Clinical trial NCT02414854
Conditions: Asthma
Sponsor: Sanofi
Start date: 2015-04-27; Completion date: 2017-11-23
Enrollment: 1902 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of dupilumab (SAR231893 / REGN668) in participants with persistent asthma.

Secondary Objectives:

* To evaluate the safety and tolerability of dupilumab.
* To evaluate the effect of dupilumab on improving participant-reported outcomes including health-related quality of life.
* To evaluate dupilumab systemic exposure and incidence of anti-drug antibodies.

Detailed description:
The total duration of study period for each participant is 67 to 69 weeks, including a screening period of 3 to 5 weeks, treatment period of 52 weeks, and post-treatment follow-up period of 12 weeks.

Arms: arm 1: 2 subcutaneous injections of matched Placebo (for Dupilumab 200 mg) as a loading dose on Day 1 (Week 0), followed by a single injection every 2 weeks (q2w) from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. arm 2: 2 subcutaneous injections of Dupilumab 200 mg (for a total of 400 mg) as a loading dose on Day 1 (Week 0), followed by a single 200 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. arm 3: 2 subcutaneous injections of matched Placebo (for Dupilumab 300 mg) as a loading dose on Day 1 (Week 0), followed by a single injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. arm 4: 2 subcutaneous injections of Dupilumab 300 mg (for a total of 600 mg) as a loading dose on Day 1 (Week 0), followed by a single 300 mg injection q2w from Week 2 to Week 50 in combination with stable ICS and up to 2 other controller medicines . Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication.
Interventions: intervention 1: Dupilumab intervention 2: Placebo intervention 3: Inhaled corticosteroid (ICS) therapy intervention 4: Albuterol/Salbutamol intervention 5: Levalbuterol/Levosalbutamol
Intervention descriptions: intervention 1: Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm. intervention 2: Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm. intervention 3: Oral inhalation, stable dose (medium or high dose) of ICS in combination with up to 2 other controller medicines (second or third controller therapy) intervention 4: Oral inhalation as needed intervention 5: Oral inhalation as needed

Protocol documents:
Prot_000.pdf: 
NCT number: NCT02414854


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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 SUMMARY
COMPOUND: Dupilumab
STUDY No: EFC13579
TITLE 
A randomized, double blind, placebo-controlled, parallel group study to 
evaluate the efficacy and safety of dupilumab in patients with persistent
asthma
INVESTIGATOR/TRIAL LOCATION
Worldwide
PHASE OF DEVELOPMENT
3 
STUDY OBJECTIVE(S)
Primary Objective
x
To evaluate the efficacy of dupilumab in patients with persistent
asthma
Secondary Objective(s)
x
To evaluate the safety and tolerability of dupilumab
x
To evaluate the effect of dupilumab on improving patient reported 
outcomes (PROs) including health related quality of life (HRQoL)
x
To evaluate dupilumab systemic exposure and incidence of anti-
drug antibodies (ADA)
Exploratory Objective(s)
x
To explore the association of biomarkers with treatment response
x
To explore the association of genetic profiles with treatment 
response
x
To explore the association of vaccine response with treatment
STUDY DESIGN
General design
Multinational, multicenter, randomized, double blind, placebo-controlled, 
parallel group study assessing the effect of dupilumab administered 
subcutaneously (SC) for 52 weeks in patients with persistent asthma. 
Periods
The clinical trial consists of 3 periods:
x
Screening Period (4±1 weeks): to determine a patient’s eligibility 
status and establish level of asthma control before randomization
x
Treatment Period (52 weeks): treat with dupilumab or placebo SC 
injection     
x
Post-treatment Period (12 weeks): to monitor a patient’s status 
when off study drug treatment for patients not participating in the 
long term extension study
Screening Period
Prior to screening, patients must be on a stable background therapy of a 
medium to high dose of inhaled corticosteroid (ICS) in combination with a 
second controller medication (eg, long-acting beta agonist [LABA], leukotriene 
receptor antagonist [LTRA], methylxanthines, etc) for at least 3 months with a 
stable dose PRQWKSULRUWR9LVLW3DWLHQWVUHTXLULQJDWKLUGFRQWUROOHUDUH
allowed to participate in this study. The third controller should also be used for 
at least 3 months with a stable dose PRQWKSULRUWR9LVLW(patients 
requiring systemic steroids as controller medication or biologics are 


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excluded).
The Screening Period will be 4±1 weeks (21-35 days) in duration.
Randomized Treatment Period
Patients will be randomized to either dupilumab or matching placebo 
administered SC for a treatment duration of 52 weeks.
During the Randomized Treatment Period, patients will continue the stable 
dose(s) of controller medication used during the Screening Period. 
Patients who permanently discontinue the study medication will be asked and 
encouraged to return to the site for study visits and participate in assessments 
according to the visit schedule until the end of the study with a +/-5 day 
window (See study flowchart for patients after permanent treatment
discontinuation in Section 1.3). At the time of permanent treatment 
discontinuation, patients will perform early treatment discontinuation visit 
(ETD) with all the assessments defined for Visit 18 (EOT). Under exceptional 
circumstances when a patient cannot come to the site for the scheduled visit, 
a phone contact can be made after sponsor approval is given. During the 
phone contact, at least information about AEs, concomitant medication and 
asthma exacerbation events should be collected. In addition, patients who 
discontinue early from treatment or patients who choose not to participate in 
the open label extension (OLE) study may be asked to return to the clinic to 
have additional ADA samples collected for analysis based on the overall 
assessment of antibody titers and/or clinical presentation at the time of
discontinuation or at the time of last study visit.
Post-treatment Period
After completing the treatment period, patients will be evaluated for 12 weeks 
in the post-treatment period. During this follow-up period, patients could 
continue treatment with their stable dose of controller medication or it can be 
modified based on their level of asthma control, as determined by the 
Investigator.
During the post-treatment period, patients will continue to collect diary 
information that can be used to determine asthma control.
Eligible patients who complete the treatment period will be offered the 
opportunity to participate in the OLE study with dupilumab. Patients 
subsequently enrolled in the OLE study will not participate in the post-
treatment period of this trial.
STUDY POPULATION 
Main selection criteria
Inclusion criteria:
Adults and adolescHQWSDWLHQWVZLWKDSK\VLFLDQGLDJQRVLVRIDVWKPDIRU
months, based on the Global Initiative for Asthma (GINA) 2014 Guidelines 
and the following criteria:
A)
Existing treatment with medium to KLJKGRVH,&6PFJRI
fluticasone propionate twice daily or equipotent ICS daily dosage to 
a maximum of 2000 mcg/day of fluticasone propionate or 
equivalent) in combination with a second controller (eg, LABA, 
LTRA) for at least 3 PRQWKVZLWKDVWDEOHGRVHPRQWKSULRUWR
Visit 1.
-
Note for Japan: for subjects aged 18 years and older, ICS 
must be on PFJRIIOXWLFDVRQHSURSLRQDWHWZLFHGDLO\RU
equivalent; for subjects aged 12 to 17 years, ICS must be 
 mcg of fluticasone propionate twice daily or equivalent.


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-
Patients requiring a third controller for their asthma will be 
considered eligible for this study, and it should also be used for 
at least 3 months with a stable dose PRQWKSULRUWR9LVLW  
B)
Pre-bronchodilator forced expiratory volume (FEV1)  80% of 
predicted normal for adults and  90% of predicted normal for 
adolescents at Visits 1 and 2, prior to randomization.
C)
Asthma Control Questionnaire 5-question version (ACQ-5) score 
DW9LVLWVDQGSULRUWRUDQGRPL]DWLRQ. 
D)
Reversibility of at least 12% and 200 mL in FEV1 after the 
administration of 200 to 400 mcg albuterol/salbutamol or 
levalbuterol/levosalbutamol (2 to 4 inhalations of 
albuterol/salbutamol or levalbuterol/levosalbutamol, or of a 
nebulized solution of albuterol/salbutamol or 
levalbuterol/levosalbutamol, if considered as a standard office 
practice) before randomization.
E)
Must have experienced, within 1 year prior to Visit 1, any of the 
following events:
-
Treatment with a systemic steroid (oral or parenteral) for 
worsening asthma at least once.
-
Hospitalization or emergency medical care visit for worsening 
asthma.
Exclusion Criteria:
x
Patients <12 years of age or the minimum legal age for adolescents 
in the country of the investigative site, whichever is higher (For 
those countries where local regulations permit enrollment of adults 
only, subject recruitment will be restricted to those who are 
 years of age). 
x
Weight is less than 30 kilograms.
x
Chronic obstructive pulmonary disease (COPD) or other lung 
diseases (eg, idiopathic pulmonary fibrosis, Churg-Strauss 
Syndrome, etc) which may impair lung function.
x
A subject who experiences a severe asthma exacerbation (defined 
as a deterioration of asthma that results in emergency treatment, 
hospitalization due to asthma, or treatment with systemic steroids at
any time from 1 month prior to the Screening Visit up to and 
including the Baseline Visit).
x
Evidence of lung disease(s) other than asthma, either clinical 
evidence or imaging [eg, Chest X-ray, computed tomography (CT), 
Magnetic resonance imaging(MRI)] within 12 months of Visit 1 as 
per local standard of care.  
x
Note for Japan: According to the request from the health authority, 
chest X-ray should be performed at screening visit if there is no 
chest imaging (Chest X-ray, CT, MRI) available within 3 months 
prior to screening to exclude patients with suspected active or 
untreated latent tuberculosis.
x
Current smoker or cessation of smoking within 6 months prior to 
Visit 1.
x
Previous smoker with a smoking history >10 pack-years.
x
Comorbid disease that might interfere with the evaluation of IMP.


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Total expected number of patients
At least 1638 patients will be randomized to dupilumab or placebo with at 
least 690 patients with a baseline blood eosinophil count ıFHOOV/
(0.3 giga/L) and with approximately 84 adolescent patients. In addition, 
recruitment for patients on medium dose of ICS will be stopped at 
approximately 819 to ensure at least 50% patients are on high dose of ICS. 
In addition, in order to have additional patients treated with drug 
manufactured using the intended commercial process, approximately 220 
patients will be randomized in addition to the originally planned sample size 
(1638).
STUDY TREATMENT(s)
Investigational medicinal 
product(s) 
Formulation 
Dupilumab (SAR231893/REGN668) or matching placebo
Dupilumab: 150 mg/mL in a prefilled syringe to deliver 300 mg in 2 mL;
175 mg/mL in pre-filled syringe to deliver 200 mg in 1.14 mL 
Placebo: Prefilled syringe to deliver 2 mL and 1.14 mL respectively.
Route(s) of administration
Subcutaneous
Dose regimen
Randomized 2:2:1:1 to the following regimens:
x
dupilumab 300 mg SC q2w with a 600 mg loading dose
x
dupilumab 200 mg SC q2w with a 400 mg loading dose 
x
placebo SC q2w in pre-filled syringe to deliver 2 mL with placebo 
loading dose
x
placebo SC q2w in pre-filled syringe to deliver 1.14 mL with placebo 
loading dose
Noninvestigational medicinal 
product(s) (if applicable)
Formulation 
Inhaled corticosteroid in combination with other controllers
Screening Period
Prior to and during the Screening Period, patients must be on a stable dose of 
medium to high dose ICS in combination with a second controller medication 
(eg, LABA, LTRA, methylxanthines, etc). Patients needing a third controller 
are elligible for this study.
Randomized Treatment Period
During this period, patients will continue taking their controller medication(s)
at stable dose used during screening period.
Post-treatment Period
Upon completing the Randomized Treatment Period, patients not continuing 
with the OLE study, will continue treatment with the controller medication 
regimen and dose used during the randomized period, which could be 
adjusted based on the medical judgement of the Investigator of the 
patients‘ asthma control status.
Reliever Medication
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol 
metered dose inhaler (MDI) as reliever medication as needed during the 
study. Nebulizer solutions may be used as an alternative delivery method.


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Route(s) of administration
Oral inhalation, nebulizer: ICS, ICS combination, albuterol/salbutamol or 
levalbuterol/levosalbutamol; for other  background controllers: according to 
label
Dose regimen
ICS: medium to high dose
Albuterol/salbutamol or levalbuterol/levosalbutamol: as needed
Other background controllers: referring to label
ENDPOINT(S)
Primary Endpoints: 
x
Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period
x
Absolute change from baseline in pre-bronchodilator FEV1 at 
Week 12
Key Secondary Endpoint:
x
Percent change from baseline in pre-bronchodilator FEV1 at week 
12
Secondary Endpoint(s):
Efficacy
x
Annualized rate of severe exacerbations events during the 52-week
placebo-controlled treatment period for patients with a baseline 
blood eosinophil count JLJD/
x
Absolute change from baseline in pre-bronchodilator FEV1 at 
Week 12 in patients with a baseline blood eosinophil count 
0.3 giga/L
x
Percent change from baseline in pre-bronchodilator FEV1 at 
Week 12 in patients with a baseline blood eosinophil count 
0.3 giga/L
x
Annualized rate of severe exacerbations events during the 52-week 
placebo-controlled treatment period for patients on high dose of ICS
x
Absolute change from baseline in pre-bronchodilator FEV1 at 
Week 12 in patients on high dose of ICS
x
Percent change from baseline in pre-bronchodilator FEV1 at 
Week 12 in patients on high dose of ICS
x
Annualized rate of severe exacerbations events during the 52-week 
placebo-controlled treatment period for patients with a baseline 
EORRGHRVLQRSKLOFRXQWJiga/L 
x
Absolute change from baseline in pre-bronchodilator FEV1 at 
Week 12 in patients with a baseline blood eosinophil count 
 giga/L
x
Percent change from baseline in pre-bronchodilator FEV1 at 
Week 12 in patients with a baseline blood eosinophil count
0.15 giga/L
x
Absolute change from baseline in pre-bronchodilator FEV1 at 
Weeks 2, 4, 8, 24, 36, and 52
x
Percent change from baseline in pre-bronchodilator FEV1 at Weeks 
2, 4, 8, 24, 36, and 52
x
Change from baseline in other lung function measurements (% 
predicted FEV1, morning [AM]/evening [PM] peak expiratory flow 
[PEF], forced vital capacity [FVC], forced expiratory flow [FEF] 25-
75%, post-bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 52


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x
Annualized rate of loss of asthma control (LOAC) event during the 
52-week placebo-controlled treatment period
x
Annualized rate of severe exacerbation events resulting in 
hospitalization or emergency room visit during the 52-week 
placebo-controlled treatment period
x
Time to first severe exacerbation event 
x
Time to first loss of asthma control event (LOAC) 
x
Change from baseline in Asthma Control Questionnaire (ACQ)-5 
score and ACQ-7 score at Weeks 2, 4, 8, 12, 24, 36, and 52
x
Change from baseline at Weeks 2, 4, 8 12, 24, 36, and 52 in:
-
Morning/evening asthma symptom score and nocturnal 
awakenings (e-diary)
-
Use of daily puffs of rescue medication
x
Change from baseline in Health care resource utilization at Weeks 
12, 24, 36, and 52
x
Change from baseline in PROs at Week 12, 24, 36, and 52:
-
Asthma Quality Of Life Questionnaire with Standardized 
Activities (AQLQ (S)) Self-Administered \HDUV
-
European Quality of Life Working Group Health Status 
Measure 5 Dimensions, 5 Levels (EQ-5D-5L) 
-
Hospital Anxiety and Depression Scale (HADS)
-
22-item Sino Nasal Outcome Test (SNOT-22) in those patients 
with comorbid bilateral nasal polyposis and/or chronic 
rhinosinusitis
-
Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, 
ages 12+ (RQLQ(S)+12) in those patients with comorbid 
allergic rhinitis
Safety and tolerability
x
Adverse events (AEs) 
x
Vital signs
x
Physical examination
x
Electrocardiogram (ECG)
x
Clinical laboratory tests
Systemic drug concentration and Anti-drug antibodies
x
Serum functional dupilumab concentrations
x
ADA
Biomarkers and others
x
Fractional exhaled nitric oxide (FENO) levels
x
Blood eosinophils
x
Total and antigen-specific IgE
x
Thymus and activation-regulated chemokine (TARC)
x
Periostin
x
Eosinophil cationic protein (ECP)
x
Eotaxin-3 
x
(Optional). Blood samples for exploratory genetic analysis of DNA 
and RNA to assess the relationship of DNA variants and/or RNA 
expression with asthma and response to dupilumab treatment.
x
(Optional). Blood samples for exploratory analysis of vaccine IgG 
response during treatment.


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Criteria for asthma exacerbations during the study
Two types of asthma exacerbation events are defined:
x
A severe exacerbation event during the study is defined as a 
deterioration of asthma requiring:
-
8VHRIV\VWHPLFFRUWLFRVWHURLGVIRUGD\VRU
-
Hospitalization or emergency room visit because of asthma, 
requiring systemic corticosteroids
x
A LOAC event during the study is defined as any of the following:
-
DGGLWLRQDOUHOLHYHUSXIIVRIVDOEXWDPRODOEXWHURORU
levosalbutamol/levalbuterol in a 24-hour period (compared with 
baseline) on 2 consecutive days; 
-
GHFUHDVHLQSUH-bronchodilator FEV1 compared with 
baseline;
-
,QFUHDVHLQ,&6GRVHWLPHVWKDQWKHGRVHDW9LVLW
-
A decrease in AM or PM PEF of 30% or more on 
2 consecutive days of treatment, based on the defined stability 
limit. The Treatment Period stability limit is defined as the 
respective mean AM or PM PEF obtained over the last 7 days 
prior to Day 1(randomization).
-
Severe exacerbation event
Two events will be considered as different if the interval between their start
dates is equal or greater than 28 days.
ASSESSMENT SCHEDULE
x
Screening Period (4±1 weeks, 21-35 days) 
x
Randomized Treatment Period (52 weeks)
x
Post-treatment Period (12 weeks)
STATISTICAL CONSIDERATIONS
Sample size determination:  
The sample size calculation of this study was based on a comparison 
between dupilumab 300 mg q2w versus placebo with regard to the 2 primary 
endpoints: annualized rate of severe exacerbations during the 52-week 
treatment period and absolute change from baseline in FEV1 at Week 12. 
Assuming the number of severe exacerbations follows a negative binomial 
distribution with a dispersion parameter of 2, a placebo annualized rate of 
exacerbations being 0.6, a randomization ratio of 2:2:1:1, with 1638 
randomized patients (546 for each dupilumab dose and 273 for each 
matching placebo group), the study will have 99% power to detect a 55% 
relative risk reduction (ie, annualized rate of 0.27 for the dupilumab group) in 
the annualized rate of severe exacerbations at the 2-tailed significance level 
RIĮ $VVXPLQJSDWLHQWVZLWKDEDVHOLQHHRVLQRSKLOFRXQW
cells/μL (0.3 giga/L), approximately 690 patients (230 for dupilumab 300mg 
q2w and 115 for the matching placebo) will provide 91% power to detect a 
55% relative risk reduction for the subgroup. Assuming a common standard 
deviation of 0.5 L, 1638 patients will provide 98% power to detect a treatment 
difference of 0.15 L in the change of FEV1 from baseline at Week 12 for the 
overall population, and 690 patients will provide 88% power to detect a 
treatment difference of 0.18 L for patients with a baseline eosinophil count 
FHOOVō(0.3 giga/L). The overall study recruitment will continue until at 
least 1638 patients in total and 690 patientVZLWKHRVLQRSKLOVFHOOVμL
(0.3 giga/L) are randomized. The recruitment for patients on treatment of 
medium dose of ICS will stop when approximately 819 patients in this 
category have been randomized into the study. In addition, approximately 84 


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adolescent patients will be randomized.
Patients will be randomized using a 2:2:1:1 randomization ratio for dupilumab 
300 mg q2w, dupilumab 200 mg q2w, placebo q2w in 2 mL and placebo q2w 
in 1.14 mL. 
Randomization will be stratified by age (<18 years, \HDUV at screening, 
central eosinophil count (<300 cells/μL, FHOOVμL) at screening, ICS 
dose level (medium, high) and country.
In addition, in order to have additional patients treated with drug 
manufactured using the intended commercial process, approximately 220 
patients will be randomized in addition to the originally planned sample size 
(1638).
Analysis populations:
The primary analysis population for the efficacy endpoints will be intent-to-
treat (ITT) population defined as all randomized patients. The efficacy 
analyses will be conducted according to the treatment to which they are 
randomized.
The secondary analysis population for the efficacy endpoints will be HEos
(High Eosinophils) ITT defined as all randomized patients with baseline 
eosiQRSKLOFRXQW cells/PL 
The analysis population for the safety endpoints will be the safety population, 
defined as all patients exposed to study medication, regardless of the amount 
of treatment administered. The safety analyses will be conducted according to 
the treatment that patients actually received.
Analysis of the primary endpoints: 
The annualized rate of severe exacerbation events will be analyzed using a 
negative binomial regression model. The model will include the total number 
of events occurring during the 52 weeks as the response variable, with the 
treatment group, age, region (pooled country), baseline eosinophil strata, 
baseline ICS dose level and number of severe exacerbation events within 1 
year prior to the study as covariates. Log transformed treatment duration will 
be the offset variable. Patients who permanently discontinue the study 
medication will be asked and encouraged to return to the clinic for all 
remaining study visits and the additional off-treatment severe exacerbation 
events up to Week 52 will be included in the analysis and the last contact date 
at Week 52 will be used to calculate the offset variable. The change from 
baseline in FEV1 at Week 12 will be analyzed using a mixed-effect model with 
repeated measures (MMRM) approach. The model will include change from 
baseline FEV1 values up to Week 12 as response variables, and factors for 
treatment, age, sex, height, region (pooled country), baseline eosinophil
strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline 
FEV1 value, and baseline-by-visit interaction as covariates. An unstructured 
correlation matrix will be used to model the within-patient errors. Parameters 
will be estimated using restricted maximum likelihood method using the 
Newton-Raphson algorithm. Statistical inferences on treatment comparisons 
for the change from baseline in FEV1 at Week 12 will be derived from the 
mixed-effect model. For patients discontinuing the treatment before Week 12, 


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off study-treatment FEV1 values measured up to Week 12 will be included in 
the primary analysis. 
Subgroup analyses will be performed for the two primary endpoints using the 
same methods by baseline HRVLQRSKLOOHYHOVFHOOVȝL YVFHOOVȝL 
DQG15FHOOVȝL vs. <15FHOOVȝL). 
Multiplicity considerations 
To strongly control the type-I error rate for the primary family (2 primary 
endpoints and 2 doses), a hierarchical testing procedure will be applied at a 
2-sided 5% significant level, ie, each hypothesis will be formally tested only if 
the preceding one is significant at the 5% level. The hierarchy of the tests will 
be: 1) annualized severe exacerbation rate for 300mg q2w versus placebo, 2) 
absolute change from baseline in FEV1 at Week 12 for 300mg q2w versus 
placebo, 3) annualized severe exacerbation rate for 200mg q2w versus 
placebo and 4) absolute change from baseline in FEV1 at Week 12 for 200mg 
q2w versus placebo.
If both doses are significant for both primary endpoints, a selective set of 
secondary endpoints will be tested following a hierarchical testing procedure 
at a 2-sided 5% significant level. The first four tests will be 1) % change from 
baseline in FEV1 at Week 12 for 300 mg q2w versus placebo 2) absolute 
change from baseline in AQLQ global score at Week 12 for 300 mg q2w 
versus placebo 3) % change from baseline in FEV1 at Week 12 for 200 mg 
q2w versus placebo, 4) absolute change from baseline in AQLQ global score 
at Week 12 for 200 mg q2w versus placebo. The remaining list of secondary 
endpoints to be tested in the hierarchical order will be specified in SAP. The 
overall familywise error rate will be strongly controlled at a 2-sided 5% level 
for all tested endpoints across dose groups.
Handling of missing data
Sensitivity analyses excluding the additional off-treatment measurements will 
be performed to corroborate the primary analyses. The reason and pattern of 
missing data will be carefully examined and tipping point analyses and other 
sensitivity analyses may be performed.
Analysis of other secondary endpoints 
The annualized rate of exacerbation events, including severe exacerbation 
events resulting in hospitalization or emergency room visit and LOAC events, 
will be analyzed using the same way as for severe exacerbation events.
Time to severe exacerbation will be analyzed using a Cox regression model
with time to event as the dependent variable, and treatment, age, region 
(pooled country), baseline eosinophil strata, baseline ICS dose level and
number of asthma events prior to the study as covariates. The Kaplan-Meier 
method will be used to derive the proportion of patients with an asthma 
exacerbation event at Weeks 12, 24, 36, and 52, specific to each treatment 
group.
The change from baseline for continuous endpoints will be analyzed using a 
MMRM in the same fashion as for the endpoint of FEV1. Sex and height will 
be included as covariates only in the models for spirometry parameters. .
The safety variables, including AEs, laboratory parameters, vital signs, ECG, 
and physical examinations will be summarized using descriptive statistics.
Interim Analysis
There is no interim analysis planned for this study. 


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Planned database lock date: 
The database lock is planned based on the time when approximately 1638 
patients (originally planned sample size) complete week 52 visit or 
discontinue from the study before week 52. Analyses will be based on all data 
collected up to this database lock and will be considered as the final analyses 
in the CSR (Clinical Study Report). Additional data between database lock 
and last patient completing last visit will be summarized in a CSR addendum.
DURATION OF STUDY PERIOD (per 
patient) 
The total duration of the study (per patient) is expected to be up to 69 weeks:
x
4±1 weeks for screening
x
52 weeks of treatment
x
12 weeks of post-treatment follow-up










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Note for Japan: According to the request from the health authority, chest X-ray should be performed at screening visit if there is no chest imaging (Chest X-ray, CT, MRI) available within 3 months prior to screening 
to exclude patients with suspected active or untreated latent tuberculosis.
h
Prior to screening, patients must be on a stable background therapy of a medium to high dose of inhaled corticosteroid (ICS) in combination with a second controller medication (eg, long-acting beta agonist 
[LABA], leukotriene receptor antagonist [LTRA], methylxanthine  , etc) for at least 3 months with a stable GRVHPRQWKSULRUWR9LVLW3DWLHQWVUHTXLULQJDWKLUGFRQWUROOHUDUHDOORZHGWRSDUWLFLSDWHLQWKLVVWXG\
The tKLUGFRQWUROOHUVKRXOGDOVREHXVHGIRUDWOHDVWPRQWKVZLWKDVWDEOHGRVHPRQWKSULRUWR9LVLW (patients requiring systemic steroids as controller medication or biologics are excluded). 
i
Every 2 week (q2w) investigational product administrations must be separated by at least 11 days. The randomized Treatment Period visits occur every 2 weeks up to Week 12 and then every 4 weeks, alternating 
with q2w home administration of IMP (patient, caregiver, or health care professional) without study visit up to the end of treatment period at Week 52. After Week 12, if the patient or Investigator decides not to 
administer IMP at home, the IMP injections can be performed at the site by way of unscheduled visits. Patients will be monitored at the study site for a minimum of 30 minutes after injections in the first 12 weeks. 
j
Electronic diary/PEF meter is used for daily recording of salbutamol/albuterol or levosalbutamol/levalbuterol use, asthma controller drug use, oral steroid requirements, nocturnal awakenings due to asthma 
symptoms, morning and evening asthma symptom NRS scores and AM and PM PEF. This device is dispensed at Visit 1 and information is downloaded from this device on the other indicated days.
k
ACQ-7 is completed in the patient’s electronic diary during clinic visits. ACQ-7 (Asthma Control Questionnaire 7-question version) score will be used to follow up evaluations in all patients.  ACQ-5 (the first 5 items 
of the ACQ-7) score is used for eligibility evaluation at visit 1 and visit 2 for all patients and follow up evaluations in all patients.  
l
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast of 1 hour.
m Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius) and body weight (kg) will be measured at the screening and 
randomization visits (Visits 1 and 2) and every subsequent visit. Height (cm) will be measured only at screening (Visit 1) for adults, and be measured at the screening and randomization visits (Visits 1 and 2) and 
every subsequent visit for adolescents. Vital signs will be measured in the sitting position using the same arm at each visit, and will be measured prior to receiving investigational product at the clinic visits.
n
Serum pregnancy test at Visit 1 and urine dipstick pregnancy tests at other visits. A negative result must be obtained at Visits 1 and 2 prior to randomization.
o
Hematology: hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with five-part differential count, differential count, and total red blood cell count. Serum chemistry: creatinine, blood urea 
nitrogen, glucose, uric acid, total cholesterol, total protein, albumin, total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. Clinical laboratory testing at Visit 1 and Visit 17 
(only applicable for patients who plan to participate in the OLE study) include hepatitis screen covering hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody (HBc
Ab) including HBcAb IgM and total, hepatitis C virus antibodies (HCV Ab), Human Immunodeficiency Virus (HIV) screen (Anti-HIV-1 and HIV-2 antibodies) and anti-nuclear antibody (ANA). In case of results 
showing HBs Ag (negative), and HBc Ab total (positive), a hepatitis B virus DNA (HBV DNA) testing must be performed prior to randomization to determine eligibility. In case of results showing HCV Ab (positive), a 
HCV virus RNA (HCV RNA) testing must be performed prior to randomization to determine eligibility. Note: Anti-GV'1$DQWLERG\ZLOOEHWHVWHGLI$1$LVSRVLWLYHWLWHU The blood sample for serum 
chemistry must be taken with the patient in fasting state which means no intake of any food or drink except for water for at least 8 hours (if the visit can only be done at a different time of the day and the patient is 
not fasting, then he/she should be advised to eat light food and the site should document that serum chemistry was not obtained under fasting conditions).
p
This is only applicable for patients in Japan or other countries/regions if there is local regulatory requirement who are HBs Ag negative and HBs Ab positive at the screening visit.
q
Urine dipstick analysis including specific gravity, pH, glucose, ketones, blood protein, nitrite, leukocyte esterase, urobilinogen and bilirubin. If any assessment on the dipstick is abnormal, a urine sample should be 
sent to the central laboratory for testing.  If positive for proteins, microscopic analysis will be performed by central laboratory.
r
Systemic drug concentration and ADA samples are to be collected prior to dosing. In the event of any SAE or any AESI of anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment, or severe injection site reaction lasting longer than 24 hours, samples will be collected near the onset and resolution of the event for any additional analysis if required or for archival purposes.. See 
Section 9.3.1 for more details. 
s
Biomarker set includes Eotaxin-3, eosinophil cationic protein (ECP), total IgE, Thymus and Activation-Regulated Chemokine (TARC). Blood eosinophil count will be measured as part of hematology test. Exhaled 
nitric oxide assessment is described separately in the flowchart.
t
Archival serum in case needed for retrospective safety follow-up or additional biomarker analysis, and this is optional and a separate written consent form must be signed.
u
This is optional and a separate written consent form must be signed before sampling. For those who consented, the sample should be drawn at Week 0, before IMP administration. 
v
HADS includes Hospital Anxiety and Depression Scale- Anxiety subscale (HADS-A) and Hospital Anxiety and Depression Scale- Depression subscale. 
w For those patients with bilateral nasal polyposis and/or chronic rhinosinusitis. 
x
For those patients with comorbid allergic rhinitis. 






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i
Urine dipstick analysis including specific gravity, pH, glucose, ketones, blood protein, nitrite, leukocyte esterase, urobilinogen and bilirubin. If any assessment on the dipstick is abnormal, a urine sample should be 
sent to the central laboratory for testing.  If positive for proteins, microscopic analysis will be performed by central laboratory.
j
In the event of any SAE, or any AESI of anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment, or severe injection site reaction lasting longer than 24 hours, samples will 
be collected near the onset and resolution of the event for any additional analysis if required or for archival purposes. See Section 9.3.1 for more details. 
k
Biomarker set includes Eotaxin-3, eosinophil cationic protein (ECP), total IgE, Thymus and Activation-Regulated Chemokine (TARC). Blood eosinophil count will be measured as part of hematology test. Exhaled 
nitric oxide assessment is described separately in the flowchart.
l
Archival serum in case needed for retrospective safety follow-up or additional biomarker analysis, and this is optional and a separate written consent form must be signed.
m HADS includes Hospital Anxiety and Depression Scale- Anxiety subscale (HADS-A) and Hospital Anxiety and Depression Scale- Depression subscale. 
n
For those patients with bilateral nasal polyposis and/or chronic rhinosinusitis. 
o
For those patients with comorbid allergic rhinitis.
p
It indicates the sampling of post vaccination and if it is within 6 weeks after vaccination as applicable.


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2 
TABLE OF CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL 04 ..............................................................................................1 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART FOR PATIENTS WHO WILL COMPLETE TREATMENT .......................14 
1.3 
STUDY FLOW CHART FOR PATIENTS AFTER EARLY PERMANENT TREATMENT
DISCONTINUATION......................................................................................................................18 
2 
TABLE OF CONTENTS ................................................................................................................21 
3 
LIST OF ABBREVIATIONS ..........................................................................................................28 
4 
INTRODUCTION AND RATIONALE.............................................................................................32 
4.1 
INTRODUCTION............................................................................................................................32 
4.2 
RATIONALE...................................................................................................................................32 
4.2.1 
Population rationale .......................................................................................................................33 
4.2.2 
Design rationale .............................................................................................................................33 
4.2.3 
Endpoint rationale ..........................................................................................................................33 
4.2.4 
Rationale for dose and regimen selection .....................................................................................34 
5 
STUDY OBJECTIVES ...................................................................................................................36 
5.1 
PRIMARY.......................................................................................................................................36 
5.2 
SECONDARY ................................................................................................................................36 
5.3 
EXPLORATORY ............................................................................................................................36 
6 
STUDY DESIGN ............................................................................................................................37 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................37 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................37 
6.2.1 
Duration of study participation for each patient .............................................................................37 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................37 
6.3 
INTERIM ANALYSIS......................................................................................................................37 
6.4 
STUDY COMMITTEES..................................................................................................................37 
6.4.1 
Data monitoring committee............................................................................................................37 
6.4.2 
Executive advisory committee .......................................................................................................38 


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7 
SELECTION OF PATIENTS ..........................................................................................................39 
7.1 
INCLUSION CRITERIA..................................................................................................................39 
7.2 
EXCLUSION CRITERIA ................................................................................................................39 
7.2.1 
Exclusion criteria related to study methodology ............................................................................40 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......41 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................42 
7.2.4 
Additional exclusion criteria during or at the end of screening ......................................................43 
8 
STUDY TREATMENTS .................................................................................................................44 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................44 
8.1.1 
Dupilumab......................................................................................................................................44 
8.1.2 
Placebo ..........................................................................................................................................44 
8.1.3 
Preparation of investigational product............................................................................................44 
8.1.4 
Dosing schedule.............................................................................................................................44 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................45 
8.2.1 
Inhaled corticosteroid in combination with one or two other controllers ........................................45 
8.2.1.1 
Screening period............................................................................................................................45 
8.2.1.2 
Randomized treatment period........................................................................................................46 
8.2.1.3 
Post-treatment period ....................................................................................................................46 
8.2.2 
Reliever medication........................................................................................................................46 
8.3 
BLINDING PROCEDURES............................................................................................................48 
8.3.1 
Methods of blinding........................................................................................................................48 
8.3.2 
Randomization code breaking during the study.............................................................................48 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................49 
8.5 
PACKAGING AND LABELING ......................................................................................................49 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................50 
8.7 
RESPONSIBILITIES ......................................................................................................................50 
8.7.1 
Treatment accountability and compliance .....................................................................................50 
8.7.2 
Return and/or destruction of treatments ........................................................................................51 
8.8 
CONCOMITANT MEDICATION.....................................................................................................51 
8.8.1 
Prohibited Concomitant Medication ...............................................................................................51 
8.8.2 
Permitted concomitant medication................................................................................................. 52 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................53 
9.1 
PRIMARY ENDPOINT ...................................................................................................................53 


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9.1.1 
Primary endpoints ..........................................................................................................................53 
9.1.1.1 
Asthma exacerbation events..........................................................................................................53 
9.2 
SECONDARY ENDPOINT(S)........................................................................................................53 
9.2.1 
Efficacy endpoints..........................................................................................................................54 
9.2.1.1 
Disease-specific efficacy measures...............................................................................................55 
9.2.1.2 
Disease-specific, daily efficacy assessments................................................................................57 
9.2.1.3 
Health care resource utilization......................................................................................................59 
9.2.1.4 
Patient-reported outcomes.............................................................................................................59 
9.2.2 
Safety and tolerability endpoints....................................................................................................61 
9.2.2.1 
Adverse events ..............................................................................................................................61 
9.2.2.2 
Vital signs.......................................................................................................................................61 
9.2.2.3 
Physical examination .....................................................................................................................62 
9.2.2.4 
ECG ...............................................................................................................................................62 
9.2.2.5 
Clinical laboratory tests..................................................................................................................62 
9.2.2.6 
Hepatitis B viral load ......................................................................................................................63 
9.2.2.7 
Pregnancy test ...............................................................................................................................63 
9.3 
OTHER ENDPOINTS.....................................................................................................................63 
9.3.1 
Systemic drug concentration and anti-drug antibodies..................................................................63 
9.3.1.1 
Sampling time ................................................................................................................................63 
9.3.1.2 
Handling procedures......................................................................................................................64 
9.3.1.3 
Bioanalytic method.........................................................................................................................65 
9.3.2 
Pharmacodynamics........................................................................................................................65 
9.3.2.1 
Whole blood biomarkers ................................................................................................................66 
9.3.2.2 
Plasma biomarkers ........................................................................................................................66 
9.3.2.3 
Serum biomarkers..........................................................................................................................66 
9.3.2.4 
Exhaled nitric oxide........................................................................................................................66 
9.3.3 
Pharmacogenetics .........................................................................................................................66 
9.3.3.1 
Optional stored DNA and RNA samples........................................................................................66 
9.3.4 
Vaccine response...........................................................................................................................67 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................67 
9.5 
APPROPRIATENESS OF MEASUREMENTS..............................................................................68 
10 
STUDY PROCEDURES ................................................................................................................69 
10.1 
VISIT SCHEDULE..........................................................................................................................69 
10.1.1 
Visit 1 (Week -4 ± 1, -35 days to -21 days) ....................................................................................70 
10.1.2 
Visit 2 (Week 0, Day1) ...................................................................................................................73 
10.1.3 
Visit 3 (Week 2)..............................................................................................................................75 
10.1.4 
Visit 4 (Week 4)..............................................................................................................................76 
10.1.5 
Visit 5 (Week 6)..............................................................................................................................77 
10.1.6 
Visit 6 (Week 8)..............................................................................................................................78 


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10.1.7 
Visit 7 (Week 10)............................................................................................................................79 
10.1.8 
Visit 8 (Week 12)............................................................................................................................81 
10.1.9 
Visit 9 (Week 16)............................................................................................................................83 
10.1.10 Visit 10, 12, 13, 15, 16, 17 (Week 20, 28, 32, 40, 44, 48) .............................................................84 
10.1.11 Visit 11, 14, 18 (Week 24, 36, 52 / End-of-Treatment Visit) ..........................................................86 
10.1.12 Visit 19 and Visit 20 (Week 56 and Week 60, Post-Treatment Period).........................................88 
10.1.13 Visit 21 (Week 64, End-of-Study Visit)...........................................................................................89 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................90 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT  
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................90 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................90 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................91 
10.3.3 
List of criteria for permanent treatment discontinuation................................................................. 91 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................92 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................92 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................93 
10.4.1 
Definitions of adverse events.........................................................................................................93 
10.4.1.1 Adverse event ................................................................................................................................93 
10.4.1.2 Serious adverse event ...................................................................................................................93 
10.4.1.3 Adverse event of special interest...................................................................................................94 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................95 
10.4.3 
General guidelines for reporting adverse events...........................................................................95 
10.4.4 
Instructions for reporting serious adverse events..........................................................................97 
10.4.5 
Guidelines for management of specific laboratory abnormalities..................................................97 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................98 
10.6 
SAFETY INSTRUCTIONS.............................................................................................................98 
10.6.1 
Hypersensitivity..............................................................................................................................98 
10.6.2 
Severe injection site reactions .......................................................................................................99 
10.6.3 
Infections........................................................................................................................................99 
10.6.4 
Elevated liver function tests .........................................................................................................100 
10.7 
ADVERSE EVENTS MONITORING............................................................................................101 
11 
STATISTICAL CONSIDERATIONS............................................................................................102 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................102 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................102 


