Clinical trial NCT03620747
Conditions: Asthma
Sponsor: Sanofi
Start date: 2018-08-30; Completion date: 2022-02-18
Enrollment: 393 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To describe the long-term safety of dupilumab in treatment of participants with moderate to severe asthma who completed the previous asthma clinical trial (TRAVERSE-LTS12551).

Detailed description:
Duration per participant was until dupilumab approval for use in asthma and market availability to the participant, or a maximum of 144 weeks (i.e., about 3 years) after the start of treatment (Visit 1), whichever came first.

Arms: arm 1: Participants received subcutaneous (SC) dose of dupilumab 300 milligrams (mg) every 2 weeks (q2w) from Week 0 up to Week 132. Participants who discontinued treatment for greater than or equal to (\>=) 6 weeks after study LTS12551 (NCT02134028), received a 600 mg loading dose of dupilumab on Week 0. Participants were also on background dose of medium or high dose inhaled corticosteroid (ICS) as maintained in study LTS12551 in combination with controllers (and/or oral corticosteroid \[OCS\] for those participants from the original parent study EFC13691 \[NCT02528214\]). Salbutamol/albuterol hydrofluoroalkane pressurized metered dose inhalers (MDI) or levosalbutamol/levalbuterol hydrofluoroalkane pressurized MDI were given as reliever medication as needed during the study.
Interventions: intervention 1: Dupilumab SAR231893 (REGN668)
Intervention descriptions: intervention 1: Pharmaceutical form: prefilled syringes

Route of administration: subcutaneous

Protocol documents:
Prot_000.pdf: 


Clinical Trial Protocol  
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Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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Clinical Trial Protocol  
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Page 3 
CLINICAL TRIAL SUMMARY 
COMPOUND: Dupixent® 
STUDY No.: LPS15023 
STUDY NAME: LONG-TERM FOLLOW-UP 
TITLE 
Open-label, interventional, cohort study to evaluate long-term safety of 
dupilumab in patients with moderate to severe asthma who completed 
the TRAVERSE-LTS12551 clinical trial 
INVESTIGATOR/TRIAL LOCATION 
International 
PHASE OF DEVELOPMENT 
Phase IIIb 
STUDY OBJECTIVE 
 
Primary objective: 
• 
To describe the long-term safety of dupilumab in the 
treatment of patients with moderate to severe asthma who 
completed the previous asthma clinical trial, 
TRAVERSE-LTS12551. 
STUDY DESIGN 
Open-label, interventional, outpatient, prospective, multinational, 
multicenter, noncomparative, single-arm, safety study. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
I 01. 
Patient with asthma who completed the treatment period in 
the previous dupilumab asthma clinical study 
TRAVERSE-LTS12551. 
I 02. 
Patient is on background dose of medium or high dose 
inhaled corticosteroid (ICS), as maintained during study 
TRAVERSE-LTS12551, in combination with a second 
controller (and/or oral corticosteroid [OCS] for those patients 
from the original parent study EFC13691). Patients requiring 
a third controller medication will be allowed (eg, long-acting 
β-adrenoceptor agonists [LABA], leukotriene receptor 
antagonist [LTRA], methylxanthines). 
I 03. 
Signed written informed consent. 
Exclusion criteria: 
E 01. 
Current smoker or cessation of smoking within 6 months 
prior to enrollment. 
E 02. 
Clinically significant comorbidity/lung disease other than 
asthma. 
E 03. 
Alcohol abuse or drug abuse. 
E 04. 
Inability to follow drug administration 
procedures/noncompliance (eg, due to language problems or 
psychological disorders). 
E 05. 
Patient who have received, in the last 3 months, concomitant 
prohibited treatment: 
• 
Anti-immunoglobulin (Ig) E therapy (eg, omalizumab); 
• 
Biologic therapy. 
• 
Systemic immunosuppressants. 
• 
Intravenous Ig therapy. 
• 
Nonselective β-adrenergic blockers. 
• 
Other investigational drugs. 
• 
Live/attenuated vaccines. 
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E 06. 
Patient who develops: a new medical condition or a change 
in status of an established medical condition; a laboratory 
abnormality, or requires a new treatment or medication prior 
to enrollment, which (per Investigator's medical judgment) 
would adversely affect the participation in this study or would 
require permanent investigational medicinal product (IMP) 
discontinuation. 
E 07. 
Pregnant or breastfeeding women. 
E 08. 
Women of child-bearing potential (WOCBP, following 
menarche and until becoming post menopausal unless 
permanently sterile) who: 
• 
Do not have a confirmed negative urine test at enrollment. 
• 
Who are not protected by one of the following acceptable 
forms of effective contraception during the study (from Visit 1 
to End-of-treatment [EOT]/End-of-study [EOS]):             
- 
Established use of oral, injected, implanted, or inserted 
hormonal contraceptive. 
- 
Intrauterine device with copper or intrauterine system 
with progestogen. 
- 
Contraceptive barrier (condom, diaphragm, or 
cervical/vault caps) used with spermicide (foam, gel, 
film, cream, or suppository). 
- 
Female sterilization (eg, tubal occlusion, hysterectomy, 
or bilateral salpingectomy). 
- 
Male sterilization with post vasectomy documentation of 
the absence of sperm in the ejaculate; for female 
patients in the study, the vasectomized male partner 
should be the sole partner of that patient. 
- 
True abstinence; periodic abstinence (eg, calendar, 
ovulation, symptothermal, post ovulation methods) is 
not an acceptable method of contraception. 
- 
Menopausal women (defined as at least 12 consecutive 
months without menses) are not required to use 
additional contraception. 
E 09. 
Diagnosed active parasitic infection; suspected or high risk of 
parasitic infection, unless clinical and (if necessary) 
laboratory assessments have ruled out active infection 
before the enrollment. 
E 10. 
Patients with active autoimmune disease (eg, rheumatoid 
arthritis, inflammatory bowel disease, primary biliary 
cirrhosis, systemic lupus erythematosus, multiple sclerosis) 
or patients who, as per Investigator's medical judgment, are 
suspected of having high risk for developing autoimmune 
disease. 
E 11. 
Patients who experienced any systemic hypersensitivity 
reactions to the IMP in the previous dupilumab asthma study 
TRAVERSE-LTS12551, which, in the opinion of the 
Investigator, could indicate that continued treatment with 
dupilumab may present an unreasonable risk for the patient. 
E 12. 
Blood eosinophils >1500 cells/mm3 at the latest available 
test. 
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E 13. 
History of malignancy within 5 years before enrollment 
except completely treated in situ carcinoma of the cervix, 
completely treated and resolved nonmetastatic squamous or 
basal cell carcinoma of the skin. 
Total expected number of patients 
750 
STUDY TREATMENTS 
 
Investigational medicinal product 
Dupilumab 
Formulation 
Dupilumab 300 mg prefilled syringes of 150 mg/mL (2.25 mL total 
volume) to deliver 300 mg in the extractable 2 mL volume. 
Route of administration 
Subcutaneous (SC). 
Dose regimen 
300 mg SC every 2 weeks (q2w) with a 600 mg loading dose on Visit 1 
(Start-of-treatment Visit) for patients who discontinued treatment for 
≥6 weeks after study TRAVERSE-LTS12551. 
Noninvestigational medicinal products  
 
Asthma background controller therapy: 
Inhaled corticosteroid, in combination with a second controller. 
Patients requiring a third controller medication will be allowed 
(eg, LABA, LTRA, methylxanthines); OCS will be allowed only for 
those patients from original parent study EFC13691. 
Asthma reliever medication: 
Patients may receive salbutamol/albuterol hydrofluoroalkane 
pressurized metered dose inhalers (MDI) or 
levosalbutamol/levalbuterol hydrofluoroalkane pressurized MDI as 
reliever medication (as needed) during the study. Nebulizer solutions 
with either albuterol/salbutamol or levalbuterol/levosalbutamol may be 
used as an alternative delivery method. 
Post trial access to study medication 
By continuing to describe long-term safety, this study provides post 
trial access to study medication for patients from 
TRAVERSE-LTS12551.  
ENDPOINTS 
 
Primary safety endpoint: 
Incidence rates, defined as percentage of patients with 
treatment-emergent adverse events (TEAEs) and event rates per 
100 patient-years. 
Secondary endpoints: 
• 
Incidence rates and event rates per 100 patient-years for 
adverse events of special interest (AESIs) over the study. 
• 
Incidence rates for serious adverse events (SAEs)/death 
over the study. 
• 
Incidence rates for adverse events (AEs) leading to study 
discontinuation over the study. 
ASSESSMENT SCHEDULE 
Visit schedule:  
On-site visits every 12 weeks throughout the study, for a maximum of 
12 post baseline visits. The Start-of-treatment (Visit 1) may be 
performed on the same day as the TRAVERSE-LTS12551 EOT Visit. 
Early termination:  
Patients who prematurely and permanently discontinue IMP 
administration should have the EOT/EOS Visit (Visit 13) performed. 
Women of child-bearing potential discontinuing treatment will be 
advised to avoid pregnancy for at least 12 weeks following the last 
IMP dose. 
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Clinical Trial Protocol  
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STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Qualifying patients completing the treatment period of study 
TRAVERSE-LTS12551 will be offered to continue in this study. 
Primary analysis population: 
Safety: All patients receiving at least one dose of study medication 
during this study.  
Primary/key analysis: 
All TEAEs, AESIs, SAEs, and AEs leading to treatment discontinuation 
will be summarized. 
DURATION OF STUDY PERIOD (per patient) Until dupilumab approval for use in asthma and market availability to 
the patient, or for a maximum of 144 weeks (ie, about 3 years) after 
the Start-of-treatment (Visit 1), whichever comes first. 
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1 
FLOW CHARTS 
1.1 
STUDY FLOW CHART 
Study periods 
Start-of-
Treatment 
Treatment Period  
(144 weeks) 
End-of-Treatment / 
End-of-Study  
Week (W) 
W0 
W12-W132 (Visit every 12 weeks) 
W144 
 
