Clinical trial NCT03930732
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Sanofi
Start date: 2019-04-15; Completion date: 2023-05-02
Enrollment: 939 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 and 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 anti-drug 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 administered as SC injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, EOT visit occurred 2 weeks after last administration of treatment i.e., at Week 52). arm 2: Participants received placebo matched to dupilumab 300 mg as subcutaneous (SC) injections q2w up to a maximum of 52 weeks (last dose administered at Week 50, end of treatment \[EOT\] visit occurred 2 weeks after last administration of treatment i.e., at Week 52).
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° 2.0 (11-OCT-2018) based on TransCelerate CPT version 5
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CLINICAL TRIAL PROTOCOL
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:
EFC15804 (BOREAS)
Amendment number:
Not applicable
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 (BOREAS)
Sponsor name:
 
 
Legal registered 
address:
 
 
Monitoring Team’s 
Representative Name 
and Contact Information
 
 
Regulatory agency identifier number(s):
IND:
105379
EudraCT:
2018-001953-28
NCT:
Not yet available
WHO:
U1111-1211-8804
Other:
Not applicable
Approval Date:
07-Nov-2018
Total number of pages:
108
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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL.......................................................................................................................1
TABLE OF CONTENTS..................................................................................................................................2
LIST OF TABLES ...........................................................................................................................................6
LIST OF FIGURES..........................................................................................................................................6
1
PROTOCOL SUMMARY .................................................................................................................7
1.1
SYNOPSIS.......................................................................................................................................7
1.2
SCHEMA........................................................................................................................................12
1.3
SCHEDULE OF ACTIVITIES (SOA)..............................................................................................13
1.3.1
Schedule of activities for patients who complete the planned treatment.......................................13
1.3.2
Reduced schedule of events for patients after early treatment discontinuation ............................18
2
INTRODUCTION............................................................................................................................21
2.1
STUDY RATIONALE......................................................................................................................21
2.2
BACKGROUND .............................................................................................................................21
2.2.1
Dupilumab anti-IL4Rα monoclonal antibody..................................................................................23
2.3
BENEFIT/RISK ASSESSMENT.....................................................................................................24
3
OBJECTIVES AND ENDPOINTS .................................................................................................25
3.1
APPROPRIATENESS OF MEASUREMENTS ..............................................................................26
4
STUDY DESIGN ............................................................................................................................27
4.1
OVERALL DESIGN........................................................................................................................27
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................28
4.3
JUSTIFICATION FOR DOSE ........................................................................................................28
4.4
END OF STUDY DEFINITION.......................................................................................................29
5
STUDY POPULATION ..................................................................................................................30
5.1
INCLUSION CRITERIA..................................................................................................................30
5.2
EXCLUSION CRITERIA.................................................................................................................31
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5.3
LIFESTYLE CONSIDERATIONS...................................................................................................35
5.4
SCREEN FAILURES......................................................................................................................35
6
STUDY INTERVENTION ...............................................................................................................36
6.1
STUDY INTERVENTION(S) ADMINISTERED..............................................................................36
6.1.1
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................36
6.1.2
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................37
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY.......................................................39
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................40
6.3.1
Methods of assigning patients to treatment group.........................................................................40
6.3.2
Methods of blinding........................................................................................................................41
6.3.3
Randomization code breaking during the study.............................................................................41
6.4
STUDY INTERVENTION COMPLIANCE ......................................................................................42
6.5
CONCOMITANT THERAPY ..........................................................................................................42
6.6
DOSE MODIFICATION..................................................................................................................43
6.7
INTERVENTION AFTER THE END OF THE STUDY...................................................................43
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...........................................................................................44
7.1
DISCONTINUATION OF STUDY INTERVENTION ......................................................................44
7.1.1
Permanent discontinuation ............................................................................................................44
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................46
7.3
LOST TO FOLLOW UP..................................................................................................................47
8
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................48
8.1
EFFICACY ASSESSMENTS .........................................................................................................48
8.1.1
Disease-specific efficacy measures...............................................................................................48
8.1.2
Clinical outcome assessments.......................................................................................................50
8.2
SAFETY ASSESSMENTS .............................................................................................................52
8.2.1
Physical examinations....................................................................................................................52
8.2.2
Vital signs.......................................................................................................................................53
8.2.3
Electrocardiograms ........................................................................................................................53
8.2.4
Clinical safety laboratory assessments..........................................................................................53
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................54
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8.3.1
Adverse event of special interest...................................................................................................54
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...........................................................................................................56
8.3.5
Regulatory reporting requirements for SAEs .................................................................................56
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 ...........57
8.3.9
Guidelines for reporting product complaints / medical device incidents (including 
malfunctions)..................................................................................................................................57
8.4
TREATMENT OF OVERDOSE......................................................................................................57
8.5
PHARMACOKINETICS..................................................................................................................58
8.5.1
Systemic drug concentration and anti-drug antibodies..................................................................58
8.6
PHARMACODYNAMICS ...............................................................................................................59
8.6.1
Pharmacodynamic variables/biomarkers.......................................................................................59
8.7
PHARMACOGENOMICS...............................................................................................................60
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 ............................................................................................................64
9.4.1
Efficacy analyses ...........................................................................................................................64
9.4.2
Safety analyses..............................................................................................................................66
9.4.3
Other analyses ...............................................................................................................................67
9.5
INTERIM ANALYSES ....................................................................................................................68
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................69
10.1
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......69
10.1.1
Regulatory and Ethical Considerations..........................................................................................69
10.1.2
Informed consent process..............................................................................................................69
10.1.3
Data protection...............................................................................................................................70
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10.1.4
Committees structure.....................................................................................................................70
10.1.5
Dissemination of clinical study data...............................................................................................71
10.1.6
Data quality assurance...................................................................................................................71
10.1.7
Source documents .........................................................................................................................72
10.1.8
Study and site closure....................................................................................................................72
10.1.9
Publication policy ...........................................................................................................................72
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................73
10.3
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING.................................................74
10.4
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................79
10.5
APPENDIX 5: GENETICS..............................................................................................................81
10.6
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND  FOLLOW-UP 
ASSESSMENTS ............................................................................................................................82
10.7
APPENDIX 7: LIST OF PROHIBITED LIVE ATTENUATED VACCINES......................................83
10.8
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS..............................................................84
10.9
APPENDIX 9: ABBREVIATIONS...................................................................................................84
10.10
APPENDIX 10: ST. GEORGE’S RESPIRATORY QUESTIONNAIRE ..........................................86
10.11
APPENDIX 11: THE EXACT AS FORMATTED FOR PERSONAL DIGITAL ASSISTANT 
(PDA)..............................................................................................................................................92
10.12
APPENDIX 12: EXACT QUESTIONNAIRE...................................................................................94
10.13
APPENDIX 13: BODE..................................................................................................................100
10.14
APPENDIX 14:  EQ-5D................................................................................................................101
10.15
APPENDIX 15: DEFINITION OF ANAPHYLAXIS .......................................................................104
10.16
APPENDIX 16: LIST OF OPPORTUNISTIC INFECTIONS.........................................................104
10.17
APPENDIX 17: FUTURE USE OF SAMPLES.............................................................................105
11
REFERENCES.............................................................................................................................106
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LIST OF TABLES
Table 1 - Objectives and endpoints...............................................................................................................25
Table 2 - Overview of study interventions administered ...............................................................................36
Table 3 - Reliever medication - Salbutamol/Albuterol nebulizer solution......................................................38
Table 4 - Reliever medication - Levosalbutamol/Levalbuterol nebulizer solution .........................................38
Table 5 - Reliever medication - Lpratropium or Ipratropium/short-acting β agonists [SABA] nebulizer 
solutions.........................................................................................................................................................39
Table 6 - Summary of handling procedures for dupilumab ...........................................................................58
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 .............................................................................................................................68
Table 12 - Protocol-required safety laboratory assessments........................................................................73
Table 13 - Highly effective contraceptive methods .......................................................................................79
LIST OF FIGURES
Figure 1 - Graphical study design .................................................................................................................12
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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
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 
neutrophils, there has been an identified subgroup of COPD which is characterized with a 
concomitant elevation in blood eosinophils which suggests a Type 2 inflammatory component of 
the disease. This study is designed to investigate the efficacy and safety of dupilumab over one 
year in patients with COPD with Type 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)