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11.3 
ANALYSIS POPULATIONS.........................................................................................................103 
11.3.1 
Efficacy populations .....................................................................................................................103 
11.3.2 
Safety population .........................................................................................................................103 
11.3.3 
Systemic drug concentration population......................................................................................103 
11.3.4 
Anti-drug antibody population ......................................................................................................103 
11.4 
STATISTICAL METHODS ...........................................................................................................104 
11.4.1 
Extent of study treatment exposure and compliance...................................................................104 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................104 
11.4.1.2 Compliance ..................................................................................................................................104 
11.4.2 
Analyses of efficacy endpoints .....................................................................................................104 
11.4.2.1 Analysis of primary efficacy endpoints.........................................................................................104 
11.4.2.2 Multiplicity considerations ............................................................................................................105 
11.4.2.3 Handling of missing data.................................................................................................................106 
11.4.2.4 Loading dose evaluation..............................................................................................................106 
11.4.3 
Analyses of safety data................................................................................................................106 
11.4.3.1 Adverse events ............................................................................................................................107 
11.4.3.2 Vaccine response.........................................................................................................................108 
11.4.4 
Analyses of systemic drug concentration, anti-drug antibodies and pharmacodynamic 
variables.......................................................................................................................................108 
11.4.4.1 Drug concentration analysis.........................................................................................................108 
11.4.4.2 Anti-drug antibodies analysis.......................................................................................................108 
11.4.4.3 Pharmacodynamics......................................................................................................................109 
11.4.5 
Analyses of Patient Reported Outcomes (Health-related Quality of Life/health  economics 
variables.......................................................................................................................................110 
11.5 
INTERIM ANALYSIS....................................................................................................................110 
12 
ETHICAL AND REGULATORY CONSIDERATIONS................................................................. 111 
12.1 
ETHICAL AND REGULATORY STANDARDS............................................................................111 
12.2 
INFORMED CONSENT ...............................................................................................................111 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ............112 
13 
STUDY MONITORING.................................................................................................................114 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................114 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................114 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................114 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL
REQUEST....................................................................................................................................115 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................115 


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14 
ADDITIONAL REQUIREMENTS ................................................................................................. 116 
14.1 
CURRICULUM VITAE..................................................................................................................116 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................116 
14.3 
CONFIDENTIALITY .....................................................................................................................116 
14.4 
PROPERTY RIGHTS...................................................................................................................117 
14.5 
DATA PROTECTION...................................................................................................................117 
14.6 
INSURANCE COMPENSATION..................................................................................................118 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................118 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT  OF 
A SITE..........................................................................................................................................118 
14.8.1 
By the Sponsor.............................................................................................................................118 
14.8.2 
By the Investigator .......................................................................................................................119 
14.9 
CLINICAL TRIAL RESULTS........................................................................................................119 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................119 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................121 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................122 
17 
APPENDICES..............................................................................................................................124 
APPENDIX A 
LIST OF PROHIBITED LIVE ATTENUATED VACCINES.................................................125 
APPENDIX B 
LOW, MEDIUM AND HIGH DOSE INHALED CORTICOSTEROIDS  ADULTS AND
$'2/(6&(176 YEARS)....................................................................................................126 
APPENDIX C 
EXAMPLES OF CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE ...........128 
APPENDIX D 
ASTHMA CONTROL QUESTIONNAIRE (ACQ)...............................................................129 
APPENDIX E 
ASTHMA SYMPTOM SCORE NUMERICAL RATING SCALE (NRS)..............................132 
APPENDIX F 
ASTHMA QUALITY OF LIFE QUESTIONNAIRE..............................................................133 
APPENDIX G 
22-ITEM SINONASAL OUTCOME TEST (SNOT-22) ......................................................139 
APPENDIX H 
HOSPITAL ANXIETY AND DEPRESSION SCALE..........................................................141 
APPENDIX I 
EUROQUAL QUESTIONNAIRE (EQ-5D-5L) .....................................................................143 
APPENDIX J 
STANDARDIZED RHINOCONJUNCTIVITIS QUALITY OF LIFE QUESTIONNAIRE  
RQLQ(S)+12 ................................................................................................................................146 


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APPENDIX K 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES  BY SANOFI ...................................................................................................151 
APPENDIX L 
VACCINATION RECORD FORM ......................................................................................156 
APPENDIX M 
DEFINITION OF ANAPHYLAXIS......................................................................................158 
APPENDIX N 
LIST OF OPPORTUNISTIC INFECTIONS .......................................................................159 
APPENDIX O 
EXAMPLES OF COMMONLY USED ASTHMA CONTROLLER THERAPIES ................160 


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3 
LIST OF ABBREVIATIONS 
ACQ-5
Asthma Control Questionnaire 5-question version
ACQ-7
Asthma Control Questionnaire 7-question version
AD
Atopic dermatitis
ADA
Anti-drug Antibodies 
AE
Adverse Event
AESI
Adverse Event of Special Interest 
ALT
Alanine Aminotransferase
ANA
Anti-nuclear Antibodies
ATS
American Thoracic Society
AQLQ(S) 
Asthma Quality Of Life Questionnaire with Standardized Activities (AQLQ 
(S)) Self-$GPLQLVWHUHG\HDUV
BCG
Bacillus Calmette-Guérin
CDMS
Clinical Data Management System 
CI
Confidence Interval
COPD
Chronic Obstructive Pulmonary Disease
CRFs
CPK
Case Report Forms 
Creatine phosphokinase
CSR
Clinical Study Report
CV
Curriculum Vitae
CV%
Coefficient of Variation
CYP
Cytochrome P450
CT
Computed Tomography
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid
DRF
Discrepancy Resolution Form
ECG
Electrocardiography 
ECP
Eosinophil Cationic Protein 
e-CRF
Electronic Case Report Form
ERS
European Respiratory Society
EQ-5D-5L
EuroQoL Working Group Health Status Measure 5 Dimensions, 5 Levels


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EOS
End-of-Study
EOT
End-of-Treatment
ETD
Early Treatment Discontinuation
FEF
Forced expiratory flow
FENO
Fractional Exhaled Nitric Oxide 
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity 
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma 
GSO
Global Safety Officer
HADS
Hospital Anxiety and Depression Scale
HADS-A
Hospital Anxiety and Depression Scale- Anxiety subscale
HADS-D 
Hospital Anxiety and Depression Scale- Depression subscale
HBc Ab
Hepatitis B Core Antibody
HBs Ab
Hepatitis B Surface Antibody
HBs Ag
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HCV Ab
Hepatitis C Virus Antibody
HEos
High Eosinophils
HLGT
High-Level Group Term 
HLT
High Level Term
HIV
Human Immunodeficiency Virus 
HRQoL
Health related quality of life 
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroid 
ID
De-identification Code
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IL-4
Interleukin 4
IL-5Į
Interleukin 4 Receptor Alpha Subunit
IL-13
Interleukin 13


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IMP
Investigational Medicinal Product
IRB/IEC
Institutional Review Board / Institutional Ethics Committee 
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System 
IUD
Intrauterine Device
IUS
Intrauterine System 
ITT
Intent-To-Treat
K-M
Kaplan-Meier
LABA
Long-Acting Beta Agonist
LAMA
Long-Acting Muscarinic Antagonist
LFT
Liver Function Test
LOAC
Loss Of Asthma Control
LTRA
Leukotriene receptor antagonist
MCID
Minimal Clinically Important Difference
MDI
Metered Dose Inhaler
MID
Minimal Important Difference
MMR
Measles, Mumps, Rubella
MMRM
Mixed-effect Model with Repeated Measures 
MMRV
Measles, Mumps, Rubella, Varicella
MRI
Magnetic Resonance Imaging
NIMP
Noninvestigational Medicinal Product
NRS                       Numerical Rating Scale
OLE
Open label extension
PCSA
Potentially Clinically Significant Abnormalities  
PD
Pharmacodynamics
PEF
Peak Expiratory Flow 
PK
Pharmacokinetics 
Pop
Population
PROs
Patient-Reported Outcomes 
PT
Preferred Term
RNA
Ribonucleic Acid
RQLQ(S)+12
Standardized Rhinoconjunctivitis Quality Of Life Questionnaire , ages 12+
SAP
Statistical Analysis Plan


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SAE
Serious Adverse Event 
SEM
Standard Error of the Mean 
SC
Subcutaneously
SD
Standard Deviation
SNOT-22
Sinonasal Outcomes Test 22-item scale
SOC
System Organ Class 
SUSAR
Suspected Unexpected Serious Adverse Reaction
TARC
Thymus and Activation-Regulated Chemokine 
TEAE
Treatment-Emergent Adverse Event
Th2
Type 2 T-helper cell
ULN
Upper Limit of Normal 
VAS
Visual Analogue Scale 
WBC
White Blood Cell 


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4 
INTRODUCTION AND RATIONALE
4.1 
INTRODUCTION
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyperresponsiveness, 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, and 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. These patients account for up to 50% of the total health cost through 
hospital admissions, use of emergency services, and unscheduled physician visits (1). 
The long term adverse effects of systemic and inhaled corticosteroids on bone metabolism, 
adrenal function, and growth in children lead to attempts to minimize the amount of corticosteroid 
usage. Additionally, the consequences of unresponsiveness to therapy or lack of compliance with 
therapy is loss of asthma control and ultimately, asthma exacerbation. 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-4 (IL-4) and interleukin-13 (IL-13) activity has been 
implicated as an important inflammatory component of asthma disease progression. Dupilumab is 
under development as a potential novel treatment for asthma. Dupilumab, a fully human 
monoclonal antibody, is directed against the IL-4 receptor alpha subunit (IL-5ĮZKLFKLVD
component of IL-4 receptors Type I and Type II, as well as the IL-13 receptor. The binding of 
dupilumab to IL-5ĮUHVXOWVLQEORFNDGHRIGRZQVWUHDPVLJQDOLQJLQLWLDWHGE\ERWK,/-4 and 
IL-13. For complete information regarding the preclinical and clinical evaluation of dupilumab to 
date, see the Investigator’s Brochure. 
4.2
RATIONALE
This is a phase 3, randomized, placebo-controlled efficacy and safety study to be conducted in 
patients with persistent asthma while on a medium to high dose ICS, in combination with a 
second controller. This study is designed to investigate the efficacy and safety profile of 
dupilumab over one year in a patients with asthma who are in need for an additional of another 
treatment added to their current management. The presence of a placebo arm is appropriate for the 
objectives of this study, since it will provide the most robust assessment of the efficacy and safety 
of dupilumab. 
The proposed study design provides the opportunity to confirm the efficacy of dupilumab on 
multiple asthma domains including lung function, prevention of severe exacerbations and 


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symptom control. The effect on lung function and symptom control will be evaluated over short 
term and long terms.  
4.2.1
Population rationale 
In this study, dupilumab will be added-on to an inhaled corticosteroid in combination with one or 
two other controller medications in patients with persistent asthma.  The population is comprised 
of patients with a physician diagnosis of DVWKPDIRUPonths, based on the Global Initiative for 
Asthma (GINA) 2014 Guidelines (3) and entry criteria described in Section 7. As described 
above, in addition to suffering the symptoms associated with a lack of asthma control, such 
patients utilize a disproportionate level of health care services, may suffer the long term adverse 
effects of systemic and inhaled corticosteroids, and ultimately, are at increased risk of a severe 
asthma exacerbation.
4.2.2
Design rationale
This study is a randomized, double blind, placebo-controlled, parallel group study. The clinical 
trial consists of three periods, using an add-on therapy approach to inhaled corticosteroid in 
combination with one or two other controller medicines: 
x
Screening Period (4±1 weeks)
x
Randomized Treatment Period (52 weeks)
x
Post-treatment Period (12 weeks)
This study has two arms of placebo with different volume, which is to match the different dose 
regimens of dupilumab 300 mg q2w and 200 mg q2w respectively. Both the patient and 
investigator will be blinded to assigned active drug or placebo, but will not be blinded to the dose 
level of  dupilumab 300 mg/matching placebo or  dupilumab 200 mg/matching placebo due to 
different volume size (2 mL vs 1.14 mL).  
4.2.3
Endpoint rationale
There are two primary endpoints for this study. One primary endpoint is the annualized rate of 
severe exacerbation events during the 52-week placebo-controlled treatment period, as this is one 
of the most clinically relevant endpoints to evaluate an asthma controller medication. The 
treatment period of 52 weeks is sufficient for assessing this type of event and avoiding the 
potential impact of seasonality. The other primary endpoint is the absolute change from baseline 
in pre-bronchodilator FEV1 at Week 12, as this is a well-accepted parameter to determine the 
effect of a drug on lung function. Safety endpoints are typical for investigational drugs at the 
current stage of clinical development.
Other endpoints including systemic drug concentration/ADA and biomarkers of drug action have 
been used previously to evaluate the exposure/effect relationship of dupilumab in asthma patients.


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4.2.4
Rationale for dose and regimen selection 
The dose regimens of subcutaneous (SC) dupilumab selected for this study are 300 mg every 
2 weeks (q2w) or 200 mg q2w. Patients randomized to 300 mg q2w will get an initial loading 
dose of 600 mg on Day 1 while patients randomized to 200 mg q2w will get an initial loading 
dose of 400 mg on Day 1, and  q2w dosing will commence 2 weeks after the loading dose. The 
administration of the loading dose of dupilumab will allow systemic concentrations to reach target 
saturation, potentially reducing the time to onset of clinical effect. 
Proof of concept has been established in the ACT11457 study at 300 mg weekly. One hundred 
and four patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at 
least 300 cells per microliter or a sputum eosinophil level of at least 3%, partially controlled or 
uncontrolled by medium-to-high doses of ICS plus LABA (fluticasone/salmeterol, 
budesonide/formoterol, or mometasone/formoterol) were randomized to the study. The study 
showed significant efficacy in a population of mostly severe asthmatics with poor asthma control 
and decreased lung function with mostly high doses of ICS in combination with a LABA.  
In the dose ranging study (DRI12544 study), 776 patients with asthma uncontrolled by medium-
to-high dose ICS plus LABA were randomized in the study. Four dose regimens (300 mg q2w 
with 600mg loading dose, 200 mg q2w with 400mg loading dose, 300mg q4w with 600 mg 
loading dose and 200mg q4w with 400 mg loading dose) were tested in the study. The results 
showed that 300 mg q2w and 200 mg q2w treatment with dupilumab provided a significant 
improvement on FEV1 at week 12 and a statistically significant reduction in the annualized rate of 
severe exacerbations when compared to placebo. Both dose regimens provided comparable 
efficacy on most of the efficacy endpoints regardless of the eosinophil count at baseline. Both 
doses were safe and well tolerated with a profile comparable to that seen with placebo except for 
an increased number of injection site reactions. To further characterize the optimal regimen for 
patients, both regimens will be assessed in the current trial.
The Pop PK model predictions demonstrated that exposure in adolescents at the highest proposed 
adult Phase 3 dose (300 mg q2w) is not expected to exceed the observed adult exposure at the
dupilumab dose regimen of 300 mg once weekly, which was observed to be generally well 
tolerated in adults. Therefore, adolescent dosing at 300 mg q2w or 200 mg q2w regimen is 
expected to yield dupilumab exposure that is expected to result in efficacious exposures and
unlikely to be associated with a heightened safety risk in this age population. 
Dupilumab has been safe and well-tolerated in all clinical trials completed to date in healthy 
volunteers and patients with Atopic dermatitis (AD) or asthma who were dosed for up to 16 weeks 
with a maximum dose of 300 mg administered every week. The phase 3 study will utilize less 
frequent dosing. No important identified risks have been established during the dupilumab clinical 
program. A low discontinuation rate has been observed across the completed clinical trials in 
dupilumab treated patients.  The reported rate of suspected unexpected serious adverse reaction
(SUSAR) has also been low. In addition, no imbalance in the frequency of TEAEs between 
patients treated with dupilumab versus placebo has been observed, with the exception of injection 
site reactions, nasopharyngitis and headache. In summary, the safety data observed so far in 
completed and currently ongoing studies in AD and asthma patients (at the same or even higher 


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doses than that proposed for this study) have demonstrated a positive benefit-risk profile for 
dupilumab in comparison to placebo. 


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5 
STUDY OBJECTIVES
5.1
PRIMARY
To evaluate the efficacy of dupilumab in patients with persistent asthma
5.2
SECONDARY
To evaluate the safety and tolerability of dupilumab 
To evaluate the effect of dupilumab on improving PROs including HRQoL 
To evaluate dupilumab systemic exposure and incidence of anti-drug antibodies  
5.3
EXPLORATORY
To explore the association of biomarkers with treatment response
To explore the association of genetic profiles with treatment response
To explore the association of vaccine response with treatment


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6 
STUDY DESIGN
6.1
DESCRIPTION OF THE PROTOCOL
This study is a multinational, multicenter, randomized, double blind, placebo-controlled, parallel 
group study assessing the effect of dupilumab administered subcutaneously (SC) for 52 weeks in 
patients with persistent asthma with a medium to high dose of ICS in combination with a second 
controller medication (a third controller is allowed).
6.2
DURATION OF STUDY PARTICIPATION
6.2.1
Duration of study participation for each patient
The clinical trial consists of three periods:
Screening Period (4±1 weeks): to determine a patient’s eligibility status and establish level of 
asthma control before randomization. 
Treatment Period (52 weeks): treat with dupilumab or placebo SC injection.     
Post-treatment Period (12 weeks): to monitor a patient’s status when off study drug treatment 
for patients not participating in the long term extension study.
6.2.2
Determination of end of clinical trial (all patients)
The last patient last visit will occur at last patient who has completed 52 weeks treatment and 
elect to enter the long term extension study or at the end of a 12-week safety follow-up period for 
those patients who complete the treatment and elect not to enter extension study as well as for 
those who permanently discontinue medication and continue for all the remaining visits. 
6.3
INTERIM ANALYSIS
Not applicable. 
6.4
STUDY COMMITTEES
6.4.1
Data monitoring committee
A data monitoring committee (DMC) is independent from sponsor and is commissioned for the 
dupilumab clinical development program. This committee is comprised of externally-based 
individuals with expertise in the diseases under study, biostatistics, or clinical research. The 
primary responsibilities of the DMC are to review and evaluate the safety data during the course 


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of the trial and make appropriate recommendations regarding the conduct of the clinical trial to 
the Sponsor. 
The DMC procedures and safety data to be reviewed by the DMC are described in the DMC 
charter. In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible 
for promptly reviewing and for taking into account in a timely manner the recommendations of 
the DMC in terms of trial continuation with or without alterations or of potential trial termination. 
6.4.2 Executive advisory committee
An executive advisory committee is commissioned for the dupilumab clinical development 
program. The executive advisory committee is made up of 5-7 key academic clinicians, with 
selection criteria including a key opinion leader in strategic regions including Japan, US, 
Europe and Latin America. These clinicians have been selected based on their publications, 
experience in conducting clinical asthma/nasal polyps studies, and their ability to both challenge 
and provide input during the protocol review process, speak to heath authority/ethics committee
for operational issues/challenges/unexpected safety issues.  Furthermore, they can speak with 
credibility to feasibility issues and impact the recruitment. These clinicians will provide 
invaluable insight and direction to ensure a successful clinical program. 


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7 
SELECTION OF PATIENTS 
7.1
INCLUSION CRITERIA
I 01.
AdXOWVDQGDGROHVFHQWSDWLHQWVZLWKDSK\VLFLDQGLDJQRVLVRIDVWKPDIRUPRQWKVEDVHG
on the Global Initiative for Asthma (GINA) 2014 Guidelines and the following criteria:
A) Existing treatment with medium to KLJKGRVH,&6PFJRIIOXWLFDVRQHSURSLRQDte 
twice daily or equipotent ICS daily dosage to a maximum of 2000 mcg/day of fluticasone 
propionate or equivalent) in combination with a second controller (eg, LABA, LTRA) for 
at least 3 PRQWKVZLWKDVWDEOHGRVHPRQWKSULRUWR9LVLW
-
Note for Japan: IRUVXEMHFWVDJHG\HDUVDQGROGHU,&6PXVWEHRQPFJRI
fluticasone propionate twice daily or equivalent; for subjects aged 12 to 17 years, ICS 
PXVWEH mcg of fluticasone propionate twice daily or equivalent. 
-
Patients requiring a third controller for their asthma will be considered eligible for this 
VWXG\DQGLWVKRXOGDOVREHXVHGIRUDWOHDVWPRQWKVZLWKDVWDEOHGRVHPRQWK
prior to Visit 1. 
B) Pre-bronchodilator forced expiratory volume (FEV1RISUHGLFWHGQRUPDOIRUDGXOWV
DQG 90% of predicted normal for adolescents at Visits 1 and 2, prior to randomization.
C) Asthma Control Questionnaire 5-question version (ACQ-5VFRUHDW9LVLWVDQG
prior to randomization. 
D) Reversibility of at least 12% and 200 mL in FEV1 after the administration of 200 to 400 
mcg albuterol/salbutamol or levalbuterol/levosalbutamol (2 to 4 inhalations of 
albuterol/salbutamol or levalbuterol/levosalbutamol, or of a nebulized solution of 
albuterol/salbutamol or levalbuterol/levosalbutamol, if considered as a standard office 
practice) before randomization.
E) Must have experienced, within 1 year prior to Visit 1, any of the following events: 
-
Treatment with a systemic steroid (oral or parenteral) for worsening asthma at least 
once. 
-
Hospitalization or emergency medical care visit for worsening asthma.
I 02.
Signed written informed consent. 
7.2
EXCLUSION CRITERIA
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections:  


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7.2.1
Exclusion criteria related to study methodology
E 01. Patients <12 years of age or the minimum legal age for adolescents in the country of the 
investigative site, whichever is higher (For those countries where local regulations permit 
HQUROOPHQWRIDGXOWVRQO\VXEMHFWUHFUXLWPHQWZLOOEHUHVWULFWHGWRWKRVHZKRDUH years 
of age). 
E 02. Weight is less than 30 kilograms. 
E 03. Chronic obstructive pulmonary disease (COPD) or other lung diseases (eg, idiopathic 
pulmonary fibrosis, Churg-Strauss Syndrome, etc) which may impair lung function. 
E 04. A subject who experiences a severe asthma exacerbation (defined as a deterioration of 
asthma that results in emergency treatment, hospitalization due to asthma, or treatment 
with systemic steroids at any time from 1 month prior to the Screening Visit up to and 
including the Baseline Visit).
E 05. Evidence of lung disease(s) other than asthma, either clinical evidence or imaging (Chest
X-ray, CT, MRI) within 12 months of Visit 1 or at the screening visit,  as per local 
standard of care. 
Note for Japan: According to the request from the health authority, chest X-ray should be 
performed at screening visit if there is no chest imaging (Chest X-ray, CT, MRI) available 
within 3 months prior to screening to exclude patients with suspected active or untreated 
latent tuberculosis.
E 06. A subject who has experienced an upper or lower respiratory tract infection within the 
4 weeks prior to Visit 1 or during the screening period.   
E 07. Current smoker or cessation of smoking within 6 months prior to Visit 1. 
E 08. Previous smoker with a smoking history >10 pack-years.
E 09. Comorbid disease that might interfere with the evaluation of IMP.
E 10. Known or suspected alcohol and/or drug abuse. 
E 11. Inability to follow the procedures of the study (eg, due to language problems or 
psychological disorders). 
E 12. Patients requiring non-selective beta-1 adrenergic receptor blockers for any reason, or 
initiation or change in dose of a selective beta-1 adrenergic receptor blocker within 1 
month prior to Visit 1 or plan to initiate or change in dose of a selective beta-1 adrenergic 
receptor blocker during the screening period or the randomized treatment period. 
E 13. Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to Visit 1 or 
any other biologic therapy/immunosuppressant to treat inflammatory disease or 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary 


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cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) as well as other diseases 
within 2 months or 5 half-lives prior to Visit 1, whichever is longer. 
E 14. Initiation of allergen immunotherapy within 3 months prior to Visit 1 or dose change from 
1 month prior to Visit 1 or a plan to begin allergen immunotherapy or to change its dose 
during the Screening Period or the Randomized Treatment Period. 
E 15. Patients on or initiation of Bronchial thermoplasty within 3 years prior to Visit 1 or plan to 
begin therapy during the Screening Period or the Randomized Treatment Period.
E 16. Exposure to another investigative antibody within a time period prior to Visit 1 that is less 
than 5 half-lives of the antibody. In case the half-life is not known, then the minimum 
interval since exposure to the prior investigative antibody is 6 months. The minimum 
interval since exposure to any other (non-antibody) investigative study medication is 
30 days prior to Visit 1.
E 17. Patients receiving medications or therapy that are prohibited as concomitant medications 
(See Section 8.8).
E 18. Patients who have previously been treated in any clinical trial of dupilumab. 
E 19. Patient is the Investigator or any Sub-Investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study. 
7.2.2
Exclusion criteria related to the active comparator and/or mandatory background 
therapies 
E 20. Non-compliance with use of the mandatory background therapy, eg, ICS/LABA 
combination, during the screening period, as defined as: 
x
<80% of total number of prescribed doses of background medication taken during the 
screening period. Compliance is verified based on background medication use recorded on 
the patient electronic diary during the screening period.
E 21. A subject with a history of clinically significant renal, hepatic, cardiovascular, metabolic, 
neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular or 
other significant medical illness or disorder which, in the judgment of the investigator, 
could interfere with the study or require treatment that might interfere with the study. 
Specific examples include but are not limited to uncontrolled diabetes, uncontrolled 
hypertension, bronchiectasis. Active tuberculosis or non-tuberculous mycobacterial 
infection, latent untreated tuberculosis or a history of incompletely treated tuberculosis will 
be excluded from the study unless it is well documented by a specialist that the patient has 
been adequately treated and can now start treatment with a biologic agent, in the medical 
judgment of the investigator and/or infectious disease specialist. Tuberculosis testing 
would be performed on a country by country basis according to local guidelines if required 
by regulatory authorities or ethic committees. Other conditions that are well controlled and 
stable will not prohibit participation if deemed appropriate per the investigator’s judgment.


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7.2.3
Exclusion criteria related to the current knowledge of Sanofi compound
E 22. Pregnant or breast-feeding women. 
E 23. Women of childbearing potential (pre-menopausal female biologically capable of 
becoming pregnant) who: 
x
Do not have a confirmed negative serum beta-hCG test at Visit 1.
x
Who are not protected by one of the following acceptable forms of effective contraception 
during the study: 
-
Established use of oral, injected, implanted or inserted hormonal contraceptive. 
-
Intrauterine device (IUD) with copper or intrauterine system (IUS) with progestogen
-
Barrier contraceptive (condom, diaphragm or cervical/vault caps) used with spermicide 
(foam, gel, film, cream or suppository), if allowed by local regulation
-
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 the study, the vasectomized male partner should be the 
sole partner for that patient
-
True abstinence in keeping with the preferred and usual lifestyle and if allowed by 
local regulation; periodic abstinence (eg calendar, ovulation, symptothermal, post-
ovulation methods) is not an acceptable method of contraception 
-
Postmenopausal women (defined as at least 12 consecutive months without menses) 
are not required to use additional contraception  
E 24. Deleted. 
E 25. Diagnosed active parasitic infection (helminthes), suspected or high risk of parasitic 
infection, unless clinical and (if necessary) laboratory assessments have ruled out active 
infection before randomization. 
E 26. History of HIV infection or positive HIV serology at Visit 1.
E 27. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, 
penumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per investigator’s judgment.  
E 28. Evidence of acute or chronic infection requiring systemic treatment with antibacterials, 
antivirals, antifungals, antiparasitics, or antiprotozoals within 4 weeks before Visit 1 or 
during the screening period, significant viral infections within 4 weeks before Visit 1 or 
during the screening period that may not have received antiviral treatment (eg, influenza 
receiving only symptomatic treatment). 


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E 29. Live attenuated vaccinations within 4 weeks prior to Visit 1 or planned live attenuated 
vaccinations during the study; see Appendix A for list of prohibited live attenuated 
vaccines. 
E 30. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary 
cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc.) or patients with high titer 
autoantibodies at screening who are suspected of having high risk for developing 
autoimmune disease at the discretion of the Investigator or the Sponsor. 
E 31. History of malignancy within 5 years before the screening visit, except completely treated 
in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous or 
basal cell carcinoma of the skin. 
E 32. Patients with a history of a systemic hypersensitivity reaction, other than localized
injection site reaction, to any biologic drug. 
E 33. Patients with any of the following result at screening: 
x
Positive (or indeterminate) HBs Ag or,  
x
Positive IgM HBc Ab or 
x
Positive total HBc Ab confirmed by positive HBV DNA or 
x
Positive HCV Ab confirmed by positive HCV RNA 
E 34. Liver injury related criteria: 
x
Clinically significant/active  hepatobiliary disease or 
x
Alanine Aminotransferase (ALT) >3 Upper Limit of Normal (ULN) 
E 35. Abnormal lab values at Screening: 
x
Creatine phosphokinase (CPK) >10 ULN or 
x
Platelets <100,000 cells/mm3 or 
x
Eosinophils >1500 cells/mm3
7.2.4
Additional exclusion criteria during or at the end of screening
E 36. Patient who has withdrawn consent before enrollment/randomization. 


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8 
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S)
8.1.1
Dupilumab
Sterile dupilumab of various concentrations will be provided in 150 mg/mL in glass pre-filled 
syringe to deliver 300 mg in 2 mL and 175 mg/mL in glass pre-filled syringe to deliver 200 mg in 
1.14 mL. 
8.1.2
Placebo
Sterile placebo for dupilumab will be provided in identically matched glass pre-filled syringe to 
deliver 2 mL or 1.14 mL, which will match dupilumab 300 mg (2 mL) and 200 mg (1.14 mL)
respectively. 
8.1.3
Preparation of investigational product
Dupilumab or matching placebo in glass pre-filled syringes will be dispensed to the patients.
8.1.4
Dosing schedule
Two injections of IMP will be administered on Day 1 at Visit 2 as a loading dose. Subsequently 
one injection of IMP will be given every 14 ± 3 days (q2w). The doses of investigational product 
PXVWEHVHSDUDWHGE\GD\VWRDYRLGDQRYHUGRVH
The Investigator or delegate will train the patient (or caregiver(s)) how to prepare and inject IMP 
at Visit 2 and will inject the first of the 2 injections. The patient (or caregiver(s)) will perform the 
second injection under the supervision of the Investigator or delegate. This training must be 
documented in the patient’s study file. At subsequent study visits, patients are trained to self-inject 
IMP, and the patients are allowed to self-inject IMP at home after 6 injections at investigational 
site, counting from Visit 3.
Patients should be instructed to avoid missing any doses of medication during the study. Any 
patient who misses one dose should be reminded to be diligent, in order to avoid further missing 
doses thereafter. In case of missed dose(s) no loading dose of 2 injections will be administered 
when restarting the treatment, whatever the number of missed doses. The patients should continue 
on their scheduled IMP treatment and visit, even if more than 2 consecutive doses are missed. 
When the patient has a study visit, the IMP will be administered following clinic procedures and 
blood collection. Patients should be monitored for at least 30 minutes after each study-site 
administered investigational product administration for any signs or symptoms of a 
hypersensitivity reaction.   


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For doses not given at the study site, diaries will be provided to record information related to the 
injections. The diary will be kept as source data in the patient’s study file.  
If the patient (or caregiver) is unable or unwilling to administer IMP, arrangements must be made 
for qualified site personnel and/or health care professionals (eg, visiting nurse service) to 
administer IMP for the doses that are not scheduled to be given at the study site.  
If the study visit is not performed at the site as scheduled, the dose will be administered by the 
patient and/or their caregiver/health care professional, or arrangements must be made for an 
unscheduled visit at the site to administer the IMP. When IMP is administered at home, the 
patients must be advised by the site staff to self-monitor for potential signs and symptoms that 
may suggest a hypersensitivity reaction for at least 30 minutes after administration.
If the patient, or caregiver(s) do not develop the comfort to inject the investigational drug at home, 
or the Investigator determines that patient (or caregiver) injection at home is not appropriate, 
injections can be performed at the site by way of unscheduled visits. 
Subcutaneous injection sites should be alternated among the 4 quadrants of the abdomen 
(avoiding navel and waist areas), the upper thighs or the upper arms, 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 trained by Investigator or Delegate) or health care professional but not the 
patient themselves. This instruction pertains to the day that the loading dose is injected as well as 
the administration of q2w injections. For each injection, the anatomic site of administration will 
be recorded in the electronic case report form (e-CRF) and, as applicable, the home diary. 
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the patient. Patients will complete a dosing diary to document compliance with self-injection (or 
caregiver) injection of IMP.
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)
8.2.1
Inhaled corticosteroid in combination with one or two other controllers
On a daily basis throughout the study, the patient uses an electronic diary to record daily use of 
ICS in combination with other controllers as used just prior to screening. The controller drugs will 
not be dispensed or supplied by the sponsor. 
The recognized asthma controllers for the study will include the following 5 classes: ICS, LABA, 
LAMA, Anti-leukotrienes and methylxanthines. Please refer to Appendix O for a list of 
commonly used asthma controller medication. 
8.2.1.1
Screening period
Prior to screening, patients must be on a stable background therapy of a medium to high dose of
ICS PFJRIIOXWLFDVRQHSURSLRQDWHWZLFHGDLO\RUHTXLSRWHQW,&6GDLO\GRVDJHWRD
maximum of 2000 mcg/day of fluticasone propionate or equivalent) [Note for Japan: subjects 


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aged 18 years and older, ICS must be PFJof fluticasone propionate twice daily or 
equivalent; subjects aged 12 to 17 years, ICS must be 100 mcg of fluticasone propionate twice 
daily or equivalent] in combination with a second controller medication (Refer to Appendix O on 
the recognized controller medication classIRUDWOHDVWPRQWKVZLWKDVWDEOHGRVHPRQWKSULRU
to Visit 1. Patients requiring a third controller are allowed to participate in this study. The third 
controller should also be used for at least 3 months with a stable dRVHPRQWKSULRUWR9LVLW
1(patients requiring systemic steroids as controller medication or biologics are excluded). If 
patients take two different ICS, the total daily dose of ICS should be calculated to evaluate the 
eligibility criteria on daily dose of ICS which will be still considered as one controller. Please 
refer to medium and high dose of ICS in Appendix B. The minimum daily dose of flucticasone 
SURSLRQDWHLVPFJPFJRIIOXWLFDVRQHSURSLRQDWe twice daily), which is equal to the 
upper limit of medium daily dose for fluticasone propionate as instructed in Appendix B. For ICS 
other than fluticasone propionate, please refer to the table in Appendix B which indicates the 
upper limit of the medium daily dose for each ICS which is equivalent to 500 mcg/day of 
fluticasone propionate.
If the Study Investigator based on his/her medical judgment, decides to optimize use of asthma 
medications prior to Visit 1 irrespective of potential participation in the study, note that changes in 
ongoing asthma medications must occur at least 1 month prior to Visit 1. The introduction of new 
controller medications must occur at least 3 months prior to Visit 1 with a stable dose for at least 1 
month prior to Visit 1.
8.2.1.2
Randomized treatment period
During this period, patients will continue to take their controller medication(s) used during the 
screening period. The dose and regimen should not be changed. Only a transient increase in dose 
of ICS in addition to other rescue medication will be allowed to treat acute symptoms of asthma 
as per investigator's guidance. This will be recorded in the eDiary.
8.2.1.3
Post-treatment period
Upon completing the randomized treatment period, patients not continuing with the open label 
extension study will proceed to be treated with the controller medication regimen and dose used 
during the randomized treatment period, which could be adjusted based on the medical judgment 
of the investigator of the patients’ asthma control status. 
8.2.2 Reliever medication
The reliever medication will not be dispensed or supplied by the sponsor. 
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol MDI as reliever 
medication as needed during the study. Nebulizer solutions may be used as an alternative delivery 
method.  
The description of the criterion for qualifying an asthma exacerbation event based on nebulizer 
using, will use the nebulizer-to-puff conversion factor for application to loss of asthma control 
(LOAC) definition. 


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Study personnel should convert salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol 
nebulizer use as shown on the following table:   
Salbutamol/Albuterol Nebulizer Solution -Total Daily Dose (mg)
Number of Puffs*
2.5 
4
5.0
8
7.5
12
10
16
*Conversion factor:  salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs
x
Example of salbutamol/albuterol Nebulizer-to-Puff Conversion: Patient received 3 
salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. Total 
daily = 7.5 mg ->12 puffs 
Levosalbutamol/Levalbuterol Nebulizer Solution  -Total Daily Dose (mg)
Number of 
Puffs*
1.25 
4
2.5
8
3.75
12
5 
16
*Conversion factor:  levosalbutamol/levalbuterol nebulizer solution (1.25 mg) corresponds to 4 puffs
x
Example of levosalbutamol/levalbuterol Nebulizer-to-Puff Conversion: Patient received 3 
levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 and 11 
AM.  Total daily = 3.75 mg ->12 puffs.
Criterion used to specify an asthma exacerbation event in eCRF based on nebulizer use:
After conversion of nebulizer-to-SXIILQHYHU\LQVWDQFHWKDWWKHQXPEHURISXIIVLVDGGLWLRQDO
puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period (compared to 
baseline) on 2 consecutive days, tick the “Qualifying criteria box” on the asthma exacerbation 
event.
All other reliever medications rather than albuterol/salbutamol or levalbuterol/levosalbutamol 
should be avoided. 


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8.3
BLINDING PROCEDURES
8.3.1
Methods of blinding
Dupilumab and placebo will be provided in identically matched 2 mL or 1.14 mL pre-filled 
syringes. To protect the blind, each treatment kit of 2 mL (dupilumab / placebo) or 1.14 mL
(dupilumab / placebo) glass pre-filled syringes will be prepared such that the treatments 
(dupilumab and its matching placebo according to its dose) are identical and indistinguishable and 
will be labeled with a treatment kit number.  The randomized treatment kit number list will be 
generated by Sanofi.     
Both the patient and investigator will be blinded to assigned active drug or placebo, but will not 
be blinded to the dose level of  dupilumab 300 mg/matching placebo or  dupilumab 
200 mg/matching placebo due to different volume size (2 mL vs 1.14 mL).  
Study patients, Investigators, and study site personnel will not have access to the randomization 
(treatment codes) except under circumstances described in Section 8.3.2. 
8.3.2
Randomization code breaking during the study
In case of an adverse event (AE), the code should only be broken in circumstances when 
knowledge of the IMP is required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the interactive voice 
response system (IVRS)/interactive web response system (IWRS) and/or by calling any other 
phone number provided by the Sponsor for that purpose.  If the blind is broken, the Investigator 
should document the date, time of day and reason for code breaking.   
Subject withdrawal will only occur when the code break call is made at the site level, not the 
study level. This means that if the Emergency Unblinding transaction is performed by the 
investigator (ie, at the site level), then the subject will be withdrawn from treatment. However, if 
the Emergency Unblinding transaction is performed by the Global Safety Officer (GSO) (ie, at the 
study level, as the GSO is not site based), then the subject will not be withdrawn from treatment.
At the facilities where the systemic drug concentration measurements, anti-drug antibodies and 
selected biomarkers are determined, the samples will be analyzed prior to data base lock leading 
to unblinding of responsible bioanalysts. Bioanalysts are excluded from the clinical trial team.
Patients, investigators and site personnel will not have access to assay results for 
immunoglobulins (IgG, IgG subclasses, IgA and IgM) after the first administration of study 
medication because these values have the potential for unblinding.  Furthermore, neither patients, 
investigators nor site personnel will have access to eotaxin-3, antigen-specific IgE, total IgE, 
Eosinophil Cationic Protein (ECP), TARC or periostin while the study is ongoing, as the related 
data are not essential for patient care and have the potential for unblinding. 