VISIT 
V1a 
V2–V12b 
V13c 
Enrollment 
Informed consent 
X 
Patient demography 
X 
Eligibility criteria 
X 
Treatment 
Contact IRT 
X 
X 
X 
IMP dispensation/administrationd 
X 
X 
IMP accountability  
X 
X 
X 
Injection training/technique observatione 
X 
X 
Dispense home-dosing diaryf  
X 
X 
Safety 
Clinical laboratoryg 
Xh 
X  
X  
Adverse event reporting 
X 
X 
X 
Symptom-driven physical examination and vital signs 
X 
X 
X 
Concomitant medications 
X 
X 
X 
AE = adverse events; eCRF = electronic case report form; EOS = end-of-study; EOT = end-of-treatment; IMP = investigational medicinal product; 
IRT = interactive response technology; q2w = every 2 weeks; V = (study) visit; W = (study) week; WOCBP = women of child-bearing potential. 
a After completing the EOT Visit (V17) in study TRAVERSE-LTS12551, eligible patients should perform Start-of-treatment (V1) in LPS15023. 
Additional on-site IMP administration visits may be scheduled at the Investigator’s discretion for patients who experience hypersensitivity 
reactions upon retreatment at this visit, or for patients with long off-treatment interval after the completion of study TRAVERSE-LTS12551. 
b Visit window is ±7 days with respect to V1, ensuring at least an 11-day interval between 2 consecutive dupilumab administrations. 
c Patients who prematurely and/or permanently discontinue treatment will be scheduled for the EOT Visit, and the EOS Visit will be scheduled 
for 12 weeks later for follow-up on AEs. 
d Dispensation of IMP at every visit (except at EOT/EOS). Administration of 300 mg q2w. Loading dose of 600 mg at V1 for patients who 
discontinued treatment for ≥6 weeks after TRAVERSE-LTS12551. For administrations coinciding with site visits, patients will be monitored at 
the study site for a minimum of 30 minutes after injections. 
e The Investigator or delegate must train the patient (or parent/caregiver[s]) at V1, if starting self-administration, on the preparation and 
injection of IMP, and review the patient’s administration technique at subsequent visits if needed.  
f 
The home-dosing diary should be dispensed at the time of injection training/technique observation. 
g Local laboratory tests: Hematology (blood count: erythrocytes, hemoglobin, hematocrit, leukocytes with differential blood count [neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils], and platelets), and pregnancy test (urine or blood, for WOCBP only). Only clinically 
significant values will be captured in the eCRF. 
h Only for patients who do not roll-over into the study within 4 weeks of EOT or EOS Visit for study TRAVERSE-LTS12551 
(see  Section 10.1.1). 
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2 
TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS...............................................................................................................................7 
1.1 
STUDY FLOW CHART ....................................................................................................................7 
2 
TABLE OF CONTENTS ..................................................................................................................8 
3 
LIST OF ABBREVIATIONS ..........................................................................................................13 
4 
INTRODUCTION AND RATIONALE.............................................................................................14 
4.1 
INTRODUCTION............................................................................................................................14 
4.2 
RATIONALE...................................................................................................................................14 
5 
STUDY OBJECTIVES ...................................................................................................................16 
5.1 
PRIMARY.......................................................................................................................................16 
6 
STUDY DESIGN ............................................................................................................................17 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................17 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................17 
6.2.1 
Duration of study participation for each patient .............................................................................17 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................17 
6.3 
INTERIM ANALYSIS......................................................................................................................17 
6.4 
STUDY COMMITTEES..................................................................................................................17 
7 
SELECTION OF PATIENTS..........................................................................................................18 
7.1 
INCLUSION CRITERIA..................................................................................................................18 
7.2 
EXCLUSION CRITERIA ................................................................................................................18 
8 
STUDY TREATMENTS .................................................................................................................20 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................20 
8.1.1 
Dupilumab......................................................................................................................................20 
8.1.2 
Preparation of investigational medicinal product ...........................................................................20 
8.1.3 
Dose schedule ...............................................................................................................................20 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................21 
8.2.1 
Inhaled corticosteroid and controller therapies ..............................................................................21 
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8.2.2 
Albuterol or levalbuterol reliever medication..................................................................................21 
8.3 
BLINDING PROCEDURES............................................................................................................21 
8.3.1 
Methods of blinding........................................................................................................................21 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................21 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................22 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................22 
8.7 
RESPONSIBILITIES ......................................................................................................................22 
8.7.1 
Treatment accountability and compliance......................................................................................23 
8.7.2 
Return and/or destruction of treatments ........................................................................................23 
8.8 
CONCOMITANT MEDICATION.....................................................................................................23 
8.8.1 
Prohibited concomitant medication................................................................................................23 
8.8.2 
Permitted concomitant medication.................................................................................................24 
8.8.3 
Cytochrome P450 precaution ........................................................................................................24 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................25 
9.1 
PRIMARY ENDPOINT ...................................................................................................................25 
9.1.1 
Primary safety endpoint .................................................................................................................25 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................25 
9.2.1 
Adverse events ..............................................................................................................................25 
9.2.2 
Laboratory safety variables............................................................................................................25 
9.3 
FUTURE USE OF SAMPLES ........................................................................................................25 
9.4 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................25 
10 
STUDY PROCEDURES ................................................................................................................27 
10.1 
VISIT SCHEDULE..........................................................................................................................27 
10.1.1 
Visit 1 (Start-of-treatment, Week 0) ...............................................................................................27 
10.1.2 
Additional on-site visits ..................................................................................................................28 
10.1.3 
Visits 2 to 12 (Treatment period, Weeks 12 to 132) ......................................................................28 
10.1.4 
Visit 13 (End-of-treatment/End-of-study, Week 144).....................................................................29 
10.1.5 
End-of-study Visit...........................................................................................................................30 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................30 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................30 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................30 
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10.3.2 
Permanent treatment discontinuation with investigational medicinal product ...............................31 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................31 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................32 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................32 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................33 
10.4.1 
Definitions of adverse events.........................................................................................................33 
10.4.1.1 Adverse event ................................................................................................................................33 
10.4.1.2 Serious adverse event ...................................................................................................................33 
10.4.1.3 Adverse event of special interest...................................................................................................34 
10.4.2 
General guidelines for reporting adverse events ...........................................................................35 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................35 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................36 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................36 
10.4.6 
Guidelines for reporting investigational medicinal product complaints..........................................37 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................37 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................37 
10.6.1 
Hypersensitivity..............................................................................................................................38 
10.6.2 
Severe injection site reactions .......................................................................................................38 
10.6.3 
Infections........................................................................................................................................38 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................39 
11 
STATISTICAL CONSIDERATIONS..............................................................................................40 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................40 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................40 
11.3 
ANALYSIS POPULATIONS...........................................................................................................40 
11.3.1 
Efficacy populations .......................................................................................................................40 
11.3.2 
Safety population ...........................................................................................................................40 
11.4 
STATISTICAL METHODS .............................................................................................................40 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................40 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................41 
11.4.1.2 Compliance ....................................................................................................................................41 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................41 
11.4.3 
Analyses of safety data..................................................................................................................41 
11.4.3.1 Adverse events ..............................................................................................................................41 
11.4.4 
Concomitant medications...............................................................................................................42 
11.5 
INTERIM ANALYSIS......................................................................................................................42 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................43 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................43 
12.2 
INFORMED CONSENT .................................................................................................................43 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE ...................................................................................................................44 
13 
STUDY MONITORING...................................................................................................................45 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .........................................................................45 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................45 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................45 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST .............46 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................46 
14 
ADDITIONAL REQUIREMENTS...................................................................................................47 
14.1 
CURRICULUM VITAE....................................................................................................................47 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................47 
14.3 
CONFIDENTIALITY .......................................................................................................................47 
14.4 
PROPERTY RIGHTS.....................................................................................................................48 
14.5 
DATA PROTECTION.....................................................................................................................48 
14.6 
INSURANCE COMPENSATION....................................................................................................48 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................49 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................49 
14.8.1 
By the Sponsor...............................................................................................................................49 
14.8.2 
By the Investigator .........................................................................................................................50 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................50 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................50 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................51 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................52 
17 
APPENDICES................................................................................................................................53 
APPENDIX A. 
LIST OF PROHIBITED LIVE, ATTENUATED VACCINES.................................................54 
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APPENDIX B. 
EXAMPLES OF COMMONLY USED ASTHMA CONTROLLER THERAPIES ..................55 
APPENDIX C. 
EXAMPLES OF CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE ............57 
APPENDIX D. 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI......................................................................................................58 
APPENDIX E. 
LIST OF OPPORTUNISTIC INFECTIONS.........................................................................60 
APPENDIX F. DEFINITION OF ANAPHYLAXIS........................................................................................61 
LIST OF TABLES 
Table 1 - Summary of adverse event reporting instructions..........................................................................36 
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3 
LIST OF ABBREVIATIONS 
 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
CYP: 
cytochrome P450 
DRF: 
discrepancy resolution form 
eCRF: 
electronic case report form 
EOS: 
end-of-study 
EOT: 
end-of-treatment 
GCP: 
good clinical practice 
HLGT: 
high level group term 
IB: 
investigator’s brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
ICS: 
inhaled corticosteroids  
IEC: 
Independent Ethics Committee 
Ig: 
immunoglobulin 
IL: 
interleukin 
IL-4Rα: 
interleukin-4 receptor alpha 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
LABA: 
long-acting β-adrenoceptor agonists  
LTRA: 
leukotriene receptor antagonist 
MDI: 
metered dose inhalers 
NIMP: 
noninvestigational medicinal products 
OCS: 
oral corticosteroids 
PT: 
preferred term 
q2w: 
every 2 weeks 
SAEs: 
serious adverse events 
SC: 
subcutaneously 
SD: 
standard deviation 
SOC: 
system organ class 
TB: 
tuberculosis 
TEAEs: 
treatment-emergent adverse events 
Th2: 
Type 2 T-helper cell 
WOCBP: 
women of child-bearing potential 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyper-responsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. 
The inflammatory component of asthma involves many cell types, including mast cells, 
eosinophils, T-lymphocytes, neutrophils, epithelial cells, and their biological products. For most 
asthma patients, a regimen of controller therapy and reliever therapy provides adequate long-term 
control. However, it is estimated that 5% to 10% of asthma patients have symptomatic disease 
despite maximum recommended treatment with combinations of anti-inflammatory and 
bronchodilator drugs (1). 
The poor response of some patients with asthma may reflect the number of cellular and molecular 
mechanisms operative in asthma. There is increasing interest in distinct phenotypes because 
targeted therapy is more likely to be successful in patients with similar underlying pathobiologic 
features (2). Recent therapeutic approaches in asthma have been focused on trying to control the 
Type 2 T-helper cell (Th2) response. Up-regulation of interleukin(IL)-4 and IL-13 has been 
implicated as an important inflammatory component of asthma disease progression. 
Dupilumab, a fully human monoclonal antibody that binds specifically to the shared interleukin-4 
receptor alpha (IL-4Rα) subunit of the IL-4 and IL-13 receptor complexes, is under development 
as a potential novel treatment for asthma. Dupilumab inhibits IL-4 signaling via the Type I 
receptor, and both IL-4 and IL-13 signaling through the Type II receptor. Dupilumab belongs to 
the pharmacological class of immunomodulators, IL inhibitors. 
For complete information regarding the preclinical and clinical evaluation of dupilumab to date, 
including ongoing studies, see the current version of the Investigator’s Brochure (IB). 
4.2 
RATIONALE 
From an efficacy perspective, the dosing regimen of 300 mg every 2 weeks (q2w), added to a 
medium-to-high dose inhaled corticosteroids (ICS) + long-acting β-adrenoceptor agonists 
(LABA) in adult patients with uncontrolled persistent asthma, showed a clinically meaningful and 
highly statistically significant reduction versus placebo in the relative risk of severe exacerbations, 
improvement in lung function ie, forced expiratory volume and asthma symptoms 
(Asthma Control Questionnaire 5-question Version) (3). 
From a safety perspective, dupilumab 300 mg q2w demonstrated an acceptable safety profile and 
was well tolerated in pivotal trials for asthma and other indications (3, 4), as well as in the 
long-term safety study TRAVERSE-LTS12551 at the time of the interim analysis at median 
treatment duration of 51 weeks (data collection cut-off on 31 January 2016).  
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Overall, approximately 7004 subjects had been enrolled into the dupilumab development program 
as of 31 May 2017: 222 healthy volunteers, 3392 patients with atopic dermatitis (AD), 
3009 patients with asthma, 334 patients with nasal polyposis, and 47 patients with eosinophilic 
esophagitis. The estimated total number of subjects exposed to dupilumab in clinical studies was 
6250 (3286 in AD, 2546 in asthma, 193 in nasal polyposis and 23 in eosinophilic esophagitis, and 
202 in healthy volunteer studies). 
Study TRAVERSE-LTS12551 (the “parent” study) was designed as an open-label extension study 
to evaluate the long-term safety and tolerability of dupilumab in patients with asthma who 
participated in previous dupilumab studies (DRI12544, PDY14192, EFC13579, and EFC13691).  
The current LPS15023 study will provide further long-term clinical safety data (adverse events 
[AEs]/serious adverse events [SAEs] reporting) on dupilumab and extended dupilumab treatment 
to patients who continue to benefit from treatment. Therefore, a simplified study design is 
adopted, focusing on long-term clinical safety and late-onset events, while removing the burden of 
efficacy and patient reported outcome assessments. Safety monitoring will include continued 
focus on AEs, SAEs, and adverse events of special interest (AESIs, see Section 10.4.1.3). 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
The primary objective of this study is to describe the long-term safety of dupilumab in the 
treatment of patients with moderate to severe asthma who completed the previous asthma clinical 
trial, TRAVERSE-LTS12551. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
The LPS15023 study is a Phase IIIb, open-label, interventional, outpatient, prospective, 
multinational, multicenter, noncomparative, single-arm, safety study in patients with moderate to 
severe asthma who completed the parent study, TRAVERSE-LTS12551, from here on referred to 
as TRAVERSE.  
This study will evaluate the long-term safety of dupilumab 300 mg q2w administered 
subcutaneously (SC) over a maximum of 144 weeks. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The LPS15023 study consists of 3 periods: 
• 
Start-of-treatment (Visit 1). 
• 
Treatment period (Visit 2 to Visit 12). 
• 
End-of-treatment (EOT)/End-of-study (EOS) (Visit 13). 
Patients who prematurely and/or permanently discontinue treatment will be scheduled for the 
EOT Visit, and the EOS Visit will be scheduled for 12 weeks later for follow-up on AEs. 
After completing the treatment period in TRAVERSE, eligible patients who have signed the 
informed consent form (ICF) should perform the assessments of the Start-of-treatment Visit 
(Visit 1). Patients will receive treatment until dupilumab approval for use in asthma and market 
availability to patients, or for a maximum of 144 weeks (ie, about 3 years) after the 
Start-of-treatment (Visit 1), whichever comes first. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of clinical trial is defined as the “last patient last visit” planned in the protocol, ie, the 
EOT/EOS Visit (Visit 13). The Sponsor reserves the right to discontinue the study at any time. 
6.3 
INTERIM ANALYSIS 
Interim analyses of data may be conducted to support regulatory submissions or publication 
activities. 
6.4 
STUDY COMMITTEES 
Not applicable.  
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patient with asthma who completed the treatment period in TRAVERSE. 
I 02. Patient is on background dose of medium or high dose ICS, as maintained during 
TRAVERSE, in combination with a second controller (and/or oral corticosteroids [OCS] 
for those patients from the original parent study EFC13691). Patients requiring a third 
controller medication will be allowed (eg, LABA, leukotriene receptor antagonist [LTRA], 
methylxanthines). 
I 03. Signed informed consent. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all inclusion criteria listed in Section 7.1 will be screened for the following 
exclusion criteria:  
E 01. Current smoker or cessation of smoking within 6 months prior to enrollment. 
E 02. Clinically significant comorbidity/lung disease other than asthma. 
E 03. Alcohol abuse or drug abuse. 
E 04. Inability to follow drug administration procedures/noncompliance (eg, due to language 
problems or psychological disorders). 
E 05. Patient who have received, in the last 3 months, concomitant prohibited treatment: 
• 
Anti-immunoglobulin (Ig) E therapy (eg, omalizumab). 
• 
Biologic therapy. 
• 
Systemic immunosuppressants. 
• 
Intravenous Ig therapy. 
• 
Nonselective β-adrenergic blockers. 
• 
Other investigational drugs. 
• 
Live/attenuated vaccines (see Appendix A). 
E 06. Patient who develops: a new medical condition or a change in status of an established 
medical condition; a laboratory abnormality, or requires a new treatment or medication 
prior to enrollment, which (per Investigator's medical judgment) would adversely affect the 
participation in this study or would require permanent investigational medicinal product 
(IMP) discontinuation. 
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E 07. Pregnant or breastfeeding women. 
E 08. Women of child-bearing potential (WOCBP, following menarche and until becoming post 
menopausal unless permanently sterile) who: 
• 
Do not have a confirmed negative urine test at enrollment. 
• 
Who are not protected by one of the following acceptable forms of effective contraception 
during the study (from Visit 1 to EOT/EOS): 
- 
Established use of oral, injected, implanted, or inserted hormonal contraceptive. 
- 
Intrauterine device with copper or intrauterine system with progestogen. 
- 
Contraceptive barrier (condom, diaphragm, or cervical/vault caps) used with 
spermicide (foam, gel, film, cream, or suppository). 
- 
Female sterilization (eg, tubal occlusion, hysterectomy, or bilateral salpingectomy). 
- 
Male sterilization with post vasectomy documentation of the absence of sperm in the 
ejaculate; for female patients in the study, the vasectomized male partner should be the 
sole partner of that patient. 
- 
True abstinence; periodic abstinence (eg, calendar, ovulation, symptothermal, post 
ovulation methods) is not an acceptable method of contraception. 
- 
Menopausal women (defined as at least 12 consecutive months without menses) are 
not required to use additional contraception. 
E 09. Diagnosed active parasitic infection; suspected or high risk of parasitic infection, unless 
clinical and (if necessary) laboratory assessments have ruled out active infection before the 
enrollment. 
E 10. Patients with active autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel 
disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis) or 
patients who, as per Investigator's medical judgment, are suspected of having high risk for 
developing autoimmune disease. 
E 11. Patients who experienced any systemic hypersensitivity reactions to the IMP in 
TRAVERSE, which, in the opinion of the Investigator, could indicate that continued 
treatment with dupilumab may present an unreasonable risk for the patient. 
E 12. Blood eosinophils >1500 cells/mm3 at the latest available test. 
E 13. History of malignancy within 5 years before enrollment except completely treated in situ 
carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or basal 
cell carcinoma of the skin. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT  
By continuing to describe long-term safety, this study provides post trial access to study 
medication for patients from TRAVERSE. 
8.1.1 Dupilumab 
Dupilumab is supplied as a sterile aqueous solution for SC injection at the concentration of 
150 mg/mL in a 2 mL glass prefilled syringe to deliver 300 mg. 