Pre-bronchodilator forced expiratory volume in 1 
second (FEV1) over 12 weeks compared to placebo

Annualized rate of moderate* or severe** COPD 
exacerbations over the 52-week treatment period
compared to placebo

Change in pre-bronchodilator FEV1 from baseline to 
Week 12 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. 
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**Severe exacerbations are recorded by the Investigator 
and defined as AECOPD requiring hospitalization, 
emergency medical care visit 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.
Key secondary
To evaluate the effect of  dupilumab 300 mg q2w on
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 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 and by ICS use (yes or no) at baseline.
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 
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 
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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 partial of a 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), asthma history (Yes or 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 included in the 
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primary 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 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), asthma history (Yes or 
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.

Analysis of key secondary endpoints: 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 be analyzed in a similar 
way except that the MMRM model will include the following covariates: treatment group, 
region (pooled country), asthma history (Yes or 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), asthma history (Yes or 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.

Interim analysis: An interim analysis (IA) in the study is planned to be performed when 
approximately 408 patients would have completed Week 12 visit. Further details are 
provided in Section 9.5.
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 
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review and evaluate the safety data during the course of the trial, review IA results and make 
appropriate recommendations regarding the conduct of the clinical trial to the Sponsor.
1.2
SCHEMA
Figure 1 - Graphical study design
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β-hCG = Human chorionic gonadotropin-beta; BID = twice daily assessments; continuous = subsequent visits during the treatment period; COPD = chronic obstructive pulmonary disease; cont. = 
continuous; DNA = Deoxyribonucleic acid ; EDTA = Ethylenediaminetetraacetic acid ; EOS = End of Study; EOT = End of treatment; EQ-5D= Euro Quality of Life-5 Dimension questionnaire; EXACT 
= Exacerbations of COPD tool; FeNO = Fractional exhaled nitric oxide; HIV = human immunodeficiency virus; IgE = Immunoglobulin E; IMP = Investigational Medicinal Product; IVRS = Interactive 
Voice Response System; IWRS = Interactive Web Response System; LABA = Long-acting β2 agonists; LAMA = Long-acting muscarinic antagonist ; PARC = Pulmonary and activation-regulated 
chemokine; PGX = pharmacogenetic; PK = Pharmacokinetic; RNA = Ribonucleic acid; SABA = Short-acting β-agonists; SAEs = Serious adverse events; SC = subcutaneous; SGRQ = St. George's 
Respiratory Questionnaire.
a
Randomization/baseline Visit is defined as Day 1. The visit schedule should be adhered to within ±1 week for the screening period, ±3 days for the randomized IMP treatment period and ±5 
days for the post IMP treatment period.
b
All assessments at Visit 2 (Day 1) are to be conducted pre-IMP dose with the exception of the assessment of local tolerability of SC injections.
c
End-of-treatment visit: See Section 7.1.1 for patients who discontinue treatment prematurely.
d
ECG to be centrally collected & read.  
e
Chest X-ray to be performed unless a <6 month old chest x-ray/chest CT/chest MR is available. In case chest-X-ray is not feasible due to local regulations, magnetic resonance imaging (MRI) 
will be performed. 
f
IMP (Dupilumab or placebo) is to be administered every 2 weeks by patient, caregiver or healthcare professional at the patient’s home or in a health care facility.  Last dose will be given at Week 
50. After Week 8, if the patient or Investigator decides not to administer IMP at home, the IMP injections can be performed at the site by way of unscheduled visits. Patients will be monitored at 
the study site for a minimum of 30 minutes after injections. See Section 6.1.1 for details.
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 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.
m Optional sputum sample at Visit 2 should be collected post-randomization and prior to dosing with IMP, as long as patient consents to the optional collection.  Only available at select sites in 
some countries. See Section 8.1.1.3 for details.
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n
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). 
o
Following randomization and during the treatment period - if spirometry is not performed at the scheduled visit it should be performed at the following visit during the treatment period.
p
PK and ADA samples to be collected prior to the administration of the drug.
q
If collection is not completed at randomization, sample can be taken at a following visit. 
r
Includes collection of sick days, lost usual activities, and additional physician visits or other health care utilization.
s
To be completed prior to IMP administration
t
To be done for 2 weeks after screening, 4 weeks after randomization (i.e Week 0 to Week 4) and between Weeks 12 and 14.
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h
Only for women of childbearing potential. Urine pregnancy test at ETD and every 4 weeks through Visit 16 and at EOS. In case of positive urinary test, a serum pregnancy test should be 
performed as soon as possible to confirm the pregnancy.
i
Optional sputum sample at ETD should be collected post-randomization and prior to dosing with IMP, as long as patient consents to the optional collection.  Only available at select sites in some 
countries See Section 8.1.1.3 for details. .
j
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). 
k
The EXACT and SGRQ are to be completed in the patient’s electronic diary.
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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 neutrophils, there has been an identified subgroup of COPD 
which is characterized with 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. 
Dupilimab 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 and asthma and is in 
late-stage development for chronic rhinosinusitis with nasal polyposis (CRSwNP), and 
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
Dupilumab has shown clinically relevant benefit in several Type 2 mediated immune disorders 
including atopic dermatitis, 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 (e.g. 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 
atopic dermatitis, 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 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.
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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)

Pre-bronchodilator forced expiratory volume in 1 
second (FEV1) over 12 weeks compared to placebo

Annualized rate of moderate* or severe** COPD
exacerbations over the 52-week treatment period 
compared to placebo

Change in pre-bronchodilator FEV1 from baseline to 
Week 12 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, 
emergency medical care visit 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.
Key Secondary
To evaluate the effect of  dupilumab 300 mg q2w on
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 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 (i.e. Weeks 2, 4, 8, 16, 20, 24, 
28, 36, 44 and 48) 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, 12,16, 24, 28, 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

Induced sputum for RNA expression (optional for patients 
at a subset of sites).