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The Data Monitoring Committee will receive blinded by treatment group or unblinded (if 
necessary) confidential reports from an independent statistician for review, which have to be 
handled 
 None of these reports can be delivered to unauthorized persons. 
8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP
A randomized treatment kit number list will be generated centrally by Sanofi. The investigational 
product (dupilumab or placebo) will be packaged in accordance with this list.
The Sanofi Clinical Supplies team will provide the randomized treatment kit number list and the 
Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system. This centralized treatment allocation system will generate the patient 
randomization list according to which it will allocate the treatments to the patients.
Patients who meet the entry criteria will be randomized to receive either dupilumab or placebo.  
Patients who meet exclusion criteria may be re-screened once during the open screening period of 
the study; a different patient identification will be issued. Re-screening is not permitted if the 
patient fails to meet inclusion criteria. There is no requirement for a waiting period between the 
screen-failure date and the re-screening date. The IVRS/IWRS report will flag re-screened 
patients. Patients that are re-screened must sign a new consent form and all Visit 1 procedures 
must be repeated.  
The Investigator obtains treatment kit numbers at randomization and subsequent scheduled visits 
via an Interactive Voice Response System/Interactive Web Response System (IVRS/IWRS) that 
will be available 24 hours a day.   
Patients will be randomized using a 2:2:1:1 randomization ratio for dupilumab 300 mg q2w, 
dupilumab 200 mg q2w, placebo q2w in 2 mL and placebo q2w in 1.14 mL. Randomization will 
EHVWUDWLILHGE\DJH\HDUV\HDUV at screening, central eosinophil count (<300 cells/μL,
300 cells/μL) at screening, ICS dose level (medium, high) and country.  
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file. A 
patient cannot be randomized more than once in the study. 
8.5
PACKAGING AND LABELING
Dupilumab and placebo will be supplied as one glass pre-filled syringe packed in a patient kit 
box.  Both glass pre-filled syringe and box will be labeled.  
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 


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8.6
STORAGE CONDITIONS AND SHELF LIFE
All investigational products should be stored at a temperature between 2°C and 8°C in an 
appropriate, locked room under the responsibility of the Investigator or other authorized persons 
(eg, pharmacists) in accordance with local regulations, policies and procedures.  
Control of investigational product storage conditions, especially control of temperature 
(eg, refrigerated storage) and information on in-use stability and instructions for handling the 
Sanofi compound should be managed according to the rules provided by the Sponsor. 
8.7
RESPONSIBILITIES
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
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 IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, to 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: 
x
Proper recording of treatment kit number as required on appropriate e-CRF page for 
accounting purposes; 
x
All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit when a treatment dispensing is planned. 
-
The completed patient injection diary (returned to the site at each visit), returned 
treatment kit boxes and any unused prefilled syringes will be used for drug 
accountability purposes. 
x
The Investigator or designee tracks treatment accountability/compliance, either by diary, 
or by counting the number of used treatment kits and fills in the appropriate page of the 
patient treatment log.


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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
All partially used or unused treatment kits will be retrieved by the Sponsor or destroyed at study 
site. All used prefilled syringes should be kept in a sharp container by the patients and be returned
to sites for destroy. The Investigator will not destroy any unused IMP unless the Sponsor provides 
written authorization.  
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 unused IMP unless the Sponsor provides written authorization. 
For non-investigational medicinal product not provided by the Sponsor, tracking and 
reconciliation has to be achieved by the Investigator and need to be captured in standard site 
documents and records (eg, medical notes). 
8.8
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s).
8.8.1
Prohibited Concomitant Medication
The following concomitant treatments are not permitted during the Screening Period or the 
Randomized Treatment Period:
x
Systemic steroids (systemic steroids can only be used to treat an asthma exacerbation, and 
are not allowed to be used for other conditions from 1 month or at least 5 half-lives prior 
to Visit 1, whichever is longer, or during the screening period or the randomized treatment 
period. Intra-articular steroids are considered as systemic steroids and are not allowed to 
be used in the above mentioned period.) 
x
Anti-immunoglobulin E (IgE) therapy (eg, omalizumab, is not allowed to be used from 
130 days prior to Visit 1, or during the screening period or the randomized treatment 
period) 
x
Biologic therapy (Biologic therapy is not allowed to be used from 2 months or at least 5 
half-lives prior to Visit 1, whichever is longer, or during the screening period or the 
randomized treatment period).
x
Systemic immunosuppressant (immunosuppressants are not allowed to be used from 2 
months or at least 5 half-lives prior to Visit 1, whichever is longer, or during the screening 
period or the randomized treatment period) 
x
Allergen immunotherapy (except if initiated more than 3 months prior to Visit 1 and dose 
stabled 1 month prior to Visit 1) 
x
Bronchial thermoplasty


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x
Intravenous immunoglobulin (IVIG) therapy 
x
Live Attenuated Vaccines:  refer to Appendix A
x
Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor 
blocker used with dose stabled 1 month prior to Visit 1)
x
Asthma relievers other than salbutamol/albuterol or levosalbutamol/levalbuterol: their use 
is not recommended during the study period. In case of use in exceptional circumstances 
(eg, prescribed by a physician not participating in the study), their use will be documented 
in the patient's file and reported in the eCRF. 
x
Other investigational drugs
8.8.2  Permitted concomitant medication
x
Antihistamines are permitted as concomitant medication.
x
Topical, ocular or intranasal corticosteroids are permitted during the study.
CYP substrates:
The impact of dupilumab on cytochrome P450 (CYP) enzyme activity has not been studied and 
the effect of dupilumab on levels of IL-4 and IL-13 has not been fully characterized. However, 
interleukin-4 (IL-4) was reported to upregulate CYP2E1, 2B6, 3A4 mRNA expression or 
downregulate CYP1A2 mRNA (4), (5). Human peripheral blood mononuclear cells (PBMC) 
incubated with various Th2 cytokines showed that IL-4 and IL-13 increased mRNA expression of 
CYP2B6 and CYP3A4 (6).  Since the clinical significance of the limited in vitro findings for IL-4 
and IL-13 involvement in CYP regulation and the impact of dupilumab on CYP enzymes is not 
fully understood, during the study treatment and at least up to the end of follow-up, caution should 
be used for drugs which are metabolized via these CYP isoforms and which have a narrow 
therapeutic index.  This means that close clinical observation and/or laboratory monitoring as 
applicable are required in order to enable early detection of toxic manifestations or lack of 
activity/efficacy of these drugs, followed by dose adjustment or their withdrawal if needed (4), (5),
(6). 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 endpoints  
There are two primary endpoints for this study, the annualized rate of severe exacerbation events 
during the 52-week placebo-controlled treatment period and the absolute change from baseline in
pre-bronchodilator FEV1 at week 12.
9.1.1.1
Asthma exacerbation events
Two types of asthma exacerbation events are defined:
A severe exacerbation event during the study is defined as a deterioration of asthma requiring: 
x
8VHRIV\VWHPLFFRUWLFRVWHURLGVIRUGD\V; or 
x
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids 
A loss of asthma control (LOAC) event during the study is defined as any of the following: 
x
DGGLWLRQDOUHOLHYHUSXIIVRIVDOEXWDPRODOEXWHURORUOHYRVDOEXWamol/levalbuterol in a 
24 hour period (compared to baseline) on 2 consecutive days;  
x
 decrease in pre-bronchodilator FEV1 compared with baseline;  
x
,QFUHDVHLQ,&6GRVHWLPHVWKDQWKHGRVHDW9LVLW; 
x
A decrease in AM or PM peak flow of 30% or more on 2 consecutive days of treatment, 
based on the defined stability limit. The Treatment Period stability limit is defined as the 
respective mean AM or PM PEF obtained over the last 7 days prior to randomization
(Day1);
x
Severe exacerbation event 
Two events will be considered as different if the interval between their start dates is equal or 
greater than 28 days. 
The reasons (ex, infections including viral and bacterial, allergen exposure, exercise and others) of 
the exacerbation events will be collected in eCRF.
9.2
SECONDARY ENDPOINT(S) 
Key secondary Endpoints:
x
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 


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9.2.1
Efficacy endpoints
x
Annualized rate of severe exacerbations events during the 52-week placebo-controlled 
treatment period for patients with a baseline blood eosinophil count JLJD/
x
Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline EORRGHRVLQRSKLOFRXQW0.3 giga/L 
x
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline blood eosinophil cRXQW0.3 giga/L 
x
Annualized rate of severe exacerbations events during the 52-week placebo-controlled 
treatment period for patients on high dose of ICS 
x
Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in patients on high 
dose of ICS 
x
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 in patients on high 
dose of ICS 
x
Annualized rate of severe exacerbations events during the 52-week placebo-controlled 
WUHDWPHQWSHULRGIRUSDWLHQWVZLWKDEDVHOLQHEORRGHRVLQRSKLOFRXQWJiga/L 
x
Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
EDVHOLQHEORRGHRVLQRSKLOFRXQWJLJD/
x
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline blood eosinophil count 0.15 giga/L 
x
Absolute change from baseline in pre-bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 
52
x
Percent change from baseline in pre-bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52 
x
Change from baseline in other lung function measurements (% predicted FEV1, morning 
[AM]/evening [PM] peak expiratory flow [PEF], forced vital capacity [FVC], forced 
expiratory flow [FEF]25-75%, post-bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 
52
x
Annualized rate of loss of asthma control (LOAC) event during the 52-week placebo-
controlled treatment period 
x
Annualized rate of severe exacerbation events resulting in hospitalization or emergency 
room visit during the 52-week placebo-controlled treatment period
x
Time to first severe exacerbation event 
x
Time to first loss of asthma control event (LOAC) 
x
Change from baseline in Asthma Control Questionnaire (ACQ)-5 score and ACQ-7 score 
at Weeks 2, 4, 8, 12, 24, 36, and 52 
x
Change from baseline at Weeks 2, 4, 8 12, 24, 36, and 52 in: 
-
Morning/evening asthma symptom score and nocturnal awakenings (e-diary) 
-
Use of daily puffs of rescue medication
x
Change from baseline in Health care resource utilization at Weeks 12, 24, 36, and 52. 
x
Change from baseline in PROs at Week 12, 24, 36, and 52: 


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-
Asthma Quality Of Life Questionnaire with Standardized Activities (AQLQ (S)) Self-
Administered \HDUV
-
European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 
Levels (EQ-5D-5L) 
-
Hospital Anxiety and Depression Scale (HADS) 
-
22-item Sino Nasal Outcome Test (SNOT-22) in those patients with comorbid bilateral 
nasal polyposis and/or chronic rhinosinusitis 
-
Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, ages 12+ 
(RQLQ(S)+12) in those patients with comorbid allergic rhinitis
9.2.1.1
Disease-specific efficacy measures 
9.2.1.1.1 Spirometry 
A spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory 
Society (ERS) recommendations will be used. Spirometry should be performed in accordance 
with the ATS/ ERS guidelines (7). For pre-bronchodilator measured parameters, including FEV1,
PEF, FVC and FEF 25-75%, spirometry will be performed after a wash out period of 
bronchodilators according to their action duration, for example, withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding the last 
dose of LABA for at least 12 hours (ultra-long acting LABA like vilanterol should be withheld for 
at least 24 hours) and withholding the last dose of LAMA for at least 24 hours. This will be 
verified before performing the measurements.
For post-bronchodilator FEV1, the measure should follow the steps as that at screening test for 
reversibility validation. 
At all visits, spirometry should be performed in the morning if possible, but if it could only be 
done at a different time of the day, the spirometry should be done at approximately the same time 
of the day at each visit throughout the study. The same spirometer and standard spirometric 
techniques, including calibration, will be used to perform spirometry at all visits and, whenever 
possible, the same person should perform the measurements.  
Pulmonary function tests will be measured in the sitting position; however, if necessary to 
undertake the testing with the subject standing or in another position, this should be noted on the 
spirometry report. For any subject, the position should be consistent throughout the study. 
Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained 
at every visit, if possible. The acceptability criteria must be applied before the repeatability 
criteria. Unacceptable maneuvers must be discarded before applying the repeatability criteria. If a 
subject fails to provide repeatable and/or acceptable maneuvers, an explanation should be 
recorded.  
The largest FEV1 and largest FVC should be recorded after the data are examined from all of the 
acceptable curves, even if they do not come from the same curve. The FEF 25-75% should be 


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obtained from the single curve that meets the acceptability criteria and gives the largest sum of 
FVC plus FEV1 (best test).
Automated best efforts, which combine FEV1 and FVC are not acceptable.
The spirometer must be calibrated following the principles of the ATS/ERS guidelines every day
that a study subject is seen and spirometry is carried out. The calibration records should be kept in 
a reviewable log. It is preferred that the calibration equipment (ie, 3-liter syringe) that is used to 
calibrate the spirometer be subjected to a validated calibration according to the manufacturer’s 
specifications.
Spirometry will be performed centrally and all recordings will be centrally read by independent 
experts. Further details on spirometry will be available in a separate operational manual provided
to the sites.
9.2.1.1.2 Reversibility/Post-bronchodilator FEV1
A reversibility test will be administered following pulmonary function testing after asthma 
medications have been withheld for the appropriate intervals. Subjects will receive two to up to 
four puffs of albuterol/salbutamol or levalbuterol/levosalbutamol from a primed MDI. 
Alternatively and only if it is consistent with usual office practice (to be documented), 
reversibility may be performed using inhalation of nebulized albuterol/salbutamol or 
levalbuterol/levosalbutamol. Spirometry may be repeated several times within 30 minutes after 
administration of bronchodilator. Reversibility, which is defined as an increase in absolute FEV1
of 12% over the baseline value, with an absolute increase of at least 200 mL, must be 
demonstrated within 30 minutes of bronchodilator administration. If the subject does not meet the 
reversibility at Visit 1, up to 3 assessments can be performed at any time during the screening 
period until the Baseline Visit (Visit 2).Whenever the reversibility was repeated, the pre-
bronchodilator FEV1 should again meet the inclusion criteria of  of predicted normal for 
DGXOWVDQG% of predicted normal for adolescents. 
For post-bronchodilator FEV1, the measure should follow the steps as that at screening test for 
reversibility validation. If other attempt for reversibility test was performed at Baseline visit, then 
the post-bronchodilator FEV1 will come from the result of this reversibility test.
9.2.1.1.3 ACQ (Asthma Control Questionnaire)
The ACQ was designed to measure both the adequacy of asthma control and change in asthma
control which occurs either spontaneously or as a result of treatment. 
9.2.1.1.3.1 ACQ-7 (Asthma Control Questionnaire, 7-question version)
The ACQ-7 has 7 questions- the first 5 items assess the most common asthma symptoms: 
1. frequency in past week awoken by asthma during the night, 2. severity of asthma symptoms in 
the morning, 3. limitation of daily activities due to asthma, 4. shortness of breath due to asthma 
and 5. wheeze, plus 6. short-acting bronchodilator use and 7. FEV1 (pre-bronchodilator use, % 


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and % predicted use). Patients are asked to recall how their asthma has been during the previous 
week and to respond to the symptom questions on a 7-point scale (0=no impairment, 6= 
maximum impairment) (see Appendix D).
Clinic staff scores the FEV1% predicted on a 7-point scale. The questions are equally weighted 
and the ACQ score is the mean of the 7 questions and therefore between 0 (totally controlled) and 
6 (severely uncontrolled).
A global score is calculated: the questions are equally weighted and the ACQ-7 score is the mean 
of the 7 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). 
Higher score indicates lower asthma control. Patients with a score below 1.0 reflect adequately 
controlled asthma and patients with scores above 1.0 reflect inadequately controlled asthma. On 
the 7-point scale of the ACQ-7, a change or difference in score of 0.5 is the smallest change that 
can be considered clinically important, corresponding to the Minimal Clinically Important 
Difference (MCID) defined by the developer.
Measurement properties such as reliability and ability to detect change have been documented in 
the literature (8). 
The ACQ-7 questionnaire will be put into eDiary to be completed by all patients regardless of 
adults or adolescents. Patients should complete ACQ-7 before spirometry test.
9.2.1.1.3.2 ACQ-5 (Asthma Control Questionnaire, 5-question version)
The ACQ-5 is short version of ACQ-7, and ACQ-5 score is the mean of the first 5 questions and, 
therefore, between 0 (totally controlled) and 6 (severely uncontrolled). Higher score indicates 
lower asthma control. Patients with a score below 1.0 reflect adequately controlled asthma and 
patients with scores above 1.0 reflect inadequately controlled asthma. On the 7-point scale of the 
ACQ-5, a change or difference in score of 0.5 is the smallest change that can be considered 
clinically important, corresponding to the Minimal Clinically Important Difference (MCID) 
defined by the developer. 
Measurement properties such as reliability and ability to detect change have been documented in 
the literature (9). 
9.2.1.2
Disease-specific, daily efficacy assessments
9.2.1.2.1 Electronic diary/ PEF meter  
On a daily basis throughout the study, the patient uses an electronic diary / PEF meter to:
x
Measure morning and evening PEF 
x
Respond to the morning and evening asthma symptom scale questions 
x
Indicate the number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief
x
Record the number of inhalations/day of background product used 


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x
Record the number of nocturnal awakenings due to asthma symptoms 
x
Record oral steroids use for exacerbation event 
At screening (Visit 1), patients will be issued an electronic diary/PEF. Patients will be instructed 
on the use of the device, and written instructions on the use of the electronic PEF meter will be 
provided to the patients. In addition, the investigator will instruct the patients on how to record the 
following variables in the electronic PEF meter: 
x
AM PEF performed within 15 minutes after arising (between 5:30 AM and 12:00 PM) prior 
to taking any albuterol/salbutamol or levalbuterol/levosalbutamol 
x
PM PEF performed in the evening (between 5:30 PM and 12 AM) prior to taking any 
albuterol/salbutamol or levalbuterol/levosalbutamol  
x
Patients should try to withhold albuterol/salbutamol or levalbuterol/levosalbutamol for at 
least 6 hours prior to measuring their PEF 
x
Three PEF efforts will be performed by the patient; all 3 values will be recorded by the 
electronic PEF meter, and the highest value will be used for evaluation 
Baseline AM PEF will be the mean AM measurement recorded for the 7 days prior to the first 
dose of investigational product, and baseline PM PEF will be the mean PM measurement recorded 
for the 7 days prior to the first dose of investigational product. Period stability limit is defined as 
the respective mean AM or PM PEF obtained over the last 7 days prior to Day1. There should be 
at least 4 days’ measurement for setting up the stability limit, and the first dosing visit should be 
rescheduled until data for 4 days are available. 
Information derived from the electronic PEF meter will be evaluated by the Investigator at study 
visits.   
9.2.1.2.2 Asthma Symptom Score Numerical Rating Scale (NRS)
Patients will record overall symptom scores in an electronic diary/PEF meter twice a day prior to 
measuring PEF. The patient’s overall asthma symptoms experienced during the waking hours will 
be recorded in the evening (PM symptom score). Baseline symptom scores will be the mean AM 
and mean PM scores recorded for the 7 days prior to randomization. The baseline AM/PM 
symptom score will be computed following the same algorithm used for baseline AM/PM PEF. 
Scores range between 0-4 with 0 indicating more mild symptoms and 4 indicating more severe 
symptoms. There is no global score, just an AM score and a PM score. An MCID of 0.35 is being 
used (10) (see Appendix E). 
9.2.1.2.3 Use of rescue medicine
The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations will be recorded 
daily by the patients in an electronic diary/PEF meter. Each patient should be reminded that 
salbutamol/albuterol or levosalbutamol/levalbuterol should be used only as needed for symptoms, 
not on a regular basis or prophylactically. The baseline number of salbutamol/albuterol or 


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levosalbutamol/levalbuterol inhalations/day will be based on the mean of the 7 days prior to 
randomization.  
9.2.1.3
Health care resource utilization
A questionnaire of health care resource utilization (reliever medication, specialist visit, 
hospitalization, emergency or urgent medical care facility visit, outcome, sick leaves, school days’ 
loss, etc) will be administered at Visit 2 and every 4 weeks thereafter. 
9.2.1.4
Patient-reported outcomes
Patients should complete the following PROs before spirometry test. 
9.2.1.4.1 Asthma Quality of Life Questionnaire (AQLQ (S)
The AQLQ (S) was designed as a self-administered patient reported outcome to measure the 
functional impairments that are most troublesome to patients as a result of their asthma (see
Appendix F). The instrument is comprised of 32 items, each rated on a 7-point Likert scales from 
1 to 7. The AQLQ(S) has 4 domains. The domains and the number of items in each domain are as 
follows: 
x
Symptoms (12 items)
x
Activity limitation (11 items)
x
Emotional function (5 items) 
x
Environmental Stimuli (4 items) 
A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate 
better quality of life.
The instrument has been used in many clinical trials, and it has been shown to be reliable, valid 
(patient interviews), and sensitive to change. The MCID for AQLQ(S) is 0.5 (11). 
9.2.1.4.2 22-item Sinonasal Outcome Test in those patients comorbid with bilateral nasal 
polyposis and/or chronic rhinosinusitis
SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis on health-
related quality of life (see Appendix G). The SNOT-22 has 22 items, 5 domains and a global 
score. The 5 domains include Nasal (range 0-30) with MID of -2.5, Ear (range 0-15) with MID of 
-1.25, Sleep (0-20) with MID of -1.67, General and Practical (0-30) with MID of -2.50, and 
Emotional (0-15) with MID of -1.25. The range of the global score is 0-110 and an MID (the 
smallest difference between clinical trial arms mean change from baseline [point estimates] that 
will be interpreted as important) of 8.9 (12). Lower scores indicate less impact and the recall 
period is past 2 weeks. 


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9.2.1.4.3 Hospital Anxiety and Depression Scale
The HADS is a general scale to detect states of anxiety and depression already used and validated 
in asthma, which includes HADS-A and HADS-D subscales (see Appendix H). The instrument is 
comprised of 14 items: 7 related to anxiety and 7 to depression. Each item on the questionnaire is 
scored from 0-3; one can score between 0 and 21 for either anxiety or depression. 
The HADS was found to perform well in assessing anxiety disorders and depression in both 
somatic and psychiatric cases and (not only in hospital practice for which it was first designed) in 
primary care patients and the general population (13). The MID for the HADS-A (anxiety) has 
been reported to be in the range of 0.41 (anxious and depressed subjects in active treatment 
controlled studies) to 1.32 (COPD patients), in the range of 0.50 (anxious and depressed subjects 
in active treatment controlled studies) to 1.40 (COPD patients) for HADS-D (depression) and 
approximately 1.5 (COPD patients) for the HADS Total score (14, 15) 
Alternatively, a significant improvement in treatment versus placebo group was defined as the %
of subjects who moved from a defined category of moderate to severe dHSUHVVLRQRUDQ[LHW\WR
not having the disease (<8) (16). Using this methodology Stelara (Ustekinumab) was able to make 
the claim in summary of product characteristics that “HADS was significantly improved in the 
treatment group compared with placebo” (17).
9.2.1.4.4 EQ-5D-5L 
EQ-5D-5L is a standardized health-related quality of life questionnaire developed by the EuroQol 
Group in order to provide a simple, generic measure of health for clinical and economic appraisal 
(18). EQ-5D is designed for self-completion by patients. 
The EQ-5D essentially consists of 2 pages – the EQ-5D descriptive system and the EQ VAS (see
Appendix I). The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. The EQ Visual 
Analogue Scale (VAS) records the respondent’s self-rated health on a vertical visual analogue 
scale. The EQ VAS ‘thermometer’ has endpoints of 100 (Best imaginable health state) at the top 
and 0 (Worst imaginable health state) at the bottom. The MCID for the EQ-5D in asthma patients 
has been reported to be in the range of .001 to 0.074 (19, 20)  
9.2.1.4.5 Standardized Rhinoconjunctivitis Quality Of Life Questionnaire (RQLQ(S))+12 in those 
patients with comorbid allergic rhinitis. 
RQLQ(S)+12 (see Appendix J) is a self-administered questionnaire with standardized activities 
developed to measure health-related quality of life signs and symptoms that are most problematic 
in those 12 to 75 years of age, as a result of perennial or seasonal allergic rhinitis. There are 28 
items on the RQLQ(S) in 7 domains: 1. Activities (3 items), 2. Sleep (3 items), 3. Non-Hay Fever 
Symptoms (7 items), 4. Practical Problems (3 items), 5. Nasal Symptoms (4 items), 5. Eye 
Symptoms (4 items) and 7. Emotional (4 items). The RQLQ(S)+12 responses are based on 7-point 
Likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). Higher scores 
indicated more health-related quality of life impairment (lower scores better). The instrument 


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takes approximately 7 minutes to complete. An MID of 0.5 has been established as the minimal 
important difference indicative of a clinically meaningful change (21).
9.2.2
Safety and tolerability endpoints
The same safety assessments will be applied across all arms.  Adverse events, including serious 
adverse events (SAEs) and adverse events of special interest (AESI), will be collected at every 
visit. The Investigator will ask the patient how he/she has felt since the last study visit. The study 
specific and general safety criteria are detailed in Section 10.4.1. To assure the continuing safety 
of patients in this study, an independent DMC will be responsible for reviewing the safety data on 
a periodic basis throughout the course of the study as outlined in Section 6.4.
Safety observations 
x
The Investigator should take all appropriate measures to ensure the safety of the patients. 
Notably, he/she should follow up the outcome of SAEs /AESI until clinical recovery is 
complete and laboratory results have returned to normal or until progression has been 
stabilized or death. In all cases, this may imply that observations will continue beyond the 
last planned visit per protocol, and that additional investigations may be requested by the 
Sponsor. 
x
When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
x
In case of any SAE/AESI with immediate notification 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 investigational product with a reasonable possibility, this should be 
reported to the Sponsor. 
9.2.2.1
Adverse events
Adverse events for each patient will be monitored and documented from the time the subject gives 
informed consent at Visit 1 until the End-of Study Visit or till the rollover to the extension study,  
except for: 
x
SAEs 
x
AEs that are ongoing at database lock.
Adverse events, adverse events with special interest (AESI) and serious adverse events (SAEs) 
will be reported as described in Section 10.4.
9.2.2.2 Vital signs
Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate 
(breaths per minute), body temperature (degrees Celsius), body weight (kg) and height (cm) will 
be measured. Vital signs will be measured in the sitting position using the same arm at each visit, 
and will be measured prior to receiving investigational product at the clinic visits if applicable.  


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9.2.2.3
Physical examination
Physical examinations will include an assessment of general appearance, skin, eyes, 
ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, and extremities. All 
deviations from normal will be recorded, including those attributable to the patient’s disease.  
9.2.2.4
ECG
One recording of a standard 12-lead ECG will be performed centrally. At the post-randomization 
visits, ECGs will be performed prior to investigational product administration if applicable.  A 
minimum of 3 complexes in an appropriate lead (lead II) will be averaged to determine the PR-
interval, QT/QTc-interval, QRS-complex and heart rate will be measured for each ECG. All ECG 
recordings will be centrally read by independent experts. Refer to central ECG reading manual for 
more details.
9.2.2.5
Clinical laboratory tests
The clinical laboratory tests will be conducted by an accredited (College of American Pathologists 
or equivalent) central laboratory with national and regional clinical licenses as required for 
diagnostic testing and must provide evidence of participation in proficiency testing, as 
appropriate. After reviewing the laboratory report and evaluating any results that are outside the 
normal range, the Investigator must sign and date the laboratory report. Abnormal laboratory 
values that are considered to be clinically significant by the Investigator should be repeated as 
soon as possible after receiving the laboratory report to rule out laboratory error. Persistent 
abnormal laboratory values should be repeated until they return to normal or until an etiology of 
the persistent abnormality is determined.
The clinical laboratory parameters that will be measured are:
x
Hematology: To include hemoglobin, hematocrit, platelet count, total white blood cell 
count with five-part differential count, differential count, and total red blood cell count. 
x
Serum chemistry: To include: creatinine, blood urea nitrogen, glucose, uric acid, total 
cholesterol, total protein, albumin, total bilirubin (in case of values above the normal 
range, differentiation in conjugated and non-conjugated bilirubin), alanine 
aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase,
electrolytes (sodium, potassium, chloride), bicarbonate, and creatine phosphokinase. The 
blood sample must be taken with the patient in fasting state which means no intake of any 
food or drink except for water for at least 8 hours (If the visit can only be done at a 
different time of the day and the patient is not fasting, then he/she should be advised to eat 
light food and the site should document that serum chemistry was not obtained under 
fasting conditions). 
x
Urine dipstick analysis including specific gravity, pH, glucose, ketones, blood, protein, 
nitrite, leukocyte esterase, urobilinogen and bilirubin (by dipstick).  If any assessment on 
the dipstick is abnormal, a urine sample should be sent to the central laboratory for testing. 
If positive for proteins, microscopic analysis is performed by central laboratory.  


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x
Serum immunoglobulins: quantitative immunoassays for total IgG, IgG subclasses 1-4, 
IgM, and IgA.  
x
Hepatitis screening: HBs Ag, HBs Ab, HBc Ab including HBcAb IgM and total, HCV Ab. 
In case of results showing HBs Ag (negative) and HBc Ab total (positive), a HBV DNA 
testing must be performed prior to randomization to determine eligibility. In case of results 
showing HCV Ab (positive), a HCV RNA testing must be performed prior to 
randomization to determine eligibility.
x
HIV screening (Anti-HIV-1 and HIV-2 antibodies)  
x
Anti-nuclear antibody (ANA). Note: Anti-ds DNA antibody will be tested if ANA is 
SRVLWLYHWLWHU
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in
Appendix K.
9.2.2.6
Hepatitis B viral load
Hepatitis B viral load (HBV DNA) must be tested at Visit 1 and Visit 17 (only applicable for 
patients who plan to participate in the OLE study) in case of results showing HBs Ag (negative), 
HBs Ab (negative or positive) and HBc Ab total (positive), refer to Section 9.2.2.5 for details.  
In Japan or other countries/regions if there is local regulatory requirement, hepatitis B viral load 
(HBV DNA) will be tested at Visit 2, then every 12 weeks until Visit 14 and at end of treatment 
visit for patients who are HBs Ag negative and HBs Ab positive at screening.   
9.2.2.7
Pregnancy test
$VHUXPSUHJQDQF\WHVWȕ-human chorionic gonadotrophin) will be performed at screening 
(Visit 1) in women of childbearing potential, and a urine dipstick pregnancy test will be 
performed at Visit 2 prior to randomization and other visits. A negative result must be obtained at 
Visit 1 and 2 prior to randomization.  
9.3
OTHER ENDPOINTS
9.3.1
Systemic drug concentration and anti-drug antibodies
9.3.1.1
Sampling time
Serum samples for determination of functional dupilumab and anti-dupilumab antibodies (also 
known as anti-drug antibodies (ADA)) will be collected as per study flow chart (see Section 1.2
and Section 1.3). The date of collection should be recorded in the patient e-CRF.  The date and 
time also will be collected on the central laboratory requisition form and entered into the database 
through data transfers from the central laboratory. Patients who discontinue early from treatment 
or patients who choose not to participate in the long term extension study may be asked to return 
to the clinic to have additional ADA samples collected for analysis based on the overall


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assessment of antibody titers and/or clinical presentation at the time of discontinuation or at the 
time of last study visit.  
In the event of any SAE or any AESI of anaphylactic reactions or systemic allergic reactions that 
are related to IMP and require treatment, or severe injection site reaction lasting longer than 24 
hours, samples will be collected near the onset and resolution of the event for any additional 
analysis if required or for archival purposes. An unscheduled systemic drug concentration page in 
the e-CRF must be completed as well.
Pre-existing anti-drug antibodies are defined as:  
x
An ADA positive response in the assay at baseline with all post treatment ADA results 
negative, OR 
x
An ADA positive response at baseline with all post treatment ADA responses less than 4-
fold over baseline titer levels.
Treatment-emergent anti-drug antibodies are defined as:  
x
An ADA positive response in the assay post first dose, when baseline results are negative
or missing. 
Treatment-boosted anti-drug antibodies are defined as:  
x
An ADA positive response in the assay post first dose that is greater-than or equal to 4-
fold over baseline titer levels, when baseline results are positive.
Treatment-emergent (TE) ADA responses are further classified as Transient, Persistent or 
Indeterminate
a) Persistent Response- defined as a treatment-emergent response with two or more 
consecutive ADA positive sampling time points, separated by more than 12-week period 
(with no ADA negative samples in between).
b) Indeterminate Response- defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay 
c) Transient Response - defined as a treatment-emergent response that is not considered 
persistent OR indeterminate
Unused samples collected for drug concentration or ADA analyses may be used for research 
purpose. 
9.3.1.2
Handling procedures
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals.  An overview of handling procedure of samples used in the determination of 
functional dupilumab concentration and ADA is provided in Table 1. 


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Table 1 - Summary of handling procedures for dupilumab
Sample type
Functional dupilumab
Anti-dupilumab antibody
Matrix 
Serum
Serum
Blood sample volume
5 mL
5 mL
Anticoagulant
None
None
Blood handling procedures
See Operational Manual
See Operational Manual
Serum aliquot split
2 aliquots
2 aliquots
Storage conditions
<6 months: below -20°C
<24 months: below -80°C (preferred)
<6 months: below -20°C
<24 months: below -80°C (preferred)
Serum shipment condition
In dry ice
In dry ice
9.3.1.3
Bioanalytic method
Serum PK and ADA samples will be assayed using validated methods as described in Table 2. 
Table 2 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody
Analyte
Functional dupilumab
Anti-dupilumab antibody
Matrix 
Serum
Serum
Analytical technique
ELISA
Electrochemiluminescence
Lower limit of quantification
0.078 mg/L
Not applicable
Site of bioanalysis
Regeneron
Regeneron
ELISA=enzyme-linked immunosorbent assay.
9.3.2
Pharmacodynamics
Several biomarkers related to asthmatic inflammation and Th2 polarization will be assessed for 
their value in predicting therapeutic response and/or in documenting the time course of drug 
response. In a prior asthma trial (ACT11457), treatment with dupilumab significantly suppressed 
systemic levels of serum TARC (CCL17; a ligand of CCR4 receptors that attracts Th2 cells), 
plasma eotaxin-3 (CCL26; a ligand of CCR3 receptors that attracts eosinophils and lung mast 
cells), and serum total IgE (a product of immunoglobulin class switching driven by IL-4), as well 
as reduced the concentrations of fractional exhaled nitric oxide (a marker of airway 
inflammation).  Now added to these are the following serum biomarkers: eosinophil cationic 
protein (ECP; a stored protein released from activated eosinophils) and periostin, a protein 
reported to be elevated at baseline in patients responsive to treatment with anti-IL-13 antibodies. 
Assay methodologies are briefly summarized below. More detailed information on the collection, 
handling, transport and preservation of samples (eg, minimum volumes required for blood 
collection and for aliquots for each biomarker assay) will be provided in a separate laboratory 
manual. 


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Eotaxin-3, eosinophil cationic protein (ECP), total IgE and Thymus and Activation-Regulated 
Chemokine (TARC) will all be assayed at the same time points as a biomarker set and as 
indicated in the study flow chart. Periostin and antigen-specific IgE panels will be collected 
individually per the study flow chart.  
9.3.2.1
Whole blood biomarkers
Blood eosinophil count will be measured as part of the standard 5-part WBC differential cell 
count on a hematology autoanalyzer. 
9.3.2.2
Plasma biomarkers  
Eotaxin-3 will be measured in heparinized plasma with a validated enzyme immunoassay (Human 
Eotaxin-3 Quantikine ELISA kit; R&D Systems).
9.3.2.3
Serum biomarkers  
Concentrations of eosinophil cationic protein (ECP) will be measured using a quantitative 
ImmunoCAP assay (Phadia).  
Antigen-specific IgE will be detected using panels of antigens appropriate to the location of the 
clinical site (ImmunoCAP test; Phadia).
Total IgE will be measured with a quantitative method (eg, ImmunoCAP) approved for diagnostic 
testing. 
TARC and periostin will be assayed with validated immunoassays. 
9.3.2.4
Exhaled nitric oxide
Exhaled nitric oxide will be performed centrally and analyzed using a NIOX instrument 
(Aerocrine AB, Solna, Sweden), or similar analyzer using a flow rate of 50 mL/s, and reported in 
parts per billion (ppb). This assessment should be conducted prior to spirometry and following a 
fast of at least 1 hour. All exhaled nitric oxide recordings will be centrally read by independent 
experts. Further details on the procedure for measuring exhaled nitric oxide with NIOX will be 
provided in a separate instruction manual. 
9.3.3
Pharmacogenetics
9.3.3.1
Optional stored DNA and RNA samples
Pharmacogenetic testing is optional and voluntary. A separate written informed consent form 
must be signed before sampling.  
For those patients who signed the optional pharmacogenetic informed consent form, blood 
samples for exploratory genetic analysis of DNA or RNA will be collected at the study visit as 


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specified in the study flow chart, and these samples will be stored for up to 15 years after 
completion of the final report of the main clinical trial or for a shorter time if there is local 
requirement. Specific procedures for collection, storage and shipping of pharmacogenetic samples 
will be provided in a lab manual.  
DNA or RNA samples may be used to determine a possible relationship between genes and 
response to treatment with dupilumab, possible adverse reactions to dupilumab, and to study the 
genetics of asthma. The DNA may be subjected to a genome-wide association study by 
microarray analysis and/or to whole exome sequencing or whole genome analysis in order to 
thoroughly explore genetic associations with disease progression or treatment response. The RNA 
may be subjected to discrete panels of PCR analyses, microarray analyses or RNA sequencing 
analyses.
The blood DNA sample, and the DNA or RNA that is extracted, will be assigned a second
number, a Genetic ID (de-identification code) that is different from the Subject ID. This “double 
coding” is performed to separate a subject’s medical information and DNA data.
The clinical study data (coded by Subject ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking Subject ID and 
Genetic ID will be maintained by a third party, under appropriate access control.  The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality.
9.3.4
Vaccine response
Patients will be encouraged to provide vaccination plans for the following vaccines, tetanus (alone 
or combined), any injectable influenza, any pneumococcal and any meningococcal, which are in 
line with the patients age and local medical practice (live attenuated vaccines are excluded) during 
the study. Subjects planning to receive any of the above listed vaccines during the study may 
optionally sign a separate informed consent for collection of 2 blood samples for assay of vaccine
IgG in serum for each vaccine: the first should be drawn within 6 weeks prior to vaccination and 
then the second should be drawn 3 to 4 weeks after vaccination (up to 6 weeks afterward allowed).
Vaccinations should preferably occur after completion of at least 12 weeks of treatment, while 
remaining in compliance with the patient’s recommended immunization schedule. Pre-vaccine 
blood sample collection will not take place until patient is on treatment of IMP for at least 6 
weeks. Blood collections should be conducted at regularly scheduled study visits but, if this is not 
feasible, could also be done at unscheduled visits. The details on the date(s) of vaccination and the 
specific vaccines that are administered, such as brand and antigenic strains, should be collected 
(see Appendix L).  
9.4
FUTURE USE OF SAMPLES 
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For subjects who have consented to it, the samples that are archived, unused or left 


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over after planned testing may be used for additional research purposes (any genetic analysis 
subject to additional consent per Section 9.3.3). For subjects who have consented to it, archival 
blood samples will be collected at the visit specified in the study flow chart, 15 mL each, will be 
collected into a dry, red topped tube (or into smaller tubes of equivalent total volume) kept at 
room temperature for 30 minutes and then centrifuged at approximately 1500 g for 10 minutes at 
room temperature.  The serum will then be transferred, in equal portions, into 3 storage tubes, 
which will be immediately capped and frozen in an upright position at -20°C or colder. 
These archived serum samples, and any residual or leftover serum, plasma or blood remaining 
from planned laboratory work, may be used for research purposes related to asthma 
(eg, exploratory biomarkers of disease or drug effect), additional drug safety assessments or 
development and validation of bioassay methods beyond those defined in the present protocol. 
These samples will remain labelled with the same identifiers as the ones used during the study 
(ie, subject ID, sample ID). They will be transferred to a Sanofi site (or a subcontractor site) 
which can be located outside of the country where the study is conducted. The Sponsor has 
included safeguards for protecting subject confidentiality and personal data (see Section 14.3 and 
Section 14.5).
9.5
APPROPRIATENESS OF MEASUREMENTS  
The efficacy and safety assessments used in this study are standard for the evaluation of therapy in 
patients with asthma.