8.1.2 Preparation of investigational medicinal product 
The IMP will be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) until use. Instructions for 
IMP administration will be provided in the pharmacy manual and Patient User Instructions for 
self-administration. 
8.1.3 Dose schedule 
The IMP will be administered every 14±3 days (q2w). The consecutive doses of the IMP must be 
separated by ≥11 days to avoid an overdose. If in TRAVERSE the patient was already 
self-injecting, and/or parent/caregiver(s) was already injecting the patient, the Investigator or 
delegate will supervise the injection, or the Investigator or delegate will train the patient (and/or 
parent/caregiver[s]) on how to prepare and inject IMP at Start-of-treatment Visit (Visit 1) and will 
inject the first injection. For patients who discontinued treatment for ≥6 weeks after TRAVERSE 
ie, patients requiring a loading dose, the first injection is the first of the 2 injections of IMP 
(for the 600 mg dose). 
Reminder: patients will be monitored for any signs or symptoms of hypersensitivity reactions for 
a minimum of 30 minutes after IMP injection on-site visit days. For patients who experience 
hypersensitivity reactions upon retreatment, ie, at the Start-of-treatment Visit (Visit 1), or for 
patients with long off-treatment interval after the completion of TRAVERSE, additional on-site 
IMP administration visits may be scheduled at the Investigator’s discretion. 
Subcutaneous injection sites should be alternated between the 4 quadrants of the abdomen 
(avoiding navel and waist areas), the upper thighs, or upper arms (lateral side), so that the same 
site is not injected twice consecutively. Injection in the upper arms could be done only by a trained 
person (parent/caregiver[s] trained by the Investigator or delegate) or health care professional but 
not the patient themselves. This instruction pertains to the day of the loading dose as well as for 
subsequent q2w injections. For each injection, the anatomic site of administration will be recorded 
in the electronic case report form (eCRF) and in the home-dosing diary.  
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Detailed instructions for transport, storage, and administration of IMP will be provided to the 
patient, and Investigators should ensure that these instructions are followed. Patients will 
complete a home-dosing diary to document compliance with self-injection (or parent/caregiver 
injection) of IMP. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
8.2.1 Inhaled corticosteroid and controller therapies 
Inhaled corticosteroid and other controller therapies (eg, LABA, LTRA, methylxanthines) and 
OCS for patients from EFC13691 will be collected in the eCRF. 
Patients will continue on background therapy of moderate or high-dose ICS as maintained in 
TRAVERSE. Background therapy may be modified at any time during the study based on 
Investigator's judgment. Patients will also be using additional asthma controller therapies initiated 
during TRAVERSE.  
Please see Appendix B for a list of commonly used asthma controller medications. 
8.2.2 Albuterol or levalbuterol reliever medication 
Patients may receive salbutamol/albuterol hydrofluoroalkane pressurized metered dose inhalers 
(MDI) or levosalbutamol/levalbuterol hydrofluoroalkane pressurized MDI as reliever medication 
(as needed) during the study. 
Nebulizer solutions with either albuterol/salbutamol or levalbuterol/levosalbutamol may be used 
as an alternative delivery method. 
All other reliever medications other than albuterol/salbutamol or levalbuterol/levosalbutamol 
should be avoided. 
8.3 
BLINDING PROCEDURES 
Not applicable. 
8.3.1 Methods of blinding 
Not applicable. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
The patient will be considered enrolled in the study once a treatment kit number has been assigned 
by the Interactive Response Technology (IRT). Therefore, it is important that all 
inclusion/exclusion criteria are confirmed and all required procedures are completed prior to the 
enrollment contact to the IRT. Detailed IRT procedure will be provided in the IRT Site Manual. 
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The study medication will be administered only to patients included in this study following the 
procedures described in the clinical study protocol. The treatment kit number list will be 
generated centrally by Sanofi Clinical Supply team. The IMPs are packaged in accordance with 
this list.  
Patients will be enrolled at Visit 1. Patients will be identified by the same identification number 
used in TRAVERSE. The investigational site will enter the patient tracking information (patient 
identification number and date of birth) into the IRT during each scheduled protocol visit. The 
clinical site coordinator will document the patient number and the treatment kit number in the 
eCRF and in the patient’s source documents, and the site patient number on the IMP labels prior 
to dispensing the IMP to the patient.  
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING 
The IMP dupilumab will be packaged in single-use prefilled syringes. One kit box will contain 
2 prefilled syringes. Enough kit boxes will be given to the patients for the treatment period until 
the next study visit.  
Each packaging component will be labeled with the project name and study number, a medication 
kit number, packaging reference number, Sponsor name, quantity or contents, dispensing 
instruction, caution statement, “use by” date, and storage conditions.  
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
The IMP should be stored at a temperature between 2°C and 8°C in an appropriate and locked 
room under the responsibility of the Investigator or other authorized persons (eg, pharmacists) 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 IMP must be managed according 
to the rules provided by the Sponsor. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, patient (or parent/caregiver[s]), or other personnel 
allowed to store and/or 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. 
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 10.4.6). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document treatment compliance and IMP accountability include: 
• 
Proper recording of treatment kit number as required on appropriate screen(s) of eCRF for 
accounting purposes: 
- 
All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit that treatment dispensing is planned. 
- 
The completed patient injection sheet (returned to the site at each visit), returned 
treatment kit boxes, and any unused prefilled syringes will be used for drug 
accountability purposes. 
- 
The Investigator or designee tracks treatment accountability/compliance, either by the 
injection sheet or by counting the number of used treatment kits, and fills in the 
appropriate page of the patient treatment log. 
- 
The monitor in charge of the study then checks the data entered on the IMP 
administration page by comparing them with the IMP that has been retrieved and the 
patient treatment log form. 
8.7.2 Return and/or destruction of treatments 
Whenever possible all used, partially used, or unused IMP will be destroyed on site according to 
the standard practices of the site. A detailed treatment log of the destroyed IMP will be 
established with the Investigator (or the pharmacist) and countersigned by the Investigator and the 
monitoring team. The Investigator will not destroy the used and unused IMP unless the Sponsor 
provides written authorization. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the IMP. 
8.8.1 Prohibited concomitant medication 
The following concomitant treatments are not permitted during the study:  
• 
Anti-IgE therapy (eg, omalizumab). 
• 
Biologic therapy. 
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• 
Systemic immunosuppressants. 
• 
Intravenous Ig therapy. 
• 
Nonselective β-adrenergic blockers. 
• 
Other investigational drugs. 
• 
Live/attenuated vaccines (see Appendix A). 
8.8.2 Permitted concomitant medication 
The following asthma-related and other relevant concomitant treatments are permitted: 
• 
Leukotriene antagonists/modifiers. 
• 
Long-acting β-adrenoceptor agonists. 
• 
Allergen immunotherapy stable dose. 
• 
Antihistamines. 
• 
Systemic (oral or injectable) corticosteroids: 
- 
Oral corticosteroids are allowed as background controller medication for the patients 
from the original parent study EFC13691 only. 
- 
Oral corticosteroids are allowed as treatment for asthma exacerbations and/or AEs as 
per Investigator's decision, for any patient. 
• 
Ocular, intranasal, or topical corticosteroids. 
• 
Methylxanthines (eg, theophylline, aminophyllines). 
• 
Lipoxygenase inhibitors (eg, zileuton). 
• 
Cromones for asthma (eg, cromolyn sodium solution for nebulization, nedocromil 
dry-powder inhaler). 
• 
Cromones for other reasons (eg, ophthalmic formulations for allergic conjunctivitis, nasal 
formulations for allergic rhinitis). 
• 
Short- and long-acting anti-cholinergic drugs (ipratropium bromide and tiotropium). 
8.8.3 Cytochrome P450 precaution 
The risk of indirect effects of dupilumab, via modulation of IL-4 and IL-13 activities, on the 
pharmacokinetics of selected cytochrome P450 (CYP) substrates (midazolam, omeprazole, 
warfarin, caffeine, and metoprolol) has been studied in 14 adult patients with moderate to severe 
AD. 
The results of this study showed no evidence for a clinically meaningful effect of dupilumab on 
the activity of CYP3A, CYP2C19, CYP2C9, CYP1A2, or CYP2D6. Some examples of CYP450 
substrates with narrow therapeutic index are provided in Appendix C. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINT 
9.1.1 Primary safety endpoint 
Incidence rates, defined as the percentage of patients reporting any treatment-emergent adverse 
events (TEAEs), and event rates per 100 patient-years. 
9.2 
SECONDARY ENDPOINTS 
• 
Incidence rates and event rates per 100 patient-years for AESIs over the study. 
• 
Incidence rates for SAEs/death over the study. 
• 
Incidence rates for AEs leading to study discontinuation over the study. 
Note: AEs, SAEs, AESIs, AEs leading to IMP discontinuation, and death will be collected from 
the time of informed consent signature and then at each visit until the EOT/EOS (Visit 13). The 
safety analysis will be based on the reported AEs and clinical laboratory data. The study specific 
and general safety criteria are detailed in Section 10.4.1.  
Adverse events, AESIs, SAEs, AEs leading to IMP discontinuation and deaths will be reported as 
described in Section 10.4.2 and analyzed as in Section 11.4.3.1. 
9.2.1 Adverse events 
Refer to Section 10.4 to Section 10.7 for further details. 
9.2.2 Laboratory safety variables 
Clinical laboratory data will be limited to hematology (blood count: erythrocytes, hemoglobin, 
hematocrit, leukocytes with differential blood count [neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils] and platelets), and pregnancy testing.  
Only clinically significant laboratory test results will be recorded as AEs in the eCRF. 
9.3 
FUTURE USE OF SAMPLES 
Not applicable. 
9.4 
APPROPRIATENESS OF MEASUREMENTS  
This is an open-label extension study with no comparator or control group.  
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The study aims to collect long-term clinical safety data and extended dupilumab treatment to 
patients who may continue to benefit from treatment. Local laboratories will be used to support 
identification and follow-up of clinically significant findings captured as AEs in the eCRF. 
Likewise, symptom-driven physical examination findings, and vital signs at each visit that are 
deemed clinically significant will be captured as AEs in the eCRF. Further clinical procedures 
required to identify and follow-up AE, may be performed at the discretion of the Investigator.  
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The LPS15023 study consists of 3 periods: 
• 
Start-of-treatment Visit (Visit 1): After completing the EOT Visit (Visit 17) in 
TRAVERSE, eligible patients should rollover into LPS15023. 
• 
Treatment period (Visit 2 to Visit 12): Open-label treatment for up to 144 weeks (Visit 13, 
approximately 3 years). 
• 
End-of-treatment/End-of-study (Visit 13). 
Patients who prematurely and/or permanently discontinue treatment will be scheduled for the 
EOT Visit, and the EOS Visit will be scheduled for 12 weeks later for follow-up on AEs. 
It is preferred that all study visits take place in the morning.  
Safety blood tests will be performed at a local laboratory; depending on the site’s local laboratory 
and facilities, either blood or urine may be assessed for pregnancy testing for WOCBP. 
10.1.1 Visit 1 (Start-of-treatment, Week 0) 
There is no time limit between the TRAVERSE EOT Visit and the evaluation for eligibility to 
participate in this study. 
Ideally, patients should be evaluated for eligibility to participate in this study as soon as they 
complete the TRAVERSE EOT Visit. The Start-of-treatment (Visit 1) for this study may be 
performed on the same day as the TRAVERSE EOT Visit. If this is not possible or if the patient 
completed participation in TRAVERSE prior to the opening of enrollment in this study, and more 
than 4 weeks have elapsed between TRAVERSE EOT Visit date and the LPS15023 
Start-of-treatment (Visit 1) date, the following additional assessments will be required:  
• 
Collect blood samples for hematology: Blood count (erythrocytes, hemoglobin, 
hematocrit, and leukocytes), differential blood count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), and platelets. 
• 
For WOCBP only, blood or urine pregnancy test.  
Following a discussion of participation in the clinical trial, the written informed consent (and 
assent in case of adolescents) form must be signed and dated before the following activities are 
performed: 
• 
Review inclusion and exclusion criteria to assess eligibility. 
• 
If the patient meets all inclusion and does not meet any exclusion criteria, contact IRT to 
register the visit, confirm the patient’s number and receive the first treatment kits’ 
numbers assignment. 
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• 
Confirm and update (if required) previously collected patient’s demographic information, 
asthma history (including allergy history and smoking habits), and other medical and 
surgical history (including significant prior and concurrent illnesses). 
• 
Symptom-driven physical examination and vital signs should be performed in patients 
presenting with signs or symptoms. 
• 
Commence AE reporting from the time of the signature of the informed consent for 
participation in LPS15023. 
• 
Record study IMP/noninvestigational medicinal products (NIMP) and all other 
concomitant medication use with start date/dose in the eCRF. 
• 
Instruct the patient to continue the background ICS/LABA or ICS and controller therapy 
stabilized during TRAVERSE. 
• 
Dispense and administer IMP (see Section 8.1.3): 
- 
For patients starting to perform self-injection, the Investigator or delegate should train 
the patient (or parent/caregiver[s]) regarding injection of IMP. The patient 
(or parent/caregiver[s]) may perform the injection under the supervision of the 
Investigator or delegate, if the patient (or parent/caregiver[s]) was already (self) 
injecting in TRAVERSE. 
- 
Patients should be monitored for at least 30 minutes after each administration of IMP 
for any signs or symptoms of a hypersensitivity reaction. 
• 
Schedule appointment for next visit. 
• 
Reminder: Sexually active WOCBP are required to practice an acceptable contraception 
(as defined in E 08) during the entire study duration, while taking dupilumab and for 
12 weeks after the last IMP dose. Study investigators should counsel all study patients, 
with special attention towards adolescent patients, regarding the importance of practicing 
responsible and effective contraception during the entire study duration. 
• 
Dispense home-dosing diary and instruct the patient to take the study IMP/NIMP 
medication regularly, fill in the diary, and call the site in case of any signs and symptoms 
of AEs and/or any problems with the injection/IMP. 
10.1.2 Additional on-site visits 
Additional on-site IMP administration visits may be scheduled at the Investigator’s discretion for 
patients who experience hypersensitivity reactions upon retreatment, ie, at the Start-of-treatment 
Visit (Visit 1), or for patients with long off-treatment interval after the completion of 
TRAVERSE. 
10.1.3 Visits 2 to 12 (Treatment period, Weeks 12 to 132) 
These will be the treatment period visits. Patients should attend an onsite visit every 12 weeks. 
The following procedures will be performed during these visits: 
• 
Contact IRT to register the visit and obtain treatment kits’ numbers. 
• 
Inquire for any AEs. In case of any such occurrences, AEs should be recorded and 
reported. 
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• 
Symptom-driven physical examination and vital signs should be performed in patients 
presenting with signs or symptoms. 
• 
Collect the home-dosing diary and check for regular administration of study IMP/NIMP 
medication. 
• 
Collect all used and unused IMP (applicable to all interim visits). 
• 
Record study IMP/NIMP and all other concomitant medication use with start date/dose in 
the eCRF. 
• 
Collect blood samples for hematology: Blood count (erythrocytes, hemoglobin, 
hematocrit, and leukocytes), differential blood count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), and platelets. 
• 
For WOCBP only, blood or urine pregnancy test. 
• 
Capture as AEs all clinically significant laboratory values in the eCRF. 
• 
Dispense and administer IMP: 
- 
Review the patient’s administration technique. 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind the patient to continue the background ICS/LABA or ICS and controller therapy 
stabilized during TRAVERSE. 
• 
Schedule appointment for next visit. 
• 
Dispense home dosing dairy and instruct the patient to take the study IMP/NIMP 
medication regularly, fill in the home-dosing diary, and call the site in case of any signs 
and symptoms of AEs and/or any problems with the injection/IMP. 
• 
Patients who discontinue study medication prematurely and permanently should be 
scheduled for the EOT/EOS Visit. 
10.1.4 Visit 13 (End-of-treatment/End-of-study, Week 144) 
This will be the end of treatment and the last study visit (except for patients who prematurely 
and/or permanently discontinue treatment, see Section 10.1.5). 
The following procedures will be performed during this visit: 
• 
Contact IRT to register the EOT/EOS Visit. 
• 
Inquire for any AEs. In case of any such occurrences, AEs should be recorded and 
reported. 
• 
Symptom-driven physical examination and vital signs should be performed in patients 
presenting with signs or symptoms. 
• 
Collect the home-dosing diary and check for regular administration of study IMP/NIMP 
medication. 
• 
Collect all used and unused IMP. 
• 
Record study IMP/NIMP and all other concomitant medication use with start date/dose in 
the eCRF. 
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• 
Collect blood samples for hematology: Blood count (erythrocytes, hemoglobin, 
hematocrit, and leukocytes), differential blood count (neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils), and platelets. 
• 
For WOCBP only, blood or urine pregnancy test; WOCBP discontinuing treatment must 
be advised to avoid pregnancy for at least 12 weeks following the last IMP dose. 
• 
Capture as AEs all clinically significant laboratory values in the eCRF. 
10.1.5 End-of-study Visit 
Patients who prematurely and/or permanently discontinue treatment will be scheduled for the 
EOT Visit, and the EOS Visit will be scheduled for 12 weeks later for follow-up on AEs.  
The following procedure will be performed during this visit: 
• 
Inquire for any AEs. In case of any such occurrences, AEs should be recorded and 
reported. 
10.2 
DEFINITION OF SOURCE DATA 
Source data is all information in original records and certified copies of original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents. Source 
documents are original documents, data and records such as hospital records, clinic and office 
charts, laboratory notes, memoranda, pharmacy dispensing records, recorded data from 
automated instruments, etc. 
All data collected in the eCRF should be transcribed directly from source documents. Data 
recorded on the patient home-dosing diary will be transcribed to the eCRF. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF.  
• 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
• 
Stopping rules described in Appendix D should be applied.  
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation of treatment with the IMP will be done under close and appropriate clinical 
and/or laboratory monitoring once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the IMP in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2). 
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For all temporary treatment discontinuations, number of missed injections and duration must be 
recorded by the Investigator in the appropriate screen(s) of the eCRF.  
The following definition can be considered: 
Eg, temporary treatment discontinuation decided by the Investigator corresponds to more than 
1 dose not administered to the patient. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product 
Permanent treatment discontinuation is any treatment 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. 
10.3.3 List of criteria for permanent treatment discontinuation 
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. 
Any abnormal laboratory value will be rechecked for confirmation before making a decision of 
permanent discontinuation of the IMP for the concerned patient.  
The following criteria will lead to permanent treatment discontinuation: 
• 
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 (see Section 10.6). 
• 
At the specific request of the Sponsor. 
• 
In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor. 
• 
Pregnancy (Note: dupilumab should be stopped but patient should be followed up until 
delivery). 
• 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment. 
• 
Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin. 
• 
Any opportunistic infection, such as tuberculosis (TB) or other infections whose nature or 
course may suggest an immunocompromised status (see Appendix E). 
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10.3.4 Handling of patients after permanent treatment discontinuation 
If possible, and after the permanent discontinuation of treatment, patients will be assessed using 
the procedure normally planned for the last dosing day with the IMP (Visit 13). In case of an 
ongoing AE at the EOT/EOS Visit, patients may be followed up to recovery or stabilization of the 
AE. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate screen(s) of the eCRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study 
Patients may withdraw from the study before study completion if they decide to do so or if they 
no longer wish to take the IMP, at any time and irrespective of the reason without any effect on 
their care.  
The Investigators should discuss with them about attending the EOT/EOS Visit. The value of their 
study data collected at the the EOT/EOS Visit will be emphasized as important to the public 
health value of the study. 
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must be documented.  
All study withdrawals must be recorded by the Investigator in the appropriate screens of the eCRF 
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, ie, patient 
will not attend the EOT/EOS Visit. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for the EOT/EOS Visit 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. 
For patients who fail to return to the site, unless the patient withdraws consent, the Investigator 
must make the best effort to recontact the patient (eg, contact patient’s family or private physician, 
review available registries or health care databases), and to determine his/her health status, 
including at least his/her vital status. Attempts to contact such patients must be documented in the 
patient’s records (eg, times and dates of attempted telephone contact, receipt for sending a 
registered letter).  
Patients who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or, 
• 
Is life-threatening, or, 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or, 
• 
Results in persistent or significant disability/incapacity, or, 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
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: 
- 
Allergic bronchospasm. 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.).  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.). 
• 
Development of drug dependence or drug abuse. 
• 
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 or aggravated during the study (only if judged 
unusual/significant by the Investigators).  
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10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them; AESIs may be added, modified or removed during a study by 
protocol amendment. 
The following is a list of AESIs for this study. For these AESIs, the Sponsor will be informed 
immediately (ie, within 24 hours), per SAE notification described in Section 10.4.1.2, even if not 
fulfilling a seriousness criterion, using the corresponding screens of the eCRF: 
• 
Anaphylactic reactions or acute allergic reactions that require immediate treatment 
(see Appendix F). 
• 
Injection site reactions that are severe and last longer than 24 hours. 
• 
Any serious infection, any bacterial infection requiring treatment with parenteral 
antibiotics for longer than 2 weeks, any parasitic infection, any systemic opportunistic 
infection (see Appendix E), any viral infection requiring antiviral treatment, or any 
uncommon, atypical, or unusually frequent or persistent infection and TB that requires 
anti-TB medication. For details, refer to Section 10.6.3.  
Note: Candidiasis – all cases should be collected as AEs (or SAEs if requirements met), 
however, only cases which are NOT cutaneous (systemic or mucous membranes involved) 
unless involvement is extensive, will be considered as AESI.  
• 
Pregnancy (female patient or female partner): 
- 
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 Section 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be permanently 
discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
• 
Symptomatic overdose (serious or nonserious) with the IMP/NIMP. 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient and defined as at least twice 
the planned dose during an interval of less than 11 days. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms.  
Of note, asymptomatic overdose has to be reported as a standard AE.  
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10.4.2 General guidelines for reporting adverse events  
• 
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding screen(s) of the eCRF. 
• 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
• 
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• 
Patients who experience an ongoing SAE or an AESI with immediate notification, at the 
pre specified study end-date (EOT/EOS Visit), should be followed until resolution, 
stabilization, or death and related data will be collected. 
• 
When treatment is prematurely and permanently discontinued, the patient’s observations 
will continue until the end of the study as defined by the protocol for that patient. 
• 
The following laboratory abnormalities are considered clinically significant and will be 
recorded as AEs:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI.  
Instructions for AE reporting are summarized in Table 1 in Section 10.4.5. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
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• 
All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding screen(s) of the eCRF. 
Instructions for AE reporting are summarized in Table 1 in Section 10.4.5.  
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of neutropenia and thrombocytopenia by Sanofi are provided 
in Appendix D. These abnormalities should be monitored, documented, and managed according to 
the related flow chart in Appendix D.  
In addition, eosinophil counts >3000 cells/µL (3.0 giga/L) at any time during the study are to be 
reported as AEs. 
Table 1 - Summary of adverse event reporting instructions 
Case report form completion 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
AE form 
Safety  
complementary 
form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, non-
AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI 
or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
Acute hypersensitivity/anaphylaxis 
Yes 
Yes 
No 
 
