A Randomized, Double-blind, Placebo-controlled, Parallel-group, Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety and Tolerability of SAR440340, in Patients With Moderate-to-severe Chronic Obstructive Pulmonary Disease (COPD)
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Sanofi

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: Version Sanofi dated 12-SEP-2017 based on TransCelerate CPT version 4 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01  
Protocol title: 
A randomized, double-blind, placebo-controlled, 
parallel-group, Proof-of-Concept (PoC) study to assess 
the efficacy, safety and tolerability of SAR440340, in 
patients with moderate-to-severe chronic obstructive 
pulmonary disease (COPD) 
Protocol number: 
ACT15104 
Amendment number: 
01 
Compound number 
(Trademark/INN): 
SAR440340/REGN3500 
Short title: 
Proof-of-Concept study to assess the efficacy, safety 
and tolerability of SAR440340 (anti-IL-33 mAb) in 
patients with moderate-to-severe chronic obstructive 
pulmonary disease (COPD) 
Sponsor name: 
Legal registered 
address: 
Regulatory agency identifying number(s): 
EudraCT number: 
2017-003290-34 
IND number: 
134401 
UTN number: 
Not yet available 
Approval Date: 11-Jun-2018 
Total number of pages: 113 
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Sponsor signatory: 
 
Please refer to the last page of this document for electronic signatures including date and time 
 
Monitoring Team’s Representative 
Name and Contact Information: 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01 
All 
11-Jun-2018, Version 1 (electronic 1.0) 
Original Protocol 
 
30-Mar-2018, Version 1 (electronic 2.0) 
Amended protocol [01] (Day Month Year) 
This amended protocol (Amendment 01) is considered to be non-substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
This amendment incorporates recommendation from the European Union clinical trial review. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.3.1 
Schedule of 
Activities  
Footnote added to blood  eosinophils and 
neutrophils to specify that a complete hematology 
panel will be performed at Visit 4, Visit 12 and 
follow-up Visit F1 
Clarification for the biomarker (blood eosinophils and 
neutrophils) collection visits is provided in order to 
address the request from the Health Agencies review. 
4.3 
Justification 
for Dose  
Details added to the justification for dose 
Requested during the Health Agencies review of the 
clinical trial application. 
5.2 Exclusion 
Criteria 
Deleted E08: Participants with COPD diagnosed 
within the 6 months prior to randomization 
During the Health Agencies' review of the clinical trial 
application, an inconsistency was identified in the 
duration of COPD diagnosis required for study inclusion. 
As per inclusion criterion I01, patients with a diagnosis of 
COPD for at least 1 year are eligible for inclusion, 
whereas exclusion criterion E08 excluded participants 
with COPD diagnosed within the 6 months prior to 
randomization. The study intends to include patients 
diagnosed with for at least 1 year, therefore E08 is now 
deleted. 
 
Modified E26: Known allergy to doxycycline or 
related compounds. 
Per the Healthy Agencies' request, the criterion is being 
modified to also exclude patients with a history of 
systemic hypersensitivity to any excipients of the IMP. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
 
Modified E34: Patients with cardiovascular 
diseases/conditions:  for uncontrolled hypertension 
Per the Health Agencies' request, the exclusion criterion 
related to uncontrolled hypertension has been modified in 
order to exclude patients with grade 3 hypertension (high 
cardiovascular risk). 
6.5 
Concomitant 
Therapy 
Removed intra-articular steroids from permitted 
concomitant therapy 
Resolve an inconsistency as relevant systemic exposure 
may occur with intra-articular steroids. Systemic steroids 
are not permitted during the screening or treatment 
phases. 
8.1.1.1 COPD 
exacerbation 
Added “Any course of systemic steroids/antibiotics 
started <7 days of finishing a previous course 
should be considered as treatment for a single 
exacerbation” 
Further clarification has been provided as regards 
reporting of COPD exacerbations. 
8.1.2 Patient 
reported 
outcomes 
questionnaires 
Added “Record use of systemic corticosteroids 
and/or antibiotics taken for COPD exacerbation” 
An inconsistency between set-up of e-diary and the 
protocol e-diary language has been corrected. 
Section 10.10 
- Appendix 10 
Added Appendix 10  and renumbered other 
appendices 
This is the appendix for Protocol Amendment History 
All sections 
Minor inconsistencies corrected, spelling and 
grammar corrected 
Improve the quality of the document 
 
 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL ......................................................................................................................1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................3 
DOCUMENT HISTORY...................................................................................................................................3 
OVERALL RATIONALE FOR THE AMENDMENT........................................................................................3 
TABLE OF CONTENTS..................................................................................................................................5 
LIST OF TABLES ...........................................................................................................................................9 
LIST OF FIGURES..........................................................................................................................................9 
1 
PROTOCOL SUMMARY ...............................................................................................................10 
1.1 
SYNOPSIS.....................................................................................................................................10 
1.2 
SCHEMA........................................................................................................................................16 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................17 
1.3.1 
Schedule of Activities (SoA) for Patients who complete the Planned Treatment..........................17 
1.3.2 
Schedule of Activities (SoA) for Patients After Early Treatment Discontinuation ..........................21 
2 
INTRODUCTION............................................................................................................................24 
2.1 
STUDY RATIONALE......................................................................................................................24 
2.2 
BACKGROUND .............................................................................................................................24 
Chronic obstructive pulmonary disease ........................................................................................................24 
SAR440340 - Anti-IL-33 monoclonal antibody ..............................................................................................25 
2.3 
BENEFIT/RISK ASSESSMENT.....................................................................................................26 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................27 
3.1 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................29 
4 
STUDY DESIGN ............................................................................................................................30 
4.1 
OVERALL DESIGN........................................................................................................................30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................31 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................32 
4.4 
END OF STUDY DEFINITION.......................................................................................................32 
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5 
STUDY POPULATION ..................................................................................................................33 
5.1 
INCLUSION CRITERIA..................................................................................................................33 
5.2 
EXCLUSION CRITERIA ...............................................................................................................34 
5.3 
LIFESTYLE CONSIDERATIONS...................................................................................................38 
5.4 
SCREEN FAILURES......................................................................................................................38 
6 
STUDY INTERVENTION ...............................................................................................................40 
6.1 
STUDY INTERVENTION(S) ADMINISTERED..............................................................................40 
INVESTIGATIONAL MEDICINAL PRODUCT(S)..........................................................................................40 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)..................................................................................41 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY.......................................................43 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................44 
6.3.1 
Methods of assigning patients to treatment group.........................................................................44 
6.3.2 
Methods of blinding........................................................................................................................45 
6.3.3 
Randomization code breaking during the study.............................................................................46 
6.4 
STUDY INTERVENTION COMPLIANCE ......................................................................................46 
6.5 
CONCOMITANT THERAPY ..........................................................................................................46 
6.6 
DOSE MODIFICATION..................................................................................................................47 
6.7 
INTERVENTION AFTER THE END OF THE STUDY...................................................................47 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...........................................................................................48 
7.1 
DISCONTINUATION OF STUDY INTERVENTION .....................................................................48 
7.1.1 
Permanent discontinuation ............................................................................................................48 
7.1.2 
Temporary discontinuation.............................................................................................................50 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................50 
7.3 
LOST TO FOLLOW UP .................................................................................................................51 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................52 
8.1 
EFFICACY ASSESSMENTS ........................................................................................................52 
8.1.1 
Disease-specific efficacy measures...............................................................................................52 
8.1.2 
Patient reported outcomes questionnaires ....................................................................................54 
8.2 
SAFETY ASSESSMENTS ............................................................................................................56 
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8.2.1 
Physical examinations ...................................................................................................................57 
8.2.2 
Vital signs.......................................................................................................................................57 
8.2.3 
Electrocardiograms ........................................................................................................................57 
8.2.4 
Clinical safety laboratory assessments..........................................................................................57 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................58 
8.3.1 
Adverse event of special interest...................................................................................................58 
8.3.2 
Time period and frequency for collecting AE and SAE information...............................................62 
8.3.3 
Method of detecting AEs and SAEs...............................................................................................63 
8.3.4 
Follow-up of AEs and SAEs...........................................................................................................63 
8.3.5 
Regulatory reporting requirements for SAEs .................................................................................63 
8.3.6 
Pregnancy......................................................................................................................................63 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ...........64 
8.3.8 
Guidelines for reporting product complaints / medical device incidents (including 
malfunctions)..................................................................................................................................64 
8.4 
TREATMENT OF OVERDOSE......................................................................................................64 
8.5 
PHARMACOKINETICS..................................................................................................................64 
8.6 
PHARMACODYNAMICS ...............................................................................................................66 
8.6.1 
Pharmacodynamic variables/Biomarkers.......................................................................................66 
8.6.2 
Whole blood biomarkers ................................................................................................................66 
8.6.3 
Plasma/serum biomarkers .............................................................................................................66 
8.7 
PHARMACOGENOMICS...............................................................................................................67 
8.8 
BIOMARKERS ...............................................................................................................................67 
8.8.1 
Immunogenicity assessments........................................................................................................67 
8.9 
HEALTH ECONOMICS..................................................................................................................68 
9 
STATISTICAL CONSIDERATIONS .............................................................................................69 
9.1 
STATISTICAL HYPOTHESES.......................................................................................................69 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................69 
9.3 
POPULATIONS FOR ANALYSES.................................................................................................71 
9.4 
STATISTICAL ANALYSES ............................................................................................................71 
9.4.1 
Efficacy analyses ...........................................................................................................................71 
9.4.2 
Safety analyses..............................................................................................................................73 
9.4.3 
Other analyses...............................................................................................................................74 
9.5 
INTERIM ANALYSES ...................................................................................................................75 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................76 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......76 
10.1.1 
Regulatory and Ethical Considerations..........................................................................................76 
10.1.2 
Informed Consent Process ............................................................................................................76 
10.1.3 
Data Protection ..............................................................................................................................77 
10.1.4 
Committees Structure ....................................................................................................................77 
10.1.5 
Dissemination of Clinical Study Data.............................................................................................77 
10.1.6 
Data Quality Assurance .................................................................................................................78 
10.1.7 
Source documents .........................................................................................................................78 
10.1.8 
Study and Site Closure ..................................................................................................................78 
10.1.9 
Publication Policy...........................................................................................................................79 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................79 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................80 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................85 
10.5 
APPENDIX 5: PHARMACOGENOMICS .......................................................................................88 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ...........................................................................................................................89 
10.7 
APPENDIX 7: LIST OF PROHIBITED LIVE ATTENUATED VACCINES......................................94 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................94 
10.9 
APPENDIX 9: ABBREVIATIONS...................................................................................................94 
10.10 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY ................................................................95 
10.11 
APPENDIX 11: COPD ASSESSMENT TEST ...............................................................................96 
10.12 
APPENDIX 12: ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) ............................97 
10.13 
APPENDIX 13: EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY 
DISEASE TOOL (EXACT) ...........................................................................................................103 
10.14 
APPENDIX 14: EUROQOL QUESTIONNAIRE (EQ-5D-5L) .......................................................106 
10.15 
APPENDIX 15: DEFINITION OF ANAPHYLAXIS .......................................................................109 
10.16 
APPENDIX 16: LIST OF OPPORTUNISTIC INFECTIONS.........................................................110 
10.17 
APPENDIX 17: FUTURE USE OF SAMPLES.............................................................................111 
11 
REFERENCES.............................................................................................................................112 
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LIST OF TABLES 
Table 1 - Objectives and endpoints...............................................................................................................27 
Table 2 - Overview of Investigational Medicinal Products administered.......................................................40 
Table 3 – Reliever Medication –Salbutamol/Albuterol Nebulizer Solution....................................................42 
Table 4 - Reliever Medication - Levosalbutamol/Levalbuterol Nebulizer Solution........................................42 
Table 5 - Reliever Medication - Ipratropium or Ipratropium/short-acting β agonists [SABA] Nebulizer 
Solutions........................................................................................................................................................43 
Table 6 - Safety instructions for Adverse Events of Special Interest ............................................................60 
Table 7 – Adverse event reporting ................................................................................................................62 
Table 8 - Summary of handling procedures for pharmacokinetic (PK) samples...........................................65 
Table 9 - Summary of bioanalytical methods for pharmacokinetics samples ...............................................65 
Table 10 - Summary of handling procedures for antidrug antibody (ADA) samples.....................................67 
Table 11 - Summary of bioanalytical methods antidrug antibody .................................................................68 
Table 12 - Power calculation for various event rates in the placebo group ..................................................70 
Table 13 - Populations for analyses ..............................................................................................................71 
Table 14 - Efficacy analyses .........................................................................................................................72 
Table 15 - Safety analyses............................................................................................................................73 
Table 16 - Other analyses .............................................................................................................................74 
Table 17 - Protocol-required safety laboratory assessments........................................................................80 
Table 18 - Highly effective contraceptive methods .......................................................................................86 
 
LIST OF FIGURES 
Figure 1 - Graphical study design .................................................................................................................16 
 
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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol title: A randomized, double-blind, placebo-controlled, parallel-group, Proof-of-
Concept (PoC) study to assess the efficacy, safety and tolerability of SAR440340, 
in patients with moderate-to-severe chronic obstructive pulmonary disease 
(COPD) 
Short title: 
Proof-of-Concept study to assess the efficacy, safety and tolerability of 
SAR440340 (anti-IL-33 mAb) in patients with moderate-to-severe chronic 
obstructive pulmonary disease (COPD) 
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. Interleukin-33 (IL-33) is a pro-inflammatory cytokine that initiates and 
amplifies innate and adaptive inflammatory cascades, in response to epithelial cell stress or 
damage due to exposure to airborne allergens, viruses, cigarette smoke, and air pollutants. The 
objective of the current study is to investigate the effects of 300 mg SAR440340 (a human 
monoclonal antibody that targets IL-33), administered SC once every 2 weeks as compared to 
placebo on reducing the incidence of exacerbations in patients with moderate-to-severe COPD. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
• To investigate effects of SAR440340 (anti-IL33 mAb) 
compared with placebo, on the annualized rate of 
moderate-to-severe acute exacerbations of COPD 
(AECOPD) over up to 52 weeks of treatment. 
 
 
- Annualized rate of moderate*-to-severe** AECOPD over the 
treatment period. 
 