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10
STUDY PROCEDURES
10.1
VISIT SCHEDULE
The clinical trial consists of three periods, using an add-on therapy approach to inhaled 
corticosteroid in combination with one or two other controller medications:
x
Screening Period (4±1 weeks; Visit 1) 
x
Randomized Treatment Period ( 52 weeks; Visits 2-18) 
x
Post-treatment Period (12 weeks; Visits 19-21) 
The study visits occur on the planned dates (relative to the first injection), as scheduled. The visit 
schedule should be adhered to within the ± 3 day visit window. 
All the study visits should be scheduled in the morning, to have the spirometry performed and the 
patient should be fasting for serum chemistry tests. However, if the visit can only be done at a 
different time of the day and the patient is not fasting, then he/she should be advised to have a 
light meal and the site should document that serum chemistry was not obtained under fasting 
conditions. For spirometry, it should be performed at approximately the same time of the day at 
each visit throughout the study. 
Patients who permanently discontinue the study medication will be asked and encouraged to 
return to the clinic for study visits and participate in assessments according to the visit schedule 
until the end of the study with a +/-5 day window (See Section 1.3). Under exceptional 
circumstances when a patient cannot come to the site for the scheduled visit, a phone contact can 
be made after sponsor approval is given. During the phone contact, at least information about 
AEs, concomitant medication and asthma exacerbation events should be collected. 
Patients who discontinue early from treatment or patients who choose not to participate in the 
OLE study may be asked to return to the clinic to have additional ADA samples collected for 
analysis based on the overall assessment of antibody titers and/or clinical presentation at the time 
of discontinuation or at the time of last study visit.
Reminder: sexually active female patients of reproductive potential are required to practice an 
effective contraception throughout the participation in the study including a 12-week period after
last IMP dose. Sites should counsel these patients, with special attention towards adolescent 
patients regarding the importance of practicing responsible and effective contraception throughout 
the participation in the study including a 12-week period after last IMP dose.
Prior to all screening assessments, after discussion of participation in the study, the written 
consent form (including voluntary participation in pharmacogenetic testing/future use of blood 
samples/vaccination testing) must be signed and dated. 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as


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long as the screening visit window prior to randomization (Day 1) is respected. If certain dynamic 
laboratory tests do not meet the eligibility criteria, these laboratory assessments may be repeated, 
at the discretion of the investigator, if it is judged to be likely to return to acceptable range for 
study inclusion within the screening visit window (35 days) prior to Day1. These patients do not 
need to sign a new ICF and be allocated a new patient number within this same screening 
window.  
Patients that fail the initial screening for exclusion criteria, eg, concomitant medications, may be 
rescreened for study eligibility 1 additional time. Patients that are re-screened must sign a new 
consent form and will be allocated a new patient number; all of the Visit 1 procedures must be 
repeated (refer to Section 8.4 for further instructions related to rescreening) unless a prior 
assessment is performed within the time frame permitted prior to study entry. 
Patients that fail the Screening Visit (Visit 1) or Randomization Visit (Visit 2) because of eDiary 
/spirometry equipment malfunction, or patient-related / site personnel-related unintentional errors 
may be rescreened one time after approval is granted by the Sponsor’s clinical study director. In 
every case of rescreen allowance due to technical equipment malfunction and/or unintentional 
human error(s), the Study Investigator must document receipt of Sponsor approval and when 
applicable, document the site’s corrective action plan to prevent future occurrences.  
When approaching the season appropriate for influenza vaccination, patients will be reminded to 
inform the clinic staff about vaccination plans. Similarly, when approaching the planned date of 
tetanus (alone or combined), any pneumococcal and any meningococcal vaccination, patients will 
be reminded about the related pre- and post-vaccination blood sampling for vaccine IgG testing. 
Those who have not yet signed the separate consent for collection of blood pre-vaccination (eg, 
those who make mid-study decisions about vaccinations) may do so just prior to blood collection.
It is recommended that assessments/procedures at a site visit are performed in the following order 
if applicable, and these assessments/procedures should be done prior to IMP administration: 
1. Patient-reported outcomes and other questionnaires 
2. Procedures: 
a) ECG
b) FENO
c) Spirometry
d) Reversibility/Post-bronchodilator FEV1
e) eDiary download 
3. Safety and laboratory assessments
4. IMP administration
10.1.1 Visit 1 (Week -4 ± 1, -35 days to -21 days) 
Following a discussion of participation in the clinical trial, informed consent must be obtained and 
documented. These steps precede any study procedures.


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The following procedures will then be performed: 
x
Call IVRS/IWRS to assign patient number and register screening visit
x
Interview to collect patient demographic information, asthma history (including smoking 
habits), other medical history and surgical history, and prior and concomitant medications 
x
Interview to collect vaccination information and vaccination plan during the treatment 
period for patient who agree to participate to the vaccine response assessment. 
x
Review entry criteria to assess eligibility, with special attention to verify the following:
-
Prescribed treatment dosage meets the pre-protocol definition of  medium to high dose 
,&6PFJRIIOXWLFDVRQHSURSLRQDWHWZLFHGDLO\RUHTXLSRWHQW,&6GDLO\GRVDJH to 
a maximum of 2000 mcg/day of fluticasone propionate or equivalent) [Note for Japan: 
subjects aged 18 years and older, ICS must be PFJof fluticasone propionate 
twice daily or equivalent; subjects aged 12 to 17 years, ICS must be 100 mcg of 
fluticasone propionate twice daily or equivalent] in combination with a second 
controller (eg, /$%$/75$IRUDWOHDVWPRQWKVZLWKDVWDEOHGRVHPRQWKSULRU
to Visit 1. In addition, patients requiring a third controller for their asthma are 
considered eligible for this study. The third controller should also be used for at least 3 
months with a stable dose PRQWKSULRUWR9LVLWSDWLHQWVUHTXLULQJsystemic
steroids as controller medication or biologics are excluded). 
-
3DWLHQWKDVH[SHULHQFHGZLWKLQ\HDUSULRUWR9LVLW7UHDWPHQWZLWKV\VWHPLF
(oral or parenteral) steroids bursts for worsening asthma and/or 2) Hospitalization or 
an emergency/urgent medical care visit for worsening asthma.
x
Measure vital signs [blood pressure, heart rate, respiration rate, body temperature, 
weight (kg), height (cm)] 
x
Perform physical examination
x
Administer ACQ-7  
-
Verify ACQ-5 VFRUHLV
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Entry criteria at Visit 1 include the requirement of a specific FEV1 and demonstration 
of reversibility as specified in Section 7.1. See below for additional directions. 
-
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example, withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-long acting LABA like vilanterol should be withheld for at 
least 24 hours) and withholding the last dose of LAMA for at least 24 hours. This will 
be verified before performing the measurements.


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-
Pre-bronchodilator Forced expiratory volume (FEV1) must be  80% of predicted 
normal for adults and  90% of predicted normal for adolescents.
x
Establish reversibility
-
Reversibility must be at least 12% and 200 mL in FEV1 after 200 mcg to 400 mcg 
albuterol/salbutamol or levalbuterol/levosalbutamol (2 to 4 inhalations of 
albuterol/salbutamol or levalbuterol/levosalbutamol, or of a nebulized solution of 
albuterol/salbutamol or levalbuterol/levosalbutamol, if considered as a standard office 
practice.
x
Perform 12-lead electrocardiography (ECG)
x
Perform chest X-ray or MRI (MRI is for Germany only) if no chest imaging (X-ray, CT, 
MRI) available within the previous 12 months as per local standard of care or if there is 
local requirement. 
x
Note for Japan: According to the request from the health authority, chest X-ray should be 
performed at screening visit if there is no chest imaging (Chest X-ray, CT, MRI) available 
within 3 months prior to screening to exclude patients with suspected active or untreated 
latent tuberculosis.
x
Obtain (fasting if morning visit) blood samples for screening clinical laboratory 
determinations:
-
Hematology (see Section 9.2.2.5 for details)
-
Serum chemistry (see Section 9.2.2.5 for details)
x
Obtain blood samples for hepatitis screen (HBs Ag, HBs Ab, HBc Ab including HBcAb 
IgM and total, and HCV Ab). In case of results showing HBs Ag (negative) and HBc Ab 
total (positive), a HBV DNA testing must be performed prior to randomization to
determine eligibility. In case of results showing HCV Ab (positive), a HCV RNA testing 
must be performed prior to randomization to determine eligibility.  
x
Obtain blood sample for HIV screen (Anti-HIV-1 and HIV-2 antibodies)  
x
Obtain blood sample for ANA test. Note: Anti-ds DNA antibody will be tested if ANA is 
SRVLWLYHWLWHU
x
Obtain blood sample for serum immunoglobulins (total IgG, IgG subclasses1-4, IgM and 
IgA)
x
2EWDLQVHUXPȕ-HCG pregnancy test if female of childbearing potential 
x
Obtain urine for urinalysis (dipstick) If any assessment on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. 
x
Dispense electronic diary/PEF meter, provide instructions for daily use, and remind patient 
to bring the device to the next visit. 
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 


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x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit within 21 to 35 days (Visit 2, Week 0) and request patient to come at 
approximately the same time of this visit (fasting if morning visit). 
10.1.2 Visit 2 (Week 0, Day1) 
x
Record all medication use with start date and dose in eCRF; inquire about AEs/SAEs and 
background asthma therapy tolerability. 
x
Review entry criteria and reconfirm eligibility based on review of Inclusion/Exclusion 
Criteria. 
x
Administer ACQ-7 and all other scales (AQLQ(S), health care resource utilization 
questionnaire, EQ-5D-5L, SNOT-22 (only for those patients with bilateral nasal polyposis
and/or chronic rhinosinusitis), RQLQ(S) +12 in those patients with allergic rhinitis and 
HADS (HADS-A and HADS-D subscales)). Verify ACQ-5 score is 1.5. 
x
Compliance with use of the mandatory background therapy, ICS in combination with one 
or two other controller product as used just prior to screening, as defined as:
-
RIWRWDOQXPEHURISUHVFULEHGGRVHVRIEDFNJURXQGPHGLFDWLRQWDNHQGXULQJWKH
screening period. Compliance is verified based on background medication use 
recorded on the patient electronic diary during the screening period. 
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Perform spirometry
Entry criteria at Visit 2 include the requirement of a specific FEV1 and demonstration of 
reversibility as specified in Section 7.1. See below for additional directions. 
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements. 


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-
Pre-bronchodilator Forced expiratory volume (FEV1) mXVWEH 80% of predicted 
normal for adults and  90% of predicted normal for adolescents.
-
Post-bronchodilator FEV1 should be determined 
-
Treatment Period stability limits will be established for FEV1 and PEF (The Treatment 
Period stability limit for PEF is defined as the respective mean AM or PM PEF 
obtained over the last 7 days prior to Day 1).
If the patient meets all inclusion and does not meet any exclusion criteria:
x
Call IVRS/IWRS to register visit, randomize the patient if entry criteria are met, and 
receive the first assignment for 2 treatment kit numbers.
-
Note: Please screen-fail the patient if entry criteria are not met.
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests:
-
Clinical lab testing: hematology/biochemistry (refer to Section 9.2.2.5) 
-
Hepatitis B viral load for patients in Japan or other countries/regions if there is local 
regulatory requirement who are HBs Ag negative and HBs Ab positive at screening.  
-
Systemic drug concentration and ADA (refer to Section 9.3.1) 
-
Biomarker set, Periostin and Antigen-specific IgE (refer to Section 9.3.2) 
-
Archival serum for those patients who have signed a specific Future Use of Specimens 
informed consent (refer Section 9.4).
-
For those patients who have signed a specific pharmacogenetic informed consent form, 
collect blood samples for DNA and RNA sampling (prior to administration of 
investigational product during the Randomized Treatment Period), please refer to 
Section 9.3.3.
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit. 
x
Dispense and administer IMP
-
For those patients willing to perform self-injection:  The Investigator or delegate will 
train the patient (or caregiver) regarding preparation and injection of IMP at Visit 2 
and will inject the first of the 2 injections. The patient (or caregiver) will perform the 
second injection under the supervision of the Investigator or delegate. Document the 
training for IMP self-injection in the patient’s study file.
-
Patients should be monitored for at least 30 minutes after each study-site administered 
investigational product administration for any signs or symptoms of a hypersensitivity 
reaction.   
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary.


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x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 2 weeks later (Week 2 ± 3 days) at approximately the same time of 
this visit.  
10.1.3 Visit 3 (Week 2)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements. 
-
Post-bronchodilator FEV1 should be determined 
x
Perform 12-lead electrocardiography (ECG)
x
Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following test: 
-
Systemic drug concentration. 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain next treatment kit number 
x
Dispense and administer IMP. 
-
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection.


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-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection under the supervision of the Investigator or 
delegate. 
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 2 weeks later (Week 4 ± 3 days) and ask patient to come in at 
approximately the same time of this visit (fasting if morning visit). 
10.1.4 Visit 4 (Week 4)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements. 
-
Post-bronchodilator FEV1 should be determined 
x
Perform 12-lead electrocardiography (ECG)
x
Administer health care resource utilization questionnaire
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests: 


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-
Clinical laboratories, systemic drug concentration and Periostin (refer to Section
9.3.2). 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit. 
x
Call IVRS/IWRS to register visit and obtain treatment kit number
x
Dispense and administer IMP
-
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection.
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP under the supervision of the Investigator 
or delegate.  
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit two weeks later (Week 6 ± 3 days) at approximately the same time of 
this visit. 
10.1.5 Visit 5 (Week 6)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements. 
x
Perform blood sampling for the following test: 


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-
Blood sample for pre-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who plan to receive a vaccine in the coming 6 
weeks (refer to Section 9.3.4) 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number
x
Dispense and administer IMP
-
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection.
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP under the supervision of the Investigator 
or delegate.  
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 2 weeks later (Week 8 ± 3 days) and ask patient to come in at 
approximately the same time of this visit (fasting if morning visit). 
10.1.6 Visit 6 (Week 8)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements. 


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-
Post-bronchodilator FEV1 should be determined 
x
Administer health care resource utilization questionnaire
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests:
-
Clinical laboratories and systemic drug concentration  
-
Blood sample for pre-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who plan to receive a vaccine in the coming 6 
weeks (refer to Section 9.3.4) 
-
Blood sample for post-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who have received a vaccine in the past 3 to 4 
weeks (preferred but up to 6 weeks allowed) (refer to Section 9.3.4) 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number
x
Dispense and administer IMP
-
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection.
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP under the supervision of the Investigator 
or delegate. 
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 2 weeks later (Week 10 ± 3 days) at approximately the same time of 
this visit. 
10.1.7 Visit 7 (Week 10)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 


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x
Administer ACQ-7  
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements. 
x
Perform blood sampling for the following tests:
-
Blood sample for pre-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who plan to receive a vaccine in the coming 6 
weeks (refer to Section 9.3.4) 
-
Blood sample for post-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who have received a vaccine in the past 3 to 4 
weeks (preferred but up to 6 weeks allowed) (refer to Section 9.3.4) 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number 
x
Dispense and administer IMP
-
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection.
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP under the supervision of the Investigator 
or delegate.  
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 2 weeks later (Week 12 ± 3 days) and ask patient to come in at 
approximately the same time of this visit (fasting if morning visit). 


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10.1.8 Visit 8 (Week 12)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements.
-
Post-bronchodilator FEV1 should be determined.
x
Administer AQLQ(S), health care resource utilization questionnaire, EQ-5D-5L, SNOT-
22 (only for those patients with bilateral nasal polyposis and/or chronic rhinosinusitis), 
RQLQ(S) +12 in those patients with allergic rhinitis and HADS (HADS-A and HADS-D
subscales).
x
Perform 12-lead electrocardiography (ECG)
x
Obtain urine for urinalysis (dipstick) If any assessment on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. 
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests:
-
Clinical laboratories,   
-
Serum immunoglobulins (total IgG, IgG subclasses1-4, IgM and IgA), 
-
Systemic drug concentration,  
-
Anti-drug antibodies,
-
Biomarker set, Periostin and Antigen-specific IgE (refer to Section 9.3.2) 
-
Archival serum for those patients who have signed a specific Future Use of Specimens 
informed consent (refer to Section 9.4).


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Blood sample for pre-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who plan to receive a vaccine in the coming 6 
weeks (refer to Section 9.3.4) 
-
Blood sample for post-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who have received a vaccine in the past 3 to 4 
weeks (preferred but up to 6 weeks allowed) (refer to Section 9.3.4) 
-
Hepatitis B viral load for patients in Japan or other countries/regions if there is local 
regulatory requirement who were HBs Ag negative and HBs Ab positive at screening.  
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number 
x
Dispense and administer IMP
-
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection.
-
For patients (or caregivers) willing to self-administer IMP:
x
Provide instructions on preparation, self-injection and dose. Allow the patient (or 
caregiver) to perform the injection under the supervision of the Investigator or 
delegate, and provide feedback on technique. Verify that the training for IMP self-
injection is documented in the patient’s study file. Instruct patients to administer 
IMP at q2w intervals.
-
For patients (or caregivers) unable or unwilling to self-administer IMP: Arrangements 
must be made for the patient to receive IMP injections at the study site as unscheduled 
visits, or for qualified site personnel and/or a professional caregiver to administer IMP 
at home at q2w intervals.   
x
Dispense patient (self-injection) Home Dosing Diary
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary.
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 4 weeks later (Week 16 ± 3 days) and ask patient to come in at 
approximately the same time of this visit (fasting if morning visit). 


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10.1.9 Visit 9 (Week 16)
x
Check compliance to IMP; record all concomitant medication use; inquire about 
AEs/SAEs and background asthma therapy tolerability 
x
Review patient Home Dosing Diary for content and completeness 
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements.
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit, prior to IMP administration) for the 
following tests:
-
Clinical laboratories,  
-
Systemic drug concentration  
-
Blood sample for pre-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who plan to receive a vaccine in the coming 6 
weeks (refer to Section 9.3.4) 
-
Blood sample for post-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who have received a vaccine in the past 3 to 4 
weeks (preferred but up to 6 weeks allowed) (refer to Section 9.3.4) 
x
Administer health care resource utilization questionnaire. 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number
x
Review instructions on self-injection and dosing and dispense patient (self-injection) 
Home Dosing Diary
x
Dispense and administer IMP
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP at q2w intervals.  


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For patients (or caregivers) unable or unwilling to self-administer IMP: Arrangements 
must be made for the patient to receive IMP injections at the study site as unscheduled 
visits, or for qualified site personnel and/or a professional caregiver to administer IMP 
at home at q2w intervals.   
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 4 weeks later (Week 20 ± 3 days) and ask patient to come in at 
approximately the same time of this visit (fasting if morning visit). 
10.1.10
Visit 10, 12, 13, 15, 16, 17 (Week 20, 28, 32, 40, 44, 48)
x
Check compliance to IMP; record all concomitant medication use; inquire about 
AEs/SAEs and background asthma therapy tolerability
x
Review patient Home Dosing Diary for content and completeness 
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Measure exhaled nitric oxide (only applicable for Visit 10 and Visit 17) 
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements.
x
Administer health care resource utilization questionnaire. 
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit, prior to IMP administration) for the 
following tests:


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Clinical laboratories include hematology and serum chemistry (see Section 9.2.2.5 for 
details)
-
At Visit 17, for patients who will continue in the OLE study, obtain blood samples for 
hepatitis screen (HBs Ag, HBs Ab, HBc Ab including HBcAb IgM and total, and HCV
Ab). In case of results showing HBs Ag (negative) and HBc Ab total (positive), a HBV 
DNA testing must be performed prior to inclusion to OLE in order to determine 
eligibility. In case of results showing HCV Ab (positive), a HCV RNA testing must be 
performed prior to inclusion to OLE in order to determine eligibility.  
-
At Visit 17, for patients who will continue in the OLE study, obtain blood sample for 
HIV screen (Anti-HIV-1 and HIV-2 antibodies)  
-
At Visit 17, for patients who will continue in the OLE study, obtain blood sample for 
ANA test. Note: Anti-GV'1$DQWLERG\ZLOOEHWHVWHGLI$1$LVSRVLWLYHWLWHU
-
Obtain blood sample for pre-vaccine IgG for patients who have signed a specific 
informed consent for vaccine assessment and who plan to receive a vaccine in the 
coming 6 weeks (refer to Section 9.3.4). 
-
Obtain blood sample for post-vaccine IgG for patients who have signed a specific 
informed consent for vaccine assessment and who have received a vaccine in the past 3 
to 4 weeks (preferred but up to 6 weeks allowed) (refer to Section 9.3.4) 
x
At Visit 17, for patients who plan to participate in the OLE study, perform chest X-ray or 
MRI (MRI is for Germany only) if available chest imaging (X-ray, CT, MRI) is over 12 
months from entry into the OLE study. 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number
x
Review instructions on self-injection and dosing and dispense patient (self-injection) 
Home Dosing Diary
x
Dispense and administer IMP
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP at q2w intervals.  
-
For patients (or caregivers) unable or unwilling to self-administer IMP: Arrangements 
must be made for the patient to receive IMP injections at the study site as unscheduled 
visits, or for qualified site personnel and/or a professional caregiver to administer IMP 
at home at q2w intervals.   
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period and instruct patient to record daily usage in 
the electronic diary. 


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x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 4 weeks later (±3 days) and ask patient to come in at approximately 
the same time of this visit (fasting if morning visit). 
10.1.11
Visit 11, 14, 18 (Week 24, 36, 52 / End-of-Treatment Visit)
x
Check compliance to IMP; record all concomitant medication use; inquire about 
AEs/SAEs and background asthma therapy tolerability 
x
Review patient Home Dosing Diary for content and completeness 
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Perform physical examination (only applicable for Visit 11 and EOT visit)
x
Administer ACQ-7  
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements.
-
Post-bronchodilator FEV1 should be determined. 
x
Administer AQLQ(S), health care resource utilization questionnaire, EQ-5D-5L, SNOT-
22 (only for those patients with bilateral nasal polyposis and/or chronic rhinosinusitis), 
RQLQ(S) +12 in those patients with allergic rhinitis and HADS (HADS-A and HADS-D
subscales).
x
Perform 12-lead electrocardiography (ECG)
x
Obtain urine for urinalysis (dipstick) If any assessment on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. 
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling(fasting if morning visit, prior to administration of IMP) for the 
following tests:
-
Clinical laboratories,


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Serum immunoglobulins (total IgG, IgG subclasses1-4, IgM and IgA), 
-
Systemic drug concentration,  
-
Anti-drug antibodies (only applicable for Visit 11 and Visit 18),
-
Biomarker set, Periostin (Only applicable for Visit 18, refer to Section 9.3.2) and 
Antigen-specific IgE (only applicable for Visit 11 and Visit 18, refer to Section 9.3.2) 
-
Archival serum for those patients who have signed a specific Future Use of Specimens 
informed consent (refer to Section 9.4) 
-
Blood sample for pre-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who plan to receive a vaccine in the coming 
6 weeks (refer to Section 9.3.4) 
-
Blood sample for post-vaccine IgG for patients who have signed a specific informed 
consent for vaccine assessment and who have received a vaccine in the past 3 to 
4 weeks (preferred but up to 6 weeks allowed) (refer to Section 9.3.4) 
-
Blood sampling for hepatitis B viral load for patients in Japan or other 
countries/regions if there is local regulatory requirement who are HBs Ag negative and 
HBs Ab positive at screening. 
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Call IVRS/IWRS to register visit and obtain treatment kit number (applicable for Visit 11 
and Visit 14) 
x
Dispense and administer IMP (only applicable for Visit 11 and Visit 14) 
-
For those patients willing and trained to perform self-injection:  The patient (or 
caregiver) will perform the injection of IMP at q2w intervals.  
-
For patients (or caregivers) unable or unwilling to self-administer IMP: Arrangements 
must be made for the patient to receive IMP injections at the study site as unscheduled 
visits, or for qualified site personnel and/or a professional caregiver to administer IMP 
at home at q2w intervals.   
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
x
Remind patient to continue their stable dose of ICS in combination with one or two other 
controllers as used during the screening period (only applicable for Visit 11, Visit 14 and 
EOT visit  after which patients continue to participate the open label extension trial ) and 
instruct patient to record daily usage in the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.


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x
Schedule a site visit 4 weeks (±3 days) and ask patient to come at approximately the same 
time of this visit (only for Visit 11 and Visit 14: fasting if morning visit). 
x
Call IVRS/IWRS to register the EOT date (only applicable for EOT visit)
At Visit 18 (EOT visit), for patients who will not continue with the open label extension, the 
controller medication regimen and dose used during the randomized period  could be adjusted 
based on medical judgment of the patients’ asthma control status. 
Patients who permanently discontinue the study treatment will perform early treatment 
discontinuation visit (ETD) at the time of permanent treatment discontinuation as well as EOT 
visit (visit 18) at planned Week 52. See section 1.3 for assessments to be performed at ETD and 
EOT visits and Section 10.3.4 for additional details. 
10.1.12
Visit 19 and Visit 20 (Week 56 and Week 60, Post-Treatment Period)
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Administer ACQ-7  
x
Administer health care resource utilization questionnaire
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements.
x
Perform blood sampling (fasting if morning visit) for the following tests:
-
Clinical laboratories,  
-
Systemic drug concentration  
x
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit
x
Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary.


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x
Remind patient to continue the stable dose of ICS in combination with one or two other 
controller which was maintained over the randomized treatment period (unless treatment 
modified based on medical judgment) and record daily usage in the electronic diary. 
x
Remind patient to withhold bronchodilators according to their action duration, for example, 
withhold last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 
hours and withhold last dose of LABA for at least 12 hours (ultra-long acting LABA like 
vilanterol should be withheld for at least 24 hours) and withhold the last dose of LAMA 
for at least 24 hours prior to next visit.
x
Schedule a site visit 4 weeks later (±3 days) and ask patient to come in at approximately 
the same time of this visit (fasting if morning visit). 
10.1.13
Visit 21 (Week 64, End-of-Study Visit) 
x
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability
x
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight 
for all patients and height for adolescents only) 
x
Perform physical examination
x
Administer ACQ-7  
x
Measure exhaled nitric oxide
-
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
RIKRXU
x
Perform spirometry
-
Spirometry will be performed at approximately the same time of last visit after a wash 
out period of bronchodilators according to their action duration, for example, 
withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours and withholding the last dose of LABA for at least 12 hours (ultra-long 
acting LABA like vilanterol should be withheld for at least 24 hours) and withholding 
the last dose of LAMA for at least 24 hours and prior to administration of 
investigational product. This will be verified before performing the measurements.
-
Post-bronchodilator FEV1 should be determined. 
x
Administer AQLQ(S), health care resource utilization questionnaire, EQ-5D-5L, SNOT-
22 (only for those patients with bilateral nasal polyposis and/or chronic rhinosinusitis), 
RQLQ(S)+12 in those patients with allergic rhinitis and HADS (HADS-A and HADS-D
subscales).
x
Perform 12-lead electrocardiography (ECG)
x
Obtain urine for urinalysis (dipstick) If any assessment on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for testing. 
x
Perform urine dipstick pregnancy test (for women of childbearing potential) 
x
Perform blood sampling (fasting if morning visit) for the following tests:


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clinical laboratories, 
-
serum immunoglobulins (total IgG, IgG subclasses1-4, IgM and IgA),  
-
Systemic drug concentration,  
-
Anti-drug antibodies 
x
Download electronic diary/PEF meter and take back the device
x
Call IVRS/IWRS to register the EOS date  
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 the data collected in the e-CRF should be transcribed directly from source documents.  Data 
downloaded from the study-associated central laboratories, spirometry, nitric oxide measurement, 
ECG, and patient electronic diary / PEF meter will be considered source data.
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 should be fully documented in the CRF. In any case, the 
patient should remain in the study as long as possible.  
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)
Temporary treatment discontinuation may be considered by the Investigator because of AEs. 
Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that AE is sufficiently resolved and unlikely to recur after resuming therapy with IMP. 
In addition, the following conditions(s) will be causes for temporary treatment discontinuation: 
x
Infections or infestations that do not respond to medical treatment  
x
Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Appendix K


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10.3.2 Permanent treatment discontinuation with investigational medicinal product(s)
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.3.3 List of criteria for permanent treatment discontinuation
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the CRF or 
e-CRF.
Patients must be withdrawn from the treatment (ie, from any further investigational product 
administration) for the following reasons:  
x
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).
x
If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being 
x
At the specific request of the Sponsor 
x
In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor 
x
Any code broken requested by the Investigator will lead to permanent treatment 
discontinuation. 
x
Pregnancy 
x
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require
treatment.
x
Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin. 
x
Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (See Appendix N). 
x
Serum ALT >3 ULN and Total Bilirubin > 2ULN (See Appendix K). 
x
Serum ALT > 5 ULN if baseline ALT < 2 ULN or ALT >8 ULN if baseline ALT > 2 
ULN (Appendix K).
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient.  


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10.3.4 Handling of patients after permanent treatment discontinuation
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last.
Patients who permanently discontinue the study medication will be asked and encouraged to 
return to the clinic for study visits and participate in assessments according to the visit schedule 
until the end of the study with a +/-5 day window (See Section 1.3). Under exceptional 
circumstances when a patient cannot come to the site for the scheduled visit, a phone contact can 
be made after sponsor approval is given. During the phone contact, at least information about 
AEs, concomitant medication and asthma exacerbation events should be collected.  
Patients who discontinue early from treatment may be asked to return to the clinic to have 
additional ADA samples collected for analysis based on the overall assessment of antibody titers 
and/or clinical presentation at the time of discontinuation. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
10.3.5  Procedure and consequence for patient withdrawal from study
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. 
Withdrawal of consent for follow-up should be accompanied by documentation of the reason for 
withdrawal. Withdrawal of consent for treatment should be distinguished from withdrawal of 
consent for follow-up visits and from withdrawal of consent for non-patient contact follow-up, eg, 
medical records checks. Patients requesting withdrawal should be informed that withdrawal of 
consent for follow-up will jeopardize the public health value of the study. 
Patients who withdraw should be explicitly asked about the contribution of possible adverse 
events to their decision to withdraw consent, and any adverse event information elicited should be 
documented.  
Patients may withdraw consent verbally or in writing and, if verbal, then the site needs to 
document in source records that patient withdrew consent verbally. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit including a systemic drug concentration sample, if appropriate, and three Post-treatment 
Period Visits.
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (eg, contacting patient’s family or private physician, reviewing 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). 


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A subject should only be designated as lost to follow-up if the site is unable to establish contact 
with the subject after 3 documented attempts via 2 different methods (phone, text, e-mail, certified 
letter, etc). 
The statistical analysis plan (SAP) will specify how these patients lost to follow-up for their 
primary endpoints will be considered. Patients who have withdrawn from the study cannot be 
rerandomized (treated) in the study. Their inclusion and treatment numbers must not be reused.  
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event
An adverse event (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.
Protocol defined asthma exacerbation events are collected as efficacy endpoints via the “Asthma 
Exacerbation Events” form. These events should not be reported as AEs unless they fulfill a 
seriousness criterion.
For this study, asthma exacerbations should be managed by the Investigators based on their 
medical judgment and applicable national / international asthma management guidelines.
10.4.1.2 Serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:
x
Results in death, or 
x
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.
x
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x
Results in persistent or significant disability/incapacity, or
x
Is a congenital anomaly/birth defect 
x
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. 


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Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 
-
Intensive treatment in an emergency room or at home for: 
-
Allergic bronchospasm  
-
Anaphylaxis (refer to Appendix M for Definition of Anaphylaxis) 
-
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
-
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
-
Development of drug dependence or drug abuse 
-
ALT >3 x ULN + total bilirubin >2 x ULN or ALT increase > 10 x ULN 
-
Suicide attempt or any event suggestive of suicidality 
-
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
-
Bullous cutaneous eruptions 
-
Cancers diagnosed during the study 
-
Chronic neurodegenerative diseases (newly diagnosed)  
10.4.1.3 Adverse event of special interest
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described Section 10.4.4, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the e-CRF. 
x
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (refer to Appendix M for Definition of Anaphylaxis) 
x
Severe injection site reactions that last longer than 24 hours
x
Any infection meeting at least one of the following criteria:
-
Any serious infection (SAE) 
-
Requires parenteral (intravenous, intramuscular, subcutaneous) antimicrobial therapy 
-
Requires oral antimicrobial therapy for longer than 2 weeks 
-
Is a parasitic infection 
-
Is an opportunistic infection (see Appendix N) 


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Note:  antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents
x
Significant ALT elevation
-
ALT >5 x the upper limit of normal (ULN) in patients with baseline ALT 2 x ULN;
or 
- ALT >8 x ULN if baseline ALT >2 x ULN
x
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/Noninvestigational medicinal 
product (NIMP);
-
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2).
-
In the event of pregnancy in a female participant, IMP should be discontinued.  
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
x
Symptomatic overdose (serious or non-serious) with IMP/NIMP
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose  during an interval of less than 11 days. The circumstances (ie, 
accidental or intentional) should be clearly specified in the verbatim and symptoms, if 
any, entered on separate adverse event forms.
-
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice of the 
intended dose within the intended therapeutic interval. 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.
10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities
Not applicable.
10.4.3 General guidelines for reporting adverse events
x
All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the CRF.
x
When a safety event is categorized as a primary outcome, the event will be reported as an 
AE but will be waived from reporting to health authorities providing an agreement has 
been reached with them.


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x
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). In studies that require the use of 
combined/multiple IMPs/NIMPs, the Global Safety Officer (GSO) with input from other 
appropriate study team members must determine if the causal relationship will either be 
assessed for the combined product as a regimen or as distinct entities. The GSO must 
communicate this decision to the study team for inclusion in the protocol and AE CRF.
x
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 
prespecified study end-date, should be followed until resolution, stabilization, or death and 
related data will be collected.
x
When treatment is prematurely discontinued, the patient’s observations will continue until
the end of the study as defined by the protocol for that patient. 
x
Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if: 
-
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
The following table summarizes the reporting timelines: 


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Adverse event / laboratory abnormality
Reporting timeline
Serious adverse event
Within 24 hours
Pregnancy
Within 24 hours
Overdose
Symptomatic
Within 24 hours
Asymptomatic
Routine
ALT elevation
$/7!8/1LIEDVHOLQH$/7LV8/1
ALT  > 8 ULN  if baseline ALT is > 2 ULN
Within 24 hours
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require  treatment
Within 24 hours
Severe injection site reactions that last longer than 24 hours
Within 24 hours
Infections as defined in Section 10.4.1.3.
Within 24 hours
10.4.4 Instructions for reporting serious adverse events
In the case of occurrence of an SAE, the Investigator must immediately:
x
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay.
x
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. 
x
All further data updates should be recorded in the e-CRF 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.
x
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF 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. 
10.4.5 Guidelines for management of specific laboratory abnormalities
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in
Appendix K.
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
x
Neutropenia 


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x
Thrombocytopenia 
x
Increase in ALT
x
Acute renal insufficiency
x
Suspicion of rhabdomyolysis 
Note: In some clinical trials these laboratory abnormalities can be considered as AESIs. For this 
study, only significant ALT increase will be considered as AESIs (see Section 10.4.1.3)  
In addition, on treatment eosinophil counts >3000 cells/μL (3.0 giga/L) are to be reported as AEs.
10.5
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
x
All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IECs/IRBs as appropriate and to the Investigators.    
x
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations.
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected [eg, wheezing related to asthma].
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health
Authority of any suspected unexpected serious adverse drug reaction (SUSAR) and reasonably 
associated with the use of the IMP according to either the judgment of the Investigator and/or the 
Sponsor. 
In case of a SUSAR, Sanofi Global Pharmacovigilance and Epidemiology will utilize XGRID to 
reveal medication assignment for regulatory reporting requirements for the particular case.
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report.
10.6
SAFETY INSTRUCTIONS
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 


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or shortly after therapeutic administration. Anaphylaxis may represent the most severe form of 
allergic reactions, refer to Appendix M “Definition of Anaphylaxis”, which describes the clinical 
criteria for the diagnosis of anaphylaxis. 
Patients should be monitored for at least 30 minutes after each study-site administered 
investigational product administration for any signs or symptoms of a hypersensitivity reaction. 
Trained personnel and medications should be available to treat anaphylaxis or any severe allergic 
reaction if it occurs.  Furthermore, the patients will be advised, when the IMP is administered at 
home, to self-monitor for potential signs and symptoms that may suggest a hypersensitive reaction 
for 30 minutes after administration.  
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment 
must be reported as an adverse event of special interest (AESI) (within 24 hours, for further 
details, see AESI definition in Section 10.4.1.3 and Appendix M) and study medication must be 
permanently discontinued. ADA and PK samples will be collected near the onset and resolution of 
the AESI for any additional analysis. 
10.6.2  Severe injection site reactions
Based on the subcutaneous 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. ADA and PK samples will be collected near the 
onset and resolution of the AESI for any additional analysis. 
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.
Since dupilumab binds to IL-5ĮSUHYHQWLQJ,/-4 and IL-13 activation of their respective 
receptors, it inhibits the T-helper 2 (Th2) cytokines production. Infections with a diversity of 
helminthic parasites elicit eosinophilia via stimulation of Th2-like lymphocyte responses. The Th2 
response is characterized by production of IL-4, IL-13 and IL-5, subsequently generating IgG1 
and IgE-secreting cells, and eliciting eosinophilia.  Eosinophilia is prominent in a number of 
helminthic parasitic diseases. The eosinophilic response to helminths is determined both by the 
host's immune response and by the parasite, including its distribution, migration, and development 
within the infected host. Therefore, patients treated with dupilumab may potentially have an 
increased risk of parasitic infection. 


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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 
have ruled out active infection before randomization. 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, especially 
when conditions are conducive to infection (eg, extended stay, rural or slum areas, lack of running 
water, consumption of uncooked, undercooked, or otherwise potentially contaminated food, close 
contact with carriers and vectors, etc.). Subsequent medical assessments (eg, stool exam, blood 
tests, etc.) must be performed in order to rule out parasitic infection/infestation. 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 (i.e., cultures, histopathological or 
cytological evaluation, antigen detection and serum antibody titers).  Patients should be referred to 
an infectious disease specialist if deemed necessary for diagnostic work up and appropriate 
treatment.
Infections or infestations that do not respond to medical treatment should have study drug 
discontinued until the infection is resolved. 
For any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (See Appendix N), patients must be permanently 
discontinued from study medication. 
10.6.4 Elevated liver function tests
No pre-clinical and clinical data has suggested any hepatic toxicity of dupilumab; however, as a 
general consideration of clinical development, the administration of immunosuppressant or 
immunomodulating agents may represent an additional risk factor for hepatotoxicity.  
Hepatitis virus tests and liver function tests (LFT) will be performed at Visit 1, prior to 
randomization to exclude those patients with high risk of hepatitis infection or severe liver injury 
from this study (Refer to Section 7.2 and Section 9.2.2.5).
In order to closely follow potential liver abnormalities, assessment of total protein, albumin, total 
bilirubin (in case of values above the normal range, differentiation in conjugated and 
non-conjugated bilirubin), alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase are measured as part of the clinical laboratory testing (Refer to Section 9.2.2.5 ).  
Guidance for the investigation of elevated ALT as well as concurrent management of IMP is 
provided in Appendix K.