 
Injection site reactions 
Yes 
Yes 
No 
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Case report form completion 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
AE form 
Safety  
complementary 
form 
Other 
specific 
forms 
 
 
Infections (see  Section 10.4.1.3 for 
details)  
Yes 
Yes 
No 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; SAE = serious adverse event 
10.4.6 Guidelines for reporting investigational medicinal product complaints 
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction), to the regulatory authorities, Independent Ethics 
Committee (IECs)/Institutional Review Boards (IRBs) as appropriate and to the 
Investigators.  
• 
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Exacerbations of asthma, as pre-existing condition, will be considered expected for purposes of 
regulatory reporting, unless the event is life-threatening or with fatal outcome (refer to the 
current IB). 
Any other AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
During the study, all patients will be monitored for safety signals and will be instructed to call the 
site in case of any signs and symptoms of AEs and/or any problems with the injection/IMP.  
In addition, any problems related to dupilumab injection administration should be documented in 
the specific screen(s) of the eCRF for local injection reactions recording. 
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10.6.1 Hypersensitivity 
Allergic reaction is a potential risk associated with the administration of most therapeutic 
monoclonal antibodies. 
Allergic reactions may be defined as an immunologically mediated response to a pharmaceutical 
and/or formulation agent in a sensitized person. Signs and symptoms are often experienced during 
or shortly after therapeutic administration. Anaphylaxis may represent the most severe form of 
allergic reactions; see Appendix F, which describes the clinical criteria for the diagnosis of 
anaphylaxis. 
Patients should be monitored for at least 30 minutes after each study-site IMP administration for 
any signs or symptoms of a hypersensitivity reaction. Furthermore, the patients will be advised, 
when the IMP is administered at home, to self-monitor for 30 minutes after administration for 
potential signs and symptoms that may suggest a hypersensitive reaction. 
10.6.2 Severe injection site reactions 
Based on the SC mode of administration of high doses of protein and on a higher incidence of 
local injection site reactions observed at the highest dose level (300 mg weekly), severe injection 
site reactions are considered as a potential risk. Patients who experience an injection site reaction 
must be closely monitored for the possibility of a more intense injection site reaction with a future 
injection. Any severe injection reaction that lasts over 24 hours will be reported as an AESI with 
immediate notification.  
Prophylactic treatment/premedication for an injection site reaction is not permitted. 
10.6.3 Infections 
Some biologic therapies have been associated with an increased risk of infection, including 
opportunistic infection. 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. 
Infections with a diversity of helminthic parasites elicit eosinophilia via stimulation of Th2-like 
lymphocyte responses. The Th2 response is characterized by production of IL-4, IL-13, and IL-5, 
subsequently generating IgG1 and IgE-secreting cells, and eliciting eosinophilia. 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. Since dupilumab 
binds to IL-4Rα, preventing IL-4 and IL-13 binding and activation of their respective receptors, it 
inhibits Th2 cytokine production. Therefore, patients treated with dupilumab may potentially have 
an increased risk of parasitic infection. 
In order to minimize this risk, any patient with an active parasitic infection should be excluded 
from the study. Similarly, patients with suspected parasitic infection, or those at high risk of 
parasitic infection are also excluded, unless clinical and (if necessary) laboratory assessments 
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have ruled out active infection before enrollment. During the study, appearance of signs or 
symptoms (such as abdominal pain, cough, diarrhea, fever, fatigue, 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, particularly 
when conditions are conducive to infection (eg, extended stay, rural or heavily populated informal 
settlements, lack of running water, consumption of uncooked, undercooked, or otherwise 
potentially contaminated food, close contact with carriers and vectors). Subsequent medical 
assessments (eg, stool exam, blood tests) must be performed in order to rule out parasitic 
infection/infestation. Patients with confirmed parasitic infections during the study should be 
reported as AESI with immediate notification. 
Infections defined in Section 10.4.1.3 should be reported as AESIs within 24 hours. 
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 IMP 
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 Appendix E), patients must be permanently 
discontinued from IMP. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The objective of the study is to continue to evaluate the long-term safety and tolerability of 
dupilumab in patients with asthma who participated in the previous long-term study TRAVERSE. 
Therefore, all qualifying patients completing the treatment period in TRAVERSE will be offered 
to enroll in this study.  
It is expected that approximately 750 patients will enroll in this study. 
11.2 
DISPOSITION OF PATIENTS 
Enrolled patients consist of all the patients who signed informed consent and had a treatment kit 
number allocated and recorded in IRT database, and regardless of whether the treatment kit was 
used or not. 
The safety population consists of the patients who actually received at least one dose or part of a 
dose of dupilumab in the current study. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
Not applicable. 
11.3.2 Safety population 
The primary analysis population is the safety population, which is defined as all patients who have 
actually received at least one dose or part of a dose of dupilumab during this study. 
The treatment-emergent period is defined as the time from the first dose of dupilumab during this 
study up to the EOT/EOS (Visit 13). 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be summarized using the safety 
population. 
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11.4.1.1 Extent of investigational medicinal product exposure 
Duration of exposure to IMP is defined as: last dose date – first dose date of dupilumab + dose 
interval, regardless of unplanned intermittent discontinuations. Duration of exposure will be 
summarized using descriptive statistics such as mean, standard deviation (SD), median, minimum, 
and maximum. 
11.4.1.2 Compliance  
A given administration of IMP will be considered "noncompliant" if the patient did not take the 
planned dose of treatment as required by the protocol.  
Percentage of compliance for a patient will be defined as 100 x (the number of administrations the 
patient was compliant divided by the total number of administrations the patient was to take 
during the treatment period). 
Treatment compliance will be summarized by categories (eg, >80% compliant, 
>60-80% compliant, >40-60% compliant, <40% compliant). The percentage of patients with 
compliance <80% will be summarized. In addition, the number and percentage of patients with at 
least 1 above-planned dosing administration will be given, as well as the number and percentage 
of patients with 0, (0, 20%, and >20%) under-planned dosing administrations. In addition, overall 
compliance will be summarized descriptively (N, mean, SD, median, minimum, and maximum). 
11.4.2 Analyses of efficacy endpoints 
Not applicable. 
11.4.3 Analyses of safety data 
All safety analysis will be performed on the safety population.  
11.4.3.1 Adverse events 
Adverse events reported in this study will be coded using the version of the Medical Dictionary 
for Regulatory Activities in effect at Sanofi at the time of database lock. Adverse events occurred 
during the treatment-emergent period will be considered as TEAE. 
11.4.3.1.1 Treatment-emergent adverse events 
Incidence of TEAE and the number of TEAEs per 100 patient-years (total number of events 
adjusted for the total duration of exposure) will be presented by system organ class (SOC), 
high level group term (HLGT), and preferred term (PT) sorted in alphabetical order, the number 
and percentage (%) of patients experiencing a TEAE.  
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In the derivation of incidence of AEs, multiple occurrences of the same event in the same patient 
will be counted only once in the tables. The denominator will be based on the total number of 
patients in the safety population.  
The proportion of patients with at least one TEAE, serious TEAE, and TEAE leading to 
discontinuation of the study will be tabulated. In addition TEAEs will be described according to 
maximum intensity and relationship to the study drug. 
11.4.3.1.2  Adverse events 
An overview summary will be presented of the number (%) of patients with: 
• 
Any TEAE. 
• 
Any SAE and AEs leading to death (regardless of treatment-emergent status). 
• 
Any treatment-emergent SAEs. 
• 
Any AE leading to permanent study discontinuation. 
11.4.3.1.3 Adverse events of special interest 
The incidence of each AESI and the number of AESIs per 100 patient-years will be presented; 
AESI definitions can be found in Section 10.4.1.3. 
11.4.3.1.4 Death 
The following summaries for deaths will be presented: 
• 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death. 
• 
TEAE leading to death (death as an outcome on the AE eCRF screen as reported by the 
Investigator) by primary SOC, HLGT, and PT showing number (%) of patients. 
11.4.3.1.5 Clinical laboratory evaluations, vital signs, and physical examination findings 
Clinically significant test results will be recorded as AEs; overall AE summaries will include all 
AEs.  
11.4.4 Concomitant medications 
All concomitant medications will be summarized according to the World Health Organization 
Drug Dictionary, by anatomic class and therapeutic category using the number (%) of patients 
taking the medication. Asthma controller and reliever medication use will be summarized 
separately, in addition to all concomitant medications used. 
11.5 
INTERIM ANALYSIS 
Interim analyses of data may be conducted to support regulatory submissions or publication 
activities. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), all applicable 
laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient (and the 
parent[s] or guardian[s], if applicable) of all pertinent aspects of the clinical trial including the 
written information giving approval/favorable opinion by the ethics committee (IRB/IEC). 
All participants should be informed to the fullest extent possible about the study, in language and 
terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient, by the patient’s parent(s) or by the patient’s legally 
acceptable representative, and by the person who conducted the informed consent discussion. 
A copy of the signed and dated written ICF will be provided to the patient (for adult patients) or 
patient’s parent(s) or patient's legally accepted representative for pediatric patients. Local law 
must be observed in deciding whether 1 or both parents/guardians consent is required. If only 
1 parent or guardian signs the consent form, the Investigator must document the reason for only 
1 parent or guardian’s signature. 
In addition, participants will assent as detailed below or will follow the ethics committee 
(IRB/IEC) approved standard practice for pediatric participants at each participating center (age of 
assent to be determined by the IRB’s/IEC’s or be consistent with the local requirements): 
• 
Participants who can read the assent form will do so before writing their name and dating 
or signing and dating the form. 
• 
Participants who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• 
Participants who can understand but who can neither write nor read will have the assent 
form read to them in presence of an impartial witness, who will sign and date the assent 
form to confirm that assent was given. 
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The ICF and the assent form used by the Investigator for obtaining the Patient’s Informed Consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical, and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s curriculum vitae, etc) and the date of the 
review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the IB will be sent to the IRB/IEC 
and to health authorities (competent regulatory authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use, and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre identified source data directly recorded in the eCRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the eCRFs (eg, patient's medical file, appointment 
books, original laboratory records). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. 
The requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification, and training of 
each Investigator and Subinvestigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the IB, and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
• 
The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). 
They may be further processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio. 
• 
Patient enrollment is unsatisfactory. 
• 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• 
Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• 
The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be recollected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with 
severity: A 1-yr prospective study. Eur Respir J. 2002;19(1):61-7. 
2. Levine SJ and Wenzel SE. Narrative review: the role of Th2 immune pathway modulation in 
the treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152(4):232–7. 
3. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β 2 agonist: a randomised double-blind placebo 
controlled pivotal Phase 2b dose-ranging trial. Lancet. 2016;388(10039):31-44. 
4. Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al; SOLO 1 and 
SOLO 2 Investigators. Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis. 
N Engl J Med. 2016;375(24):2335-48.  
 
