening (current smokers or not), baseline disease severity (as % predicted post-bronchodilator 
FEV1), and number of moderate or severe COPD exacerbation events within one year prior to the 
study (≤2, 3, or ≥4) as covariates. Hazard ratio and corresponding 95% CI and p values will be 
estimated for dupilumab versus placebo. The Kaplan-Meier method will be used to derive the 
probabilities that a patient would experience an event up to specific timepoints for each treatment 
group. Kaplan-Meier curves will be generated; point probabilities will be calculated. Interval 
estimates will be calculated using 95% point wise confidence intervals. 


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2.4.4.4.4 Analyses of annualized rate of severe COPD exacerbations over the 52-week 
treatment period  
The annualized event rate of severe COPD exacerbations will be analyzed in the same way as the 
primary analysis for the annualized rate of moderate or severe COPD exacerbation events. The 
estimated event rate for each treatment group and its two-sided 95% confidence intervals will be 
provided. The event rate ratio of dupilumab against placebo, two-sided 95% confidence intervals 
of the rate ratio and the corresponding p-value will also be provided. 
2.4.4.4.5 Additional subgroup analyses by smoking status  
Additional analyses based on smoking status at screening (current smokers, former smokers) will 
be performed other than the subgroup analyses specified in Section 2.4.4.1 and Section 2.4.4.2, In 
each subgroup (current smokers, former smokers), the endpoints will be analyzed using the same 
primary analysis approach for their corresponding endpoints in the total population.  
 For continuous endpoints, descriptive statistics including number of patients, mean, 
standard error, and least squares (LS) means for each subgroup will be provided. In 
addition, difference in LS means and the corresponding 95% confidence intervals (CI) will 
be provided for each subgroup. 
 For proportion type endpoints, odds ratio of being a responder comparing dupilumab to 
placebo will be provided for each subgroup along with the corresponding 95% CI and 
p-value. Descriptive statistics including number and percentage of responders will also be 
provided for each subgroup. 
 For time to event endpoints, hazard ratio and corresponding 95% CI and p values will be 
estimated for dupilumab versus placebo for each subgroup. The Kaplan-Meier method will 
be used to derive the probabilities that a patient would experience an event up to specific 
timepoints for each treatment group within the subgroup. Kaplan-Meier curves will be 
generated; point probabilities will be calculated. Interval estimates will be calculated using 
95% point wise confidence intervals. 
2.4.4.5 Analyses of exploratory efficacy endpoints  
2.4.4.5.1 Analyses of other continuous endpoints  
 For post-bronchodilator FEV1, the rate of change in FEV1 (termed as FEV1 slope) will be 
compared between dupilumab against placebo. Repeated post-bronchodilator FEV1 after 
Week 4 and after Week 8 up to Week 52 will be analyzed correspondingly using linear 
mixed-effects model with treatment, age, sex, height, region (pooled country), ICS dose at 
baseline (high dose ICS [yes/no]), smoking status at screening (current smokers or not), 
time since randomization, and treatment-by-time interaction and baseline post-
bronchodilator FEV1 as covariates. Intercept and time since randomization are random 
effects. Individual post-BD FEV1 slope will be calculated as the slope of a linear 
regression model with the post-BD FEV1 (L) at each visit as the response variable and the 
time since randomization as the independent variable. Descriptive statistics including 
number of patients, mean, standard error of the individual post BD FEV1 slopes will be 
provided. Estimated from the linear mixed-effects model, least squares (LS) means, 


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difference in LS means and the corresponding 95% confidence intervals (CI) will also be 
provided. 
 Change from baseline in FVC (percent predicted and absolute change in ml), weekly E-RS 
symptom scores at all time-points will be analyzed in a similar way as change from 
baseline in pre-bronchodilator FEV1 at Week 52. Age, sex and height will be included as 
covariates only in the models for spirometry parameters. Descriptive statistics including 
number of patients, mean, standard error, and least squares (LS) means will be provided. 
In addition, difference in LS means and the corresponding 95% confidence intervals (CI) 
will be provided. 
 Change from baseline in BODE index score at Week 52 will be analyzed using the 
ANCOVA model with the following covariates: treatment group, region (pooled country), 
ICS dose at baseline (high dose ICS [yes/no]), smoking status at screening (current 
smokers or not), and baseline BODE index score. Descriptive statistics including number 
of patients, mean, standard error, and least squares (LS) means will be provided. In 
addition, difference in LS means and the corresponding 95% confidence intervals (CI) will 
be provided. 
 EQ-5D-5L single index and EQ visual analog scale score will be analyzed using MMRM 
model with the following covariates: treatment group, region (pooled country), ICS dose at 
baseline (high dose ICS [yes/no]), smoking status at screening (current smokers or not), 
visit, treatment-by-visit interaction, baseline EQ-5D-5L single index (or EQ visual analog 
scale score), and corresponding baseline-by-visit interaction. Descriptive statistics 
including number of patients, mean, standard error, and least squares (LS) means will be 
provided. In addition, difference in LS means and the corresponding 95% confidence 
intervals (CI) will be provided. 
2.4.4.5.2 Analyses of time to first severe COPD exacerbation compared to placebo during the 
52-week treatment period  
The time to first severe COPD exacerbation will be analyzed using the same approach as that for 
the analyses of time to first moderate or severe COPD exacerbation compared to placebo during 
the 52-week treatment period. Hazard ratio and corresponding 95% CI and p values will be 
estimated for dupilumab versus placebo. The Kaplan-Meier method will be used to derive the 
probabilities that a patient would experience an event up to specific timepoints for each treatment 
group. Kaplan-Meier curves will be generated; point probabilities will be calculated. Interval 
estimates will be calculated using 95% point wise confidence intervals. 
2.4.4.5.3 Analyses of COPD exacerbation utilizing the Exacerbations of Chronic Pulmonary 
Disease Tool (EXACT)  
COPD exacerbation will be derived using EXACT method as specified in the Exacerbations of 
Chronic Pulmonary Disease Tool (EXACT) Patient-Reported Outcome (PRO) User Manual- 
Scoring guide (Version 8.0), March 2016.  
The annualized event rate of COPD exacerbations assessed by the EXACT over 52 weeks 
(a tertiary/exploratory endpoint) will be analyzed in the same way as the primary analysis for the 