- *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. 
Key secondary 
• To investigate effects of SAR440340 compared with 
placebo, on improving respiratory function, as assessed by 
prebronchodilator FEV1 over 24 weeks. 
• Average change from baseline to Week 16-24*** in FEV1 
(pre-bronchodilator)  
 
*** Model-based averages across Weeks 16, 20 and 24 
will be compared between the treatment groups 
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Overall design: 
Multinational, randomized, double-blind, placebo controlled, parallel group (2 groups), Proof of 
Concept (PoC) study that is designed to assess the efficacy, safety, and tolerability of SAR440340 
in patients with moderate-to-severe COPD on an established Long-acting β2 adrenergic agonist 
(LABA), Long-acting muscarinic antagonist (LAMA), and/or ICS background therapy (double or 
triple therapy). Patients will be treated with SAR440340 or placebo for a minimum of 24 weeks 
and up to a maximum of 52 weeks*, and a 20-week safety follow-up period. 
* This study employs a variable treatment duration from 24 to 52 weeks to maximize data for the 
primary endpoint (annualized rate of exacerbation) in a time-efficient manner. Patients enrolled 
in the trial will remain in the treatment period for up to a maximum of 52 weeks or until the last 
patient randomized completes a minimum treatment period of 24 weeks. Of note, the accrual and 
drop-out rates will be closely monitored. If the accrual rates are significantly lower than planned 
and/or the drop-out rates are higher than expected, the minimum treatment duration may be 
extended to achieve the desired amount of total exposure. The maximum treatment duration of 52 
weeks will not be changed. 
The study duration is outlined below: 
• 
Screening period (10 days to 4 weeks)  
• 
Randomized investigational medicinal product (IMP ) treatment period (24 to 52 weeks) 
• 
Post IMP safety follow-up treatment period (20 weeks). 
At screening, patients must be on standard of care background therapy, for 3 months prior to Visit 
2/Randomization and at a stable dose for at least 1 month prior to the Screening Visit 1, including 
either: 
• 
Double therapy: LABA + LAMA or ICS + LABA or ICS + LAMA. 
OR 
• 
Triple therapy: ICS + LABA + LAMA. 
Patients who satisfy the inclusion and exclusion criteria will be randomized (1:1) to:  
• 
SAR440340 (300 mg) administered as 2 SC injections every 2 weeks (q2w) for 24 to 52 
weeks  
• 
Matching placebo for SAR440340 administered as 2 SC injections q2w for 24 to 52 weeks  
It is planned to enroll approximately 50% of patients on ICS-containing background therapy 
(ICS+LABA; ICS+LAMA or ICS +LABA+LAMA). 
Patients must be willing to stay on their established background medication for COPD throughout 
the duration of the study. 
Visits up to 52-week IMP treatment period will occur every other week and will be followed by a 
20-week observational follow-up period. 
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Treatment discontinuation follow-up:  
Patients who withdraw from study treatment (prior to completing the planned duration of IMP 
treatment) will perform, as soon as possible, the early treatment discontinuation visit (ETD) with 
all assessments normally planned for the EOT visit, to assure a complete clinical assessment in 
close temporal proximity to the premature termination of study treatment is available. In addition, 
and to allow assessment of patient outcomes over the stipulated study period, patients will be 
asked and encouraged to complete all remaining study treatment visits, and participate in all 
safety follow-up assessments according to the visit schedule with a +/-5 day window.  For such 
patients the assessment schedule will be reduced (See study flowchart for patients after permanent 
treatment discontinuation in Section 1.3.2) and alternate visits during the planned treatment period 
may be conducted by phone (those with odd visit numbers, except for the planned EOT), as can 
visits F1 and F2.  
Under exceptional circumstances when a patient cannot come to the site for a scheduled visit, a 
phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication and COPD exacerbation events should be collected. 
Post IMP treatment follow-up: 
Upon completing the 24-52 weeks randomized IMP treatment, patients will continue background 
therapy and enter the 20-week safety follow-up period.  
Number of participants: 
Approximately 340 patients will be randomized in this study (170 patients per arm) of which 
approximately 50% of patients should present with a blood eosinophil count of ≥ 250 /mm3 and 
about 50% of patients with a blood eosinophil count of <250 /mm3. All randomized participants 
who receive at least 1 dose of IMP will be included in the efficacy and safety analysis. See 
Section 9.2 for sample size determination and Section 9.3 for analysis populations. 
Intervention groups and duration: 
Study participation for each patient will be up to a total of approximately 46 weeks to 76 weeks, 
including up to 4 weeks of screening, 24 weeks to 52 weeks of IMP treatment period, and 20 
weeks of post IMP treatment period. 
Study intervention(s) 
Investigational medicinal products(s) 
SAR440340 
• 
Formulation: Sterile SAR440340 will be provided in one 20 mL vial containing 287 mg of 
lyophilisate drug product. One vial of lyophilisate drug product (287 mg) is reconstituted 
with 2.5 mL of sterile water for injection resulting in 2.9 mL of 100 mg/mL SAR440340. 
A volume of 1.5 mL per injection will be withdrawn from the vial. Patients will receive 2 
injections per dose 
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• 
Route(s) 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) 
• 
Dose regimen: 2 SC injections q2w for 24-52 weeks. 
Matching placebo for SAR440340 
• 
Formulation: Sterile placebo will be provided in one 20 mL vial containing lyophilisate 
placebo. One vial of lyophilisate is reconstituted with 2.5 mL of sterile water for injection 
resulting in 2.9 mL IMP. A volume of 1.5 mL per injection will be withdrawn from the 
vial. Patients will receive 2 injections per dose 
• 
Route(s) 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) 
• 
Dose regimen: 2 SC injections q2w for 24-52 weeks. 
Noninvestigational medicinal products(s) 
Background therapy  
Patients should continue their established standard of care background therapy for COPD 
throughout the study (double therapy [LABA + LAMA or ICS + LABA or ICS + LAMA] or 
triple therapy [ICS + LABA + LAMA]). 
• 
Formulation: Dry powder inhaler (DPI), metered dose inhaler (MDI) or pocket nebulizer  
• 
Route(s) of administration: Oral inhalation 
• 
Dose regimen: As prescribed 
Patients must be willing to stay on their established background medication for COPD throughout 
the duration of the study. 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. 
Reliever Medication 
Patients may use albuterol/salbutamol or levalbuterol/levosalbutamol (including ipratropium or 
ipratropium/short-acting β agonists [SABA] combinations) as reliever medication as needed 
during the study. Nebulizer solutions may be used as an alternative delivery method. 
• 
Formulation: Dry powder inhaler (DPI), metered dose inhaler (MDI) or pocket nebulizer  
• 
Route(s) of administration: Oral inhalation 
Dose regimen: As prescribed. 
 
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Statistical considerations:  
• 
Primary efficacy analysis: 
For the primary efficacy endpoint the annualized exacerbation rate, a negative binomial 
regression model will be used to assess treatment differences. The model will include the 
total number of events occurring during the treatment period (up to Week 52) as response 
variable, and the treatment group, the baseline eosinophil strata and region (pooled 
countries) as covariates. Log-transformed observation duration will be the offset variable. 
Parameters will be estimated using the maximum likelihood method with the Newton-
Raphson algorithm.  
Comparison of the annualized event rates between the treatment group and the placebo 
group will be made within this model and the rate ratios and their 95% confidence 
intervals will be estimated.  
In the case of premature discontinuation of study drug, a secondary analysis will include 
events up to 14 days after the last dose. 
Using the same method, subgroup analyses will be performed separately by the baseline 
eosinophil levels (≥250 /mm3 versus <250 /mm3). 
• 
Analysis of secondary endpoints: 
Key secondary endpoint 
The key secondary efficacy endpoint the average change from baseline to Week 16- 24 in 
pre-bronchodilator FEV1  will be analyzed using a mixed-effect model with repeated 
measures (MMRM) approach. Model-based averages across Weeks 16, 20 and 24 will be 
compared between the treatment groups. The dependent variable is the change from 
baseline in pre-bronchodilator FEV1 at each time points. The model will include baseline 
FEV1 value, treatment group, visit, and treatment-by-visit interaction, the baseline 
eosinophil strata, and region (pooled countries), as covariates. An unstructured correlation 
matrix will be used to model the within-patient correlations. Parameters will be estimated 
using restricted maximum likelihood method with the Newton-Raphson algorithm. 
Additional covariates such as the background medications, age, height, gender, race and 
smoking status will be considered for inclusion in the analysis model based on evaluation 
of blinded data and the final analysis model documented in the statistical analysis plan 
(SAP). 
Comparison between the treatment group and the placebo group will be made within this 
model and the least square mean difference and their 95% confidence intervals will be 
estimated. 
In the case of premature discontinuation of study drug the primary analysis will include 
data up to 14 days after the last dose. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01 
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Page 15 
 
Subgroup analyses will be performed using the same method by baseline eosinophil levels 
(≥250 /mm3 versus <250 /mm3). 
Other secondary efficacy endpoints:  
Change from baseline to Week 24 in FEV1 post-bronchodilator will be analyzed in the 
same way as the key secondary endpoint.  
Similar analytic method will be applied to analyze change from baseline to time points 
past Week 24 in FEV1 (both pre-bronchodilator and post-bronchodilator).    
Time to first moderate or severe AECOPD will be analyzed using a Cox regression model 
with treatment, baseline eosinophil strata, and region (pooled country) as covariates. The 
Kaplan-Meier (K-M) method will be used to estimate the probabilities of first AECOPD at 
specific time points for each group. Additional covariates will be considered based on 
evaluation of blinded data and the final analysis model documented in the SAP. 
• 
Safety analysis 
Safety analyses will be descriptive, based on the safety population. The safety analysis 
will focus on the treatment-emergent adverse event (TEAE) period. This period is defined 
as the time from the first administration of the IMP to 22 weeks after the last 
administration of the IMP. During the study, unblinded data will be reviewed on an 
ongoing basis for safety and efficacy by a Data Monitoring Committee (DMC). 
Data Monitoring Committee: Yes 
An internal DMC will be comprised of individuals with expertise in the diseases under study, 
biostatistics, or clinical research. The DMC members are independent of the project/study teams 
and are not involved in the study conduct. The primary responsibilities of the DMC are to review 
and evaluate the study data during the course of the trial and make appropriate recommendations 
regarding the conduct of the clinical trial to project/study team.    
 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 01 
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Version number: 1 
 
 
1.2 
SCHEMA 
 
 
Figure 1 - Graphical study design 
 
                    Treatment consisting of 2 injections of 1.5 mL each of SAR440340 or placebo. 
1 Variable treatment period determined by either completion of a 52 week treatment duration or the end of treatment of the last patient completing 
planned treatment (EOT visit), whichever occurs earlier, whichever occurs earlier Section 4.1.  
2 End of Treatment (EOT) visit to occur 2 weeks after last administration of IMP.
(electronic 
 
 
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Amended Clinical Trial Protocol 01 
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Page 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA)  
The Schedule of Activities (SoA) for patients who complete the planned treatment is described in Section 1.3.1. Patients who withdraw treatment 
must complete the Early Treatment Discontinuation (ETD) visit and follow the assessment in Section 1.3.2  for the remaining visits.   
1.3.1 Schedule of Activities (SoA) for Patients who complete the Planned Treatment  
 
 
S 
R/
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 
1 
2a,
b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
EOT 
c 
F1 
F2d 
EOS 
WEEK 
W-4  
to  
W-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52  
60 
66 
72 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous medical and 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COPD Assessment Test 
(CAT)f 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking status 
X 
X 
X 
X 
X 
X
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Prior & concomitant 
medications 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study treatment 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Call IVRS/IWRS 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationg 
 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Dispense or upload 
electronic diaryh 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationi 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Vital signsj 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram  
(12 lead)k 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Hematology, biochemistry, 
urinalysis including 
X 
X 
 
 
 
X
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
(electronic 
 
 
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Amended Clinical Trial Protocol 01 
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Page 18 
 
S 
R/
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 
1 
2a,
b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
EOT 
c 
F1 
F2d 
EOS 
WEEK 
W-4  
to  
W-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52  
60 
66 
72 
cotininel 
Hepatitis and HIV 
Serology testsm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantiferon Gold  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (β-HCG blood) 
testn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testn 
 
X 
 
X 
 
X
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Adverse event reporting, 
including SAEs 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum samples for SAR440340 
concentrationo 
 
X 
X 
X 
 
X
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Anti-SAR440340 
antibodyp 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood eosinophils and 
neutrophils 
X 
X 
 
X
q 
 
X
 
X
q 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xq 
 
X 
Total IL33 and sST2o 
X 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Calcitonin 
X 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
PARC 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Eotaxin-3 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Total IgE 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Fibrinogen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
FeNO pre-bronchodilator 
(optional)r 
 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
FeNO post-bronchodilator 
(optional) r 
 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Induced sputum (optional)s 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for RNA 
sample (optional) 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood sample archival for 
exploratory research 
(optional)t 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
(electronic 
 
 
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ACT15104 – SAR440340 
11-Jun-2018      
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 19 
 
S 
R/
B 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 
1 
2a,
b 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
EOT 
c 
F1 
F2d 
EOS 
WEEK 
W-4  
to  
W-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52  
60 
66 
72 
DNA Pharmacogenomics 
analysis (optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COPD exacerbation 
reporting by the 
Investigator 
 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry (pre-BD)u, v 
X 
X 
X 
X 
 
X
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Spirometry (post-BD) u, v 
X 
X 
X 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
EXACTw 
Every day (diary) from screening to week 52 
 
 
 
SGRQw 
 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
EQ-5D-5Lw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Actigraphy  
Optional assessments 
(US/Canada only) 
Co
n-
tin
uos 
 
 
 
 
 
Con-
tinuos 
 
 
 
 
Con-
tinuos 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At-home spirometry 
(FEV1) 
Optional assessments 
(US/Canada only) 
BI
D 
 
 
 
 
 
BID 
 
 
 
 
BID 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S= Screening; R/B= Randomization/Baseline; F=Follow-up 
β-hCG = Human chorionic gonadotropin-beta; BID = twice daily assessments; CAT = COPD Assessment Test; 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 (EXACT); HIV = human immunodeficiency virus; IgE = Immunoglobulin E; IMP = Investigational Medical Product; IVRS = Interactive Voice Response System; IWRS = Interactive Web 
Response System; LABA = Long-acting β2 adrenergic agonist; LAMA = Long-acting muscarinic antagonist ;PARC = Pulmonary and activation-regulated chemokine; PK = Pharmacokinetic; RNA = Ribonucleic acid; 
SABA = Short-acting beta-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 ±3 days for the screening period and randomized IMP treatment period, and ±5 days for the 2 visits during 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 4.1 for patients who discontinue treatment. 
d Can be performed with a phone call. 
e Chest X-ray to be performed unless a <6 month old chest x-ray/chest CT/chest MRI is available. In case chest-X-ray is not feasible due to local regulations, magnetic resonance imaging (MRI) will be performed.  
f 
The COPD Assessment Test (CAT) is to be registered through the patient’s electronic diary. 
g IMP (SAR440340 or placebo) to be administered every 2 weeks at the site.  Last dose will be given 2 weeks prior to planned EOT visit eg, for patients with 52-week treatment period the last dose will be taken at 
Week 50, or earlier, as directed by the sponsor. Patients should be monitored by site personnel for at least 30 minutes after administration of all IMP injections.  Monitoring period may be extended as per country 
specific requirements.  
(electronic 
 
 
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Page 20 
h Electronic diary is used for recording of patient’s answers to the EXACT, SGRQ and EQ-5D-5L questionnaires, CAT assessment as well as for recording reliever medication. This device is dispensed at Screening 
Visit 1 (including instructions for use) and recorded information is downloaded from this device on the other indicated days. At EOS visit the electronic diary is downloaded and returned to the site.  
i 
Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
j 
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. 
k ECG to be centrally collected & read.  
l 
Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell count with 5-part differential count, and total red blood cell count. Serum chemistry will include creatinine, blood urea nitrogen, 
glucose, lactate dehydrogenase, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, 
chloride), bicarbonate, and creatine phosphokinase. Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen and bilirubin. If any parameter on the 
dipstick is abnormal, a urine sample should be sent to the central laboratory for quantitative measurement. If positive for protein and/or red blood cells, microscopic analysis will be performed by the central 
laboratory. Cotinine will be tested using the urine sample collected. 
m 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 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).  
n Only for women of childbearing potential: serum pregnancy test at Screening/V1 and urine pregnancy tests at every 4 weeks from Randomization through EOT and at EOS. A negative result must be obtained at 
V1 and at 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. 
o Refer to central lab manual for collection details. 
p If ADA assessment at week 12 is positive, additional measurements may be performed from PK samples collected at Week 4. 
q The complete hematology panel will be performed.  
r 
FeNO: measurement at sites only with access to FeNO equipment. 
s Optional sputum sample at V2 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.  
t 
Archived samples 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.   
u 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). 
v 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. 
w The EXACT, SGRQ and EQ-5D-5L are to be completed in the patient’s electronic diary. 
 