Optional: Messenger ribonucleic acid (mRNA) sequencing 
or whole transcriptome analysis from blood and sputum

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 moderate to severe 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 and by asthma history (yes or no).
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 
scheduled visit.
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.
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4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
A randomized, placebo-controlled study design where the effects of the IMP is 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. 
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 
COPD patient population.
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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 ≤80 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:
-
Current or former smokers with a smoking history of ≥10 pack-years
-
Moderate to severe COPD (post-bronchodilator FEV1/FVC ≤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.  
*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 / emergency room / urgent care visit. 
-
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 current diagnosis of asthma according to the 2018 Global Initiative for Asthma (GINA) 
guidelines or other accepted guidelines; or any history of asthma diagnosis  ≥ 40 years of 
age
E 03. Significant pulmonary disease other than COPD (e.g. 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.
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E 04. Cor pulmonale, evidence of right cardiac failure
E 05. Treatment with oxygen of more than 12 hours per day.
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.
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 (e.g., 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 (e.g., 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, prolonged QTc interval [male 
>450 msec, female >470 msec, Fredericia correction].
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E 18. A patient with a history of clinically significant renal, hepatic, cardiovascular, metabolic, 
neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular, 
substance and/or alcohol abuse, 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, or 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.
E 19. Active tuberculosis or non-tuberculous mycobacterial infection, latent untreated 
tuberculosis or a history of incompletely treated tuberculosis will be excluded from the 
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.
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, e.g. 
antiarrythmics, antihypertensives, and antidiuretics, etc. Dose modification of cholesterol-
modifying agents and anticoagulants is allowed.
E 25.
Cardiac arrhythmias including paroxysmal (e.g. 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 (i.e., 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
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
Who are not protected by one following acceptable forms of effective contraception during 
the study:
o
Established use of oral, injected or implanted or inserted hormonal contraceptive.
o
Intrauterine device (IUD) with copper or intrauterine system (IUS) with 
progestogen
o
Barrier contraceptive (condom, diaphragm or cervical vault caps) used with 
spermicide (foam, gel, film, cream or suppository), if allowed by local regulation
o
Female sterilization (eg, tubal occlusion, hysterectomy or bilateral salpingectomy)
o
Male sterilization with post-vasectomy documentation of the absence of sperm in 
the ejaculate; for female patients in the study, the vasectomized male partner 
should be the sole partner for that patient
o
True abstinence in keeping with the preferred and usual lifestyle and if allowed by 
local regulation; periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) is not an acceptable method of contraception

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 (e.g. tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, 
penumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per investigator’s judgment.
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 
(e.g., 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 (e.g. 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
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
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/randomization (Visit 1):

Alanine transaminase (ALT) >3 times upper limit of normal range (ULN)

Hemoglobin <10g /100 mL for male and < 9g/ 100 mL for female

Platelets <100 000/mm3,

Creatinine ≥150 μmol/L
E 39. Patients on macrolide (e.g. 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
Not applicable.
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 for any reason. In the case of 
technical malfunction of equipment, the patient may be rescreened.  Patients who fail the 
exclusion criteria may be rescreened during the open screening period of the study; a different 
patient identification number will be issued.
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 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 
visits
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 visits
Dosing instructions
Every 14 ± 3days
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 visits. 
To train patients how to prepare and inject IMP the investigator will first train the patient at an 
on-site visit during the treatment period.  At this visit the patient will perform the injection under 
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the supervision of the investigator or delegate.  This training must be documented in the patient’s 
study file.  At subsequent study visits, patients are trained to self-inject IMP, and the patients are 
allowed to self-inject IMP at home after 4 injections at investigational site, counting from their 
initial training visit.  Patient or caregiver 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.
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.
6.1.2
NONINVESTIGATIONAL 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 (e.g. 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 by Sponsor’s local affiliate as locally required or by sites.  
Reimbursement will be provided when deemed necessary and as per country regulation.
Reliever Medication
Reliever medications will be supplied by sites and reimbursed as per country regulation or by 
Sponsor’s local affiliate as locally required.
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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
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
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. 
Table 5 - Reliever medication - Lpratropium 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 (e.g., 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 
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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
Dupilumab or matching placebo in glass pre-filled syringes will be dispensed to the patients.
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), 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 
Biostatician will provide the randomization scheme to the centralized treatment allocation system 
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(Interactive Voice Response System/Interactive Web Response 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 and by asthma history (yes or no). 
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).
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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. 
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-live 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 (e.g. 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) 

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
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Note: The following is a list of permitted concomitant medications during the study

Maintenance treatment of COPD with ICS, LABA, LAMA, at a stable dosage, are allowed 
during the study

Systemic corticosteroids in case of acute exacerbation up to a maximum of 6 weeks

Rescue medication with SABA or short acting antimuscarinics (e.g. atrovent)
6.6
DOSE MODIFICATION
Not applicable.
6.7
INTERVENTION AFTER THE END OF THE STUDY
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Withdrawal of consent for treatment (ie, treatment discontinuation at 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
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 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 in the study 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

Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment.
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
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).
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 (i.e. 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.
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.
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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 the patient misses more than 3 consecutive doses, the patient will be permanently discontinued 
from the study. 
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 visit, 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.
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.
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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).
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, emergency medical care visit 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.
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).
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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 (e.g. 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. 
Optional home spirometry will be available for patients in the US and Canada only. Patients will 
receive documented in-clinic training for use of ambulatory at-home spirometry during screening. 
Further details on spirometry will be available in a separate operational manual provided to the 
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8.1.1.3
Optional Sputum Collection
A subset of study sites will be selected to perform evaluations of induced/spontaneous sputum, 
and patients at these selected sites will have the option to participate in this assessment. Sputum 
induction is a relatively noninvasive method to obtain sputum for cell or fluid phase inflammatory 
indices, culture or cytology. It is performed with an aerosol of normal or hypertonic saline 
generated by an ultrasonic nebulizer. As this aerosol is a potential bronchoconstrictive stimulus, it 
is made safe by pretreatment with salbutamol and inhalation in a dose response manner. 
Collection will be performed according to protocol flowchart.
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" 
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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.
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), and

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 (17). 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: 
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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 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.
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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. Refer to ECG reading manual for 
more details. All ECG recordings will be centrally read by independent experts.
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 
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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 
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 8.5.1.3 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 
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-
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

Significant ALT elevation
-
ALT >5 x the upper limit of normal (ULN) in patients with baseline ALT ≤2 x ULN; 
or
-
ALT >8 x ULN if baseline ALT >2 x 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. 
-
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 8 days. The circumstances (ie, accidental or 
intentional) should be clearly specified in the verbatim and symptoms, if any, entered on 
separate adverse event forms.