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annualized rate of moderate or severe COPD exacerbation events but based on exacerbation 
defined by EXACT method instead of the adjudicated data of AECOPD page in eCRF. The 
estimated event rate for each treatment group and its two-sided 95% confidence intervals will be 
provided. The event rate ratio of dupilumab against placebo, two-sided 95% confidence intervals 
of the rate ratio will also be provided. 
2.4.4.5.4 Analyses of controller medication change after exacerbation  
Increase in number of controller medication and/or total daily dose after adjudicated exacerbation 
during the treatment period will respectively be summarized by treatment group in terms of 
number of exacerbation events. For patients who discontinue treatment, data collected during the 
off- treatment period will also be used. Descriptive statistics including number, mean, median, 
standard deviation, min, and max will be provided, and no statistical testing will be conducted.  
2.4.4.6 Missing data handling  
For all continuous efficacy endpoints, the details of missing data handling are described in  
Section 2.4.4.1. 
For responder type endpoints, the details of missing data handling are described in  
Section 2.4.4.4.2. 
In addition, the reason and pattern of missing data will be carefully examined and pattern mixture 
modeling approach and other sensitivity analyses will also be performed as specified in  
Section 2.4.4.1. 
2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment group. All safety data collected up 
to the primary analysis cut-off date (either the IA cut-off date or cut-off date when last patient 
completes Week 52) will be included. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
 The baseline value is defined as the last available value before the first dose of IMP. 
 The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs and ECG [Appendix A] 
 PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.  
The number of all such patients will be the numerator for the on-treatment PCSA 
percentage 


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 The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. 
 For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the endpoint value and/or the worst 
on-treatment value.  The endpoint value is commonly defined as the value collected at the 
end of treatment.  If this value is missing, this endpoint value will be the closest value 
prior to the end of treatment epoch.  The worst value is defined as the nadir and /or the 
peak post-baseline (up to the end of treatment epoch or EOT) according to the direction 
(minimum or maximum) of the abnormality as defined in the PCSA list 
 The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned.  Relative risks versus placebo and their 95% confidence intervals may 
be provided, if relevant 
 All safety values including unscheduled measurements will be assigned to the appropriate 
safety analysis visit window defined in Section 2.5.3.  
2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment. The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.2. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an 
adverse event.  Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase.  The denominator for computation of percentages is 
the safety population within each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified. Sorting will be based on results 
for the dupilumab 300 mg q2w group. 
Risk differences (constructed using the Miettinen and Nurminen method) and hazard ratios 
(Cox proportional hazards model) for dupilumab versus placebo with corresponding 95% CIs will 
be provided for the overview table, common TEAEs (PT ≥1%, 2%, 5% in any intervention 


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group), and AESIs and other selected AE grouping events table. Participants without an event will 
be censored at the end of the treatment-emergent period in the Cox model. Forest plots will also 
be presented.  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
 Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any: 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
 All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
 Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT. 
 All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC in the 300 q2w 
treatment group.  
 All treatment-emergent adverse events regardless of relationship and related by primary 
SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 treatment-
emergent adverse event, sorted by the internationally agreed SOC order.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order. 
 All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC in the 300 q2w treatment 
group. 
 Number (%) of patients experiencing treatment-emergent adverse event(s) presented by 
primary and secondary SOC, HLGT, HLT, and PT sorted by the internationally agreed 
SOC order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
A listing of all treatment-emergent adverse events will be presented. 
Analysis of all treatment emergent serious adverse event(s) 
 All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order. 


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 All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
 All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 treatment-emergent serious adverse event, sorted by 
the internationally agreed SOC order and by decreasing incidence of PTs within each SOC 
in the 300 q2w treatment group.   
A listing of all treatment-emergent serious adverse events will be presented 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
 All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
 All treatment-emergent adverse events leading to permanent treatment discontinuation or 
drug interruption, by primary SOC and PT, showing number (%) of patients with at least 
one TEAE, will be presented by SOC internationally agreed order and by decreasing 
incidence of PTs within each SOC in the 300 q2w treatment group. 
Analysis of Major Cardiovascular Adverse Events (MACE) 
 The number and percentage (%) of patients with any treatment-emergent event selected for 
adjudication will be summarized by primary SOC and PT. 
 All events submitted for adjudication will be listed, including the final adjudicated result. 
 The number and percentage (%) of patients experiencing a treatment-emergent adjudicated 
event will be summarized within each treatment group. 
 The risk difference (asymptotic 95% CI with continuity correction) will be computed for 
the dupilumab dose versus placebo. Kaplan-Meier plots to depict the course of onset over 
time will also be provided. 
Analysis of adverse events of special interests (AESI)and other selected AE groupings 
 All treatment-emergent adverse events, by selected standardized MedDRA query (SMQ) 
and PT or by laboratory values (as in ALT elevation), showing the number (%) of patients 
with at least 1 PT, sorted by decreasing incidence of PTs within each SMQ in the 300 q2w 
treatment group. 
 For each AESI and other selected AE groupings,  
- 
Number (%) of patients with any specific TEAE  
- 
Number (%) of patients with any specific serious AE (regardless of treatment emergent 
status) 
- 
Number (%) of patients with any specific treatment emergent serious AE 
- 
Number (%) of patients with any specific AE leading to death 
- 
Number (%) of patients with any specific TEAE leading to permanent study drug 
discontinuation 


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- 
Number (%) of patients with any specific TEAE related to IMP reported by 
investigator 
- 
Number (%) of patients with any specific TEAE by maximum intensity, corrective 
treatment, and final outcome 
- 
Number of any specific TEAE adjusted by the exposure duration 
- 
Number of patients with any specific TEAE adjusted by the exposure duration at risk. 
For each specific TEAE, Kaplan-Meier estimates of cumulative incidence at Week 12, 
24, 36 and 52 and K-M plot may be provided to depict the course of onset over time if 
the number of events is large enough. 
- 
Number (%) of patients with injection site reactions by the related injection. 
- 
Number (%) of patients with different number of injection site reactions. 
 In addition, AESIs reported by the investigator in CRF will be summarized separately. 
Analysis of pretreatment adverse events  
 All pretreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC in the 300 q2w treatment 
group. 
 All serious pretreatment adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC. 
 All pretreatment adverse events leading to permanent treatment discontinuation by 
primary SOC and PT, showing the number (%) of patients, sorted by the internationally 
agreed SOC order and decreasing incidence of PTs within each SOC. 
 All pretreatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
 If only a few patients have pretreatment adverse events leading to permanent treatment 
discontinuation, a listing will be presented instead of the summary table above. 
2.4.5.2 Deaths  
The following summaries of deaths will be generated for the safety population. 
 Number (%) of patients who died by study period (TEAE, on-study, on-treatment, 
poststudy).  
 Deaths in nonrandomized patients or randomized but not treated patients. 
 Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC, HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC.  
 All pretreatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 