 
 
 
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Page 21 
1.3.2 Schedule of Activities (SoA) for Patients After Early Treatment Discontinuation  
 
 
ETD
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 
 
 
3
b
 
4 
5
b 
6 
7
b 
8 
9
b 
10 
11
b 
12 
13
b 
14 
15
b 
16 
17
b 
18 
19
b 
20 
21
b 
22 
23
b 
24 
25
b 
26 
27
b 
EOT 
c 
F1 
b 
F2
b 
EOS 
WEEK 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52  
60 
66 
72 
Smoking status 
X 
X 
X 
X 
X
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Prior 
& 
concomitant 
medications 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Call IVRS/IWRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Upload electronic diaryd 
Every on-site visit up to 12 weeks after ETD 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinatione 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Vital signsf 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Electrocardiogram  
(12 lead)g  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Hematology, biochemistry, 
urinalysis 
including 
cotinineh 
X 
 
 
 
X
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Urine pregnancy testi 
X 
 
X 
 
X
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Adverse event reporting, 
including SAEs 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum samples for SAR440340 
concentrationj 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Anti-SAR440340 
antibodyk 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
eosinophils 
and 
neutrophils 
X 
 
 
 
X
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Total IL33 and sST2j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calcitonin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eotaxin-3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fibrinogen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
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Amended Clinical Trial Protocol 01 
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11-Jun-2018      
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Property of the Sanofi Group - strictly confidential 
Page 22 
 
ETD
a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 
 
 
3
b
 
4 
5
b 
6 
7
b 
8 
9
b 
10 
11
b 
12 
13
b 
14 
15
b 
16 
17
b 
18 
19
b 
20 
21
b 
22 
23
b 
24 
25
b 
26 
27
b 
EOT 
c 
F1 
b 
F2
b 
EOS 
WEEK 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
26 
28 
30 
32 
34 
36 
38 
40 
42 
44 
46 
48 
50 
52  
60 
66 
72 
Induced sputum (optional) 
m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood samples for RNA 
sample (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample archival for 
exploratory 
research 
(optional)n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COPD 
exacerbation 
reporting 
by 
the 
Investigator 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry (pre-BD)o, p 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
Spirometry (post-BD) o, p 
X 
 
X 
 
X
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
EXACTq  
Every day (diary) up to 12 weeks after ETD 
SGRQq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5Lq 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Actigraphy  
Optional 
assessments 
(US/Canada only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At-home 
spirometry 
(FEV1) 
Optional 
assessments 
(US/Canada only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F=Follow-up 
β-hCG = Human chorionic gonadotropin-beta; BID = twice daily assessments; CAT = COPD Assessment Test; 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 (EXACT); HIV = human immunodeficiency virus; IgE = Immunoglobulin E; IMP = Investigational Medical Product; IVRS = Interactive Voice Response System; IWRS = Interactive Web 
Response System; LABA = Long-acting β2 adrenergic agonist; LAMA = Long-acting muscarinic antagonist; PARC = Pulmonary and activation-regulated chemokine; PK = Pharmacokinetic; RNA = Ribonucleic acid; 
SABA = Short-acting beta-agonists; SAEs = Serious adverse events; SC = subcutaneous; SGRQ = St. George's Respiratory Questionnaire. 
a Patients who withdraw from study treatment (prior to completing the planned duration of IMP treatment) will perform, as soon as possible, the early treatment discontinuation visit (ETD) visit. Once the ETD is 
performed, patients should follow the ETD SoA based on their original visit number, and the visit schedule should be adhered to within ±5 days. 
b Visit may be performed by a phone call. 
c End-of-treatment visit. For patients who discontinue treatment, this visit corresponds to the planned EOT visit. 
(electronic 
 
 
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d Electronic Diary will be used on daily basis for period of 12 weeks after ETD. The CAT assessment, and reliever medication will not be collected in patients after early treatment discontinuation. 
e Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
f 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), body temperature (°C), and respiratory rate will be measured at on-site visits. Body weight (kg) will be measured at 
EOT/EOS visits. 
g ECG to be centrally collected & read.  
h Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell count with 5-part differential count, and total red blood cell count. Serum chemistry will include creatinine, blood urea nitrogen, 
glucose, lactate dehydrogenase, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, 
chloride), bicarbonate, and creatinine 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. Cotinine will be tested using the urine sample collected. 
i 
Only for women of childbearing potential: urine pregnancy test at ETD and every 4 weeks through EOT and at EOS. 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. 
j 
Refer to central lab manual for collection details. 
k If ADA assessment at week 12 is positive, additional measurements may be performed from PK samples from Week 4. 
l 
FeNO: measurement at sites only with access to FeNO equipment. 
m 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.  
n Archived samples 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.   
o 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). 
p 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. 
q The EXACT, SGRQ and EQ-5D-5L are to be completed in the patient’s electronic diary.
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2 
INTRODUCTION 
SAR440340 (also known as REGN3500 or R3500) is a human monoclonal antibody (mAb) that 
targets IL-33 and is under development as a potential novel treatment for both asthma and COPD. 
2.1 
STUDY RATIONALE 
Chronic obstructive pulmonary disease (COPD) is a highly prevalent disease worldwide that is 
associated with significant economic burden and for which available standard-of-care therapy 
shows insufficient efficacy on symptoms, lung function, exacerbations and long-term evolution of 
the disease. IL-33 is a pro-inflammatory cytokine that initiates and amplifies innate and adaptive 
inflammatory cascades in response to epithelial cell stress or damage due to exposure to airborne 
allergens, viruses, cigarette smoke, and air pollutants. The objective of the current study is to 
investigate the effects of 300 mg SAR440340 administered SC once every 2 weeks as compared 
to placebo on reducing the incidence of exacerbations in patients with moderate-to-severe COPD.  
2.2 
BACKGROUND 
2.2.1 Chronic obstructive pulmonary disease  
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with an 
abnormal inflammatory immune response of the lung to noxious particles and gases (1). Chronic 
inflammation causes structural changes, 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. It results in progressive airflow obstruction that is only partly reversible or 
even irreversible. The inflammation component of COPD is thought to involve many cell types 
including structural cells, T lymphocytes, neutrophils, macrophages, and their biological products. 
In some patients, there may also be an increase of eosinophils, T-helper (Th) 2 or Group 2 Innate 
Lymphoid cells, especially where there is clinical overlap with asthma. The main cause of COPD 
is smoking tobacco, but other factors have been identified, such as air pollution, occupational 
exposure, and genetic susceptibility. The most common respiratory symptoms include chronic 
dyspnea, cough and/or sputum production. The disease is further aggravated by exacerbations, 
particularly for severe COPD. These are most often due to viral and bacterial infections of the 
lungs which trigger the inflammatory response, tissue destruction, and the resultant hypoxia. 
Exacerbations in COPD patients are associated with rapid disease progression (rate of lung 
function decline over time) and increased risk of mortality. 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.  
Chronic obstructive pulmonary disease is a highly prevalent, serious and progressive disease 
resulting in significant morbidity, mortality, and economic burden (2, 3). 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 
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mortality. 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. 
The standard of care for moderate COPD starts with bronchodilators (such as long-acting 
muscarinic antagonists [LAMA] or long-acting β2 agonists [LABA]), and as disease progresses 
bronchodilators are combined with other drugs such as inhaled corticosteroids (ICS), and 
phosphodiesterase type 4 (PDE-4) inhibitors (roflumilast) (4, 5, 6). The major limitations of the 
existing agents for COPD include modest efficacy and risk of respiratory infections (ICS). Oral or 
systemic corticosteroids are reserved for treatment of exacerbations given their unacceptable long-
term safety profile in the COPD population. No approved therapeutic agent blocks the decline in 
forced expiratory volume in 1 second (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. The anti-interleukin (IL)-5 mAb mepolizumab shows a modest 18%-20% 
reduction of exacerbations in COPD patients with high blood eosinophils. The anti-IL-5 receptor 
mAb benralizumab is still in Phase 3 clinical trials, and preliminary data from Phase 2a trial 
suggest that the FEV1 improvement versus placebo averaging approximately 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 (7, 8).  
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. 
2.2.2 SAR440340 - Anti-IL-33 monoclonal antibody 
SAR440340 is a human mAb that targets IL-33. IL-33 is a proinflammatory cytokine that initiates 
and amplifies innate and adaptive inflammatory cascades (9) in response to epithelial cell stress or 
damage (“alarmin”) due to exposure to airborne allergens, viruses, cigarette smoke, and air 
pollutants. Accumulating evidence from human studies and animal models suggests that IL-33 is 
potentially implicated in the pathogenesis of COPD, and provides the rationale for the use of 
SAR440340 in patients with COPD. Studies from the Regeneron Genetics Center provide 
evidence that genetic variation in the IL-33 and IL1RL1 genes are common risk factors for 
COPD. In humans, increased levels of IL-33 have been reported in bronchial cells of COPD 
patients (10, 11). It is also known that IL-33 protein expression in the lungs correlates with COPD 
severity and is a negatively correlated with FEV1 (11). A separate study has found that plasma IL-
33 level in patients with stable COPD was related to eosinophil count and chronic bronchitis 
phenotype (12). Supporting data from a preclinical murine smoking model of COPD suggests a 
dual role for IL-33 in amplifying lung inflammation during viral exacerbations of COPD. Initially, 
smoke inhalation upregulates intracellular IL-33 in mice, as well as the proportion of epithelial 
cells expressing IL-33; secondly, viral infection leads to focal cellular necrosis, release of IL-33, 
and increased production of proinflammatory cytokines such as IL-6 and tumor necrosis factor-α 
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(TNF-α) in the lung (11). Therefore, it is hypothesized that blockade of IL-33 which is locally 
released in the airway in the setting of environmental triggers such as infection or toxic inhalants 
may be a novel therapeutic approach to prevent exacerbations. 
2.3 
BENEFIT/RISK ASSESSMENT 
The Phase 1 study in healthy subjects suggests that SAR440340 is well-tolerated at doses up to 10 
mg/kg administered IV as single dose. Unblinded safety data from the ongoing multiple 
ascending dose study (R3500-AS-1619, data as of February 23, 2018) in asthma patients have 
demonstrated that weekly doses of 75 mg and 150 SC are so far well tolerated. No SAEs or deaths 
have been reported in any of the Phase 1 studies. SAR440340 is expected to inhibit the 
proinflammatory activity of IL-33, which is elevated in COPD patients. Thus, the benefit/risk 
profile for SAR440340 in this study supports its evaluation as a potential agent for treatment of 
COPD. 
There is a potential risk of infection associated with blocking of host defense pathways by 
SAR440340. The preliminary safety data from the first in human (FIH) study of SAR440340 have 
revealed no safety signals. Therefore, the anticipated safety of SAR440340 is considered 
reasonable, with close monitoring of adverse events (AEs) and laboratory results throughout the 
study and follow-up period. The safety data and other potential risks (systemic hypersensitivity, 
embryo-foetal toxicity, immunogenicity) for SAR440340 are summarized in the Investigator's 
Brochure (IB). 
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3 
OBJECTIVES AND ENDPOINTS 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
• To investigate effects of SAR440340 (anti-IL33 mAb) 
compared with placebo, on the annualized rate of 
moderate-to-severe acute exacerbations of COPD 
(AECOPD) over up to 52 weeks of treatment. 
 
 
- Annualized rate of moderate*-to-severe** AECOPD over the 
treatment period. 
 
*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. 
Secondary 
• To investigate effects of SAR440340 compared with 
placebo, on improving respiratory function, as assessed 
by prebronchodilator FEV1 over 24 weeks. 
• Average change from baseline to Week 16-24*** in FEV1 
(pre-bronchodilator)  
 
*** Model-based averages across Weeks 16, 20 and 24 
will be compared between the treatment groups 
• To evaluate effects of SAR440340  compared with placebo, 
on  Post-bronchodilator FEV1 over 24 weeks 
 
• Change from baseline to Week 24 in FEV1 (post-
bronchodilator****)  
**** Post-bronchodilator means 30 minutes after either 400 
mcg of salbutamol/albuterol (4 puffs of 100 mcg each) or 
80 mcg of ipratropium bromide (4 puffs of 20 mcg each). 
• To evaluate effects of SAR440340  compared with placebo, 
on duration from baseline to first moderate or severe 
AECOPD event over up to 52 weeks 
• Time to first moderate or severe AECOPD. 
• To evaluate effects of SAR440340 compared with placebo, 
on safety and tolerability 
• Treatment-emergent adverse events (TEAE)  
• Serious adverse events (SAE) 
• Tertiary/exploratory  
• To evaluate the effects of SAR440340 compared with 
placebo, on patient reported symptoms and quality of life 
as documented by e-Diary and utilizing Exacerbations of 
Chronic Obstructive Pulmonary Disease Tool (EXACT), 
St. George’s Respiratory Questionnaire (SGRQ) and 
Euroqol-5Dimension (EQ 5D) questionnaire 
- 
in all patients treated with SAR440340/placebo 
- 
in subpopulations with high blood eosinophil level 
(≥250 /mm3) and low blood eosinophil level (<250 
/mm3) 
• Change from baseline in the EXACT scores at Week 24 
• Change from baseline in the SGRQ scores at Week 24 
• Change from baseline in the EQ-5D scores at Week 24 
• To evaluate the pharmacokinetic (PK) profile of SAR440340 
in serum 
• Serum functional SAR440340 concentrations 
• To evaluate the effects of SAR440340 Antidrug antibodies 
(ADA ) 
• Antidrug antibodies (ADA) against SAR440340 
• To evaluate the effects of SAR440340 compared with 
placebo, on FEV1, AECOPD, and other relevant endpoints 
- 
 in subpopulations with high blood eosinophil level 
(≥250 /mm3) and low blood eosinophil level (<250 
/mm3) 
- 
in subpopulations according to use/no use of ICS 
• Change from baseline to Week 24 in FEV1 (pre-
bronchodilator and post-bronchodilator) 
• Rate of moderate-to-severe AECOPD 
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Objectives 
Endpoints 
with bronchodilators as background therapy, 
fibrinogen levels, and smoking status. 
• To evaluate the effects of pharmacogenomics on 
SAR440340  
• Future Assessment of DNA or RNA samples for the 
pharmacogenomics sub study to identify genomic 
associations with clinical or biomarker response, other 
clinical outcome measures and possible AEs 
• To evaluate the effects of SAR440340 compared with 
placebo on other respiratory assessments (expanded 
AECOPD endpoint) 
 
• Change from baseline to Week 16-24 in FVC (% predicted 
and absolute values in mL). 
• Time to the first moderate and severe exacerbations or time 
to study drug discontinuation (after Week 4) due to lack of 
efficacy, based on the investigator’s judgement (expanded 
AECOPD endpoint) 
• To evaluate the clinical symptoms of COPD in patients 
treated with SAR440340 versus placebo 
- 
in all patients treated with SAR440340/placebo 
- 
in subpopulations with high blood eosinophil level 
(≥250 /mm3) and low blood eosinophil level (<250 
/mm3) 
- 
in subpopulations according to use/no use of ICS 
with bronchodilators as background therapy, 
fibrinogen levels, and smoking status 
• Time to first Clinically Important Deterioration (CID) as 
defined by decrease of >100 mL from baseline in trough 
FEV1 and /or deterioration in SGRQ by 4 units and/or 
moderate-to-severe AECOPD up to Week 24 (and over 
the 52 week variable treatment period 
• To evaluate the pharmacodynamics effects of SAR440340 
• Blood eosinophil and neutrophil counts. 
• Levels of biomarkers of the interleukin (IL)-33 and/or Type 2 
inflammation pathway 
- 
Total IL-33, sST2 levels 
- 
Calcitonin levels 
- 
PARC levels 
- 
Eotaxin-3 levels 
- 
Total IgE levels 
- 
Fibrinogen levels 
• Induced sputum for RNA expression (optional for patients at 
a subset of sites). 
• Optional: Messenger ribonucleic acid sequencing or whole 
transcriptome analysis. 
• Optional: DNA/RNA sample will be collected for 
pharmacogenomic effects. 
• Optional actigraphy (sleep and activity) and home 
spirometry (available for patients in US and Canada only): 
To evaluate the effects of SAR440340 compared to 
placebo on parameters of sleep, activity, and at-home 
spirometry. 
 