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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 sample size calculation of this study was based on a comparison between dupilumab 300 mg 
q2w versus placebo with regard to the 2 primary endpoints: annualized rate of severe 
exacerbations during the 52-week treatment period and absolute change from baseline in FEV1 at 
Week 12. Assuming the number of severe exacerbations follows a negative binomial distribution 
with a dispersion parameter of 2, a placebo annualized rate of exacerbations being 0.6, a 
randomization ratio of 2:2:1:1, with 1638 randomized patients (546 for each dupilumab dose and 
273 for each matching placebo group), the study will have 99% power to detect a 55% relative 
risk reduction (ie, annualized rate of 0.27 for the dupilumab group) in the annualized rate of 
severe exacerbations at the 2-WDLOHGVLJQLILFDQFHOHYHORIĮ 05.  Assuming 42% patients with a 
baseline eosinophil count FHOOV/ giga/L), approximately 690 patients (230 for 
dupilumab 300mg q2w and 115 for the matching placebo) will provide 91% power to detect a 
55% relative risk reduction for the subgroup. Assuming a common standard deviation of 0.5 L, 
1638 patients will provide 98% power to detect a treatment difference of 0.15 L in the change of 
FEV1 from baseline at Week 12 for the overall population, and 690 patients will provide 88% 
power to detect a treatment difference of 0.18 L for patients with a baseline eosinophil count 
cells/ /μL (0.3 giga/L). The overall study recruitment will continue until at least 1638 patients in 
total and 690 patientVZLWKHRVLQRSKLOVFHOOVμL (0.3 giga/L) are randomized. The 
recruitment for patients on treatment of medium dose of ICS will stop when approximately 819 
patients in this category have been randomized into the study. In addition, approximately 84 
adolescent patients will be randomized.
Patients will be randomized using a 2:2:1:1 randomization ratio for dupilumab 300 mg q2w and 
dupilumab 200 mg q2w, placebo q2w in 2 mL and placebo q2w in 1.14 mL respectively.  
Randomization will be stratified by age (<18 years, \HDUV at screening, central eosinophil 
count (FHOOV/FHOOVμL) at screening, ICS dose level (medium, high) and country. 
In addition, in order to have additional patients treated with drug manufactured using the intended 
commercial process, approximately 220 patients will be randomized in addition to the originally 
planned sample size (1638). 
11.2
DISPOSITION OF PATIENTS
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all patients with a treatment kit number allocated and recorded in 
IVRS database, and regardless of whether the treatment kit was used or not.


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Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population, but will be included in the safety population.   
11.3
ANALYSIS POPULATIONS
11.3.1 Efficacy populations
The analysis population for the efficacy endpoints will be intent-to-treat (ITT) population. The 
two primary endpoints will also be analyzed in the HEos ITT population. 
ITT population: all randomized population analyzed according to the treatment group allocated by 
randomization regardless of whether treatment kit is used or not.
HEos ITT population:  ITT population with baseline eosiQRSKLOVFHOOVPL. 
11.3.2 Safety population
The analysis population for the safety endpoints will be safety population defined as all patients 
exposed to study medication, regardless of the amount of treatment administered. The safety 
analyses will be conducted according to the treatment patients actually received.
Treatment emergent period for safety population is defined as the time between the first 
administration of study medication to the end of the Post-treatment Period or till the rollover to 
the extension study. 
In addition:  
x
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
11.3.3 Systemic drug concentration population
The systemic drug concentration population will consist of all patients in the safety population 
with at least one evaluable functional dupilumab concentration result. Patients will be analyzed 
according to the treatment actually received.
11.3.4 Anti-drug antibody population
The anti-drug antibody population will consist of all patients in the safety population with at least 
one qualified ADA result in the ADA assay following the first dose of the study medication. 
Patients will be analyzed according to the treatment actually received.


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11.4
STATISTICAL METHODS
11.4.1 Extent of study treatment exposure and compliance
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population.
11.4.1.1 Extent of investigational medicinal product exposure
Duration of IMP exposure is defined as:  last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations. 
11.4.1.2 Compliance 
An administration is considered compliant if an injection is performed, regardless the actual 
amount of solution injected. The loading dose will be considered as two administrations. No 
imputation will be made for patients with missing or incomplete data. 
Treatment compliance will be summarized descriptively (N, Mean, SD, Median, Min, and Max). 
The percentage of patients with compliance is <80% will be summarized.  
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoints 
The annualized rate of severe exacerbation events will be analyzed using a negative binomial 
regression model. The model will include the total number of events occurring during the 
52 weeks as the response variable, with the treatment group, age, region (pooled country), 
baseline eosinophil strata, baseline ICS dose level and number of severe exacerbation events 
within 1 year prior to the study as covariates. Log transformed treatment duration will be the 
offset variable. Patients who permanently discontinue the study medication will be asked and 
encouraged to return to the clinic for all remaining study visits and the additional off-treatment 
severe exacerbation events up to Week 52 will be included in the analysis and the last contact date 
at Week 52 will be used to calculate the offset variable. 
The absolute change from baseline in FEV1 at Week 12 will be analyzed using a mixed-effect 
model with repeated measures (MMRM) approach. The model will include change from baseline 
in FEV1 values up to Week 12 as response variables, and treatment, age, sex, height, region 
(pooled country), baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit 
interaction, baseline FEV1 value and baseline-by-visit interaction as covariates. An unstructured 
correlation matrix will be used to model the within-patient errors. Parameters will be estimated 
using restricted maximum likelihood method with the Newton-Raphson algorithm. Statistical 
inferences on treatment comparisons for the change from baseline in FEV1 at Week 12 will be 
derived from the mixed-effect model. For patients discontinuing the treatment before Week 12, 
off study-treatment FEV1 values measured up to Week 12 will be included in the primary 
analysis. 


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Subgroup analyses will be performed for the two primary endpoints using the same methods by 
EDVHOLQHHRVLQRSKLOOHYHOVFHOOVȝ/YVFHOOVȝ/DQGFHOOVȝ/YVFHOOVȝL). 
11.4.2.1.1Analysis of annualized event rate
The annualized rate of exacerbation events, including severe exacerbation events resulting in 
hospitalization or emergency room visit and LOAC events, will be analyzed using the same way 
as for severe exacerbation events.  
11.4.2.1.2Analysis of Time to event variables
Time to event (eg, LOAC, severe exacerbation) will be analyzed using a Cox regression model 
with time to event as the dependent variable, and treatment, age, number of asthma exacerbation 
events within 1 year prior to the study, region (pooled country), baseline eosinophil strata and 
baseline ICS dose level as covariates. The Kaplan-Meier method will be used to respectively 
estimate the probabilities that a patient would experience events at Week 12, 24, 36 and 52 per 
each treatment group. 
11.4.2.1.3Analysis of change from baseline for other continuous variables
The change from baseline for other continuous endpoints will be analyzed using MMRM in the 
same fashion as for the endpoint of FEV1. The covariates to be included are treatment, age, region 
(pooled country), baseline eosinophil strata, baseline ICS dose level, visit, treatment-by-visit 
interaction, corresponding baseline value and baseline-by-visit interaction. Sex and height will be 
included as covariates only in the models for spirometry parameters.  
Descriptive statistics including number of patients, mean, standard error and LS means will be 
provided. In addition, differences in LS means, the corresponding 95% CI and the p-value will be 
derived from the MMRM model for comparison of dupilumab against placebo.
Change from baseline at other time points will be analyzed in the same way.
11.4.2.1.4Subgroup analysis
To assess the consistency in treatment effects across the subgroup levels, subgroup analyses will 
be performed for the primary efficacy endpoints with respect to baseline eosinophil level 
FHOOVȝL YVFHOOVȝL DQGFHOOVȝ/YVFHOOVȝ/age group, gender, region, 
race, background ICS dose levels, background controller medication type, baseline FEV1,
predicted FEV1 %, ACQ-5, weight, BMI, smoking history, atopic medical history, age of onset of 
asthma and number of asthma exacerbation events within 1 year prior to the study. 
11.4.2.2 Multiplicity considerations
To strongly control the type-I error rate for the primary family (two primary endpoints and two 
doses), a hierarchical testing procedure will be applied at a 2-sided 5% significant level, ie, each 
hypothesis will be formally tested only if the preceding one is significant at the 5% level. The 


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hierarchy of the tests will be: 1) annualized severe exacerbation rate for 300 mg q2w versus 
placebo, 2) absolute change from baseline in FEV1 at Week 12 for 300 mg q2w versus placebo, 3) 
annualized severe exacerbation rate for 200 mg q2w versus placebo, 4) absolute change from 
baseline in FEV1 at Week 12 for 200 mg q2w versus placebo. 
If both doses are significant for both primary endpoints, a selective set of secondary endpoints 
will be tested following a hierarchical testing procedure at a 2-sided 5% significant level. The list 
of secondary endpoints to be tested in the hierarchical order will be specified in SAP. The overall 
familywise error rate will be strongly controlled at a 2-sided 5% level for all tested endpoints 
across dose groups.
11.4.2.3 Handling of missing data 
Sensitivity analyses excluding the additional off-treatment measurements up to Week 52 will be 
performed to corroborate the primary analyses. The reason and pattern of missing data will be 
carefully examined and tipping point analysis and additional sensitivity analyses may be 
performed. The details will be specified in the SAP. 
11.4.2.4 Loading dose evaluation
To examine if inclusion of the loading dose may impact demonstration sustained efficacy regard 
to exacerbations, additional sensitivity analyses of the annualized rate of severe exacerbation will 
be performed by excluding severe exacerbation events occurring during the first four weeks and 
12 weeks, respectively. The analyses will be performed the same way as the primary analysis. To 
avoid possible confounding effect due to off-treatment data, only on-treatment events will be 
included. Due to potential insufficient number of events after excluding data from the first 12 
weeks, two dupilumab groups will be combined and two placebo groups will be combined.   
11.4.3 Analyses of safety data
The summary of safety results will be presented by treatment group. The results of the two 
placebo groups will be presented separately. All safety analyses will be performed on the safety 
population using the following common rules:
The baseline value is defined generally as the last available value before the first dose of IMP.  
The following definitions will be applied to laboratory parameters, vital signs and ECG.
x
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs and ECG. 
x
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.  


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11.4.3.1 Adverse events
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE.  Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
Proportion of patients with at least one treatment emergent adverse event (TEAE), serious TEAE
and TEAE leading to discontinuation of the study will be tabulated by treatment group. In
addition TEAEs will be described according to maximum intensity and relation to the study drug. 
None treatment emergent serious AE, None treatment emergent AE leading to study 
discontinuation will be summarized separately.
11.4.3.1.1 AESI 
The following summaries will be generated: 
x
Incidence of each AESI will be tabulated by treatment group.  
x
The time-to-first event analyzed using K-M methods and displayed as K-M plots 
(cumulative incidence (%) versus time based on K-M estimates) will be provided to depict
the course of onset over time. When TEAE start date or worsening date is partially
available, the maximum of the earliest possible TEAE start date and the treatment start
date will be used. When TEAE start date or worsening date is completely missing, the 
treatment start date will be used. 
x
An overview summary of the number (%) of patients with 
-
any TEAE
-
any serious AE (regardless of treatment-emergent status)
-
any treatment-emergent SAE
-
any AE leading to death 
-
any TEAE leading to permanent study drug discontinuation 
-
any TEAE by maximum intensity, corrective treatment, and final outcome 
-
cumulative incidence at specified time points (K-M estimates at 1 week, 4 weeks, 
12 weeks, 24 weeks and 52 weeks) 
AESI definitions and the method to identify AESIs will be specified in the SAP. 
11.4.3.1.2Death
The following deaths summaries will be generated:
x
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population by treatment received 


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x
Death in nonrandomized patients or randomized and not treated patients   
x
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
Patient data listings will be provided for all AEs, TEAEs, SAE, AEs leading to study 
discontinuation, AESIs and deaths. 
11.4.3.1.3Clinical Laboratory Evaluation, Vital Signs and electrocardiogram data 
Results and change from baseline for the parameters will be summarized by treatment group for 
baseline and each post baseline time point, endpoint, minimum and maximum value. Summary 
statistics will include number of patients, mean, standard deviation, median, Q1, Q3, minimum 
and maximum.  
The proportion of patients who had at least one incidence of PCSA at any time during the TEAE
period will be summarized by treatment group. Shift tables showing changes with respect to the 
baseline status will be provided.
Listings will be provided with flags indicating clinically out-of range values, as well as PCSA
values.
11.4.3.2 Vaccine response
For patients who receive vaccination, vaccine response parameters will be summarized by 
treatment groups with descriptive statistics.
11.4.4 Analyses of systemic drug concentration, anti-drug antibodies and 
pharmacodynamic variables
11.4.4.1 Drug concentration analysis
Concentrations of functional dupilumab in serum will be summarized using arithmetic and 
geometric means, SD, standard error of the mean (SEM), coefficient of variation (CV%), 
minimum, median, and maximum by treatment per visit. 
Concentrations of functional dupilumab in serum will be used for population PK analysis by non-
linear mixed effects modeling if warranted. Additional details of the analysis plan and the results 
will be provided in a separate document.
11.4.4.2 Anti-drug antibodies analysis
Incidence of positivity in the ADA assay will be assessed as absolute occurrence (n) and percent 
of patients (%), presented by study cohorts. Listing of all ADA titer levels will be provided for


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patients positive in the ADA assay. All samples that are positive in the ADA assay will be further 
tested for the presence of anti-dupilumab neutralizing antibodies.  
Plots of concentrations of functional dupilumab will be examined and the potential influence of 
ADA on individual concentration-time profiles will be evaluated. Assessment of the potential 
impact of ADA on safety and efficacy may be provided.   
ADA at baseline will be summarized by:
x
Number (%) of patients with a baseline sample negative in the ADA assay. 
x
Number (%) of patients with a baseline sample positive in the ADA assay.
x
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the titer for patients positive in the ADA assay at baseline. 
ADA incidence and titer will be provided for the following: 
x
Number (%) of patients negative in ADA assay at all times
x
Number (%) of patients positive in ADA assay at any time
x
Number (%) of patients with treatment-emergent ADA
x
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for patients with treatment-emergent ADA
x
Number (%) of  patients with transient treatment-emergent ADA
x
Number (%) of patients with persistent treatment-emergent ADA
Titer values (Titer value category)
The minimum titer for samples positive in the ADA assay is based on the minimum required 
dilution of the assay. 
     Low (Titer < 1000) 
0RGHUDWH7LWHU
     High (Titer > 10,000) 
More details will be specified in SAP.
11.4.4.3 Pharmacodynamics
The values to be used as baselines will be those collected on Day 1 (predose assessments). If any 
of the scheduled assessments on Day 1 are technically disqualified (eg, insufficient sample), then 
values determined at Screening can be used as baseline.
For all parameters, raw data, absolute changes from baseline and percent changes from baseline 
will be summarized in descriptive statistics by treatment group and time point. 
Summary plots (mean +/- standard error of the mean) on raw data, absolute changes from baseline 
and percent changes from baseline will be provided by treatment group. 


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11.4.5 Analyses of Patient Reported Outcomes (Health-related Quality of Life/health
economics variables
Change from baseline in the following variables: global measure of AQLQ(S) and the four 
domains, the quantitative variables of EQ-5D-5L (single index utility), the anxiety and depression 
scores of HADS will be analyzed with an MMRM approach described previously for the 
continuous efficacy variables. Descriptive statistics including number of patients, mean, standard 
error and LS means will be provided.  In addition, difference in LS means, the corresponding 95% 
CI’s and the p-values will be provided for comparison between dupilumab and placebo. 
SNOT-22 (only for those patients with bilateral nasal polyposis and/or chronic rhinosinusitis) and 
RQLQ(S)+12 (only for those patients with comorbid allergic rhinitis) will be analyzed using the 
similar approach.
11.5
INTERIM ANALYSIS
There is no interim analysis planned for this study.  


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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, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the 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, should fully inform the patient (and the parent[s] or guardian[s] for pediatric 
patients) of all pertinent aspects of the clinical trial including the written information given 
approval/favorable opinion by the Institutional Review Board / Institutional 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 informed consent form should be signed, 
name filled in and personally dated by the patients (for adult patients) or patient’s parent(s) for 
pediatric patients 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 informed 
consent form will be provided to the patient (for adult patients) or patient’s parent(s) for pediatric 
patients. Local law must be observed in deciding whether 1 or both parents/guardians consent is 
required for pediatric patients.  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):
Pediatric participants who can read the assent form will do so before writing their name and 
dating or signing and dating the form. 
Pediatric participants who can write but cannot read will have the assent form read to them before 
writing their name on the form. 


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Pediatric 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.
The informed consent form and the assent form used by the Investigator for obtaining the 
pediatric 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.
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic informed consent 
form (written) should be signed, name filled in, and personally dated by the patient or by the 
subject’s legally acceptable representative, and by the person who conducted the informed 
consent discussion. A copy of the signed and dated written optional informed consent form will be 
provided to the subject. 
Prior to collection of blood for evaluation of vaccine response, the optional vaccine response 
informed consent form (written) should be signed, name filled in, and personally dated by the 
patient or by the subject’s legally acceptable representative, and by the person who conducted the 
informed consent discussion. A copy of the signed and dated written optional informed consent 
form will be provided to the subject. 
Prior to collection of blood for archiving of serum, the optional Future Use of Specimens 
informed consent form (written) should be signed, name filled in, and personally dated by the 
patient or by the subject’s legally acceptable representative, and by the person who conducted the 
informed consent discussion. A copy of the signed and dated written optional informed consent 
form will be provided to the subject. 
The main study informed consent form, the optional Pharmacogenetic informed consent form, 
optional Vaccine Response informed consent form and the Future Use of Specimens informed 
consent form to be 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. 
If the race/ethnic origin of the patients will be collected in the clinical trial, the scientific 
justification should be specified. 
12.3
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to 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. 


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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion.
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 IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It 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 
Investigator’s Brochure will be sent to the IRB/IEC.
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 INVESTIGATOR(S)
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 CRF, 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 CRFs. 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 CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 


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personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records  which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). 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 (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (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 CRFs 
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 e-CRF 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 e-CRF.
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 e-CRF.
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 and Investigator study files.


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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 Investigator's Brochure 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.


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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. 
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
x
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations;
x
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. 
x
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.
Subject race or ethnicity will be collected in this study because these data are required by several 
regulatory authorities (eg, on Afro-American population for FDA, on Japanese population for the 
PMDA in Japan, or on Chinese population for the CFDA in China). 
Analyses of subject genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purpose of the study or by regulatory authorities. 
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. 


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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.  
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice 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:  
x
The information on the product leads to doubt as to the benefit/risk ratio; 
x
Patient enrollment is unsatisfactory;


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x
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; 
x
Non-compliance 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;
x
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. 
14.8.2 By the Investigator
The Investigator may terminate his/her participation upon thirty (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 twelve (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 


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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 of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, 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 some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary.


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16
BIBLIOGRAPHIC REFERENCES
 1. Godard P, Chanez P, Siraudin L, Nicoloyannis L, Duru G. Costs of asthma are correlated with 
severity: A 1 year prospaective study. Eur Respir J. 2002;19:61-7 
2. Levine SJ, Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the 
treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152:232-7 
3. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention. Ed 2014, available at www.ginasthma.org 
4. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-
regulate expression of major cytochrome p-450 enzymes in adult human hepatocytes in 
primary culture. Mol. Pharmacol. 1993;44(4):707-715. 
5. Christensen H, Hermann M. Immunological response as a source to variability in drug 
metabolism and transport. 2012 Frontiers in pharmacology, February 2012, Vol 3, Art 8 
6. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, et al.  The impact of cytokines 
on the expression of drug transporters, cytochrome P 450 enzymes and chemokine receptors in 
human PBMC. British Journal of Pharmacology. 2009;156(3):497-508 
7. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coateset A,et al. Standardization 
of spirometry. Series ‘‘ATS/ERS TASK FORCE: Standardization of Lung Function Testing"  
Edited by Brusasco V, Crapo R, and Viegi G. Eur Resir J. 2005;26:319-338. 
8. Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-7. 
9. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire.  Respir Med. 2005;99:553-8. 
10. Norman GR, Sloan JA, Wyrwich KW. Point/Counterpoint, Interpretation of Changes in 
Health-related Quality of Life, The Remarkable Universality of Half a Standard Deviation 
Medical Care, (41):5,582–592 
11. Juniper EH, Guyatt GH, Willan A, Griffith LE.   Determining a minimal important change in a 
disease-specific quality of life questionnaire.  J Clin Epidemiol. 1994;47(1):81-7 
12. Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Pshycometric validity of the 22-item 
Sinonasal Outcome Test. Clin Otolar. 2009;34(5):447-54 
13. Zigmond AS, Snaith PR. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 
1983;67(6):361–70 


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14. Stefan G. Hofmann, Alice T. Sawyer, Ashley A. Witt, Diana Oh.The Effect of Mindfulness-
Based Therapy on Anxiety and Depression: A Meta-Analytic Review.J Consult Clin Psychol. 
2010 April ; 78(2): 169–83. 
15. Milo A Puhan, Martin Frey, Stefan Büchi, Holger J Schünemann.The minimal important 
difference of the hospital anxiety and depression scale in patients with chronic obstructive 
pulmonary disease. Health and Quality of Life Outcomes 2008, 6:46. 
16. Langley RG, Feldman SR, Han C, Schenkel B, Szapary P, Hsu MC, et al. Ustekinumab 
significantly improves symptoms of anxiety, depression, and skin-related quality of life in 
patients with moderate-to-severe psoriasis: Results from a randomized, double-blind, placebo-
controlled phase III trial 2010 J AM ACAD DERMATOL 63(3): 457-65. 
17. Stelara EMA approved Summary of Product Characteristics (SmPC or SPC), available at 
http://www.ema.europa.eu. 
18. EUroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16(3):199-208 
19. Sullivan P, Lawrence WF, Ghushchyan A. A National Catalog of Preference-Based Scores for 
Chronic Conditions in the United States Med Care 2005 43(7):736–49. 
20. Brusselle G, Michils A, Louis R,  Dupont L, Van de Maele B, Delobbe A, et al. ‘‘Real-life’’ 
effectiveness of omalizumab in patients with severe persistent allergic asthma: The PERSIST 
study 2009 Respiratory Medicine 103(5):1633-42
21. Juniper EF, Guyatt GH, O'Byrne PM, Viveiros M. Aqueous beclomethasone dipropionate 
nasal spray" regular versus "as required" use in the treatment of seasonal allergic rhinitis J 
Allergy Clin Imunol 1990:863 (3Pr1) :380-6. 

SAP_001.pdf: 
NCT number: NCT02414854


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 ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................7 
1.2.1 
Primary objectives............................................................................................................................7 
1.2.2 
Secondary objectives .......................................................................................................................7 
1.2.3 
Exploratory objectives ......................................................................................................................7 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................8 
1.4.1 
Graphic study design........................................................................................................................8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN......................12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................15 
2.1 
ANALYSIS ENDPOINTS................................................................................................................15 
2.1.1 
Demographic and baseline characteristics ....................................................................................15 
2.1.2 
Prior or concomitant medications...................................................................................................17 
2.1.2.1 
Inhaled corticosteroid in combination with one or two other controllers.........................................17 
2.1.2.2 
Reliever medication........................................................................................................................18 
2.1.3 
Efficacy endpoints ..........................................................................................................................19 
2.1.3.1 
Primary efficacy endpoint(s)...........................................................................................................19 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................20 
2.1.4 
Safety endpoints.............................................................................................................................28 
2.1.4.1 
Adverse events variables ...............................................................................................................29 
2.1.4.2 
Deaths............................................................................................................................................30 
2.1.4.3 
Laboratory safety variables ............................................................................................................30 
2.1.4.4 
Vital signs variables........................................................................................................................32 
2.1.4.5 
Electrocardiogram variables...........................................................................................................32 
2.1.4.6 
Physical Examination .....................................................................................................................32 
2.1.5 
Pharmacokinetic variables .............................................................................................................33 
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2.1.6 
Anti-drug antibody (ADA) variables ................................................................................................33 
2.1.7 
Pharmacodynamics/genomics endpoints ......................................................................................34 
2.1.8 
Vaccine response...........................................................................................................................34 
2.1.9 
Health economic endpoints............................................................................................................35 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................35 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................36 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................37 
2.3.1 
Efficacy populations .......................................................................................................................37 
2.3.1.1 
Intent–to-treat population ...............................................................................................................37 
2.3.2 
Safety population............................................................................................................................37 
2.3.3 
Population for pharmacokinetics/pharmacodynamics analyses ....................................................38 
2.4 
STATISTICAL METHODS .............................................................................................................38 
2.4.1 
Demographics and baseline characteristics ..................................................................................38 
2.4.2 
Prior or concomitant medications...................................................................................................39 
2.4.2.1 
ICS in combination with other controllers.......................................................................................39 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................41 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................41 
2.4.3.2 
Compliance ....................................................................................................................................42 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................43 
2.4.4.1 
Analysis of primary efficacy endpoint(s).........................................................................................43 
2.4.4.2 
Analyses of secondary efficacy endpoints .....................................................................................50 
2.4.4.3 
Multiplicity issues............................................................................................................................52 
2.4.5 
Analyses of safety data ..................................................................................................................53 
2.4.5.1 
Analyses of adverse events ...........................................................................................................54 
2.4.5.2 
Deaths............................................................................................................................................57 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................58 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................59 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................60 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamics variables...................................................60 
2.4.6.1 
Pharmacokinetic analyses .............................................................................................................60 
2.4.6.2 
Pharmacodynamics/genomics analyses........................................................................................62 
2.4.7 
Analyses of vaccine response........................................................................................................62 
2.4.8 
Analyses of health economics variables ........................................................................................62 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................63 
2.5.1 
General conventions ......................................................................................................................63 
2.5.2 
Data handling conventions for secondary efficacy variables..........................................................64 
2.5.3 
Missing data ...................................................................................................................................65 
2.5.4 
Windows for time points.................................................................................................................67 
2.5.5 
Unscheduled visits .........................................................................................................................73 
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2.5.6 
Pooling of centers for statistical analyses ......................................................................................73 
2.5.7 
Statistical technical issues .............................................................................................................73 
3 
INTERIM ANALYSIS .....................................................................................................................74 
4 
DATABASE LOCK ........................................................................................................................75 
5 
SOFTWARE DOCUMENTATION..................................................................................................76 
6 
REFERENCES...............................................................................................................................77 
7 
LIST OF APPENDICES .................................................................................................................78 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITY CRITERIA FOR 
INCLUDED LABORATORY PARAMETERS: COMBINED ADULT ( 18) AND 
ADOLESCENT ( 12 TO < 18) CRITERIA ABSTRACTED FROM BTD-009536 V3.0 WITH 
APPROVED MODIFICATIONS......................................................................................................79 
APPENDIX B 
LIST OF RECOGNIZED CONTROLLER MEDICATIONS...................................................86 
APPENDIX C 
LOW, MEDIUM AND HIGH DOSE INHALED CORTICOSTEROIDS- ADULTS AND 
ADOLESCENTS (12 YEARS)......................................................................................................87 
APPENDIX D 
HANDLING OF MISSING DATA .........................................................................................89 
APPENDIX E 
ASTHMA CONTROL QUESTIONNAIRE (ACQ) .................................................................94 
APPENDIX F 
ASTHMA SYMPTOM SCORE NUMERICAL RATING SCALE (NRS).................................97 
APPENDIX G 
ASTHMA QUALITY OF LIFE QUESTIONNAIRE................................................................98 
APPENDIX H 
22-ITEM SINONASAL OUTCOME TEST (SNOT-22).......................................................104 
APPENDIX I 
HOSPITAL ANXIETY AND DEPRESSION SCALE ............................................................106 
APPENDIX J 
EUROQUAL QUESTIONNAIRE (EQ-5D-5L).....................................................................108 
APPENDIX K 
STANDARDIZED RHINOCONJUNCTIVITIS QUALITY OF LIFE QUESTIONNAIRE 
RQLQ(S)+12 ................................................................................................................................111 
APPENDIX L 
VACCINATION RECORD FORM.......................................................................................116 
APPENDIX M 
DEFINITION OF ANAPHYLAXIS......................................................................................118 
APPENDIX N 
LIST OF OPPORTUNISTIC INFECTIONS........................................................................119 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACQ-5: 
Asthma Control Questionnaire 5-question version 
ACQ-7: 
Asthma Control Questionnaire 7-question version 
ADA: 
Anti-drug antibody 
AE: 
Adverse Event 
AESI: 
Adverse Event of Special Interest 
ALT: 
Alanine Aminotransferase 
ANA: 
Antinuclear Antibodies 
AQLQ(S): 
Asthma Quality Of Life Questionnaire with Standardized Activities 
ATS: 
American Thoracic Society 
CI: 
Confidence Interval 
CRF: 
Case Report Form 
CV: 
Coefficient of Variation 
DNA: 
Deoxyribonucleic acid 
DPI: 
Dry Powder Inhaler 
ECG: 
Electrocardiography 
ECP: 
Eosinophil Cationic Protein 
eCRF: 
electronic Case Report Form 
EOT: 
End of Treatment 
EQ-5D-5L: 
European Quality of Life Working Group Health Status Measure 5 Dimensions, 
5 Levels 
ERS: 
European Respiratory Society 
FeF: 
Forced Expiratory Flow 
FeNO: 
Fractional Exhaled Nitric Oxide 
FEV1: 
Forced Expiratory Volume in One Second 
FVC: 
Forced Vital Capacity 
GINA: 
Global Initiative for Asthma 
HADS: 
Hospital Anxiety and Depression Scale 
HADS-A: 
Hospital Anxiety and Depression Scale- Anxiety subscale 
HADS-D: 
Hospital Anxiety and Depression Scale- Depression subscale 
HBc Ab: 
Hepatitis B Core Antibody 
HBs Ab: 
Hepatitis B Surface antibody 
HBs Ag: 
Hepatitis B Surface Antigen 
HBV: 
Hepatitis B Virus 
HCV: 
Hepatitis C Virus 
HCV Ab: 
Hepatitis C Virus Antibody 
HFA: 
Hydrofluoroalkane 
HIV: 
Human Immunodeficiency Virus 
HLGT: 
High-Level Group Term 
HLT: 
High Level Term 
HRQoL: 
Health related quality of life 
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ICS: 
Inhaled Corticosteroid 
IgA: 
Immunoglobulin A 
IgE: 
Immunoglobulin E 
IgG: 
Immunoglobulin G 
IgM: 
Immunoglobulin M 
IMP: 
Investigational Medicinal Product 
IRT: 
Interactive Response Technologies 
ITT: 
Intent-To-Treat 
IVRS/IWRS: 
Interactive Voice Response System/Interactive Web Response System 
K-M: 
Kaplan-Meier 
LABA: 
Long-Acting Beta Agonist 
LAMA: 
Long-Acting Muscarinic Antagonist 
LLQ: 
Lower Limit of Quantitation 
LLT: 
Lower-Level Term 
LOAC: 
Loss Of Asthma Control 
LTRA: 
Leukotriene Receptor Antagonist 
MCID: 
Minimal Clinically Important Difference 
MDI: 
Metered Dose Inhaler 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MID: 
Minimal Important Difference 
MMRM: 
Mixed-effect Model with Repeated Measures 
NRS: 
Numerical Rating Scale 
NSAID: 
Nonsteroidal Anti-inflammatory Drug 
OLE: 
Open Label Extension 
PCSA: 
Potentially Clinically Significant Abnormalities 
PEF: 
Peak Expiratory Flow 
PK: 
Pharmacokinetics 
Post-BD: 
Post-bronchodilator 
Pre-BD: 
Pre-bronchodilator 
PROs: 
Patient-Reported Outcomes 
PT: 
Preferred Term 
RBC: 
Red Blood Cell 
RNA: 
Ribonucleic Acid 
RQLQ(S)+12: 
Standardized Rhinoconjunctivitis Quality Of Life Questionnaire , ages 12+ 
SC: 
subcutaneously 
SD: 
Standard Deviation 
SEM: 
Standard Error of the Mean 
SNOT-22: 
22-item Sino Nasal Outcome Test 
SOC: 
System Organ Class 
TARC: 
Thymus and Activation-Regulated Chemokine 
TEAE: 
Treatment-Emergent Adverse Event 
ULN: 
Upper Limit of Normal 
VAS: 
Visual Analogue Scale 
WBC: 
White Blood Cell 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
EFC13579 is a multinational, multicenter, randomized, double blind, placebo-controlled, parallel 
group study assessing the effect of dupilumab administered subcutaneously (SC) for 52 weeks in 
patients with persistent asthma. Both the patient and investigator will be blinded to assigned active 
drug or matching placebo, but will not be blinded to the dose level of dupilumab 300 mg/matching 
placebo or dupilumab 200 mg/matching placebo due to different volume size (2 mL vs 1.14 mL). 
After a screening phase of 4±1 weeks, patients will be centrally randomized using permuted block 
randomization schedule via Interactive Voice Response System/Interactive Web Response System 
(IVRS/IWRS) in a 2:2:1:1 randomization ratio to dupilumab 300 mg q2w in 2mL, dupilumab 200 
mg q2w in 1.14 mL, placebo q2w in 2 mL or placebo q2w in 1.14 mL. Randomization will be 
stratified by age (<18 years, 18 years) at screening, blood eosinophil count (<0.3 Giga/L, 0.3 
Giga/L) done at the central laboratory at screening, ICS dose level (medium, high) and country. 
At least 1638 patients, including approximately 84 adolescent patients, will be randomized to 
dupilumab or placebo, with at least 690 patients with a baseline blood eosinophil count 0.3 
Giga/L. Recruitment for patients on medium dose of ICS will be stopped at approximately 819 to 
ensure at least 50% patients are on high dose of ICS. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
x 
To evaluate the efficacy of dupilumab in patients with persistent asthma. 
1.2.2 Secondary objectives 
x 
To evaluate the safety and tolerability of dupilumab 
x 
To evaluate the effect of dupilumab on improving PROs including HRQoL 
x 
To evaluate dupilumab systemic exposure and incidence of anti-drug antibodies 
1.2.3 Exploratory objectives 
x 
To explore the association of biomarkers with treatment response 
x 
To explore the association of genetic profiles with treatment response 
x 
To explore the association of vaccine response with treatment 
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1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size was calculated on a comparison between dupilumab 300 mg q2w versus placebo 
with regard to the 2 primary endpoints: annualized rate of severe asthma exacerbations during the 
52-week treatment period, and absolute change from baseline in FEV1(L) at Week 12. Assuming 
the number of severe asthma exacerbations follows a negative binomial distribution with a 
dispersion parameter of 2, a placebo annualized rate of exacerbations being 0.6, a randomization 
ratio of 2:2:1:1, with 1638 randomized patients (546 for each dupilumab dose and 273 for each 
matching placebo group), the study will have 99% power to detect a 55% relative risk reduction 
(ie, annualized rate of 0.27 for the dupilumab group) in the annualized rate of severe asthma 
exacerbations at the 2-tailed significance level of Į=0.05. Assuming 42% patients with a baseline 
blood eosinophil count 0.3 Giga/L, approximately 690 patients (230 for dupilumab 300mg q2w 
and 115 for the matching placebo) will provide 91% power to detect a 55% relative risk reduction 
for this subgroup. Assuming a common standard deviation of 0.5 L, 1638 patients (546 for each 
dupilumab dose and 273 for each matching placebo group) will provide 98% power to detect a 
treatment difference of 0.15 L in the change of FEV1 from baseline at Week 12 for the overall 
population, and 690 patients (230 for dupilumab 300mg q2w and 115 for the matching placebo) 
will provide 88% power to detect a treatment difference of 0.18 L for patients with a baseline 
blood eosinophil count 0.3 Giga/L. The overall study recruitment will continue until at least 
1638 patients in total and 690 patients with blood eosinophils 0.3 Giga/L are randomized. The 
recruitment for patients on treatment of medium dose of ICS will stop when approximately 819 
patients in this category have been randomized into the study. In addition, approximately 84 
adolescent patients will be randomized. 
In addition to the originally planned sample size of 1638 patients, approximately 220 patients will 
be randomized in order to have additional patients treated with the drug product manufactured 
using the intended commercial process. 
1.4 
STUDY PLAN 
The clinical trial consists of three periods: 
Screening Period (4±1 weeks): to determine a patient’s eligibility status and establish level of 
asthma control before randomization. 
Treatment Period (52 weeks): treat with dupilumab or placebo SC injection. 
Post-treatment Period (12 weeks): to monitor a patient’s status when off study drug treatment for 
patients not participating in the long term extension study. 
1.4.1 Graphic study design 
Please refer of Section 1.2 of the study protocol for the detailed study flow chart.
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). These changes are not based on any 
unblinded study data.   
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section. “Principal features of the analysis” encompass the confirmatory 
aspects of the trial, including the primary and key secondary endpoints/analyses, and the analysis 
populations associated with these analyses. 
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
2 
21-May-2015 
To address the feedback from 
European health authority (EMA) on 
stratification for patients on medium 
and high doses of ICS to ensure 
that the benefit/risk is positive for 
both asthma populations. 
The following text: 
 
Randomization will be stratified by age (<18 
years, 18-64 years, 65 years), central 
eosinophil count (<150 cells/μL, 150 – 299 
cells/μL, and 300 cells/μL) at screening 
and country.  
 
Was replaced with: 
 
Randomization will be stratified by age (<18 
years, 18 64 years, 65 years18 years), 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
central eosinophil count (<150 cells/ μL, 150 
 299 cells/ μL, and <300 cells/μL, 300 
cells/ μL) at screening, ICS dose level 
(medium, high) and country. 
 
 
 
 
4 
21-Sep-2015 
To address the feedback from 
European health authority (EMA) 
and Pharmaceuticals and Medical 
Devices Agency (PMDA) not to pool 
the placebo arms 
The following text was deleted: 
 
The two placebo groups will be compared for 
the two primary efficacy endpoints: 
annualized rate of severe exacerbation 
events during the 52 weeks, and absolute 
change from baseline in FEV1 at Week 12. If 
they are similar for both endpoints based on 
the predefined criteria, the two placebo 
groups will be pooled together and all 
efficacy analyses will be performed with the 
pooled placebo group. The criteria to 
determine if the two placebo groups are 
similar will be specified in the SAP prior to 
database lock. 
 
 
 
 
4 
21-Sep-2015 
To further meet the 
recommendation from EMA on 
stratification for patients on medium 
and high dose ICS to ensure that 
the benefit/risk is positive for both 
asthma populations, in addition to 
the added stratification factor of ICS 
dose level (medium, high). 
The following text was added: 
 
The recruitment for patients on treatment of 
medium dose of ICS will stop when 
approximately 819 patients in this category 
have been randomized. 
 
 
 
 
 
4 
21-Sep-2015 
To meet the request from Food and 
Drug Administration (FDA) to control 
overall type I error rate at a 2-sided 
alpha of 0.05. 
The following text was deleted: 
The secondary endpoints will be tested follow 
the predefined hierarchical order for the dose 
that meets the statistical significance for both 
primary endpoints: annualized event rate of 
severe exacerbation and absolute change 
from baseline in FEV1 at Week 12. 
The primary family error rate will be 
controlled at 2 sided 5% level for 2 primary 
endpoints and 2 doses. The family error rate 
will be controlled at 2 sided 5% level for 
primary and secondary endpoints within the 
dose group. The overall family error rate will 
be controlled at 1 sided 5% level for all 
endpoints across dose groups. 
 
The following text was added: 
If both doses are significant for both primary 
endpoints, a selective set of secondary 
endpoints will be tested following a 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
hierarchical testing procedure at a 2-sided 
5% significant level. The first four tests will be 
1) % change from baseline in FEV1 at Week 
12 for 300 mg q2w versus placebo 2) 
absolute change from baseline in AQLQ 
global score at Week 12 for 300 mg q2w 
versus placebo 3) % change from baseline in 
FEV1 at Week 12 for 200 mg q2w versus 
placebo, 4) absolute change from baseline in 
AQLQ global score at Week 12 for 200 mg 
q2w versus placebo. The remaining list of 
secondary endpoints to be tested in the 
hierarchical order will be specified in SAP. 
The overall familywise error rate will be 
strongly controlled at a 2-sided 5% level for 
all tested endpoints across dose groups. 
 