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A listing of deaths will be provided. 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or worst on-treatment value) by treatment group.  For each continuous 
parameters listed in Section 2.1.4.3, mean changes from baseline with the corresponding standard 
error will be plotted over time in each treatment group. This section will be organized by 
biological function as specified in Section 2.1.4.3. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  
 Normal/missing 
 Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
For PCSA analyses, the laboratory measurements obtained at either scheduled or unscheduled 
visits should be used; and, both the centralized and local test results should be used, as long as 
their available dates/time is different from each other’s. Centralized data will be used 
preferentially to the local measures in the PCSA analyses when measurements are performed on 
the same date and at the same time for a given laboratory test. 
Additional analyses for potential drug-induced liver injury 
The following additional analyses will be performed for potential drug-induced liver injury:  
 Time to onset of the initial ALT elevation (>3 x ULN), AST elevation (>3 x ULN) and 
total bilirubin elevation (>2 x ULN) will be analyzed with K-M curves, presented by 
intervention group. 
 A graph of distribution of peak values of ALT versus peak values of total bilirubin will 
also be presented.   
 For each liver function test (eg, ALT), participants having a PCSA (eg, ALT >5 ULN) will 
be summarized using the following categories: Returned to baseline PCSA status (or 
returned to value ≤ ULN in case of missing baseline) before last IMP dose, Returned to 
baseline PCSA status after last IMP dose, Never returned to baseline PCSA status, No 
assessment after elevation. This summary will be performed by categories of elevation 
(ALT >3, >5, >10, >20 ULN). 
2.4.5.4 Analyses of vital sign variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables (values and changes from baseline) will be calculated 


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for each visit or study assessment (baseline, each postbaseline time point, last on-treatment and/or 
worst on-treatment value) by treatment group.  For all parameters, mean changes from 
baseline with the corresponding standard error will be plotted over time (at same time points) in 
each treatment group.  
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and/or according to the 
following baseline status categories:  
 Normal/missing 
 Abnormal according to PCSA criterion or criteria 
2.4.5.5 Analyses of electrocardiogram variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all ECG variables (central laboratory values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each postbaseline time point, last on-
treatment and/or worst on-treatment value) by treatment group. For all parameters, mean changes 
from baseline with the corresponding standard error will be plotted over time (at the same time 
points) in each treatment group. 
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and/or according to the 
following baseline status categories: 
 Normal/missing 
 Abnormal according to PCSA criterion or criteria 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables  
2.4.6.1 Pharmacokinetic analyses  
2.4.6.1.1 Analyses of serum concentrations of SAR231893 (REGN668)  
Serum concentrations of SAR231893 (REGN668) will be summarized in the PK population using 
arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation 
(CV), minimum, median and maximum per sampling time. If date and/or time of the drug 
injection and/or sampling is missing then the concentration will not be taken into account. For 
drug-treated patients, where concentration values are below the lower limit of quantification 
(LLOQ), one-half of the LLOQ will be used. Values will be expressed in the tables with no more 
than three significant figures. For patients in the placebo group, concentration values are below 
the LLOQ will be taken into account with a plasma concentration considered equal to 0. 


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2.4.6.1.2 Analyses of ADA variables  
The following summary will be provided based on ADA population: 
 Number (%) of patients with pre-existing immunoreactivity 
 Number (%) of patients with treatment-emergent ADA  
 The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for patients with treatment-emergent ADA, and patients with 
persistent, indeterminate and transient ADA response 
 Number (%) of patient with transient treatment-emergent ADA  
 Number (%) of patients with persistent treatment-emergent ADA  
 Number (%) of patients with indeterminate treatment-emergent ADA  
 Number (%) of patients with treatment-boosted ADA  
 The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for patients with treatment-boosted ADA  
 The summary statistics (including number, mean, SD, median, Q1, Q3, minimum and 
maximum) of the ratio of peak post-baseline titer to baseline titer for patients with 
treatment-boosted ADA  
 Listing of ADA peak titer levels and neutralizing antibody status  
 Number (%) of patients with neutralizing antibody status  
Kinetics of treatment-emergent ADA response 
Number (%) of patients with treatment-emergent ADA positive response at each visit will be 
summarized by each treatment group. 
Plot of percentage of patients with treatment-emergent ADA positive response at each visit will be 
provided by each treatment group. 
Impact of ADA on PK  
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
serum concentration of dupilumab may be explored for each dupilumab dose group. Plot of serum 
concentration of functional SAR231893 (REGN668) versus visit will be provided by ADA 
classifications for each dupilumab dose group. Individual patient plots of PK according to ADA 
status will be provided to determine which individuals may have had PK impacted by ADAs. 
Association of ADA with clinical efficacy endpoints 
Associations between the ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and the 
primary efficacy endpoint may be explored for the dupilumab dosed group. 


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Association of ADA with clinical safety endpoints 
Association of safety versus ADA status may be analyzed in the ADA population. The safety 
assessment may focus on the following events: 
Severe injection site reactions last longer than 24 hours or serious injection site reactions 
 Hypersensitivity reactions (SMQ (20000214) hypersensitivity narrow search confirmed by 
medical review) 
 Anaphylactic reactions (SMQ (20000021) anaphylactic reaction narrow search) 
 In response to AESI like anaphylaxis or hypersensitivity additional ADA samples closer to 
the event may be analyzed, based on the judgment of the medical investigator and/or 
medical monitor. 
 Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent and treatment-boosted) and safety may be explored. 
2.4.6.2 Pharmacodynamics/genomics analyses  
All biomarkers listed in Section 2.1.6 will be summarized in the Safety population defined as 
patients who actually received at least 1 dose or part of a dose of the IMP.  Baseline values will be 
the last value collected prior to the first IMP. Descriptive statistics (including number, mean, SD, 
median, Q1, Q3, min, max) of biomarkers at baseline will be summarized. 
Summary plots (mean +/- standard error of the mean) on values at each visit, absolute changes 
from baseline and percent changes from baseline will be provided for each biomarker by 
treatment group and visit. 
Exploratory analysis of DNA/RNA will be addressed in a separate document. 
2.4.7 Analyses of health economics variables  
Analyses of healthcare resource utilization will be performed outside of CSR under the 
responsibility of the Health Economics and Value Assessment (HEVA) department of Sanofi.  
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Demographic formulas 
Age is calculated as: 
Integer part of (informed consent date -birth date)/365.25 


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Age of onset of COPD is calculated as: 
Integer part of (COPD diagnosis date - birth date)/365.25 
BMI is calculated as: 
Weight in kg / (height2 in meters) 
Smoking quantity (pack-year) is calculated as following: 
Number of pack-year= (packs smoked per day) × (years as a smoker) 
Renal function formulas  
For patients ≥18 years old, creatinine clearance (CLcr) value will be derived using the equation of 
Cockroft and Gault: 
CLcr (ml/min) = (140 - age) × weight (kg) × (1 - 0.15 × sex (0-M, 1-F))/ (0.814 × creatinine 
(μmol/L)) 
CLcr will be calculated using the last weight measurement on or before the visit of the creatinine 
measurement and age at the lab sampling date. Here age is calculated as following: 
Age = integer part of (lab sampling date - birth date)/365.25 
2.5.2 Data handling conventions for secondary efficacy variables  
Periodical average of daily efficacy endpoints at designated study days 
For the daily efficacy endpoints, the time period used to calculate the periodical average at each 
designated study day is summarized in Table 5. 
Randomization day is used as the reference day (Day 1). 
Table 5 - Periodical average of daily efficacy assessment  
Time point 
EXACT, E-RS:COPD 
Day 8 (Week 1) 
2-8 
Day 15 (Week 2) 
9-15 
Day 22 (Week 3) 
16-22 
Day 29 (Week 4) 
23-29 
Day 36 (Week 5)  
30-36 
Day 43 (Week 6) 
37-43 
… 
… 
Day 365 (Week 52) 
359-365 
… 
… 
Day 449 (Week 64) 
443-449 