• Change from average measurement over baseline (2 weeks 
prior to randomization) to average measurements over 
Weeks 10-12 (2 weeks prior to Visit 8) and Weeks 22-24 
(2 weeks prior to Visit 14) of sleep and activity parameters.  
- Sleep: Total sleep time, wake after sleep onset, 
overnight activity counts 
- Activity: Daytime activity counts, percent of time spent in 
sedentary activity, percent of time spent in moderate to 
vigorous physical activity 
- Spirometry: FEV1 
• Optional actigraphy (sleep and activity) and home 
spirometry (available for patients in US and Canada only): 
To compare the utility of at-home spirometry against in-clinic 
spirometry 
• FEV1 (Spirometry performed at home)  
• FEV1 (Spirometry performed at the clinic) 
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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 group (2 groups), Proof of 
Concept (PoC) study that is designed to assess the efficacy, safety, and tolerability of SAR440340 
in patients with moderate-to-severe COPD on an established LABA, LAMA and/or ICS 
background therapy (double or triple therapy). Patients will be treated with SAR440340 or 
placebo for a minimum of 24 weeks and up to a maximum of 52 weeks*, and a 20-week safety 
follow-up period. 
*This study employs a variable treatment duration from 24 to 52 weeks to maximize data for the 
primary endpoint (annualized rate of exacerbation) in a time-efficient manner. Patients enrolled 
in the trial will remain in the treatment period for up to a maximum of 52 weeks or until the last 
patient randomized completes a minimum treatment period of 24 weeks. Of note, the accrual and 
drop-out rates will be closely monitored. If the accrual rates are significantly lower than planned 
and/or the drop-out rates are higher than expected, the minimum treatment duration may be 
extended to achieve the desired amount of total exposure. The maximum treatment duration of 52 
weeks will not be changed. 
The study duration is outlined below: 
• 
Screening period (10 days to 4 weeks)  
• 
Randomized IMP treatment period (24 to 52 weeks) 
• 
Post IMP safety follow-up treatment period (20 weeks). 
The randomization/baseline Visit is defined as Day 1. The visit schedule should be adhered to 
within ±3 days for the screening period and randomized IMP treatment period, and ±5 days for the 
2 visits during the post IMP treatment period.  
At screening, patients must be on Standard of Care background therapy, for 3 months prior to 
Visit 2/Randomization and at a stable dose for at least 1 month prior to the Screening Visit 1, 
including either: 
• 
Double therapy: LABA + LAMA or ICS + LABA or ICS + LAMA. 
OR 
• 
Triple therapy: ICS + LABA + LAMA. 
Patients who satisfy the inclusion and exclusion criteria will be randomized (1:1) to:  
• 
SAR440340 (300 mg) administered as 2 SC injections every 2 weeks (q2w) for 24 to 52 
weeks  
• 
Matching placebo for SAR440340 administered as 2 SC injections q2w for 24 to 52 weeks  
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It is planned to enroll approximately 50% of patients on ICS-containing background therapy (ICS 
+ LABA; ICS + LAMA or ICS + LABA + LAMA). 
Patients must be willing to stay on their established background medication for COPD throughout 
the duration of the study.  
Treatment discontinuation follow-up:  
Patients who withdraw from study treatment (prior to completing the planned duration of IMP 
treatment) will perform, as soon as possible, the early treatment discontinuation visit (ETD) with 
all assessments normally planned for the EOT visit, to assure a complete clinical assessment in 
close temporal proximity to the premature termination of study treatment is available. In addition, 
and to allow assessment of patient outcomes over the stipulated study period, patients will be 
asked and encouraged to complete all remaining study treatment visits, and participate in all 
safety follow-up assessments according to the visit schedule with a +/-5 day window.  For such 
patients the assessment schedule will be reduced (See study flowchart for patients after permanent 
treatment discontinuation in Section 1.3.2) and alternate visits during the planned treatment period 
may be conducted by phone (those with odd visit numbers, except for the planned EOT), as can 
visits F1 and F2.  
Under exceptional circumstances when a patient cannot come to the site for a scheduled visit, a 
phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication and COPD exacerbation events should be collected. 
 Post IMP treatment follow-up: 
Upon completing the 24-52 weeks randomized IMP treatment, patients will continue their 
established ICS/LABA/LAMA therapy and enter the 20-week safety follow-up period. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The first-in-human study (R3500-HV-1551) to investigate safety and pharmacokinetics (PK) of a 
single intravenous (IV) infusion of 0.3, 1, 3 or 10 mg/kg or a single subcutaneous (SC) injection 
of 150 mg of SAR440340 in normal healthy volunteers was completed. Treatment with 
SAR440340 was generally well-tolerated. No deaths and no serious adverse events (SAEs) were 
reported. 
The first-in-patient study (R3500-AS-1619) to investigate safety, tolerability, PK, and 
pharmacodynamic (PD) effects of a repeated SC administration of SAR440340 at 2 dose levels 
(75 and 150 mg), every week for 4 weeks, in adult patients with moderate asthma is ongoing, with 
all patients in the postdosing follow-up period. Unblinded safety data (as of February 23, 2018) 
have demonstrated that SAR440340 is so far well tolerated. No SAE’s or deaths have been 
reported. 
A PD study (R3500-AS-1633) to assess the effects of a single IV dose of 10 mg/kg SAR440340, 
2 repeated SC doses of dupilumab (600 mg loading dose then 300 mg dose), and the 
coadministration of SAR440340 with dupilumab on markers of inflammation after Bronchial 
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Allergen Challenge in patients with mild allergic asthma is ongoing. At the time of writing this 
protocol, acceptable safety and tolerability was observed from the blinded assessments in this 
study. 
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 (7, 8). 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 dose regimen of SAR440340 selected for this study is 300 mg SC administered every 2 
weeks (q2w).  This dosage regimen is predicted to achieve single-dose exposure which falls well 
within the maximum exposure achieved by the single 10 mg/kg IV dose shown to be safe in the 
FIH (R3500-HV-1551) single-ascending dose study.  Safety after repeated dose administration of 
SAR440340 can be inferred from the results of the chronic safety study in cynomolgus monkeys 
where doses as high as 100 mg/kg were administered weekly SC for 26 weeks. Based on systemic 
drug exposures (area under the concentration [AUC]-time curves) in the toxicology studies, the 
proposed SC dose of 300 mg q2w provides a safety margin (exposure multiple based on predicted 
human exposure) of 13.7-29.8 for a proposed 24-52 week study. 
In addition to safety, PK-PD factors were considered.  Based on modeling and simulation of 
SAR440340 HV-1551 FIH drug concentration, the 300 mg q2w regimen is expected to achieve a 
minimum concentration at steady state which is approximately 5-fold higher than the 
concentration of SAR440340 (17 mg/L) that showed efficacy consistently across all endpoints in 
an HDM-induced chronic lung inflammation mouse model.  The higher-fold exposure of the 300 
mg q2w regimen should conservatively ensure all patients are above this efficacy threshold when 
taking into account PK inter-individual variability, as well as the uncertainty in translating the PD 
of SAR440340 from the HDM mouse model to COPD in humans. 
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.  This study has a variable treatment period, therefore all 
participants who complete the planned treatment period of 24 to 52 weeks and all phases for the 
follow-up including the end of study visit are completers. 
The end of this study is defined as completion of the last patient last visit which will occur at the 
end of a 20-week safety follow-up period for the final patient(s) who complete(s) the study as per 
protocol.  
For patients who 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 
Participant must be 40 to 75 years of age inclusive, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 01. Participants with a diagnosis of COPD for at least 1 year (based on Global Initiative for 
Chronic Obstructive Lung Disease [GOLD] definition, see (1). 
I 02. Participants with moderate-to-severe COPD (post-bronchodilator FEV1/forced vital 
capacity [FVC] <70% and post-bronchodilator FEV1 % predicted <80%, but ≥30%) at 
Visits 1 and 2. 
I 03. Participants with COPD Assessment Test (CAT) score ≥10 at Screening Visit 1 and 
Visit 2/Randomization.   
I 04. Participants with reported history of signs and symptoms of chronic bronchitis (chronic 
productive cough for 3 months in the year up to screening in a patient in whom other 
causes of chronic cough [eg, gastroesophageal reflux, chronic rhinosinusitis, 
bronchiectasis] have been excluded).  
I 05. Participants with a documented history  (eg. medical record verification) of ≥2 moderate 
exacerbations or ≥1 severe exacerbation within the year prior to screening 
- 
a moderate exacerbation is defined as an AECOPD requiring systemic corticosteroids 
(oral, intravenous, or intramuscular) and/or treatment with antibiotics (however, use of 
antibiotics alone does not qualify as a "moderate exacerbation" unless documentation 
is available that use of antibiotics was necessary for treatment of worsening symptoms 
of COPD) 
- 
a severe exacerbation is defined as an AECOPD that required a hospitalization.  
I 06. Participants with Standard of Care background therapy, for 3 months prior to 
Visit 2/Randomization and at a stable dose for at least 1 month prior to the screening, 
including either: 
- 
Double therapy: LABA + LAMA or ICS + LABA or ICS + LAMA. 
OR 
Triple therapy: ICS + LABA + LAMA. 
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I 07. Current or former smokers with a smoking history of ≥10 packs-year. 
Weight 
I 08. Body mass index (BMI) ≥18.0 kg/m2 (inclusive).  
Sex 
I 09. Male or Female 
See E 28 for required contraceptive measures. 
Informed Consent 
I 10. 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: 
Active comparator and/or mandatory background therapy  
E 01. Clinically significant abnormal electrocardiogram (ECG) at Visit 1 that may affect the 
conduct of the study in the judgment of the Investigator. 
E 02. Concomitant severe diseases or diseases for which the use of ICS (eg, active pulmonary 
tuberculosis [E 07]) or LABA are contraindicated (eg, diagnosis of a history of significant 
cardiovascular diseases, insulin-dependent diabetes mellitus, hyperthyroidism, 
thyrotoxicosis, pheochromocytoma, hypokalemia).  
E 03. Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 1 month 
prior to Visit 1/Screening or more than 4 courses of IV glucocorticosteroids within the 
6 months prior to Visit 1. 
E 04. Participants receiving medications or therapy that are prohibited as concomitant 
medications (see Section 6.5). 
E 05. A participant with a history of clinically significant renal, hepatic, cardiovascular, 
metabolic, neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, 
cerebrovascular 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. A specific example includes but is not limited to poorly controlled insulin-
dependent diabetes.  
E 06. Participants with Bronchial thermoplasty procedure (up to 3 years prior to Visit 1). 
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E 07. Exclusion related to tuberculosis (TB): 
• 
Active TB or a history of incompletely treated TB. 
• 
Confirmed Quantiferon-positive patients (no active disease) are excluded from the study 
unless the following conditions are met: 
- 
Patients with a history of prior documented completed chemoprophylaxis for latent 
tuberculosis infection (with a treatment regimen as per local guidelines) or treatment of 
active TB infection, and 
- 
Has obtained consultation with a specialist to rule out or treat active TB infection. 
• 
Suspected extrapulmonary TB infection. 
• 
Patients at high risk of contracting TB, such as close contact with individuals with active 
or latent TB. 
Study Methodology  
E 08. The exclusion criterion was deleted (Amended Protocol 01). 
E 09. A current diagnosis of asthma according to the Global Initiative for Asthma (GINA) 
guidelines (13). 
E 10. Significant pulmonary disease other than COPD (eg, lung fibrosis, sarcoidosis, interstitial 
lung disease, pulmonary hypertension, bronchiectasis, eosinophilic granulomatosis with 
polyangiitis, significant sleep apnea on Bilevel Positive Airway Pressure, etc) or another 
diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil 
counts. 
E 11. Diagnosis of α-1 anti-trypsin deficiency. 
E 12. Advanced COPD with need for chronic (>15 hours/day) oxygen support. 
E 13. Participant with a moderate or severe AECOPD event (for definition, see Table 1, primary 
objective) within 4 weeks prior to screening. 
E 14. A participant who has experienced an upper or lower respiratory tract infection within 
4 weeks prior to Screening/Visit 1 or during the screening period. 
E 15. Prior history of or planned pneumonectomy or lung volume reduction surgery. 
E 16. Participants with a history of a systemic hypersensitivity reaction to a mAb drug. 
E 17. Anti-IgE therapy (eg, omalizumab [Xolair®]) within 130 days prior to Visit 1 or any other 
biologic therapy (including anti-IL5 mAb, e.g. benralizumab [Fasenra®] or mepolizumab 
[Nucala®]) for asthma or systemic immunosuppressant (e.g., methotrexate) to treat other 
inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory 
bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, 
etc) and other diseases, within 2 months or 5 half-lives prior to Visit 1, whichever is 
longer. 
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E 18. Current history of substance and/or alcohol abuse. 
E 19. Inability to follow the procedures of the study (eg, due to language problems, 
psychological disorders) or unable to read, understand and fill a questionnaire or use an 
electronic diary without any help. 
E 20. Exposure to another investigative drug (small molecules as well as mAbs, including 
dupilumab) within a time period prior to Visit 1 that is <5 PK half-lives of the antibody. In 
case the half-life is not known, then the minimum interval since the exposure to the prior 
investigative antibody is 6 months. The minimum interval since exposure to any other 
(nonantibody) investigative study medication is 30 days prior to Visit 1. 
E 21. Patients who are participating in the acute phase of a pulmonary rehabilitation program, 
i.e. who started rehabilitation <4 weeks prior to screening (Note: patients in the 
maintenance phase of a rehabilitation program can be included). 
E 22. Clinically relevant (based on study Investigator’s judgment) abnormal laboratory values 
suggesting an unknown disease and requiring further evaluation. 
E 23. Participants previously treated in any clinical trial of SAR440340. 
E 24. Participant is the Investigator, or any Subinvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study. 
E 25. Prisoners and participants who are legally institutionalized.  
Current knowledge of Sanofi compounds  
E 26. Known allergy to doxycycline or related compounds, or known allergy to SAR440340 
excipients. 
E 27. Females who are lactating, breastfeeding or who are pregnant. 
E 28. For Women in the study 
Women of childbearing potential (premenopausal female biologically capable of 
becoming pregnant) who  
Do not have: 
• A confirmed negative serum β-human chorionic gonadotropin (β-hCG) test at 
Visit 1. 
• Negative urine pregnancy test prior to Visit 2/Randomization. 
Who are not protected by one of the acceptable forms of effective contraception 
(Appendix 4: Contraceptive guidance and collection of pregnancy information, see 
Section 10.4) (during the protocol-defined time frame from the signing of the ICF until the 
end of study visit). 
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Postmenopausal women (defined as at least 12 consecutive months without menses) are 
not required to use additional contraception. 
For men in the study: 
Male participants with female partners of childbearing potential are not eligible to 
participate unless they agree to ONE of the following (during the protocol-defined time 
frame [Appendix 4, Section 10.4]) 
• Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a 
failure rate of <1% per year (Appendix 4, see Section 10.4) when having 
penile-vaginal intercourse with a woman of childbearing potential who is not 
currently pregnant. 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
(during the protocol-defined time frame from the signing of the ICF until the end of study 
visit). 
E 29. 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 30. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology. 
E 31. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, TB, histoplasmosis, listeriosis, coccidioidomycosis, 
penumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per Investigator’s judgment. 
E 32. Live, attenuated vaccinations within 12 weeks prior to Visit 1 or planned live, attenuated 
vaccinations during the study (see Appendix 7: List of prohibited live, attenuated vaccines, 
Section 10.7). 
E 33. Patients with autoimmune disease or patients using systemic immunosuppressive therapy 
for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary 
biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) or patients with 
high titer autoantibodies at screening who are suspected of having high risk for developing 
autoimmune disease at the discretion of the Investigator or the Sponsor. 
E 34. Patients with cardiovascular diseases/conditions: 
• 
Unstable ischemic heart disease, including acute myocardial infarction within past 1 year 
or unstable angina in the last 6 months.  
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• 
Cardiac arrhythmias including paroxysmal (eg, intermittent) atrial fibrillation are 
excluded. Patients with persistent atrial fibrillation as defined by continuous atrial 
fibrillation for at least 6 months and controlled with a rate control strategy (ie, selective β 
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.  
• 
Cardiomyopathy, as defined by stage III-IV (New York Heart Association) cardiac failure, 
or other relevant cardiovascular disorder that in Investigator's judgment may put the 
patient at risk or negatively affect the study outcome 
• 
Uncontrolled hypertension (i.e. systolic blood pressure [BP] >180 mm Hg or diastolic BP 
>110 mm Hg despite use of anti-hypertensive therapy). 
E 35. Hepatitis B and/or C serologies indicative of active or chronic infection. 
E 36. Any prior history of malignancy or active malignancy, including lymphoproliferative 
diseases (except successfully-treated carcinoma in-situ of the cervix, nonmetastatic 
squamous cell or basal cell carcinoma of the skin) within 5 years prior to Visit 2. 
E 37. Clinically significant laboratory tests at Screening/Visit 1: 
• 
Alanine transaminase (ALT) or aspartate transaminase (AST) >3 times upper limit of 
normal range (ULN). 
• 
Hemoglobin <10 g/dL for male and <9 g/dL for female. 
• 
Neutrophils <1.5 K/mm3 (<1 K/mm3 for those of African descent). 
• 
Platelets <100 K/mm3. 
• 
Creatinine ≥150 µmol/L. 
E 38. Patients on macrolide (eg, azithromycin) therapy, unless on stable therapy for >1 year. 
E 39. Patients on PDE-4 inhibitors (roflumilast) or leukotriene blockers (montelukast; Singulair 
etc). 
E 40. 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, reason for screen failure, 
eligibility criteria, and any serious adverse event (SAE). 
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Patients can be rescreened if they do not meet an exclusion criterion. Patients may be rescreened 
one time if they do not meet the eligibility criteria (I 02) at the Screening Visit (Visit 1) or 
Randomization Visit (Visit 2) due to a spirometry equipment malfunction, or because the patient 
is unable to provide sufficient reproducible efforts. Up to 3 total attempts during the screening 
visit (V1) are allowed for the reasons mentioned above. 
Patients who meet eligibility criteria (either meet an exclusion criterion, or who do not meet ([I 
02]) may be rescreened only once during the open screening period of the study; a different 
patient identification number will be issued. Rescreening is not permitted if the patient fails to 
meet inclusion criteria, except for I 02 (see Section 6.3.1). 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 
The IMP includes SAR440340 and placebo for SC injection during the course of the study. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Table 2 - Overview of Investigational Medicinal Products administered 
Investigational Medicinal Product 
name 
SAR440340 
Placebo 
Dosage formulation 
Sterile SAR440340 will be provided in 
one 20 mL vial containing 287 mg of 
lyophilisate drug product.  
One vial of lyophilisate drug product 
(287 mg) is reconstituted by an 
unmasked site pharmacist or 
designee (not involved in any study 
related assessments/activities except 
preparation of IMP) with 2.5 mL of 
sterile water for injection resulting in 
2.9 mL of 100 mg/mL SAR440340. 
 A volume of 1.5 mL per injection will 
be withdrawn from the vial. Patients 
will receive 2 injections per dose. 
Sterile placebo will be provided in one 
20 mL vial containing lyophilisate 
placebo.  
One vial of lyophilisate is reconstituted 
by an unmasked site pharmacist or 
designee (not involved in any study 
related assessments/activities except 
preparation of IMP) with 2.5 mL of 
sterile water for injection resulting in 
2.9 mL IMP.  
A volume of 1.5 mL per injection will be 
withdrawn from the vial. Patients will 
receive 2 injections per dose. 
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 
14±3 days (q2w) 
14±3 days (q2w) 
Packaging and labeling 
SAR440340 will be supplied in a glass 
vial packed in a kit box. Each kit box 
will be labeled as required per country 
requirement. 
Matched placebo will be supplied in a 
glass vial packed in a kit box. Each kit 
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).  
Investigational medicinal product (IMP) will be administered by the Investigator or designee 
following clinic procedures and blood collection. Patients should be monitored by site personnel 
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. Trained personnel and 
medications should be available to treat anaphylaxis or any severe allergic reaction if it occurs. 
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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. 
6.1.2 NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Background therapy  
Formulation: Dry powder inhaler (DPI), metered dose inhaler (MDI) or pocket nebulizer 
Route(s) of administration: Oral inhalation 
Dose regimen: As prescribed. 
At Screening Visit 1, all patients must be on Standard of Care background therapy, for 3 months 
prior to Visit 2/Randomization and at a stable dose for at least 1 month prior to the 
Screening/Visit 1, including either: 
• 
Double therapy: LABA + LAMA or ICS + LABA or ICS + LAMA. 
OR 
• 
Triple therapy: ICS + LABA + LAMA. 
Throughout the study, patients should continue their established background therapy for COPD. 
Patients must be willing to stay on their established background medication for COPD throughout 
the duration of the study. 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. 
Reliever Medication 
Formulation: Dry powder inhaler (DPI), metered dose inhaler (MDI) or pocket nebulizer  
Route(s) of administration: Oral inhalation 
Dose regimen: As prescribed. 
The reliever medication will not be dispensed or supplied by the Sponsor. 
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol (including 
ipratropium or ipratropium/short-acting β agonists [SABA] combinations) as needed during the 
study. Nebulizer solutions may be used as an alternative delivery method. 
Study personnel will convert salbutamol/albuterol nebulizer, levosalbutamol/levalbuterol 
nebulizer or ipratropium or ipratropium/short-acting β agonists [SABA] combination nebulizer, 
use as shown on the following tables:  
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Table 3 – Reliever Medication –Salbutamol/Albuterol Nebulizer Solution 
Salbutamol/Albuterol  Nebulizer Solution -Total Daily Dose (mg) 
Number of Puffs* 
2.5 
4 
5.0 
8 
7.5 
12 
10 
16 
*Conversion factor: Salbutamol/Albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs 
• 
Example of salbutamol/albuterol nebulizer-to-puff conversion: Patient received 
3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. 
Total daily = 7.5 mg or 12 puffs. 
 