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17 
APPENDICES 
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Appendix A. 
List of prohibited live, attenuated vaccines 
• 
Bacillus Calmette-Guérin anti-TB vaccine. 
• 
Chickenpox (Varicella). 
• 
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection 
is permitted. 
• 
Measles (Rubella). 
• 
Measles-mumps-rubella combination. 
• 
Measles-mumps-rubella-varicella combination. 
• 
Mumps. 
• 
Oral polio (Sabin). 
• 
Oral typhoid. 
• 
Rotavirus. 
• 
Rubella. 
• 
Smallpox (Vaccinia). 
• 
Varicella Zoster (shingles). 
• 
Yellow fever. 
This list is indicative and not exhaustive. 
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Appendix B. 
Examples of commonly used asthma controller therapies 
Controller groups 
Medications 
CS 
Beclomethasone dipropionate CFC 
CS 
Beclomethasone dipropionate HFA 
CS 
Budesonide 
CS 
Ciclesonide 
CS 
Fluticasone propionate 
CS 
Mometasone furoate 
CS 
Triamcinolone acetonide 
CS 
Fluticasone furoate 
CS/LABA 
Fluticasone propionate/salmeterol 
CS/LABA 
Fluticasone propionate/formoterol 
CS/LABA 
Fluticasone puroate /ilanterol 
CS/LABA 
Budesonide /formoterol 
CS/LABA 
Mometasone furoate/formoterol 
CS/LABA 
Beclomethasone dipropionate/formoterol 
LABA 
Salmeterol 
LABA 
Formoterol 
LABA 
Bambuterol 
LABA 
Clenbuterol 
LABA 
Tulobuterol 
LABA 
Vilanterol 
LABA 
Olodaterol 
LABA 
ndacaterol 
LAMA 
Tiotropium 
LAMA 
Glucopyrronium bromide 
LAMA 
Aclidinium bromide 
LAMA 
Umeclidinium 
Anti-Leukotrienes 
Montelukast 
Anti-Leukotrienes 
Pranlukast 
Anti-Leukotrienes 
Zafirlukast 
Anti-Leukotrienes 
Zileuton 
Methylxanthines 
Aminophylline 
Methylxanthines 
Theophylline 
Methylxanthines 
Dyphylline 
Methylxanthines 
Oxtriphylline 
Methylxanthines 
Diprophylline 
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Controller groups 
Medications 
Methylxanthines 
Acebrophylline 
Methylxanthines 
Bamifylline 
Methylxanthines 
Doxofylline 
This list is indicative and not exhaustive. 
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Appendix C. 
Examples of CYP substrates with narrow therapeutic range 
 