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2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page.  If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be 
classified as treatment-emergent.  No imputation of adverse event end dates/times will be 
performed.  These data imputations are for categorization purpose only and will not be used in 
listings.  No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.  
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 


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Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points  
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be the date of first IMP administration. Selected safety variables will be summarized 
by the analysis window define in Table 6 for the by visit descriptive analysis. All available values 
from central lab will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. For procedures planned on Visit 2, if it is done on the same date as the first IMP 
injection but the performance time is missing, it will belong to Visit 2 time window. 
Table 6 - Time window for safety endpoints  
 
Target 
Day 
 
 
Time windows for 
Visit 
Vital 
signs 
Hematology, 
biochemistry, 
urinalysis  
Serum 
Pregnancy test, 
Hepatitis and 
HIV serology 
tests, height 
Urine 
Pregnancy 
test 
Physical 
examination 
Body 
weight 
ECG 
Visit 1  
(Week -
4±1) 
-28±7 
<-14 
<-14 
1- 
 
<-14 
1- 
<-14 
Visit 2  
(Week 0) 
1 
-14-1- 
-14-1- 
 
1- 
-14-1- 
 
-14-1- 
Visit 3  
(Week 2) 
15 
1+-21 
 
 
 
 
 
 


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Target 
Day 
 
 
Time windows for 
Visit 
Vital 
signs 
Hematology, 
biochemistry, 
urinalysis  
Serum 
Pregnancy test, 
Hepatitis and 
HIV serology 
tests, height 
Urine 
Pregnancy 
test 
Physical 
examination 
Body 
weight 
ECG 
Visit 4  
(Week 4) 
29 
22-42 
1+-42 
 
1+-42 
 
 
 
Visit 5  
(Week 8) 
57 
43-70 
43-70 
 
43-70 
 
 
 
Visit 6  
(Week 12) 
85 
71-126 
71-126 
 
71-98 
 
 
1+-126 
Visit 7  
(Week 16) 
113 
 
 
 
99-126 
 
 
 
Visit 8  
(Week 20) 
141 
 
 
 
127-154 
 
 
 
Visit 9  
(Week 24) 
169 
127-210 
127-210 
 
155-182 
1+-266 
 
127-210 
Visit 10 
(Week 28) 
197 
 
 
 
183-210 
 
 
 
Visit 11 
(Week 32) 
225 
 
 
 
211-238 
 
 
 
Visit 12 
(Week 36) 
253 
211-280 
211-308 
 
239-266 
 
 
211-308 
Visit 13 
(Week 40) 
281 
 
 
 
267-294 
 
 
 
Visit 14 
(Week 44) 
309 
281-336 
 
 
295-322 
 
 
 
Visit 15 
(Week 48) 
337 
 
 
 
323-350 
 
 
 
Visit 16 
(Week 52) 
365 
337-406 
309-406 
 
351-406 
267-406 
1+-406 
309-406 
Visit 17 
(Week 56) 
393 
 
 
 
 
 
 
 
Visit 18 
(Week 60) 
421 
 
 
 
 
 
 
 
Visit 19 
(Week 64) 
449 
>406 
>406 
 
>406 
>406 
>406 
>406 
1-: up to 1st dose date/time;  
1+: after 1st dose date/time; 
For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the randomization day. If a patient receives IMP prior to the randomization by 
mistake, the reference date of efficacy assessment will be the date of the first IMP administration 
for that patient. For the primary analyses, all available values of scheduled measurements will be 
assigned to the appropriate visit window according to Table 7. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 


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be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. 
Table 7 - Time window for efficacy variables  
Visit 
Target 
Day 
Time windows for  
 
 
Pre-bronchodilator 
Spirometry 
Post-bronchodilator 
Spirometry 
SGRQ 
EQ-5D-5L 
BODE 
Visit 1  
(Week -4±1) 
-28±7 
<-14 
<-14 
 
 
 
Visit 2  
(Week 0) 
1 
-14-1- 
-14-1- 
1- 
1- 
1- 
Visit 3  
(Week 2) 
15 
1+-21 
1+-21 
 
 
 
Visit 4  
(Week 4) 
29 
22-42 
22-42 
1+-56 
 
 
Visit 5  
(Week 8) 
57 
43-70 
43-70 
 
 
 
Visit 6  
(Week 12) 
85 
71-126 
71-126 
57-126 
 
 
Visit 7  
(Week 16) 
113 
 
 
 
 
 
Visit 8  
(Week 20) 
141 
 
 
 
 
 
Visit 9  
(Week 24) 
169 
127-210 
127-210 
127-210 
1+-266 
 
Visit 10  
(Week 28) 
197 
 
 
 
 
 
Visit 11  
(Week 32) 
225 
 
 
 
 
 
Visit 12  
(Week 36) 
253 
211-280 
211-308 
211-308 
 
 
Visit 13  
(Week 40) 
281 
 
 
 
 
 
Visit 14  
(Week 44) 
309 
281-336 
 
 
 
 
Visit 15  
(Week 48) 
337 
 
 
 
 
 
Visit 16  
(Week 52) 
365 
337-406 
309-406 
309-406 
>266 
>1+ 
Visit 17  
(Week 56) 
393 
 
 
 
 
 
Visit 18 
(Week 60) 
421 
 
 
 
 
 
Visit 19  
(Week 64) 
449 
>406 
>406 
>406 
 
 
1-: up to randomization and before 1st dose date/time;  
1+: after randomization or 1st dose date/time 


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For the pharmacokinetics/pharmacodynamics variables summary, the reference date for the 
derivation of relative days of measurements will be the date of first IMP administration if the 
patient is treated with study treatment, or the randomization date if the patient is not treated. 
Pharmacokinetics /pharmacodynamics variables will be summarized by the analysis window 
defined in Table 8 for the by visit descriptive analyses. All available values of measurements will 
be assigned to the appropriate visit window. In the event of multiple measurements of the same 
test in the same window, the one closest to the targeted visit date will be used for the by-visit 
summary. If they are at the same distance to the target day, the latest one will be used. For 
procedures planned on Visit 2, if it is done on the same date as the first IMP injection but the 
performance time is missing, it will belong to Visit 2 time window. 
Table 8 - Time window for pharmacokinetics/pharmacodynamics variables  
Visit 
Target 
day 
Time windows for 
FeNO post- 
Bronchodilator 
Serum 
dupilumab 
concentration 
Anti-drug 
antibodies 
Total 
IgE 
PARC 
Eotaxin-3 
Fibrinogen 
Visit 1  
(Week -4±1) 
-28±7 
 