Table 4 - Reliever Medication - Levosalbutamol/Levalbuterol Nebulizer Solution 
Levosalbutamol/Levalbuterol Nebulizer Solution -Total Daily Dose (mg) 
Number of Puffs* 
0.63 
2 
1.25 
4 
2.5 
8 
3.75 
12 
5 
16 
*Conversion factor:  levosalbutamol/levalbuterol nebulizer solution (1.25 mg) corresponds to 4 puffs 
• 
Example of levosalbutamol/levalbuterol nebulizer-to-puff conversion: Patient received 
3 levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 and 
11 AM. Total daily = 3.75 mg or 12 puffs.  
 
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Table 5 - Reliever Medication - Ipratropium or Ipratropium/short-acting β agonists [SABA] Nebulizer 
Solutions 
Total Daily Dose of Ipratropium (mg) in Ipratropium or 
Ipratropium/SABA Nebulizer Solutions  
Number of Puffs* 
0.5 
4 
1.0 
8 
1.5 
12 
2.0 
16 
*Conversion factor: ipratropium or ipratropium/short-acting β agonists (SABA)  nebulizer solution (with 0.5 mg 
Ipratropium) corresponds to 4 puffs 
• 
Example of ipratropium or ipratropium/short-acting β agonists [SABA] nebulizer-to-puff 
conversion: Patient received 3 ipratropium or ipratropium/short-acting β agonists [SABA] 
nebulizer treatments (0.5 mg Ipratropium/treatment) between 7 and 11 AM. Total daily = 
1.5 mg or 12 puffs. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Storage and handling 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/non-investigational 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 and in the instruction leaflet. 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all IMP received and any discrepancies are reported and 
resolved before use of the IMP. 
2. Only participants enrolled in the study may receive IMP and only authorized site staff 
may supply or administer IMP. All IMP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the labeled 
storage conditions with access limited to the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
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4. Further guidance and information for the final disposition of unused IMPs are provided in 
a Pharmacy manual.  
Preparation of IMP 
SAR440340 or matching placebo lyophilisate will be reconstituted by an unmasked site 
pharmacist or designee (not involved in any study related assessments/activities except 
preparation of IMP) as per instruction provided in study pharmacy manual. 
Administration will be performed by blinded nurse or designee as per instruction provided in 
study pharmacy manual.  
Responsibilities 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP 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 issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP/NIMP/device (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 8.3.8). 
A potential defect in the quality of IMP/NIMP/device 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/device and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP/device to a third party, 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. The investigational 
product (SAR440340 or matching placebo) will be packaged in accordance with the list. The 
Sanofi Clinical Supplies team will provide the randomized treatment kit number list to the 
centralized treatment allocation system (Interactive Voice Response System [IVRS]/Interactive 
Web Response System [IWRS]). This centralized treatment allocation system will generate the 
patient randomization list according to which it will allocate the treatments to the patients. 
Patients who meet the entry criteria will be randomized to receive either SAR440340 or matching 
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placebo. 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: 
• 
SAR440340 300 mg q2w 
• 
Matching placebo for SAR440340. 
Investigational medicinal products will be dispensed at the study visits summarized in SoA 
(Section 1.3).  
Returned IMP should not be re-dispensed to the participants. 
Patients can be rescreened if they do not meet an exclusion criterion. Patients may be rescreened 
one time if they do not meet the eligibility criteria (I 02) at the Screening Visit (Visit 1) or 
Randomization Visit (Visit 2) due to a spirometry equipment malfunction, or because the patient 
is unable to provide sufficient reproducible efforts. Up to 3 total attempts during the screening 
visit (V1) are allowed for the reasons mentioned above. 
Patients who meet exclusion criteria or who do not meet I 02 as specified above, may be 
rescreened only once during the open screening period of the study. Rescreening is not permitted 
if the patient fails to meet inclusion criteria (except for I 02, as described above). For rescreening, 
see Section 5.4. 
Randomization will be stratified by Screening/Visit 1 eosinophil count (see below) and by 
country.  
To ensure scientific validity, alerts will be built into the IVRS/IWRS to control the number of 
patients enrolled into each stratification group, as follows: 
1. Eosinophil <250 /mm3: approximately 50% (170) patients  
2. Eosinophil ≥250 /mm3: approximately 50% (170) patients 
6.3.2 Methods of blinding 
SAR440340 and matching placebo will be provided in treatment kits indistinguishable in 
appearance and will be labeled with a treatment kit number. The randomized treatment kit number 
list will be generated by Sanofi. 
In accordance with the double-blind design, study patients, Investigators, and study site personnel 
(except the personnel who conduct the reconstitution of the IMP and preparation of syringes for 
injection) will remain blinded to study treatment and will not have access to the randomization 
(randomized treatment kit number) except under circumstances described in Section 6.3.3. 
To maintain blinding, the personnel involved with dose preparation will be required to agree not 
to reveal to other study personnel the type of IMP solution (SAR440340 versus placebo) in the 
vials/syringes.  
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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 interactive 
response technology (IRT) and/or by calling any other phone number provided by the Sponsor for 
that purpose. If the blind is broken, the Investigator must document the date, time of day, and 
reason for code breaking.  
Patient withdrawal will only occur when the code break call is made at the site level, not the study 
level. This means that if the Emergency Unblinding transaction is performed by the Investigator 
(ie, at the site level), then the patient will be withdrawn from treatment. However, if the 
Emergency Unblinding transaction is performed by the Global Safety Officer (GSO) (ie, at the 
study level, as the GSO is not site based), then the patient will not be withdrawn from treatment. 
Patients who are withdrawn from treatment should be encouraged to remain in the study and the 
Investigator should discuss with them the key visits to attend (see Section 7.2). 
6.4 
STUDY INTERVENTION COMPLIANCE 
The Investigator or pharmacist will also keep accurate records of the quantities of the IMP 
dispensed, used, and unused. The product accountability and inventory form is to be updated each 
time investigational product is dispensed. The study monitor will periodically check the supplies 
of the IMP held by the Investigator or pharmacist to verify accountability. 
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.  
All used, partially used, or unused treatments will be destroyed according to the standard practice 
at the site or per local regulations. A detailed treatment log of the IMP will be established with the 
Investigator or other personnel designated by the Investigator, and countersigned by the 
Investigator and the Monitoring Team. Confirmation of destruction will be provided to the 
Sponsor. 
For NIMP not provided by the Sponsor, tracking, reconciliation and destruction will be managed 
according to local regulation. 
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 
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The following concomitant treatments are not permitted during the screening or treatment phases: 
• 
Systemic steroids (except when used to treat exacerbations) 
Note: one short-term course of systemic corticosteroids (up to 6 days) is permitted in 24 
weeks, when medically necessary for reasons not related to AECOPD, eg. in the case of 
severe poison ivy exposure. 
• 
PDE-4 inhibitor such as roflumilast  
• 
Methylxanthines (theophylline, aminophyllines) 
• 
Leukotriene receptor antagonists or leukotriene synthesis inhibitors 
• 
Lipoxygenase inhibitors 
• 
Anti-IL5 mAb (eg, benralizumab; mepolizumab) 
• 
Anti-IgE therapy (eg, omalizumab)  
• 
Anti-IL4R mAb (eg, dupilumab) 
• 
Systemic immunosuppressants (eg, methotrexate, any anti-TNF mAbs, B and/or T cell 
targeted immunosuppressive therapies) 
• 
Bronchial thermoplasty  
• 
Intravenous immunoglobulin (IVIG) therapy 
• 
Live Attenuated Vaccines: refer to Appendix 7: List of Prohibited Live Attenuated 
Vaccines, Section 10.7. 
• 
β-adrenergic receptor blockers (except for a selective β-1 adrenergic receptor blocker used 
with dose stable 1 month prior to Visit 1) 
• 
COPD relievers other than salbutamol/albuterol, levosalbutamol/levalbuterol or 
ipratropium: their use is not recommended during the study period. In case of use in 
exceptional circumstances (eg, prescribed by a physician not participating in the study), 
their use will be documented in the patient's file and reported in the eCRF. 
• 
Other investigational drugs 
Note: The following is a list of permitted concomitant medications during the study: 
• 
Antihistamines are permitted as concomitant medication 
• 
Ocular, intranasal, and topical corticosteroids are permitted during the study. 
6.6 
DOSE MODIFICATION 
Not applicable for this study.  
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 CRF or eCRF. In any case, the patient should remain in the study as long as 
possible. 
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 treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
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. 
• 
Pregnancy. 
• 
Anaphylactic reaction or systemic allergic reactions or acute allergic reactions that are 
related to IMP and require immediate treatment (Appendix 14: Definition of anaphylaxis, 
see Section 10.15). 
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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 situation that meets permanent discontinuation rule as outlined in Appendix 6: Liver 
and other safety: suggested actions and follow-up assessments (Appendix 6, Section 10.6). 
• 
Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (Appendix 15: List of Opportunistic Infections, 
See Section 10.16). 
• 
Serum ALT >3 ULN and total bilirubin >2 ULN (Appendix 6, see Section 10.6). 
• 
Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(Appendix 6, see Section 10.6). 
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 intervention discontinuation 
Patients who withdraw from study treatment (prior to completing the planned duration of IMP 
treatment) will perform, as soon as possible, the early treatment discontinuation visit (ETD) with 
all assessments normally planned for the EOT visit, to assure a complete clinical assessment in 
close temporal proximity to the premature termination of study treatment is available. In addition, 
and to allow assessment of patient outcomes over the stipulated study period, patients will be 
asked and encouraged to complete all remaining study treatment visits, and participate in all 
safety follow-up assessments according to the visit schedule with a +/-5 day window.  For such 
patients the assessment schedule will be reduced (See study flowchart for patients after permanent 
treatment discontinuation in Section 1.3.2) and alternate visits during the planned treatment period 
may be conducted by phone (those with odd visit numbers, except for the planned EOT), as can 
visits F1 and F2.  
Under exceptional circumstances when a patient cannot come to the site for a scheduled visit, a 
phone contact can be made. During the phone contact, at least information about AEs, 
concomitant medication and COPD exacerbation events should be collected. 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion (ie, EOS, see Section 1.3), or up to recovery or 
stabilization of any AE to be followed-up as specified in this protocol, whichever comes last. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the CRF or eCRF when considered as confirmed. 
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7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs.  
If patient is unable to return to clinic for a given visit within the specified visit window, patient 
should follow-up with all visit procedures planned for the subsequent visit (excluding 
randomization and EOT). 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 the responsibility of the IMP(s) in the occurrence 
of the concerned event was unlikely and if the selection criteria for the study are still met (refer to   
Section 5.1 and Section 5.2). For all temporary treatment discontinuations, duration must be 
recorded by the Investigator in the CRF or eCRF. 
Following a temporary interruption or a missed dose, the IMP treatment should be reinitiated at 
the next scheduled visit, maintaining the original dosing schedule.  
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. The 
investigator should also inform the Sponsor that appropriate actions are taken regarding 
these samples. 
• 
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 treatment visits (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 
CRF or e-CRF 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 stop participating in the study. Withdrawal 
of consent for intervention should be distinguished from withdrawal of consent for follow-up 
visits and from withdrawal of consent for non-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 re-randomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
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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 
IMP. 
• 
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 COPD exacerbation 
 
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”. 
 
