Clinical trial NCT02948959
Conditions: Asthma
Sponsor: Sanofi
Start date: 2017-04-21; Completion date: 2020-08-26
Enrollment: 408 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of dupilumab in children 6 to less than (\<) 12 years of age with uncontrolled persistent asthma.

Secondary Objective:

To evaluate in children 6 to \<12 years of age with uncontrolled persistent asthma:

* The safety and tolerability of dupilumab.
* The evaluate the effect of dupilumab in improving participant reported outcomes including health related quality of life.
* The dupilumab systemic exposure and incidence of anti-drug antibodies.
* The evaluate the association between dupilumab treatment and pediatric immune responses to vaccines: any vaccination for tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza vaccine.

Detailed description:
The total study duration per participant was up to 69 weeks, consisted of a screening period of 3-5 weeks, a randomized treatment period of 52 weeks and a post-treatment period of 12 weeks.

Arms: arm 1: Placebo (for Dupilumab), subcutaneous (SC) injection every 2 weeks (q2w) for 52 weeks in combination with stable-dose background therapy of medium-dose inhaled corticosteroids (ICS) with a second controller medication (i.e., long-acting β2 agonist \[LABA\], long acting muscarinic antagonist \[LAMA\], leukotriene receptor antagonist \[LTRA\] or methylxanthines) or high-dose ICS alone or high-dose ICS with second controller medication. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. Participants were followed up for 12 weeks after last dose (i.e. up to Week 64). arm 2: Dupilumab 200 milligrams (mg) (in 1.14 milliliters \[mL\] for \>30 kilograms \[kg\] bodyweight \[BW\]) or 100 mg (in 0.67 mL for less than or equal to (\<=) 30 kg BW), SC injection q2w for 52 weeks in combination with stable-dose background therapy of medium-dose ICS with a second controller medication (i.e., LABA, LAMA, LTRA\] or methylxanthines) or high-dose ICS alone or high-dose ICS with second controller medication. Albuterol/salbutamol or levalbuterol/levosalbutamol was given as reliever medication. Participants were followed up for 12 weeks after last dose (i.e. up to Week 64).
Interventions: intervention 1: Dupilumab intervention 2: Placebo intervention 3: Asthma Controller Therapies intervention 4: Asthma Reliever Therapies
Intervention descriptions: intervention 1: Pharmaceutical form: Solution

Route of administration: Subcutaneous intervention 2: Pharmaceutical form: Solution

Route of administration: Subcutaneous intervention 3: Pharmaceutical form: Aerosol, capsules, tablets, oral solution

Route of administration: Inhaled, oral intervention 4: Pharmaceutical form: Nebulized, aerosol

Route of administration: Inhaled

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 
COMPOUND: DUPILUMAB/SAR231893 
A randomized, double-blind, placebo-controlled, parallel group study to evaluate 
the efficacy and safety of dupilumab in children 6 to <12 years of age with 
uncontrolled persistent asthma 
STUDY NUMBER: EFC14153 
VERSION DATE / STATUS: 18 October 2019 / Final 
Version Number: 
1 
EudraCT  
2016-001607-23 
IND Number 
105379 
WHO universal trial number: 
U1111-1179-4851 
Date: 
18-Oct-2019
Total number of pages: 
182 
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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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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/Countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
18-Oct-2019, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 02 
All 
18-Jun-2018, version 1 (electronic 5.0) 
Protocol Amendment 03 
All 
18-Jun-2018, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
Brazil 
02-Feb-2018, version 1 (electronic 1.0) 
Protocol Amendment 02 
Brazil 
02-Feb-2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 
All 
10-Mar-2017, version 1 (electronic 1.0) 
Protocol Amendment 01 
All 
10-Mar-2017, version 1 (electronic 1.0) 
Original Protocol 
 
04-Aug-2016, version 1 (electronic 1.0) 
AMENDED PROTOCOL 03 (18 October 2019) 
This amended protocol (amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
To change the study primary efficacy analysis population from an overall uncontrolled persistent 
asthma population to the subpopulation with evidence of either asthma with an eosinophilic 
phenotype or, more broadly, asthma with type 2 inflammatory phenotype. This is to be consistent 
with the observed efficacy seen in the pivotal Study EFC13579 (QUEST) as well as approved 
label indications for adults and adolescents with asthma. 
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Protocol amendment summary of change table 
 
Section # and Name 
Description of 
Change 
Brief Rationale 
Clinical Trial Summary 
11.3.1 Analysis population 
11.4.2.1 Analysis of Primary 
Efficacy Endpoint(s) 
11.4.2.2 Analyses of 
Secondary Efficacy 
Endpoints 
 
 
Change of primary efficacy 
analysis population from 
full intent-to-treat (ITT) to 
patients with either “asthma 
with an eosinophilic 
phenotype” or with “asthma 
with type 2 inflammatory 
phenotype”.  
4 Introduction and Rationale 
Description of type 2 
inflammatory phenotype 
population 
To support the change of primary efficacy analysis population 
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Clinical trial summary  
1 Flow chart 
1.1 Overview of study design 
11.1 Determination of 
sample size 
Change of study sample 
size. 
  
The population of interest is asthma patients with either “asthma 
with an eosinophilic phenotype” or “asthma with type 2 
inflammatory phenotype” based on the observed efficacy from 
the QUEST study and on the approved indications in different 
regions. With regard to these populations, the sponsor has 
designated a primary analysis population and additional 
secondary analysis populations based on these two populations 
of interest. The sponsor has updated the sample size needed to 
demonstrate efficacy based on these definitions for the primary 
analysis populations.  
The sample size calculation assumes a linear discontinuation 
rate (20% at 1 year), thus the average exposure duration for 
patients is 0.9 year. 
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Section # and Name 
Description of 
Change 
Brief Rationale 
Clinical trial summary 
11.4.2.3 Multiplicity 
considerations 
To specify that different 
hierarchy orders are to be 
used for US and US 
reference countries and EU 
and EU reference 
countries. 
Clinical trial summary 
8.4 Method of assigning 
patients to treatment group 
11.1 Determination of 
sample size 
 
 
Removal of the limit in 
enrolling patients according 
to background therapy with 
medium-dose ICS or blood 
eosinophil count level  
 
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Section # and Name 
Description of 
Change 
Brief Rationale 
Clinical trial summary 
To describe the Planned 
Database lock  
To define a date for database lock when all randomized patients 
complete the week 52 visit or discontinue from the study before 
week 52. 
Clinical trial summary  
9.3.1.3 Biomarker endpoints 
9.4.1 Exploratory endpoints 
 
To classify FeNO as a 
secondary endpoint instead 
of an exploratory endpoint. 
Based on the strong pharmacodynamics effect of FeNO on 
QUEST, the Sponsor anticipates similar effect in this population 
and feels appropriate to investigate it as secondary endpoint. 
1.2 Study flow chart 
footnote y  
9.2.3.5 Clinical Laboratory 
Safety Variables  
To describe the fasting 
status 
Fasting status will be described as no intake of any food or drink 
except for water for at least 8 hours. 
1.2 Study Flow Chart; 
footnote m 
8.1.4 Dosing schedule  
To allow for home dosing 
start after Visit 9 
 
IMP home administration is allowed at any visit following Visit 9 
after parents have been trained and PI has allowed.  
Clinical trial summary 
7.1 Inclusion Criteria 
To clarify that ACQ 5 data 
collected on V2 can be 
used for inclusion criterion 
01 
To clarify that ACQ 5 value at V2 shall be considered for the 
evidence of uncontrolled asthma described in inclusion criterion 
01 
9.2.2.4.1.1 ACQ-7-IA 
(Asthma Control 
Questionnaire–Interviewer 
Administered, 7-question 
version) 
To clarify how ACQ-7 value 
is calculated for statistical 
analysis 
 
To add the information that for statistical analysis, ACQ-7 global 
score is calculated by sponsor using the BMS post central 
reading value for %predicted FEV1 for the question 7 of the 
questionnaire.  
 
 
 
 
  
 
 
 
10.3.5 Procedure and 
Consequence for Patient 
Withdrawal from Study 
To remove a sentence on 
the possible hurdle to 
public health value of the 
study in case of study 
withdrawal  
To remove the sentence due to the change in Protocol template  
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CLINICAL TRIAL SUMMARY 
COMPOUND: Dupilumab 
STUDY No.: EFC14153 
TITLE 
A randomized, double-blind, placebo-controlled, parallel group study to 
evaluate the efficacy and safety of dupilumab in children 6 to <12 years of 
age with uncontrolled persistent asthma. 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
 
Primary objective: 
 
The primary objective is to evaluate the efficacy of dupilumab in 
children 6 to <12 years of age with uncontrolled persistent asthma 
Secondary objectives: 
 
To assess the safety and tolerability of dupilumab 
 
To evaluate the effect of dupilumab in improving patient reported 
outcomes (PROs) including health related quality of life (HRQoL) 
 
To assess the dupilumab systemic exposure and incidence of 
anti-drug antibodies (ADA).  
 
To evaluate the association between dupilumab treatment and 
pediatric immune responses to vaccines: any vaccination for 
tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent 
influenza vaccine   
Exploratory objectives: 
 
To explore baseline and on-treatment levels of biomarkers for their 
potential to predict and to associate with a treatment response 
 
 
 
 
To evaluate the proportion of patients requiring increased dose of 
inhaled corticosteroids (ICS) or step up in the second controller 
medication regimen.  
 
To evaluate the effect of dupilumab on additional PROs 
STUDY DESIGN 
General Design 
Multinational, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study assessing the effect of dupilumab administered 
subcutaneously (SC) for a maximum of 52 weeks in children 6 to <12 years of 
age with uncontrolled asthma. 
Periods 
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 to 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 who choose not to participate in 
the 1-year long-term extension study 
 
 
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Screening Period 
Prior to and during the Screening Period, patients must be on one of the 
following: stable-dose background therapy of medium-dose ICS with second 
controller medication (ie, long-acting β2 agonist [LABA], leukotriene receptor 
antagonist [LTRA], long-acting muscarinic antagonist [LAMA], or 
methylxanthines) or high-dose ICS alone or high-dose ICS with second 
controller, for at least 3 months with a stable dose ≥1 month prior to 
Screening Visit 1.  
The Screening Period will be of 4 (±1) weeks in duration. 
Randomized Treatment Period 
Patients are randomized to either dupilumab or matching placebo 
administered SC for a maximum treatment duration of 52 weeks.  
During the Randomized Treatment Period, patients continue the stable 
dose(s) of controller medication used during the Screening Period. For 
patients experiencing a deterioration of asthma during the study, the ICS dose 
may temporarily be increased up to 4-fold (recorded as a loss of asthma 
control [LOAC] event) for a maximum of 10 days, as indicated and upon 
recommendation of the physician and/or Investigator. Treatment may then be 
changed to systemic corticosteroids (severe exacerbation event) or revert 
back to the original ICS dose depending on asthma symptom progression.  
Patients may be placed on systemic corticosteroids at any time as clinically 
indicated based on the presence of symptoms consistent with a severe 
asthma exacerbation event, as per the Investigator’s judgment. 
If a patient experiences 2 or more severe asthma exacerbation events 
anytime during the study, a permanent change (ie, step up in medium- to 
high-dose ICS or addition of second controller for patients on high-dose ICS 
monotherapy) on their stable-dose background controller medication may 
occur, as indicated and upon recommendation of the physician and/or 
Investigator. 
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 (EOS) 
with a ±5 day window or up to recovery or stabilization of any adverse event 
(AE). At the time of permanent treatment discontinuation, patients will perform 
the early treatment discontinuation (ETD) visit with all the assessments 
defined for the end-of-treatment (EOT) Visit 28. Patients who permanently 
discontinue early from treatment will not be eligible for the 1-year long-term 
extension study. 
For patients who permanently discontinue the study, under exceptional 
circumstances where there is no possibility for a patient and 
parent(s)/caregiver(s)/legal guardian(s) to come to the site for the scheduled 
follow-up visit, a phone contact may be made after Sponsor’s approval is 
given. During that phone contact, at least information about AEs, concomitant 
medication and asthma exacerbation events must be collected, and the 
schedule for these calls should still reflect the visit schedule.  
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 clinical presentation at the time of 
discontinuation. 
 
 
 
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Post-treatment Period 
After completing the treatment period, patients are evaluated for 12 weeks 
(± 5 days) in the post-treatment period. During this follow-up period, patients 
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. 
Eligible patients who complete the Randomized Treatment Period will be 
offered the opportunity to participate in the 1-year long-term extension study 
with dupilumab. Patients subsequently enrolled in the 1-year long-term 
extension study will not participate in the post-treatment period of this trial. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
I 01. 
Children 6 to <12 years of age, with an Investigator diagnosis of 
persistent asthma for ≥12 months prior to Screening, based on 
clinical history and examination, pulmonary function parameters 
according to Global initiative for asthma (GINA) 2015 Guidelines 
and the following criteria: 
- 
Existing background therapy of medium-dose ICS with second 
controller medication (ie, LABA, LTRA, LAMA, or 
methylxanthines) or high-dose ICS alone or high-dose ICS with 
second controller, for at least 3 months with a stable dose 
≥1 month prior to Screening Visit 1. 
- 
Pre-bronchodilator forced expiratory volume in 1 second 
(FEV1) ≤95% of predicted normal or pre-bronchodilator 
FEV1/forced vital capacity (FVC) ratio <0.85 at Screening and 
Baseline Visits. 
- 
Reversibility of at least 10% in FEV1 after the administration of 
200 to 400 mcg (2 to 4 puff inhalations with metered-dose 
inhaler [MDI]) of albuterol/salbutamol or 45 to 90 mcg (2 to 
4 puffs with MDI) of levalbuterol/levosalbutamol reliever 
medication before randomization (up to 3 opportunities during 
the same visit are allowed with a maximum of 12 puffs of 
reliever medication if tolerated by the patient).  
Note: A maximum of 3 visits to meet the qualifying criterion of 
reversibility may be made during the screening period and 
prior to the patient's randomization. 
Note: Documented reversibility or positive airway 
hyperresponsiveness to methacholine within 12 months prior 
to Screening V1 is considered acceptable. 
- 
Must have experienced, within 1 year prior to Screening 
Visit 1, any of the following events:  
a) 
Treatment with a systemic corticosteroid (SCS, oral 
or parenteral), as prescribed by a healthcare 
professional for worsening asthma at least once or, 
b) 
Hospitalization or emergency room visit for 
worsening asthma. 
- 
Evidence of uncontrolled asthma, with at least one of the 
following criteria during the 4 (±1)-week Screening Period: 
a) 
Asthma Control Questionnaire–Interviewer 
Administered (ACQ-IA) ACQ-5 score ≥1.5 on at 
least one day of the Screening Period including V2. 
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b) 
Use of reliever medication (ie, albuterol/salbutamol 
or levalbuterol/levosalbutamol), other than as a 
preventive for exercise induced bronchospasm, on 
3 or more days per week, on at least one week 
during the Screening Period. 
c) 
Sleep awakening due to asthma symptoms 
requiring use of reliever medication at least once 
during the Screening Period. 
d) 
Asthma symptoms 3 or more days per week on at 
least one week during the Screening Period. 
Exclusion Criteria: 
E 01. 
Patients <6 or ≥12 years of age. 
E 02. 
Patients <16 kg body weight (bw). 
E 03. 
Any other chronic lung disease (cystic fibrosis, bronchopulmonary 
dysplasia, etc) which may impair lung function. 
E 04. 
A subject with any history of life threatening asthma (ie, extreme 
exacerbation that requires intubation). 
E 05. 
Co-morbid disease that might interfere with the evaluation of IMP 
Total expected number of patients 
 
Approximately 402 patients will be randomized in a 2:1 ratio to receive 
dupilumab (268) or placebo (134).  
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
Dupilumab (SAR231893/REGN668) or matching placebo 
Formulation:   
Dupilumab for children ≤30 kg bw at randomization: 150 mg/mL in pre-filled 
syringe to deliver a once every 2 weeks (q2w) dose of 100 mg in a 0.67 mL 
subcutaneous injection. 
Dupilumab for children >30 kg bw at randomization:  175 mg/mL in pre-filled 
syringe to deliver a once q2w dose of 200 mg in a 1.14 mL subcutaneous 
injection. 
Placebo: Matching placebo in a prefilled syringe to deliver a once q2w dose of 
placebo in a 0.67 or 1.14 mL subcutaneous injection for children with ≤30 or 
>30 kg bw at randomization, respectively. 
Route(s) of administration: 
Subcutaneous (SC) injection 
Dose Regimen 
Randomized 2:1 to the following regimens:  
 
Dupilumab 200 or 100 mg SC once q2w for children with bw >30 kg 
or ≤30 kg, respectively. 
 
Placebo SC q2w 
After randomization, dose regimen will not be adjusted for patient’s age or 
weight during the Randomized Treatment Period of this study.  
Noninvestigational medicinal 
products (Background Therapy) 
 
Formulation: 
 
Inhaled corticosteroid in combination with a second controller 
medications 
Screening Period 
Prior to and during the Screening Period, patients must be on stable-dose 
background therapy of medium-dose ICS with a second controller medication 
(ie, long-acting β2 agonist (LABA), long acting muscarinic antagonist (LAMA), 
leukotriene receptor antagonist (LTRA) or methylxanthines) or high-dose ICS 
alone or high-dose ICS with second controller.  
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Randomized Treatment Period 
During this period, patients will continue taking their controller medication(s) 
For patients experiencing deterioration of asthma during the study, the ICS 
dose may temporarily be increased up to 4-fold (recorded as LOAC event) for 
a maximum of 10 days, as indicated and upon recommendation of the 
physician and/or Investigator. Treatment may then be changed to systemic 
corticosteroids (severe exacerbation event) or revert back to the original ICS 
dose depending on asthma symptom progression.  
Patients may be placed on SCS at any time as clinically indicated based the 
presence of symptoms consistent with a severe asthma exacerbation event, 
as per the Investigator’s judgment. 
If a patient experiences 2 or more severe asthma exacerbation events 
anytime during the study, a permanent change (ie, step up in medium- to 
high-dose ICS or addition of second controller for patients on high-dose ICS 
monotherapy) on their stable-dose background controller medication may 
occur, as indicated and upon recommendation of the physician and/or 
Investigator. 
Post-treatment Period 
Upon completing the randomized treatment period, patients not continuing 
with the 1-year long-term extension study, will continue treatment with the 
controller medication regimen and dose used during the randomized period, 
which could be adjusted based on medical judgment of the patients’ asthma 
control status. 
Reliever Medication 
Patients may use albuterol/salbutamol or levalbuterol/levosalbutamol MDI as 
reliever medication as needed during the study. Nebulizer solutions may be 
used as an alternative delivery method. 
Route(s) of administration: 
 
Oral inhalation by puff inhalation with MDI (eg, ICS, ICS combination, 
albuterol/salbutamol or levalbuterol/levosalbutamol; for other background 
controllers according to label) 
Dose regimen: 
ICS: medium to high-dose in combination with a second controller 
Reliever medication: Albuterol/salbutamol or levalbuterol/levosalbutamol: as 
needed 
ENDPOINT(S) 
 
Primary Endpoint: 
 
Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period. 
 
Key Secondary Efficacy Endpoint: 
 
Change from Baseline in pre-bronchodilator % predicted forced 
expiratory volume in 1 second (FEV1) at Week 12. 
 
Secondary Endpoints: 
Efficacy 
 
Change from Baseline in pre-bronchodilator % predicted forced 
expiratory volume in 1 second (FEV1) at Weeks 2, 4, 8, 24, 36 and 
52 and other time points assessed. 
 
Time to first severe exacerbation event during 52-week treatment 
period. 
 
Time to first LOAC during 52-week treatment period. 
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 
Change from Baseline in other lung function measurements 
(absolute and relative FEV1, AM/PM peak expiratory flow (PEF), 
FVC, forced expiratory flow (FEF) 25-75%, post-bronchodilator 
% predicted FEV1) at Weeks 2, 4, 8, 12, 24, 36, 52 and other time 
points assessed. 
 
The effect of dupilumab on healthcare resource utilization 
 
Change from Baseline at Weeks 2, 4, 8, 12, 24, 36, 52, and other 
time points assessed, in: 
- 
Morning/evening asthma symptom score (electronic diary) 
- 
PRO: 
• 
Asthma Control Questionnaire–Interviewer Administered 
 
(ACQ-IA), for children 6 to <12 years old 
- 
Use of reliever medication 
- 
Number of nocturnal awakenings due to asthma symptoms 
requiring the use of reliever medication 
 
Change from Baseline at Weeks 12, 24, 36, 52, 64 in: 
- 
PRO: 
• 
Paediatric Asthma Quality of Life Questionnaire With 
 
Standardised Activities–Interviewer Administered 
 
(PAQLQ(S) IA) score, for children ≥7 to <12 years old at 
 
randomization. 
Safety and tolerability 
 
Adverse events (AEs) 
 
Vital signs (including height, weight) 
 
Physical examination 
 
Electrocardiogram (ECG) 
 
Clinical laboratory tests 
Systemic drug concentration, anti-drug antibodies and  
IgG responses to vaccination during drug treatment 
 
Serum functional dupilumab concentrations 
 
ADA 
 
IgG responses to vaccination with any vaccination for tetanus, 
diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza 
vaccine during dupilumab treatment (may be analyzed as 
exploratory endpoint if insufficient power). 
Biomarkers 
 
Change from baseline in fractional exhaled nitric oxide (FeNO) at 
Week 12. 
Exploratory endpoints: 
 
Change from baseline and blood biomarkers (thymus and activation 
regulated chemokine [TARC], serum total immunoglobulin E [IgE]). 
 