 
 
 
4 
21-Sep-2015 
To meet the request from Food and 
Drug Administration (FDA) to 
include treated but not randomized 
patients in the safety population 
The following text: 
 
The analysis population for the safety 
endpoints will be the safety population, 
defined as all randomized patients exposed 
to study medication, regardless of the 
amount of treatment administered. The 
safety analyses will be conducted according 
to the treatment that patients actually 
received. 
 
Was replaced with: 
 
The analysis population for the safety 
endpoints will be the safety population, 
defined as all randomized patients exposed 
to study medication, regardless of the 
amount of treatment administered. The 
safety analyses will be conducted according 
to the treatment that patients actually 
received. 
 
7 
9-Aug-2016 
To meet the request from FDA to 
provide data on patients treated 
with dupilumab manufactured with 
the intended commercial process 
In order to have additional patients treated 
with dupilumab manufactured using the 
intended commercial process, more patients 
may be randomized than the originally 
planned sample size (1638) 
. 
7 
9-Aug-2016 
Examine if inclusion of the loading 
dose impacts duration of sustained 
efficacy with regard to 
exacerbations 
Additional analysis to assess the sustained 
treatment effect was added. 
 
 
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1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
This section summarizes major changes in statistical analysis features made in approved SAP 
versions from statistical considerations in protocol or previous SAP versions, with emphasis on 
changes after study start (after the first patient was enrolled). These changes are made before 
database lock.  
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan.   
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Table 2 - Statistical analysis plan statistical changes 
SAP version  
number 
Date 
approved 
Rationale 
Description of statistical 
changes 
1 
24-Jun-2016 
Expand the multiplicity control 
procedure for additional 
secondary endpoints, sub-
populations.  
The testing order of secondary endpoints 
was expanded from protocol, and the 
complete list of endpoints to be tested in 
the hierarchical order was specified in 
Table 6  
 
 
 
 
1 
24-Jun-2016 
 
To be aligned with 
protocol amendment 07 
 Anti-dupilumab antibody (ADA) status 
(negative or titer value, if positive in the 
ADA assay) at Visit 2 (Day 1), Week 12, 
Week 24, Week 52 and follow up at 
Week 64 will be provided. 
1 
24-Jun-2016 
To meet the request from FDA 
to assess any potential 
confounding effects of the 
loading dose on efficacy.  
Sensitivity analyses were added to 
examine if the treatment effect of 
dupilumab is sustained throughout the 
52-week treatment period or if there is 
any confounding effect of the use of the 
loading dose resulting in a larger 
treatment effect in the early part of the 
study. Annualized rates of severe 
exacerbation will also be analyzed 
versus placebo excluding efficacy data 
obtained during the first 4 weeks and 12 
weeks of treatment of 
dupilumab/placebo respectively.  
1 
24-Jun-2016 
To meet the request from FDA 
to provide data on patients 
treated with dupilumab 
manufactured with the intended 
commercial process 
 
In order to have additional 
patients treated with dupilumab 
manufactured using the intended 
commercial process, more patients may 
be randomized than the originally 
planned sample size (1638). The 
database lock is planned based on the 
time when approximately 1638 patients 
(originally planned sample size) 
complete Week 52 visit or discontinue 
from the study before Week 52. 
Analyses will be based on all data 
collected up to this database lock and 
will be considered as the final analyses 
in the CSR. Additional data between 
database lock and last patient 
completing last visit will be summarized 
in CSR addendum. 
 
2 
This version 
The analyses for the intended 
commercial manufacture 
process will be specified in a 
separate SAP  
Analyses of PK and FEV1 for the 
intended commercial manufacture 
process are removed from Section 
2.4.4.1.2 and Section 2.4.6.1.1 in this 
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SAP version  
number 
Date 
approved 
Rationale 
Description of statistical 
changes 
SAP  
2 
This version 
Expand the multiplicity control 
procedure for additional 
secondary endpoints 
Exacerbation requiring hospitalization or 
ER visit is added in the hierarchy of the 
multiplicity control procedure in Section 
2.4.4.3  
2 
This version 
Add analysis for severe 
exacerbation events resulting in 
hospitalization or ER visit. 
The endpoint, Annualized rate of severe 
exacerbation events resulting in 
hospitalization or emergency room visit, 
is added in Section 2.1.3.2.2.2  
2 
This version 
To solve the potential for non-
convergence in the analysis of 
exacerbation event 
Procedures of model handling are added 
when GLIMMIX procedure fails to 
achieve convergence in Section 
2.4.4.1.1. 
2 
This version 
Include multiple imputation in 
the sensitivity analysis of 
severe exacerbation per FDA 
feedback 
PMM, control based PMM and tipping 
point analysis for severe exacerbation 
events are updated in Section 2.4.4.1.1. 
2 
This version 
To solve the potential for non-
convergence in MMRM models  
Alternative model specification is added 
when  MMRM model fails to achieve 
convergence in Section 2.4.4.1.2  
2 
This version 
To add additional subgroup 
analysis and update subgroup 
definition based on 
characteristics of patient 
population. 
Additional subgroup analysis based on 
Ethnicity (Hispanic, non-Hispanic) and 
baseline weight (<60kg, >=60kg) are 
added, definition of subgroups based on 
background controller medications are 
updated, subgroup with Baseline 
BMI<30 is split into two subgroups (<25, 
25-<30) in Section 2.4.4.1.1. 
2 
This version 
To obtained group-level 
estimate of post-bronchodilator 
FEV1 slope in treatment arm 
Baseline by time interaction is removed 
from the mixed-effects model for post-
bronchodilator FEV1 in Section 2.4.4.2.1 
2 
This version 
To include additional handling  
of missing data in ACQ07 
Spirometry data from the same day will 
be used to impute the 7th question if the 
value is missing in Section 2.5.3  
2 
This version 
To be consistent with ISS SAP 
The definition of AESI and selected AE 
groupings are updated in Section 
2.1.4.1. 
2 
This version 
 To include combined PCSA 
criteria for adult and 
adolescence.  
PCSA criteria in Appendix A are updated 
2 
This version 
To be aligned with protocol 
amendment 07 
Change from baseline in Health care 
resource utilization at Week 4 and 8 are 
removed in Section 2.1.3.2.2.  
 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value of efficacy parameters is defined as the last available value up to 
randomization but prior to the first dose of study medication unless otherwise specified. The 
baseline value of safety parameters is defined as the last available value prior to the first dose of 
investigational medicinal product (IMP). The baseline value of the other parameters is defined as 
the last available value prior to the first dose of IMP if the patient is treated, or the last available 
value up to randomization if the patient is not exposed to IMP. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the post-baseline summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are  
x 
Gender (Male, Female),  
x 
Race (Caucasian/white, Black/of African descent, Asian/Oriental, American Indian or 
Alaska Native, Native Hawaiian or other Pacific Island, other) 
x 
Age in years (quantitative and qualitative variable : <18, 18-64, 65–74, 75-84, and 85 
years) 
x 
Ethnicity (Hispanic, non-Hispanic) 
x 
Region (Asia: Japan, South Korea and Taiwan; Latin America: Argentina, Brazil, 
Colombia, Chile and Mexico; East Europe: Hungary, Poland, Russia, Turkey and Ukraine; 
Western Countries: Australia, Canada, France, Germany, Italy, South Africa, Spain, United 
Kingdom and USA) 
x 
Territory (North America: Canada and USA; European Union: France, Germany, Hungary, 
Italy, Poland, Spain and United Kingdom; Rest of World: Argentina, Australia, Brazil, 
Colombia, Chile, Japan, Mexico, Russia, South Africa, South Korea, Taiwan, Turkey and 
Ukraine) 
x 
Weight in kg (quantitative and qualitative variable : <50, 50-<100 and 100 kg) 
x 
BMI in kg/m2 (quantitative and qualitative variable: <30, 30 kg/m2) 
x 
Alcohol drinking frequency (Never, At least monthly, At least weekly and At least daily) 
and number of standard alcohol drinks on a typical day when drinking (1 OR 2, >2) 
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Medical or surgical history 
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the patient. 
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Comorbidity history will be summarized separately. The following comorbid diseases will be 
summarized. 
x 
Atopic dermatitis history (Yes, Ongoing condition) 
x 
Allergic conjunctivitis history (Yes, Ongoing condition) 
x 
Allergic rhinitis history (Yes, Ongoing condition) 
x 
Allergic conjunctivitis and/or rhinitis history (Yes, Ongoing condition) 
x 
Chronic rhinosinusitis history (Yes, Ongoing condition) 
x 
Nasal polyposis history (Yes, Ongoing condition) 
x 
Eosinophillic esophagitis history (Yes, Ongoing condition) 
x 
Food allergy history (Yes, Ongoing condition) 
x 
Hives history (Yes, Ongoing condition) 
A patient is considered to have atopic medical condition if he/she has any of the following: atopic 
dermatitis, allergic conjunctivitis or rhinitis, eosinophilic esophagitis, food allergy, hives; or has 
baseline total IgE 100 IU/mL and at least one aeroantigen specific IgE is positive (0.35 IU/mL) 
at baseline.  
Disease characteristics at baseline   
The following baseline disease characteristics will be summarized by treatment group separately: 
x 
ICS dose level (medium, high as defined in Appendix C)  
x 
Age of asthma onset 
x 
Time since first diagnosis of asthma (years)  
x 
Smoking history (Never, Former*), time since cessation of smoking (months) and smoking 
quantity in pack-years for former smokers  
* Current smokers are excluded from this study. 
x 
Time since last severe asthma exacerbation (months) 
x 
Number of severe asthma exacerbation experienced within1 year before Visit 1 
(quantitative variable and qualitative variable: 0, 1, 2, 3, 4) 
x 
Eosinophil stratum at randomization (<0.3, 0.3 Giga/L) 
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x 
Baseline spirometry data including pre-bronchodilator FEV1 (L), percent predicted FEV1, 
post-bronchodilator FEV1 (L) and FEV1 reversibility (%). 
x 
AM and PM PEF (L/min) 
x 
AM and PM symptom scores 
x 
Number of nocturnal awakenings/night 
x 
ACQ-5 score 
x 
ACQ-7 score 
x 
AQLQ global score 
x 
Number of inhalations of salbutamol/albuterol and levosalbutamol/levabuterol per day 
x 
Hypersensitivity to aspirin/NSAID (Yes, Ongoing condition) 
Severe asthma exacerbation prior to the study is defined as any treatment with 1 systemic (oral or 
parenteral) steroid bursts or more for worsening asthma or hospitalization or an emergency/urgent 
medical care visit for worsening asthma. Any technical details related to computation, dates, and 
imputations for missing dates are described in Section 2.5.  
2.1.2 Prior or concomitant medications 
All medications taken within 30 days before screening and until the end of the study, including 
asthma controller medications, systemic corticosteroids are to be reported in the case report form 
pages. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version currently in effect at Sanofi at the time of database lock. 
x 
Prior medications are those the patient used prior to first IMP injection.  Prior medications 
can be discontinued before first administration or can be ongoing during treatment phase.   
x 
Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the first administration of IMP to the last administration of IMP + 98 days or 
until rollover to the LTS12551 study. A given medication can be classified as a prior 
medication, concomitant medication and posttreatment medication at the same time. 
x 
Posttreatment medications are those the patient took in the period from the last 
administration of IMP + 99 days to the end of the study 
2.1.2.1 Inhaled corticosteroid in combination with one or two other controllers 
On a daily basis throughout the study, the patient uses an electronic diary to record daily use of 
ICS in combination or concurrently with other controllers as used just prior to screening. The 
controller drugs will not be dispensed or supplied by the sponsor, but the sponsor will reimburse 
investigators for patients’ use of controller drugs in the study to ensure all patients have access to 
their controllers. 
Prior to screening, patients must be on a stable background therapy of a medium to high dose of 
ICS (250 mcg of fluticasone propionate twice daily or equipotent ICS daily dosage to a 
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maximum of 2000 mcg/day of fluticasone propionate or equivalent) [Note for Japan: subjects aged 
18 years and older, ICS must be 200 mcg of fluticasone propionate twice daily or equivalent; 
subjects aged 12 to 17 years, ICS must be 100 mcg of fluticasone propionate twice daily or 
equivalent] in combination with a second controller medication (eg, long-acting beta agonist 
[LABA], leukotriene receptor antagonist [LTRA], theophylline, etc) for at least 3 months at a 
stable dose 1 month prior to Visit 1. Patients requiring a third controller are allowed to 
participate in this study. The third controller should also be used for at least 3 months at a stable 
dose 1 month prior to Visit 1(patients requiring systemic steroids as controller medication or 
biologics are excluded). If patients take two different ICS, the total daily dose of ICS should be 
calculated to evaluate the eligibility criteria on daily dose of ICS which will be still considered as 
one controller. Please refer to medium and high dose of ICS in Appendix C. The minimum daily 
dose of fluticasone propionate is 500 mcg (250 mcg of fluticasone propionate twice daily), which 
is equal to the upper limit of medium daily dose for fluticasone propionate as instructed in 
Appendix C. For ICS other than fluticasone propionate, please refer to the table in Appendix C 
which indicates the upper limit of the medium daily dose for each ICS which is equivalent to 
500 mcg/day of fluticasone propionate. A list of recognized controller medications is provided in 
Appendix B. Number of controllers taken by each patient will be counted by therapeutic drug 
class. All drugs in a therapeutic class will be only counted once. 
During the randomized treatment period, patient will continue to take their controller 
medication(s) used during the screening period. The dose and regimen should not be changed. 
Only a transient increase in dose of ICS in addition to other rescue medication will be allowed to 
treat acute symptoms of asthma as per investigator's guidance.  
Upon completing the 52-week randomized treatment period, controller medication regimen for 
patients not continuing with the open label extension could be adjusted based on the investigator’s 
medical judgment. . 
2.1.2.2 Reliever medication 
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol MDI as reliever 
medication as needed during the study. Nebulizer solutions may be used as an alternative delivery 
method. 
Salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol nebulizer use recorded in the 
electronic diary will be converted to number of puffs as shown on the following table: 
 
Salbutamol/Albuterol Nebulizer Solution -Total 
Daily Dose (mg) 
Number of Puffs* 
2.5 
4 
5.0 
8 
7.5 
12 
10 
16 
*Conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs 
 
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Example of salbutamol/albuterol Nebulizer-to-Puff Conversion: Patient received 3 
salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. Total daily = 
7.5 mg ->12 puffs. 
 
Levosalbutamol/Levalbuterol Nebulizer Solution 
-Total Daily Dose (mg) 
Number of 
Puffs* 
1.25 
4 
2.5 
8 
3.75 
12 
5 
16 
*Conversion factor: levosalbutamol/levalbuterol nebulizer solution (1.25 mg) corresponds to 4 puffs 
 
Example of levosalbutamol/levalbuterol Nebulizer-to-Puff Conversion: Patient received 3 
levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 and 11 AM. 
Total daily = 3.75 mg ->12 puffs. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Baseline for efficacy endpoints is defined as the last non-missing value up to randomization but 
prior to the administration of the first IMP unless otherwise specified. 
2.1.3.1 Primary efficacy endpoint(s) 
There are two primary endpoints for this study, the annualized rate of severe exacerbation events 
during the 52-week placebo-controlled treatment period and the absolute change from baseline in 
pre-bronchodilator FEV1 at week 12. 
A severe exacerbation event during the study is defined as a deterioration of asthma requiring: 
x 
Use of systemic corticosteroids for 3 days; or 
x 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids 
Two events are considered as different if the start dates are separated by at least 4 weeks. 
The annualized rate of severe exacerbation events during the 52-week treatment period is defined 
as the number of severe exacerbation events with onset during the 52-week treatment period per 
patient-year. Patients who permanently discontinue the study medication will be asked and 
encouraged to return to the clinic for all remaining study visits and their additional off-treatment 
severe exacerbation events up to Visit 18(Week 52) will be included.  
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2.1.3.2 Secondary efficacy endpoint(s) 
2.1.3.2.1 Key secondary endpoint 
The key secondary endpoint of this study is percent change from baseline in pre-bronchodilator 
FEV1 at Week 12. 
2.1.3.2.2 Other secondary efficacy endpoints 
The other secondary efficacy endpoints include: 
x 
Annualized rate of severe exacerbations events during the 52-week placebo-controlled 
treatment period for patients with a baseline blood eosinophil count 0.3 Giga/L 
x 
Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline blood eosinophil count 0.3 Giga/L 
x 
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline blood eosinophil count 0.3 Giga/L 
x 
Annualized rate of severe exacerbations events during the 52-week placebo-controlled 
treatment period for patients on high dose of ICS 
x 
Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in patients on high 
dose of ICS 
x 
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 in patients on high 
dose of ICS 
x 
Annualized rate of severe exacerbations events during the 52-week placebo-controlled 
treatment period for patients with a baseline blood eosinophil count 0.15 Giga/L 
x 
Absolute change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline blood eosinophil count 0.15 Giga/L 
x 
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 in patients with a 
baseline blood eosinophil count 0.15 Giga/L 
x 
Absolute change from baseline in pre-bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 
52 
x 
Percent change from baseline in pre-bronchodilator FEV1 at Weeks 2, 4, 8, 24, 36, and 52 
x 
Change from baseline in other lung function measurements (% predicted FEV1, morning 
[AM]/evening [PM] peak expiratory flow [PEF], forced vital capacity [FVC], forced 
expiratory flow [FEF] 25-75%, post-bronchodilator FEV1 at Weeks 2, 4, 8, 12, 24, 36, and 
52 
x 
Annualized rate of loss of asthma control (LOAC) event during the 52-week 
placebo-controlled treatment period 
x 
Annualized rate of severe exacerbation events resulting in hospitalization or emergency 
room visit during the 52-week placebo-controlled treatment period 
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x 
Time to first severe exacerbation event 
x 
Time to first loss of asthma control event (LOAC) 
x 
Change from baseline in Asthma Control Questionnaire (ACQ)-5 score and ACQ-7 score 
at Weeks 2, 4, 8, 12, 24, 36, and 52 
x 
Change from baseline at Weeks 2, 4, 8 12, 24, 36, and 52 in: 
- 
Morning/evening asthma symptom score and nocturnal awakenings (e-diary) 
- 
Use of daily puffs of rescue medication 
x 
Change from baseline in Health care resource utilization at Weeks 12, 24, 36, and 52 
x 
Change from baseline in PROs at Week 12, 24, 36, and 52: 
- 
Asthma Quality Of Life Questionnaire with Standardized Activities (AQLQ (S)) Self-
Administered (12 years) 
- 
European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 
Levels (EQ-5D-5L) 
- 
Hospital Anxiety and Depression Scale (HADS) 
- 
22-item Sino Nasal Outcome Test (SNOT-22) in those patients with comorbid bilateral 
nasal polyposis and/or chronic rhinosinusitis 
- 
Standardized Rhinoconjunctivitis Quality Of Life Questionnaire, ages 12+ 
(RQLQ(S)+12) in those patients with comorbid allergic rhinitis 
Endpoints to be formally tested with multiplicity adjustments are listed in the testing order in 
Section 2.4.4.3 and Table 6. 
2.1.3.2.2.1 Annualized rate of loss of asthma control (LOAC) event  
LOAC event during the study is defined as any of the following: 
x 
6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 
24 hour period (compared to baseline) on 2 consecutive days or 
x 
20% decrease in pre-bronchodilator FEV1 compared to baseline or 
x 
Increase in ICS dose 4 times than the dose at Visit 2 or 
x 
A decrease in AM or PM peak flow of 30% or more on 2 consecutive days of treatment, 
based on the defined stability limit. The Treatment Period stability limit is defined as the 
respective mean AM or PM PEF obtained over the last 7 days prior to randomization 
(Day1); or 
x 
Severe exacerbation event 
The annualized rate of LOAC events during the 52-week treatment period is defined as the 
number of LOAC events with onset during the 52-week treatment period per patient-year. 
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2.1.3.2.2.2 Annualized rate of severe exacerbation events resulting in hospitalization or 
emergency room visit  
Annualized rate of severe exacerbation event requiring hospitalization or emergency room visit 
(requiring systemic corticosteroids) during the 52-week treatment period and annualized rate of 
severe exacerbation event requiring hospitalization during the 52-week treatment period will also 
be analyzed. 
2.1.3.2.2.3 Time to first severe exacerbation event/first LOAC event 
If a patient has an event during the 52-week treatment period, regardless the patient is on the study 
treatment or discontinues the study treatment but remains in the study,  the time to first severe 
exacerbation event/first LOAC event is defined as (onset date of the first severe 
exacerbation/LOAC event – randomization date +1). 
If a patient has no severe exacerbation event/LOAC event during the study up to Visit 18/Week 
52, then the patient will be considered as free of event until the date of visit at Visit 18 or the last 
contact date, whichever happens earlier. 
2.1.3.2.2.4 Disease-specific efficacy measures 
2.1.3.2.2.4.1 Spirometry 
A spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory 
Society (ERS) recommendations will be used. Spirometry should be performed in accordance with 
the ATS/ ERS guidelines (1). For pre-bronchodilator measured parameters, including FEV1, PEF, 
FVC and FEF 25-75%, spirometry will be performed after a wash out period of bronchodilators 
according to their duration of action, for example, withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding the last 
dose of LABA for at least 12 hours (ultra-long acting LABA like vilanterol should be withheld for 
at least 24 hours) and withholding the last dose of LAMA for at least 24 hours. This will be 
verified before performing the measurements. 
At least three measurements fulfilling the ATS acceptability and repeatability criteria should be 
obtained at every visit, if possible. The acceptability criteria must be applied before the 
repeatability criteria. Unacceptable maneuvers must be discarded before applying the repeatability 
criteria. If a subject fails to provide repeatable and/or acceptable maneuvers, an explanation 
should be recorded. The largest FEV1 and largest FVC will be recorded after the data are 
examined from all of the acceptable curves, even if they do not come from the same curve. The 
FEF 25-75% should be obtained from the single curve that meets the acceptability criteria and 
gives the largest sum of FVC plus FEV1 (best test). 
Japanese Respiratory Society predicted set are used for Japanese patients to calculated percent 
predicted FEV1 and NHANES III predicted set for all other patients. 
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2.1.3.2.2.4.2 Reversibility 
A reversibility test will be administered following pulmonary function testing after asthma 
medications have been withheld for the appropriate intervals. Subjects will receive two to up to 
four puffs of albuterol/salbutamol or levalbuterol/levosalbutamol from a primed MDI. 
Alternatively and only if it is consistent with usual office practice (to be documented), reversibility 
may be performed using inhalation of nebulized albuterol/salbutamol or 
levalbuterol/levosalbutamol. Spirometry may be repeated several times within 30 minutes after 
administration of bronchodilator. FEV1 reversibility is calculated as Post-bronchodilator FEV1 - 
Pre-bronchodilator FEV1 and percent FEV1 reversibility is calculated as (Post-bronchodilator 
FEV1 - Pre-bronchodilator FEV1) / Pre-bronchodilator FEV1 * 100. 
2.1.3.2.2.4.3 Post-bronchodilator (Post-BD) FEV1 
Post-BD FEV1 is obtained from the spirometry performed after administration of reliever 
medications for reversibility test.  The largest FEV1 will be recorded after the data are examined 
from all of the acceptable curves. 
2.1.3.2.2.4.4 ACQ (Asthma Control Questionnaire) 
The ACQ was designed to measure both the adequacy of asthma control and change in asthma 
control which occurs either spontaneously or as a result of treatment. 
2.1.3.2.2.4.4.1 ACQ-7 (Asthma Control Questionnaire, 7-question version) 
The ACQ-7 has 7 questions- the first 5 items assess the most common asthma symptoms: 1. 
frequency in past week awoken by asthma during the night, 2. severity of asthma symptoms in the 
morning, 3. limitation of daily activities due to asthma, 4. shortness of breath due to asthma and 
5. wheeze, plus 6. short-acting bronchodilator use and 7. FEV1 (pre-bronchodilator % predicted). 
Patients are asked to recall how their asthma has been during the previous week and to respond to 
the symptom questions on a 7-point scale (0=no impairment, 6=maximum impairment) (see 
Appendix E). 
Clinic staff scores the FEV1% predicted on a 7-point scale. The questions are equally weighted 
and the ACQ score is the mean of the 7 questions and therefore between 0 (totally controlled) and 
6 (severely uncontrolled). 
Higher score indicates lower asthma control. Patients with a score below 1.0 reflect adequately 
controlled asthma and patients with scores above 1.0 reflecting inadequately controlled asthma. 
On the 7-point scale of the ACQ-7, a change or difference in score of 0.5 at patient level is the 
smallest change that can be considered clinically important, corresponding to the Minimal 
Clinically Important Difference (MCID) defined by the developer. 
Based on the manual of ACQ (2), any more than one missing value is not acceptable. If more than 
one of the questions have missing value, the global score is invalid and will be considered as 
missing. If only one question has missing score, it will be imputed (pro-rated) using the completed 
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questionnaires from the previous visit. For instance, answer to question 5 is missing at Visit 2, and 
all questions are completed at Visit 1. Then the question 5 score at Visit 2 is imputed as: (sum of 
score at Visit 2/sum of scores excluding question 5 at Visit 1) × score of question 5 at Visit 1. If 
the questionnaire from the previous visit is not complete either, the missing value will be imputed 
as the average of the completed questions within the current visit. 
2.1.3.2.2.4.4.2 ACQ-5 (Asthma Control Questionnaire, 5-question version) 
The ACQ-5 is short version of ACQ-7, and ACQ-5 score is the mean of the first 5 questions of 
ACQ-7 and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). The last two 
questions on the ACQ-7, assessing lung functions, are not included in ACQ-5. Higher score 
indicates lower asthma control. Patients with a score below 1.0 reflect adequately controlled 
asthma and patients with scores above 1.0 reflect inadequately controlled asthma. On the 7-point 
scale of the ACQ-5, a change or difference in score of 0.5 at patient level is the smallest change 
that can be considered clinically important, corresponding to the Minimal Clinically Important 
Difference (MCID) defined by the developer. 
Missing scores will be handled in the same way as for ACQ-7 score. 
2.1.3.2.2.5 Disease-specific, daily efficacy assessment 
On a daily basis throughout the study, the patient uses an electronic diary / PEF meter to: 
x 
Measure morning and evening PEF 
x 
Respond to the morning and evening asthma symptom scale questions 
x 
Indicate the number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief 
x 
Record the number of nocturnal awakenings due to asthma symptoms 
2.1.3.2.2.5.1 Morning (AM) and Evening (PM) Peak expiratory flow (PEF) 
At screening (Visit 1), patients will be issued an electronic diary/PEF. Patients will be instructed 
on the use of the device, and written instructions on the use of the electronic PEF meter will be 
provided to the patients. In addition, the investigator will instruct the patients on how to record the 
following variables in the electronic PEF meter: 
x 
AM PEF performed within 15 minutes after arising (between 5:30 AM and 10 AM) prior 
to taking any albuterol or levalbuterol 
x 
PM PEF performed in the evening (between 5:30 PM and 10 PM) prior to taking any 
albuterol or levalbuterol 
x 
Patients should try to withhold albuterol or levalbuterol for at least 6 hours prior to 
measuring their PEF 
x 
Three PEF efforts will be performed by the patient; all 3 values will be recorded by the 
electronic PEF meter, and the highest value will be used for evaluation 
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Baseline AM PEF will be the mean AM measurement recorded in the 7 days prior to 
randomization including the morning diary completed on the randomization day prior to the first 
administration of IMP, and baseline PM PEF will be the mean PM measurement recorded for the 
7 days prior to the randomization. There should be at least 4 days’ measurement out of the 7 days 
for setting up the period stability limit/baseline, and the first dosing visit should be rescheduled 
until data for 4 days are available. In case less than 4 days’ measurement is available during the 7 
days prior to randomization, the baseline AM/PM PEF is the mean of the 4 AM/PM PEF prior to 
and closest to randomization during the whole screening period. Calculation of periodical average 
of post-baseline AM/PM PEF is specified in Section 2.5.2. 
2.1.3.2.2.5.2 Asthma Symptom Score Numerical Rating Scale (NRS) 
Patients will record overall symptom scores in an electronic diary twice a day prior to measuring 
PEF. The patient’s overall asthma symptoms experienced during the waking hours will be 
recorded in the evening (PM symptom score). Symptoms experienced during the night will be 
recorded upon arising (AM symptom score). The baseline AM/PM symptom score will be 
computed following the same algorithm used for baseline AM/PM PEF. Scores range between 0-4 
with 0 indicating more mild symptoms and 4 indicating more severe symptoms. Calculation of 
periodical average of post-baseline AM/PM symptom score is specified in Section 2.5.2. 
2.1.3.2.2.5.3 Use of rescue/reliever medicine 
The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations will be recorded 
daily by the patients in an electronic diary/PEF meter. In the case that Nebulizer solutions are used 
as an alternative delivery method, the nebulizer dose will be converted to number of puffs 
according to Section 2.1.2.2. Each patient should be reminded that salbutamol/albuterol or 
levosalbutamol/levalbuterol should be used only as needed for symptoms, not on a regular basis or 
prophylactically. The baseline number of salbutamol/albuterol or levosalbutamol/levalbuterol 
inhalations/day will be based on the mean of the 7 days prior to randomization. 
A diary day is defined as the period beginning with an Evening diary, and ending with the 
following day’s Morning Diary. The baseline reliever med use will be calculated as follows: The 
mean of reliever puffs taken in each of the 7 diary days (minimum 4 diary days) prior to 
randomization, including the diary day that ends with the morning diary completed on the 
randomization day. A diary day cannot be included in the calculation if it is not complete, 
meaning if an evening or morning diary is missing for that diary day. Out of the 7 diary days, if 
less than 4 are incomplete, the baseline reliever use is the mean of reliever puffs in each of the 
complete dairy days. If 4 or more diary days are incomplete, the baseline reliever use is the mean 
of reliever puffs taken in the closest 4 diary days with complete reliever use information prior to 
randomization. Calculation of periodical average of post-baseline use of reliever puffs is specified 
in Section 2.5.2. 
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2.1.3.2.2.6 Patient-reported outcomes 
2.1.3.2.2.6.1 Asthma Quality of Life Questionnaire) Asthma Quality Of Life Questionnaire with 
Standardized Activities (AQLQ (S)) Self-Administered (12 years) 
The AQLQ(S) was designed as a self-administered patient reported outcome to measure the 
functional impairments that are most troublesome to adolescents and adults 12 years of age as a 
result of their asthma (see Appendix G). The instrument is comprised of 32 items, each rated on a 
7-point Likert scales from 1 to 7. The AQLQ(S) has 4 domains. The domains and the number of 
items in each domain are as follows: 
x 
Symptoms (12 items) 
x 
Activity limitation (11 items) 
x 
Emotional function (5 items) 
x 
Environmental Stimuli (4 items) 
Individual items are equally weighted. The overall score is the mean of response to each of the 32 
questions. The score of each domain is the mean of response to each of the questions in that 
domain. The overall score and domain scores ranges from 1 to 7. Higher scores indicate better 
quality of life.  
To have a valid overall score, it is not acceptable to have more than three missing responses or 
more than one missing response per domain. For the symptoms and activity limitation domain 
score, only one missing value per domain is acceptable. For the emotional function and 
environmental stimuli domain scores, no missing value is acceptable. For responses with more 
than acceptable amount of missing value(s), the overall or the domain score will be considered as 
missing. For responses with amount of missing value(s) within accept range, the missing score 
will be interpolated using the previous completions of the questionnaire following the similar 
algorithm used for ACQ. 
The instrument has been used in many clinical trials, and it has been shown to be reliable, valid 
(patient interviews), and sensitive to change. The patient level MCID for AQLQ(S) is 0.5 (3). 
2.1.3.2.2.6.2 22-item Sinonasal Outcome Test in those patients comorbid with bilateral nasal 
polyposis and/or chronic rhinosinusitis 
SNOT-22 is a validated questionnaire to assess the impact of chronic rhinosinusitis with or 
without nasal polyposis on health-related quality of life (see Appendix H). The SNOT-22 has 22 
items, 5 domains and a global score. The 5 domains include Nasal (range 0-30), Ear (range 0-15), 
Sleep (0-20), General and Practical (0-30), and Emotional (0-15). The range of the global score is 
0-110. Lower scores indicate less impact and the recall period is past 2 weeks. The domains and 
the items in each domain are as follows: 
x 
Nasal: item 2, 3, 4, 6, 7, 12 
x 
Ear: item 8, 9, 10 
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x 
Sleep: item 13, 14, 15, 16 
x 
General and Practical: item 1, 5, 11, 17, 18, 19 
x 
Emotional: item 20, 21, 22 
The global score is the sum of response to each of the 22 questions. For responses with some item 
scores are missing, the global score will be imputed as mean of the completed scoresu 22, 
providing at least 50% of items have been completed. If more than 50% of items are missing, the 
global score is set to missing. The score for each domain is the sum of response to each question 
in that domain. Missing score will be imputed as mean of the completed items in that 
domainu total number of items in that domain, providing at least 50% of items in that domain 
have been completed. If more than 50% of items in a domain are missing, the score for that 
domain is set to missing. 
2.1.3.2.2.6.3 Hospital Anxiety and Depression Scale 
The HADS is a general scale to detect states of anxiety and depression already used and validated 
in asthma, which includes HADS-A and HADS-D subscales (see Appendix I). The instrument is 
comprised of 14 items: 7 related to anxiety and 7 to depression. Each item on the questionnaire is 
scored from 0-3. The anxiety/depression score is the sum of the scores of the 7 related items; one 
can score between 0 and 21 for either anxiety or depression. And the total score is the sum of the 
scores of the 14 items ranging from 0-42. 
The HADS was found to perform well in assessing anxiety disorders and depression in both 
somatic and psychiatric cases and (not only in hospital practice for which it was first designed) in 
primary care patients and the general population (4). 
2.1.3.2.2.6.4 EQ-5D-5L 
EQ-5D-5L is a standardized health-related quality of life questionnaire developed by the EuroQol 
Group in order to provide a simple, generic measure of health for clinical and economic appraisal 
(5). EQ-5D is designed for self-completion by patients. 
The EQ-5D essentially consists of 2 pages - the EQ-5D descriptive system and the EQ VAS (see 
Appendix J). The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, and extreme problems. EQ-5D-5L health 
status will be converted into a single index value by using EQ-5D-5L value sets based on UK 
population. The EQ Visual Analogue Scale (VAS) records the respondent’s self-rated health on a 
vertical visual analogue scale. The EQ VAS ‘thermometer’ has endpoints of 100 (Best imaginable 
health state) at the top and 0 (Worst imaginable health state) at the bottom. 
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2.1.3.2.2.6.5 Standardized Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ(S))+12 in 
those patients with comorbid allergic rhinitis. 
RQLQ(S)+12 (see Appendix K) is a self-administered questionnaire with standardized activities 
developed to measure health-related quality of life signs and symptoms that are most problematic 
in those 12 to 75 years of age, as a result of perennial or seasonal allergic rhinitis. There are 28 
items on the RQLQ(S) in 7 domains: 1. Activities (3 items), 2. Sleep (3 items), 3. Non-nose/eye 
Symptoms (7 items), 4. Practical Problems (3 items), 5. Nasal Symptoms (4 items), 6. Eye 
Symptoms (4 items) and 7. Emotional (4 items). The RQLQ(S)+12 responses are based on 7-point 
Likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). Individual 
items within the RQLQ(S)+12 are equally weighted. The overall score is calculated as the mean 
score of all items. And the score for each domain is calculated as the mean score of the items in 
each of the domains. No interpolation will be performed for missing scores. Higher scores 
indicated more health-related quality of life impairment (lower scores better). The instrument 
takes approximately 7 minutes to complete. An MID of 0.5 has been established as the minimal 
important difference indicative of a clinically meaningful change (6). 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, such 
as clinical laboratory data, vital signs, ECG and physical examination. 
Observation period  
The observation period will be divided into 4 epochs: 
x 
The screening epoch is defined as the time from the signed informed consent date up to 
the time prior to first administration of the IMP. 
x 
 The treatment epoch is defined as the time from the first administration of the IMP to the 
last administration of the IMP + 14 days or until rollover to the LTS12551 study.  
x 
The residual treatment epoch is defined as the time from the last administration of the 
IMP +15 days to the last administration of the IMP + 98 days or until rollover to the 
LTS12551 study. 
x 
The treatment-emergent adverse event period will include both treatment and residual 
treatment epochs. 
x 
The posttreatment epoch is defined as the period of time starting the day after the end of 
the treatment-emergent adverse event period up to the end of the study (defined as last 
protocol planned visit or the resolution/stabilization of all serious adverse events and 
adverse events with pre-specified monitoring). 
The on-study observation period is defined as the time from start of treatment until the end of the 
study (defined as last protocol planned visit or lost to follow-up or the resolution/stabilization of 
all serious adverse events and adverse events with pre-specified monitoring).  
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2.1.4.1 Adverse events variables 
Adverse event observation period  
x 
Pretreatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of IMP 
x 
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period 
x 
Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period 
All adverse events (including serious adverse events and adverse events with pre-specified 
monitoring/of special interests) will be coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the version of Medical Dictionary for Regulatory Activities (MedDRA) currently in 
effect at Sanofi at the time of database lock. 
Adverse events of special interest (AESI) and other selected AE groupings will be searched 
based on the criteria in Table 3:  
Table 3 - Criteria for adverse events of special interest and other selected AE groupings 
AE Grouping 
Criteria 
AESI 
 
Anaphylactic reaction 
Anaphylactic reaction algorithmic approach (Introductory Guide for 
Standardised MedDRA Queries (SMQs) Version 18.1): includes 
anaphylactic reaction narrow SMQ (20000021) terms; for selection 
based on occurrence of multiple events, the events must have occurred 
within 24 hours of each other 
Hypersensitivity (medically 
reviewed) 
SMQ hypersensitivity (20000214) narrow search and [AE corrective 
treatment/therapy=’Y’ or Action taken with IMP=’Drug withdrawn’ or 
Action taken with IMP=’Drug interrupted’] followed by blinded medical 
review (documented process) for selection of relevant events  
Serious injection site 
reactions or severe 
injection site reactions that 
last longer than 24 hours  
HLT = ‘Injection site reaction’ and either with serious status, or with 
severe status and (AE end date/time - AE start date/time)  24 hours or 
ongoing 
Severe or serious infection Primary SOC = ‘Infections and infestations’ and with severe or 
serious status 
Parasitic infection 
Infection Type ‘Parasitic’ checked on eCRF Infection Defined as AESI 
Complementary Form 
Opportunistic infection 
Infection Type ‘Opportunistic’ checked on eCRF Infection Defined as 
AESI Complementary Form 
Drug-related hepatic 
disorder 
Drug-related hepatic disorders-Comprehensive search narrow SMQ 
(20000006) 
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AE Grouping 
Criteria 
Pregnancy 
Primary SOC = ‘Pregnancy, puerperium and perinatal conditions’ or PT 
in (Aborted pregnancy, False negative pregnancy test, Pregnancy test 
positive, Pregnancy test urine positive, Ectopic pregnancy termination) 
Symptomatic overdose with 
IMP 
Is the event a Symptomatic Overdose with IMP? is answered Yes on 
AE eCRF. 
Symptomatic overdose with 
non-IMP 
Is the event a Symptomatic Overdose with non-IMP? is answered Yes 
on AE eCRF 
Other selected AE 
grouping 
 
Injection site reaction  
HLT = ‘Injection site reaction’  
Malignancy 
Sub-SMQ (20000091)– Malignant or unspecified tumors 
Suicidal behavior 
PT in (Completed suicide, Suicidal ideation, Depression suicidal, 
Suicidal behavior, Suicide attempt) 
Partner pregnancy 
PT in (Pregnancy of partner, Miscarriage of partner) 
Conjunctivitis (narrow) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, 
Conjunctivitis viral, Atopic keratoconjunctivitis) 
Conjunctivitis (broad) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, 
Conjunctivitis viral, Atopic keratoconjunctivitis, Blepharitis, Dry eye, Eye 
irritation, Eye pruritus, Lacrimation increased, Eye discharge, Foreign 
body sensation in eyes, Photophobia, Xerophthalmia, Ocular 
hyperaemia, Conjunctival hyperaemia) 
Hypereosinophilia 
HLT = ‘Eosinophilic disorders’ or PT = ‘Eosinophil count increased’ 
In addition, AESIs reported by the investigator in CRF will be summarized separately. 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
x 
Death on-study:  deaths occurring during the on-study observation period 
x 
Death on-treatment:  deaths occurring during the treatment-emergent adverse event period  
x 
Death poststudy:  deaths occurring after the end of the study  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values after conversion will be analyzed in standard international 
units and international units will be used in listings and tables. The same set of analysis will also 
be prepared in US units. 
 