 
 
 
 
 
 
Visit 2  
(Week 0) 
1 
1- 
1- 
1- 
1- 
1- 
1- 
1- 
Visit 3  
(Week 2) 
15 
 
1+-21 
 
 
 
 
 
Visit 4  
(Week 4) 
29 
1+-42 
22-42 
 
 
 
1+-56 
 
Visit 5  
(Week 8) 
57 
43-70 
43-70 
 
 
 
 
 
Visit 6  
(Week 12) 
85 
71-126 
71-126 
1+-126 
1+-224 
 
57-126 
 
Visit 7  
(Week 16) 
113 
 
 
 
 
 
 
 
Visit 8  
(Week 20) 
141 
 
 
 
 
 
 
 
Visit 9  
(Week 24) 
169 
127-210 
127-210 
127-266 
 
 
127-266 
1+-266 
Visit 10  
(Week 28) 
197 
 
 
 
 
 
 
 
Visit 11  
(Week 32) 
225 
 
 
 
 
 
 
 
Visit 12  
(Week 36) 
253 
211-308 
211-308 
 
 
 
 
 
Visit 13  
(Week 40) 
281 
 
 
 
 
 
 
 
Visit 14  
(Week 44) 
309 
 
 
 
 
 
 
 
Visit 15  
(Week 48) 
337 
 
 
 
 
 
 
 


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Visit 
Target 
day 
Time windows for 
FeNO post- 
Bronchodilator 
Serum 
dupilumab 
concentration 
Anti-drug 
antibodies 
Total 
IgE 
PARC 
Eotaxin-3 
Fibrinogen 
Visit 16  
(Week 52) 
365 
309-406 
309-406 
267-406 
225-
406 
1+-406 
267-406 
267-406 
Visit 17  
(Week 56) 
393 
 
 
 
 
 
 
 
Visit 18  
(Week 60) 
421 
 
 
 
 
 
 
 
Visit 19  
(Week 64) 
449 
>406 
>406 
>406 
>406 
>406 
>406 
>406 
1-: up to 1st dose date/time or randomization if patient is not treated;  
1+: after 1st dose date/time or randomization date if patient is not treated; 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be included in the 
by-visit summaries, computation of baseline, worst values, and PCSAs. 
2.5.6 Pooling of centers for statistical analyses  
Due to the large number of centers, the randomization is stratified by country. Due to small 
sample size in some countries, the countries will be pooled into regions as defined below for the 
analyses: 
 Latin America: Argentina, Colombia, Peru, Chile, Brazil and Mexico;  
 East Europe: Russia, Ukraine, Poland, Bulgaria, Lithuania, Latvia, Czech Republic, 
Slovakia, Hungary, Romania, Serbia;  
 Western Countries: Australia, Belgium, France, Portugal, Spain, Germany, Netherlands, 
United Kingdom, South Africa, Canada, USA, Greece. 
2.5.7 Statistical technical issues  
Not applicable. 


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3 
INTERIM ANALYSIS  
An interim analysis is planned when the information fraction is ≥0.92 based on follow-up time for 
the primary endpoint of annualized rate of moderate or severe COPD exacerbations over a 
52-week treatment period. The information fraction at the time of interim analysis will be 
estimated using a conservative approach assuming all ongoing patients complete the 52-week 
treatment period. All participants will have complete follow-up for the key secondary endpoint of 
change from baseline in FEV1 at Week 12. The purpose of this interim analysis is to potentially 
demonstrate efficacy when ≥92% of the information fraction for the primary endpoint is available, 
but prior to all patients completing the 52-week treatment period, as COPD is a disease with a 
high unmet medical need.  
To control the overall type I error at α=0.05, the Kim DeMets approach (9) will be used with the 
power parameter rho (ρ) determined based on the information fraction observed at the time of the 
interim analysis and to maintain an α=0.049 at the final analysis (Table 9). The details of the 
hierarchical testing strategy at interim analysis and final analysis are specified in Section 2.4.4.3. 
Table 9 - Kim-DeMets alpha spending function to control the overall alpha at 0.05  
Information fraction 
Rho (ρ) 
α at interim analysis  
α at final analysis 
0.92 to <0.93 
12 
0.018 
0.049 
0.93 to <0.94 
12 
0.020 
0.049 
0.94 to <0.95 
13 
0.022 
0.049 
0.95 to <0.96 
14 
0.024 
0.049 
0.96 to <0.97 
15 
0.027 
0.049 
 
This interim analysis will be performed by independent statisticians that support the DMC and are 
separated from personnel involved in the trial conduct. The DMC will review the unblinded result 
of the primary endpoint and will communicate if the criterion for efficacy is met. The DMC is 
established and will continue the regular review of unblinded safety data as described in the DMC 
charter. In the event that statistical significance is demonstrated on the primary endpoint the 
additional inferential analyses will be performed by the unblinded Sponsor team. To maintain 
study integrity with respect to the subsequent visits, follow-up and final analyses after this interim 
analysis, a dissemination plan will be written. This plan will clearly identify two independent 
study teams (blinded team and unblinded team) and provide further details on the unblinding plan. 
People involved in the conduct of the study (patients, Investigators, Site Staff, and the blinded 
Study and Project Team) will have no access to unblinded patient level data, individual patient 
treatment codes, or unblinded tables or figures (details described in the Dissemination plan).  


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4 
DATABASE LOCK  
The database lock for primary analysis is planned based on the results of the interim analysis (see 
more details in Section 3).  
If efficacy at the interim analysis is not demonstrated, the database lock for the primary analysis 
will be planned based on the date when the last patient completes the Week 52 visit or 
discontinues from the study before Week 52. Analyses will be based on all data collected up to 
this database lock and will be considered as the final analysis of the CSR. Additional data 
between this database lock and last patient completing last visit will be summarized in a CSR 
addendum. 
If efficacy at the interim analysis is demonstrated, then the interim analysis database lock will be 
considered the primary analysis for all endpoints. The database lock for final analysis is planned 
when all patients complete the Week 52 visit or discontinue from the study before Week 52 but 
may occur when all patients complete the Week 64 visit or discontinue from the study.  


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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 


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6 
REFERENCES  
 
1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation 
of spirometry. Eur Respir J. 2005;26:319-38. 
2. Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir 
Med. 1991;85 Suppl B:25-31; discussion 33-7. 
3. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status 
for chronic airflow limitation. The St. George's Respiratory Questionnaire. Am Rev Respir 
Dis.1992;145(6):1321-7. 
4. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma 
and COPD. Eur Respir J. 2002;19:398-404. 
5. Jones PW. St George’s Respiratory Questionnaire: MCID. 2005;2(1):75-9. 
6. The Exacerbations of Chronic Pulmonary Disease Tool (EXACT) Patient-Reported Outcome 
(PRO) User Manual-Scoring guide (Version 8.0), March 2016. 
7. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-
mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive 
pulmonary disease. N Engl J Med. 2004;350(10):1005-12. 
8. Van Agthoven M, Fokkens WJ, Van de Merwe JP, Marijke Van Bolhuis E, Uyl-de Groot CA, 
Busschbach JJ. Am J Rhinol. 2001;15:231-7. 
9. Kyungmann K, DeMets DL. Design and analysis of group sequential tests based on the type I 
error spending rate function. Biometrika. 1987;74(1):149-54. 
 