 
 
 
 
The proportion of patients requiring a permanent step up in 
background controller medication after 2 or more severe asthma 
exacerbation events. 
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 
The effect of dupilumab on additional PROs: 
- 
Pediatric Asthma Caregiver's Quality of Life Questionnaire 
(PACQLQ) score, for caregivers of children ≥7 years old at 
randomization 
- 
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire – 
Interviewer Administered (PRQLQ-IA) score, in children 6 to 
<12 years old, with history of allergic rhinitis) 
- 
EuroQol 5 dimension youth questionnaire (EQ-5D-Y) for 
children 
 
Change from Baseline in antigen-specific IgE, antigen-specific 
immunoglobulin G subtype 4 (IgG4) and  
ratio of IgE:IgG4 
 
Slope of % predicted FEV1 
Criteria for Asthma Exacerbations during the study: 
Two types of asthma exacerbation are defined in this study, as outlined 
below: 
1)  A severe exacerbation event during the study is defined as a deterioration 
of asthma requiring:  
 
Use of systemic corticosteroids for ≥3 days; or  
 
Hospitalization or emergency room visit because of asthma, 
requiring systemic corticosteroids  
2)  A LOAC event is defined as any of the following: 
 
≥6 additional reliever puffs of salbutamol/albuterol or 
levosalbutamol/levalbuterol in a 24 hour period (compared to 
baseline) on 2 consecutive days;  
 
Increase in ICS dose ≥4 times than the dose at Visit 2; 
 
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 peak expiratory flow obtained over the last 7 days 
prior to randomization (Day1); 
 
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 
 
Screening Period (4 [±1] weeks) 
 
Randomized Treatment Period (up to 52 weeks)  
 
Post-treatment Period (12 weeks) 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size of this study was based on a comparison between 
dupilumab versus placebo with regard to the primary endpoint of annualized 
rate of severe exacerbations over 52 weeks of treatment for the 3 populations 
of interest: patients with baseline blood eosinophils ≥300 cells/µL, patients 
with baseline blood eosinophils ≥150 cells/µL, and patients with type 2 
inflammatory phenotype (baseline blood eosinophils ≥150 cells/μL or baseline 
FeNO ≥20 ppb), with assuming the number of severe exacerbations follows a 
negative binomial distribution and a randomization ratio of 2:1. 
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The sample size calculation assumes a linear discontinuation rate (20% at 
1 year), thus the average exposure duration for patients is 0.9 year. The 
assumed relative risk reductions are based on the results in the phase 3 
asthma EFC13579 QUEST study. 
To achieve target sample size for each of the populations stated above, 
approximately 402 patients in the overall population (268 for dupilumab and 
134 for placebo) need to be randomized assuming approximately 86% of the 
randomized patients with type 2 inflammatory phenotype (baseline blood 
eosinophils ≥150 cells/μL or baseline FeNO ≥20 ppb), assuming 
approximately 81% of the randomized patients have baseline blood 
eosinophils ≥150 cells/μL, and approximately 64% of the randomized patients 
have baseline blood eosinophils ≥300 cells/μL. 
Patients will be randomized (2:1 ratio) to receive dupilumab or matching 
placebo. After a patient is randomly assigned to dupilumab or matching 
placebo, the dosage of dupilumab or matching placebo for the patient, 200 or 
100 mg SC once q2w, will be determined based on body weight >30 kg or 
≤30 kg, respectively. 
Randomization will be stratified by ICS dose (medium-dose versus high-dose) 
and eosinophil count (<300 cells/μL versus ≥300 cells/μL) at Screening, and 
by region.  
Analysis populations: 
In order to confirm the efficacy of dupilumab with appropriate multiplicity 
control, there will be two primary analysis populations to evaluate the efficacy 
endpoints: 
1) Population with type 2 inflammatory phenotype will be defined as 
randomized patients with baseline blood eosinophils ≥150 cells/μL 
or baseline FeNO ≥20 ppb (1). This multiplicity control will be 
applied to the analysis in countries that use the same or similar 
indication as approved in the EU.  
2) Population with baseline blood eosinophil ≥300 cells/µL, which is 
defined as the randomized patients with baseline blood eosinophil 
≥300 cells/µL, will be the primary analysis population that the 
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sponsor uses for US and US reference countries, similar to the 
approach taken for evaluating these patients in the QUEST study. 
In addition, patients with baseline blood eosinophils ≥150 cells/µL 
will be tested in the hierarchy. This multiplicity will be used in 
countries with the same or similar indication wordings as approved 
in the US.  
The efficacy analyses will be conducted according to the treatment to which 
they are randomized. 
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 and regardless of whether they are randomized. 
The safety analyses will be conducted according to the treatment patients 
actually received.  
Analysis of the primary endpoint 
The estimand of the dupilumab treatment effect compares the annualized 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. 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 asked and 
encouraged to return to the clinic for all remaining study visits. If a patient 
stays in study till the end of 52-week treatment period, all severe exacerbation 
events that happen up to Week 52 will be included in the primary analysis, 
regardless if the patient is on-treatment or not. 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.  
The annualized rate of severe asthma exacerbation events will be analyzed 
using a negative binomial regression model. The analysis of the primary 
endpoint will be conducted in the type 2 inflammatory phenotype, baseline 
blood eosinophils ≥300 cells/μL, baseline blood eosinophils ≥150 cells/μL, 
baseline FeNO ≥20 ppb and full intent-to-treat (ITT) populations using 
appropriate multiplicity control. When performing the primary endpoint 
analysis in the type 2 inflammatory phenotype, baseline blood eosinophils 
≥150 cells/μL or the full ITT populations, the model will include the total 
number of events of each patient occurring during the 52 weeks as the 
response variable, with the treatment group, age, weight (≤30kg, >30kg), 
region, baseline eosinophil level (<300 cells/μL, ≥300 cells/μL), baseline 
FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose level (medium/high) and 
number of severe asthma exacerbation events prior to the study as 
covariates. When performing the primary endpoint analysis in the baseline 
blood eosinophils ≥300 cells/μL population, the baseline eosinophil level will 
be removed from the model covariates. When performing the primary 
endpoint analysis in the baseline FeNO ≥20 ppb population, the baseline 
FeNO level will be removed from the model covariates. 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 this protocol). Log transformed observation duration will be the 
offset variable. 
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A supportive analysis to assess the treatment effect of dupilumab if patients 
adhere to the treatment and background asthma medication as directed is 
also provided. In this approach, the severe exacerbation events reported after 
the premature treatment discontinuation will be excluded from the analysis. 
Any measurement obtained after the first permanent step up of background 
asthma medication will also be excluded from the analysis. The supportive 
analysis will be performed in the type 2 inflammatory phenotype and baseline 
blood eosinophils ≥300 cells/μL populations and will use a negative binomial 
model with the same set of covariates as specified for the primary analysis in 
the two populations. This model will include severe exacerbation events 
occurring during the treatment epoch before any permanent stepping-up of 
background asthma medication as the response variable and the log 
transformed duration of the treatment or from randomization to first 
permanent stepping-up of background asthma medication whichever is 
shorter will be the offset variable. 
The analysis of the primary endpoint will be conducted in the type 2 
inflammatory phenotype, baseline blood eosinophils ≥300 cells/μL, baseline 
blood eosinophils ≥150 cells/μL, baseline FeNO ≥20 ppb, and full ITT 
populations using appropriate multiplicity control. 
Multiplicity considerations  
The hypothesis testing on the primary endpoint of annualized severe 
exacerbation rate will be controlled with a two-sided type I error of 0.05 by 
incorporating a sequential testing procedure as below: 
For US and US reference countries: 
1st: Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period based on the patients with baseline blood 
eosinophils ≥300 cells/µL. 
2nd: Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period based on the patients with baseline blood 
eosinophils ≥150 cells/µL. 
3rd: Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period based on the patients with type 2 
inflammatory phenotype (baseline blood eosinophils ≥150 cells/µL or 
baseline FeNO ≥20 ppb). 
For EU and EU reference countries: 
1st: Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period based on the patients with type 2 
inflammatory phenotype (baseline blood eosinophils ≥150 cells/µL or 
baseline FeNO ≥20 ppb). 
2nd: Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period based on the patients with baseline blood 
eosinophils ≥150 cells/µL population. 
 3rd:  Annualized rate of severe exacerbation events during the 52-week 
placebo-controlled treatment period based on the patients with baseline blood 
eosinophils ≥300 cells/µL population. 
Multiplicity control for any secondary endpoints if considered will be specified 
in the SAP. Otherwise, nominal p-values will be provided. 
Handling of missing data 
If patients withdraw from the study before Week 52 with severe exacerbation 
events that may occur after study discontinuation, these patients are 
considered as patients with missing data on severe exacerbation. Number, 
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reasons and timing of the missing data will be summarized by treatment 
groups. In the primary analysis, all observed data will be used regardless of 
treatment adherence or increase of asthma background medication. No 
imputation will be conducted for the missing severe exacerbation information 
after a patient prematurely withdraws from the study up to Week 52. In 
addition, sensitivity analyses based on pattern mixture model, placebo based 
pattern mixture model and tipping point analysis based on the same negative 
binomial model as being used in the primary analysis may be conducted to 
assess the robustness of the conclusion of the main model. Details of these 
sensitivity analyses will be described in the SAP. 
Analysis of other secondary endpoints 
The change from baseline for continuous endpoints will be analyzed using a 
mixed-effect model with repeated measures (MMRM) approach. The model 
will include change from baseline as response variables, and for treatment, 
age, weight (≤30kg, >30kg), region, baseline eosinophil level (<300 cells/μL, 
≥300 cells/μL), baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose 
level (medium/high), visit, treatment-by-visit interaction, baseline value, and 
baseline-by-visit interaction as covariates; unless otherwise specified (details 
will be documented in SAP). Sex, height, and ethnicity will also be included as 
covariates in the models for spirometry parameters. 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 at Weeks 12 will be derived from the mixed-
effect model with Kenward and Roger degree of freedom adjustment 
approach. Treatment comparisons at other timepoints, 8, 12, 24, 36 and 52 
Week and other timepoints in between will also be provided from the mixed-
effect model for descriptive purpose. Data up to Week 52 will be included as 
response variables. 
Time to first severe asthma exacerbation event and time to first LOAC will be 
analyzed using a Cox regression model with time-to-event as the dependent 
variable, and treatment, age, weight (≤30kg, >30kg), region, baseline 
eosinophil level (<300 cells/μL, ≥300 cells/μL), baseline FeNO level (<20 ppb, 
≥20 ppb), baseline ICS dose level (medium/high) and number of asthma 
events prior to the study as covariates. The estimated hazard ratio (dupilumab 
versus placebo) along with its 95% confidence interval will be presented. The 
Kaplan-Meier method will be used to derive the proportion of patients with a 
severe asthma exacerbation event at Weeks 12, 24, 36, and 52, specific to 
each treatment group. 
The safety variables, including AEs, laboratory parameters, vital signs, ECG, 
and physical examinations will be summarized using descriptive statistics. 
The analysis of safety variables will be performed based on the safety 
population. 
Interim Analysis 
There is no interim analysis planned for this study. 
Planned database lock 
The database lock is planned based on the time when all randomized patients 
reach 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. 
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DURATION OF STUDY PERIOD (per 
patient)  
Total duration of study (per patient) is expected to be up to 68±1 weeks: 
 
4 (±1) weeks for screening 
 
52 weeks of treatment  
 
12 weeks of post-treatment follow-up 
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1 
FLOW CHARTS  
1.1 
OVERVIEW OF STUDY DESIGN   
 
Background medication:  medium dose ICS + second controller or high dose ICS alone or  + second controller 
D: day; EOT: end of treatment; EOS: end of study; ICS: inhaled corticosteroids; q2w: every 2 week; R: randomization; SC: subcutaneous 
 
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1.2 
STUDY FLOW CHART  
 
SCRa 
Randomized Treatment Period 
Post-
treatment 
Periodd 
 
 
RNDb 
 
EOTc 
 
EOS 
Week 
–4 (±1) 
0 
2 
4 
6 
8 
10 12 14 
16 18 
20 22 24 
26 28 
30 32 34 
36 38 
40 42 
44 46 
48 
50 
52 
56 60 
64 
Visite 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 13 14 
15 16 
17 18 19 
20 21 
22 23 
24 25 
26 
27 
28 
29 30 
31 
Informed Consent/Assentf 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Demography 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical Historyg, and 
Reversibilityh 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Menstruation statusi  
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
x 
Vital Signsj (including height and weight) 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x x 
x 
Dispense or download electronic diary/ 
PEF meterk 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x x 
x 
Health Care Resource Utilization (HCRU) 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
x 
 
 
x 
Randomizationb 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Call IVRS/IWRS 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
x 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigational Product Administrationl 
 
x 
x 
x 
x 
x 
x 
x 
xm 
x 
xm 
x 
xm x 
xm x 
xm x 
xm 
x 
xm 
x 
xm 
x 
xm 
x 
xm 
 
 
 
 
Dispense/review of diary for Home Dosingm 
(optional) by parent/caregiver 
 
 
 
 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometryn 
x 
xo 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x x 
x 
Post-bronchodilator FEV1n 
 
x 
x 
x 
 
x 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
Patient Reported Outcomes / HRQoL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACQ-IAp 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
x 
PAQLQ(S)-IA (for patients ≥7 years old 
at Randomization V2)p 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
PRQLQ-IA q 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
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SCRa 
Randomized Treatment Period 
Post-
treatment 
Periodd 
 
 
RNDb 
 
EOTc 
 
EOS 
Week 
–4 (±1) 
0 
2 
4 
6 
8 
10 12 14 
16 18 
20 22 24 
26 28 
30 32 34 
36 38 
40 42 
44 46 
48 
50 
52 
56 60 
64 
Visite 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 13 14 
15 16 
17 18 19 
20 21 
22 23 
24 25 
26 
27 
28 
29 30 
31 
EQ-5D-Y for children 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Patient Reported Outcomes (Caregiver) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PACQLQ (for caregivers of patients ≥7 
years old at Randomization V2) 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
PK, PD, Pharmacogenetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood biomarkersr 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Total IgE, and antigen-specific IgEs 
 
x 
 
 
 
 
 
  
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Antigen-specific IgG4 panels 
 
x 
 
 
 
 
 
  
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Systemic drug concentrationt 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Exhaled NOu 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x x 
x 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total IgG, IgG subclasses, IgM, IgA 
 
x 
 
 
 
 
 
  
 
 
 
 
 
x 
 
 
 
 
 
  
 
 
 
 
 
 
 
x 
 
 
x 
Anti-drug antibodiesw 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
Pregnancy test for girls who are 
menstruatingx 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
x 
Prior and concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x x 
x 
AE/SAE recording 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x x 
x 
Clinical lab testingy  
(hematology/biochemistry) 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
Urinalysis 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
x 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
x 
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SCRa 
Randomized Treatment Period 
Post-
treatment 
Periodd 
 
 
RNDb 
 
EOTc 
 
EOS 
Week 
–4 (±1) 
0 
2 
4 
6 
8 
10 12 14 
16 18 
20 22 24 
26 28 
30 32 34 
36 38 
40 42 
44 46 
48 
50 
52 
56 60 
64 
Visite 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 11 
12 13 14 
15 16 
17 18 19 
20 21 
22 23 
24 25 
26 
27 
28 
29 30 
31 
Vaccines Record Review / 
Schedulingz,aa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any planned vaccination for tetanus, 
diphtheria, pertussisz 
 
 
 
 
 
 
 
 
 
 
 <–––––––– Xz   ––––––––> - - - - - - - - - - - - - - - - > 
 
 
 
 
 
 
 
Any planned vaccination for seasonal 
trivalent / quadrivalent influenzaz 
 
 
 
 
 <––––––––––––––––––– Xz   ––––––––––––––––> - - - - - - - - - - - - - - - - > 
 
 
 
 
 
 
 
Blood sample collectionaa for 
assessment of IgG response to 
vaccination  
 
 
 
 
Xaa 
 
 Xaa  
 
 
 
 
Xaa  
 
 
 
 
Xaa  
 
 
 
 
 
Xaa 
 
 
 
 
AE: Adverse event; AESI: Adverse Events of Special Interest ; EQ-5D-Y: EuroQol 5-dimensions questionnaire for children; ETD: early treatment discontinuation visit; FEV1: Forced expiratory volume in 1 second; HRQol: 
health-related quality of life; IgA: Immunoglobulin A; IgE: IgG: Immunoglobulin E; Immunoglobulin G; IgM: Immunoglobulin M; IVRS: Interactive voice response system; IWRS: Interactive web response system, NO: Nitric 
oxide;  ACQ-IA: Asthma Control Questionnaire–Interviewer Administered; PACQLQ: Pediatric Asthma Caregivers Quality of Life Questionnaire; PAQLQ(S)-IA: Pediatric Asthma Quality of Life Questionnaire With 
Standardised Activities–Interviewer Administered; PD: Pharmacodynamics; PK: Pharmacokinetics; PRQLQ-IA: Pediatric Rhinoconjunctivitis Quality of Life Questionnaire–Interviewer Administered; PEF: Peak expiratory 
flow; SAE: Serious adverse event;  
a The Screening Period is 4±1 weeks (21-35 days) in duration to collect baseline data on asthma control and assure eligibility criteria. Prior to and during the Screening Period, patients must be on one of the 
following: stable-dose background therapy of medium-dose inhaled corticosteroid (ICS) with second controller medication (ie, long-acting β2 agonist [LABA], leukotriene receptor antagonist [LTRA], long-acting 
muscarinic antagonist (LAMA), or methylxanthines) or high-dose ICS alone or high-dose ICS with second controller, for at least 3 months with a stable dose ≥1 month prior to Screening Visit 1. 
b Randomization Visit (Visit 2) is defined as Day 1. The randomization will be stratified by eosinophil count (<300 cells/ µL and ≥300 cells/µL) and stable dose-level of ICS (medium/high) at Screening, and by 
region. 
c 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 (EOS) with a ±5 day window or up to recovery or stabilization of any adverse event. At the time of permanent treatment discontinuation, patients will perform the early treatment discontinuation (ETD) visit 
with all the assessments defined for the end-of-treatment (EOT) Visit 28. However, patients who discontinue early from treatment will not be eligible for the 1-year long-term extension study.  
For patients who permanently discontinue the study, under exceptional circumstances where there is no possibility for a patient and parent(s)/caregiver(s)/legal guardian(s) to come to the site for the scheduled 
follow-up visit, a phone contact may be made after Sponsor’s approval is given. During that phone contact, at least information about adverse events (AEs), concomitant medication and asthma exacerbation 
events must be collected, and the schedule for these calls should still reflect the visit schedule.  
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 clinical presentation 
at the time of discontinuation. 
d Eligible patients who complete the Randomized Treatment Period will be offered the opportunity to participate in the 1-year long-term extension study with dupilumab. Patients subsequently enrolled in the 1-year 
long-term extension study will not participate in the post-treatment period of this trial. 
e The visit windows for all subsequent visits post-randomization on Day 1 will be ±3 days during the treatment period and ±5 days during the post-treatment period. 
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f 
Prior to any screening assessments: all patient ≥6 years of age (or above an age determined by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and in according with the local regulations 
and requirements) and their parent(s)/caregiver(s)/legal guardian(s) will receive information about the study, on study objective(s) and procedures, to the fullest extent possible, in their language and in terms they 
are able to understand, and must sign and date the IRB/IEC approved Informed Assent Form (IAF) and Informed Consent Form (ICF), respectively. For girls who have started menstruating, a specific assent form 
must be obtained. 
 
 
.  
g Medical history, asthma-specific medical history (ie, family history of atopy & Ig E mediated disease [particularly maternal], premature birth and/or, low birthweight, exposure to tobacco smoke, recurring viral 
infections in early childhood), surgical history. 
h Reversibility of at least 10% in FEV1 after the administration of 200 to 400 mcg (2 to 4 puff inhalations with metered-dose inhaler [MDI]) of albuterol/salbutamol or 45 to 90 mcg  (2 to 4 puffs with MDI) of 
levalbuterol/levosalbutamol reliever medication before randomization (up to 3 opportunities during the same visit are allowed with a maximum of 12 puffs of reliever medication if tolerated by the patient). 
Documented reversibility or positive airway hyper-responsiveness to methacholine within 12 months prior to Screening V1 is considered acceptable. If the subject does not meet this reversibility criterion at 
Screening V1, up to 2 additional assessment attempts can be performed at any time between Screening and Baseline Visit 2. 
i 
A separate assent must be obtained from female patients at the earliest visit when the investigator is notified that the first menses have occurred. 
j 
Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius), height (cm) and body weight (kg) will be measured at the 
Screening and Randomization visits (Visits 1 and 2) and every subsequent visit. 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.  
k 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 requiring the use of reliever medications, 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. 
l 
During the Randomized Treatment Period IMP administrations, every 2 week (q2w), will be performed by the Investigator at scheduled study site visits (must be separated by at least 11 days) up to Week 50. In 
the first 12 weeks (up to V8), patients will be monitored at the study site for a minimum of 30 minutes after injection of IMP, to assess any injection reactions (see Section 8.1.4 for more details). After 
randomization, dose regimen will not be adjusted for patient’s age or weight until the randomized treatment will be completed. 
m Home Dosing and training of parent(s)/caregiver(s)/legal guardian(s): For all visits scheduled only for IMP administration (ie, at Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50), parent(s)/caregiver(s)/legal 
guardian(s) may decide to do the injection of IMP at home (ie, home administration of IMP). These parent(s)/caregiver(s)/legal guardian(s) will be trained by the Investigator or designee to administer IMP, by 
demonstration at V2, V3, and V4 (injections performed by Investigator). After parent(s)/caregiver(s)/legal guardian(s) have successfully administered IMP under close supervision of the Investigator at V5-V8 
(Weeks 6, 8, 10, and 12), the Investigator may approve them to perform home administration of IMP at all further visits that do not require a scheduled visit. It is possible to start home administration at any visit 
following V9, provided parent(s)/caregiver(s)/legal guardian(s) have been trained by the investigator or designee to administer IMP by demonstration at not less than 3 visits followed by a successful IMP 
administration under close supervision of the investigator or designee at not less than 3 visits.  
However, if parent(s)/caregiver(s)/legal guardian(s) do not develop the comfort to inject the IMP at home, or the Investigator determines that injection by parent(s)/caregiver(s)/legal guardian(s) at home is not 
appropriate, alternative arrangements may be made: for example for qualified site personnel and/or healthcare professionals (eg, visiting nurse service) to administer IMP at these timepoints at the patient's home. 
n Forced expiratory volume (FEV1), PEF, forced vital capacity (FVC), forced expiratory flow between 25% to 75% of vital capacity (FEF25%-75%) at all visits; pulmonary function tests 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. Spirometry will be 
performed after a wash out period of bronchodilators according to their action duration, for example, withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding 
the last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at least 24 hours. This will be verified before performing the PEF measurements. 
o Treatment Period stability limits will be established for FEV1 and PEF. Period stability limit for PEF is defined as the respective mean AM or PM PEF obtained over the last 7 days prior to Visit 2 (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.  
p Asthma Control Questionnaire–Interviewer Administered (ACQ-IA, for children 6 to <12 years), ACQ-7 and ACQ-5 scores and Paediatric Asthma Quality of Life Questionnaire With Standardised Activities–
Interviewer Administered (PAQLQ(S)-IA) score, for children ≥7 years old at Randomization V2, are administered by the interviewer during the study visits at the clinical site. The ACQ-7 score will be used to follow 
up evaluations in all patients.  The ACQ-5 (the first 5 items of the ACQ-7) score is used for eligibility evaluation at Screening V1 and Baseline V2 for all patients.  
q Pediatric rhinoconjunctivitis quality of life questionnaire–Interviewer Administered (PRQLQ-IA): For those patients with comorbid allergic rhinitis, administered by the interviewer during the study visits at the clinical 
site. 
r 
Biomarker set includes serum Thymus and Activation-Regulated Chemokine (TARC).  
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s Assessment of total IgE, antigen-specific IgE, antigen-specific IgG4, and ratio of IgE:IgG4. 
t 
Systemic drug concentration samples are to be collected prior to dosing and in case of SAE and AESI. 
u Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast of ≥1 hour.  
 