An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the 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". 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
Adverse event will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (Section 7). 
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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.
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 (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.
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
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.
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 and thus will not be 
considered unexpected. 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).
Any other AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected.
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
Overdose is an AESI (defined in Section 8.3.1). No antidote is available for dupilumab.
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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
Systemic drug concentration and anti-drug antibodies
8.5.1.1
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.
8.5.1.2
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
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8.5.1.3
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: 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. 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 AE.
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.
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

Induced sputum for RNA expression (optional for patients at a subset of sites).
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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 
phramcodynamics 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 conducted prior to spirometry and following a fast of at least 1 hour. Further details on 
the procedure for measuring exhaled nitric oxide with NIOX will be provided in a separate 
instruction manual.
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. 
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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 primary analyses of the study compare the treatment effect of dupilumab 300 mg q2w against 
placebo on two primary endpoints.
The statistical hypotheses used to test dupilumab 300 mg q2w against placebo on reducing the 
annualized rate of moderate-to-severe COPD exacerbations over the 52-week treatment period are 
as follows:

Null hypothesis: 

Alternative hypothesis: 
Where 
and 
represent exacerbation rate in the dupilumab and placebo groups, 
respectively.
The statistical hypotheses used to test dupilumab 300 mg q2w against placebo on improving pre-
bronchodilator FEV1 from baseline to Week 12 are as follows:

Null hypothesis: 

Alternative hypothesis: 
Where 
and 
represent change in pre-bronchodilator FEV1 in the dupilumab and 
placebo groups, respectively.
The statistical hypotheses to be tested on the key secondary endpoints, change in 
pre-bronchodilator FEV1 from baseline to Week 52 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 endpoints.
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For the 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=0.049 (an administrative penalty of 0.001 will be taken from the significance level used at final 
analysis due to a planned interim analysis; details are provided in Section 9.5). For the endpoint of 
change from baseline in FEV1 at Week 12, the study will have 99% power to detect a 0.1L 
improvement at the significance level of α=0.049, assuming a common standard deviation of 0.35 
and 5% of patients with missing data.
Patients will be randomized using a 1:1 randomization ratio to dupilumab 300 mg q2w or placebo. 
Randomization will be stratified by country and asthma history (Yes or No). 
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.
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.
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.
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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 (either ‘ADA negative’ or ‘ADA positive’) 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 and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints.
9.4.1
Efficacy analyses
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), asthma history 
(Yes or 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.
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), asthma history (Yes or 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.
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, disease severity (as % predicted post-bronchodilator FEV1), number of moderate-or-severe 
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Endpoint
Statistical Analysis Methods
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 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), asthma history (Yes or No), smoking status at screening (current 
smokers or not), visit, treatment-by-visit interaction, baseline SGRQ total score, and SGRQ baseline-by-visit 
interaction.
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), asthma history (Yes or 
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), asthma history (Yes or 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.
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9.4.1.1
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. 
An IA is planned in this study (details are provided in Section 9.5), and an administrative penalty 
of 0.001 will be taken from the significance level used at final analysis and thus two-sided 0.049 
will be used. A sequential testing procedure will be used for testing the two primary endpoints in 
the following order:
E 01. Annualized rate of moderate and severe COPD exacerbations over 52 week treatment 
period
E 02. Change in pre-bronchodilator FEV1 from baseline to Week 12
The annualized rate of moderate and severe COPD exacerbations over the 52 week treatment 
period will be first tested at the two-sided 0.049 significance level. Only upon rejection of the null 
hypothesis for the annualized rate of moderate and severe COPD exacerbations can the change in 
pre-bronchodilator FEV1 from baseline to Week 12 be tested at the same two-sided 0.049 level.
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
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Endpoint
Statistical Analysis Methods
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.
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.
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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 positive ADA response for SAR231893 (REGN668) will be provided by treatment groups. 
The neutralizing antibody status will be summarized and the association of ADA with PK, efficacy and 
safety variables may be explored. The 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.
9.5
INTERIM ANALYSES 
A nonbinding futility IA in the study is planned to be performed when approximately 408 patients 
would have completed Week 12 visit. Guideline for the futility will be provided in the DMC 
charter. The purpose of the IA is to obtain an understanding of the possible drug effect in this 
population. There is no plan to change the conduct of this trial except a possibility to stop the trial 
due to unfavorable benefit- risk. The IA will be performed by independent statisticians that 
support the IDMC and are separated from personnel involved in the trial conduct. DMC will 
review the unblinded IA results and recommend action based on the non-binding futility criterion 
that will be specified in the IDMC charter and SAP. Unblinded results can only be viewed by a 
small group of senior sponsor individuals, who are separate from sponsor personnel involved in 
the conduct of the study, if the non-binding futility criterion is met. A detailed plan will be 
defined in the IDMC charter and SAP, including plan to describe the processes intended to control 
access to comparative interim results to preserve trial integrity. People involved in the conduct of 
the study (patients, Investigators, Study Team, and Project Team) will have no access to the IA 
results.
At the IA, the efficacy endpoints will be analyzed using the same methods described in the 
efficacy analyses section (Section 9.4.1). The analysis population for the IA will be the first 408 
patients randomized.  The analysis of the endpoints will use all the data collected for the analysis 
population up to the IA cutoff time. An administrative penalty of 0.001 will be taken from the 
significance level used at final analysis (i.e., two-sided 0.049 will be used for the final analysis).
The database lock for final analysis is 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 in the CSR. 
Additional data between this database lock and last patient completing last visit will be 
summarized in a CSR addendum.
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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 to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.

The Investigator will be responsible for the following:
-
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
-
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

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.
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 
data during the course of the trial, review IA results and make appropriate recommendations 
regarding the conduct of the clinical trial to the Sponsor.
The DMC procedures and safety data to be reviewed by the DMC are described in the DMC 
charter. In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible 
for promptly reviewing and for taking into account in a timely manner the recommendations of 
the DMC in terms of trial continuation with or without alterations or of potential trial termination.
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 
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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 
clinicalstudydatarequest.com.
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. 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: clinicalstudydatarequest.com.
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.

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

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.
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
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion 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.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:

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 recruitment of participants by the Investigator

Discontinuation of further study intervention development
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.
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
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 12 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.
Table 12 - 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, 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).
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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).

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.
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
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 even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a)
Results in death
b) Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c)
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d) Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
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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.

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.
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
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.
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.
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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 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.

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 13.
Table 13 - 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
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Progestogen only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly effective methods that are user independenta
Implantable progestogen only hormonal contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion
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 for 
subsequent visits
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 
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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 
discontinue study intervention.
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 
reported in the CSR.
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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.
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
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
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
ADA:
antidrug antibody
AE:
adverse event
AECOPD:
acute exacerbation of chronic obstructive pulmonary disease
AESI:
adverse event of special interest
CAT:
COPD assessment test
COPD:
chronic obstructive pulmonary disease
CRSwNP:
chronic rhinosinusitis with nasal polyposis
DMC:
data monitoring committee
DPI:
dry powder inhaler
EOT:
end of treatment
ERS:
Evaluating Respiratory Symptoms
ETD:
early treatment discontinuation
EXACT:
Exacerbations of Chronic Pulmonary Disease Tool
FEF:
forced expiratory flow
FeNO:
fractional exhaled nitric oxide
FVC:
forced vital capacity
ICS:
inhaled corticosteroid
IL-4:
interleukin 4
IMP:
investigational medicinal product
ITT:
intent-to-treat
LABA:
long acting beta agonist
LAMA:
long acting muscarinic antagonist
MDI:
metered dose inhaler
MMRM:
mixed-effect model with repeated measures
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NIMP:
noninvestigational medicinal product
PARC:
pulmonary and activation-regulated chemokine
SABA:
short-acting β agonists
SGRQ:
St. George's Respiratory Questionnaire
SoA:
schedule of activities
TEAE:
treatment emergent adverse event
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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."
(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-
397)
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
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
Nontuberculosis mycobacteria