 


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7 
LIST OF APPENDICES  
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
St. George’s respiratory questionnaire 
Appendix C: 
SGRQ scoring algorithm 
Appendix D: 
EXACT questionnaire 
Appendix E: 
EQ-5D 
Appendix F: 
BODE 
Appendix G: 
High dose of inhaled corticosteroids: adults 
Appendix H: 
Definition of anaphylaxis 
Appendix I: 
List of opportunistic infections 
Appendix J: 
Selection criteria for AE groupings 
Appendix K: 
Handling of missing data 
Appendix L: 
Summary of primary estimand for main endpoints 


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Appendix A 
Potentially clinically significant abnormalities criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014) 
Parameter 
PCSA 
Comments 
CLcr (mL/min) 
(Estimated 
creatinine clearance 
based on the 
Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014) 
Parameter 
PCSA 
Comments 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male); ≤0.32 v/v (Female) 
≥0.55 v/v (Male); ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White 
Paper on PR and QRS (Nada et al. Am Heart J. 
2013; 165(4): 489-500) 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014) 
Parameter 
PCSA 
Comments 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
>220 ms 
>220 ms and increase from baseline ≥25% 
>240 ms 
>240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
Absolute values (ms) 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 


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Appendix B 
St. George’s respiratory questionnaire  


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Appendix C 
SGRQ scoring algorithm  


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Appendix D 
EXACT questionnaire  


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Appendix E 
EQ-5D  






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Appendix F 
BODE  
 


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Appendix G 
High dose of inhaled corticosteroids: Adults  
The following list of high dose of ICS is not a comprehensive list; the ICS that are not part of the 
list should be discussed with the Sponsor to confirm high vs. lower dose prior to randomization. 
 
Inhaled corticosteroid 
Daily dose (mcg) 
  
High 
Lower doses 
Beclometasone dipropionate (CFC) 
>1000 
</=1000 
Beclometasone dipropionate (HFA) 
>400 
</=400 
Budesonide (DPI) 
>800 
</=800 
Ciclesonide (HFA) 
>320 
</=320 
Fluticasone propionate (DPI or HFA) 
>500 
</=500 
Mometasone furoate  
>440 
</=440 
Triamcinolone acetonide 
>2000 
</=2000 
(Adapted from GINA 2014 Guidance) 
High dose of inhaled corticosteroids:  Adults (Japan) 
Inhaled corticosteroid 
Daily dose (mcg) 
High dose 
lower doses 
Beclometasone dipropionate (HFA) 
401-800 
</= 400 
Fluticasone propionate (HFA) 
401-800 
</=400 
Ciclesonide (HFA) 
401-800 
</=400 
Fluticasone propionate (DPI) 
401-800 
</=400 
Budesonide (DPI) 
801-1600 
</=800 
Budesonide inhalation suspension  
1<x<=2 
</=1.0 
(Adapted from Japanese Asthma Prevention and Management Guideline 2018) 
CFC – chlorofluorocarbon; HFA – hydrofluoroalkane; DPI – dry powder inhaler;  
 


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Appendix H 
Definition of anaphylaxis  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death.” 
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum 
A, et al.  Second symposium on the definition and management of anaphylaxis: Summary report—
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol  2006;117: 391-7)  
Clinical criteria for diagnosing anaphylaxis 
 
 
 
 
 


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Appendix I 
List of opportunistic infections  
 Aspergillosis 
 Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
 Candidiasis – Note that all cases should be collected as AEs. only systemic or extensive 
mucosal or cutaneous candidiasis is considered opportunistic infections 
 Coccidioides immitis (endemic south-western US and Central and South America) 
 Cryptococcus 
 Cytomegalovirus 
 Herpes Simplex (disseminated) 
 Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
 Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
 Listeriosis 
 Mycobacterium avium 
 Nontuberculosis mycobacteria 
 Pneumocystis pneumonia (PCP) 
This list is indicative and not exhaustive 


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Appendix J 
Selection criteria for AE groupings  
 
Grouping 
Preferred Term Code 
Preferred Term 
Conjunctivitis 
10001257 
Adenoviral conjunctivitis 
Conjunctivitis 
10010725 
Conjunctival irritation 
Conjunctivitis 
10010726 
Conjunctival oedema 
Conjunctivitis 
10010736 
Conjunctival ulcer 
Conjunctivitis 
10010741 
Conjunctivitis 
Conjunctivitis 
10010744 
Conjunctivitis allergic 
Conjunctivitis 
10010745 
Conjunctivitis chlamydial 
Conjunctivitis 
10010749 
Conjunctivitis gonococcal neonatal 
Conjunctivitis 
10010754 
Conjunctivitis tuberculous 
Conjunctivitis 
10010755 
Conjunctivitis viral 
Conjunctivitis 
10018258 
Giant papillary conjunctivitis 
Conjunctivitis 
10021629 
Inclusion conjunctivitis 
Conjunctivitis 
10030861 
Ophthalmia neonatorum 
Conjunctivitis 
10048908 
Seasonal allergy 
Conjunctivitis 
10049458 
Herpes simplex virus conjunctivitis neonatal 
Conjunctivitis 
10051625 
Conjunctival hyperaemia 
Conjunctivitis 
10053991 
Inclusion conjunctivitis neonatal 
Conjunctivitis 
10061784 
Conjunctivitis bacterial 
Conjunctivitis 
10062889 
Pingueculitis 
Conjunctivitis 
10063669 
Photoelectric conjunctivitis 
Conjunctivitis 
10067317 
Oculorespiratory syndrome 
Conjunctivitis 
10067817 
Acute haemorrhagic conjunctivitis 
Conjunctivitis 
10069166 
Blebitis 
Conjunctivitis 
10071570 
Ligneous conjunctivitis 
Conjunctivitis 
10074701 
Noninfective conjunctivitis 
Conjunctivitis 
10075264 
Oculoglandular syndrome 
Conjunctivitis 
10080825 
Conjunctivitis fungal 
Conjunctivitis 
10084034 
Conjunctival suffusion 
 
 