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Blood samples for clinical laboratories will be taken at Visit 1(Week -4±1), Visit 2 (Week 0), 
Visit 4 (Week 4), Visit 6 (Week 8), Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 20), 
Visit 11 (Week 24), Visit 12 (Week 28), Visit 13 (Week 32), Visit 14 (Week 36), Visit 15 (Week 
40), Visit 16(Week 44), Visit 17(Week 48), Visit 18(Week 52), Visit 19(Week 56), Visit 20(Week 
60), Visit 21(Week 64) and early termination unless otherwise specified.  The laboratory 
parameters will be classified as follows:   
x 
Hematology  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood 
cell count, platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
x 
Clinical chemistry  
- 
Metabolism:  glucose, total cholesterol, total protein, creatine phosphokinase 
- 
Electrolytes:  sodium, potassium, chloride, bicarbonate 
- 
Renal function:  creatinine, blood urea nitrogen, uric acid 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin (in case of values above the normal 
range, differentiation in conjugated and non-conjugated bilirubin), albumin 
- 
Pregnancy test: serum ȕ-human chorionic gonadotropin (all female patients) will be 
performed at screening (Visit 1) in women of childbearing potential  
- 
Hepatitis screen: clinical laboratory testing at Visit 1 and Visit 17 (only applicable for 
patients planned to participate in the OLE study) add hepatitis screen including 
hepatitis B surface antigen (HBs Ag), hepatitis B Surface antibody (HBs Ab), hepatitis 
B core antibody (HBc Ab), hepatitis C virus antibodies (HCV Ab), In case of results 
showing HBs Ag (negative), HBs Ab (negative) and HBc Ab (positive), an HBV DNA 
testing may be performed prior to randomization to rule out a false positivity if the 
investigator believes the patient is a false positive, or to clarify the serological status if 
the investigator finds it unclear to interpret in absence of known HBV infection. In 
case of results showing HCV Ab (positive), an HCV RNA testing may be performed to 
rule out a false positivity, if the investigator believes the patient is a false positive. 
- 
Hepatitis B viral load will be tested at Visit 2, then every 12 weeks until Visit 14 and 
end of treatment period for patients in Japan or other countries/regions if there is local 
regulatory requirement who are HBs Ag negative and HBs Ab positive at screening. 
- 
HIV screen: anti-HIV-1 and HIV-2 antibodies will be tested at Visit 1 and Visit 17 
(only applicable for patients planned to participate in the OLE study) 
- 
Anti-nuclear antibody (ANA) will be tested at Visit 1 and Visit 17 (only applicable 
for patients planned to participate in the OLE study) 
Note: Anti-ds DNA antibody will be tested if ANA is positive (1:160 titer).  
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x 
Serum immunoglobulins (limited to Visit 1(Week -4±1), Visit 8 (Week 12), Visit 11 
(Week 24), Visit 14 (Week 36), Visit 18(Week 52), and Visit 21 (Week 64)): quantitative 
immunoassays for total IgG, IgG subclasses 1-4, IgM, and IgA. 
Urine samples will be collected as follows:  
x 
Urinalysis (limited to Visit 1(Week -4±1), Visit 8 (Week 12), Visit 11 (Week 24), Visit 14 
(Week 36), Visit 18(Week 52), and Visit 21 (Week 64)): Urine dipstick analysis specific 
gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen and 
bilirubin (by dipstick). If any parameter on the dipstick is abnormal, a urine sample should 
be sent to the central laboratory for testing. If positive for proteins, microscopic analysis is 
performed by central laboratory.  
x 
A urine dipstick pregnancy test will be performed at Visit 2 prior to randomization and 
Visit 4 (Week 4), Visit 6 (Week 8), Visit 8 (Week 12), Visit 9 (Week 16), Visit 10 (Week 
20), Visit 11 (Week 24), Visit 12 (Week 28), Visit 13 (Week 32), Visit 14 (Week 36), 
Visit 15 (Week 40), Visit 16(Week 44), Visit 17(Week 48), Visit 18(Week 52),Visit 
21(Week 64)  
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include:  including blood pressure (mmHg), heart rate (beats per minute), respiratory 
rate (breaths per minute), body temperature (degrees Celsius) and body weight (kg) will be 
measured at the screening and randomization visits (Visits 1 and 2) and every subsequent visit. 
Height (cm) will be measured at screening (Visit 1) for all patients and will be measured 
throughout the study for adolescent patients. Vital signs will be measured in the sitting position 
using the same arm at each visit, and will be measured prior to receiving investigational product at 
the clinic visits. 
2.1.4.5 Electrocardiogram variables 
One recording of a standard 12-lead ECG will be performed centrally at Visit 1(Week -4±1), Visit 
3 (Week 2), Visit 4 (Week 4), Visit 8 (Week 12), Visit 11 (Week 24), Visit 14 (Week 36), Visit 
18(Week 52), and Visit 21 (Week 64). At the post-randomization visits, ECGs will be performed 
prior to investigational product administration. A minimum of 3 complexes in an appropriate lead 
(lead II) will be averaged to determine the PR-interval, QT/QTc-interval, QRS-complex and heart 
rate will be measured for each ECG. All ECG recordings will be centrally read by independent 
experts.  
2.1.4.6 Physical Examination 
Physical examinations will be performed at Visit 1(Week -4±1), Visit 11 (Week 24), Visit 
18(Week 52), and Visit 21 (Week 64) including an assessment of general appearance, skin, eyes, 
ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, and extremities. All 
deviations from normal will be recorded, including those attributable to the patient’s disease. 
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Refer to Section 1.2 Study Flow Chart for the schedule of physical examination performed 
throughout this study. 
2.1.5 Pharmacokinetic variables  
Predose serum dupilumab concentrations at Visit 2 (Day 1), dupilumab trough levels at Week 2, 
Week 4, Week 8, Week 12, Week 16, Week 24, Week 36, Week 52 and follow-up serum 
dupilumab at Week 56, Week 60, Week 64 will be provided. 
2.1.6 Anti-drug antibody (ADA) variables  
Anti-dupilumab antibody (ADA) status (negative or titer value, if positive in the ADA assay) at 
Visit 2 (Day 1), Week 12, Week 24, Week 52 and follow up at Week 64 will be provided. Patients 
who discontinue early from treatment or patients who choose not to participate in the OLE study 
visit may be asked to return to the clinic to have additional ADA samples collected for analysis 
based on the overall clinical presentation at that time.  
Status in the ADA assay will be classified as the following: 
1. Pre-existing immunoreactivity is defined as:  
An ADA positive response in the assay at baseline with all post treatment ADA results 
negative, OR an ADA positive response at baseline with all post treatment ADA responses 
less than 4-fold over baseline titer levels. 
2. Treatment-emergent response is defined as:  
An ADA positive response in the assay post first dose, when baseline results are negative 
or missing. 
3. Treatment-emergent ADA responses are further classified as Persistent, Indeterminate or 
Transient 
a) Persistent Response - defined as a treatment-emergent ADA response with two or more 
consecutive ADA positive sampling time points, separated by greater than (>) 12-week 
period (84 days), with no ADA negative samples in between. 
b) Indeterminate Response - defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay  
c) Transient Response - defined as a treatment-emergent response that is not considered 
persistent OR indeterminate 
4. Treatment-boosted response is defined as:   
An ADA positive response in the assay post first dose that is greater-than or equal to 4-fold 
over baseline titer levels, when baseline results are positive. 
Titer values (Titer value category) 
x 
Low (Titer < 1000) 
x 
Moderate (1,000  Titer  10,000) 
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x 
High (Titer > 10,000) 
ADA positive samples will be further characterized for presence of neutralizing antibody response 
in the NAb assay. 
2.1.7 Pharmacodynamics/genomics endpoints  
Eotaxin-3, eosinophil cationic protein (ECP), total IgE and Thymus and Activation-Regulated 
Chemokine (TARC) will all be assayed at Visit 2(Week 0), Visit 8 (Week 12), Visit 11 (Week 
24), Visit 14 (Week 36) and Visit 18(Week 52). 
Periostin will be assayed at Visit 2(Week 0), Visit 4 (Week 4), Visit 8 (Week 12) and Visit 
18(Week 52). And antigen-specific IgE panels will be collected at Visit 2(Week 0), Visit 8 (Week 
12) and Visit 18(Week 52). 
Blood eosinophil count will be measured as part of the standard 5-part WBC differential cell count 
on a hematology autoanalyzer. 
Exhaled nitric oxide will be analyzed using a NIOX instrument (Aerocrine AB, Solna, Sweden), 
or similar analyzer using a flow rate of 50 mL/s, and reported in parts per billion (ppb). This 
assessment should be conducted prior to spirometry and following a fast of at least 1 hour at Visit 
1(Week -4±1), Visit 2 (Week 0), Visit 3 (Week 2),Visit 4 (Week 4), Visit 8 (Week 12), Visit 9 
(Week 16), Visit 10 (Week 20), Visit 11 (Week 24), Visit 14 (Week 36), Visit 17(Week 48), Visit 
18(Week 52), Visit 19(Week 56), Visit 20(Week 60), Visit 21(Week 64) 
Pharmacogenetic testing is optional and voluntary. A separate written informed consent form must 
be signed before sampling. For those patients who signed the optional pharmacogenetic informed 
consent form, blood samples for exploratory genetic analysis of DNA or RNA will be collected at 
the study visit as specified in the study flow chart, and these samples will be stored for future 
analysis. 
2.1.8 Vaccine response 
Subjects planning to receive vaccinations for tetanus (alone or combined), influenza, 
pneumococcus or meningococcus during the study may optionally sign a separate informed 
consent for collection of 2 blood samples for assay of vaccine IgG in serum for each vaccine: the 
first should be drawn within 6 weeks prior to vaccination and then the second should be drawn 3 
to 4 weeks after vaccination (up to 6 weeks afterward allowed). Vaccinations should preferably 
occur after completion of at least 12 weeks of treatment, while remaining in compliance with the 
patient’s recommended immunization schedule. Blood collections should be conducted at 
regularly scheduled study visits but, if this is not feasible, could also be done at unscheduled 
visits. The details on the date(s) of vaccination and the specific vaccines that are administered, 
such as brand and antigenic strains, should be collected (see Appendix L). 
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2.1.9 Health economic endpoints  
A questionnaire of health care resource utilization (reliever medication, specialist visit, 
hospitalization, emergency or urgent medical care facility visit, outcome, sick leaves, school days 
loss, etc) will be administered at Visit 2 and every 4 weeks thereafter. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients signed the informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report summary table: 
x 
Screened patients 
x 
Screen failure patients and reasons for screen failure 
x 
Nonrandomized but treated patients 
x 
Randomized patients 
x 
Randomized but not treated patients 
x 
Randomized and treated patients 
x 
Patients who did not complete the 52-week treatment as per protocol 
x 
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
x 
Patients who withdraw from study prior to Week 52 
x 
Patients who withdraw from study prior to Week 52 by main reason for study 
discontinuation. 
x 
Patients who withdraw from study 
x 
Patients who withdraw from study by main reason for study discontinuation 
x 
Status at last study contact 
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.  This summary will be provided by treatment group and may also be further subgrouped by 
region/stratum as applicable. 
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Randomization by error 
Patient randomized twice 
Stratification error 
Patient switched to another site 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population, but will be included in the safety population. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
2.3.1 Efficacy populations 
The primary efficacy analysis population will be the ITT population as defined in Section 2.3.1.1. 
2.3.1.1 Intent–to-treat population  
The intent-to-treat population is the randomized population analyzed according to the treatment 
group allocated by randomization.  
Patients will be analyzed in the treatment group to which they are randomized. 
2.3.2 Safety population 
The safety population is defined as:  
x 
All patients who actually received at least 1 dose or part of a dose of the IMP, analyzed 
according to the treatment patients actually received. 
In addition:  
x 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized 
x 
For patients on placebo but accidentally exposed to dupilumab, the treatment group 
allocation for as-treated analysis will be the lowest exposed dupilumab dose group. 
x 
For patients on placebo but accidentally exposed to the other placebo dose, the treatment 
group allocation for as-treated analysis will be the treatment as randomized. 
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x 
For patients on dupilumab but accidentally receive different treatment from the planned, 
the actual treatment group allocation for as-treated analysis will be the lowest exposed 
dupilumab dose group. 
2.3.3 Population for pharmacokinetics/pharmacodynamics analyses 
The PK population will consist of all patients in the safety population with at least one evaluable 
serum concentration data. Patients will be analyzed according to the treatment actually received. 
ADA population will consist of all patients in the safety population who had at least one 
reportable ADA results (either ‘ADA negative’ or ‘ADA positive’) after first dose of the study 
treatment.  
Biomarkers will be analyzed in the exposed population, consisting of patients in the safety 
population. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group.  
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.  Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population for any treatment group. 
Parameters described in Section 2.1.1  will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  
Medical and surgical history will be summarized by treatment group and by system organ class 
(SOC) and preferred term (PT) sorted by internationally agreed order of SOC and by the 
decreasing frequency of PT within SOC based on the overall incidence across treatment groups. 
Atopic medical history will be summarized separately.  
No statistical testing on demographic and baseline characteristic data will be performed.  
No specific description of the safety parameters will be provided at baseline.  If relevant, the 
baseline values will be described along with each safety analysis. 
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2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be presented for the randomized population.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 3 
digits of the ATC class (therapeutic category).  All ATC codes corresponding to a medication will 
be summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore patients may be counted several times for the same 
medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
Concomitant medication received during first IMP to last IMP +14 days and concomitant 
medication received during first IMP to last IMP +98 days will be summarized separately. The 
tables for concomitant medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the incidence in the dupilumab 300 q2w group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
In addition, inhaled corticosteroid in combination with other controllers and reliever medications 
will be summarized separately. 
On a daily basis throughout the study, the patient uses an electronic diary to record daily use of 
ICS in combination with other controllers as used just prior to screening. The controller drugs will 
not be dispensed or supplied by the sponsor. 
2.4.2.1 ICS in combination with other controllers  
ICS and other asthma controller medications will be identified as the medications reported on the 
‘Prescribed Asthma Controller Medications’ eCRF page. 
Prior asthma controller medications will be summarized by treatment group sorted by decreasing 
frequency of standard medication name on the incidence in the overall treatment group. 
Concomitant asthma controller medications will be summarized by treatment group sorted by 
decreasing frequency of standard medication name on the incidence in the dupilumab 300 q2w 
group. 
The total daily dose of ICS in asthma controller medication at randomization will be classified as 
medium-dose or high-dose according to Appendix C. If a patient takes more than one medication 
containing ICS, the ICS dose of different products will be standardized according to equivalent 
dose specified in Table 4 and Table 5. The equivalent dose is determined based on the thresholds 
in Appendix C.  After conversion, the total daily dose for inhaled corticosteroid will be calculated 
and classified as medium or high dose. 
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Table 4 – Equivalent dose for inhaled corticosteroids for adults and adolescents ( 12 years) 
Inhaled corticosteroid  
Equivalent dose (mcg) to 500 mcg Fluticasone 
propionate (DPI or HFA) 
FLUTICASONE FUROATE 
200-* 
BECLOMETASONE DIPROPIONATE (CFC) 
1000 
BECLOMETASONE DIPROPIONATE (HFA) 
400 
BUDESONIDE (DPI) 
800 
CICLESONIDE (HFA) 
320 
MOMETASONE FUROATE 
440 
TRIAMCINOLONE ACETONIDE 
2000 
ADAPTED FROM GINA 2016 GUIDELINES 
HFA=hydrofluoroalkane, DPI= Dry Powder Inhaler 
* Fluticason furoate (FF) dose >=200 mcg is converted to equivalent fluticasone propionate(DPI or HFA) dose of  (FF dose +1)u2.5; FF dose 
<200 mcg is converted to equivalent fluticasone propionate (DPI or HFA) dose of FF dose u2.5. 
Example: A patient received 400 mcg budesonide (DPI) and 440 mcg mometasone furoate. They are equivalent to 250 mcg and 500 mcg 
fluticasone propionate correspondingly. The combined total daily dose is equivalent to 750 mcg fluticasone propionate and classified as high 
dose. 
Table 5 – Equivalent dose of inhaled corticosteroid for adults and children (Japan) 
Inhaled corticosteroid 
Equivalent dose (mcg) to 400 Fluticasone 
propionate (DPI or HFA) 
FLUTICASONE FUROATE 
100 
BECLOMETHASONE DIPROPIONATE -HFA 
400 
CICLESONIDE -HFA 
400 
BUDESONIDE-DPI 
800 
BUDESONIDE INHALATION SUSPENSION 
1.0 mg 
BUDESONIDE INHALATION SOLUTION 
1000 
MOMETASONE FUROATE-DPI 
400 
Adapted from Japanese Guideline for Adult Asthma 2014 and Japanese Guideline for Childhood Asthma 2014 
Example: A patient received 400 mcg Beclomethasone dipropionate -HFA and 400 mcg Ciclesonide-HFA. They are both equivalent to 400 
fluticasone propionate. The combined total daily dose is equivalent to 800 fluticasone propionate. 
Number and percentage of patients on high-dose ICS, medium-dose ICS, any non-ICS controller 
medication, LABA, LAMA and LTRA at baseline will also be summarized. 
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2.4.2.1.1 Compliance 
During the study, the daily intake of each prescribed asthma controller medication will be 
recorded on the electronic diary every evening. Compliance for the controller medications with 
ICS component and overall compliance to all prescribed controller medications will be calculated 
for each patient. For each day, a patient is considered as compliant with the prescribed controller 
medication with ICS component if the actual dose of each controller medication with ICS 
component is same as or greater than the prescribed dose. Similarly, a patient is considered as 
compliant with all controller medication if the actual dose of each controller medication is same as 
or greater than the prescribed dose.  
Compliance for controller medication(s) with ICS component is defined as the number of days 
when the patient is compliant with the prescribed controller medication(s) with ICS component 
divided by the number of days the patient stays in the treatment period (from first dose to last dose 
+ 14 days). Overall controller medication(s) compliance is defined as the number of days when 
the patient is compliant with all prescribed controller medication divided by the number of days 
the patient stays in the treatment period. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data).  
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum).  In addition, duration of treatment exposure will 
also be summarized categorically by numbers and percentages for each of the following categories 
and cumulatively according to these categories:  
>0 and 2 weeks 
>2 and 4 weeks 
>4 and 8 weeks 
>8 and 12 weeks 
>12 and 16 weeks 
… 
…. 
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>48 and 52 weeks 
>52 weeks 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
2.4.3.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Percentage of compliance for a patient will be defined as the number of administrations that the 
patient was compliant divided by the total number of administrations that the patient was planned 
to take during the treatment epoch defined in Section 2.1.4. 
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.  
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum).  
The percentage of patients whose compliance is <80% will be summarized.  In addition, numbers 
and percentages of patients with at least 1 above-planned dose administration will also be 
provided, as well as numbers and percentages of patients with 0, (0, 20%], and >20% under-
planned dose administrations. 
Cases of overdose (defined as at least twice the intended dose during an interval of less than 11 
days) will constitute serious adverse events and will be listed as such.  More generally, dosing 
irregularities will be listed in Section 2.2.1. 
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2.4.4 Analyses of efficacy endpoints 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
2.4.4.1.1 Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period 
Primary statistical model (ITT analysis) and adjustment for covariates 
The primary analysis of the annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period is to assess the efficacy of dupilumab in an intention-to-treat 
setting. In this primary approach, off-treatment measurements of patients who prematurely 
discontinue treatment will be included for the analysis. Patients who permanently discontinue the 
study medication will be encouraged to return to the clinic for all remaining study visits. If a 
patient stays in study until the end of 52-week treatment period, all severe exacerbation events that 
happen  up to Visit 18 will be included in the primary analysis, regardless if the patient is on 
treatment or not. And the observation duration is defined as from randomization to Visit 18. If a 
patient withdraws from study prior to the end of 52-week treatment period, all observed severe 
exacerbation events up to the last contact date will be included in the analysis, and the observation 
duration is defined as from randomization to the last contact date. No imputation will be 
performed for the unobserved events that may happen after study discontinuation and up to Week 
52. This estimand compares the rate of severe exacerbation for the patients randomized to the 
dupilumab and placebo arms, regardless of what treatment patients actually received. It assesses 
the benefits of the treatment policy or strategy relative to placebo (7). 
The annualized rate of severe exacerbation events will be analyzed using a negative binomial 
regression model. The model will include the total number of events occurring during the 
observation period defined above as the response variable, with the four treatment groups, age, 
region (pooled country), baseline eosinophil strata, baseline ICS dose level and number of severe 
exacerbation events within 1 year prior to the study as covariates. Treatment groups, region, 
baseline eosinophil strata and baseline ICS dose level will be treated as categorical variable. Age 
and number of severe exacerbation events within 1 year prior to the study will be treated as 
continuous variable. Severe asthma exacerbation event prior to the study is defined as treatment 
with a systemic steroid (oral or parenteral) for worsening asthma at least once or hospitalization or 
emergency medical care visit for worsening asthma (as defined in section Section 2.1.1). Log 
transformed observation duration will be the offset variable.  
Pairwise comparisons of the annualized event rates between each dose of dupilumab and its 
matching placebo will be derived by testing each dupilumab group versus its matching placebo 
separately. The estimated annualized event rate for each treatment group and its two-sided 95% 
confidence intervals will be derived from the negative binominal model. The event rate ratio of 
each dupilumab group and its matching placebo, two-sided 95% confidence interval of the rate 
ratio based on the negative binomial model and its p-value will be provided.  
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Based on EMEA feedback, the rate difference between each dupilumab group and its matching 
placebo, two-sided 95% confidence intervals of the rate difference and its p-value derived using 
delta method will also be provided as supportive information.  
Sample SAS code can be found below: 
 
proc glimmix data=event; 
  class eosblgpn ics trt01pn cntygr1n; 
  model numevents=trt01pn age eosblgpn ics cntygr1n asmanum       
                  /offset=logdur dist=negbin link=log solution;                       
run; 
If the model fails to achieve convergence, different estimation algorithms will be applied 
following the order: defaultĺLAPLACEĺQUAD(8). If the issue still exists, other handling may 
be considered. The adjustment will be added to the footnote of the corresponding outputs. 
The gross estimated of annualized events rate will also be presented by each treatment group. 
Mean cumulative function plot will be provided for descriptive purpose. 
 
Estimand of clinical efficacy of dupilumab versus placebo 
An analysis to assess the efficacy of dupilumab if patients adhere to the treatment as directed is 
also specified. In this approach, off-treatment measurements of patients who prematurely 
discontinue treatment will be excluded from the analysis. A negative binomial model with the 
same set of covariates as specified in the primary analysis will be used. This model will include 
severe exacerbation events occurring during the treatment epoch as the response variable and the 
log transformed duration of the treatment epoch will be the offset variable. This approach defines 
the estimand to be the efficacy of dupilumab with treatment adherence (7).  
Handling of missing data 
If patients withdraw from the study before Visit 18 (Week 52), severe exacerbation events that 
may occur after study discontinuation will not be observed.  These patients are considered as 
patients with missing data on severe exacerbation. Number of patients with missing data, reasons 
and timing for patient withdrawals will be summarized by treatment groups. Summary statistics of 
selected demographic and baseline disease characteristics will be provided for patients with 
missing data and patients with complete data separately. Graphical summaries of the dropout 
patterns such as Kaplan-Meier plots of time to study discontinuation with different reasons of 
discontinuation may be provided to examine if there is any different missing pattern between 
treatment groups. In addition, following sensitivity analyses will be conducted to assess the 
robustness of the conclusion of the main model 
x 
Pattern mixture model - multiple imputation (PMM-MI) 
For each patient with missing data of severe exacerbation events, individual monthly event 
probability will be estimated using observed data with adjustment of the planned treatment 
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group, age, region (pooled country), baseline eosinophil strata, baseline ICS dose level, and 
number of severe exacerbation events within 1 year prior to the study. And binary event will 
be imputed on monthly basis using multiple imputation.  
x 
Control-based PMM-MI 
For each patient with missing data of severe exacerbation events, individual monthly event 
probability will be estimated using observation in the matching placebo arms only, with 
adjustment of age, region (pooled country), baseline eosinophil strata, baseline ICS dose level, 
and number of severe exacerbation events within 1 year prior to the study. And binary event 
will be imputed on monthly basis using multiple imputation. 
x 
Tipping point analysis 
For each patient with missing data of severe exacerbation events, the monthly event will be 
imputed in a similar fashion as PMM-MI based on various odds values. If the patient is on 
dupilumab, the predicted odds will be increased; if the patient is on Placebo, the predicted  
odds value will be decreased. The adjusted rate will then be used to impute the number of 
events that would occur during the missing observation period. A sequence of 
increasing/decreasing ratio will be used to generate different imputed datasets.  
For each of the above methods, a negative binomial model will be fitted using each of the 
complete datasets composed of observed and imputed data, including the total number of observed 
and imputed events during the 52 weeks as the response variable, with the treatment group, age, 
region (pooled country), baseline eosinophil strata, baseline ICS dose level and number of severe 
exacerbation events within 1 year prior to the study as covariates. Log transformed observation 
duration will be the offset variable for patients who complete the 52-Week treatment/study period, 
and log transformed 52 weeks will be the offset variable for patients who discontinue the study 
before Visit 18 (Week 52). SAS MIANALYZE procedure will be used to generate statistical 
inferences by combining results from the analysis with each dataset using Rubin’s formula. 
More details of the imputation and analyses methods are provided in Appendix D. 
 
Subgroup analyses 
To assess consistency of treatment effects across the subgroup levels, subgroup analyses will be 
performed for the annualized rate of severe exacerbation event during the 52-week treatment 
period by: 
x 
Age group: < 18, 18-64,  65 years; < 18 ,  18 years 
x 
Gender (Male, Female) 
x 
Region (Asia: Japan, South Korea and Taiwan; Latin America: Argentina, Brazil, 
Colombia, Chile and Mexico; East Europe: Hungary, Poland, Russia, Turkey and Ukraine; 
Western Countries: Australia , Canada, France, Germany, Italy, South Africa, Spain, 
United Kingdom and USA) 
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x 
Territory (North America: Canada and USA; European Union: France, Germany, Hungary, 
Italy, Poland, Spain and United Kingdom; Rest of World: Argentina, Australia, Brazil, 
Colombia, Chile, Japan, Mexico, Russia, South Africa, South Korea, Taiwan, Turkey and 
Ukraine) 
x 
Race (Caucasian/White, Black/of African descent, Asian/Oriental, all the other) 
x 
Ethnicity (Hispanic, non-Hispanic) 
x 
Baseline blood eosinophil level ( 0.3 Giga/L, <0.3 Giga/L;   0.15 Giga/L, < 0.15 Giga/L) 
x 
Background ICS dose levels at randomization (medium, high) 
x 
Background controller type at randomization (ICS and LABA only, ICS and LABA and 
Anti-leukotrienes only, Other; ICS, LABA and any third controller, Other) 
x 
Baseline FEV1 ( 1.75, > 1.75 L) 
x 
ACQ-5 ( 2, >2) 
x 
Number of severe asthma exacerbation prior to the study as defined in Section 2.1.1  
(1,>1) 
x 
Baseline weight (< 70,  70 - < 90,  90 kg; <60,  60 kg) 
x 
Baseline BMI (< 25, 25- <30,  30 kg/m2) 
x 
Smoking history (Former, Never) 
x 
Atopic medical condition (Yes, No) 
x 
Age of onset of asthma (<18, 18-40, >40 years) 
x 
Baseline predicted FEV1% (<60%, 60%-90%) 
x 
Baseline periostin(NG/ML) (< median,  median) 
x 
Baseline fractional exhaled nitric oxide (FeNO) (< 25,  25- < 50, 50 ppb) 
Treatment by subgroup interaction and its p-value will be derived from a negative binomial 
model. This model will include the total number of events occurring during the observation period 
as the response variable, with the four treatment groups, age, region (pooled country), baseline 
eosinophil strata, baseline ICS dose level, number of severe exacerbation events within 1 year 
prior to the study, subgroup (if different than the aforementioned covariates) and treatment by 
subgroup interaction as covariates. Log transformed observation duration will be the offset 
variable. If quantitative treatment by subgroup interaction is detected with nominal p-value < 0.05 
for any subgroup factor, the Gail-Simon test will be performed to evaluate possible qualitative 
interaction. Summary statistics of severe exacerbations will be provided within each subgroup. 
Forest plot of relative risks and corresponding CIs and forest plot of risk differences and 
corresponding CIs comparing each dupilumab dose group vs. its matching placebo for the 
subgroups will be provided. 
For local submission, efficacy analyses may be performed in specific countries/regions, eg, Japan. 
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Loading dose evaluation (Sustained treatment effect evaluation) 
To examine if the loading dose has any confounding effect on annualized rate of severe 
exacerbation during the 52-week randomized treatment period, a sensitivity analysis for the 
annualized rate of severe asthma exacerbation will be performed. It will include severe 
exacerbation events occurring after the first four weeks and 12 weeks, respectively, and only on-
treatment events will be included to avoid possible confounding effect due to off-treatment data. 
Due to potential insufficient number of events after excluding data from the first 12 week, two 
dupilumab groups will be combined and two placebo groups will be combined. Results of the 
sensitivity analysis will be compared to the result of on-treatment analysis including all on-
treatment severe exacerbation events during the study. 
2.4.4.1.2 Absolute change from baseline in pre-bronchodilator (pre-BD) FEV1 at Week 12 
Primary statistical model (ITT analysis) and adjustment for covariates 
The primary analysis of change from baseline in pre-BD FEV1 at Week 12 is to assess the efficacy 
of dupilumab in a real-world setting. The absolute change from baseline in FEV1 at Week 12 will 
be analyzed using a mixed-effect model with repeated measures (MMRM) approach. The model 
will include change from baseline in pre-BD FEV1 values up to Week 12 as response variables, 
and treatment, age, sex, baseline height, region (pooled country), baseline eosinophil strata, 
baseline ICS dose level, visit, treatment by-visit interaction, baseline pre-BD FEV1 value and 
baseline-by-visit interaction as covariates. Treatment groups, sex, region, baseline eosinophil 
strata, baseline ICS dose level, and visit will be treated as categorical variables. Age and height 
will be treated as continuous variable. For patients who discontinue the treatment before Week 12, 
they will be asked and encouraged to return to the clinic for all remaining study visit and the 
additional off study-treatment pre-BD FEV1 values measured up to Week 12 will be included in 
the primary analysis. For patients who withdraw from the study before Week 12, pre-BD FEV1 
values will be missing after study discontinuation. No imputation will be performed for missing 
values in the primary analysis. This estimand compares the change from baseline in pre-BD FEV1 
for the patients randomized to the dupilumab and placebo arms, regardless of what treatment 
patients actually received. It assesses the benefits of the treatment policy or strategy relative to 
placebo (7). 
An unstructured correlation matrix will be used to model the within-patient errors. Parameters will 
be estimated using restricted maximum likelihood method with the Newton-Raphson algorithm. 
Statistical inferences on treatment comparisons for the change from baseline in pre-BD FEV1 at 
Week 12 will be derived from the mixed-effect model. Difference in LS mean change from 
baseline, the corresponding 95% CI and the p-value with Kenward-Roger adjustment will be 
provided for comparison for each dupilumab group against its matching placebo. In addition, 
descriptive statistics including number of patients, mean, standard error and LS mean of change 
from baseline will be provided.  
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A sample SAS code can be found below: 
 
proc mixed data=adsd.adre method=reml; 
 
where paramcd='FEV1' and avisitn ge 3 and avisitn le 8 and ittfl='Y'; 
 
class subjid sex eosblgpn ics trt01pn avisitn cntygr1n; 
 
model chg = trt01pn sex age height ics eosblgpn cntygr1n avisitn 
trt01p*avisitn base base*avisitn/ddfm=kr residual; 
 
repeated avisitn/type=un subject=subjid; 
 
lsmeans trt01pn*avisitn /pdiff cl ; 
     estimate '300 mg q2w vs Placebo 2ml q2w at Week 12 Visit 8'  
     trt01pn 0 -1 0 1  trt01pn*avisitn   0 0 0  0 
 
 
 
      
           0 0 0 -1   
                                         0 0 0  0 
                                         0 0 0  1/ cl;   
run; 
 
If MMRM model fails to achieve convergence due to complexity of model specification, we may 
add some procedures to handle this issue including:  1) using maximum likelihood estimation 
instead of restricted maximum likelihood method; 2) covariance structure selection to reduce the 
number of unknown parameters to be estimated, the path is UNĺTOEPHĺTOEPĺAR(1)ĺCS. 
The adjustment will be added to the footnote of the corresponding outputs. 
Estimand of clinical efficacy of dupilumab versus placebo  
To assess the treatment effect when the patients adhere to the study treatment as directed, 
on-treatment pre-BD FEV1 measurements will be analyzed using the similar MMRM model as for 
the primary analyses, including same set of covariates and estimation algorithm. The model will 
include on-treatment change from baseline in pre-BD FEV1 values up to Visit 8 (Week 12) as 
response variables. A pre-BD FEV1 value is considered as on-treatment if it’s measured before or 
on the last dose date + 14 days. 
 
Sensitivity analyses with different censoring methods for pre-BD FEV1 potentially 
confounded by systemic corticosteroid use 
In addition, two sets of sensitivity analyses with different methods of handling pre-BD FEV1 
measurements confounded by the systemic corticosteroid use will be performed: 
x 
Censoring method 1: pre-BD FEV1 measurements collected from systemic corticosteroid 
start date to systemic corticosteroid end date + 14 days   will be excluded in order to 
reduce the confounding effect of systemic corticosteroids 
x 
Censoring method 2: All pre-BD FEV1 measurements collected on and after first day of 
systemic corticosteroid use will be excluded. 
The above two censoring methods will be applied to both primary analyses and on-treatment 
analysis. On-treatment analysis with data censoring method 1 will be used to provide treatment 
effect size estimates without confounding effect of systemic corticosteroid use. 
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Handling of missing data 
If a patient misses scheduled pre-BD FEV1 measurement during the first 12-week treatment, or 
withdraws from the study before Visit 8 (Week 12), he/she will have missing pre-BD FEV1 data 
at some time points up to Week 12. Descriptive statistics of pre-BD FEV1 by visit up to Week 12 
will be summarized for patients with some missing data and patients with complete data up to 
Week 12 separately.  Number of patients with missing pre-BD FEV1, reasons and timing for 
missing pre-BD FEV1 will be summarized by treatment groups. In addition, following sensitivity 
analyses will be conducted to assess the robustness of the conclusion of the main model: 
x 
Pattern mixture model-multiple imputation (PMM-MI) 
Missing pre-BD FEV1 values will be imputed multiple times with adjustment for covariates 
including treatment groups, baseline eosinophil groups, age, sex, height, region, baseline ICS 
dose level and reason of treatment discontinuation. Each of the complete datasets will be 
analyzed using the ANCOVA model with change from baseline in pre-BD FEV1 at Week 12 
as the response variable,  treatment, age, sex, height, region (pooled country), baseline 
eosinophil strata, baseline ICS dose level, and baseline pre-BD FEV1 value as covariates. 
Then the SAS MIANALYZE procedure will be used to generate statistical inference by 
combining results using Rubin’s formula. 
x 
Control based PMM-MI 
The analysis is similar as the standard PMM-MI described above, except that it assumes that 
after withdrawal from the study, patients from the dupilumab groups would exhibit the same 
future evolution of pre-BD FEV1 as patients on the placebo who were not exposed to 
dupilumab. 
x 
Tipping point analysis 
First, missing values will be imputed by PMM-MI as illustrated above. The imputed values in 
placebo group will then be shifted by adding a sequence of positive values and the imputed 
values in dupilumab group will be shifted by subtracting a sequence of positive values. For 
each combination of the shift parameters, each of the imputed and shifted datasets will be 
analyzed with the ANCOVA model and their results will be combined using Rubin’s formula 
to generate statistical inference. LS mean difference between dupilumab and placebo in change 
from baseline in pre-BD FEV1 at week 12 and the corresponding p-values will be provided for 
each combination of shift parameters. 
More details of the imputation and analyses methods are included in Appendix D. 
Subgroup analysis 
To assess the consistency treatment effects across the subgroup levels, subgroup analyses will be 
conducted for the change from baseline in pre-BD FEV1 at Week 12 with the same set of 
subgroups as defined for the annualized rate of severe exacerbation events. Treatment-by-
subgroup interaction at Week 12 and its p-value will be derived from a MMRM model. The model 
will include change from baseline in pre-BD FEV1 values up to Week 12 as response variables, 
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and treatment, age, sex, height, region (pooled country), baseline eosinophil strata, baseline ICS 
dose level, visit, treatment by-visit interaction, baseline pre-BD FEV1 value,  baseline-by-visit 
interaction, subgroup (if different than the aforementioned covariates), subgroup-by-treatment 
interaction and subgroup-by-treatment-by-visit interaction as covariates. If quantitative treatment 
by subgroup interaction at Week 12 is detected with nominal p-value < 0.05 for any subgroup 
factor, the Gail-Simon test will be used to test the qualitative interaction. Summary statistics of 
change from baseline in pre-bronchodilator FEV1 will be provided within each subgroup. Forest 
plot of LS mean difference and corresponding CIs comparing each dupilumab dose group vs. its 
matching placebo for the subgroups will be provided. 
Distribution of change from baseline in pre-BD FEV1 
Cumulative distribution function of change from baseline in pre-BD FEV1 at Week 12 and Week 
52 will be presented. 
For each subgroup, a MMRM model will be used to analyze change from baseline in pre-BD 
FEV1 at Week 12. Change from baseline in pre-BD FEV1 up to Week 12 will be included as 
response variable. Treatment groups, age, sex, height, region (pooled country), baseline eosinophil 
strata, baseline ICS dose level, visit, treatment by-visit interaction, baseline pre-BD FEV1 value 
and baseline-by-visit interaction will be included as covariates. LS mean change from baseline in 
pre-BD FEV1 at Week 12 for each treatment group and LS mean difference in change from 
baseline in pre-BD FEV1 at Week 12 for each dupilumab treatment group compared to placebo 
will be derived from the MMRM model for each subgroup. 
2.4.4.2 Analyses of secondary efficacy endpoints 
2.4.4.2.1 Absolute/percent change from baseline for continuous endpoints 
The key secondary endpoint, percent change from baseline in pre-bronchodilator FEV1 at Week 
12, will be analyzed in the same way as for change from baseline in FEV1 at Week 12, with the 
only difference that percent changes, instead of absolute changes, from baseline in FEV1 up to 
Week 12 will be included as the response variables. MMRM model including measurements up to 
Week 52 will also be used to derive LS mean change at all time-points. Differences in LS means, 
the corresponding 95% CI and the p-value will be provided for comparisons of each dupilumab 
dose against its matching placebo along with descriptive statistics. 
Change from baseline in ACQ-5 and AQLQ at Week 24 will be analyzed using MMRM including 
change from baseline up to Week 24 as response variables, regardless if the patient is on treatment 
or not when the endpoint is measured. The model will include treatment, age, region (pooled 
country), baseline eosinophil strata, baseline ICS dose level, visit, treatment by-visit interaction, 
baseline endpoint value, and baseline-by-visit interaction as covariates. MMRM model including 
measurements up to Week 52 will also be used to derive LS mean change at all time-points. 
Differences in LS means, the corresponding 95% CI and the p-value will be provided for 
comparisons of each dupilumab dose against its matching placebo along with descriptive statistics. 
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Change from baseline in other continuous endpoint at all time-points will be analyzed using 
MMRM model including measurements up to Week 52. The model will include change from 
baseline in the endpoint values from Week 2 to Week 52 as response variables, regardless if the 
patient is on treatment or not when the endpoint is measured, and treatment, age, sex, baseline 
height, region (pooled country), baseline eosinophil strata, baseline ICS dose level, visit, treatment 
by-visit interaction, baseline endpoint value and baseline-by-visit interaction as covariates. Sex 
and baseline height will be included as covariates only in the models for spirometry parameters. 
Differences in LS means, the corresponding 95% CI and the p-value will be provided for 
comparisons of each dupilumab dose against its matching placebo along with descriptive statistics. 
For post-bronchodilator FEV1, the rate of change in FEV1 (termed as FEV1 slope) will be 
compared between each dupilumab dose against its matching placebo. Change from baseline in 
post-bronchodilator FEV1 after Week 4 and after Week 8 will be analyzed correspondingly using 
linear mixed-effects model with treatment, age, sex, height, region (pooled country), baseline 
eosinophil strata, baseline ICS dose level, time since randomization, and treatment-by-time 
interaction and  baseline post-bronchodilator FEV1 as covariates. 
In addition to the MMRM analyses for change from baseline in ACQ-5, ACQ-7 and AQLQ total 
score a responder analysis will also be performed for these endpoints at Week 12, 24, 36 and 52.  
For ACQ-5 score, a logistic regression model will be used to compare percentage of patients who 
reached MCID (responders) in each dupilumab dose group against its matching placebo at the 
time points aforementioned correspondingly. Patients with change from baseline in ACQ-5  -0.5 
will be considered as responders. Patients with change from baseline in ACQ-5 >-0.5 or with 
missing value will be considered as non-responders. The model will include treatment, age, region 
(pooled country), baseline eosinophil strata, baseline ICS dose level, and baseline ACQ-5 score as 
covariates. Odds ratio of being a responder comparing each dupilumab dose group to its matching 
placebo group will be provided along with the corresponding 95% CI and p-value. Descriptive 
statistics including number and percentage of responders will also be provided. Responder 
analysis for ACQ-7 and AQLQ global score will be performed in the same way. For ACQ-7, a 
patient is considered as a responder if change from baseline in ACQ-7 score  -0.5, or as a non-
responder if change from baseline in ACQ-7 score > -0.5 or missing. For AQLQ global score, a 
patient is considered as a responder if change from baseline in AQLQ global score 0.5, or as a 
non-responder if change from baseline < 0.5 or missing. ACQ-7 score will also be analyzed in 
adolescent patient population separately. 
2.4.4.2.2 Annualized event rate 
Annualized rate of loss of asthma control (LOAC) event and annualized rate of severe 
exacerbation events resulting in hospitalization or emergency room visit during the 52-week 
placebo-controlled treatment period will be analyzed in the similar method as for the annualized 
rate of severe exacerbation events using a negative binomial regression model. The model will 
include the total number of events occurring during the 52 weeks as the response variable, with 
the treatment group, age, region (pooled country), baseline eosinophil strata, baseline ICS dose 
level and number of severe exacerbation events within 1 year prior to the study as covariates. Log 
transformed observation duration will be the offset variable.  
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Pairwise comparisons of the annualized event rates between each dose of dupilumab and its 
matching placebo will be derived by testing each dupilumab group versus its matching placebo 
separately. The estimated event rate for each treatment group and its two-sided 95% confidence 
intervals will be provided. The event rate ratio of each dupilumab group and its matching placebo, 
two-sided 95% confidence intervals of the rate ratio and its p-value will also be provided.  
2.4.4.2.3 Time to event variables 
A Cox regression model will be used to assess treatment differences in time to events defined in 
Section 2.1.3.2.2.3. 
The model will include the time to the first event as the dependent variable, and four treatment 
groups, age, region (pooled country), baseline eosinophil strata, baseline ICS dose level and 
number of severe exacerbation events within 1 year prior to the study as covariates.  Hazard ratio 
will be estimated for pairwise comparison between each dose of dupilumab and its matching 
placebo. The Kaplan-Meier method will be used to derive the probabilities that a patient would 
experience events up to Week 12, 24, 36 and 52 per each treatment group. Kaplan-Meier curves 
will be generated; quartiles and point probabilities will be calculated. Interval estimates will be 
calculated using 95% point wise confidence intervals. 
Sample SAS codes can be found as below: 
 
proc phreg data=timeto; 
class subjid eosblgpn ics trt01pn cntygr1n /param=GLM; 
model aval*CNSR(1) =trt01pn age eosblgpn ics cntygr1n asmanum; 
contrast ‘200 mg q2w vs Placebo rate ratio’ trt01pn –1 0 1 0 
0/estimate=exp; 
contrast ‘300 mg q2w vs Placebo rate ratio’ trt01pn 0 -1 0 1 
1/estimate=exp; 
run; 
2.4.4.3 Multiplicity issues 
To strongly control the type-I error rate for the primary family (two primary endpoints and two 
doses), a hierarchical testing procedure will be applied at a 2-sided 5% significant level, ie, each 
hypothesis will be formally tested only if the preceding one is significant at the 5% level. The 
hierarchy of the tests will be: 1) annualized severe exacerbation rate for 300 mg q2w versus 
placebo, 2) absolute change from baseline in FEV1 at Week 12 for 300 mg q2w versus placebo, 3) 
annualized severe exacerbation rate for 200 mg q2w versus placebo, 4) absolute change from 
baseline in FEV1 at Week 12 for 200 mg q2w versus placebo. 
If both doses are significant for both primary endpoints, a selective set of secondary endpoints will 
be tested following a hierarchical testing procedure at a 2-sided 5% significant level. The 
complete list of the endpoints with their testing order is specified in Table 6.   
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Table 6 – Hierarchical testing order 
 