Clinical symptoms of exacerbations of COPD 
 
In addition to the protocol-defined exacerbations of COPD listed above, clinical signs and 
symptoms of exacerbations of COPD will be captured in the eCRF (including, but not limited to 
increase in dyspnea, increase in wheezing, increase in cough, increase in sputum volume and/or 
increase in sputum purulence). 
 
Management of exacerbations of COPD 
 
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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 page. These events should not be reported as AEs unless they fulfill a 
seriousness criterion. Any course of systemic steroids/antibiotics started <7 days of finishing a 
previous course should be considered as treatment for a single exacerbation. 
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 (14) and prior to 
administration of investigational product.  
For pre-bronchodilator measured parameters, including FEV1, peak expiratory flow (PEF), 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 other 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.  
Further details on spirometry will be available in a separate operational manual provided to the 
sites. 
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8.1.1.3 Optional Fractional exhaled nitric oxide (FeNO)  
Fractional 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. 
FeNO will be measured at sites only with access to FeNO equipment. 
8.1.1.4 Disease-specific, daily efficacy assessments 
See Patient Reported Outcomes (Section 8.1.2) 
8.1.1.5 Optional actigraphy and home spirometry assessments 
Optional assessments of actigraphy (sleep and activity) and home spirometry will be available for 
patients in the US and Canada only. Patient will be issued an actigraphic wristband and asked to 
wear it continuously (including at night) throughout three monitoring periods defined in study 
flowchart (Section 1.3) on the nondominant hand, including at night. The actigraphic data is used 
to measure sleep parameters and daytime activity. The actigraph will be worn during the screening 
period as well as two monitoring periods during the treatment phase. Data from the device will be 
uploaded to a computer at each clinic visit following a monitoring period. 
Patients will receive documented in-clinic training for use of ambulatory at-home spirometry 
during screening. During the study patients will be required to use at-home spirometry with 
electronic data storage to measure FEV1. Patients will be instructed to perform expiratory flow 
maneuvers as described in the study manual at least twice daily between 06:00 and 12:00 hour and 
between 18:00 and 24:00 hour during the screening period and for 2 week intervals during the 
treatment and follow-up period as indicated in the study flowchart. 
8.1.1.6 Optional Sputum Collection 
A subset of study sites will be selected to perform evaluations of induced 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. 
Further details will be provided in the site procedure manual.  
8.1.2 Patient reported outcomes questionnaires 
At screening (Visit 1), patients will be issued an electronic diary. Patients will be instructed on the 
use of the device, and written instructions on the use of the electronic device will be provided to 
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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 uses an electronic diary to: 
• 
Respond to the COPD symptom scale questions of the EXACT tool 
• 
Record the daily use of COPD reliever medication 
• 
Record use of systemic corticosteroids and/or antibiotics taken for COPD exacerbation. 
The electronic diary will be used for patient reported outcome questionnaires.  
In the Post IMP Treatment Period, the patient's response in the electronic diary will not be 
recorded daily; questionnaires will only be administered at on-site visits. When completed at 
study site, PRO assessments should be completed as part of the visit (per SoA, Section 1.3) but 
prior to any meaningful communication with a health care professional or any other study 
procedures. 
8.1.2.1 COPD Assessment Test (CAT) 
The CAT (15) is a new questionnaire that is designed for patients with COPD to measure the 
effects of the disease on their quality of lives. The CAT™ is an 8-item self-administered 
questionnaire which has been developed for use in routine clinical practice to measure the health 
status of patients with COPD (see Appendix 10: COPD Assessment Test, Section 10.11).  
The CAT™ score ranges from 0 to 40, a higher score indicating a higher impact on health status. 
The test is about cough, phlegm, chest tightness, dyspnea, activity limitation, confidence, sleep 
and energy (16). Patients scored questions from 1-5 according to their own feelings about the 
disease (1 = I am very happy; 5 = I am very sad). 
8.1.2.2 St. George's Respiratory Questionnaire (SGRQ) 
The St. George's Respiratory Questionnaire (SGRQ [(17), (18)]) is a 50-item questionnaire 
designed to measure and quantify health-related 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 11: St. George's Respiratory 
Questionnaire, Section 10.12).  
The first part ("Symptoms") evaluates symptomatology, including frequency 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 activities that cause breathlessness or are limited because of breathlessness. The 
"Impacts" section covers a range of factors including influence on employment, being in control 
of health, panic, stigmatization, the need for medication, side effects of prescribed therapies, 
expectations for health and disturbances of daily life. The recall period of the questionnaire is over 
the past 4 weeks.  
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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. 
8.1.2.3 Exacerbations of chronic obstructive pulmonary disease tool (EXACT) 
The EXACT Total Score measures symptoms of acute bacterial exacerbations of chronic 
bronchitis-COPD (ABECB-COPD), ie, an acute, sustained, and worsening of signs and symptoms 
beyond day-to-day variability (see Appendix 12: Exacerbations of Chronic obstructive pulmonary 
disease tool [EXACT], Section 10.13). The instrument’s total score is made up 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 is a daily diary, completed each evening before bedtime. The instrument was 
developed with e-diary administration in mind, with cognitive interviews performed with paper 
pen booklet and personal digital assistant (PDA) to document respondent understanding in either 
mode and user acceptance of the PDA. 
8.1.2.4 Euro Quality of Life-5 Dimension questionnaire (EQ-5D) 
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 (19). 
EQ-5D is designed for self-completion by patients, (Appendix 13: Euroquol Questionnaire, see 
Section 10.14). 
8.2 
SAFETY ASSESSMENTS  
The same safety assessments will be applied across all 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). 
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8.2.1 Physical examinations 
A complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. All 
deviations from normal will be recorded, including those attributable to the patient’s disease. 
Refer to Section 1.3 for the schedule of physical examinations performed throughout this study. 
Investigators should pay special attention to clinical signs related to previous serious illnesses or 
signs of infection.  
Any new clinically significant finding or worsening of previous finding should be reported as a 
new adverse event. 
8.2.2 Vital signs 
Vital signs, including systolic and diastolic BP (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. 
Vital signs will be measured in the sitting position using the same arm (preferably), at each visit 
detailed in the SoA (Section 1.3), and will be measured prior to receiving investigational product 
at the clinic visits.  
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: Clinical Laboratory Tests (Section 10.2) for the list of clinical laboratory tests to 
be performed and to the SoA (Section 1.3) for the timing and frequency.  
• 
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition. 
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• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 22 weeks after the last dose of IMP should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the Investigator or medical monitor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA.  
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.  
The clinical laboratory parameters that will be measured are described in Appendix 2: Clinical 
laboratory tests (Section 10.2). Decision trees for the management of certain laboratory 
abnormalities by Sanofi are provided in Appendix 6: Liver and Other Safety: Suggested Actions 
and Follow-up Assessments (Section 10.6). 
For patient(s) who have consented to it, the samples that are archived, unused or left over after 
planned testing may be used for additional research purposes (Appendix 16: 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 (see 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. 
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For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described Section 8.3.2, even if not fulfilling a seriousness criterion, using the screens 
in the eCRF. 
Anaphylactic reactions, systemic allergic reactions that require treatment (refer to Section 10.15 
for definition of anaphylaxis). 
• 
Anaphylactic reactions, systemic allergic reactions that require treatment (refer to 
Section 10.15 for definition of anaphylaxis). 
• 
Severe injection site reactions (ISR) that last longer than 24 hours 
Note: A severe ISR (for AE reporting) is any event that meets one of the following 
criteria: 
- 
With a diameter of at least 10 cm. 
- 
Impacting daily activities. 
- 
With ulceration or necrosis.  
- 
For which operative intervention is required. 
• 
Any infection meeting at least one of the following criteria: 
- 
Any serious infection (SAE). 
- 
Requires parenteral (IV, intramuscular, SC) antimicrobial therapy  
Note:  Antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents. 
- 
Requires oral antimicrobial therapy for longer than 14 days. 
- 
Is a parasitic infection. 
- 
Is an opportunistic infection (see Appendix 15: List of Opportunistic Infections, 
Section 10.16). 
• 
Significant ALT elevation. 
- 
ALT >3 x the upper limit of normal (ULN) associated with Total Bilirubin >2 x ULN; 
or 
- 
ALT >5 x ULN in patients with baseline ALT ≤2 x ULN; or 
- 
ALT >8 x ULN if baseline ALT >2 x ULN. 
• 
Malignancy 
• 
Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
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- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (Appendix 4: 
Contraceptive guidance and collection of pregnancy Information, see 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/noninvestigational medicinal 
product (NIMP) 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the intended dose during an interval of <8 days.  
“The circumstances (ie, accidental or intentional) should be clearly specified in the 
overdose form”. 
- 
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”.  
- 
Of note, asymptomatic overdose has to be reported as an AE. 
Table 6 - Safety instructions for Adverse Events of Special Interest 
AESI 
Description 
Hypersensitivity 
Allergic reaction is a potential risk associated with the administration of most therapeutic mAbs. 
Acute allergic reactions may be defined as allergic reaction-mediated signs and symptoms experienced by 
patients during or shortly after the pharmacologic or biologic agent given. These reactions may present in a 
variety of ways, including dizziness, headache, anxiety, dyspnea, hypotension, tachycardia, pruritus, rash, 
urticaria/angioedema, flushing, nausea, or vomiting. Anaphylaxis may represent the most severe form of 
allergic reaction, but these events may also occur via non-IgE mediated mechanisms (eg, anaphylactoid 
reactions), or may occur via other immune-mediated mechanisms (eg, cytokine-mediated). Allergic 
reactions may begin within a few hours and persist up to 24 hours post dosing. Refer to Section 10.15 
“Definition of Anaphylaxis”, which describes the clinical criteria for the diagnosis of anaphylaxis. Delayed 
onset or late phase hypersensitivity reactions (ie, Type 1 hypersensitivity reaction) may manifest between 
10 and 12 hours post dosing. 
Patients should be monitored for at least 30 minutes after IMP dose administration for any signs or 
symptoms of a hypersensitivity reaction throughout the study. Trained personnel and medications should 
be available to treat anaphylaxis or any severe allergic reaction if it occurs. Anaphylactic reactions, 
systemic allergic reactions that require treatment must be reported as an AESI with immediate notification 
(for further details, see Table 7). If an anaphylactic reaction, systemic allergic reaction requiring treatment 
occurs and is considered related to IMP by the investigator the study treatment should be permanently 
discontinued. 
Anti-drug antibodies and PK samples will be collected near the onset and resolution of the AESI for any 
additional analysis. 
Severe injection 
site reactions 
Based on the SC mode of administration of high doses of protein ISRs are considered as a potential risk for 
SAR440340.  
Patients who experience an ISR must be closely monitored for the possibility of a more intense ISR with a 
future injection. Any severe ISR that lasts over 24 hours will be reported as an AESI with immediate 
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notification (for further details please see Table 7). Anti-drug antibodies and PK samples will be collected 
near the onset and resolution of the AESI for any additional analysis 
If there is any consideration being given to premedicating before the next dose (for preceding an injection 
site reaction, please contact Sponsor prior to dosing patients). 
Infections, including 
opportunistic 
infections 
Some biologic therapies have been associated with an increased risk of infection, including opportunistic 
infection.  
IL-33 is a proinflammatory cytokine released by damaged epithelial cells in response to insults such as 
allergens, viruses, or bacteria. IL-33 signaling initiates and amplifies multiple downstream inflammatory 
pathways resulting in effects characteristic of both type 1 and type 2 immune inflammations. Although 
blockade or knockout of IL-33 signaling in mice did not reveal any unique role for IL-33 in mounting an 
acute immune response to viral challenge and did not lead to worsening of symptoms or outcome, patients 
will be monitored for signs or symptoms of infection. 
SAR440340 inhibits the T-helper 2 (Th2) cytokines production. Infections with a diversity of helminthic 
parasites elicit eosinophilia via stimulation of Th2-like lymphocyte responses. The Th2 response is 
characterized by production of IL4, IL13, and IL5, subsequently generating IgG1 and IgE-secreting cells, 
and eliciting eosinophilia. Eosinophilia is prominent in a number of helminthic parasitic diseases. The 
eosinophilic response to helminths is determined both by the host's immune response and by the parasite, 
including its distribution, migration, and development within the infected host. Therefore, patients treated 
with SAR440340 may potentially have an increased risk of parasitic infection.  
To minimize the risk, patients with certain type of infections are not allowed to participate in the study (eg, 
patients with active opportunistic or parasitic infections or at high risk of developing the infections, patients 
with medical history of invasive opportunistic infections, patients with HIV infection or HIV seropositivity, 
patients with positive screening for hepatitis B and C). 
As a precautionary measure, the Investigator is required to carefully monitor for any signs or symptoms of 
infection such as, but not limited to, increased body temperature, malaise, weight loss, sweats, cough, 
dyspnea, pulmonary infiltrates, or serious febrile systemic illness. 
During the study, appearance of signs or symptoms (such as abdominal pain, cough, diarrhea, fever, 
fatigue and hepatosplenomegaly) that could be associated with a parasitic infection should be carefully 
evaluated, especially if there is a history of parasitic exposure through recent travel to/or residence in 
endemic areas, especially when conditions are conducive to infection (eg, extended stay, rural or slum 
areas, lack of running water, consumption of uncooked, undercooked, or otherwise potentially 
contaminated food, close contact with carriers and vectors, etc). Subsequent medical assessments (eg, 
stool exam, blood tests, etc) must be performed in order to rule out parasitic infection/infestation.  
Infections defined in Section 8.3.1 should be reported as AESIs with immediate notification. A complete 
diagnostic work-up should be performed (ie, cultures, histopathological or cytological evaluation, antigen 
detection and serum antibody titers). Patients should be referred to an infectious disease specialist if 
deemed necessary for diagnostic work up and appropriate treatment. 
Infections or infestations that do not respond to medical treatment should have study drug discontinued 
until the infection is resolved.  
For any opportunistic infection, such as TB, or other infections whose nature or course may suggest an 
immunocompromised status (see Section 10.16), patients must be permanently discontinued from study 
medication. 
Elevated liver 
function tests 
No preclinical and clinical data has suggested any hepatic toxicity of SAR440340; however, as a general 
consideration of clinical development, the administration of immunosuppressant or immunomodulating 
agents may represent an additional risk factor for hepatotoxicity.  
In order to closely follow liver function tests (LFT), assessment of total protein, albumin, total bilirubin (in 
case of values above the normal range, differentiation in conjugated and nonconjugated bilirubin), alanine 
aminotransferase, aspartate aminotransferase, and alkaline phosphatase are measured as part of the 
clinical laboratory testing. 
Guidance for the investigation of elevated LFTs as well as concurrent management of IMP is provided in 
Section 10.6. 
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ALT elevations defined in Section 8.3.1 should be reported as AESIs with immediate notification. 
Malignancy 
In toxicology studies on SAR440340-mediated IL-33 blockade, the effect of SAR440340 administration has 
not demonstrated the development of malignancy. Long term use has not been studied. 
The investigator should carefully monitor for any signs or symptoms of malignancy. Malignancy should be 
reported as AESI with immediate notification. 
Pregnancy 
In case of positive urinary test, the study treatment will be withheld and a serum pregnancy test should be 
performed as soon as possible to confirm the pregnancy. Pregnancy will lead to definitive treatment 
discontinuation in all cases. Refer to Section 1.3 for the schedule of pregnancy tests performed throughout 
this study. 
 