CYPa enzymes 
Substrates with narrow therapeutic rangeb 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin 
CYP3Ac 
Alfentanil, astemizoled, cisaprided, cyclosporinee, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimuse, 
terfenadined 
CYP2D6 
Thioridazine 
CYP = cytochrome 
a Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm 
b CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that small changes in their 
exposure levels by the concomitant use of CYP inhibitors or inducers may lead to either serious safety concerns (eg, Torsades de Pointes) or 
loss of therapeutic effect 
c Because a number of CYP3A substrates (eg, darunavir, maraviroc) are also substrates of P-glycoprotein, the observed increase in exposure 
could be due to inhibition of both CYP3A and P-glycoprotein 
d Withdrawn from the United States market because of safety reasons 
e Prohibited medication during the study 
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Appendix E. 
List of opportunistic infections 
This list is indicative and not exhaustive. 
• 
Aspergillosis. 
• 
Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers). 
• 
Candidiasis – only systemic or extensive mucosal or cutaneous candidiasis. 
• 
Coccidioides immitis (endemic south-western US and Central and South America). 
• 
Cryptococcus. 
• 
Cytomegalovirus. 
• 
Herpes Simplex (disseminated). 
• 
Herpes Zoster (disseminated; ophthalmic; involvement of ≥2 dermatomes). 
• 
Histoplasmosis (pulmonary or disseminated; most common tropical areas 
Tennessee-Ohio-Mississippi river basins). 
• 
Listeriosis. 
• 
Mycobacterium avium. 
• 
Nontuberculosis mycobacteria. 
• 
Pneumocystis pneumonia.  
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Appendix F. 
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(2): 391-7) 
 
Clinical criteria for diagnosing anaphylaxis: 
 
 
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SAP_001.pdf: 
 