Pneumocystis pneumonia (PCP)
This list is indicative and not exhaustive.
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).
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11
REFERENCES
1. Global strategy for the diagnosis, management, and prevention of chronic obstructive 
pulmonary disease (2017 report).
2. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, et al.  Effects of 
smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of 
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3. Fahy JV. Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol. 
2015 Jan;15(1):57-65.
4. Dunican EM, Fahy JV. The Role of Type 2 Inflammation in the Pathogenesis of Asthma 
Exacerbations. Ann Am Thorac Soc. 2015 Nov;12 Suppl 2:S144-9.
5. Ghebre MA, Pang PH, Diver S, Desai D, Bafadhel M, Haldar K, et al. Biological exacerbation 
clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct 
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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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therapy in COPD. Respiration. 2009;78(3):256-62.
7. Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-Singer R. Eosinophilic 
inflammation in COPD: prevalence and clinical characteristics. Eur Respir J. 
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Genome-wide profiling identifies epithelial cell genes associated with asthma and with 
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10. Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Global and regional 
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11. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic 
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according to blood eosinophil counts. Lancet Respir Med. 2015;3(6):416-7.
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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 
of Chronic Obstructive Pulmonary Disease. Ann Intern Med. 2007;146(8):545-55.
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Eosinophilic Chronic Obstructive Pulmonary Disease. N Engl J Med. 2017 Oct 
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Chronic Obstructive Pulmonary Disease. Identification of Biologic Clusters and Their 
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Asthma-COPD Overlap. Clinical Relevance of Genomic Signatures of Type 2 Inflammation 
in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2015;191:758-66.
20. Bade G, Khan MA, Srivastava AK, Khare P, Solaiappan KK, Guleria R, et al. Serum cytokine 
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21. Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J COPD 2006;1:39-
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of spirometry. Series ‘‘ATS/ERS TASK FORCE: Standardization of Lung Function Testing"  
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23. Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir 
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24. 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 Jun;145(6):1321-7.
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25. 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 Mar 4;350(10):1005-12.
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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: QSD-002643 VERSION 7.0 (20-FEB-2019) 
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)-EFC15804 
STATISTICIAN: 
 
DATE OF ISSUE: 23-Mar-2020 
 
 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 8 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 8 
1.2 
OBJECTIVES ................................................................................................................................... 8 
1.2.1 
Primary objectives ............................................................................................................................ 8 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.2.3 
Exploratory objectives ...................................................................................................................... 9 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 9 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.4.1 
Graphic study design ..................................................................................................................... 10 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................ 10 
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 ................................................................................................... 14 
2.1.2.1 
COPD controller medication .......................................................................................................... 15 
2.1.2.2 
Reliever medication........................................................................................................................ 15 
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 .......................................................................................................... 25 
2.1.4.6 
Physical Examination ..................................................................................................................... 25 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 25 
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2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................ 26 
2.1.7 
Health Related Quality-of-life endpoints ........................................................................................ 27 
2.1.7.1 
Euro-QOL-5D ................................................................................................................................. 27 
2.1.7.2 
Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index (BODE 
Index) ............................................................................................................................................. 27 
2.1.8 
Health economic endpoints ............................................................................................................ 27 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 28 
2.2.1 
Protocol deviations ......................................................................................................................... 29 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 29 
2.3.1 
Efficacy populations ....................................................................................................................... 29 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 29 
2.3.2 
Safety population ........................................................................................................................... 29 
2.3.3 
Pharmacokinetics (PK) population ................................................................................................. 30 
2.3.4 
Anti-drug antibody population ........................................................................................................ 30 
2.4 
STATISTICAL METHODS ............................................................................................................. 30 
2.4.1 
Demographics and baseline characteristics .................................................................................. 30 
2.4.2 
Prior or concomitant medications ................................................................................................... 31 
2.4.2.1 
ICS in combination with other controllers ...................................................................................... 31 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 33 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 33 
2.4.3.2 
Compliance .................................................................................................................................... 34 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 34 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 34 
2.4.4.2 
Analyses of key secondary efficacy endpoints .............................................................................. 38 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 41 
2.4.4.4 
Additional efficacy analyses ........................................................................................................... 42 
2.4.4.5 
Analyses of exploratory efficacy endpoints .................................................................................... 44 
2.4.4.6 
Missing data handling .................................................................................................................... 45 
2.4.5 
Analyses of safety data .................................................................................................................. 46 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 46 
2.4.5.2 
Deaths ............................................................................................................................................ 50 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 50 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 51 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 52 
2.4.6 
Abnormal Analyses of pharmacokinetic and pharmacodynamic variables .................................... 52 
2.4.6.1 
Pharmacokinetic analyses ............................................................................................................. 52 
2.4.6.2 
Pharmacodynamics/genomics analyses ........................................................................................ 54 
2.4.7 
Analyses of health economics variables ........................................................................................ 54 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 54 
2.5.1 
General conventions ...................................................................................................................... 54 
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2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 55 
2.5.3 
Missing data ................................................................................................................................... 55 
2.5.4 
Windows for time points ................................................................................................................. 57 
2.5.5 
Unscheduled visits ......................................................................................................................... 63 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 64 
2.5.7 
Statistical technical issues ............................................................................................................. 64 
3 
INTERIM ANALYSIS ..................................................................................................................... 65 
4 
DATABASE LOCK ........................................................................................................................ 66 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 67 
6 
REFERENCES ............................................................................................................................... 68 
7 
LIST OF APPENDICES ................................................................................................................. 69 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 70 
APPENDIX B 
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE ......................................................... 75 
APPENDIX C 
SGRQ SCORING ALGORITHM .......................................................................................... 81 
APPENDIX D 
EXACT QUESTIONNAIRE .................................................................................................. 86 
APPENDIX E 
EQ-5D .................................................................................................................................. 92 
APPENDIX F 
BODE ................................................................................................................................... 95 
APPENDIX G 
HIGH DOSE OF INHALED CORTICOSTEROIDS : ADULTS ............................................ 96 
APPENDIX H 
DEFINITION OF ANAPHYLAXIS ........................................................................................ 98 
APPENDIX I 
LIST OF OPPORTUNISTIC INFECTIONS ........................................................................... 99 
APPENDIX J 
HANDLING OF MISSING DATA ........................................................................................ 100 
 