 
 
w ADA samples are to be collected prior to dosing and in case of SAE and AESI.  
x For female patients who have commenced menstruating (ie, are of child-bearing potential) at Screening, a urine pregnancy test is mandatory at the Screening Visit 1 with negative result obtained prior to 
randomization at Visit 2 (Week 0) and at every subsequent visits defined in the flowchart. For female patients who happen to commence menstruating after Screening, a negative urine dipstick pregnancy test will 
be obtained prior to administration of IMP. 
y Hematology: hemoglobin, hematocrit, platelet count, total white blood cell (WBC) count with five-part 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. Patients’ fasting (considering fasting as no intake of any food 
or drink except for water for at least 8 hours) or non-fasting status at blood sample collection will be recorded on the Central Laboratory Requisition Form. Clinical laboratory testing only at Screening Visit 1 will 
include hepatitis screen covering hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C virus antibodies (HCV Ab), Human Immunodeficiency 
Virus (HIV) screen (Anti-HIV-1 and HIV-2 antibodies) and anti-nuclear antibody (ANA). 
z At Screening, parent(s)/caregiver(s)/legal guardian(s) will be asked to provide information on their child’s vaccination schedule, and assess whether immunizing their children with any vaccination for tetanus, 
diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza (as per local medical practice) will result in vaccination during the study.  
The timing of these vaccinations should be adjusted to fit into the IMP treatment period if appropriate. Any planned tetanus, diphtheria and pertussis vaccination should be administered between Visit 12 (Week 20) 
and Visit 18 (Week 32), as administration after Visit 18 (Week 32) may require an additional blood draw (refer to Section 9.3.1.2) for assessment.  Any planned seasonal trivalent/Quadrivalent influenza should be 
administered between Visit 6 (Week 8) and Visit 18 (Week 32) as administration after Visit 18 (Week 32) may require an additional blood draw (refer to Section 9.3.1.2) for assessment. 
aa Scheduled blood sample collection for pre- and post-vaccine antibody titers (ie, for IgG response assessment), for both vaccinations (ie, any tetanus, diphtheria and pertussis and/or seasonal trivalent/quadrivalent 
influenza) should be drawn within 8 weeks prior to vaccination and at 3-4 weeks (up to 6 weeks) after the respective vaccination(s); however, all blood titer samples must be drawn between Week 6 and Week 50 
(ie, Visit 5 and Visit 27, respectively). 
Depending on patient’s vaccination schedule during the course of this study, every effort should be made to draw pre-vaccination titers at either Weeks 6, 12, or 24 (V5, V8, V14) of the Randomized Treatment 
Period, and to draw post-vaccination titers at either Weeks 12, 24, or 36 (V8, V14, V20) of the Randomized Treatment Period. 
For patient(s) requiring urgent/emergency vaccination with any seasonal trivalent/quadrivalent influenza and/or any tetanus, diphtheria and pertussis vaccine (eg, flu season approaching, animal bite, emergency 
room standard procedures) please refer to Section 9.3.1.2. 
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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
DOCUMENT HISTORY ................................................................................................................................... 3 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 3 
1 
FLOW CHARTS ............................................................................................................................. 20 
1.1 
OVERVIEW OF STUDY DESIGN .................................................................................................. 20 
1.2 
STUDY FLOW CHART .................................................................................................................. 21 
2 
TABLE OF CONTENTS ................................................................................................................ 26 
2.1 
LIST OF TABLES ........................................................................................................................... 33 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ...................................................... 34 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 37 
4.1 
RATIONALE ................................................................................................................................... 37 
4.2 
RATIONALE FOR DOSE SELECTION ......................................................................................... 38 
5 
STUDY OBJECTIVES ................................................................................................................... 41 
5.1 
PRIMARY ....................................................................................................................................... 41 
5.2 
SECONDARY ................................................................................................................................ 41 
5.3 
OTHER ........................................................................................................................................... 41 
6 
STUDY DESIGN ............................................................................................................................ 42 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 42 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 42 
6.2.1 
Duration of study participation for each patient ............................................................................. 42 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 42 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 42 
6.4 
STUDY COMMITTEES .................................................................................................................. 42 
6.4.1 
Data Monitoring Committee ........................................................................................................... 42 
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7 
SELECTION OF PATIENTS .......................................................................................................... 44 
7.1 
INCLUSION CRITERIA .................................................................................................................. 44 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 45 
7.2.1 
Exclusion Criteria Related to Study Methodology .......................................................................... 45 
7.2.2 
Exclusion Criteria Related to the Active Comparator and/or Mandatory Background 
Therapies ....................................................................................................................................... 46 
7.2.3 
Exclusion Criteria Related to the Current Knowledge of Sanofi Compound.................................. 47 
7.2.4 
Additional Exclusion Criteria During or at the end of Screening or Run-in phase before 
randomization ................................................................................................................................. 48 
8 
STUDY TREATMENTS ................................................................................................................. 49 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 49 
8.1.1 
Dupilumab ...................................................................................................................................... 49 
8.1.2 
Placebo .......................................................................................................................................... 49 
8.1.3 
Preparation of investigational product............................................................................................ 49 
8.1.4 
Dosing schedule ............................................................................................................................. 49 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 50 
8.2.1 
Inhaled Corticosteroids and Second Controller Medication ........................................................... 50 
8.2.2 
Reliever Medication(s) ................................................................................................................... 52 
8.3 
BLINDING PROCEDURES ............................................................................................................ 53 
8.3.1 
Methods of blinding ........................................................................................................................ 53 
8.3.2 
Randomization code breaking during the study ............................................................................. 53 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 54 
8.5 
PACKAGING AND LABELING ...................................................................................................... 55 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 55 
8.7 
RESPONSIBILITIES ...................................................................................................................... 55 
8.7.1 
Treatment Accountability and Compliance .................................................................................... 56 
8.7.2 
Return and/or Destruction of Treatments....................................................................................... 56 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 57 
8.8.1 
Prohibited Concomitant Medication ............................................................................................... 57 
8.8.2 
Permitted Concomitant Medication ................................................................................................ 57 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 59 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 59 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 59 
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9.2.1 
Key Secondary Efficacy Endpoint .................................................................................................. 59 
9.2.2 
Secondary Efficacy Endpoints ....................................................................................................... 59 
9.2.2.1 
Disease-specific Efficacy Measures .............................................................................................. 60 
9.2.2.2 
Disease-specific, Daily Efficacy Assessments ............................................................................... 62 
9.2.2.3 
Health Care Resource Utilization ................................................................................................... 63 
9.2.2.4 
Patient Reported Outcomes, Including Health Related Quality of Life (Secondary 
Endpoints) ...................................................................................................................................... 64 
9.2.3 
Safety and Tolerability Endpoints .................................................................................................. 65 
9.2.3.1 
Adverse Events .............................................................................................................................. 66 
9.2.3.2 
Vital Signs ...................................................................................................................................... 66 
9.2.3.3 
ECG Variables ............................................................................................................................... 66 
9.2.3.4 
Physical Examination ..................................................................................................................... 67 
9.2.3.5 
Clinical Laboratory Safety Variables .............................................................................................. 67 
9.2.3.6 
Other Safety Laboratory Tests ....................................................................................................... 68 
9.2.3.7 
Pregnancy Test .............................................................................................................................. 68 
9.3 
OTHER SECONDARY ENDPOINTS ............................................................................................. 69 
9.3.1 
Systemic Drug Concentration, Anti-drug Antibodies, and IgG responses to vaccination 
during drug treatment ..................................................................................................................... 69 
9.3.1.1 
Systemic Drug Concentration and Anti-drug Antibodies................................................................ 69 
9.3.1.2 
Humoral Immune Response to Vaccines....................................................................................... 70 
9.3.1.3 
Biomarker endpoints ...................................................................................................................... 71 
9.4 
EXPLORATORY ENDPOINTS ...................................................................................................... 71 
9.4.1 
Exploratory Endpoints .................................................................................................................... 71 
9.4.2 
Pharmacodynamics and Phenotyping ........................................................................................... 72 
9.4.2.1 
Serum Biomarkers ......................................................................................................................... 72 
 
 
9.4.2.3 
Patients Requiring a Permanent Step Up in Background Controller Medication After 2 or 
More Severe Asthma Exacerbation Events. .................................................................................. 73 
9.4.2.4 
Other Patient Reported Outcomes Including Health Related Quality of Life (Exploratory 
Endpoints) ...................................................................................................................................... 74 
 
 
9.6 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 75 
10 
STUDY PROCEDURES ................................................................................................................ 76 
10.1 
VISIT SCHEDULE .......................................................................................................................... 77 
10.1.1 
Screening Period (Week -5 to Week 0, maximum 35 days prior Day 0) ....................................... 77 
10.1.2 
Screening Visit 1 (Week -4 [± 1 week], or between Day -35 and Day -21) ................................... 78 
10.1.3 
Randomization Visit 2 (Week 0, Day 1) ......................................................................................... 80 
10.1.4 
Visit 3 (Week 2 [± 3 days]) ............................................................................................................. 82 
10.1.5 
Visit 4 (Week 4 [± 3 days]) and Visit 6 (Week 8 [± 3 days]) ........................................................... 83 
10.1.6 
Visit 5 (Week 6 [± 3 days]) ............................................................................................................. 84 
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10.1.7 
Visit 7 (Week 10 [± 3 days]) ........................................................................................................... 86 
10.1.8 
Visit 8 (Week 12 [± 3 days]) ........................................................................................................... 87 
10.1.9 
Visits 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 (Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50) –
IMP Administration at Patient Home or Investigative Site ............................................................. 89 
10.1.10 Visits 10, 12, 16, 18, 22, 24, 26 (Weeks 16, 20, 28, 32, 40, 44, 48) .............................................. 89 
10.1.11 Visit 14 (Week 24 [± 3 days]) ......................................................................................................... 91 
10.1.12 Visit 20 (Week 36 [± 3 days]) ......................................................................................................... 92 
10.1.13 Visit 28 (Week 52 [± 3 days], End of Treatment, and Early Treatment Discontinuation) .............. 94 
10.1.14 Visit 29 and Visit 30 (Weeks 56 and 60 ± 5 days), Post-Treatment Period) .................................. 95 
10.1.15 Visit 31 (Week 64, End of Study Visit) ........................................................................................... 96 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 97 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 97 
10.3.1 
Temporary Treatment Discontinuation With Investigational Medicinal Product(s) ........................ 98 
10.3.2 
Permanent Treatment Discontinuation With Investigational Medicinal Product(s) ........................ 98 
10.3.3 
List of Criteria for Permanent Treatment Discontinuation .............................................................. 98 
10.3.4 
Handling of Patients After Permanent Treatment Discontinuation ................................................ 99 
10.3.5 
Procedure and Consequence for Patient Withdrawal From Study .............................................. 100 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................ 100 
10.4.1 
Definitions of Adverse Events ...................................................................................................... 100 
10.4.1.1 Adverse Event .............................................................................................................................. 100 
10.4.1.2 Serious Adverse Event ................................................................................................................ 101 
10.4.1.3 Adverse Event of Special Interest ................................................................................................ 102 
10.4.2 
Serious Adverse Events Waived From Expedited Regulatory Reporting to Regulatory 
Authorities .................................................................................................................................... 103 
10.4.3 
General Guidelines for Reporting Adverse Events ...................................................................... 103 
10.4.4 
Instructions for Reporting Serious Adverse Events ..................................................................... 104 
10.4.5 
Guidelines for Reporting Adverse Events of Special Interest ...................................................... 105 
10.4.6 
Guidelines for Management of Specific Laboratory Abnormalities .............................................. 105 
10.5 
OBLIGATIONS OF THE SPONSOR ........................................................................................... 105 
10.6 
SAFETY INSTRUCTIONS ........................................................................................................... 106 
10.6.1 
Hypersensitivity ............................................................................................................................ 106 
10.6.2 
Severe Injection Site Reactions ................................................................................................... 106 
10.6.3 
Infections ...................................................................................................................................... 107 
10.6.4 
Elevated Liver Function Tests ...................................................................................................... 108 
10.7 
ADVERSE EVENTS MONITORING ............................................................................................ 108 
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11 
STATISTICAL CONSIDERATIONS ............................................................................................ 109 
11.1 
DETERMINATION OF SAMPLE SIZE ......................................................................................... 109 
11.2 
DISPOSITION OF PATIENTS ..................................................................................................... 110 
11.3 
ANALYSIS POPULATIONS ......................................................................................................... 110 
11.3.1 
Efficacy Populations ..................................................................................................................... 110 
11.3.2 
Safety Population ......................................................................................................................... 111 
11.3.3 
Systemic Drug Concentration Population .................................................................................... 111 
11.3.4 
Anti-drug Antibody (ADA) Population ........................................................................................... 111 
11.4 
STATISTICAL METHODS ........................................................................................................... 112 
11.4.1 
Extent of Study Treatment Exposure and Compliance ................................................................ 112 
11.4.1.1 Extent of Investigational Medicinal Product Exposure ................................................................. 112 
11.4.1.2 Compliance .................................................................................................................................. 112 
11.4.2 
Analyses of Efficacy Endpoints .................................................................................................... 112 
11.4.2.1 Analysis of Primary Efficacy Endpoint(s) ..................................................................................... 113 
11.4.2.2 Analyses of Secondary Efficacy Endpoints ................................................................................. 114 
11.4.2.3 Multiplicity Considerations ........................................................................................................... 116 
11.4.2.4 Handling of Missing Data ............................................................................................................. 117 
11.4.3 
Analyses of Safety Data ............................................................................................................... 117 
11.4.3.1 Adverse Events ............................................................................................................................ 118 
11.4.3.2 Clinical Laboratory Evaluation, Vital Signs and Electrocardiogram Data .................................... 119 
11.4.3.3 Humoral Immune Response to Vaccines..................................................................................... 119 
11.4.4 
Analyses of Systemic Drug Concentration, Anti-drug Antibodies, and Pharmacodynamic 
Variables ...................................................................................................................................... 120 
11.4.4.1 Drug Concentration Analysis ....................................................................................................... 120 
11.4.4.2 Anti-drug Antibodies Analysis ...................................................................................................... 120 
11.4.4.3 Pharmacodynamics and Phenotyping ......................................................................................... 121 
11.4.5 
Analyses of Patient Reported Outcomes (Health-related Quality of Life/Health Economics 
Variables) ..................................................................................................................................... 121 
11.5 
INTERIM ANALYSIS .................................................................................................................... 121 
11.6 
PLANNED DATABASE LOCK ..................................................................................................... 122 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 123 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 123 
12.2 
INFORMED CONSENT ............................................................................................................... 123 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 124 
13 
STUDY MONITORING................................................................................................................. 126 
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13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 126 
13.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................... 126 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 126 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST .................................................................................................................................... 127 
13.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 127 
14 
ADDITIONAL REQUIREMENTS ................................................................................................. 128 
14.1 
CURRICULUM VITAE.................................................................................................................. 128 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................. 128 
14.3 
CONFIDENTIALITY ..................................................................................................................... 128 
14.4 
PROPERTY RIGHTS ................................................................................................................... 129 
14.5 
DATA PROTECTION ................................................................................................................... 129 
14.6 
INSURANCE COMPENSATION .................................................................................................. 129 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 130 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 130 
14.8.1 
By the Sponsor ............................................................................................................................. 130 
14.8.2 
By the Investigator ....................................................................................................................... 131 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 131 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 131 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 132 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 133 
17 
APPENDICES .............................................................................................................................. 135 
APPENDIX A 
LOW, MEDIUM, AND HIGH-DOSE INHALED CORTICOSTEROIDS – CHILDREN 
(6 TO <12 YEARS) ...................................................................................................................... 136 
APPENDIX B 
EXAMPLES OF COMMONLY USED ASTHMA CONTROLLER THERAPIES ................. 137 
APPENDIX C 
LIST OF PROHIBITED LIVE ATTENUATED VACCINES ................................................ 139 
APPENDIX D 
EXAMPLES OF CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE ........... 140 
APPENDIX E 
ASTHMA SYMPTOM SCORE NUMERICAL RATING SCALE (NRS) .............................. 141 
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APPENDIX F 
ASTHMA CONTROL QUESTIONNAIRE–INTERVIEWER ADMINISTERED (ACQ-
IA) FOR CHILDREN 6 TO <12 YEARS ....................................................................................... 142 
APPENDIX G 
PAEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE WITH 
STANDARDISED ACTIVITIES–INTERVIEWER ADMINISTERED (PAQLQ[S]-IA) .................... 147 
APPENDIX H 
PAEDIATRIC ASTHMA CAREGIVER’S QUALITY OF LIFE QUESTIONNAIRE 
(PACQLQ) .................................................................................................................................... 153 
APPENDIX I 
PAEDIATRIC RHINOCONJUNCTIVITIS QUALITY OF LIFE QUESTIONNAIRE–
INTERVIEWER ADMINISTERED (PRQLQ-IA) – FOR CHILDREN WITH COMORBID 
ALLERGIC RHINITIS ................................................................................................................... 156 
APPENDIX J 
EURO QOL (EQ-5D-Y) – FOR CHILDREN ....................................................................... 162 
APPENDIX K 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 165 
APPENDIX L 
DEFINITION OF ANAPHYLAXIS ....................................................................................... 170 
APPENDIX M 
LIST OF OPPORTUNISTIC INFECTIONS ....................................................................... 171 
APPENDIX N 
COUNTRY SPECIFIC REQUIREMENTS ......................................................................... 172 
APPENDIX O 
PROTOCOL AMENDMENT HISTORY ............................................................................. 173 
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2.1 
LIST OF TABLES  
Table 1 - Eligibility interpretation for hepatitis serology ................................................................................. 68 
Table 2 - Summary of handling procedures for dupilumab ........................................................................... 70 
Table 3 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody ........................... 70 
Table 4 - Summary of Adverse Event Reporting Instructions ..................................................................... 104 
Table 5 - Summary of changes: amended protocol 02 ............................................................................... 174 
 
 
 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
 
ACQ-7 IA: 
Asthma Control Questionnaire–Interviewer Administered, 7-question version 
ACQ-IA: 
Asthma Control Questionnaire–Interviewer Administered 
AD: 
Atopic dermatitis 
ADA: 
Anti-drug antibodies  
AE: 
Adverse event(s) 
AESI: 
adverse events of special interest 
ALP: 
Alkaline phosphatase 
ALT: 
Alanine aminotransferase  
ANA: 
Anti-nuclear antibody 
AST: 
Aspartate aminotransferase 
ATS: 
American Thoracic Society 
bw: 
Body weight 
CDC-NHANES: Centers for Disease Control and Prevention-National Health and Nutrition 
Examination Survey 
CDMS: 
Clinical data management system 
CPK: 
Creatine phosphokinase  
CSD: 
Clinical Study Director 
CV: 
Curriculum vitae  
CV%: 
Coefficient of variation  
CYP: 
Cytochrome P450 
DMC: 
Data Monitoring Committee 
DRF: 
Discrepancy Resolution Form 
DTP: 
Duties and Taxes paid 
EASI: 
Eczema area and severity index 
EC: 
Ethics Committee 
ECG: 
Electrocardiogram 
e-CRF: 
Electronic-case report form 
ELISA: 
Enzyme-linked immunosorbent assay 
EOS: 
End of Study 
EOT: 
End-of-treatment  
EQ-5D-Y: 
EuroQol 5-dimensions questionnaire for children 
ERS: 
European Respiratory Society 
ETD: 
Early treatment discontinuation 
FEF: 
Forced expiratory flow 
FeNO: 
Fractional exhaled nitric oxide 
FEV1: 
Forced expiratory volume in 1 second 
FVC: 
Forced vital capacity 
GCP: 
Good Clinical Practice  
GINA: 
Global initiative for asthma  
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GSO: 
Global Safety Officer 
HBc-Ab: 
Hepatitis B core antibody 
HBs Ab: 
Hepatitis B surface antibody 
HBs-Ag: 
Hepatitis B surface antigen  
HBV DNA: 
Hepatitis B virus DNA 
HCRU: 
healthcare resource utilization 
HCV-Ab: 
Hepatitis C virus antibody 
HIV: 
Human immunodeficiency virus  
HLGT: 
high-level group term 
HLT: 
high level term 
HRQoL: 
Health related quality of life 
HVC RNA: 
Hepatitis C virus RNA 
IAF: 
Informed assent form 
ICF: 
Informed consent form 
ICH: 
The International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use  
ICS: 
Inhaled corticosteroids 
IEC: 
Independent Ethics Committee 
IgA: 
Immunoglobulin A 
IgE: 
Immunoglobulin E 
IgG: 
Immunoglobulin G  
IgM: 
Immunoglobulin M 
IL: 
interleukin 
IL-13: 
Interleukin-13 
IL-4: 
Interleukin-4 
IMP: 
Investigational medicinal product 
IRB: 
Institutional Review Board 
ITT: 
intent-to-treat  
IVIG: 
Intravenous immunoglobulin  
IVRS: 
Interactive voice response system 
IWRS: 
Interactive web response system  
LABA: 
Long-acting β2 agonist 
LAMA: 
Long acting muscarinic antagonist 
LFT: 
Liver function tests 
LOAC: 
Loss of Asthma Control 
LTRA: 
Leukotriene receptor antagonist 
MCID: 
Minimal clinically important difference 
MDI: 
Metered-dose inhaler 
MID: 
Minimally important difference 
MMRM: 
Mixed-effect model with repeated measures 
NIMP: 
Non-investigational medicinal product  
NRS: 
Numerical Rating Scale 
PACQLQ: 
Pediatric Asthma Caregiver's Quality of Life Questionnaire 
PAQLQ(S)-IA: Paediatric Asthma Quality of Life Questionnaire with Standardised Activities–
Interviewer Administered 
PBMC: 
Peripheral blood mononuclear cells 
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PCSA: 
Potentially clinically significant abnormality 
PEF: 
Peak expiratory flow 
ppb: 
Parts per billion 
PROs: 
Patient reported outcomes 
PRQLQ-IA: 
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire  – Interviewer 
Administered  
PT: 
Preferred term 
q2w: 
Once every 2 weeks  
q4w: 
Once every 4 weeks  
SAE: 
serious adverse event 
SAP: 
Statistical analysis plan 
SC: 
Subcutaneous(ly) 
SCS: 
Systemic corticosteroids 
SD: 
Standard deviation 
SEM: 
Standard error of the mean  
SOC: 
System Organ Class 
TARC: 
Thymus and Activation Regulated Chemokine 
TBV: 
Total blood volume 
TEAEs: 
Treatment-emergent adverse events 
ULN: 
Upper Limit of Normal  
 