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 up to the end of study 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 and AESI 
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 IMP 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). 
Adverse event (SAE and AESI) reporting is summarized in Table 7. 
Table 7 – Adverse event reporting 
Adverse event/laboratory abnormality 
Reporting timeframe 
Serious adverse event 
 
Within 24 hours 
Pregnancy 
 
Within 24 hours 
Overdose 
Symptomatic 
Within 24 hours 
 
Asymptomatic 
Routine 
ALT elevation 
 
 
 
ALT >3 x ULN and associated with  
total bilirubin >2 x ULN 
ALT >5 ULN if baseline ALT is ≤2 ULN 
Within 24 hours 
 
Within 24 hours 
 
ALT >8 ULN  if baseline ALT is >2 ULN 
Within 24 hours 
Anaphylactic or systemic allergic reactions that require treatment. 
Within 24 hours 
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Adverse event/laboratory abnormality 
Reporting timeframe 
Severe injection site reactions that last longer than 24 hours. 
Within 24 hours 
Infections as defined in Table 6  
Malignancy                                                                                                                                
Within 24 hours 
Within 24 hours 
ALT: alanine aminotransaminase; ULN: upper limit of normal. 
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 
an IMP 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 an IMP 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. 
• 
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). 
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8.3.7 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. 
  
8.3.8 Guidelines for reporting product complaints / medical device incidents (including 
malfunctions) 
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE 
Symptomatic overdose of IMP is an AESI (defined in Section 8.3.1). No antidote is available for 
SAR440340. 
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. 
3. Obtain a serum sample for PK analysis as soon as possible, from the date of the last dose 
of IMP 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. 
8.5 
PHARMACOKINETICS 
Blood samples will be collected for determination of functional SAR440340 in serum as specified 
in the SoA (Section 1.3). Samples may be collected at additional time points during the study if 
warranted (see Appendix 6, Section 10.6).  Special procedures for collection, storage, and 
shipping of serum are described in separate operational manuals. The actual date and time (24-
hour clock time) of each sample will be recorded.  
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 16, see Section 10.17). 
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Table 8 - Summary of handling procedures for pharmacokinetic (PK) samples 
Sample type 
PK (SAR440340) 
Matrix 
Serum 
Blood sample volume 
5 mL 
Anticoagulant 
None 
Blood handling procedures 
See Operational Manual 
Serum aliquot split 
2 aliquots  
Serum shipment condition 
In dry ice 
PK = pharmacokinetics. 
 
The bioanalytical methods for pharmacokinetics are summarized in Table 9. 
Table 9 - Summary of bioanalytical methods for pharmacokinetics samples 
Analyte 
PK (SAR440340) 
Matrix 
Serum 
Analytical technique 
ELISA 
Site of bioanalysis 
Regeneron 
ELISA: enzyme-linked immunosorbent assay; PK: pharmacokinetics. 
 
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 AESI (anaphylaxis, hypersensitivities, ISR, or certain laboratory abnormalities 
[see appendix 6,  Section 10.6]) occur in a patient, blood samples should be collected for 
determination of functional SAR440340 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. 
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8.6 
PHARMACODYNAMICS 
8.6.1 Pharmacodynamic variables/Biomarkers   
• 
Blood eosinophil and neutrophil counts. 
• 
Induced sputum for RNA expression (optional for patients at a subset of sites). 
• 
Selected biomarkers of the IL-33 and/or Type 2 inflammation pathway  
- 
Total IL-33, soluble IL-33 receptor (sST2),  
- 
Calcitonin 
- 
PARC 
- 
Eotaxin-3 
- 
Total IgE. 
- 
Fibrinogen 
• 
Optional: Messenger ribonucleic acid sequencing or whole transcriptome analysis.  
• 
Optional: DNA/RNA sample will be collected for pharmacogenomic effects (Section 8.7). 
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. 
8.6.2 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 (see Section 1.3). 
8.6.3 Plasma/serum biomarkers 
Total IL-33, sST2, PARC will be assayed using a validated enzyme immunoassay.  
Calcitonin assay: (development of assay method ongoing). 
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. 
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8.7 
PHARMACOGENOMICS 
Pharmacogenomic testing is optional and voluntary. Written informed consent must be obtained 
before sampling. 
For those patients who consent to the optional pharmacogenomic sample collection section of the 
ICF, blood samples for exploratory genetic analysis of DNA or RNA (See Appendix 5: 
Pharmacogenomics, Section 10.5) will be collected at the study visit as specified in the SoA 
(Section 1.3), and these samples will be stored for future analysis(Appendix 16: Future use of 
samples, see Section 10.17). Specific procedures for collection, storage and shipping of 
pharmacogenomic samples will be provided in a lab manual.  
For patient(s) who have consented to it, the samples that are archived, unused or left over after 
planned testing may be used for additional research purposes (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 pharmacogenomic biomarkers are described in Section 8.6 and 
Section 8.7, respectively. 
8.8.1 Immunogenicity assessments 
Blood samples will be collected for determination of antibodies to SAR440340 in serum as 
specified in the SoA (Section 1.3). Blood samples should be collected at the final visit from 
participants who discontinued IMP or were withdrawn from the study.  Samples may be collected 
at additional time points during the study if warranted (see Appendix 6, Section 10.6). Special 
procedures for the collection and handling of samples will be provided by the Sponsor. The actual 
date and time (24-hour clock time) of each sample will be recorded. 
Table 10 - Summary of handling procedures for antidrug antibody (ADA) samples 
 
 
 
 
 
 
 
 
Sample type 
ADA (SAR440340) 
Matrix 
Serum 
Blood sample volume 
5 mL 
Anticoagulant 
None 
Blood handling procedures 
See Operational Manual 
Serum aliquot split 
2 aliquots  
Serum shipment condition 
In dry ice 
ADA = antidrug antibodies 
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The bioanalytical method for antidrug antibody is summarized in Table 11. In a patient with 
treatment-emergent ADA response, if the sample at week 12 is positive in the ADA assay, then 
ADA assessments may be performed on PK samples collected at Week 4. 
Table 11 - Summary of bioanalytical methods antidrug antibody 
Analyte 
ADA (SAR440340) 
Matrix 
Serum 
Analytical technique 
ELISA/Electrochemiluminescence 
Site of bioanalysis 
Regeneron 
ADA = antidrug antibodies; ELISA: enzyme-linked immunosorbent assay 
Note: If an SAE or AESI (anaphylaxis, hypersensitivity, or an ISR lasting more than 24 hours) 
occurs in a patient, blood samples should be collected for ADA assessment at or near the event. 
The exact date and time of sample collection must be recorded and entered into the database by 
the central laboratory. An unscheduled page in the eCRF must be completed as well. If necessary 
for safety monitoring, additional ADA labs may be drawn after the EOS Visit until resolution of 
AE. 
8.9 
HEALTH ECONOMICS 
Health economics and patient related outcome (Section 8.1.2]) data, associated with medical 
encounters, will be collected in the PRO questionnaires (see Section 8.1.2) by the Investigator and 
study-site personnel for all participants throughout the study. Protocol-mandated procedures, tests, 
and encounters are excluded from the PRO questionnaires.  
When completed at study site, PRO assessments should be completed as part of the visit (per 
study flow chart) but prior to any meaningful communication with a health care professional or 
any other study procedures. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
The statistical hypothesis for the primary efficacy endpoint of annualized rate of moderate-to-
severe AECOPD is to test that SAR440340 is superior to placebo at the two-sided 5% alpha level:  
H0: Rate ratio of SAR440340 versus placebo ≥1 versus Ha: Rate ratio of SAR440340 
versus placebo <1.  
The statistical hypothesis for the key secondary efficacy endpoint, the change from baseline to 
Week 16-24 in pre-bronchodilator FEV, is to test that SAR440340 is superior to placebo at the 
two-sided 5% alpha level: 
H0: The change in the SAR440340 group is not larger than that in the placebo group 
versus Ha: The change in the SAR440340 group is larger than that in the placebo group. 
9.2 
SAMPLE SIZE DETERMINATION  
To assess the power of the primary efficacy endpoint the annualized rate of moderate-to-severe 
AECOPD, we assume 
• 
Average of 1.0 to 1.5 AECOPD per year in the placebo group of this study population 
enriched for severity and high risk of AECOPD.  
• 
The number of AECOPD follows a negative binomial distribution with dispersion 
parameter 1.5 (8) for all the groups. 
• 
A Wald-test is used to test whether the risk ratio is 1 with 2-sided 5% significance level.  
• 
Patients will be treated with a minimum of 24 weeks and a maximum of 52 weeks 
depending on their study entry times. The monthly cumulative patient accruals are 
assumed to be 1, 5, 10, 25, 50, 90, 150, 210, 270, 335 and 340 for an eleven (11)-month 
accrual period.    
• 
Cumulatively, 9%, 15% and 20% of patients drop out of the study due to discontinuation 
or other reasons by 12, 24 and 52 weeks after study entry.  
• 
Patients are randomized to the treatment group and the placebo group with a 1:1 ratio. 
With these assumptions and 170 patients per group (340 patients in total), the study will yield 
81.6% to 88.8% powers with risk reduction equal to 45% and the placebo rate ranging from 1.0 to 
1.5 per year.  To obtain at least 80% power, the minimum risk reduction is from 44.2% to 40.6%. 
The minimum detectable risk reduction (i.e. with 50% power) is from 32.7% to 30.0%. See the 
table below for more details.    
 
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Table 12 - Power calculation for various event rates in the placebo group 
 
Power for certain Risk Reduction (RR) 
Minimum RR for certain power 
Placebo rate 
RR=40% 
RR=45% 
RR=50% 
Power=80% 
Power=50% 
1.0 
69.9% 
81.6% 
90.3% 
44.2% 
32.7% 
1.2 
74.1% 
85.2% 
92.9% 
42.5% 
31.4% 
1.5 
78.5% 
88.8% 
95.2% 
40.6% 
30.0% 
RR: risk reduction 
Based on the accrual and drop-out assumptions, the mean exposure time is 35.5 (±12.8) weeks. 
Since we use variable follow-up times for patients entering at different times, the power will 
depend on the actual accrual rates and the drop-out rates. We will closely monitor these rates. If 
the accrual rates are significantly lower than planned and/or the drop-out rates are higher than 
expected, the minimum treatment period may be extended to achieve the desired amount of total 
exposure. The maximum treatment period of 52 weeks will not be changed.   
To assess the key secondary efficacy endpoint the change from baseline to Week 24 in 
post-bronchodilator FEV1, we assume that: 
• 
A common standard deviation of 0.3 L in each of the two groups is assumed, which is a 
consensus value based on the review of historical data from COPD trials. 
• 
A difference of 0.12 L between the treatment group and the placebo group. 
• 
A 2-sided t-test with 5% significance level. 
• 
Fifteen percent (15%) of patients with missing data at Week 24 due to discontinuation or 
other reasons.  
• 
Patients are randomized to the treatment group and the placebo group with a 1:1 ratio. 
With these assumptions and 170 patients per group (340 patients in total), we will have 92.6% 
power to detect the difference of 0.12 L between the treatment group and the placebo group. The 
least significant difference between groups will be 0.07 L.  
Randomization will be stratified by Screening/Visit 1 eosinophil count (see below) and by 
country.  
To ensure scientific validity, alerts will be built into the interactive voice/web response system 
(IVRS/IWRS) to control the number of patients enrolled into each stratification groups, as 
follows: 
1. Eosinophil <250 /mm3: approximately 50% (170) patients  
2. Eosinophil ≥250 /mm3: approximately 50% (170) patients. 
 