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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 
ATS 
American Thoracic Society 
BODE 
Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity 
CI 
Confidence Interval 
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  
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 
HFA 
Hydrofluoroalkane 
HLGT 
High-Level Group Term  
HLT 
High Level Term 
HIV 
Human Immunodeficiency Virus  
HRQoL 
Health Related Quality of Life  
ICH 
International Council for Harmonisation 
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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 
St. George’s Respiratory Questionnaire 
SOC 
System Organ Class  
TE 
Treatment-Emergent 
TEAE 
Treatment-Emergent Adverse Event 
Th2 
Type 2 T-helper cell 
ULN 
Upper Limit of Normal  
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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 group (2 groups), 52-week 
Phase 3 study to assess the efficacy, safety, and tolerability of dupilumab in patients with 
moderate-to-severe COPD with type 2 inflammation on an established background of triple 
therapy (LABA, LAMA and ICS unless ICS contraindicated). Study treatments are dupilumab 
300 mg q2w or placebo q2w administered SC over a 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 and by ICS dose 
(high dose ICS [yes/no]) at baseline. 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=0.049 (an administrative 
penalty of 0.001 will be taken from the significance level used at final analysis due to a planned 
interim analysis; details are provided in Section 3). 
Patients will be randomized using a 1:1 randomization ratio to dupilumab 300 mg q2w or placebo. 
Randomization will be stratified by country and by ICS dose (high dose ICS [yes/no]) at baseline. 
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 7 (dated 
06 December 2019). These changes are not based on any unblinded study data. 
The modifications to the protocol statistical section in the SAP are listed below. 
Table 1 - Modifications to the statistical section of the protocol in the SAP 
 
Text in the protocol 
Text in the SAP 
Rationale 
1 
The following description on the tertiary/exploratory 
endpoint in the protocol amendment 7 Table 1: 
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 moderate to severe 
COPD exacerbations assessed by the 
EXACT over 52 week 
 
Is changed in the SAP version 1 to: 
 
To evaluate the effects of dupilumab 
compared to placebo on annualized 
rate of 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 
 
To be aligned with 
reference manual 
for the EXACT tool 
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Text in the protocol 
Text in the SAP 
Rationale 
exacerbations assessed by 
the EXACT over 52 week 
 
 
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 questionnare 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 years) 
• 
Region (Asia: Japan, China, South Korea; Latin America: Argentina, Chile and Mexico; 
East Europe: Russia, Ukraine, Turkey, Hungary, Poland, Czech Republic, Romania, 
Bulgaria, Slovakia; Western Countries: Finland, Denmark, Spain, Israel, Sweden, 
Germany, Italy, Canada, USA)  
• 
Territory (Canada and USA: Canada and USA; European Union: Hungary, Poland, Czech 
Republic, Romania, Bulgaria, Slovakia, Spain, Sweden, Germany, Italy,  Finland, 
Denmark; Rest of World: Israel, Argentina, Chile, Japan, China, South Korea, Mexico, 
Russia, Ukraine, Turkey) 
• 
Weight in kg (quantitative and qualitative variable : <50, 50-<100 and ≥100 kg) 
• 
BMI in kg/m2 (quantitative and qualitative variable: <30, ≥30 kg/m2) 
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Medical or surgical history 
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the patient. 
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. 
Comorbidity will be summarized separately. The following comorbid diseases 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 ICS dose from medical history (Yes, No) 
• 
High ICS dose from IVRS (Yes, No) 
• 
Spirometry data including pre-bronchodilator FEV1 (L), post-bronchodilator FEV1 (L), 
forced expiratory flow (FEF) 25-75%, FEV1 reversibility (%)  
- 
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 VAS) 
• 
Body-Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index (BODE 
Index) and its domain scores 
• 
EXACT & E-RS: COPD total scores and sub-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 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  
• 
Number of treatment days with systemic steroids use for moderate or severe COPD 
exacerbations experienced within one year before Visit 1  
• 
FeNO at baseline 
• 
Eosinophil counts at baseline 
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. 
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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 
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. 
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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, 16, 20, 24, 28, 36, 44 and 48)  
• 
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, 16, 24, 
28, 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 A). 
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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 
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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 
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 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: 
• 
RS-Breathlessness (sum of items 7, 8, 9, 10, and 11; score range 0–17) 
• 
RS-Cough and Sputum (sum of items 2, 3, 4; score range 0–11) 
• 
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. 
2.1.4 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. 
• 
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 
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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. 
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. 
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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. 
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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 or PT in (Pruritus, 
Pruritus generalized) 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  
Serious injection site 
reactions or severe 
injection site reactions that 
last longer than 24 hours  
HLT = ‘Injection site reaction’ and either with serious status, or with 
severe status and (AE end date/time - AE start date/time) ≥ 24 hours or 
ongoing 
Severe or serious infection Primary SOC = ‘Infections and infestations’ and with severe or 
serious status 
Parasitic infection 
The Infection Type ‘Parasitic’ was checked on eCRF page “Infection 
Defined as AESI Complementary Form” 
Opportunistic infection 
The Infection Type ‘Opportunistic’ was checked on eCRF page 
“Infection Defined as AESI Complementary Form” 
Drug-related hepatic 
disorder 
Drug-related hepatic disorders-Comprehensive search narrow SMQ 
(20000006) 
Pregnancy 
Primary SOC = ‘Pregnancy, puerperium and perinatal conditions’ or PT 
in (Aborted pregnancy, False negative pregnancy test, Pregnancy test 
positive, Pregnancy test urine positive, Ectopic pregnancy termination) 
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.  
Eosinophilia 
HLT = ‘Eosinophilic disorders’ or PT = ‘Eosinophil count increased’ 
Other selected AE 
grouping 
 
Injection site reaction  
HLT = ‘Injection site reaction’  
Malignancy 
Sub-SMQ (20000091)–  Malignant or unspecified tumors 
Suicidal behavior 
PT in (Completed suicide, Suicidal ideation, Depression suicidal, 
Suicidal behavior, Suicide attempt) 
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AE Grouping 
Criteria 
Partner pregnancy 
PT in (Pregnancy of partner, Miscarriage of partner) 
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) 
2.1.4.2 Deaths 
The deaths observation period are 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 
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- 
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. 
- 
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 the screening (Visit 
1), randomization (Visit 2) 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. 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. 
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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 16, Week 24, Week 36, Week 52/EOT Visit and posttreatment 
serum dupilumab at Week 56, Week 60 and Week 64/EOS Visit will be provided. 
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 immunoreactivity 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. 
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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) 
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. 
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. 
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2.1.7 Health Related Quality-of-life endpoints 
2.1.7.1 Euro-QOL-5D 
The European quality of life-5D scale (EQ-5D) (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 (7). 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). 
2.1.7.2 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 (8). 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 is assess at Visit 2 (Week 0) only. 
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), 
Visit 13 (Week 40), Visit 14 (Week 44), Visit 15 (Week 48), Visit 16 (Week 52) and Visit 19 
(Week 64). 
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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 
• 
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. 
• 
Patients who withdraw from study by main reason for study discontinuation 
• 
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. 
• 
Efficacy population: intent-to-treat (ITT) population defined in Section 2.3 
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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.  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. 
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. 
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 
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• 
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 
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. 
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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 
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. 
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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. 
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 
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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 
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. 
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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 constitute serious adverse events and will be listed as such. 
2.4.4 Analyses of efficacy endpoints 
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.  
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 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 
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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 (6). 
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 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=tr
t01pn cn
tygr1n ics smoking fev1bl copdnum
 