16.1.9 
Documentation of statistical methods 
Document 
Date 
Statistical Analysis Plan, Version 2.0 
15 March 2021 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ..............................................................................................................1 
TABLE OF CONTENTS.............................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN .............................................................................5 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................5 
1.2 
OBJECTIVES ..............................................................................................................................5 
Primary objectives ......................................................................................................................................5 
Secondary objectives .................................................................................................................................5 
1.3 
DETERMINATION OF SAMPLE SIZE .........................................................................................5 
1.4 
STUDY PLAN .............................................................................................................................5 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................7 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ......................7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES....................................................................8 
2.1 
ANALYSIS ENDPOINTS .............................................................................................................8 
2.1.1 
Demographic and baseline characteristics ...................................................................................8 
2.1.2 
Prior or concomitant medications .................................................................................................9 
2.1.3 
Efficacy endpoints .......................................................................................................................9 
2.1.4 
Safety endpoints .........................................................................................................................9 
2.1.4.1 
Adverse events variables ............................................................................................................9 
2.1.4.2 
Deaths ...................................................................................................................................... 10 
2.1.4.3 
Laboratory safety variables........................................................................................................ 10 
2.1.4.4 
Vital signs variables................................................................................................................... 10 
2.1.4.5 
Electrocardiogram variables ...................................................................................................... 11 
2.2 
DISPOSITION OF PATIENTS ................................................................................................... 11 
2.2.1 
Randomization and drug dispensing irregularities ...................................................................... 11 
2.3 
ANALYSIS POPULATIONS....................................................................................................... 11 
2.3.1 
Efficacy populations .................................................................................................................. 11 
2.3.2 
Safety population ...................................................................................................................... 12 
2.4 
STATISTICAL METHODS ......................................................................................................... 12 
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2.4.1 
Demographics and baseline characteristics ............................................................................... 12 
2.4.2 
Concomitant medications .......................................................................................................... 12 
2.4.3 
Extent of investigational medicinal product exposure and compliance ........................................ 12 
2.4.3.1 
Extent of investigational medicinal product exposure ................................................................. 13 
2.4.3.2 
Compliance ............................................................................................................................... 13 
2.4.4 
Analyses of efficacy endpoints................................................................................................... 13 
2.4.5 
Analyses of safety data ............................................................................................................. 14 
2.4.5.1 
Analyses of adverse events ....................................................................................................... 14 
2.4.5.2 
Deaths ...................................................................................................................................... 16 
2.4.5.3 
Analyses of laboratory variables ................................................................................................ 16 
2.4.5.4 
Analyses of physical examination and vital sign variables .......................................................... 16 
2.4.5.5 
Analyses of electrocardiogram variables .................................................................................... 16 
2.4.5.6 
Analyses of COVID-19-related variables .................................................................................... 16 
2.5 
DATA HANDLING CONVENTIONS ........................................................................................... 17 
General conventions ................................................................................................................................ 17 
2.5.1 
Data handling conventions for secondary efficacy variables ....................................................... 17 
2.5.2 
Missing data .............................................................................................................................. 17 
2.5.3 
Windows for time points ............................................................................................................ 18 
2.5.4 
Unscheduled visits .................................................................................................................... 18 
2.5.5 
Pooling of centers for statistical analyses .................................................................................. 18 
2.5.6 
Statistical technical issues ......................................................................................................... 18 
3 
INTERIM ANALYSIS ................................................................................................................ 19 
4 
DATABASE LOCK ................................................................................................................... 20 
5 
SOFTWARE DOCUMENTATION.............................................................................................. 21 
6 
REFERENCES ......................................................................................................................... 22 
7 
LIST OF APPENDICES ............................................................................................................ 23 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
eCRF: 
electronic case report form 
EOS: 
end-of-study 
EOT: 
end-of-treatment 
HLGT: 
high level group term 
ICF: 
informed consent form 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
NIMP: 
noninvestigational medicinal products 
PT: 
preferred term 
q2w: 
every 2 weeks 
SAEs: 
serious adverse events 
SD: 
standard deviation 
SOC: 
system organ class 
TEAEs: 
treatment-emergent adverse events 
WOCBP: 
women of child-bearing potential 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
The LPS15023 study is a Phase IIIb, non-randomized, open-label, interventional, outpatient, 
prospective, multinational, multicenter, noncomparative, single-arm, safety study in patients 
with moderate to severe asthma who completed the parent study, TRAVERSE-LTS12551, 
from here on referred to as TRAVERSE.  
This study will evaluate the long-term safety of dupilumab 300 mg q2w administered 
subcutaneously (SC) over a maximum of 144 weeks. 
It is expected that approximately 750 patients will enroll in this study. 
1.2 
OBJECTIVES 
Primary objectives 
The primary objective of this study is to describe the long-term safety of dupilumab in the 
treatment of patients with moderate to severe asthma who completed the previous asthma 
clinical trial, TRAVERSE-LTS12551. 
Secondary objectives 
Not applicable 
1.3 
DETERMINATION OF SAMPLE SIZE 
The objective of the study is to continue to evaluate the long-term safety and tolerability of 
dupilumab in patients with asthma who participated in the previous long-term study 
TRAVERSE. Therefore, all qualifying patients completing the treatment period in 
TRAVERSE will be offered to enroll in this study.  
It is expected that approximately 750 patients will enroll in this study. 
1.4 
STUDY PLAN 
The LPS15023 study consists of 3 periods: 
• Start-of-treatment Visit (Visit 1): After completing the EOT Visit (Visit 17) in 
TRAVERSE, eligible patients should rollover into LPS15023. 
• Treatment period (Visit 2 to Visit 12): Open-label treatment for up to 144 weeks (Visit 
13, approximately 3 years). 
• End-of-treatment/End-of-study (Visit 13). 
Patients who prematurely and/or permanently discontinue treatment will be scheduled for the 
EOT Visit, and the EOS Visit will be scheduled for 12 weeks later for follow-up on AEs. 
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After completing the treatment period in TRAVERSE, eligible patients who have signed the 
informed consent form (ICF) should perform the assessments of the Start-of-treatment Visit 
(Visit 1). Patients will receive treatment until dupilumab approval for use in asthma and 
market availability to patients, or for a maximum of 144 weeks (i.e. about 3 years) after the 
Start of treatment (Visit 1), whichever comes first. 
The end of clinical trial is defined as the “last patient last visit” planned in the protocol, i.e. 
the EOT/EOS Visit (Visit 13). The Sponsor reserves the right to discontinue the study at any 
time. 
Study Flow Chart (copied from section 1.1 of protocol) 
Study periods 
Start-of-
Treatment 
Treatment Period  
(144 weeks) 
End-of-Treatment / 
End-of-Study  
Week (W) 
W0 
W12-W132 (Visit every 12 weeks) 
W144 
 