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4 
INTRODUCTION AND RATIONALE  
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.  
The majority of children with asthma have mild or moderate disease and can obtain adequate 
asthma control through avoidance of triggering factors and/or with the help of medications, such 
as short-acting inhaled β2-receptor agonists, inhaled corticosteroids (ICS) and, when needed, 
addition of long-acting β2-receptor agonists and leukotriene receptor antagonists (LTRA). 
However, 2-5% of all asthmatic children have uncontrolled asthma despite maximum treatment 
with conventional medications (2). Children with such severe symptoms are heterogeneous with 
respect to trigger factors, pulmonary function, inflammatory pattern and clinical symptoms (3). 
These children have a reduced quality of life, account for a large proportion of the healthcare costs 
related to asthma and represent a continuous clinical challenge to the pediatrician. 
Additionally, the long term adverse effects of systemic and ICS on bone metabolism, adrenal 
function, and growth in children lead to attempts to minimize the amount of corticosteroid usage. 
Lastly, the consequences of unresponsiveness to therapy or lack of compliance with therapy are 
evidenced by loss of asthma control (LOAC), which can be severe (ie, severe asthma exacerbation 
event) and possibly life-threatening. 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 (4). Recent therapeutic approaches in asthma have been 
focused on trying to control type 2 inflammation. A vast majority of 6-11 years old with asthma 
show evidence of type 2 inflammation characterized by upregulation of inflammatory cytokines, 
interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). The most recent GINA 
guidelines (1) for management of severe asthma report that for patients with severe asthma, type 2 
inflammation can be identified by elevated peripheral eosinophils (≥150 cells/µL) and/or elevated 
FeNO (≥20 ppb), and/or sputum eosinophils ≥2%, and/or asthma that is clinically allergen-driven. 
Up-regulation of IL-4 and 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-4Rα), which is a component of IL-4 heterodimeric receptors Type I 
(IL4-ligand only) and Type II (both IL-4 and IL-13 ligands). The binding of dupilumab to IL-4Rα 
results in blockade of downstream signaling initiated by both IL-4 and IL-13. For complete 
information regarding the preclinical and clinical evaluation of dupilumab to date, see the 
Investigator’s Brochure. 
4.1 
RATIONALE  
This is a Phase 3, randomized, double-blind, placebo-controlled efficacy and safety study to be 
conducted in children 6 to <12 years of age with uncontrolled persistent asthma while on a 
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medium dose ICS, in combination with a second controller or high-dose ICS alone or in 
combination with a second controller. This study is designed to investigate the efficacy and safety 
profile of dupilumab over one year in a population of asthmatic children in need for an additional 
treatment to their current maintenance 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 understand better the efficacy of 
dupilumab on multiple asthma domains including prevention of severe exacerbations, lung 
function and symptom control. The short and long term effects on lung function and symptom 
control will be evaluated.  
4.2 
RATIONALE FOR DOSE SELECTION  
The dose regimens for pediatric patients aged 6 to <12 years are selected based on the observed 
efficacy and safety in the dose ranging study in adult asthma patients (Phase 2b study DRI12544), 
the PK characterization and safety observation in pediatric atopic dermatitis (AD) study 
(R668-AD-1412) of 6 to <18 years, as well as the available blinded safety data of EFC13579, the 
asthma pivotal study being conducted in adults and adolescents. 
In the completed Phase 2b dose ranging study (DRI12544), dupilumab efficacy at 4 dose 
regimens (300 mg once every 4 weeks (q4w) and once every 2 weeks (q2w), and 200 mg q2w and 
q4w with a total dose on Day 1 of 600 mg for (the 300 mg regimen) and 400 mg (for the 200 mg 
regimen) respectively, was evaluated in patients with uncontrolled asthma while receiving a stable 
dose of medium to high-dose ICS/ Long-acting β2 agonist (LABA) in addition to their study 
treatment (placebo or dupilumab). Dupilumab demonstrated dose dependent improvement, 
compared with placebo, in the change from baseline in forced expiratory volume in 1 second 
(FEV1) at Week 12. In addition, consistent efficacy results in favor of dupilumab over placebo 
were observed in the majority of main secondary efficacy endpoints including annualized rate of 
severe exacerbation events. The maximum treatment effects were observed in the 200 mg and 
300 mg q2w regimens. Exposure-response analyses further supported the maximal effect for both 
endpoints of FEV1 and severe exacerbation rate approached/achieved at the steady-state exposure 
of the two q2w regimens (mean steady-state trough concentrations of 28.3 and 58.5 mg/L, 
respectively). Dupilumab was observed to be safe and well tolerated across all dose regimens 
examined. Treatment-emergent adverse events (TEAEs) were reported in 79.1% patients in the 
dupilumab groups (75.3% to 82.8%) and 74.7% patients in the placebo group. The most 
frequently reported TEAEs included injection site reactions, respiratory tract infections and 
related symptoms, headache, and back pain. There was no apparent dose relationship for any 
particular TEAE except for injection site reactions, majority of which were mild in nature.  
From the available blinded safety data of EFC13579, injection site erythema, nasopharyngitis, and 
upper respiratory tract infection were the 3 most commonly reported TEAEs among adolescents 
in this study. None of the TEAEs observed in the 26 adolescents dosed at the time of blinded 
analysis were severe or serious. No new safety signal was identified in these adolescent patients 
compared to adults. The top 3 most common TEAEs in adolescents were also the most common 
reported TEAEs in adults in this study and the DRI12544 study. 
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Study R668-AD-1412 was a Phase 2a, multicenter, open-label, ascending-dose, sequential-cohort 
study investigating the safety, tolerability, PK, immunogenicity, and efficacy of single-dose and 
repeat-doses of dupilumab administered subcutaneously (SC) in pediatric patients with moderate 
to severe AD (for adolescents 12 to <18 years old) or severe AD (for school-going children ≥6 to 
<12 years old) that was not adequately controlled with topical treatments. The 2 assessed dose 
regimens at 2 mg/kg and 4 mg/kg corresponds to the weight normalized dose in adults at 150 mg 
and 300 mg, respectively. Dupilumab administered as single and repeated weekly doses of 
2 mg/kg and 4 mg/kg for 4 weeks was generally safe and well tolerated in both pediatric age 
groups included in that study. There was a higher incidence of TEAEs following single and 
repeated weekly administration of 4 mg/kg compared to 2 mg/kg in both age-groups. However, 
most of the adverse events (AE) were mild in intensity, transient in nature and not related to study 
drug. There were no new safety signals detected with dupilumab in the pediatric age 
6 to <18 years. The most common AEs reported after both single doses and repeated weekly doses 
were nasopharyngitis and exacerbation of AD.  
In study R668-AD-1412, dupilumab administered as a single dose of either 2 mg/kg or 4 mg/kg, 
in the Study R668-AD-1412, induced significant and rapid reduction of disease activity in patients 
at Week 2 (34% and 51% reduction in eczema area and severity index (EASI) score from baseline 
for 2 mg/kg and 4 mg/kg doses respectively. Repeated weekly doses of dupilumab led to a further 
improvement in disease severity in patients in both dose groups (67% and 70% reduction in 
EASI score from baseline for 2 mg/kg and 4 mg/kg doses, respectively, at Week 12). There did 
not appear to be a clear dose response, as the 2 dose groups showed similar efficacy on the 
various endpoints evaluated during the study.  
The collective clinical data on the exposure versus efficacy and safety in the adults and pediatric 
population as observed to date supports a similar exposure-response relationship for efficacy and 
safety between the adult and pediatric populations down to 6 years of age and justify the approach 
of selecting EFC14153 dose regimen based on the criteria of matching adult efficacious and safe 
exposure. 
Dupilumab PK is not affected by disease status/population in adults. Similar PK profile was 
observed between healthy subjects, and patients with AD or asthma. Thus, the same PK profile is 
anticipated in children with asthma and AD which supports the use of AD-1412 PK data for the 
pediatric asthma dose selection. The observed pediatric PK profile analysis showed general 
similarity in dupilumab PK profile between adults and children after accounting for body size 
difference. Similar to adults, body weight (bw) was the only statistically significant covariate of 
dupilumab PK identified in the pediatric population of 6 to 17 years, where clearance and volume 
of distribution decreases with decreasing bw following an allometric relationship. There was no 
significant impact of age and gender on dupilumab PK after adjustment of the bw effect. 
A pediatric Pop PK model was developed using pediatric data alone (AD-1412) together with 
single IV dose PK data in healthy volunteers (AS-0907) to further evaluate the typical 
pharmacokinetics in the pediatric population, and to identify and quantify PK variability 
component in the pediatric population. The pediatric Pop PK model shares the same two-
compartment model structure as that of adults with the first-order absorption, and parallel linear 
and nonlinear elimination (target-mediated disposition with quasi steady-state QSS 
approximation). 
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To determine the appropriate dose regimen, the population PK simulation was conducted using 
the pediatric Pop PK model and the pediatric demographic data of Centers for Disease Control 
and Prevention-National Health and Nutrition Examination Survey (CDC-NHANES) database. 
The NHANES population of 6 to 11 years is adequate to reflect the inter-subject variability to 
inform the dosage recommendation in the age group.  
To account for body size difference in the pediatric population and taking into account the 
observed large therapeutic indices of dupilumab, a tiered fixed dosing regimen was chosen over 
weight based (mg/kg) dosing, as this approach offers a potential safety advantage of reducing the 
risk of dosing errors, as well as dosing convenience for patients by allowing self-administration 
using a prefilled syringe/device. The dosing regimen was selected as shown below:  
Dupilumab 200 or 100 mg SC once q2w for children with bw >30 kg or ≤30 kg, respectively. 
The predicted exposure at 200 mg q2w in children aged 6 to <12 years weighing more than 30 kg 
largely overlaps with the observed efficacious exposure in adults at 300 mg and 200 mg q2w and 
is expected to be well within the adult safe exposure of up to 300 mg qw. Similarly, the lower 
dose of 100 mg q2w in children less than 30 kg is predicted to provide comparable exposure to 
that in the heavier children and the adults. Moreover, the estimated range of steady-state Cmax was 
generally within the range of pediatric exposure in 6 to <12 years observed in AD-1412 which 
was well tolerated and safe.  
In summary, the proposed tiered dosing regimen (200 mg q2w weighing >30 kg and 100 mg q2w 
weighing ≤30 kg) for children aged 6 to <12 years is expected to provide significant clinical 
benefit and a safety profile similar to that of older patients. 
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
 
To evaluate the efficacy of dupilumab in children 6 to <12 years of age with uncontrolled 
persistent asthma 
5.2 
SECONDARY  
 
To assess the safety and tolerability of dupilumab 
 
To evaluate the effect of dupilumab in improving patient reported outcomes (PROs) 
including health related quality of life (HRQoL) 
 
To assess the dupilumab systemic exposure and incidence of anti-drug antibodies (ADA) 
 
To evaluate the association between dupilumab treatment and pediatric immune responses 
to vaccines: any vaccination for tetanus, diphtheria, pertussis and/or seasonal 
trivalent/quadrivalent influenza vaccine. 
5.3 
OTHER  
Exploratory Objectives: 
 
To explore baseline and on-treatment levels of biomarkers for their potential to predict and 
to associate with a treatment response 
 
 
 
 
To evaluate the proportion of patients requiring increased dose of ICS or step up in the 
second controller medication regimen 
 
To evaluate the effect of dupilumab on additional PROs 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This is a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study assessing the effect of dupilumab administered SC for a maximum of 52 weeks in children 6 
to <12 years of age with uncontrolled asthma. 
6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The study will last up to 68±1 weeks as follows: 
 
Screening Period (4±1 weeks) to determine a patient’s eligibility status and establish level 
of asthma control before randomization. 
 
Randomized Treatment Period (up to 52 weeks): treatment 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 1-year long-term extension study. 
6.2.2 Determination of end of clinical trial (all patients)  
The last patient last visit will occur when either: 
 
The last patient has completed the 12-week post-treatment period or 
 
The last patient has completed the end-of-treatment (EOT) visit and enrolled in the 1-year 
long-term extension study. 
6.3 
INTERIM ANALYSIS  
No interim analysis is planned for this study.  
6.4 
STUDY COMMITTEES  
6.4.1 Data Monitoring Committee  
A data monitoring committee (DMC) is independent from Sponsor’s 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 DMC 
will review and evaluate the safety data during the course of the trial and make appropriate 
recommendations regarding the conduct of the clinical trial to the Sponsor.  
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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. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. Children 6 to <12 years of age, with a physician diagnosis of persistent asthma for 
≥12 months prior to screening based on clinical history and examination, pulmonary 
function parameters according to Global initiative for asthma (GINA) 2015 Guidelines and 
the following criteria: 
- 
Existing background therapy of medium-dose ICS with second a controller medication 
(ie, LABA, LTRA), Long acting muscarinic antagonist (LAMA), or methylxanthines) 
or high-dose ICS alone or high-dose ICS with second controller, for at least 3 months 
with a stable dose ≥1 month prior to Screening Visit 1 (dose levels as per  
Appendix A). 
- 
Pre-bronchodilator FEV1 ≤95% of predicted normal or pre bronchodilator 
FEV1/forced vital capacity (FVC) ratio <0.85 at Screening and Baseline Visits. 
- 
Reversibility of at least 10% in FEV1 after the administration of 200 to 400 mcg 
(2 to 4 puffs with metered-dose inhaler [MDI]) of albuterol/salbutamol or 45 to 90 mcg 
(2 to 4 puffs with MDI) of levalbuterol/levosalbutamol reliever medication before 
randomization (up to 3 opportunities during the same visit are allowed with a 
maximum of 12 puffs of reliever medication if tolerated by the patient).  
Note: A maximum of 3 visits to meet the qualifying criterion of reversibility may be 
made during the screening period and prior to the patient's randomization.   
For patients that will have an additional and last attempt of reversibility testing (for 
eligibility) at the Baseline Visit 2 before patient’s randomization into the interactive 
response technology (IRT), the post-bronchodilator FEV1 will come from the result of 
this reversibility test. 
Note: Documented reversibility or positive airway hyper-responsiveness to 
methacholine within 12 months prior to Screening V1 is considered acceptable. 
- 
Must have experienced, within 1 year prior to Screening Visit 1, defined as any of the 
following events: 
a) Treatment with a systemic corticosteroid (SCS, oral or parenteral) prescribed by a 
healthcare professional for worsening asthma at least once or, 
b) Hospitalization or emergency medical care visit for worsening asthma. 
- 
Evidence of uncontrolled asthma, with at least one of the following criteria during the 
4 (±1)-week Screening Period: 
c) Asthma Control Questionnaire–Interviewer Administered (ACQ-IA) ACQ-5 score 
≥1.5 on at least one day of the Screening Period including V2. 
d) Use of reliever medication (ie, albuterol/salbutamol or 
levalbuterol/levosalbutamol), other than as a preventive for exercise induced 
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bronchospasm, on 3 or more days/per week on at least one week during the 
Screening Period. 
e) Sleep awakening due to asthma that required the use of reliever medication at least 
once during the Screening Period. 
f) Asthma symptoms 3 or more days/week on at least one week during the Screening 
Period.  
I 02. Willing and able to comply with clinic visits and study-related procedures. 
I 03. With parent(s)/caregiver(s)/legal guardian(s) able to understand the study requirements. 
I 04. Patients ≥6 years of age (or above an age determined by the Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC] and in accordance with the local regulations 
and requirements) must provide written informed assent, and their 
parent(s)/caregiver(s)/legal guardian(s) must provide written informed consent. 
I 05. Patients/parent(s)/caregiver(s)/legal guardian(s), as appropriate, must be able to understand 
and complete study-related questionnaires. 
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 subsections:  
7.2.1 Exclusion Criteria Related to Study Methodology  
E 01. Patients <6 or ≥12 years of age 
E 02. Patients <16 kg bw 
E 03. Any other chronic lung disease (cystic fibrosis, bronchopulmonary dysplasia, etc) which 
may impair lung function. 
E 04. A subject with any history of life-threatening asthma (eg, requiring intubation). 
E 05. Co-morbid disease that might interfere with the evaluation of investigational medicinal 
product (IMP) 
E 06. History of malignancy of any kind. 
E 07. Inability to follow the procedures of the study (eg, due to language problems or 
psychological disorders). 
E 08. 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, systemic lupus 
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erythematosus as well as other diseases) within 2 months or 5 half-lives prior to Visit 1, 
whichever is longer. 
E 09. 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 10. 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 11. Patients receiving medications or therapy that are prohibited as concomitant medications 
(See Section 8.8.1). 
E 12. Patients who have previously been treated in any clinical trial of dupilumab. 
E 13. Patients or his/her parent(s)/caregiver(s)/legal guardian(s) is related to the Investigator or 
any Sub-Investigator, research assistant, pharmacist, study coordinator, other staff 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 14. Non-compliance with use of the mandatory background therapy (ie, medium-dose ICS 
with a second controller medication [eg, LABA, LTRA, LAMA, or methylxanthines] or 
high-dose ICS alone or high-dose ICS with second controller), during the Screening 
Period, as defined as <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 15. Patient treated with SCS for diagnoses other than severe exacerbation of asthma, and/or 
high-potency topical steroids within 30 days before Screening Visit 1, during the Screening 
Period, and/or during the randomized treatment phase of this study. 
E 16. Patient with 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, active hepatitis, 
active or latent untreated tuberculosis, bronchiectasis. Patients with active tuberculosis, 
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 will 
be performed in every country according to their local guidelines as required by regulatory 
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authorities and/or ethic committees. Other conditions that are well controlled and stable 
will not prohibit participation if deemed appropriate per the Investigator’s judgment. 
7.2.3 Exclusion Criteria Related to the Current Knowledge of Sanofi Compound  
E 17. For female patients who have commenced menstruating at any time during the study and 
are either: 
 