/offset=logdu
r dist=negbin link=log solution;
 
run;  
If the model fails to achieve convergence, different estimation algorithms 
will be applied following the order: default→LAPLACE→QUAD (7). 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. 
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 
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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 
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 
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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 J: 
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) 
• 
Gender (Male, Female) 
• 
Region  
• 
Territory  
• 
Race (Caucasian/White, Black/of African descent, Asian/Oriental, Others) 
• 
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 (Yes, No) 
• 
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) 
• 
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) 
• 
Baseline PARC (< median, ≥ median) 
• 
Baseline Fibrinogen (< 350, ≥ 350 mg/dL) 
• 
Baseline mMRC (< median, ≥median) 
• 
Maximum eosinophils counts during screening (≥ 0.3-<0.5, ≥0.5 Giga/L) 
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 
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(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. If quantitative treatment by subgroup 
interaction is detected with nominal p-value < 0.05 for any subgroup factor, the Gail-Simon test 
will be performed to evaluate possible qualitative interaction. 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.  
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. 
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. If quantitative treatment by subgroup 
interaction at Week 12 is detected with nominal p-value < 0.05 for any subgroup factor, the Gail-
Simon test will be used to test the qualitative interaction. 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.  
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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), baseline eosinophil strata, baseline ICS 
dose level, 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 J. 
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2.4.4.2.2 Analysis of the change from baseline in pre-bronchodilator FEV1 and SGRQ total 
score 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 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. 
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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. 
Mean cumulative function plot will be provided for descriptive purpose. 
2.4.4.3 Multiplicity issues 
The multiplicity procedure is proposed to control the overall type-I error rate for testing the 
primary and selected secondary endpoints listed below. The overall alpha is 0.05. 
A non-binding futility interim analysis (IA) is planned in this study (details are provided in Section 3), 
and an administrative penalty of 0.001 will be taken from the significance level used at final analysis 
and thus two-sided 0.049 will be used. No further multiplicity adjustment will be performed for the IA. 
At the final analysis, the comparisons with placebo will be tested based on the hierarchical order 
below at 2-sided alpha=0.049. 
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 scores 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. 
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 
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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. 
2.4.4.4.4 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 
• 
Smoking status at screening (current smokers, former smokers) 
For the annualized rate of COPD exacerbation endpoints, treatment by subgroup interaction and 
its p-value will be derived from a negative binomial model respectively, same as the approach in 
subgroup analysis specified in Section 2.4.4.1. Summary statistics of 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.  
For other efficacy endpoints specified in Section 2.4.4.3 and Section 
2.4.4.4.1, treatment by subgroup interaction and its p-value will be derived 
from MMRM models (for continuous endpoints), logistic regression models (for 
proportion type endpoints) or Cox regression models (for time to event 
endpoints) respectively. The model will include all the covariates in the main statistical 
model for the corresponding endpoints plus the subgroup variable (if not one of the covariates 
adjusted in the main model already) and the subgroup-by-treatment interaction. A p-value for the 
test of interaction will be provided.  
In each subgroup, 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 
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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. 
In addition, for each subgroup analysis, the forest plot will be provided. 
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, 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. 
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 
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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 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 
week (a tertiary/exploratory endpoint) will be analyzed in the same way as the 
primary analysis for the 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. 
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2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group.  
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 
• 
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-
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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. 
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 
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• 
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 
• 
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. 
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• 
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 
- 
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 
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• 
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. 
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. 
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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. 
Possible Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  The 
proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group.  
Time to onset of the initial ALT and AST elevation (>3 x ULN) and total bilirubin elevation 
(>2 x ULN) (time to first observation of ALT >3 x ULN or total bilirubin > 2 x ULN, whichever 
comes first) will be analyzed using Kaplan-Meier estimates, presented by treatment group.  
Consideration should be given to the impact of the spacing of scheduled tests.  A graph of 
distribution of peak values of ALT versus peak values of total bilirubin will also be presented.  
Note that the ALT and total bilirubin values are presented on a logarithmic scale. The graph will 
be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and a 
horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin ≥2 x ULN) with ALT, AST, alkaline 
phosphatase, total bilirubin, and the following complementary parameters:  conjugated bilirubin 
and creatine phosphokinase, serum creatinine, complete blood count, HCV RNA. 
Summarize the normalization by parameter (to ≤1 x ULN or return to baseline) of elevated liver 
function tests by categories of elevation (3 x, 5 x, 10 x, 20 x ULN for ALT and AST, 1.5 x ULN 
for alkaline phosphatase, and 1.5 x and 2 x ULN for total bilirubin), with the following categories 
of normalization:  never normalized, normalized despite treatment continuation of IMP, or 
normalized after IMP discontinuation.  Note that a patient will be counted only under the 
maximum elevation category. 
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 
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:  
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• 
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 Abnormal 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. 
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  
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• 
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. 
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) 
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• 
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 Outcomes Research (HEOR) 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 
 
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  
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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 
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. 
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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. 
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. 
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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 
Hema-
tology, 
biochem-
istry, 
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 
 
 
 
 
 
 
Visit 4 
(Week 
4) 
29 
22-42 
1+-42 
 
1+-42 
 
 
 
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Target 
Day 
 
 
Time windows for 
Visit 
Vital 
signs 
Hema-
tology, 
biochem-
istry, 
urinalysis  
Serum Pregnancy 
test, Hepatitis and 
HIV serology tests, 
height 
Urine 
Pregnancy 
test 
Physical 
examination 
Body 
weight 
ECG 
Visit 5 
(Week 
8) 
57 
43-70 
43-70 
 
43-70 
 
 
 
Visit 6 
(Week 
12) 
85 
71-98 
71-126 
 
71-98 
 
 
1+-126 
Visit 7 
(Week 
16) 
113 
99-126 
 
 
99-126 
 
 
 
Visit 8 
(Week 
20) 
141 
127-154 
 
 
127-154 
 
 
 
Visit 9 
(Week 
24) 
169 
155-182 
127-210 
 
155-182 
1+-266 
 
127-210 
Visit 10 
(Week 
28) 
197 
183-210 
 
 
183-210 
 
 
 
Visit 11 
(Week 
32) 
225 
211-238 
 
 
211-238 
 
 
 
Visit 12 
(Week 
36) 
253 
239-266 
211-308 
 
239-266 
 
 
211-308 
Visit 13 
(Week 
40) 
281 
267-294 
 
 
267-294 
 
 
 
Visit 14 
(Week 
44) 
309 
295-322 
 
 
295-322 
 
 
 
Visit 15 
(Week 
48) 
337 
323-350 
 
 
323-350 
 
 
 
Visit 16 
(Week 
52) 
365 
351-378 
309-406 
 
351-406 
267-406 
1+-406 
309-406 
Visit 17 
(Week 
56) 
393 
379-406 
 
 
 
 
 
 
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Target 
Day 
 
 
Time windows for 
Visit 
Vital 
signs 
Hema-
tology, 
biochem-
istry, 
urinalysis  
Serum Pregnancy 
test, Hepatitis and 
HIV serology tests, 
height 
Urine 
Pregnancy 
test 
Physical 
examination 
Body 
weight 
ECG 
Visit 18 
(Week 
60) 
421 
407-434 
 