VISIT 
V1a 
V2–V12b 
V13c 
Enrollment 
Informed consent 
X 
Patient demography 
X 
Eligibility criteria 
X 
Treatment 
Contact IRT 
X 
X 
X 
IMP dispensation/administrationd 
X 
X 
IMP accountability  
X 
X 
X 
Injection training/technique observatione 
X 
X 
Dispense home-dosing diaryf  
X 
X 
Safety 
Clinical laboratoryg 
Xh 
X  
X  
Adverse event reporting 
X 
X 
X 
Symptom-driven physical examination and vital signs 
X 
X 
X 
Concomitant medications 
X 
X 
X 
AE = adverse events; eCRF = electronic case report form; EOS = end-of-study; EOT = end-of-treatment; IMP = investigational medicinal 
product; IRT = interactive response technology; q2w = every 2 weeks; V = (study) visit; W = (study) week; WOCBP = women of child-
bearing potential. 
a After completing the EOT Visit (V17) in study TRAVERSE-LTS12551, eligible patients should perform Start-of-treatment (V1) in 
LPS15023. Additional on-site IMP administration visits may be scheduled at the Investigator’s discretion for patients who experience 
hypersensitivity reactions upon retreatment at this visit, or for patients with long off-treatment interval after the completion of study 
TRAVERSE-LTS12551. 
b Visit window is ±7 days with respect to V1, ensuring at least an 11-day interval between 2 consecutive dupilumab administrations. 
c Patients who prematurely and/or permanently discontinue treatment will be scheduled for the EOT Visit, and the EOS Visit will be 
scheduled for 12 weeks later for follow-up on AEs. 
d Dispensation of IMP at every visit (except at EOT/EOS). Administration of 300 mg q2w. Loading dose of 600 mg at V1 for patients who 
discontinued treatment for ≥6 weeks after TRAVERSE-LTS12551. For administrations coinciding with site visits, patients will be 
monitored at the study site for a minimum of 30 minutes after injections. 
e The Investigator or delegate must train the patient (or parent/caregiver[s]) at V1, if starting self-administration, on the preparation and 
injection of IMP, and review the patient’s administration technique at subsequent visits if needed.  
f 
The home-dosing diary should be dispensed at the time of injection training/technique observation. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
Demographic characteristics 
Demographic variables include: 
• Age in years 
o Continuous 
o Categorical (age <18, 18≤ age <65, 65≤ age <75, 75≤ age < 85, age ≥85 years) 
• Sex (Male, Female) 
• Weight in kilograms  
o Continuous 
o Categorical (<50, ≥50-<100, ≥100) 
• BMI in kg/m2  
o Continuous 
o Categorical (<18.5, ≥18.5-<25, ≥25-<30, ≥30) 
• Subject enrollment status after ending parent study (within 4 weeks, more than 4 
weeks) 
• Alcohol Habits 
o How often subject has a drink containing alcohol in the last 12 months? 
(Never, At least monthly, At least weekly, At least daily) 
o How many standard drinks containing alcohol subject has on a typical day 
when drinking? (1 or 2, Greater than 2) 
• Smoking History 
o Smoking Status (Never, Former) 
o Average Consumption (pack per day) – continuous 
o Number of Years Smoked (years) – continuous 
• Pregnancy Test 
o Performed (Yes, No) 
o Results (Positive, Negative) 
Medical history and disease characteristics at baseline 
Relevant medical and surgical history is collected on corresponding CRF. 
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• 
Any serious infection, any bacterial infection requiring treatment with parenteral 
antibiotics for longer than 2 weeks, any parasitic infection, any systemic opportunistic 
infection (see Protocol Appendix E), any viral infection requiring antiviral treatment, 
or any uncommon, atypical, or unusually frequent or persistent infection and TB that 
requires anti-TB medication. For details, refer to Protocol Section 10.6.3.  
Note: Candidiasis – all cases should be collected as AEs (or SAEs if requirements met), 
however, only cases which are NOT cutaneous (systemic or mucous membranes 
involved) unless involvement is extensive, will be considered as AESI.  
• 
Pregnancy (female patient or female partner): 
- 
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 Protocol Section 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be permanently 
discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
• 
Symptomatic overdose (serious or nonserious) with the IMP/NIMP. 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected 
by the Investigator or spontaneously notified by the patient and defined as at least 
twice the planned dose during an interval of less than 11 days. The circumstances 
(i.e. accidental or intentional) should be clearly specified in the verbatim and 
symptoms, if any, entered on separate AE forms.  
- 
Of note, asymptomatic overdose has to be reported as a standard AE.  
2.1.4.2 Deaths 
Deaths will be collected from the time of informed consent signature and then at each visit 
until the EOT/EOS (Visit 13). 
2.1.4.3 Laboratory safety variables 
Clinical laboratory data will be limited to hematology (blood count: erythrocytes, 
hemoglobin, hematocrit, leukocytes with differential blood count [neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils] and platelets), and pregnancy testing.  
Only clinically significant laboratory test results will be recorded as AEs in the eCRF. 
2.1.4.4 Vital signs variables 
Symptom-driven physical examination and vital signs will be performed in patients presenting 
with signs or symptoms.  
2.1.4.5 Electrocardiogram variables 
Not applicable 
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2.2 
DISPOSITION OF PATIENTS 
Enrolled patients consist of all the patients who signed informed consent and had a treatment 
kit number allocated and recorded in IRT database, and regardless of whether the treatment 
kit was used or not. 
The safety population consists of the patients who actually received at least one dose or part 
of a dose of dupilumab in the current study. 
For patient study status, the total number of patients in each of the following categories will 
be presented in the clinical study report using a flowchart diagram or summary table: 
• 
Enrolled patients 
• 
Safety population: patients who received at least one dose in the current study 
• 
Patients who did not complete the study treatment period as per protocol 
• 
Patients who permanently discontinued study treatment by main reason  
• 
Patients who did not complete study follow-up period as per protocol 
• 
Patients who discontinued study by main reason 
For all categories of patients, percentages will be calculated using the number of enrolled 
patients. Reasons for treatment and/or study discontinuations will be supplied in tables giving 
numbers and percentages. 
All critical or major deviations potentially impacting analyses, enrollment, and 
drug-dispensing irregularities, and other major or critical deviations will be listed. 
A patient is considered lost to follow-up at the end of the study if he/she is not assessed at the 
last protocol planned visit.  
2.2.1 Randomization and drug dispensing irregularities 
Not applicable 
2.3 
ANALYSIS POPULATIONS 
The enrolled population includes all enrolled patients and will be used to summarize 
demographics and baseline characteristics. 
2.3.1 Efficacy populations 
Not applicable 
2.3.2 Safety population 
The primary analysis population is the safety population, defined as all patients who have 
received at least one dose or part of a dose of dupilumab during this study. 
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The treatment-emergent period is defined as the time from the first dose of dupilumab up to 
the last dose of dupilumab plus 2 weeks for completers, or plus 12 weeks for prematurely 
discontinued subjects.  
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Parameters will be summarized on the enrolled population.   
Continuous data will be summarized using the number of available data (n), mean, standard 
deviation (SD), median, minimum, and maximum.  Categorical and ordinal data will be 
summarized using the number and percentage of patients. 
Parameters described in Section 2.1.1 will be summarized for the safety population using 
descriptive statistics. 
Relevant medical or surgical history is collected on CRFs and will be summarized. The 
alcohol habits, smoking history, and pregnancy test data at baseline will also be summarized. 
2.4.2 Concomitant medications 
A concomitant medication is any treatment received by the patient concomitantly to the IMP.  
Concomitant medications will be presented for the safety population.  
Medications will be summarized according to the WHO-DD dictionary, considering the first 
digit of the anatomic category (ATC) class (anatomic category) and the first 3 digits of the 
ATC class (therapeutic category).  All ATC codes corresponding to a medication will be 
summarized, and patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication. Therefore patients may be counted more than once for 
the same medication if it was prescribed for different indications.  
The tables for concomitant medications will be sorted by decreasing frequency of ATC 
followed by all other therapeutic classes based on overall incidence.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used.  
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized within the 
safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of exposure to IMP is defined as: last dose date – first dose date of dupilumab + 14, 
regardless of unplanned intermittent discontinuations. Duration of exposure will be 
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summarized using descriptive statistics such as mean, standard deviation (SD), median, 
minimum, and maximum. 
Duration of IMP exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum).  In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories in days: >0-4, >4-12, 
>12-24, >24-48, >48-72, >72-96, >96-120, >120-142, >142. 
2.4.3.2 Compliance 
A given administration of IMP will be considered "noncompliant" if the patient did not take 
the planned dose of treatment as required by the protocol.  
Percentage of compliance for a patient will be defined as 100 x (the number of 
administrations the patient was compliant divided by the total number of administrations the 
patient was to take during the treatment period). 
Above-planned dosing percentage for a patient will be defined as the number of 
administrations that the patient took a higher dose than planned divided by the total number of 
administrations that the patient was planned to take during the treatment epoch.  
Under-planned dosing percentage for a patient will be defined as the number of 
administrations that the patient took a lower dose than planned divided by the total number of 
administrations that the patient was planned to take during the treatment epoch.  
Note:  Percentage of compliance + above-planned dosing percentage + under-planned dosing 
percentage will be lower than or equal to 100%, depending upon the definition of compliance 
(for instance, the required quantity may be administered, but too rapidly, so that the 
administration will not be counted as compliant or above-planned dose or under-planned 
dose). 
Treatment compliance will be summarized by categories (eg, >80% compliant, >60 - 80% 
compliant, >40-60% compliant, <40% compliant). The percentage of patients with 
compliance <80% will be summarized.  
In addition, the number and percentage of patients with at least 1 above-planned dosing 
administration will be given, as well as the number and percentage of patients with 0, >0 - 
20%, and >20% under-planned dosing administrations. In addition, overall compliance will be 
summarized descriptively (N, mean, SD, median, minimum, and maximum). 
2.4.4 Analyses of efficacy endpoints 
Not applicable 
2.4.5 Analyses of safety data 
The primary and secondary analyses are safety related.  All safety analysis will be performed 
on the safety population.  
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Treatment-emergent AE is defined as any AE with onset on or after the first dose of 
dupilumab up to the last dose of dupilumab plus 14 days for completers, or plus 84 days for 
prematurely discontinued subjects.    
Primary endpoint: 
•
Incidence rates, defined as the percentage of patients reporting any treatment-emergent
adverse events (TEAEs), and event rates, defined as the number of TEAE events per
100 person-years.
Secondary endpoints: 
•
Incidence rates and event rates per 100 person-years for AESIs over the study.
•
Incidence rates for SAEs/death over the study.
•
Incidence rates for AEs leading to study discontinuation over the study.
2.4.5.1 Analyses of adverse events 
Analysis of Primary Safety Endpoint 
Incidence rates of TEAEs with corresponding 95% CI (by the Clopper-Pearson method) will 
be calculated as follows: 
•
Incidence Rate (IR) = number patients with one or more TEAEs / number of subjects
at risk (i.e. safety population) × 100
Event rates per 100 person-years of TEAEs with corresponding 95% CI (two-sided exact 
Poisson CIs) will be calculated. All events reported during the study follow-up period will be 
counted, regardless of whether they are reported in the same subject (i.e., multiple events per 
subjects), or different subjects. The person-years at follow-up will be calculated using the 
standard on-treatment duration formula: (the date of last IMP – date of first dose of IMP + 14 
days)/365.25. Note that date of first dose of IMP, is in regards to first dose of this study, not 
first dose of the parent study.  Event rate per person-years will be calculated as follows: 
•
Event rate (ER) = number of TEAEs / number of person−years at follow up
Analysis of Secondary Safety Endpoints 
Incidence rates with corresponding 95% CI (Clopper-Pearson method) and event rates with 
corresponding 95% CI (exact Poisson method) will be presented for AESIs, described in 
section 2.1.4.1, using the same methodology described above. 
Incidence rates with corresponding 95% CI (Clopper-Pearson method) will be presented for 
SAEs/death over the study. 
Incidence rates with corresponding 95% CI (Clopper-Pearson method) will be presented for 
AEs leading to study discontinuation over the study. 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events. 
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• 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for 
death. 
• 
TEAE leading to death (death as an outcome on the AE eCRF screen as reported by 
the Investigator) by primary SOC, HLGT, and PT showing number (%) of patients. 
2.4.5.3 Analyses of laboratory variables  
Continuous data will be summarized by visit using the number of available data (n), mean, 
standard deviation (SD), median, minimum, and maximum and change from baseline where 
appropriate.  Categorical and ordinal data will be summarized by visit using the number and 
percentage of patients. 
Clinically significant test results will be recorded as AEs; overall AE summaries will include 
the AEs reported in the study (see Protocol 11.4.3.1) and the clinical significant test results 
that are recorded as AEs. 
2.4.5.4 Analyses of physical examination and vital sign variables 
Symptom-driven physical examination and vital signs will be performed in patients presenting 
with signs or symptoms.  Continuous data will be summarized by visit using the number of 
available data (n), mean, standard deviation (SD), median, minimum, and maximum and 
change from baseline where appropriate.  Categorical and ordinal data will be summarized by 
visit using the number and percentage of patients. 
2.4.5.5 Analyses of electrocardiogram variables 
Not applicable 
2.4.5.6 Analyses of COVID-19-related variables 
The number and percentage of patients with impact due to COVID-19 will be summarized 
using the number of patients with at least 1 impacted site visit, the number of patients with at 
least 1 visit with different impact type (visit not done, visit partially done, visit delayed), the 
number of visit types (vital signs, local laboratory hematology, pregnancy tests, physical 
examination and follow-up, investigational product administration, and contact form), and the 
number of patients impacted per visit. Wave 3 analyses will be performed by assessment and 
visit type, and stratified by country (France, Canada, and Israel). COVID-19-related analysis 
will also include Argentina and South Africa in the final analysis. 
 
2.5 
DATA HANDLING CONVENTIONS 
General conventions 
Not applicable 
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2.5.1 Data handling conventions for secondary efficacy variables 
Not applicable 
2.5.2 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing 
data is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the 
date of last administration reported on the end-of-treatment case report form page.  If this date 
is missing, last available dose date + 11 days will be used.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date 
or time is missing or partially missing and it cannot be determined whether it was taken prior 
or concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started 
prior to treatment or after the treatment-emergent adverse event period, the adverse event will 
be classified as treatment-emergent.  No imputation of adverse event end dates/times will be 
performed.  These data imputations are for categorization purpose only and will not be used in 
listings.  No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that 
occurred on or after the day of randomization should be considered as treatment-emergent 
adverse events.  The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
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Handling of missing assessment of relationship of adverse events to investigational 
medicinal product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP is 
assumed to be possibly related in summary tables, but no imputation will be presented in the 
listings. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
2.5.3 Windows for time points 
Not applicable – no analysis by visit/window. 
2.5.4 Unscheduled visits 
Not applicable – no analysis by visit/window. 
2.5.5 Pooling of centers for statistical analyses 
Not applicable 
2.5.6 Statistical technical issues 
Not applicable 
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3 
INTERIM ANALYSIS 
Interim analyses of data may be conducted to support regulatory submissions or publication 
activities. 
 
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4 
DATABASE LOCK 
The database is planned to be locked at 4 weeks after last patient last visit. 
Additional database snapshots/soft locks may be performed to support regulatory 
submissions. 
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SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS Enterprise Guide 7.1 and 
SAS studio 3.7. 
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6 
REFERENCES 
 
Not applicable 
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Statistical Analysis Plan  
15-Mar-2021 
LPS15023 - Dupilumab  
Version number: 2.0 
Property of the Sanofi Group - strictly confident al 
Page 23 
7 
LIST OF APPENDICES 
Not applicable 
 
Sanofi
Version 1.0
24
LPS15023
03 August 2022
VV-CLIN-0634066 1.0