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Appendix K 
Handling of missing data  
Annualized rate of moderate or severe exacerbation events during the 52-Week period 
 Pattern mixture model - multiple imputation (PMM-MI) 
Step 1. The 52-week observation period is partitioned into bi-weekly (2-week) 
segments. 
By clinical definition, a patient can have at maximum 1 moderate or severe exacerbation 
event per two weeks. For each patient, his/her event count over 52 weeks is broken down 
into a series of binary outcomes across each of the 26 bi-weekly segments (52 weeks). In 
the analysis, for each patient, in each bi-weekly segment, an imputation flag (imputefl) 
will indicate whether the patient needs imputation in that segment. 
Step 2. Estimation for the bi-weekly binary event probability using observed data 
Within each bi-weekly segment, the logistic regression model will be fitted to the observed 
data to model coefficient estimates and the estimated variance-covariance matrix, with 
adjusting for the planned treatment group, region (pooled country), ICS dose at baseline 
(high dose ICS [yes/no]), smoking status at screening (current smokers or not), baseline 
disease severity (as % predicted post-bronchodilator FEV1), and number of moderate or 
severe COPD exacerbation events within one year prior to the study (≤2, 3, or ≥4). From 
the posterior distribution of the model coefficients, we randomly draw 40 sets of iid 
samples. As a result, for each patient and in each bi-weekly segment, 40 estimated 
probabilities can be obtained by using the 40 samples of coefficients and the patient’s 
covariate values. 
Step 3. Multiple Imputation of binary event by bi-weekly segment after study 
withdrawal 
If a patient withdraws from the study at the kth (1≤k<14) day of Segment i prior to Week 
52, and experienced a moderate or severe exacerbation within the first k days, this patient 
will be considered as “observed” (imputefl=0) up to Segment i and will need imputations 
(imputefl=1) from Segment i+1 to Segment 26 (Week 52). 
If a patient withdraws from the study at the kth (1≤k<14) day of Segment i prior to Week 
52, and has no moderate nor severe exacerbation in Segment i, this patient will be 
considered as “observed” (imputefl=0) up to Segment i-1 and will need imputations 
(imputefl=1) from Segment i to Segment 26 (Week 52). 
For a patient who needs imputation from Segment i+1 to Segment 26, in each bi-weekly 
segment, 40 independent random samples will be respectively drawn from 40 estimated 
Bernoulli distributions, whose probabilities are obtained in Step 2. 
For each patient who early withdraws from the study, 40 sets of complete event count data 
can be obtained by summing the observed event count prior to withdrawal and each series 
of imputed binary events after withdrawal up to Week 52. 


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Step 2 and 3 can be realized by using PROC MI in SAS. Sample code can be found below: 

data=dd seed=	


nimpute=out=outdata; 
by month; 
class outcome trt01pn  cntygr1 ics copdnum; 
monotone reg (FEV1bl/details); 
logistic (outcome=trt01pn cntygr1 ics smoking FEV1bl 
copdnum/details DESCENDING); 
var  cntygr1 ics smoking FEV1bl trt01pn copdnum outcome; 
; 
Step 4. Combining MI results by Rubin’s formula 
A negative binomial model with the same set of covariates as in the primary analysis will 
be fitted with 40 sets of complete datasets obtained in Step 3, so as to obtain 40 sets of 
treatment effect estimates (in log-scale) and p-values accordingly. Log transformed 
observation duration will be the offset variable for patients who complete the 52-Week 
treatment/study period, and log transformed 52 weeks will be the offset variable for 
patients who discontinue the study before Visit 16 (Week 52). At last, the SAS 
MIANALYZE procedure will be used to generate statistical inferences by combining 
results (in log-scale) from the 40 analyses using Rubin’s formula. These and their 
confidence interval limits are then exponentiated to derive relative rates. Of note, the rule 
will be applied on the log risks and log risk ratio. 
Step 4 can be realized by using PROC MIANALYZE in SAS. Sample code can be found 
below 

data=rr_conv; 
by Label; 
modeleffects Estimate; 
stderr StdErr; 
ods output ParameterEstimates=rr_pooled; 
; 
data=aer_conv; 
by TRT01PN; 
modeleffects Estimate; 
stderr StdErr; 
ods output ParameterEstimates=aer_pooled; 
; 
/* estimated RR and corresponding 95% CI */ 
data pouttx; 
 
set rr_pooled; 
if Parameter="txval"; 
rr = exp(estimate); 
; 


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 Control-based PMM-MI 
All steps are the same as the aforementioned approach except in Step 2: the individual 
bi-weekly mean probability will be calculated based on observations in matching placebo 
arms only, with adjustment of missing observation duration. 
 Tipping point analysis 
The tipping point analysis for severe exacerbation events will use the similar approach as 
PMM-MI with tipping values for the odds. 
Step 1. Estimation for the bi-weekly binary event probability using observed data 
Within each bi-weekly segment up to Week 52, the logistic regression model will be fitted 
to the observed data to obtain the model coefficient estimates and the estimated variance 
covariance matrix, with adjusting for the planned treatment group, region (pooled 
country), ICS dose at baseline (high dose ICS [yes/no]), smoking status at screening 
(current smokers or not), baseline disease severity (as % predicted post-bronchodilator 
FEV1), and number of moderate or severe COPD exacerbation events within one year prior 
to the study (≤2, 3, or ≥4). From the posterior distribution for the model coefficients, we 
randomly draw 40 sets of iid samples. As a result, for each patient and in each segment, 
40 estimated binary event probabilities can be obtained by using the 40 samples of 
coefficients and the patient’s covariate values. 
Step 2. Tip on the bi-weekly binary odds (the probability of having an event in the 
segment over the probability of being event-free in the segment) 
Within each segment, for the patients from the placebo group and need imputation in that 
segment, the estimated odds for binary event will be deflated by decreasing a positive 
amount; for the patients from the treatment group and need imputation in that segment, the 
estimated odds for binary event will be inflated by increasing a positive amount. After the 
deflation/inflation, 40 sets of binary event probabilities can be obtained for the placebo and 
treatment groups, respectively. 
Step 3. Multiple Imputation of binary event by bi-weekly segment after study withdrawal 
For a patient who needs imputation from Segment i+1 to Segment 26, in each segment, 
40 independent random samples will be respectively drawn from 40 estimated Bernoulli 
distributions, whose probabilities are obtained in Step 2. 
For each patient who early withdraws from the study, 40 sets of complete event count data 
can be obtained by summing the observed event count prior to withdrawal and each series 
of imputed binary events after withdrawal up to Week 52. 
Step 4. A negative binomial model with the same set of covariates as in the primary 
analysis will be fitted to the 40 sets of complete datasets obtained in Step 3, so as to obtain 
40 sets of treatment effect estimates and p-values accordingly. Log transformed 
observation duration will be the offset variable for patients who complete the 52-Week 
treatment/study period, and log transformed 52 weeks will be the offset variable for 
patients who discontinue the study before Visit 16 (Week 52). Then, the SAS 
MIANALYZE procedure will be used to generate statistical inferences by combining 
results from the 40 analyses using Rubin’s formula. 