 
 
 
 
 
Visit 19 
(Week 
64) 
449 
>434 
>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 be used for the by-visit summary. If 
they are at the same distance to the target day, the latest one will be used. 
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Table 7 – Time window for efficacy variables 
Visit 
Target 
Day 
Time windows for  
Pre-bronchodilator 
Spirometry 
Post-bronchodilator 
Spirometry 
SGRQ 
Visit 1 
(Week 
-4±1) 
-28±7 
<-14 
<-14 
 
Visit 2 
(Week 
0) 
1 
-14-1- 
-14-1- 
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 
71-98 
71-126 
57-126 
Visit 7 
(Week 
16) 
113 
99-126 
 
 
Visit 8 
(Week 
20) 
141 
 
 127-154 
 
 
Visit 9 
(Week 
24) 
169 
155-182 
127-210 
127-210 
Visit 
10 
(Week 
28) 
197 
183-224 
 
 
Visit 
11 
(Week 
32) 
225 
 
 
 
Visit 
12 
(Week 
36) 
253 
225-280 
211-308 
211-308 
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Visit 
Target 
Day 
Time windows for  
Pre-bronchodilator 
Spirometry 
Post-bronchodilator 
Spirometry 
SGRQ 
Visit 
13 
(Week 
40) 
281 
 
 
 
Visit 
14 
(Week 
44) 
309 
281-322 
 
 
Visit 
15 
(Week 
48) 
337 
323-350 
 
 
Visit 
16 
(Week 
52) 
365 
351-378 
309-406 
309-406 
Visit 
17 
(Week 
56) 
393 
379-406 
 
 
Visit 
18 
(Week 
60) 
421 
407-434 
 
 
Visit 
19 
(Week 
64) 
449 
>434 
>406 
>406 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time 
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. 
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Table 8 – Time window for pharmacokinetics/pharmacodynamics variables 
 
 
Time windows for 
Visit 
Target 
day 
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 
71-98 
1+-126 
1+-
224 
 
57-126 
 
Visit 7 
(Week 
16) 
113 
 
99-140 
 
 
 
 
 
Visit 8 
(Week 
20) 
141 
 
 
 
 
 
 
 
Visit 9 
(Week 
24) 
169 
127-210 
141-210 
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 
 
 
 
 
 
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Time windows for 
Visit 
Target 
day 
FENO post- 
Bronchodilator 
 
Serum 
dupilumab 
concentration 
Anti- 
drug 
antibodies 
Total 
IgE 
PARC 
Eotaxin-
3 
Fibrinogen  
 
Visit 
13 
(Week 
40) 
281 
 
 
 
 
 
 
 
Visit 
14 
(Week 
44) 
309 
 
 
 
 
 
 
 
Visit 
15 
(Week 
48) 
337 
 
 
 
 
 
 
 
Visit 
16 
(Week 
52) 
365 
309-406 
309-378 
267-406 
225-
406 
1+-406 
267-406 
267-406 
Visit 
17 
(Week 
56) 
393 
 
379-406 
 
 
 
 
 
Visit 
18 
(Week 
60) 
421 
 
407-434 
 
 
 
 
 
Visit 
19 
(Week 
64) 
449 
>406 
>434 
>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. 
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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: 
• 
Asia: Japan, China, South Korea;  
• 
Latin America: Argentina, Chile and Mexico;  
• 
East Europe: Russia, Ukraine, Turkey, Hungary, Poland, Czech Republic, Romania, 
Bulgaria, Slovakia;  
• 
Western Countries: Finland, Denmark, Spain, Israel, Sweden, Germany, Italy, Canada, 
USA. 
2.5.7 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
A nonbinding futility IA in the study is planned to be performed when approximately 408 patients 
would have completed Week 12 visit. Guideline for the futility decision will be provided in the 
DMC charter. The purpose of the IA is to obtain an understanding of the possible drug effect in 
this population. The IA will be performed by independent statisticians that support the DMC and 
are separated from personnel involved in the trial conduct. DMC will review the unblinded IA 
results and recommend action based on the non-binding futility criterion that is specified in the 
DMC charter and DMC SAP. The DMC will inform a group of senior sponsor individuals 
whether the criterion is met. If the criterion is met, and only if the criterion is met, the unblinded 
futility analysis results as well as select additional analyses will be provided to the senior sponsor 
group. The senior sponsor group will make a decision regarding stopping or continuing the study. 
The senior sponsor group are the only sponsor individuals that are planned to view this data. A 
detailed plan will be defined in the DMC charter and DMC SAP, including a plan to describe the 
processes intended to control access to comparative interim results to preserve trial integrity. 
People involved in the conduct of the study (patients, Investigators, Study Team, and Project 
Team) will not have access to the IA results. 
At the IA, the efficacy endpoints will be analyzed using the same methods described in the 
efficacy analyses section (Section 2.4.4). The analysis population for the IA will be the first 408 
patients randomized. The analysis of the endpoints will use all the data collected for the analysis 
population up to the IA cutoff time. An administrative penalty of 0.001 will be taken from the 
significance level used at final analysis (ie, two-sided 0.049 will be used for the final analysis). 
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4 
DATABASE LOCK 
The database lock for final analysis is 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 in the CSR. 
Additional data between this database lock and last patient completing last visit will be 
summarized in a CSR addendum. 
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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 Sep;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 Jun;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. 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. 
8. 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 Mar 4;350(10):1005-12. 
 
 
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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: 
Handling of missing data 
 
 
 
 
 
 
 
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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 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014 ) 
Parameter 
PCSA 
Comments 
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 
 
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. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014 ) 
Parameter 
PCSA 
Comments 
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) 
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 
 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies  
(From BTD-009536 – 21-MAY-2014 ) 
Parameter 
PCSA 
Comments 
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 
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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-
397)  
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 
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: 
proc mi 
data =dd seed =9816388 nimpute =40 out =outdata;
 
by month;  
class 
outcome trt01pn  cnt
ygr1 ics copdnum;
 
monotone re
g (fev1bl/details)
;  
logistic 
(outcome=trt01pn cntygr1 ics smokin
g fev1bl copdnum
/details 
DESCENDING); 
var  cntygr1 ics smoking fev1bl trt01pn copdnum outcome;
 
run ;  
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 
proc mianalyze 
da t a =r r _c onv;  
by La be l ;  
mode l e f f e c t s  Es t i ma t e ;  
s t de r r  St dEr r ;  
ods  out put  Pa r a me t e r Es t i ma t e s =r r _pool e d;  
run ;  
proc mianalyze 
da t a =a e r _c onv;  
by TRT01PN;  
mode l e f f e c t s  Es t i ma t e ;  
s t de r r  St dEr r ;  
ods  out put  Pa r a me t e r Es t i ma t e s =a e r _pool e d;  
run ;  
/* estimated RR and corresponding 95% CI */ 
data pouttx; 
set r r _pool e d; 
if Parameter="txval"; 
rr = exp(estimate); 
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run ;  
• 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 
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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. 
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. 
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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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