Found to have a positive urine pregnancy test, or  
 
Sexually active, not using an established acceptable contraceptive method: 
- 
Oral, injected, inserted, or implanted hormonal contraceptive. 
- 
Intrauterine device with or intrauterine system with progestogen. 
- 
Barrier contraceptive (condom, diaphragm, or cervical/vault caps) used with 
spermicide (foam, gel, film, cream, or suppository). 
E 18. Diagnosed with 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 19. History of human immunodeficiency virus (HIV) infection or positive HIV serology at 
Visit 1. 
E 20. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per Investigator’s judgment.  
E 21. 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). 
E 22. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, juvenile idiopathic arthritis, inflammatory bowel disease, 
systemic lupus erythematosus) 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 23. Patient with a history of a systemic hypersensitivity reaction, other than localized injection 
site reaction, to any biologic drug. 
E 24. At any time: Patients with positive (or indeterminate) test for hepatitis B surface antigen 
(HBs-Ag); positive Immunoglobulin M (IgM) hepatitis B core antibody; positive total 
hepatitis B core antibody (HBc-Ab) confirmed by positive hepatitis B virus DNA (HBV 
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DNA); positive hepatitis C virus antibody (HCV-Ab) confirmed by positive hepatitis C 
virus RNA (HVC RNA). 
E 25. Liver injury related criteria: 
- 
Clinically significant/active hepatobiliary disease or 
- 
Elevated transaminases (alanine aminotransferase [ALT] and/or aspartate 
aminotransferase [AST]) >3 Upper Limit of Normal (ULN). 
E 26. Abnormal lab values at Screening: 
- 
Creatine phosphokinase (CPK) >3 ULN or 
- 
Platelets <100 000 cells/mm3 or 
- 
Eosinophils >1500 cells/mm3 or 
E 27. Patients receiving live (attenuated) vaccines within 4 weeks before the baseline visit. 
7.2.4 Additional Exclusion Criteria During or at the end of Screening or Run-in phase 
before randomization  
E 28. Patient and/or parent(s)/caregiver(s)/legal guardian(s) who has/have withdrawn consent 
before enrollment/randomization (starting from signed informed consent form 
[ICF]/informed assent form [IAF]). 
E 29. Despite screening of the patient, enrollment/randomization is stopped at the study level. 
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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
8.1.1 Dupilumab  
Dupilumab for children ≤30 kg bw at randomization:  150 mg/mL in pre-filled syringe to deliver a 
once q2w dose of 100 mg in a 0.67 mL subcutaneous injection. 
Dupilumab for children >30 kg bw at randomization:  175 mg/mL in pre-filled syringe to deliver a 
once q2w dose of 200 mg in a 1.14 mL subcutaneous injection. 
8.1.2 Placebo  
Matching placebo in a prefilled syringe to deliver a once q2w dose of placebo in a 0.67 mL or 
1.14 mL subcutaneous injection for children with ≤30 or >30 kg bw at randomization, 
respectively. 
8.1.3 Preparation of investigational product  
Dupilumab or matching placebo in glass pre-filled syringes will be dispensed to the patients. 
Additional information will be provided in the Pharmacy manual. 
8.1.4 Dosing schedule  
The IMP is administered every 14±3 days q2w. The doses of investigational product must be 
separated by ≥11 days to avoid overdose.  
The IMP administrations will be performed by the Investigator or designee at scheduled study site 
visits following clinic procedures and blood collection (see Section 1.2).  Patients will be 
monitored for a minimum of 30 minutes after each study-site administrated injection of IMP, to 
assess any injection site reactions (eg, for any signs or symptoms of a hypersensitivity reaction). 
For all visits scheduled only for IMP administration, parent(s)/caregiver(s)/legal guardian(s) may 
decide to do the injection of IMP at home (ie, home administration of IMP). These 
parent(s)/caregiver(s)/legal guardian(s) will be trained by the Investigator or designee to 
administer IMP, by demonstration at Visit 2, Visit 3, and Visit 4 (injections performed by 
Investigator). After parent(s)/caregiver(s)/legal guardian(s) have successfully administered IMP 
under close supervision of the Investigator at Visit 5-Visit 8 (Weeks 6, 8, 10, and 12), the 
Investigator may approve them to perform home administration of IMP at all further visits that do 
not require a scheduled clinic visit (ie, at Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, and 50). 
Patients should be monitored for 30 minutes after home administration of IMP. It is possible to 
start home administration at any visit following Visit 9, provided parent(s)/caregiver(s)/legal 
guardian(s) have been trained by the investigator or designee to administer IMP by demonstration 
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at not less than 3 visits followed by a successful IMP administration under close supervision of 
the investigator or designee at not less than 3 visits. 
However, if parent(s)/caregiver(s)/legal guardian(s) do not develop the comfort to inject the IMP 
at home, or the Investigator determines that injection by parent(s)/caregiver(s)/legal guardian(s) at 
home is not appropriate, alternative arrangements may be made: for example for qualified site 
personnel and/or healthcare professionals (eg, visiting nurse service) to administer IMP at these 
timepoints at the patient's home.  
For IMP doses not given at the study site, ‘home dosing diary’ (paper format) will be provided to 
record information related to the injections. Such home dosing diaries will be kept as source data 
in the patient’s study file.  
Parent(s)/caregiver(s)/legal guardian(s) should be instructed to avoid missing any site visits (ie, 
IMP doses) or doses of background therapy during the study. For any patient who misses a 
site-visit (ie, IMP dose) or doses of background therapy, the parent(s)/caregiver(s)/legal 
guardian(s) should be reminded to be diligent to avoid missed visits and doses of background 
therapy thereafter.  
The patient(s)/parent(s)/caregiver(s)/legal guardian(s) should continue their scheduled visits for 
IMP treatment (with study procedures, as detailed in Section 1.2), even if more than 2 consecutive 
doses of IMP are missed, or background medication was not taken by the patient(s) for up to 
2-4 days. 
The SC 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. For each injection, the anatomic site of administration will be recorded in the 
electronic-case report form (e-CRF) or, as applicable, the home dosing diary. 
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the patient and parent(s)/caregiver(s)/legal guardian(s). Parent(s)/caregiver(s)/legal guardian(s) 
will complete a dosing diary to document compliance with injection of IMP.  
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
8.2.1 Inhaled Corticosteroids and Second Controller Medication  
The recognized second controller medication for combined use with medium- or high-dose ICS 
(dose-levels in children 6 to <12 years old, as per Appendix A) as background therapy during this 
study (only one controller is permitted; see eligibility criterion No. 14 in Section 7.2.2) will 
include the following classes: LABA, LTRA, LAMA, or methylxanthines. Please refer to 
Appendix B for an indicative (not exhaustive) list of recognized second controller medications 
approved for this study. These second controller medications will not be dispensed or supplied by 
the Sponsor. 
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For patients experiencing a deterioration of asthma during the study, the ICS dose may 
temporarily be increased up to 4-fold (recorded as LOAC event) for a maximum of 10 days, as 
indicated and upon recommendation of the physician and/or Investigator. Treatment may then be 
changed to SCS (severe exacerbation event) or revert back to the original ICS dose depending on 
the asthma symptoms progression.  
If a patient experiences 2 or more severe asthma exacerbation events anytime during the study, a 
permanent change (ie, step up in medium- to high-dose ICS or addition of second controller for 
patients on high-dose ICS monotherapy; see Appendix A and Appendix B) on their stable-dose 
background controller medication may occur, as indicated and upon recommendation of the 
physician and/or Investigator. 
Screening Period 
Prior to and during the Screening Period, patients must be on one of the following: stable-dose 
background therapy of medium-dose ICS with a second controller medication (ie, LABA, LTRA, 
LAMA, or methylxanthines) or high-dose ICS alone or high-dose ICS with second controller, for 
at least 3 months, with a stable dose background treatment for ≥1 month prior to Screening 
Visit 1. 
If patients take 2 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 A.  
If the Investigator, based on his/her medical judgment, decides to optimize a patients use of 
asthma reliever and/or background controller medications prior to the Screening Visit, any 
changes in ongoing asthma medications must occur more than 1 month in advance of the 
Screening Visit Day 1, in order to maintain a stable dose for at least 1 month prior to Day 1 
(Section 7.1). The introduction of new controller medications must occur at least 3 months prior 
to Screening with a stable dose for at least 1 month (Section 7.1). 
Randomized Treatment Period 
During this period, patients will continue to take their controller medication(s) used during the 
Screening Period. The dose of baseline regimen should not be changed, and no adjustments will 
be made unless the patient experiences 2 or more severe exacerbations events at any time during 
the study (in which case a step up of controller medication may be allowed). This will be recorded 
in the eDiary. 
Patients may be placed on systemic corticosteroids at any time as clinically indicated based on the 
presence of symptoms consistent with a severe asthma exacerbation event, as per the 
Investigator’s judgment. 
Post-treatment Period 
Upon completing the randomized treatment period, patients not continuing with the long-term, 
open-label extension study will enter the Post Treatment Period and will proceed to be treated 
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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(s)  
The reliever medication (ie, albuterol/salbutamol or levalbuterol/levosalbutamol) will not be 
dispensed or supplied by the Sponsor. All other reliever medications other than 
albuterol/salbutamol or levalbuterol/levosalbutamol should be avoided. 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s) may administer albuterol/salbutamol or 
levalbuterol/levosalbutamol reliever medication by MDI as needed during the study. Nebulizer 
solutions may be used as an alternative delivery method.  
Criterion for Loss of Asthma Control (LOAC) – Based on Increased Nebulizer Use (in 
e-CRF): 
The criterion for LOAC based on a patients increased nebulizer use and the nebulizer-to-puff 
conversion factor (see tables below), is determined as follows: 
Study personnel will convert salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol 
nebulizer use as shown on the following tables:  
 
Salbutamol/Albuterol Nebulizer Solution -Total Daily Dose (mg) 
Number of Puffs* 
2.5  
4 
5.0 
8 
7.5 
12 
10 
16 
*Conversion factor:  salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs 
 
Example of salbutamol/albuterol nebulizer-to-puff Conversion: Patient received 
3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. 
Total daily = 7.5 mg or 12 puffs 
 
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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 or 12 puffs.  
After conversion of nebulizer-to-puff, and for every instance that the number of puffs is 
≥6 additional puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period 
(compared to Baseline) on 2 consecutive days in any week, a LOAC event should be documented.  
8.3 
BLINDING PROCEDURES  
8.3.1 Methods of blinding  
Dupilumab and placebo will be provided in identically matched pre-filled syringes. To protect the 
blind, each treatment kit of 0.67 or 1.14 mL (dupilumab/placebo) glass pre-filled syringes will be 
prepared such that the treatments (dupilumab and its matching placebo) are identical and 
indistinguishable and will be labeled with a treatment kit number. The randomized treatment kit 
number list will be generated by Sanofi. 
Patients and Investigators will be blinded to assigned treatment. Patients and Investigators will not 
be blinded to dose regimen as the volumes are different. 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s), 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 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. 
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Patient withdrawal will only occur when the code break call is made at the site level, not the study 
level. This means that if the Emergency Unblinding transaction is performed by the Investigator 
(ie, at the site level), then the 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, ADAs 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. 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s), Investigators, and site personnel will not have 
access to assay results for immunoglobulins (immunoglobulin G (IgG), IgG subclasses, 
Immunoglobulin A (IgA), IgM and IgE) after randomization and first administration of study 
medication, because these values have the potential for unblinding. Furthermore, neither 
patient(s)/parent(s)/caregiver(s)/legal guardian(s), Investigators nor site personnel will have access 
to total IgE, antigen-specific IgE, antigen-specific IgG4, Thymus and Activation-Regulated 
Chemokine (TARC) while the study is ongoing, as the related data are not essential for patient 
care and have the potential for unblinding. 
The DMC will receive blinded by treatment group or unblinded (if necessary) confidential reports 
from an independent statistician for review, which have to be handled strictly confidentially. 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 (IVRS/IWRS). This centralized treatment allocation system will generate the 
patient randomization list according to which it will allocate the treatments to the patients. 
Patients who meet the entry criteria will be randomized to receive either dupilumab or placebo. 
Rescreening is not permitted if the patient fails to meet inclusion criteria. Patients who meet 
exclusion criteria may be rescreened once during the open Screening Period of the study. There is 
no requirement for a waiting period between the screen-failure date and the rescreening date. The 
IVRS/IWRS report will flag rescreened patients. Patients that are rescreened must have 
parent(s)/caregiver(s)/legal guardian(s) resign a new ICF and sign a new IAF, and all Screening 
Visit 1 procedures must be repeated. 
The Investigator obtains treatment kit numbers at randomization and subsequent scheduled visits 
via an IVRS/IWRS that will be available 24 hours a day. 
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Patients will be randomized (2:1 ratio) to receive dupilumab or matching placebo. After a patient 
is randomly assigned to dupilumab or matching placebo, the dosage of dupilumab or matching 
placebo for the patient, 200 or 100 mg SC once q2w, will be determined based on bw >30 kg or 
≤30 kg, respectively. 
Randomization will be stratified by ICS dose (medium-dose versus high-dose) and eosinophil 
count (<300 cells/μL versus ≥300 cells/μL) at Screening, and by region.  
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/placebo is supplied as glass prefilled syringes packed in a patient kit box. Each glass 
prefilled syringe and the patient kit box is labeled. 
Packaging is in accordance with the administration schedule. The labeling is in accordance with 
the local regulatory specifications and requirements. 
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 IMP 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 IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (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. 
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A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for Duties and 
Taxes paid (DTP) shipment, for which a courier company has been approved by the Sponsor), 
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  
The Investigator or pharmacist will also keep accurate records of the quantities of the IMP 
dispensed, used and unused. The IMP tracking log and inventory form is to be updated each time 
investigational product is dispensed. The study monitor will periodically check the supplies of the 
IMP held by the Investigator or pharmacist to assess accountability. 
All medication treatment kits (whether empty or unused) are returned by the 
parent(s)/caregiver(s)/legal guardian(s) at each visit when a treatment dispensing is planned. The 
completed patient injection diary (returned diary (returned to the site at each visit), returned 
treatment kit boxes and any unused prefilled syringes will be used for drug accountability 
purposes. 
Treatment kit number has to be recorded on the appropriate page of the e-CRF and also on the 
IMP tracking log and inventory log form. 
An electronic diary is used by the parent(s)/caregiver(s)/legal guardian(s) for the daily recording 
of albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication use, daily use of 
background therapy (ie, medium-dose ICS with a second controller medication [ie, LABA, 
LTRA, LAMA, or methylxanthines] or high-dose ICS alone or high-dose ICS with second 
controller), and in case of an exacerbation event, recording of increased ICS dose and/or step up 
of second controller medication. Site personnel will review and download the electronic diary data 
at each clinic visit and will follow up with the parent(s)/caregiver(s)/legal guardian(s) accordingly. 
The Monitoring Team in charge of the study will have to check e-CRF data comparing them with 
the centralized treatment allocation system information, the IMP kit and IMP tracking log and 
inventory form. 
For non-investigational medicinal product (NIMP) not provided by the Sponsor, tracking and 
reconciliation has to be achieved by the Investigator and must be captured in standard site 
documents and records (eg, medical notes). 
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 
parent(s)/caregiver(s)/legal guardian(s) and be returned to sites for destruction. No unused IMP 
will be destructed at site unless the Sponsor provides written authorization. 
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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.  
8.8 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s) or 
during study participation. 
8.8.1 Prohibited Concomitant Medication  
The following concomitant treatments are not permitted during the Screening Period or during the 
Randomized Treatment Period: 
 
SCS for diagnoses other than severe exacerbation of asthma and/or high-potency topical 
steroids within 30 days before Screening Visit 1, during the Screening Period, and/or 
during the Randomized Treatment Phase of this study. Intra-articular steroids are not 
allowed to be used in the above mentioned period. 
 
IgE therapy (eg, omalizumab) within 130 days prior to Screening Visit 1, or any other 
biologic therapy/immunosuppressant to treat inflammatory disease or autoimmune disease 
within 2 months prior to Screening Visit 1. 
 
Allergen immunotherapy (except if initiated more than 3 months prior to Visit 1 and dose 
stable 1 month prior to Visit 1). 
 
Intravenous immunoglobulin (IVIG) therapy. 
 
Live Attenuated Vaccines: refer to Appendix C. Live (attenuated) vaccines are allowed in 
the screening period, if taken at least 4 weeks prior to the administration of the first dose 
of investigational medicinal product (ie, at least 4 weeks prior to baseline visit). 
In Brazil, for patients in the yellow fever outbreak affected area (see Appendix N). 
 
Asthma relievers other than salbutamol/albuterol or levosalbutamol/levalbuterol: their use 
is not recommended unless in exceptional circumstances during the study period (eg, 
prescribed by a physician not participating in the study). 
 
Exposure to another 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. 
 
Any investigational treatment or procedure.  
8.8.2 Permitted Concomitant Medication  
 
Antihistamines 
 
Dermatological, ocular or intranasal corticosteroids (except for high-potency 
dermatological corticosteroids) 
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 
Cytochrome P450 (CYP) enzyme substrates: 
The impact of dupilumab on 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, IL-4 
was reported to upregulate CYP2E1, 2B6, 3A4 mRNA expression or downregulate 
CYP1A2 mRNA (5, 6). 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 (5). 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 (6, 7). Some examples of CYP450 
substrates with narrow therapeutic index are provided in Appendix D. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
Two types of asthma exacerbation are defined in this study, as outlined below: 
1)   A severe exacerbation event during the study is defined as a deterioration of asthma requiring:  
 
Use of systemic corticosteroids for ≥3 days; or  
 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids  
2)   A LOAC event is defined as any of the following: 
 
≥6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 
24 hour period (compared to baseline) on 2 consecutive days;  
 
Increase in ICS dose ≥4 times than the dose at Visit 2; 
 
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 peak expiratory flow obtained over the last 7 days prior to 
randomization (Day1); 
 
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 (eg, infections including viral and bacterial, allergen exposure, exercise and others) 
for any exacerbation event will be recorded in the e-CRF. 
9.1 
PRIMARY ENDPOINT  
The primary endpoint for this study is:  
 
Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period.  
9.2 
SECONDARY ENDPOINTS  
9.2.1 Key Secondary Efficacy Endpoint  
 
Change from Baseline in pre-bronchodilator % predicted FEV1 at Week 12. 
9.2.2 Secondary Efficacy Endpoints  
 
Change from Baseline in pre-bronchodilator % predicted FEV1 at Weeks 2, 4, 8, 24, 36, 
and 52 and other time points assessed. 
 
Time to first severe exacerbation event during 52-week treatment period. 
 
Time to first LOAC Event during 52-week treatment period.  
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 
Change from Baseline in other lung function measurements (absolute and relative FEV1, 
AM/PM peak expiratory flow, FVC, forced expiratory flow (FEF) 25-75%, 
post-bronchodilator % predicted FEV1) at Weeks 2, 4, 8, 12, 24, 36, 52, and other time 
points assessed.  
 
The effect of dupilumab on healthcare resource utilization (HCRU) 
 
Change from Baseline at Weeks 2, 4, 8, 12, 24, 36, and 52 and other timepoints in: 
- 
Morning/evening asthma symptom score (electronic diary) 
- 
PRO: 
• 
ACQ-IA, for children 6 to <12 years old,  
- 
Use of reliever medication 
- 
Number of nocturnal awakenings due to asthma symptoms requiring the use of reliever 
medication 
 
Change from Baseline at Weeks 12, 24, 36, 52, 64 in: 
- 
PRO: 
• 
Paediatric Asthma Quality of Life Questionnaire with Standardised Activities–
Interviewer Administered (PAQLQ(S)-IA) score, for children ≥7 to <12 years old 
at Randomization Visit 2. 
9.2.2.1 Disease-specific Efficacy Measures  
9.2.2.1.1 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 (8). For pre-bronchodilator measured parameters, including FEV1, 
peak expiratory flow (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, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at least 
24 hours. This will be verified before performing the PEF measurements. 
For post-bronchodilator FEV1, the measure should follow the steps as that at screening test for 
reversibility validation. 
At all visits, spirometry will be performed either in the AM or PM, but preferred in the AM, and 
the spirometry should be done at approximately the same time 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.  
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Pulmonary function tests will be measured in 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 
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. 
Further details on spirometry will be available in a separate operational manual provided to the 
sites. 
9.2.2.1.2 Reversibility/Post-bronchodilator FEV1  
Reversibility is defined as an increase in absolute FEV1 of 10% over the baseline value, 
demonstrated within 30 minutes of bronchodilator administration.  
At the screening test, reversibility is tested after the administration of 200 to 400 mcg (2 to 
4 puffs) of albuterol/salbutamol or 45 to 90 mcg of (2 to 4 puffs) levalbuterol/levosalbutamol 
reliever medication from a primed MDI (up to 3 opportunities during the same visit are allowed 
with a maximum of 12 puffs of reliever medication, if tolerated by the patient). Documented 
reversibility or positive airway hyperresponsiveness to methacholine within 12 months prior to 
Visit 1 is considered acceptable.  
All reversibility tests will be administered after pulmonary function testing and after asthma 
medications have been withheld for the appropriate intervals. Patients will receive the 
albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication as puff inhalations using 
the respective MDI. Alternatively, and only if it is consistent with usual office practice (to be 
documented), reversibility testing may be performed using inhalation of nebulized 
albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication.  
The spirometry for measuring absolute FEV1 may be repeated several times within the 30 minutes 
after administration of bronchodilator.  
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Reversibility is an inclusion criterion, but if the subject does not meet this reversibility criterion at 
Screening Visit 1, up to 2 additional assessments can be performed at any time between Screening 
and Baseline Visit 2.  
For post-bronchodilator FEV1 at remaining study visits following randomization, the measure 
should follow the steps as that at screening test for reversibility validation except a maximum of 
4 puffs of reliever medication can be used. If other attempt for reversibility test was performed at 
Baseline Visit 2, then the post-bronchodilator FEV1 will come from the result of this reversibility 
test. 
9.2.2.2 Disease-specific, Daily Efficacy Assessments  
9.2.2.2.1 Electronic Diary/PEF meter  
On a daily basis throughout the study, the patient uses an electronic diary/PEF meter to: 
 
Measure morning and evening PEF. 
 
Respond to the morning and evening asthma symptom scale questions. 
 
Indicate the number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief. 
 
Record the number of inhalations/day of background product used. 
 
Record the number of nocturnal awakenings due to asthma symptoms requiring the use of 
reliever medication. 
 
Record oral steroids use for exacerbation event. 
At Screening (Visit 1), patients and parent(s)/caregiver(s)/legal guardian(s) will be issued an 
electronic diary/PEF meter. Parent(s)/caregiver(s)/legal guardian(s) 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 parent(s)/caregiver(s)/legal guardian(s). In addition, the Investigator will instruct the 
parent(s)/caregiver(s)/legal guardian(s) on how to record the following variables in the electronic 
PEF meter: 
 
AM PEF performed within 15 minutes after arising (between 5:30 AM and 11:59 AM) prior 
to taking any albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication)  
 
PM PEF performed in the evening (between 5:30 PM and 11:59 PM) prior to taking any 
albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication)  
 
Patient/Parent(s)/caregiver(s)/legal guardian(s) should try to withhold albuterol/salbutamol 
or levalbuterol/levosalbutamol reliever medication for at least 6 hours before performing 
the PEF measurements.  
 
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 
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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. 
Baseline reliever use will be the mean number of reliever use 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 PFE 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 for both measurements. 
Information derived from the electronic PEF meter will be evaluated by the Investigator at study 
visits.  
9.2.2.2.2 Asthma Symptom Numerical Rating Scale (NRS) Score  
Parent(s)/caregiver(s)/legal guardian(s) 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. A Minimal clinically important difference (MCID) of 0.35 is being used (9) (see 
Appendix E). 
9.2.2.2.3 Use of Reliever Medicine  
The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations will be recorded 
daily by the parent(s)/caregiver(s)/legal guardian(s) 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 levosalbutamol/levalbuterol inhalations/day will be based on the mean of 
the 7 days prior to randomization.   
9.2.2.3 Health Care Resource Utilization  
The HCRU questionnaire (questions on use of reliever medication, specialist visit, hospitalization, 
emergency or urgent medical care facility visit, outcome, school days’ loss, etc), as integrated part 
of the e-CRF, will be administered as shown in Section 1.2, and will additionally be used to asses 
HCRU in the event of any asthma exacerbation: severe asthma exacerbation event or evidence of 
LOAC (for detailed definitions see Section 9). 
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9.2.2.4 Patient Reported Outcomes, Including Health Related Quality of Life (Secondary 
Endpoints)  
Patients will be administered the following PRO questionnaires by their 
parent(s)/caregiver(s)/legal guardian(s) or with their help. The interviewer administered versions 
are only for children: ACQ-IA, paediatric asthma quality of life questionnaire (PAQLQ[S]-IA) 
and will be administered by an interviewer (clinic staff designated by Investigator).  
9.2.2.4.1 Asthma Control Questionnaire–Interviewer Administered  
The ACQ-IA 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, and will be used for 
children 6 years to <12 years old at Screening.  
9.2.2.4.1.1 ACQ-7-IA (Asthma Control Questionnaire–Interviewer Administered, 7-question 
version)  
The Asthma Control Questionnaire–Interviewer Administered, 7-question version (ACQ-7-IA) 
has 7 questions, with the first 5 items of ACQ-7 (ACQ-5-IA score) addressing 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. And with 2 questions on overall reliever medication use 
6) short-acting bronchodilator use, and – after spirometry assessment – current asthma status: 
7) predicted bronchodilator use of FEV1 (pre-bronchodilator use, % and % predicted use).  
Patients and/or parent(s)/caregiver(s)/legal guardian(s) are asked to recall how their asthma and/or 
their child’s asthma, respectively, has been during the previous week and to respond to the 
symptom questions 1) to 6) on a 7-point scale (0 = no impairment, 6 = maximum impairment).  
After spirometry assessment, patients and/or parent(s)/caregiver(s)/legal guardian(s) are asked to 
recall how their asthma and/or their child’s asthma has been during the previous week and to 
respond to the symptom and bronchodilator use questions on a 7-point scale (0=no impairment, 
6= maximum impairment). Clinic staff scores the % predicted FEV1 on a 7-point scale based on 
the pre-central reading spirometry result displayed immediately after the testing. Then, the 
questions are equally weighted and the global ACQ-7 score is the mean of the 7 questions and 
therefore between 0 (totally controlled) and 6 (severely uncontrolled) (see Appendix F). 
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 MCID defined by the developer. 
For statistical analysis, ACQ-7 global score is calculated by the sponsor using the BMS post 
central reading value of the %predicted FEV1 for the question 7 of the questionnaire.  
Measurement properties such as reliability and ability to detect change have been documented in 
the literature. 
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9.2.2.4.1.2 ACQ-5-IA  (Asthma Control Questionnaire–Interviewer Administered, 5-question 
version)  
The ACQ-5-IA will be deduced from the responses to the first 5 questions of ACQ-7-IA and will 
be used for children ≥6 years to <12 years old at Screening.  
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 MCID defined by the developer. 
Measurement properties such as reliability and ability to detect change have been documented in 
the literature (10). 
9.2.2.4.2 Pediatric Asthma Quality of Life Questionnaire with Standardized Activities–Interviewer 
Administered  
The PAQLQ(S)–IA was designed as an interviewer-administered PRO to measure the functional 
impairments that are most troublesome to children ≥7 years old at Randomization Visit 2, as a 
result of their asthma (see Appendix G). The instrument is comprised of 23 items, each rated on a 
7-point Likert scales from 1 to 7.  
The PAQLQ(S)-IA has 3 domains. The domains and the number of items in each domain are as 
follows: 
 
Symptoms (10 items) 
 
Activity limitation (5 items) 
 
Emotional function (8 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 PAQLQ(S)-IA is 0.5 (11). 
9.2.3 Safety and Tolerability Endpoints  
The same safety assessments will be applied across both arms. AEs, including serious adverse 
events (SAEs) and AEs of special interest (AESI), will be collected at any time during study. The 
Investigator will ask the patient and parents how he/she has felt since the last study visit. 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 6.4.1. 
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Safety observations 
 
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. 
 