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Step 2, 3 and 4 will be repeated iteratively until the p-value for combined treatment effect 
of dupilumab compared to placebo estimated in Step 4 is >0.05 or the maximum 
applicable treatment effect has been reached. 
Change from baseline in pre-BD FEV1 at Week 12 
 Pattern mixture model-multiple imputation (PMM-MI) 
Step 1. Monotone missing pattern was induced by Markov Chain Monte Carlo (MCMC) 
method using PROC MI: for patients who have missing values at intermediate visits, but 
have value at subsequent visits, the intermediate missing values were imputed assuming a 
multivariate normal distribution over observations from all visits. 40 datasets with a 
monotone missing pattern will be obtained using this method. 
Step 2. For each of the imputed dataset with monotone missing pattern obtained in Step 1, 
the remaining missing data will be imputed using the regression method for the monotone 
pattern with adjustment for covariates including treatment groups, age, sex, height, region 
(pooled country), ICS dose at baseline (high dose ICS [yes/no]), smoking status at 
screening (current smokers or not), and baseline pre-BD FEV1. All available data in the 
monotone missing pattern data will be used. 40 fully imputed datasets are obtained. 
Step 3. Each of the 40 complete datasets will be analyzed using an ANCOVA model with 
change from baseline in pre-BD FEV1 at Week 12 as the response variable, treatment, age, 
sex, height, region (pooled country), ICS dose at baseline (high dose ICS [yes/no]), 
smoking status at screening (current smokers or not), and baseline pre-BD FEV1 value as 
covariates. Then the SAS MIANALYZE procedure will be used to generate statistical 
inferences by combining results from the 40 analyses using Rubin’s formula. 
 Tipping point analysis 
Step 1. 40 imputations will be performed to generate 40 completed data sets following 
Step 1 and 2 for PMM-MI. 
Step 2. The imputed FEV1 values in Dupilumab group are subtracted by a positive amount 
d for each imputed data sets. 
Step 3. The imputed FEV1 values in placebo group are added by a positive amount p for 
each imputed data sets.  
Step 4. Change from baseline in pre-BD FEV1 will be analyzed using the ANCOVA 
model as described in the PMM-MI for each of the 40 complete datasets. Then the SAS 
MIANALYZE procedure will be used to generate statistical inferences by combining 
results from the 40 analyses using Rubin’s formula. 
Step 2 and Step 3 will be repeated iteratively until the p-value for treatment effect of 
dupilumab compared to placebo estimated in Step 4 is >0.05 or the maximum applicable 
treatment effect has been reached. 


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Appendix L 
Summary of primary estimands for main endpoints  
 
Endpoint 
Category 
Estimands 
Endpoint(s)a 
Population 
Intercurrent event(s) handling 
strategy and missing data 
handling 
Population-level 
summary 
Primary objective: The primary objective of this study is to evaluate the efficacy of dupilumab 300 mg every 2 weeks 
compared to placebo in reducing annualized rate of acute moderate or severe COPD exacerbation (AECOPD) over the 
52-week treatment period in patients with moderate or severe COPD. 
Primary 
endpoint –
Event 
Annualized rate 
of AECOPD 
exacerbation 
events over the 
52-week 
treatment period. 
ITT 
The intercurrent events will be handled 
as follows: 
 
Discontinuation of study treatment 
before Week 52: Off-study 
treatment data up to Week 52 will 
be included in the analysis 
(treatment policy strategy). 
In addition, the missing data imputation 
rules are as follows: 
 
Discontinuing the study follow-up 
before Week 52: Analyses will be 
censored at the time of study 
discontinuation. 
Negative binomial regression 
model using the total number 
of events occurred during the 
52-week planned treatment 
period as the response 
variable, with the treatment 
group, region (pooled 
country), ICS dose at 
baseline, smoking status at 
screening, baseline disease 
severity, and number of 
moderate or severe COPD 
exacerbation events within 
one year prior to the study as 
covariates. Log-transformed 
observation duration will be 
used as offset variable. 
Secondary objective: To demonstrate the efficacy of dupilumab on spirometry and health related quality of life 
endpoints, separately, at various time points or population 
Secondary 
endpoint – 
Continuous  
Change from 
baseline in FEV1 
at Week 12  
 
Change from 
baseline in FEV1 
at Week 52  
 
Change from 
baseline in 
SGRQ at 
Week 52 
 
Change from 
baseline in E-RS 
at Week 52b 
ITT  
(For FEV1 
endpoints, 
also patients 
with baseline 
FeNO 
≥20 ppb) 
The intercurrent events will be handled 
as follows: 
 
Discontinuing the study 
intervention prior to Week 12 or 
Week 52: all data collected after 
discontinuation will be used in the 
analysis (treatment policy 
strategy).  
In addition, the missing data imputation 
rules are as follows: 
 
Missing data will be imputed 
latently by MMRM based on 
missing at random assumption 
MMRM model using change 
from baseline in 
corresponding endpoint 
values up to corresponding 
weeks as response variables, 
and factors for treatment 
group, age, sex, height (age, 
sex and height are only 
included for spirometry 
endpoints analyses), region 
(pooled country), ICS dose at 
baseline, smoking status at 
screening, visit, treatment-by-
visit interaction, baseline 
value of the endpoint, and 
baseline-by-visit interaction 
as covariates. 


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Endpoint 
Category 
Estimands 
Endpoint(s)a 
Population 
Intercurrent event(s) handling 
strategy and missing data 
handling 
Population-level 
summary 
Secondary 
endpoint – 
Proportion 
Proportion of 
SGRQ 
improvement 
(≥4 points) at 
Week 52. 
ITT 
The intercurrent events will be handled 
as follows: 
 Discontinuation of study 
intervention prior to Week 52: Off-
study intervention data will be 
included in the analysis (treatment 
policy strategy). 
In addition, the missing data imputation 
rules are as follows: 
 Having missing data at Week 52:  
Participants will be considered as 
non-responders. 
Logistic regression model, 
with treatment group, region 
(pooled country), ICS dose at 
baseline, smoking status at 
screening, and baseline 
SGRQ total score as 
covariates 
Secondary objective: To evaluate the effect of dupilumab on moderate and severe COPD exacerbations 
Secondary 
endpoint – 
Time-to-event  
Time to 
AECOPD 
exacerbation 
events during 
the 52-week 
treatment period 
ITT 
The intercurrent events will be handled 
as follows: 
 Discontinuation of study 
intervention before Week 52: Off-
study intervention data up to Week 
52 will be included in the analysis 
(treatment policy strategy). 
In addition, the missing data imputation 
rules are as follows: 
 
Discontinuing the study follow-up 
before Week 52: Analyses will be 
censored at the time of study 
discontinuation 
Cox proportional hazards 
model using the time to the 
first event as the dependent 
variable, and treatment 
group, region (pooled 
country), ICS dose at 
baseline, smoking status at 
screening, baseline disease 
severity, and number of 
moderate or severe COPD 
exacerbation events within 
one year prior to the study as 
covariates 
a Additional secondary objectives/endpoints are not included in this table but would be handled with a similar strategy as the endpoint type 
(ie, Continuous, proportion, event, time-to-event) at other weeks. 
b Exploratory endpoint