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9.3 
POPULATIONS FOR ANALYSES 
For purposes of analysis, the following populations are defined (Table 13): 
Table 13 - Populations for analyses 
Population 
Description 
Screened 
All participants who sign the ICF 
Randomized 
Randomized patients consist of all patients with a treatment kit number allocated and 
recorded in the IVRS database, regardless of whether the treatment kit was used or 
not. These patients form the randomized population.  
Patients treated without being randomized will not be considered as randomized and 
will not be included in any efficacy population. Data from these patients will be 
summarized separately.  
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. 
Modified Intent-to-treat (mITT) 
The analysis population for the efficacy endpoints will be the modified intent-to-treat 
(mITT) population: all randomized patients who received at least 1 dose of IMP, 
analyzed according to the treatment group allocated by randomization.  
Randomized patients for whom it is unclear whether they took the study medication 
will be included in the mITT population according to treatment they are randomized. 
Safety 
The safety population will include all randomized patients who received at least 1 
injection of IMP.  
For safety analyses, patients will be analyzed in the treatment group for which they 
received the majority of injections. 
Pharmacokinetic (PK) 
The PK population will consist of all patients in the mITT population with at least 1 
postdose, nonmissing SAR440340 serum concentration. 
Antidrug antibody (ADA) 
The ADA population will consist of all patients in the mITT population with at least one 
qualified result in the anti-SAR440340 assay following the first dose of study 
medication. Patients will be analyzed according to the treatment actually received. 
ICF: informed consent; mITT: modified intent-to-treat; PK:pharmacokinetic; ADA: antidrug antibody. 
9.4 
STATISTICAL ANALYSES 
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
9.4.1 Efficacy analyses 
All efficacy analyses will be performed on the mITT population, unless otherwise specified. 
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Table 14 - Efficacy analyses 
Endpoint 
Statistical Analysis Methods 
Primary 
Rate of moderate-to-severe 
AECOPD over 52 weeks. 
For the primary efficacy endpoint, the annualized exacerbation rate, a negative binomial 
regression model will be used to assess treatment differences. The model will include the total 
number of events occurring during the observation period (up to Week 52) as response variable, 
and the treatment group, the baseline eosinophil strata and region (pooled countries) as 
covariates. Log-transformed observation duration will be the offset variable. Parameters will be 
estimated using the maximum likelihood method with the Newton-Raphson algorithm.  
The annualized event rate for each of the treatment groups and the ratio between the treatment 
and placebo along with its 95% confidence interval will be estimated from the model.  
In the case of premature discontinuation of study drug, a secondary analysis will include events 
up to 14 days after the last dose. 
Using the same method, subgroup analyses will be performed separately by the baseline 
eosinophil levels (≥250 /mm3 versus <250 /mm3). 
Secondary 
Key Secondary 
• 
Change from baseline 
in FEV1 to Week 16-
24 (pre-
bronchodilator*)  
 
 
 
 
 
 
 
 
 
 
Key Secondary Endpoint 
The key secondary efficacy endpoint, the average change from baseline to Week 16-24 in pre-
bronchodilator FEV1 will be analyzed using a mixed-effect model with repeated measures 
(MMRM) approach. Model-based averages across Weeks 16, 20 and 24 will be compared 
between the treatment groups. The dependent variable is the change from baseline in pre-
bronchodilator FEV1 at each time points. The model will include baseline FEV1 value, treatment 
group, visit, and treatment-by-visit interaction, the baseline eosinophil strata, and region (pooled 
countries), as covariates. An unstructured correlation matrix will be used to model the within-
patient correlations. Parameters will be estimated using restricted maximum likelihood method 
with the Newton-Raphson algorithm. Additional covariates such as the background medications, 
age, height, gender, race and smoking status will be considered for inclusion in the analysis 
model based on evaluation of blinded data and the final analysis model documented in the 
statistical analysis plan (SAP). 
Comparison between the treatment group and the placebo group will be made within this model 
and the least square mean difference and their 95% confidence intervals will be estimated. 
In the case of premature discontinuation of study drug the primary analysis will include data up 
to 14 days after the last dose. 
Subgroup analyses will be performed using the same method by baseline eosinophil levels 
(≥250 /mm3 versus <250 /mm3) 
Other Secondary 
• 
Change from baseline 
in FEV1 to Week 24  
(post-bronchodilator*)  
• 
Time to first moderate 
or severe AECOPD 
 
 
 
Other secondary endpoints 
Change from baseline to Week 24 in FEV1 post-bronchodilator will be analyzed in the same way 
as the key secondary efficacy endpoint. 
Similar analytic method will be applied to analyze change from baseline to time points past Week 
24 in FEV1 (both pre-bronchodilator and post-bronchodilator).   
Time to first moderate or severe AECOPD will be analyzed using a Cox regression model with 
treatment, baseline eosinophil strata, and region (pooled country) as covariates. The Kaplan-
Meier (K-M) method will be used to estimate the probabilities of first AECOPD at specific time 
points for each group. Additional covariates will be considered based on evaluation of blinded 
data and the final analysis model documented in the SAP. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
 
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9.4.2 Safety analyses 
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the mITT population using the following common rules: 
The baseline value is defined generally as the last available value before the first dose of IMP.  
Table 15 - Safety analyses 
Endpoint 
Statistical Analysis Methods 
AE, SAE, AE 
leading to 
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, serious TEAE, and TEAE leading to discontinuation of the 
study will be tabulated by treatment group. In addition TEAEs will be described according to maximum 
intensity and relation to the study drug. Serious AEs and AEs leading to study discontinuation that occur 
outside the treatment-emergent period will be summarized separately. 
AESI 
The following summaries will be generated: 
1.  Incidence of each AESI will be tabulated by treatment group. 
2.  The time-to-first event analyzed using K-M methods and displayed as K-M plots (cumulative incidence 
(%) versus time based on K-M estimates) will be provided to depict the course of onset over time. When 
TEAE start date or worsening date is partially available, the maximum of the earliest possible TEAE start 
date and the treatment start date will be used. When TEAE start date or worsening date is completely 
missing, the treatment start date will be used. 
3.  An overview summary of the number (%) of patients with 
- 
any TEAE 
- 
any serious AE (regardless of treatment-emergent status) 
- 
any treatment-emergent SAE 
- 
any AE leading to death 
- 
any TEAE leading to permanent study drug discontinuation 
- 
any TEAE by maximum intensity, corrective treatment, and final outcome 
- 
cumulative incidence at specified time points (K-M estimates at Week 1, 4, 12, 24, 52 and 72) 
Definitions of AESIs and the method to identify AESIs 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) and reasons for death 
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. 
PCSA 
The following definitions will be applied to laboratory parameters, vital signs, and ECG. 
- 
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, vital signs, and ECG.  
- 
The 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 
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percentage. 
Laboratory 
parameters, vital 
signs, and ECG 
The following definitions will be applied to laboratory parameters, vital signs, and ECG. 
- 
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 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. 
AE: adverse event; SAE:  serious adverse event; SOC: system organ class; HGLT: high-level group term; HLT: high 
level term; PT: preferred term; n: number; AESI: adverse event of special interest; K-M: Kaplan-Meier; SAP: statistical 
analysis plan; PCSA: potentially clinically significant abnormality; ECG: electrocardiogram. 
 
Patient data listings will be provided for all AEs, TEAEs, SAE, AEs leading to study 
discontinuation, AESIs, and deaths. 
9.4.3 Other analyses  
PK, pharmacodynamic, and biomarker exploratory analyses are described here briefly and will be 
detailed in the statistical analysis plan finalized before database lock.  
The population PK analysis and pharmacodynamic analyses be presented separately from the 
main clinical study report (CSR). 
 Table 16 - Other analyses 
Endpoint 
Statistical Analysis Methods 
Pharmacokinetics 
(PK) 
Concentrations of functional SAR440340 will be summarized using arithmetic and geometric means, 
standard deviation, standard error of the mean (SEM), coefficient of variation (CV%), minimum, median, 
and maximum by treatment per visit. 
Anti-drug 
antibodies (ADA) 
The incidence of positive ADA response for SAR440340 will be assessed as absolute occurrence (n) and 
percent of patients (%), presented by treatment groups. Listing of ADA titer levels will be provided for 
patients positive in the ADA assay.  
The ADA analysis will be detailed in the SAP. 
Pharmacodynamics 
The values to be used as baseline will be those collected on Day 1 (predose assessments). If any of the 
scheduled assessments on Day 1 are technically disqualified (eg, insufficient sample), then values 
determined at Screening can be used as baseline.  
For all parameters, raw data, 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 group. 
Patient Reported 
Outcomes (health-
related quality of 
life/health 
economics 
variables) 
Change from baseline in the following variables: EXACT, SGRQ, and EQ-5D will be analyzed with an 
MMRM approach described previously for the continuous efficacy variables. Descriptive statistics including 
number of patients, mean, standard error and LS means will be provided. In addition, difference in LS 
means, the corresponding 95% CI’s, and the p-values will be provided for comparison between the active 
treatment groups and the placebo group. 
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9.5 
INTERIM ANALYSES  
No formal interim analysis is planned.  
Analyses of study data will be performed on an ongoing basis and provided to an internal DMC 
for internal decision making. No formal stopping rules or adjustment for multiplicity will be 
applied. 
 
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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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
- 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an Institutional Review Board (IRB) 
/Independent Ethics Committee (IECs) 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 
The study data will be reviewed by an internal DMC. 
10.1.4.1 Data Monitoring Committee (DMC) 
An internal DMC will be comprised of individuals with expertise in the diseases under study, 
biostatistics, or clinical research. The DMC members are independent of the project/study teams 
and are not involved in the study conduct. The primary responsibilities of the DMC are to review 
and evaluate the study data during the course of the trial and make appropriate recommendations 
regarding the conduct of the clinical trial to project/study team.    
The DMC procedures and data to be reviewed by the DMC are described in the DMC charter. 
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. 
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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.  
• 
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 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. 
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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 IMP 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 
• 
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 17 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 IMP administration and/or response 
evaluation. Additionally, if the local laboratory results are used to make either an IMP 
decision or response evaluation, the results and normal ranges must be entered into the 
CRF. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
 
 
 
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Table 17 - Protocol-required safety laboratory assessments 
Laboratory 
assessments 
 
Parameters 
Hematology 
To include hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with 5-part 
differential count, and total red blood cell count. Neutrophil and eosinophil counts (study biomarkers) 
will be evaluated as a part of hematology testing, and are also evaluated at additional timepoints 
(see SoA Section 1.3). 
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 
nonconjugated bilirubin), ALT, AST, alkaline phosphatase, lactate dehydrogenase, electrolytes 
(sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. 
Routine urinalysis 
To 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. Cotinine will be tested using 
the urine sample collected. 
Other tests 
• Clinical laboratory testing at Screening Visit 1 will include hepatitis screen covering HBs Ag, 
hepatitis B surface antibody (HBs Ab), HBc Ab, hepatitis C virus antibodies (HCV Ab), 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 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).  
• Clinical laboratory testing at Screening Visit 1 will also include Quantiferon gold testing for all 
patients. If the result is confirmed positive, the patient should be referred to an Infectious 
Disease specialist. Please refer to the central laboratory manual for additional details. 
 
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 IMP, whether or not considered related to the IMP. 
• 
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 IMP. 
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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, Section 8.3.7). 
• 
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 IMP 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 IMP 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 
• 
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 (see Section 8.3.7). 
• 
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). 
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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 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. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered a medically important event. The list 
is not intended to be exhaustive: 
• 
Intensive treatment in an emergency room or at home for:  
- 
Anaphylaxis (refer to Section 10.10 for the definition of anaphylaxis) 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc).  
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• 
Convulsions (seizures, epilepsy, epileptic fit, etc) 
• 
Development of drug dependence or drug abuse 
• 
ALT >3 x the upper limit of normal (ULN) + total bilirubin >2 x ULN or 
asymptomatic ALT increase >10 x ULN 
• 
Suicide attempt or any event suggestive of suicidality 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• 
Bullous cutaneous eruptions 
• 
Cancers diagnosed during the study  
• 
Chronic neurodegenerative diseases (newly diagnosed). 
 
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. 
• 
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. 
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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 IMP 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 IMP 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. 
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. 
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• 
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 Protocol. 
 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION 
 DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming 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 
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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. 
CONTRACEPTION GUIDANCE 
Male participants 
• 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to ONE of the following during the protocol-defined time frame in Section 
5.1:  
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 18 when having penile-vaginal intercourse 
with a woman of childbearing potential who is not currently pregnant 
• 
In addition male participants must refrain from donating sperm for the duration of the 
study and for 22 months after the last dose of study intervention. 
• 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame (from the signing of the ICF until the 
end of study visit).  
Female participants 
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 18. 
Table 18 - 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  
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Transdermal 
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 
for subsequent visits. 
Additional pregnancy testing should be performed 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:  
Male participants with partners who become pregnant  
• 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive IMP. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
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submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
 
Female participants who become pregnant  
• 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
• 
Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention 
10.5 
APPENDIX 5: PHARMACOGENOMICS 
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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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3  is met. 
 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3  is met. 
 
 
 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening. 
• See Section 10.3 and Table 7 for guidance on safety reporting. 
• Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 
 
Note: In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done. 
 
 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
INCREASE IN SERUM CREATININE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
investigational medicinal product by 
renal route
1.
Investigational medicinal 
product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
investigational medicinal product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
 
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting adverse events in Section 10.3  is met. 
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie, stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE investigational 
medicinal product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
INCREASE IN CPK SUSPECTED TO BE OF NON-CARDIAC ORIGIN 
AND NOT RELATED TO INTENSIVE PHYSICAL ACTIVITY
 
Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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10.7 
APPENDIX 7: LIST OF PROHIBITED LIVE ATTENUATED VACCINES  
• 
Bacillus Calmette-Guérin (BCG) antituberculosis vaccine 
• 
Chickenpox (Varicella) 
• 
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection 
is permitted 
• 
Measles (Rubeola) 
• 
Measles-mumps-rubella (MMR) combination 
• 
Measles-mumps-rubella-varicella (MMRV) combination 
• 
Mumps 
• 
Oral polio (Sabin) 
• 
Oral typhoid 
• 
Rotavirus 
• 
Rubella 
• 
Smallpox (Vaccinia) 
• 
Varicella Zoster (shingles) 
• 
Yellow fever 
This list is indicative and not exhaustive. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable 
10.9 
APPENDIX 9: ABBREVIATIONS 
 
ABECB: 
acute bacterial exacerbations of chronic bronchitis  
AEs: 
Adverse events 
AESI: 
Adverse events of special interest 
ALT: 
Alanine transaminase 
AST: 
Aspartate transaminase 
BMI: 
body mass index 
BP: 
blood pressure 
CAT: 
COPD Assessment Test 
CID: 
Clinically Important Deterioration 
COPD: 
Chronic obstructive pulmonary disease 
DMC: 
Data monitoring committee 
ECG: 
Electrocardiogram 
eCRF: 
electronic Case Report Form 
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EQ-5D: 
Euroqol-5Dimension 
EXACT: 
Exacerbations of Chronic Obstructive Pulmonary Disease Tool 
FEV1: 
Forced expiratory volume in 1 second 
FVC: 
Forced vital capacity 
GSO: 
Global Safety Officer 
HIV: 
Human immunodeficiency virus 
ICF: 
Informed consent form 
ICH: 
International Council for Harmonisation 
ICS: 
Inhaled corticosteroids  
IEC: 
Independent Ethics Committee 
IL: 
Interleukin 
IL-33: 
Interleukin-33 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
ISR: 
injection site reactions(s) 
IV: 
Intravenous 
IVRS: 
Interactive Voice Response System 
IWRS: 
Interactive Web Response System 
LABA: 
Long-acting β2 adrenergic agonists 
LAMA: 
Long-acting muscarinic antagonist 
mAb: 
Monoclonal antibody 
miTT: 
Modified Intent-to-treat 
MMRM: 
Mixed-effect model with repeated measures 
NIMP: 
noninvestigational medicinal product 
PCSA: 
Potentially clinically significant abnormality 
PD: 
Pharmacodynamics 
PK: 
Pharmacokinetics 
q2w: 
Once in every 2 weeks  
QoL: 
Quality of life 
SABA: 
Short-acting β agonists 
SAEs: 
Serious adverse events  
SAP: 
Statistical analysis plan 
SC: 
Subcutaneous 
TB: 
Tuberculosis 
ULN: 
Upper limit of normal range 
 
10.10 APPENDIX 10: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
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10.11 APPENDIX 11: COPD ASSESSMENT TEST 
 
 
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10.12 APPENDIX 12: ST. GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ) 
 
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10.13 APPENDIX 13: EXACERBATIONS OF CHRONIC OBSTRUCTIVE PULMONARY 
DISEASE TOOL (EXACT) 
 
 
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10.14 APPENDIX 14: EUROQOL QUESTIONNAIRE (EQ-5D-5L) 
 
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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: 
391-7) 
Clinical criteria for diagnosing anaphylaxis 
 
 
 
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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, extensive mucosal or cutaneous candidiasis. 
• 
Coccidioides immitis (endemic south-western US and Central and South America) 
• 
Cryptococcus 
• 
Cytomegalovirus 
• 
Herpes Simplex (severe/disseminated) 
• 
Herpes Zoster 
• 
Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
• 
Listeriosis 
• 
Mycobacterium avium 
• 
Nontuberculosis mycobacteria 
• 
Pneumocystis pneumonia (PCP) 
• 
Tuberculosis (TB) 
This list is indicative and not exhaustive. 
 
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10.17 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 subjects 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. Kearley J, Silver JS, Sanden C, Liu Z, Berlin AA, White N, et al. Cigarette Smoke Silences 
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ELECTRONIC SIGNATURES 
 
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ACT15104 16.1.1 Amended Protocol 01
Clinical Approval
Clinical Approval