Patient height will be recorded at randomization as baseline value and compared with last 
height available during randomized treatment. 
 
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. 
 
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. 
9.2.3.1 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 (EOS) Visit or till the rollover to the extension 
study, except for: 
 
SAEs  
 
AEs that are ongoing at database lock. 
Adverse events, AESIs and SAEs will be reported as described in Section 10.4.  
9.2.3.2 Vital Signs  
Vital signs blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per 
minute), body temperature (degrees Celsius), and will include height (cm) and body weight (kg), 
measured at the Screening and Randomization Visits (Visits 1 and 2) and every subsequent visit. 
Height will be measured with a proper stadiometer at every visit. Stadiometer measurements will 
be made without patient wearing shoes. Vital signs will be measured at clinic visits, in sitting 
position, using the same arm at each visit, and prior to administration of investigational product. 
Refer to Section 1.2 Study Flow Chart for the schedule of vital signs performed throughout this 
study. 
9.2.3.3 ECG Variables  
One recording of a standard 12-lead electrocardiogram (ECG) will be performed at Screening, 
EOT, and EOS (see Section 1.2).  
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9.2.3.4 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, including 
menstruation status (Section 7.2.3). All deviations from normal will be recorded, including those 
attributable to the patient’s disease. Refer to Section 1.2 Study Flow Chart for the schedule of 
physical examination performed throughout this study. 
9.2.3.5 Clinical Laboratory Safety Variables  
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. 
Refer to Section 1.2 Study Flow Chart for the description of the clinical laboratory evaluations 
and the schedule of laboratory evaluations performed throughout this study. 
The clinical laboratory parameters that will be measured in safety hematology and chemistry 
blood samples are: 
 
Hematology: To include hemoglobin, hematocrit, platelet count, total white blood cell 
count with five-part differential count, and total red blood cell count. 
 
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), ALT, AST, alkaline 
phosphatase (ALP), lactate dehydrogenase, electrolytes (sodium, potassium, chloride), 
bicarbonate, and CPK. Patients’ fasting or non-fasting status at blood sample collection 
will be recorded on the Central Laboratory Requisition Form. Fasting is considered as no 
intake of food or any drink except for water for at least 8 hours. 
 
Urine dipstick analysis including 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.  
 
Clinical laboratory testing at Screening Visit 1 will include HBs-Ag, hepatitis B surface 
antibody (HBs-Ab), HBc-Ab, HCV-Ab, HIV screen (Anti-HIV-1 and HIV-2 antibodies) 
and anti-nuclear antibody (ANA).  
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Table 1 - Eligibility interpretation for hepatitis serology  
Hepatitis Serology Result 
Protocol Action 
HBs Ag positive or indeterminate 
Excluded 
HBs Ab positive, HBs Ag negative, HBc Ab negative 
Eligible 
IgM HBc Ab positive 
Excluded 
Total-HBc Ab positive (with or without HBs Ab positive) 
Test for HBV DNA 
 
If HBV DNA positive: excluded 
 
If HBV DNA negative/not detecteda: eligible 
HCV antibody positive 
Test for HCV RNA 
 
If HCV RNA positive: excluded 
 
If HCV RNA negative/not detected: eligible 
a It is recommended that patients who are receiving potentially immunosuppressive therapy and are IgG HBcAb positive and HBV DNA 
negative undergo surveillance HBV DNA studies every 1-3 months depending upon the individual potential therapeutic risk and 
comorbidities. If necessary, a hepatologist should be consulted on a case-by-case basis. 
HBc Ab: Hepatitis B core antibody; HBs Ab: HBs Ab: Hepatitis B surface antibody; HBs Ag: Hepatitis B surface antigen; HBV DNA: Hepatitis B 
virus DNA; HCV RNA: Hepatitis C virus RNA. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix K. 
9.2.3.6 Other Safety Laboratory Tests  
9.2.3.6.1 Serum Immunoglobulins and Subtypes  
Serum immunoglobulins: quantitative immunoassays for total IgG, IgG subclasses 1–4, IgM, and 
IgA.  
Please note that Total IgE, antigen-specific IgE, and antigen-specific IgG4 are assessed as 
pharmacodynamic parameters (eg, to determine the change from Baseline in IgE/IgG4 ratio; see 
Section 9.4.2). 
As a precaution for maintenance of treatment blinding, results for immunoglobulins will not be 
released to Investigators during the study, unless required for investigation of other safety findings 
in individual patients. 
9.2.3.7 Pregnancy Test  
A urine pregnancy test will be performed at Screening (Visit 1) in female patients of childbearing 
potential who have commenced menstruating, and a urine dipstick pregnancy test will be 
performed at Visit 2 prior to randomization and other clinic visits prior to administration of IMP. 
A negative result must be obtained at Visit 1 and 2 prior to randomization. Refer to Section 1.2 
Study Flow Chart for the schedule of pregnancy tests performed throughout this study. Those 
female patients who commence initial menstruation during the study will be similarly monitored 
with urine dipstick pregnancy tests and contraception consulting for the duration of the study. 
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9.3 
OTHER SECONDARY ENDPOINTS  
9.3.1 Systemic Drug Concentration, Anti-drug Antibodies, and IgG responses to 
vaccination during drug treatment  
 
Serum functional dupilumab concentrations 
 
ADA 
 
IgG responses to vaccination with any vaccination for tetanus, diphtheria, pertussis and/or 
seasonal trivalent/quadrivalent influenza vaccine during dupilumab treatment (may be 
analyzed as exploratory endpoint if insufficient power). 
9.3.1.1 Systemic Drug Concentration and Anti-drug Antibodies  
9.3.1.1.1 Sampling Time  
Predose blood samples will be collected for determination of functional dupilumab concentration 
in serum and anti-dupilumab antibodies (including neutralizing antibodies) on days designated in 
the Study Flow Chart (see Section 1.2 as well as Section 10.3.4, as needed for Brazil). 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. 
If an SAE or AESI occurs in a patient, blood samples should be collected for determination of 
functional dupilumab concentration, and anti-dupilumab antibody assessment at or near the onset 
and completion of the occurrence of the event, if possible. The exact date and time of sample 
collection must be recorded and entered into the database by the central laboratory. An 
unscheduled systemic drug concentration page in the e-CRF must be completed as well. 
Further follow-up of individual patients will be considered based on the overall assessment of 
antibody titers and clinical presentation. 
9.3.1.1.2 Handling Procedures  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and anti-drug antibodies is provided in Table 2. 
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Table 2 - Summary of handling procedures for dupilumab  
Sample type 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Blood sample volume 
2 mL 
2 mL 
Anticoagulant 
None 
None 
Blood handling procedures 
See Operational Manual 
See Operational Manual 
Serum aliquot split 
Two aliquots 
Two 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 
9.3.1.1.3 Bioanalytic Method  
Serum samples will be assayed using validated methods as described in Table 3. 
Table 3 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody  
Analyte 
Functional dupilumab 
Anti-dupilumab antibody 
Matrix 
Serum 
Serum 
Analytical technique 
ELISA 
Electrochemiluminescence 
 
Site of bioanalysis 
Regeneron 
Regeneron 
ELISA: enzyme-linked immunosorbent assay 
 
9.3.1.2 Humoral Immune Response to Vaccines  
Humoral immune responses to standard vaccines (in this study: any vaccination for tetanus, 
diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza vaccine) occurring during 
dupilumab treatment will be evaluated for those patients eligible for these vaccinations. 
At Screening, parent(s)/caregiver(s)/legal guardian(s) will be asked to provide information on 
their child’s vaccination record and schedule, and assess whether immunizing their children with 
any vaccination for tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza 
(as per local medical practice) will result in vaccination during the study.  
Any patient who will receive planned vaccination for tetanus, diphtheria, pertussis and/or seasonal 
trivalent/quadrivalent influenza during the study, will be scheduled to receive the respective 
vaccination(s) and to have blood samples for antibody titers drawn before and after the respective 
vaccination(s), as detailed below, and as shown in the Study Flow Chart (Section 1.2). 
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Scheduled blood sample collection for pre- and post-vaccine antibody titers, for both vaccinations 
(ie, any tetanus, diphtheria and pertussis and/or seasonal trivalent/quadrivalent influenza) should 
be drawn within 8 weeks prior to vaccination and at 3-4 weeks (up to 6 weeks) after the respective 
vaccination(s); however, all blood titer samples must be drawn between Week 6 and Week 50 (ie, 
Visit 5 and Visit 27, respectively).  
Depending on patient’s vaccination schedule during the course of this study, every effort should 
be made to draw pre-vaccination titers at either Weeks 6, 12, or 24 (V5, V8, V14) of the 
Randomized Treatment Period, and to draw post-vaccination titers at either Weeks 12, 24, 36 or 
50 (V8, V14, V20, V27) of the Randomized Treatment Period (see Study Flow Chart Section 1.2). 
For patient(s) requiring urgent/emergency vaccination with any seasonal trivalent/quadrivalent 
influenza and/or any tetanus, diphtheria and pertussis vaccine (eg, flu season approaching, animal 
bite, emergency room standard procedures, etc) between Week 6 and Week 44 (ie, Visit 5 and 
Visit 24, respectively), the actual vaccination(s) may be given by physicians or qualified 
caregivers outside the study clinic; however, every effort should be made to obtain blood samples 
for pre- and post-vaccine antibody titers at scheduled draws as described above. Should 
vaccination be unable to be planned in accordance with other study blood draws (eg, tetanus 
vaccination for accidental puncture wounds, etc) as outlined above, at the discretion of the 
Investigator and with agreement of patient parents or caregiver, additional blood draws may be 
performed to obtain pre-vaccination and post-vaccination titers. 
9.3.1.3 Biomarker endpoints  
 
Change from baseline in fractional exhaled nitric oxide (FeNO) at Week 12. 
Fractional exhaled nitric oxide (FeNO) will be analyzed using a NIOX instrument (Aerocrine 
AB, Solna, Sweden), or similar analyzer using a flow rate of 50 mL/s, and reported in parts 
per billion (ppb). This assessment should be conducted prior to spirometry and following a 
fast of at least 1 hour. Further details on the procedure for measuring exhaled nitric oxide with 
NIOX will be provided in a separate instruction manual. 
9.4 
EXPLORATORY ENDPOINTS  
9.4.1 Exploratory Endpoints  
 
Change from baseline in blood biomarkers (TARC and serum total IgE). 
 
 
 
 
The proportion of patients requiring a permanent step up in background controller 
medication after 2 or more severe asthma exacerbation events. 
 
To evaluate the effect of dupilumab on additional PROs: 
- 
Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ) score, for 
caregivers of children ≥7 years old at Randomization Visit 2 
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- 
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire – Interviewer 
Administered (PRQLQ-IA) score, in children 6 to <12 years old with history of 
allergic rhinitis) 
- 
EuroQol 5-dimensions questionnaire (EQ-5D-Y) for children 
 
Change from Baseline in antigen-specific IgE and antigen-specific IgG4, and ratio of 
IgE:IgG4 
 
Slope of % predicted FEV1  
9.4.2 Pharmacodynamics and Phenotyping  
Asthma is a heterogeneous disease comprised of multiple phenotypes and endotypes. To assure 
optimization of treatment in children, a set of biomarkers related to type 2 inflammation will be 
assessed at Baseline and after treatment for their association with therapeutic response. In 
previous asthma trials in adults, treatment with dupilumab significantly suppressed the levels of 
serum total IgE (a product of immunoglobulin class switching driven by IL-4), antigen-specific 
IgEs, serum TARC (CCL17; a ligand of CCR4 receptors that attracts Th2 cells), and FeNO (a 
marker of airway inflammation) baseline values, including blood eosinophil counts from 
hematology assays were used to phenotype patients.  It is feasible that children may differ from 
adults in their biomarker profile. Therefore, these biomarkers are included in the current study. 
In addition, a possible switching in antigen-specific IgE toward the corresponding antigen-specific 
IgG4 will be assessed in this study to explore the possibility that dupilumab may in part attenuate 
allergic sensitization. 
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. 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s), Investigators, and site personnel will be blinded 
and have no access to any assay results for total IgE, antigen-specific IgEs, antigen-specific IgG4, 
or TARC, while the study is ongoing, as the related efficacy data are not essential for patient care 
and have the potential for unblinding the study treatments. 
9.4.2.1 Serum Biomarkers  
Total IgE will be measured with a quantitative method (eg, ImmunoCAP) approved for diagnostic 
testing. 
Antigen-specific IgE and antigen-specific IgG4 will be detected using panels of antigens 
appropriate to the location of the clinical site (quantitative ImmunoCAP test; Phadia). 
TARC will be assayed with a validated immunoassay.  
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9.4.2.3 Patients Requiring a Permanent Step Up in Background Controller Medication 
After 2 or More Severe Asthma Exacerbation Events.  
For this study, severe asthma exacerbation events should be managed by the Investigators based 
on their medical judgment and applicable national/international asthma management guidelines, 
and as outlined in this protocol: 
For patient(s), who experience 2 or more severe asthma exacerbation events anytime during the 
Treatment Period, a permanent change (step up in medium-to high-dose ICS or addition of second 
controller for patients on high-dose ICS monotherapy) see Appendix A and Appendix B) on their 
stable-dose background controller medication may occur, as indicated and according to the 
respective Investigator's medical judgment and direction.  
The proportion of all patients with any of these treatment adjustments will be compared by 
treatment arm. 
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9.4.2.4 Other Patient Reported Outcomes Including Health Related Quality of Life 
(Exploratory Endpoints)  
9.4.2.4.1 Paediatric Asthma Caregiver's Quality of Life Questionnaire  
The PACQLQ was designed as a 13-item questionnaire for the parent(s)/caregiver(s)/legal 
guardian(s) of children ≥7 years old and <12 years of age at Randomization Visit 2), in order to 
capture the impact of the child’s asthma on their quality of life and which aspects were most 
troublesome to the parent(s)/caregiver(s)/legal guardian(s) during the time prior to this assessment 
(see Appendix H). 
A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate 
better quality of life. 
9.4.2.4.2 Pediatric Rhinoconjunctivitis Quality Of Life Questionnaire–Interviewer Administered in 
patients with comorbid allergic rhinitis.  
PRQLQ-IA (see Appendix I) is an interviewer-administered questionnaire developed to measure 
HRQoL signs and symptoms that are most problematic in children ≥6 years to <12 years old, as a 
result of perennial or seasonal allergic rhinitis. The 23-item PRQLQ-IA 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 takes approximately 7 minutes to complete. The minimally important difference (MID) 
of 0.5 has been established as the minimal important difference indicative of a clinically 
meaningful change (12).  
9.4.2.4.3 Euro Qol (EQ-5D-Y) – for Children  
The EQ-5D-Y will be completed by children (relates to the quality of life to the child). Those who 
can read are encouraged to fill the questionnaire by themselves. Those who cannot read, fill it 
with the help of their adult caregiver (parent/caregiver). 
The EQ-5D-Y consists of 2 pages, the EQ-5D-Y descriptive system and the EQ visual analogue 
scale (VAS; see Appendix J). The descriptive system assesses 5 dimensions but using a 
child-friendly wording (mobility, looking after myself, doing usual activities, having pain or 
discomfort, feeling worried, sad or unhappy). Each dimension has 3 levels: no problems, some 
problems, a lot of problems. The respondent is asked to indicate his/her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. The 
EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale where the 
endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents. Also, previously published studies by EuroQol Group members showed 
preliminary evidence of the instrument’s feasibility, reliability and validity. 
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9.6 
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  
The clinical trial consists of three periods, using an add-on therapy approach to inhaled 
corticosteroid in combination with second controller medications: 
 
Screening Period (4 [±1] weeks; Visit 1)  
 
Randomized Treatment Period (52 weeks; Visits 2-28) 
 
Post-treatment Period (12 weeks; Visits 29-31) 
The study visits occur on the planned dates (relative to the first injection), as scheduled. The visit 
schedule should be adhered to within ±3 days for randomized treatment period and ±5 days for 
post-treatment follow up period. 
Spirometry should be performed at all visits as detailed in Section 9.2.2.1.1, in order to have 
spirometry 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 all remaining study visits and participate in follow-up assessments 
according to the visit schedule until the end of the study with a ±5 day window or up to recovery 
or stabilization of any AE. At the time of permanent treatment discontinuation, patients will 
perform the early treatment discontinuation (ETD) visit with all the assessments defined for the 
EOT Visit 28. However, patients who discontinue early from treatment will not be eligible for the 
1-year long-term extension study. 
For patients who permanently discontinue the study, under exceptional circumstances where there 
is no possibility for a patient and parent(s)/caregiver(s)/legal guardian(s) to come to the site for 
the scheduled follow-up visit, a phone contact may be made after Sponsor’s approval is given.  
During that phone contact, at least information about AEs, concomitant medication and asthma 
exacerbation events must be collected, and the schedule for these calls should still reflect the visit 
schedule.  
Patients should be reminded that sexually active female patients of reproductive potential are 
required to practice effective contraception during the entire study duration, while taking 
dupilumab and for 12 weeks post last IMP dose. 
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 clinical presentation at the time of discontinuation. 
Recommended Order of Assessments: It is recommended that the order of 
assessments/procedures (as applicable) outlined below will be adhered to by the Investigator and 
site staff for every patient at each study visit at the investigative site: 
1. PROs including HRQoL 
2. Procedures: 
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a) ECG 
b) FeNO levels 
c) Spirometry 
d) Reversibility/Post-bronchodilator FEV1 
e) Electronic diary download 
3. Safety and laboratory assessments 
4. IMP administration  
10.1 
VISIT SCHEDULE  
10.1.1 Screening Period (Week -5 to Week 0, maximum 35 days prior Day 0)  
Prior to all screening assessments, the patient and the parent(s)/caregiver(s)/legal guardian(s) must 
sign and date the Ethics Committee (EC) approved ICF/IAF. The patient assent should be 
obtained depending on his/her maturity of understanding study associated information. All 
patient(s)/parent(s)/caregiver(s)/legal guardian(s) will receive information on the study 
objective(s) and procedures from the Investigator. 
 
 
 
 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol (see Section 1.2), it is possible for them to be performed over more than 1 site 
visit if necessary, as 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 (4 [±1] weeks or 
28-35 days) prior to Day 1. In such an event the patient/parent(s)/caregiver(s)/legal guardian(s) do 
not need to sign a new ICF/IAF 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 
re-screened for study eligibility one additional time (as described in Section 8.4). For patients 
re-screened a new ICF/IAF, as applicable, must be signed by patient/parent(s)/caregiver(s)/legal 
guardian(s), and a new patient number will be allocated. All of the Visit 1 procedures must be 
repeated (refer to Section 8.4 for further instructions related to re-screening).  
Patients that fail the Screening Visit due any unforseen administrative or logistic reason (eg, 
electronic diary/spirometry equipment malfunction, no IMP, etc), or patient-related/site personnel-
related unintentional errors, may be re-screened one time after approval is granted by the 
Sponsor’s clinical study director. In every case of re-screen allowance due to technical equipment 
malfunction and/or unintentional human error(s), the Study Investigator must document receipt of 
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Sponsor approval and when applicable, document the site’s corrective action plan to prevent 
future occurrences. 
At Screening, parent(s)/caregiver(s)/legal guardian(s) will be asked to provide information on 
their child’s vaccination schedule, and assess whether immunizing their children with any 
vaccination for tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza (as 
per local medical practice) will result in vaccination during the study (see Section 9.3.1.2 for more 
information). 
10.1.2 Screening Visit 1 (Week -4 [± 1 week], or between Day -35 and Day -21)  
Following a discussion of participation in the clinical trial, written IAF/ICF (as applicable per 
national requirements) must be obtained and documented, as described in Section 12.2. The 
IAF/ICF procedure must be completed prior to any screening assessments and procedures. 
The following procedures will then be performed: 
 
Call IVRS/IWRS to assign patient number and register screening visit. 
 
Interview to collect patient demographic information, medical history, asthma-specific 
medical history (ie, family history of atopy & Ig E mediated disease [particularly 
maternal], premature birth and/or, low birthweight, exposure to tobacco smoke, recurring 
viral infections in early childhood), surgical history, prior and concomitant medications 
and menstruation status for female patients of childbearing potential. 
 
Interview to collect vaccination information and vaccination plan during the treatment 
period. 
 
Review entry criteria to assess eligibility, with special attention to assess the following: 
- 
Prescribed treatment dosage meets the pre-protocol definition of medium to high-dose 
ICS (see Appendix A) in combination with a second controller (ie, LABA, LTRA, 
LAMA, or methylxanthines) for at least 3 months with a stable dose ≥1 month prior to 
Screening Visit 1.  
Note: patients requiring a third controller medication for their asthma are not 
considered eligible for this study. 
- 
Patient has experienced, within 1 year prior to Visit 1: 1) Treatment with ≥1 SCS (oral 
or parenteral) bursts for worsening asthma and/or 2) Hospitalization or an 
emergency/urgent medical care visit for worsening asthma. 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height). 
 
Perform physical examination. 
 
Administer ACQ-IA for children (6 to <12 years old).  
- 
Verify if ACQ-5 score is ≥1.5. 
 
Measure exhaled nitric oxide. 
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- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for 
at least 12 hours, and withholding the last dose of LAMA for at least 24 hours. This 
will be verified before performing the PEF measurements. 
- 
Pre-bronchodilator FEV1 must be ≤95% of predicted normal or pre-bronchodilator 
FEV1/FVC ratio <0.85. 
 