 
Dupilumab 
 
Endpoints 
200 mg q2w 
300 mg q2w 
Annualized rate of severe exacerbation events during the 52-week treatment 
period - ITT population 
3 
1 
Primary 
endpoints 
Change from baseline in pre-bronchodilator FEV1 at Week 12 - ITT population 
4 
2 
Percent change from baseline in pre-bronchodilator FEV1 at Week 12 - ITT 
population 
11 
5 
Annualized rate of severe exacerbation events during the 52-week  treatment 
period - ITT population with baseline eosinophil >=0.15 Giga/L 
12 
6 
Change from baseline in pre-bronchodilator FEV1 at Week 12 - ITT population 
with baseline eosinophil >=0.15 Giga/L 
13 
7 
Annualized rate of severe exacerbation events during the 52-week treatment 
period - ITT population with baseline eosinophil >= 0.3 Giga/L 
14 
8 
Change from baseline in pre-bronchodilator FEV1 at Week 12 - ITT population 
with baseline eosinophil >= 0.3 Giga/L 
15 
9 
Annualized rate of severe exacerbation events during the 52-week treatment 
period - ITT population with baseline eosinophil <0.3Giga/L 
16 
10 
Annualized rate of severe exacerbation events during the 52-week treatment 
period - ITT population with high dose ICS at baseline 
22 
17 
Change from baseline in pre-bronchodilator FEV1 at Week 12 - ITT population 
with high dose ICS/LABA at baseline 
23 
18 
Change from baseline in AQLQ global score at Week 24 - ITT population 
24 
19 
Change from baseline in AQLQ global score at Week 24 - ITT population with 
baseline eosinophil >= 0.3 Giga/L 
25 
20 
Change from baseline in ACQ-5 score at Week 24 - ITT population 
26 
21 
Annualized rate of severe exacerbation events resulting in hospitalization or 
emergency room visit during the 52-week treatment period - ITT population 
28 
27 
Secondary 
endpoints 
Change from baseline in pre-bronchodilator FEV1 at Week 12 - ITT population 
with baseline blood eosinophil <0.3 Giga/L 
30 
29 
 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
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x 
The baseline value is defined as the last available value before the first dose of IMP. 
x 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (Appendix A) 
x 
PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.  
The number of all such patients will be the numerator for the on-treatment PCSA 
percentage. 
x 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. Number (%) of patients 
with at least 1 PCSA will be summarized regardless of baseline PCSA status and also by 
baseline PCSA status. 
x 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the endpoint value and/or the worst on-
treatment value.  The endpoint value is commonly defined as the value collected at the end 
of treatment.  If this value is missing, this endpoint value will be the closest value prior to 
the end of treatment epoch.  The worst value is defined as the nadir and /or the peak post-
baseline (up to the end of treatment epoch or EOT) according to the direction (minimum or 
maximum) of the abnormality as defined in the PCSA list 
x 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned.  
x 
All safety values including unscheduled measurements will be assigned to the appropriate 
safety analysis visit window defined in Section 2.5.3. 
2.4.5.1 Analyses of adverse events 
General information 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.  
Pretreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment or treatment-
emergent.  The algorithm for imputing date/time of onset will be conservative and will classify an 
adverse event as treatment emergent unless there is definitive information to determine it is 
pretreatment.  Details on classification of adverse events with missing or partial onset dates are 
provided in Section 2.5.3. 
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Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each treatment group, the number (n) and percentage (%) of patients experiencing an 
adverse event.  Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase.  The denominator for computation of percentages is 
the safety population within each treatment group. Sorting will be based on results for the 
dupilumab 300 mg q2w group. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
x 
Overview of treatment-emergent adverse events, summarizing number (%) of patients with 
any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
x 
All treatment-emergent adverse events by primary system organ class, showing number 
(%) of patients with at least 1 treatment-emergent adverse event, sorted by internationally 
agreed order of primary system organ class  
x 
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the SOC 
internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
x 
Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT  
x 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC.   
x 
All treatment-emergent adverse events regardless of relationship and related by primary 
SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 treatment-
emergent adverse event, sorted by the internationally agreed SOC order.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order 
x 
All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC  
x 
Number (%) of patients experiencing treatment-emergent adverse event(s) presented by 
primary and secondary SOC, HLGT, HLT, and PT sorted by the internationally agreed 
SOC order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
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x 
A listing of all treatment-emergent adverse events will be presented 
Analysis of all treatment-emergent serious adverse event(s) 
x 
All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order 
x 
All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
x 
All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 treatment-emergent serious adverse event, sorted by 
the internationally agreed SOC order and by decreasing incidence of PTs within each SOC.   
x 
A listing of all treatment-emergent serious adverse events will be presented 
Analysis of all treatment-emergent adverse event(s) leading to permanent treatment 
discontinuation or drug interruption 
x 
All treatment-emergent adverse events leading to permanent treatment discontinuation or 
drug interruption, by primary SOC, HLGT, HLT, and PT, showing the number (%) of 
patients sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, 
PT) will be presented in alphabetical order 
x 
All treatment-emergent adverse events leading to permanent treatment discontinuation or 
drug interruption, by primary SOC and PT, showing number (%) of patients with at least 
one TEAE, will be presented by SOC internationally agreed order and by decreasing 
incidence of PTs within each SOC. 
Analysis of adverse events of special interest (AESI) and other selected AE groupings 
x 
All treatment-emergent adverse events, by selected standardized MedDRA query (SMQ) 
and PT or by laboratory values (as in ALT elevation), showing the number (%) of patients 
with at least 1 PT, sorted by decreasing incidence of PTs within each SMQ 
x 
For each prespecified AESI and selected AE grouping, 
- 
Number (%) of patients with any specific TEAE 
- 
Number (%) of patients with any specific serious AE (regardless of treatment emergent 
status) 
- 
Number (%) of patients with any specific treatment emergent serious AE 
- 
Number (%) of patients with any specific AE leading to death 
- 
Number (%) of patients with any specific TEAE leading to permanent study drug 
discontinuation 
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- 
Number (%) of patients with any specific TEAE by maximum intensity, corrective 
treatment, and final outcome 
- 
Number of any specific TEAE adjusted by the exposure duration 
- 
All of the specific TEAE, by PT, showing the number (%) of patients, sorted by 
decreasing incidence of PT 
- 
Number of patients with any specific TEAE adjusted by the exposure duration at risk. 
For each specific TEAE, Kaplan-Meier estimates of cumulative incidence at Week 12, 
24, 36 and 52 and K-M plot may be provided to depict the course of onset over time if 
the number of events is large enough 
x 
Number (%) of patients with injection site reactions by the related injection. 
x 
Number (%) of patients with different number of injection site reactions. 
Analysis of pretreatment adverse events  
x 
All pretreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC 
x 
All serious pretreatment adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC 
x 
All pretreatment adverse events leading to permanent treatment discontinuation by primary 
SOC and PT, showing the number (%) of patients, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC 
x 
All pretreatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
If only a few patients have pretreatment adverse events leading to permanent treatment 
discontinuation, a listing will be presented instead of the summary table above. 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 
x 
Number (%) of patients who died by study period (on-study, on-treatment, poststudy)  
x 
Deaths in nonrandomized patients or randomized but not treated patients 
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x 
Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC .  
x 
All pretreatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
A listing of deaths will be provided. 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or worst on-treatment value) by treatment group.  For each continuous 
parameters listed in Section 2.1.4.3, mean changes from baseline with the corresponding standard 
error will be plotted over time in each treatment group. This section will be organized by 
biological function as specified in Section 2.1.4.3.  
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
For PCSA analyses, the laboratory measurements obtained at either scheduled or unscheduled 
visits should be used; and, both the centralized and local test results should be used, as long as 
their available dates/time is different from each other’s. Centralized data will be used 
preferentially to the local measures in the PCSA analyses when measurements are performed on 
the same date and at the same time for a given laboratory test. 
A listing of PCSAs will be provided. 
Drug-induced liver injury 
If there is any imbalance in the incidence of liver-related adverse events across the treatment 
groups, analysis of liver-related adverse events will be performed. 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity.  The proportion of patients with PCSA values at any 
postbaseline visit by baseline status will be displayed by treatment group for each parameter.  The 
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proportion of patients with PCSA values at any postbaseline visit will also be displayed by 
duration of exposure for each treatment group.  
Time to onset of the initial ALT and AST elevation (>3 x ULN) and total bilirubin elevation 
(>2 x ULN) (time to first observation of ALT > 3 x ULN or total bilirubin > 2 x ULN, whichever 
comes first) will be analyzed using Kaplan-Meier estimates, presented by treatment group.  
Consideration should be given to the impact of the spacing of scheduled tests.  A graph of 
distribution of peak values of ALT versus peak values of total bilirubin will also be presented.  
Note that the ALT and total bilirubin values are presented on a logarithmic scale. The graph will 
be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and a 
horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin 2 x ULN) with ALT, AST, alkaline 
phosphatase, total bilirubin, and the following complementary parameters:  conjugated bilirubin 
and creatine phosphokinase, serum creatinine, complete blood count, HCV RNA. 
Summarize the normalization by parameter (to 1 x ULN or return to baseline) of elevated liver 
function tests by categories of elevation (3 x, 5 x, 10 x, 20 x ULN for ALT and AST, 1.5 x ULN 
for alkaline phosphatase, and 1.5 x and 2 x ULN for total bilirubin), with the following categories 
of normalization:  never normalized, normalized despite treatment continuation of IMP, or 
normalized after IMP discontinuation.  Note that a patient will be counted only under the 
maximum elevation category. 
Change in Blood Eosinophil 
Mean changes from baseline in eosinophil with the corresponding standard error will be plotted 
over time in each treatment group for patients with baseline blood eosinophil < 0.5 Giga/L and 
patients with baseline blood eosinophil >=0.5 Giga/L. Number (%) of patients with post-baseline 
peak blood eosinophil >= 1 Giga/L, >=3 Giga/L and >=5 Giga/L will also be summarized in each 
treatment group and by baseline blood eosinophil status (All, <0.5 Giga/L,>=0.5 Giga/L). 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital signs variables (values and changes from baseline) will be calculated 
for each visit or study assessment (baseline, each postbaseline time point, last on-treatment and/or 
worst on-treatment value) by treatment group.  For all parameters, mean changes from 
baseline with the corresponding standard error will be plotted over time (at same time points) in 
each treatment group.  
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and/or according to the following 
baseline status categories:  
x 
Normal/missing 
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x 
Abnormal according to PCSA criterion or criteria 
2.4.5.5 Analyses of electrocardiogram variables 
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all ECG variables (central laboratory values and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each postbaseline time point, last 
on-treatment and/or worst on-treatment value) by treatment group.  For all parameters, mean 
changes from baseline with the corresponding standard error will be plotted over time (at the same 
time points) in each treatment group.  
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and/or according to the following 
baseline status categories:  
x 
Normal/missing 
x 
Abnormal according to PCSA criterion or criteria 
2.4.6 Analyses of pharmacokinetic and pharmacodynamics variables 
2.4.6.1 Pharmacokinetic analyses 
2.4.6.1.1 Analyses of serum concentrations of SAR231893 (REGN668) 
Serum concentrations of SAR231893 (REGN668) will be summarized in the PK population using 
arithmetic and geometric means, SD, standard error of the mean (SEM), coefficient of variation 
(CV), minimum, median and maximum per sampling time. If date and/or time of the drug 
injection and/or sampling is missing then the concentration will not be taken into account. For 
drug-treated patients, where concentration values are below the lower limit of quantification 
(LLOQ), one-half of the LLOQ will be used. Values will be expressed in the tables with no more 
than three significant figures. For patients in the placebo group, concentration values are below the 
LLOQ will be taken into account with a plasma concentration considered equal to 0. 
2.4.6.1.2 Analyses of ADA variables  
The following summary will be provided based on ADA population: 
x 
Number (%) of patients with pre-existing immunoreactivity 
x 
Number (%) of patients with treatment-emergent ADA 
x 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for patients with treatment-emergent ADA, and patients with 
persistent, indeterminate and transient ADA response 
x 
Number (%) of patient with transient treatment-emergent ADA  
x 
Number (%) of patients with persistent treatment-emergent ADA 
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x 
Number (%) of patients with indeterminate treatment-emergent ADA 
x 
Number (%) of patients with treatment-boosted ADA. 
x 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for  patients with treatment-boosted ADA 
x 
The summary statistics (including number, mean, SD, median, Q1, Q3, minimum and 
maximum) of the ratio of peak post-baseline titer to baseline titer for patients with 
treatment-boosted ADA 
x 
Listing of ADA peak titer levels and neutralizing antibody status  
x 
Number(%) of patients with neutralizing antibody status  
Kinetics of treatment-emergent ADA response 
Number (%) of patients with ADA treatment-emergent ADA positive response at each visit will 
be summarized by each dose regimen group. 
Plot of percentage of patients with ADA treatment-emergent ADA positive response at each visit 
will be provided by each dose regimen group. 
Impact of ADA on PK  
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
serum concentration of dupilumab may be explored for each dupilumab dose group. Plot of serum 
concentration of functional SAR231893 (REGN668) versus visit will be provided by ADA 
classifications for each dupilumab dose group. Individual patient plots of PK according to ADA 
status will be provided to determine which individuals may have had PK impacted by ADAs. 
Association of ADA with clinical efficacy endpoints 
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
following efficacy endpoints may be explored for each dupilumab dose group: 
x 
Annualized rate of severe exacerbation events 
x 
Change from baseline in Pre-BD FEV1 
Association of ADA with clinical safety endpoints 
Association of safety versus ADA status may be analyzed in the ADA population. The safety 
assessment may focus on the following events: 
x 
Severe injection site reactions last longer than 24 hours or serious injection site reactions 
x 
Hypersensitivity reactions (SMQ hypersensitivity narrow search and confirmed by medical 
review) 
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x 
Anaphylactic reactions (SMQ anaphylactic reaction narrow search) 
In response to AESI like anaphylaxis or hypersensitivity additional ADA samples closer to the 
event may be analyzed, based on the judgment of the medical investigator and/or medical monitor. 
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent and treatment-boosted) and safety may be explored. 
2.4.6.2 Pharmacodynamics/genomics analyses 
All biomarkers listed in Section 2.1.6  will be summarized in the Exposed population defined as 
patients who actually received at least 1 dose or part of a dose of the IMP.  Baseline values will be 
the last value collected prior to the first IMP. For randomized but not treated patients, baseline 
value will be the last value collected prior to the randomization. Descriptive statistics (including 
number, mean, SD, median, Q1, Q3, min, max) of biomarkers at baseline will be summarized. 
For all parameters including antigen-specific IgEs with a positive (0.35 IU/mL) incidence of 
greater than 25% at baseline, values at each visit, absolute change from baseline and percent 
changes from baseline will be summarized in descriptive statistics by treatment group and time 
point. Values reported as below the LLQ (lower limit of quantitation) will be imputed as a value 
one half of the LLQ. 
Number and percentage of patients with no positive (0.35 IU/mL) antigen-specific IgE result, 
with positive (0.35 IU/mL) result for only one antigen, and with positive (0.35 IU/mL) results 
for at least two antigens will be summarized by treatment group and time point. Same analysis 
will also be performed using LLQ as the threshold.  
Summary plots (mean +/- standard error of the mean) on values at each visit, absolute changes 
from baseline and percent changes from baseline will be provided for each biomarker by treatment 
group. 
Exploratory analysis of DNA/RNA will be addressed in a separate document. 
2.4.7 Analyses of vaccine response 
For patients who receive vaccination, vaccine IgG in serum prior and after vaccination will be 
summarized by treatment groups with descriptive statistics. 
2.4.8 Analyses of health economics variables 
Analyses of health care resource utilization will be performed under the responsibility of the 
Health Economics and Reimbursement Argumentation department of Sanofi. Methods and results 
will be made available in a separate report. 
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2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
 
Age is calculated as: 
Integer part of (informed consent date -birth date)/365.25 
 
Age of onset of asthma is calculated as: 
Integer part of (asthma onset date - birth date)/365.25 
Time since first diagnosis of asthma (years) is calculated as: 
(Year of randomization -Year of first diagnosis of asthma) + (month of randomization -
month of first diagnosis of asthma)/12 
Time since cessation of smoking is calculated as: 
(Year of randomization - Year of cessation)×12 + (month of randomization -month of 
cessation) 
Time since last asthma exacerbation (months) is calculated as: 
(Year of randomization – Year of last asthma exacerbation)×12 + (month of randomization 
– month of last asthma exacerbation) 
 
BMI is calculated as: 
Weight in kg / (height2 in meters) 
 
Smoking quantity (pack-year) is calculated as following: 
Number of pack-year= (packs smoked per day) u   (years as a smoker) 
 
Renal function formulas  
For patients  18 years old, creatinine clearance (CLcr) value will be derived using the equation of 
Cockroft and Gault: 
CLcr (ml/min) = (140 - age) u  weight (kg) u   (1 - 0.15 u  sex (0-M, 1-F))/ (0.814 u  creatinine 
(μmol/l)) 
 
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CLcr will be calculated using the last weight measurement on or before the visit of the creatinine 
measurement and age at the lab sampling date. Here age is calculated as following: 
Age = integer part of (lab sampling date - birth date)/365.25 
For patients < 18 years old, CLcr value will be derived using the equation of GFR Bedside 
Schwartz  
GFR (mL/min/1.73 m2) = k u  height (cm) / sCr (mg/dL)] , 
Where the coefficient k=0.65 for adolescent male patients, or k=0.55 for adolescent female 
patients. 
2.5.2 Data handling conventions for secondary efficacy variables 
Calculation of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations/day 
A diary day is defined as the period beginning with an Evening diary, and ending with the 
following day’s Morning Diary. The number of salbutamol/albuterol or 
levosalbutamol/levalbuterol inhalations per day is the sum of number of inhalations recorded in 
one diary day including the evening diary and the following day’s morning diary. 
Periodical average of daily efficacy endpoints at designated study days 
For the daily efficacy endpoints, the time period used to calculate the periodical average at each 
designated study day is summarized in Table 7. Randomization day is used as the reference day 
(Day 1). 
Table 7 - Periodical average of daily efficacy assessment 
Time point 
Morning PEF, 
asthma symptom 
score, number of 
awakenings 
Evening PEF, 
asthma symptom 
score 
Number of inhalations/day of 
salbutamol/albuterol or 
levosalbutamol/levalbuterol for 
symptom relief 
Day 15 
2-15 
1-14 
Diary day 1-14 
Day 29 
16-29 
15-28 
Diary day 15-28 
Day 43 
30-43 
29-42 
Diary day 29-42 
Day 57 
44-57 
43-56 
Diary day 43-56 
Day 71 
58-71 
57-70 
Diary day 57-70 
Day 85 
72-85 
71-84 
Diary day 71-84 
Day 113 
86-113 
85-112 
Diary day 85-112 
Day 141 
114-141 
113-140 
Diary day 113-140 
Day 169 
142-169 
141-168 
Diary day 141-168 
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Time point 
Morning PEF, 
asthma symptom 
score, number of 
awakenings 
Evening PEF, 
asthma symptom 
score 
Number of inhalations/day of 
salbutamol/albuterol or 
levosalbutamol/levalbuterol for 
symptom relief 
Day 197 
170-197 
169-196 
Diary day 169-196 
Day 225 
198-225 
197-224 
Diary day 197-224 
Day 253 
226-253 
225-252 
Diary day 225-252 
Day 281 
254-281 
253-280 
Diary day 253-280 
Day 309 
282-309 
281-308 
Diary day 281-308 
Day 337 
310-337 
309-336 
Diary day 309-336 
Day 365 
338-365 
337-364 
Diary day 337-364 
Day 393 
366-393 
365-392 
Diary day 365-392 
Day 421 
394-421 
393-420 
Diary day 393-420 
Day 449 
422-449 
421-448 
Diary day 421-448 
Note: A diary day is defined as the period beginning with an Evening diary, and ending with the following day’s Morning 
Diary. For example, diary day 14 includes the evening dairy on day 14 and the morning dairy on day 15. 
 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of missing answer to the 7th question in ACQ-7  
If the score is missing from the site report, the FEV1 % predicted value from spirometry test will 
be used to derive the 7th score. Only the spirometry performed on the same day when ACQ-7 is 
evaluated will be used. And if there are multiple FEV1% predicted values available on the same 
day, the lowest one will be used to score the 7th item.  If the score of the 7th question is still 
missing but the questionnaire is complete at the prior visit, the missing score for the 7th question 
will be imputed as: (score of the 7th question at the prior visit)  (sum of scores of the first six 
questions at the current visit) / (sum of scores of the first six questions at the prior visit). If the 
questionnaire from the prior visit is not complete either or if the ACQ-7 score at the prior visit is 0, 
which makes it infeasible to implement the algorithm, the missing score will be imputed as the 
average of the other six questions at the current visit. If scores of the first six questions are missing, 
then the ACQ-7 score for the current visit will be missing.   
 
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Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the Investigational Product Administration report form page. If this 
date is missing, the exposure duration should be left as missing.  
The last dose injection 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 and concomitant 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 injection should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
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Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN if 
ULN 0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
2.5.4 Windows for time points 
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be the date of first IMP administration. Selected safety variables will be summarized 
by the analysis window define in Table 8 for the by visit descriptive analysis. All available values 
from central lab will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. For procedures planned on Visit 2, if it is done on the same date as the first IMP 
injection but the performance time is missing, it will belong to Visit 2 time window.
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Table 8 – Time window for safety endpoints 
 
 
Time windows for 
 
Visit 
Target 
Day 
Vital 
signs 
ECG 
endpoints 
Clinical 
lab testing
Serum 
Pregnancy 
test 
Urine 
Pregnancy 
test 
Urinalysis, Serum 
immunoglobulins 
Hepatitis B 
viral load 
Hepatitis 
screen, HIV 
screen, ANA 
and Anti-ds 
DNA 
antibogy 
Visit 1 
(Week -
4±1) 
-28±7 
<-14 
1- 
<-14 
1- 
 
1- 
 
1- 
Visit 2 
(Week 0) 
1 
-14-1- 
 
-14-1- 
 
1- 
 
1- 
 
Visit 3 
(Week 2) 
15 
1+-21 
1+-21 
 
 
 
 
 
 
Visit 4 
(Week 4) 
29 
22-35 
22-56 
1+-42 
 
1+-42 
 
 
 
Visit 5 
(Week 6) 
43 
36-49 
 
 
 
 
 
 
 
Visit 6 
(Week 8) 
57 
50-63 
 
43-70 
 
43-70 
 
 
 
Visit 7 
(Week 
10) 
71 
64-77 
 
 
 
 
 
 
 
Visit 8 
(Week 
12) 
85 
78-98 
57-126 
71-98 
 
71-98 
1-126 
1-126 
 
Visit 9 
(Week 
16) 
113 
99-126 
 
99-126 
 
99-126 
 
 
 
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Statistical Analysis Plan  
18-May-2017 
SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group -
 
 
Page 69 
 
 
Time windows for 
 
Visit 
Target 
Day 
Vital 
signs 
ECG 
endpoints 
Clinical 
lab testing
Serum 
Pregnancy 
test 
Urine 
Pregnancy 
test 
Urinalysis, Serum 
immunoglobulins 
Hepatitis B 
viral load 
Hepatitis 
screen, HIV 
screen, ANA 
and Anti-ds 
DNA 
antibogy 
Visit 10 
(Week 
20) 
141 
127-154 
 
127-154 
 
127-154 
 
 
 
Visit 11 
(Week 
24) 
169 
155-182 
127-210 
155-182 
 
155-182 
127-210 
127-210 
 
Visit 12 
(Week 
28) 
197 
183-210 
 
183-210 
 
183-210 
 
 
 
Visit 13 
(Week 
32) 
225 
211-238 
 
211-238 
 
211-238 
 
 
 
Visit 14 
(Week 
36) 
253 
239-266 
211-308 
239-266 
 
239-266 
211-308 
211-308 
 
Visit 15 
(Week 
40) 
281 
267-294 
 
267-294 
 
267-294 
 
 
 
Visit 16 
(Week 
44) 
309 
295-322 
 
295-322 
 
295-322 
 
 
 
Visit 17 
(Week 
48) 
337 
323-350 
 
323-350 
 
323-350 
 
 
1+ 
(electronic 


Statistical Analysis Plan  
18-May-2017 
SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group -
 
 
Page 70 
 
 
Time windows for 
 
Visit 
Target 
Day 
Vital 
signs 
ECG 
endpoints 
Clinical 
lab testing
Serum 
Pregnancy 
test 
Urine 
Pregnancy 
test 
Urinalysis, Serum 
immunoglobulins 
Hepatitis B 
viral load 
Hepatitis 
screen, HIV 
screen, ANA 
and Anti-ds 
DNA 
antibogy 
Visit 18 
(Week 
52) 
365 
351-378 
309-406 
351-378 
 
351-406 
309-406 
>308 
 
Visit 19 
(Week 
56) 
393 
379-406 
 
379-406 
 
 
 
 
 
Visit 20 
(Week 
60) 
421 
407-434 
 
407-434 
 
 
 
 
 
Visit 21 
(Week 
64) 
449 
>434 
>406 
>434 
 
>406 
>406 
 
 
 
1-: up to 1st dose date/time; 1+: after 1st dose date/time; 
 
 
 
 
 
 
 
 
 
 
(electronic 


Statistical Analysis Plan  
18-May-2017 
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Version number: 2 
 
Property of the Sanofi Group -
 
 
Page 71 
For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the randomization day. If a patient receives IMP prior to the randomization by 
mistake, the reference date of efficacy assessment will be the date of the first IMP administration 
for that patient. For the primary analyses, all available values of scheduled measurements will be 
assigned to the appropriate visit window according to Table 9. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. For the on-treatment sensitivity analyses, only scheduled measurements collected 
during the treatment epoch will be assigned to a time window.  
Table 9 – Time window for efficacy variables 
Time windows for  
Visit 
Target 
Day 
Pre-bronchodilator 
Spirometry, ACQ-5, 
ACQ-7 
Post-bronchodilator 
spirometry, 
reversibility 
AQLQ(S), EQ-5D-
5L, HADS, SNOT-
22, RQLQ(S)+12 
Visit 1 (Week -4±1) 
-28±7 
<-14 
 
 
Visit 2 (Week 0) 
1 
-14-1- 
1- 
1- 
Visit 3 (Week 2) 
15 
1+-21 
1+-21 
 
Visit 4 (Week 4) 
29 
22-35 
22-42 
 
Visit 5 (Week 6) 
43 
36-49 
 
 
Visit 6 (Week 8) 
57 
50-63 
43-70 
 
Visit 7 (Week 10) 
71 
64-77 
 
 
Visit 8 (Week 12) 
85 
78-98 
71-126 
1-126 
Visit 9 (Week 16) 
113 
99-126 
 
 
Visit 10 (Week 20) 
141 
127-154 
 
 
Visit 11 (Week 24) 
169 
155-182 
127-210 
127-210 
Visit 12 (Week 28) 
197 
183-210 
 
 
Visit 13 (Week 32) 
225 
211-238 
 
 
Visit 14 (Week 36) 
253 
239-266 
211-308 
211-308 
Visit 15 (Week 40) 
281 
267-294 
 
 
Visit 16 (Week 44) 
309 
295-322 
 
 
Visit 17 (Week 48) 
337 
323-350 
 
 
Visit 18 (Week 52) 
365 
351-378 
309-406 
309-406 
Visit 19 (Week 56) 
393 
379-406 
 
 
Visit 20 (Week 60) 
421 
407-434 
 
 
Visit 21 (Week 64) 
449 
>434 
>406 
>406 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time   
(electronic 


Statistical Analysis Plan  
18-May-2017 
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Version number: 2 
 
Property of the Sanofi Group -
 
 
Page 72 
For the pharmacokinetics/pharmacodynamics variables summary, the reference date for the 
derivation of relative days of measurements will be the date of first IMP administration if the 
patient is treated with study treatment, or the randomization date if the patient is not treated. 
Pharmacokinetics /pharmacodynamics variables will be summarized by the analysis window 
defined in Table 10 for the by visit descriptive analyses. All available values of measurements will 
be assigned to the appropriate visit window. In the event of multiple measurements of the same 
test in the same window, the one closest to the targeted visit date will be used for the by-visit 
summary. If they are at the same distance to the target day, the latest one will be used. For 
procedures planned on Visit 2, if it is done on the same date as the first IMP injection but the 
performance time is missing, it will belong to Visit 2 time window. 
Table 10 – Time window for pharmacokinetics/pharmacodynamics variables 
 
 
Time windows for 
Visit 
Target 
day 
Eotaxin-3, 
ECP, total 
IgE, 
TARC 
Exhaled 
NO 
Systemic 
drug 
concentration 
Anti-drug 
antibodies 
Antigen-
specific 
IgE 
Periostin 
Visit 1 (Week -4±1) 
-28±7 
 
<-14 
 
 
 
 
Visit 2 (Week 0) 
1 
1- 
-14-1- 
1- 
1- 
1- 
1- 
Visit 3 (Week 2) 
15 
 
1+-21 
1+-21 
 
 
 
Visit 4 (Week 4) 
29 
 
22-56 
22-42 
 
 
1+-56 
Visit 5 (Week 6) 
43 
 
 
 
 
 
 
Visit 6 (Week 8) 
57 
 
 
43-70 
 
 
 
Visit 7 (Week 10) 
71 
 
 
 
 
 
 
Visit 8 (Week 12) 
85 
1+-126 
57-98 
71-98 
1-126 
1-126 
57-224 
Visit 9 (Week 16) 
113 
 
99-126 
99-140 
 
 
 
Visit 10 (Week 20) 
141 
 
127-154 
 
 
 
 
Visit 11 (Week 24) 
169 
127-210 
155-210 
141-210 
127-266 
127-266 
 
Visit 12 (Week 28) 
197 
 
 
 
 
 
 
Visit 13 (Week 32) 
225 
 
 
 
 
 
 
Visit 14 (Week 36) 
253 
211-308 
211-294 
211-308 
 
 
 
Visit 15 (Week 40) 
281 
 
 
 
 
 
 
Visit 16 (Week 44) 
309 
 
 
 
 
 
 
Visit 17 (Week 48) 
337 
 
295-350 
 
 
 
 
Visit 18 (Week 52) 
365 
>308 
351-378 
309-378 
267-406 
>267 
>224 
Visit 19 (Week 56) 
393 
 
379-406 
379-406 
 
 
 
Visit 20 (Week 60) 
421 
 
407-434 
407-434 
 
 
 
Visit 21 (Week 64) 
449 
 
>434 
>434 
>406 
 
 
(electronic 


Statistical Analysis Plan  
18-May-2017 
SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group - 
 
 
Page 73 
 
 
Time windows for 
Visit 
Target 
day 
Eotaxin-3, 
ECP, total 
IgE, 
TARC 
Exhaled 
NO 
Systemic 
drug 
concentration 
Anti-drug 
antibodies 
Antigen-
specific 
IgE 
Periostin 
1-: up to 1st dose date/time or randomization if patient is not treated; 1+: after 1st dose date/time or randomization date if patient is 
not treated; 
 
 
 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be included in the 
by-visit summaries, computation of baseline, worst values, and PCSAs. 
2.5.6 Pooling of centers for statistical analyses 
Due to the large number of centers, the randomization is stratified by country. Due to small 
sample size in some countries, the countries will be pooled into regions as defined below for the 
analyses: 
x 
East Europe: Hungary, Poland, Russia, Turkey and Ukraine  
x 
Western Countries: Australia , Canada, France, Germany, Italy, South Africa, Spain, 
United Kingdom and USA 
x 
Asia: Japan, South Korea and Taiwan; 
x 
Latin America: Argentina, Brazil, Colombia, Chile and Mexico 
2.5.7 Statistical technical issues 
None. 
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Statistical Analysis Plan  
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SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group - 
 
 
Page 74 
3 
INTERIM ANALYSIS 
No interim analysis is planned. 
(electronic 


Statistical Analysis Plan  
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SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group - 
 
 
Page 75 
4 
DATABASE LOCK 
The database lock is planned based on the time when approximately 1638 patients (originally 
planned sample size) complete Week 52 visit or discontinue from the study before Week 52. 
Analyses will be based on all data collected up to this database lock and will be considered as the 
final analyses in the CSR. Additional data between database lock and last patient completing last 
visit will be summarized in CSR addendum. 
(electronic 


Statistical Analysis Plan  
18-May-2017 
SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group -
 
 
Page 76 
5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
(electronic 


Statistical Analysis Plan  
18-May-2017 
SAR231893 (REGN668)-EFC13579 -  dupilumab 
Version number: 2 
 
Property of the Sanofi Group -
 
 
Page 77 
6 
REFERENCES 
 
1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coateset A,et al. Standardization 
of spirometry. Series ‘‘ATS/ERS TASK FORCE: Standardization of Lung Function Testing" 
Edited by Brusasco V, Crapo R, and Viegi G. Eur Resir J. 2005;26:319-338. 
2. Juniper E. Asthma control questionnaire: Background, administration and analysis. 2012; 
QOL Technologies, West Sussex, UK. 
3. Juniper EH, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a 
disease-specific quality of life questionnaire. J Clin Epidemiol. 1994;47(1):81-7. 
4. Zigmond AS, Snaith PR. The Hospital Anxiety and Depression Scale. Acta Psychiatr 
Scand.1983;67(6):361–70. 
5. EUroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16(3):199-208. 
6. Juniper EF, Guyatt GH, O'Byrne PM, Viveiros M. Aqueous beclomethasone dipropionate 
nasal spray" regular versus "as required" use in the treatment of seasonal allergic rhinitis. J 
Allergy Clin Imunol 1990;863 (3Pr1):380-6. 
7. National Research Council of the National Academies. The Prevention and Treatment of 
Missing Data in Clinical Trials. Committee on National Statistics, Division of Behavioral and 
Social Sciences and Education. The National Academies Press, Washington, DC, 2010. 
8. Kiernan K, Tao J, Gibbs P. Tips and strategies for mixed modeling with SAS/STAT® 
procedures[C]//SAS Global Forum. 2012, 2012: 332-2012. 
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