Establish reversibility 
- 
Reversibility must be at least 10% in FEV1 after 200 to 400 mcg (2 to 4 puffs with 
MDI) of albuterol/salbutamol or 45 to 90 mcg (2 to 4 puffs with MDI) of 
levalbuterol/levosalbutamol reliever medication (up to 3 opportunities during the same 
visit are allowed with a maximum of 12 puffs of reliever medication if tolerated by the 
patient).   
Note: A total of 3 visits to meet the qualifying criterion of reversibility may be made 
between the Screening Visit 1 and up to the day of the actual Baseline Visit 2. 
Note: Documented reversibility or positive airway hyperresponsiveness to 
methacholine within 12 months prior to Screening V1 is considered acceptable. 
 
Perform 12-lead ECG 
 
Obtain blood samples for screening clinical laboratory determinations: 
- 
Hematology (see Section 9.2.3.5 for details) 
- 
Serum chemistry (see Section 9.2.3.5 for details) 
 
Obtain blood samples for screening laboratory evaluation of hepatitis screen HBs-Ag, 
HBs-Ab, HBc Ab, HCV-Ab, HIV screen (Anti-HIV-1 and HIV-2 antibodies) and ANA. 
 
Obtain urinalysis test (dipstick)  
 
Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating) 
 
Dispense electronic diary/PEF meter, provide instructions for daily use, and remind patient 
and their parent(s)/caregiver(s)/legal guardian(s) to bring the device to the next visit. 
 
Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication throughout the 
study. Instruct them and their parent(s)/caregiver(s)/legal guardian(s) to record usage in 
the electronic diary. 
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 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS alone or in combination with a second controller as used during the Screening 
Period and instruct them to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
Schedule a site visit within a maximum of 35 days (Visit 2, Week 0) and request patient 
and their parent(s)/caregiver(s)/legal guardian(s) to come at approximately the same time 
of this visit. 
10.1.3 Randomization Visit 2 (Week 0, Day 1)  
 
Reconfirm eligibility based on review of Inclusion/Exclusion Criteria.  
 
Record all medication use with start date and dose in e-CRF; inquire about AEs/SAEs and 
background asthma therapy tolerability. 
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
who commenced menstruating, ie, are of childbearing potential 
 
Administer ACQ-IA (ACQ-7) and assess if ACQ-5 score is ≥1.5 
 
Administer all additional PROs: 
PAQLQ(S)-IA, PRQLQ-IA, EQ-5D-Y for children, PACQLQ. 
 
Administer HCRU 
 
Compliance with use of the mandatory background therapy, ICS in combination with one 
controller product as used just prior to screening, as defined as: 
- 
≥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. 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height) 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
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the last dose of LAMA for at least 24 hours prior to administration of investigational 
product. This will be verified before performing the PEF measurements. 
- 
Pre-bronchodilator FEV1 must be ≤95% of predicted normal or pre-bronchodilator 
FEV1/FVC ratio <0.85. 
- 
Post-bronchodilator FEV1 should be determined.    
Note: for patients that will have an additional and last attempt of reversibility testing 
(for eligibility) at the Baseline Visit 2, the post-bronchodilator FEV1 will come from 
the result of this reversibility test. 
- 
Patients must meet the inclusion criteria for spirometry at Visit 2 prior to 
randomization. If a patient’s FEV1 does not qualify, then the patient will not be 
randomized.  
- 
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: 
 
Call IVRS/IWRS to register visit: Randomize the patient and receive the first assignment 
for 1 treatment kit number.  
- 
Note: If entry criteria are not met: Call IVRS/IWRS to register visit and Screen-fail the 
patient. 
 
Perform blood sampling (prior to administration of IMP) for the following tests: 
 
Clinical laboratory testing: hematology/biochemistry (refer to Section 9.2.3.5) 
- 
Systemic drug concentration and ADA (refer to Section 9.3.1) 
- 
Obtain blood samples for total IgG, IgG subclasses1-4, IgM and IgA. 
- 
Biomarker set, total IgE, and antigen-specific IgE, and antigen-specific IgG4 panel 
(refer to Section 9.4.2.1) 
 
 
 
 
Download electronic diary/PEF meter and remind patient/parent(s)/caregiver(s)/legal 
guardian(s) to bring the device to the next visit. 
 
Dispense and administer IMP 
- 
For those parent(s)/caregiver(s)/legal guardian(s) who wish to learn and train to 
home-administer the IMP injection (see Section 8.1.3 for details):  
They will be trained by the Investigator or designee to administer IMP, by 
demonstration at V2, V3, and V4 (injections performed by Investigator). The training 
of parent(s)/caregiver(s)/legal guardian(s) for IMP injection is to be documented in the 
patient’s study file. 
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- 
Patients should be monitored for at least 30 minutes after study-site administered 
investigational product administration for any signs or symptoms of a hypersensitivity 
reaction.  
 
Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication throughout the 
study. Instruct patient and their parent(s)/caregiver(s)/legal guardian(s) to record usage in 
the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and instruct them to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
Schedule a site visit 2 weeks later (Week 2 ± 3 days) at approximately the same time of 
this visit.  
10.1.4 Visit 3 (Week 2 [± 3 days])  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height) 
 
Assess menstruation status  
 
Administer ACQ-7  
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour 
 
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, withholding the last dose of LABA for at least 12 hours, or withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined 
 
Download electronic diary/PEF meter and remind patient/parent(s)/caregiver(s)/legal 
guardian(s) to bring the device to the next visit 
 
Call IVRS/IWRS to register visit and obtain next treatment kit number  
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 
Dispense and administer IMP.  
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
For those parent(s)/caregiver(s)/legal guardian(s) who wish to learn and train to home-
administer the IMP injection (see Section 8.1.3 for details):  
They will continue to be trained by the Investigator or designee to administer IMP, by 
demonstration at V2, V3, and V4 (injections performed by Investigator). The training 
should be documented in the patient’s medical records.  
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication throughout the 
study. Instruct the parent(s)/caregiver(s)/legal guardian(s) to record usage in the electronic 
diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and instruct them to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
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.  
10.1.5 Visit 4 (Week 4 [± 3 days]) and Visit 6 (Week 8 [± 3 days])  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height) 
 
Note for Visit 6: Any planned vaccination for seasonal trivalent/quadrivalent influenza 
may be administered at this visit or between Visit 6 and Visit 18 (Week 32; see Study 
Flow Chart Section 1.2) 
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Administer ACQ-7  
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
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 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined 
 
Download electronic diary/PEF meter and remind patient/parent(s)/caregiver(s)/legal 
guardian(s) to bring the device to the next visit. 
 
Call IVRS/IWRS to register visit and obtain treatment kit number 
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
For those parent(s)/caregiver(s)/legal guardian(s) who wish to learn and train to home-
administer the IMP injection (see Section 8.1.3 for details):  
They will continue to be trained by the Investigator or designee to administer IMP, by 
demonstration at V2, V3, and V4 (injections performed by Investigator). The training 
should be documented in the patient’s medical records.  
 
Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication throughout the 
study. Instruct the parent(s)/caregiver(s)/legal guardian(s) to record usage in the electronic 
diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and instruct them to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
Schedule a site visit 2 weeks later (± 3 days) at approximately the same time of this visit. 
10.1.6 Visit 5 (Week 6 [± 3 days])  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height) 
 
Assess menstruation status 
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 
Administer ACQ-7  
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
 
Download electronic diary/PEF meter and remind patient/parent(s)/caregiver(s)/legal 
guardian(s) to bring the device to the next visit 
 
Perform sampling for the following tests: 
- 
Blood sample for systemic drug concentration assay 
 
 
 
 
- 
Blood samples for pre-vaccination antibody titers for the patient(s) scheduled to 
receive seasonal trivalent/quadrivalent influenza during this study, and within the next 
8 weeks from Visit 5 (Study Flow Chart Section 1.2; see Section 9.3.1.2 for details). 
 
Call IVRS/IWRS to register visit and obtain new treatment kit number 
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
For those parent(s)/caregiver(s)/legal guardian(s) willing and trained to perform 
home-administration of IMP-injection (see Section 8.1.3 for details):  
Under the close supervision of the Investigator or delegate, parent(s)/caregiver(s)/legal 
guardian(s) will perform the injection, including feedback on technique by the 
Investigator or delegate. Assess that the training for IMP home administration is 
documented in the patient’s study file. 
 
Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication throughout the 
study. Instruct parent(s)/caregiver(s)/legal guardian(s) to record usage in the electronic 
diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and instruct them to record daily usage in the electronic diary. 
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 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
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. 
10.1.7 Visit 7 (Week 10 [± 3 days])  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height) 
 
Assess the menstruation status 
 
Administer ACQ-7  
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
 
Download electronic diary/PEF meter and remind patient and their 
parent(s)/caregiver(s)/legal guardian(s) to bring the device to the next visit 
 
Call IVRS/IWRS to register visit and obtain treatment kit number 
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
For those parent(s)/caregiver(s)/legal guardian(s) willing and trained to perform 
home-administration of IMP-injection (see Section 8.1.3 for details):  
Under the close supervision of the Investigator or delegate, parent(s)/caregiver(s)/legal 
guardian(s) will perform the injection, including feedback on technique by the 
Investigator or delegate. Assess that the training for IMP home administration is 
documented in the patient’s study file. 
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 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct 
parent(s)/caregiver(s)/legal guardian(s) to record usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and instruct  parent(s)/caregiver(s)/legal guardian(s) to record daily usage in the electronic 
diary 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
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. 
10.1.8 Visit 8 (Week 12 [± 3 days])  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height) 
 
Administer ACQ-7  
 
Administer all additional PROs:  
PAQLQ(S)-IA, PRQLQ-IA, PACQLQ. 
 
Administer HCRU 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined. 
 
Obtain urine for urinalysis (dipstick)  
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Perform blood sampling (prior to administration of IMP) for the following tests: 
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- 
Clinical laboratory testing (hematology/biochemistry)    
- 
Systemic drug concentration,  
- 
ADA 
- 
Biomarker set (refer to Section 9.4.2) 
 
 
 
- 
Blood samples for pre-vaccination antibody titers for the patient(s) scheduled to 
receive vaccination (ie, any tetanus, diphtheria, pertussis and/or seasonal 
trivalent/quadrivalent influenza) during this study, and within the next 8 weeks from 
Visit 8 (see Section 9.3.1.2 for details). 
- 
Blood samples for post-vaccination antibody titers for the patient(s) who received 
vaccination (ie, any tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent 
influenza) during this study, and within the previous 6 weeks prior to Visit 8 (see 
Section 9.3.1.2 for details). 
 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
For parent(s)/caregiver(s)/legal guardian(s) willing and trained to perform 
home-administration of IMP-injection (see Section 8.1.3 for details):  
Under the close supervision of the Investigator or delegate, parent(s)/caregiver(s)/legal 
guardian(s) will perform the injection, including feedback on technique by the 
Investigator or delegate. Assess that the training for IMP home administration is 
documented in the patient’s study file. 
- 
Dispense Home Dosing Diary parent(s)/caregiver(s)/legal guardian(s) willing and 
trained to perform home-administration of IMP-injection, and provide instructions on 
preparation, injection and dose.  
- 
For parent(s)/caregiver(s)/legal guardian(s) unable or unwilling to 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.  
 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct them to 
record usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and instruct them to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
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last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
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 
10.1.9 Visits 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 (Weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50) –
IMP Administration at Patient Home or Investigative Site  
 
Administer IMP 
- 
Patients should monitor themselves, or be monitored, for 30 minutes after home 
administration of IMP. 
- 
For parent(s)/caregiver(s)/legal guardian(s) willing and trained to perform 
home-administration of IMP-injection (see Section 8.1.3 for details):  
Parent(s)/caregiver(s)/legal guardian(s) will document in Home Dosing Diary. 
- 
For parent(s)/caregiver(s)/legal guardian(s) unable or unwilling to administer IMP, or 
if parent(s)/caregiver(s)/legal guardian(s) do not develop the comfort to inject the IMP 
at home, or the Investigator determines that injection by parent(s)/caregiver(s)/legal 
guardian(s) at home is not appropriate, alternative arrangements may be made: for 
example for qualified site personnel and/or healthcare professionals (eg, visiting nurse 
service) to administer IMP at these timepoints at the patient's home.  
 
Applicable for Visit 27: Blood samples for post-vaccination antibody titers for the 
patient(s) who received vaccination (ie, any tetanus, diphtheria and pertussis and/or 
seasonal trivalent/quadrivalent influenza) should be drawn at 3-4 weeks (up to 6 weeks) 
after the respective vaccination(s); however, all blood titer samples must be drawn 
between Week 6 and Week 50 (ie, Visit 5 and Visit 27, respectively) of the Randomized 
Treatment Period (Study Flow Chart Section 1.2; see Section 9.3.1.2 for details). 
10.1.10 
Visits 10, 12, 16, 18, 22, 24, 26 (Weeks 16, 20, 28, 32, 40, 44, 48)  
 
Check compliance with IMP 
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability  
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height) 
 
Note for Visit 12: Any planned vaccination for tetanus, diphtheria, pertussis may be 
administered at this visit or between Visit 12 and Visit 18 (Week 32; see Study Flow Chart 
Section 1.2) 
 
Administer ACQ-7 
 
Administer HCRU, only at Visit 26 (Week 46) 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
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 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit 
 
Call IVRS/IWRS to register visit and obtain treatment kit number 
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
Dispense Home Dosing Diary parent(s)/caregiver(s)/legal guardian(s) willing and 
trained to perform home-administration of IMP-injection, and provide instructions on 
preparation, injection and dose. And review the diary for home dosing. Re-check the 
instructions on home-administration and dosing and dispense Home Dosing Diary, as 
applicable. 
- 
For parent(s)/caregiver(s)/legal guardian(s) unable or unwilling to 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.  
 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct them to 
record usage in the electronic diary. 
 
Remind parent(s)/caregiver(s)/legal guardian(s) to continue their stable dose of ICS in 
combination with a second controller as used during the Screening Period and instruct 
them to record daily usage in the electronic diary. 
 
Remind parent(s)/caregiver(s)/legal guardian(s) to withhold bronchodilators according to 
their action duration, for example, withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours, and withholding the last dose of LAMA for at least 24 hours. This will be 
verified before performing the PEF measurements. 
 
Schedule a site visit 4 weeks later (± 3 days) and ask patient to come in at approximately 
the same time of this visit  
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10.1.11 
Visit 14 (Week 24 [± 3 days])  
 
Check compliance to IMP; record all concomitant medication use; inquire about 
AEs/SAEs and background asthma therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height) 
 
Perform physical examination  
 
Urinalysis 
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Administer ACQ-7 
 
Administer all additional PROs: 
PAQLQ(S)-IA, PRQLQ-IA, and PACQLQ : 
EQ-5D-Y for children. 
 
Administer HCRU 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined. 
 
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit 
 
Perform blood sampling for the following tests:  
- 
Clinical laboratory testing (hematology/biochemistry)    
- 
Serum immunoglobulins (total IgG, IgG subclasses, IgM and IgA)  
- 
Systemic drug concentration,  
- 
ADAs  
- 
Biomarker set, total IgE, and antigen-specific IgE, and antigen-specific IgG4 panel. 
 
 
 
- 
Blood samples for pre-vaccination antibody titers for the patient(s) scheduled to 
receive vaccination (ie, any tetanus, diphtheria, pertussis and/or seasonal 
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trivalent/quadrivalent influenza) during this study, and within the next 8 weeks from 
Visit 14 (see Section 9.3.1.2 for details). 
- 
Blood samples for post-vaccination antibody titers for the patient(s) who received 
vaccination (ie, any tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent 
influenza) during this study, and within the previous 6 weeks prior to Visit 14 
(see Section 9.3.1.2 for details). 
 
Call IVRS/IWRS to register visit and obtain treatment kit number 
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
Dispense Home Dosing Diary parent(s)/caregiver(s)/legal guardian(s) willing and 
trained to perform home-administration of IMP-injection, and provide instructions on 
preparation, injection and dose. And review the diary for home dosing. Re-check the 
instructions on home-administration and dosing and dispense Home Dosing Diary, as 
applicable. 
- 
For parent(s)/caregiver(s)/legal guardian(s) unable or unwilling to 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.  
 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct them to 
record usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and them patient to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
Schedule a site visit 4 weeks (± 3 days) and ask patient to come at approximately the same 
time of this visit 
10.1.12 
Visit 20 (Week 36 [± 3 days])  
 
Check compliance to IMP; record all concomitant medication use; inquire about 
AEs/SAEs and background asthma therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height) 
 
Obtain urine for urinalysis (dipstick)  
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 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Administer ACQ-7 
 
Administer all additional PROs: 
PAQLQ(S)-IA, PRQLQ-IA, and PACQLQ  
 
Administer HCRU 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined. 
 
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit 
 
Perform blood sampling for the following tests:  
- 
Clinical laboratory testing (hematology/biochemistry)    
 
 
 
- 
Blood samples for post-vaccination antibody titers for the patient(s) who received 
vaccination (ie, any tetanus, diphtheria, pertussis and/or seasonal trivalent/quadrivalent 
influenza) during this study, and within the previous 6 weeks prior to Visit 20 
(see Section 9.3.1.2 for details). 
 
Call IVRS/IWRS to register visit and obtain treatment kit number 
 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
Dispense Home Dosing Diary parent(s)/caregiver(s)/legal guardian(s) willing and 
trained to perform home-administration of IMP-injection, and provide instructions on 
preparation, injection and dose. And review the diary for home dosing. Re-check the 
instructions on home-administration and dosing and dispense Home Dosing Diary, as 
applicable. 
- 
For parent(s)/caregiver(s)/legal guardian(s) unable or unwilling to administer IMP: 
Arrangements must be made for the patient to receive IMP injections at the study site 
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as unscheduled visits, or for qualified site personnel and/or a professional caregiver to 
administer IMP at home at q2w intervals.  
 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct them to 
record usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and them patient to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
Schedule a site visit 4 weeks (± 3 days) and ask patient to come at approximately the same 
time of this visit 
10.1.13 
Visit 28 (Week 52 [± 3 days], End of Treatment, and Early Treatment 
Discontinuation)  
 
Check compliance to IMP; record all concomitant medication use; inquire about 
AEs/SAEs and background asthma therapy tolerability 
 
Review patient Home Dosing Diary for content and completeness 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height) 
 
Perform physical examination 
 
Obtain urine for urinalysis (dipstick)  
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Administer ACQ-7 
 
Administer all additional PROs: 
PAQLQ(S)-IA, PRQLQ-IA, and PACQLQ: 
EQ-5D-Y for children 
 
Administer HCRU 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour 
 
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 
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least 6 hours, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined 
 
Perform 12-lead ECG 
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit 
 
Perform blood sampling for the following tests:  
- 
Clinical laboratory testing (hematology/biochemistry)    
- 
Serum immunoglobulins (total IgG, IgG subclasses, IgM and IgA)  
- 
Systemic drug concentration,  
- 
ADAs  
- 
Biomarker set, total IgE, and antigen-specific IgE, and antigen-specific IgG4 panel. 
 
 
 
 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct them to 
record usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their stable 
dose of ICS in combination with a second controller as used during the Screening Period 
and them patient to record daily usage in the electronic diary. 
 
Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators according to their action duration, for example, withholding the last dose 
of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the 
last dose of LABA for at least 12 hours, and withholding the last dose of LAMA for at 
least 24 hours. This will be verified before performing the PEF measurements. 
 
Call IVRS/IWRS to register EOT visit 
At Visit 28 (EOT visit), for patients who will not continue with the 1-year long-term extension 
study, the controller medication regimen and dose used during the randomized period could be 
adjusted based on medical judgment of the patients’ asthma control status. 
10.1.14 
Visit 29 and Visit 30 (Weeks 56 and 60 ± 5 days), Post-Treatment Period)  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height) 
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 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
 
Download electronic diary/PEF meter and remind patient to bring the device to the next 
visit 
 
Remind parent(s)/caregiver(s)/legal guardian(s) to use salbutamol/albuterol or 
levosalbutamol/levalbuterol as reliever medication throughout the study. Instruct them to 
record usage in the electronic diary. 
 
Remind parent(s)/caregiver(s)/legal guardian(s) to continue the stable dose of ICS in 
combination with a second controller which was maintained over the randomized 
treatment period (unless treatment modified based on medical judgment) and record daily 
usage in the electronic diary. 
 
Remind parent(s)/caregiver(s)/legal guardian(s) to withhold bronchodilators according to 
their action duration, for example, withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours, and withholding the last dose of LAMA for at least 24 hours. This will be 
verified before performing the PEF measurements. 
 
Schedule a site visit 4 weeks later (± 5 days) and ask patient to come in at approximately 
the same time of this visit   
10.1.15 
Visit 31 (Week 64, End of Study Visit)  
 
Record all concomitant medication use; inquire about AEs/SAEs and background asthma 
therapy tolerability 
 
Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight 
and height) 
 
Perform physical examination 
 
Obtain urine for urinalysis (dipstick)  
 
Assess menstruation status and perform urine dipstick pregnancy test for female patients 
of childbearing potential (who have commenced menstruating) 
 
Administer ACQ-7  
 
Administer all additional PROs: 
PAQLQ(S)-IA, PRQLQ-IA, EQ-5D-Y for children, PACQLQ 
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 
Administer HCRU 
 
Measure exhaled nitric oxide 
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
 
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, withholding the last dose of LABA for at least 12 hours, and withholding 
the last dose of LAMA for at least 24 hours. This will be verified before performing 
the PEF measurements. 
- 
Post-bronchodilator FEV1 should be determined. 
 
Perform 12-lead ECG 
 
Perform blood sampling for the following tests:  
- 
Clinical laboratories,  
- 
Systemic drug concentration,  
- 
ADAs 
 
Download electronic diary/PEF meter and take back the device 
 
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 e-CRF. In any case, all 
efforts should be made to maintain the patient for the 12 weeks follow up. 
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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 the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 7.1 and  
Section 7.2) AE is sufficiently resolved and unlikely to recur after resuming therapy with IMP. 
In addition, the following conditions(s) will be cause for temporary treatment discontinuation: 
 
Infections or infestations that do not respond to medical treatment  
 
Any laboratory abnormality that meets temporary treatment discontinuation criteria as per 
Appendix K on Guidelines for management of specific laboratory abnormalities 
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 study (ie, from any further investigational product or study 
procedure) for the following reasons:  
 
At their own request or at the request of their legally authorized representative (Legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research). 
 
If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being 
 
At the specific request of the Sponsor 
- 
Including some specific circumstances like the Yellow Fever outbreak in Brazil, where 
patients from affected areas who are not previously vaccinated with yellow-fever 
vaccine, are to be permanently discontinued from study drug (Section 8.8.1). 
 
In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor 
 
Any code breaking requested by the Investigator will lead to permanent treatment 
discontinuation. 
 
Pregnancy 
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 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment. 
 
Diagnosis of a malignancy during study. 
 
Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (See Appendix M). 
 
Serum ALT >3 ULN and Total Bilirubin >2 ULN (See Appendix K). 
 
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. 
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. Study Investigators should 
continue background therapy after treatment discontinuation, as guided by their medical 
judgment. 
For patients in Brazil, see Appendix N.  
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 EOS with a ± 5 day window or up to recovery or stabilization of any AEs. At the time of 
permanent treatment discontinuation, patients will perform ETD visit with all the assessments 
defined for the EOT Visit 28. Patients who permanently discontinue early from treatment will not 
be eligible for the 1-year long-term extension study.  
For patients who permanently discontinue the study, under exceptional circumstances where there 
is no possibility for a patient and parent(s)/caregiver(s)/legal guardian(s) to come to the site for 
the scheduled follow-up visit, a phone contact may be made after Sponsor’s approval is given. 
During that phone contact, at least information about AEs, concomitant medication and asthma 
exacerbation events must be collected, and the schedule for these calls should still reflect the visit 
schedule.  
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 clinical presentation at the time of discontinuation. 
All cases of permanent treatment discontinuation should be entered by the Investigator in the 
e-CRF when considered as confirmed. 
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10.3.5 Procedure and Consequence for Patient Withdrawal From Study  
The patients may be withdrawn from the study at any time during the course of study if their 
parent(s)/caregiver(s)/legal guardian(s) decide to do so, 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.  
For patients who withdraw, the patient and their parent(s)/caregiver(s)/legal guardian(s) should be 
explicitly asked about the contribution of possible AEs to their decision to withdraw consent, and 
any AE information elicited should be documented.  
Patient(s)/parent(s)/caregiver(s)/legal guardian(s) 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 who withdraw consent will be assessed using the procedures normally 
planned for the EOT visit and have EOS assessments completed at the same visit or at the last 
planned visit. 
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). 
A subject should only be designated as lost to follow-up, if the site is unable to establish contact 
with the patient/parent(s)/caregiver(s)/legal guardian(s) 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 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. 
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Protocol-defined severe asthma exacerbation events and LOAC (for detailed definitions see 
Section 9) are collected as efficacy endpoints on the e-CRF. Only asthma exacerbations which 
fulfill a seriousness criterion should be reported as an AE (as per Section 10.4.1.2).   
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 SAE is any untoward medical occurrence that at any dose: 
 Results in death, or 
 Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 Results in persistent or significant disability/incapacity, or 
 Is a congenital anomaly/birth defect 
 Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
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- 
Cancers diagnosed during the study  
- 
Chronic neurodegenerative diseases (newly diagnosed)  
10.4.1.3 Adverse Event of Special Interest  
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
 Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (refer to Appendix L for the definition of anaphylaxis). 
 Severe injection site reactions that last longer than 24 hours. 
 An infection that meets at least one of the following criteria: 
- 
Any serious infection (that meet any of the SAE criteria) 
- 
Requires parenteral (intravenous, intramuscular, SC) antimicrobial therapy.  
- 
Requires oral antimicrobial therapy for >2 weeks. 
- 
Is a parasitic infection.  
- 
Is an opportunistic infection (see list in Appendix M).  
Note: antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents. 
 Significant elevation of ALT (Appendix K) 
- 
ALT >5 × ULN in patients with baseline ALT ≤2 × ULN; or 
- 
ALT >8 × ULN if baseline ALT >2 × ULN 
 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 is an unlikely event to happen but for safety 
concerns, it is imperative to query pregnancy involving a male patient entered in the trial).  
- 
It will be qualified as an SAE only if it fulfills 1 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. 
 Symptomatic overdose (serious or non-serious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the intended dose during an interval of less than 
11 days. The circumstances (ie, accidental or intentional) should be clearly specified in 
the verbatim and symptoms, if any, entered on separate AE forms. 
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- 
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  
 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 e-CRF. 
 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 regulatory authorities provided an agreement has 
been reached with them.  
 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 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. 
 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, at the prespecified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected. The duration of poststudy follow-up and reporting of AEs will be specified (eg, 
until recovery). 
 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. 
 Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
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- 
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 
Table 4 summarizes the reporting timelines for select AEs and laboratory abnormalities. 
Table 4 - Summary of Adverse Event Reporting Instructions  
Adverse event/laboratory abnormality 
Reporting timeframe 
Serious adverse event 
 
Within 24 hours 
Pregnancy 
 
Within 24 hours 
Overdose 
Symptomatic 
Within 24 hours 
 
Asymptomatic 
Routine 
ALT elevation 
ALT >5 ULN if baseline ALT is ≤2 ULN 
Within 24 hours 
 
ALT >8 ULN if baseline ALT is >2 ULN 
Within 24 hours 
 
ALT >3 ULN plus total bilirubin >2 ULN 
Within 24 hours 
Anaphylactic reactions or acute allergic reactions that require treatment 
Within 24 hours 
Severe injection site reactions that last longer than 24 hours 
Within 24 hours 
Serious infections or infections that are AESI (see Section 10.4.1.3 and Section 10.6.3) 
Within 24 hours 
AESI: adverse event of special interest; ALT: alanine aminotransaminase; ULN: upper limit of normal;  
10.4.4 Instructions for Reporting Serious Adverse Events  
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the 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. 
 
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. 
 
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. 
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 
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 Reporting Adverse Events of Special Interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
10.4.6 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.  
 Neutropenia 
 Thrombocytopenia 
 ALT increase 
 Acute renal insufficiency 
 Suspicion of rhabdomyolysis 
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: 
 All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IEC/IRBs as appropriate and to the Investigators.  
 All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
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. 
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For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health 
Authority of any 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 allergic reaction-mediated signs and symptoms experienced 
by patients during or shortly after the pharmacologic or biologic agent given. These reactions may 
present in a variety of ways, including dizziness, headache, anxiety, dyspnea, hypotension, 
tachycardia, pruritus, rash, urticaria/angioedema, flushing, nausea, or vomiting. Anaphylaxis may 
represent the most severe form of infusion reaction, but these events may also occur via non-IgE 
mediated mechanisms (eg, anaphylactoid reactions), or may occur via other immune-mediated 
mechanisms (eg, cytokine-mediated). Refer to Appendix L “Definition of Anaphylaxis”, which 
describes the clinical criteria for the diagnosis of anaphylaxis.  
Patients must 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 at least 30 minutes after administration. 
Anaphylactic reactions or, systemic allergic reactions that are related to IMP and require treatment 
must be reported as an AESI (within 24 hours, for further details, see AESI definition in  
Section 10.4.1.3 and Appendix L) and study medication should be permanently discontinued. 
Anti-drug antibodies and PK samples will be collected near the onset and resolution of the AESI 
for any additional analysis.  
10.6.2 Severe Injection Site Reactions  
Based on the SC mode of administration of high doses of protein and on a higher incidence of 
local injection site reactions observed at the highest IMP dose level evaluated in adults 
(300 mg weekly dose), 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 
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24 hours will be reported as an AESI with immediate notification. IMP must be temporarily 
interrupted until the clinical study director (CSD) has evaluated the case. 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 infections. 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. 
A complete diagnostic work-up should be performed (ie, cultures for fungi and/or mycobacteria 
other than tuberculosis, histopathological or cytological evaluation, antigen detection and serum 
antibody titers). Patients should be referred to an infectious disease specialist if deemed necessary 
for diagnostic work up and appropriate treatment. 
Infections or infestations that do not respond to medical treatment should have study drug 
discontinued until the infection is resolved. 
For any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (See Section 10.3.2) patients must be permanently 
discontinued from study medication. 
Infections as defined in Section 10.4.1.3 should be reported as AESIs within 24 hours. 
Since dupilumab binds to IL-4Rα, preventing IL-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. 
In order to minimize this risk, any patient with an active parasitic infection should be excluded 
from the study (see Section 7.2.3). 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 heavily populated informal 
settlements, lack of running water, consumption of uncooked, undercooked, or otherwise 
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potentially contaminated food, close contact with carriers and vectors). Subsequent medical 
assessments (eg, stool exam, blood tests) must be performed in order to rule out parasitic 
infection/infestation (see also Section 10.4.1.3).  
10.6.4 Elevated Liver Function Tests  
No preclinical 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 Screening Visit 1, prior to 
randomization to exclude those patients with high risk of hepatitis infection or severe liver injury 
from this study (see Section 7.2.3). 
In order to closely follow potential liver abnormalities, assessment of total protein, albumin, total 
bilirubin, ALT, AST, and ALP are measured as part of the clinical laboratory testing.  
Clinical laboratory testing at Screening Visit 1 adds hepatitis screen (HBs-Ag, HBs-Ab, IgM and 
total-HBc-Ab, and HVC-Ab).  
Guidance for the investigation of elevated LFTs is provided in Appendix K. 
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 of this study was based on a comparison between dupilumab versus placebo with 
regard to the primary endpoint of annualized rate of severe exacerbations over 52 weeks of 
treatment for the 3 populations of interest: patients with baseline blood eosinophils ≥300 cells/µL, 
patients with baseline blood eosinophils ≥150 cells/µL, and patients with type 2 inflammatory 
phenotype (baseline blood eosinophils ≥150 cells/μL or baseline FeNO ≥20 ppb), with assuming 
the number of severe exacerbations follows a negative binomial distribution and a randomization 
ratio of 2:1.  
The sample size calculation assumes a linear discontinuation rate (20% at 1 year), thus the 
average exposure duration for patients is 0.9 year. The assumed relative risk reductions are based 
on the results in the phase 3 asthma study EFC13579 (QUEST). 
To achieve target sample size for each of the populations stated above, approximately 402 patients 
in the overall population (268 for dupilumab and 134 for placebo) need to be randomized 
assuming approximately 86% of the randomized patients have type 2 inflammatory phenotype 
(baseline blood eosinophils ≥150 cells/μL or baseline FeNO ≥20 ppb), approximately 81% of the 
randomized patients have baseline blood eosinophils ≥150 cells/μL, and approximately 64% of 
the randomized patients have baseline blood eosinophils ≥300 cells/μL. 
Patients will be randomized (2:1 ratio) to receive dupilumab or matching placebo. After a patient 
is randomly assigned to dupilumab or matching placebo, the dosage of dupilumab or matching 
placebo for the patient, 200 or 100 mg SC once q2w, will be determined based on baseline body 
weight >30 kg or ≤30 kg, respectively. 
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Randomization will be stratified by ICS dose (medium-dose versus high-dose) and eosinophil 
count (<300 cells/μL versus ≥300 cells/μL) at Screening, and by region (Latin America: 
Argentina, Brazil, Colombia, Chile and Mexico; Eastern Europe: Poland, Hungary, Romania, 
Lithuania, Turkey, Russia and Ukraine; Western Countries: Australia, Canada, Italy, South 
Africa, Spain, and USA).  The final definition of region may be updated in the SAP, if additional 
countries are included in the study.  If during the study, additional countries are included, 
necessary changes will be made to the randomization algorithm. These changes will be 
documented in the SAP. 
Note that if any change is made to the definition of stratum in the future, particularly, the 
definition of region, the changes in the region definition will be included in SAP and the IVRS 
will be reconfigured to ensure a correct randomization according to the new definition. 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patient who met the inclusion criteria and whose parent(s) or 
legal guardian signed the pediatric 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. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.  
The safety experience of patients treated and not randomized will be reported in the safety 
population according to the actual treatment received. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Efficacy Populations  
The full intent-to-treat (ITT) population is defined as all randomized patients. 
Type 2 inflammatory phenotype population is defined as the randomized patients with baseline 
blood eosinophils ≥150 cells/μL or baseline FeNO ≥20 ppb. 
Baseline blood eosinophils ≥300 cells/μL population is defined as the randomized patients with 
baseline blood eosinophils ≥300 cells/μL. 
Baseline blood eosinophils ≥150 cells/μL population is defined as the randomized patients with 
baseline blood eosinophils ≥150 cells/μL. 
All efficacy endpoints will be analyzed based on both the type 2 inflammatory phenotype 
population and the population with baseline blood eosinophils ≥300 cells/μL. 
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The sponsor will implement two testing hierarchies based on the two different indication labels 
for the US and US reference countries and the EU and EU reference countries. Accordingly, for 
the US and US reference countries, the testing hierarchy will start with baseline blood eosinophils 
≥300 cells/μL population; For EU and EU reference countries, the testing hierarchy will start with 
type 2 inflammatory phenotype population (patients with baseline blood eosinophils 
≥150 cells/μL or baseline FeNO ≥20 ppb). For more details about multiplicity consideration, refer 
to Section 11.4.2.3.  
The efficacy analyses will be conducted according to the treatment to which they are randomized. 
Selected efficacy endpoints will also be analyzed based on the full ITT population. More details 
will be specified in the SAP. 
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 and regardless of 
whether they are randomized. 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 1-year long-term extension study. 
In addition: 
 
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 (ADA) Population  
The ADA 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 with the planned dose as 
required by the protocol. No imputation will be made for patients with missing or incomplete 
data. When an administration is given with a dose above the planned dose, the corresponding 
administration is defined as above-planned dose noncompliance. When an administration is given 
with a dose below the planned dose, the corresponding administration is defined as below-planned 
dose noncompliance. Percentage of treatment compliance, above-planned dose and below-planned 
dose non-compliance will be summarized descriptively (N, Mean, standard deviation [SD], 
Median, Min, and Max). The percentage of patients with compliance is <80% will be 
summarized.  
11.4.2 Analyses of Efficacy Endpoints  
Annualized rate of severe asthma exacerbation events during the 52 weeks is the primary efficacy 
endpoint of this study. Key secondary endpoints include change from baseline in 
pre-bronchodilator % predicted FEV1 at Weeks 12. Other secondary endpoints include change 
from baseline in pre-bronchodilator % predicted FEV1 at Weeks 2, 4, 8, 24, 36 and 52 and other 
time points in between; time to first severe exacerbation event; time to first LOAC event; change 
from baseline in other lung function measurements (absolute and relative FEV1, AM/PM PEF, 
FVC, FEF 25-75%, post-bronchodilator % predicted FEV1 at Weeks 2, 4, 8, 12, 24, 36, 52, and 
other time-points in between; change from baseline at Weeks 2, 4, 8, 12, 24, 36, 52, and other 
time-points for morning/evening asthma symptom score and nocturnal awakenings (electronic 
diary), use of reliever medication, and ACQ score. Change from baseline for PAQLQ(S)-IA 
score, PACQLQ score, PRQLQ-IA score (in those with history of allergic rhinitis) and health care 
resource utilization, will be assessed at Weeks 12, 24, 36, 52, 64; and percentage of patients 
requiring increase in dose or addition of background medication. 
In addition to the primary approach to analyze change from baseline in ACQ-IA and 
PAQLQ(S)-IA total score, supportive responder analyses will also be performed for these 
endpoints at Week 12, 24, 36, 52 and 64. Details of these analyses will be provided in the 
statistical analysis plan. 
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11.4.2.1 Analysis of Primary Efficacy Endpoint(s)  
The estimand of the dupilumab treatment effect compares the annualized 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. 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 asked and encouraged to return to the clinic for all 
remaining study visits. If a patient stays in study till the end of 52-week treatment period, all 
severe exacerbation events that happen up to Week 52 will be included in the primary analysis, 
regardless if the patient is on-treatment or not. 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.  
The annualized rate of severe asthma exacerbation events will be analyzed using a negative 
binomial regression model to confirm the effectiveness of dupilumab. The analysis for the 
annualized severe exacerbation rate will be performed in the type 2 inflammatory phenotype, 
baseline blood eosinophils ≥300 cells/μL, baseline blood eosinophils ≥150 cells/μL, baseline 
FeNO ≥20 ppb and full ITT populations using appropriate multiplicity control. When performing 
the primary endpoint analysis in the type 2 inflammatory phenotype, baseline blood eosinophils 
≥150 cells/μL or the full ITT populations, the model will include the total number of events of 
each patient occurring during the 52 weeks as the response variable, with the treatment group, 
age, weight (≤30kg, >30kg), region, baseline eosinophil level (<300 cells/ μL, ≥300 cells/μL), 
baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose level (medium/high), and number of 
severe asthma exacerbation events prior to the study as covariates. When performing the primary 
endpoint analysis in the baseline blood eosinophils ≥300 cells/μL population, the baseline 
eosinophil level will be removed from the model covariates. When performing the primary 
endpoint analysis in the baseline FeNO ≥20 ppb population, the baseline FeNO level will be 
removed from the model covariates. 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 this 
protocol). Log transformed observation duration will be the offset variable.   
11.4.2.1.1 Sensitivity Analysis  
A supportive analysis to assess the treatment effect of dupilumab if patients adhere to the 
treatment and background asthma medication as directed is also provided. In this approach, the 
severe exacerbation events reported after the premature treatment discontinuation will be excluded 
from the analysis. Any measurement obtained after the first permanent stepping-up of background 
asthma medication will also be excluded from the analysis. The supportive analysis will be 
performed in the type 2 inflammatory phenotype and baseline blood eosinophils ≥300 cells/μL 
populations and will use a negative binomial model with the same set of covariates as specified 
for the primary analysis in the two populations. This model will include severe exacerbation 
events occurring during the treatment epoch before any permanent stepping-up of background 
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asthma medication as the response variable and the log transformed duration of the treatment or 
from randomization to first permanent stepping-up of background asthma medication whichever 
is shorter will be the offset variable.  
If patients withdraw from the study before Week 52 with 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, reasons and timing of the missing data will be 
summarized by treatment groups. In the primary analysis, all observed data will be used 
regardless of treatment adherence or increase of asthma background medication. No imputation 
will be conducted for the missing severe exacerbation information after a patient prematurely 
withdraws from the study up to Week 52. In addition, sensitivity analyses based on pattern 
mixture model, placebo based pattern mixture model and tipping point analysis based on the same 
negative binomial model as being used in the primary analysis may be conducted to assess the 
robustness of the conclusion of the main model. Details of these sensitivity analyses will be 
described in the SAP. 
11.4.2.1.2 Subgroup Analysis  
Subgroup analyses will be performed for the primary endpoints, as appropriate, using the same 
methods by age group, gender, region, race, baseline ICS (medium/high) dose levels, baseline 
eosinophil level, baseline FeNO level, background controller medication type at randomization, 
baseline % predicted FEV1, ACQ-7, baseline body weight, atopic medical condition, age of onset 
of asthma, and number of severe asthma exacerbation events within 1 year prior to the study. 
Detailed definition of each subgroup category will be provided in the SAP. 
The subgroup analyses (except for the baseline eosinophil levels and baseline FeNO levels) will 
be conducted for both the type 2 inflammatory phenotype population and baseline blood 
eosinophils ≥300 cells/μL population; and, the subgroup analyses for the baseline blood 
eosinophil level and baseline FeNO level will be performed in the full ITT population. 
11.4.2.2 Analyses of Secondary Efficacy Endpoints  
11.4.2.2.1 Analysis of Change from Baseline in Pre-bronchodilator % Predicted FEV1  
The key secondary endpoint, change from baseline in pre-bronchodilator % predicted FEV1 at 
Week 12, will be analyzed using a mixed-effect model with repeated measures (MMRM) 
approach. The analysis for the key secondary endpoint will be performed in the type 2 
inflammatory phenotype, baseline blood eosinophils ≥300 cells/μL, baseline blood eosinophils 
≥150 cells/μL, baseline FeNO ≥20 ppb, and full ITT populations. When performing the key 
secondary endpoint analysis in the type 2 inflammatory phenotype, baseline blood eosinophils 
≥150 cells/μL, or the full ITT populations, the model will include change from baseline as 
response variables, and for treatment, age, weight (≤30kg, >30kg), region, baseline eosinophil 
level (<300 cells/μL, ≥300 cells/μL), baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose 
level (medium/high), visit, treatment by-visit interaction, baseline value, and baseline-by-visit 
interaction as covariates. When performing the analysis in the baseline blood eosinophils 
≥300 cells/μL population, the baseline eosinophil level will be removed from the model 
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covariates. When performing the analysis in the baseline FeNO ≥20 ppb population, the baseline 
FeNO level will be removed from the model covariates. Sex, height and ethnicity will also be 
included as covariates in the models for spirometry parameters. 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 at Weeks 12 will be derived 
from the mixed-effect model with Kenward and Roger degree of freedom adjustment approach. 
Treatment comparisons at other timepoints, 8, 12, 24, 36 and 52 week and other timepoints in 
between will also be provided from the mixed-effect model for descriptive purpose. Data up to 
Week 52 will be included as response variables. 
11.4.2.2.2 Analysis of Time-to-event Variables  
Time to first severe asthma exacerbation event (and time to first LOAC; for detailed definitions of 
primary and secondary endpoints, see Section 9.1 and Section 9.2, respectively) will be analyzed 
using a Cox regression model with time-to-event as the dependent variable, and treatment, age, 
weight (≤30kg, >30kg), region, baseline eosinophil level (<300 cells/μL, ≥300 cells/μL), baseline 
FeNO level (<20 ppb, ≥20 ppb),  baseline ICS dose level (medium/high) and number of severe 
asthma events prior to the study as covariates. The estimated hazard ratio (dupilumab versus 
placebo) along with its 95% confidence interval will be presented. The Kaplan-Meier method will 
be used to derive the proportion of patients with a severe asthma exacerbation event at Weeks 12, 
24, 36, and 52, specific to each treatment group. 
11.4.2.2.3 Analysis 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 pre-bronchodilator % predicted FEV1. The covariates to be 
included are treatment, age, weight (≤30kg, >30kg), region, baseline eosinophil (<300 cells/μL, 
≥300 cells/μL), baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose level (medium/high), 
visit, treatment-by-visit interaction, corresponding baseline value and baseline-by-visit 
interaction. Sex and height will be included as covariates in the models, if the endpoint belongs to 
spirometry parameters. Descriptive statistics including number of patients, mean, standard error 
and LS means will be provided for each timepoint. 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 at each timepoint. 
11.4.2.2.4 Analysis of Change from Baseline for Other Categorical Variables  
Percentage of patients requiring increase in dose or addition of background medication will be 
analyzed as a categorical variable. Descriptive statistics by treatment group will be provided 
including the number and the percentage of patients in each category. Time to the first time 
requiring increase in dose or addition of background medication may also be provided by the 
Kaplan-Meier method if there are a sufficient number of patients requiring increase in dose or 
addition of background medication. 
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11.4.2.2.5 Sensitivity Analyses  
Sensitivity analyses will only be conducted for the key secondary endpoint of change from 
baseline in pre-bronchodilator % predicted FEV1 at Week 12. A supportive analysis will be 
provided by applying the same model for the primary analysis with only on-treatment 
measurements obtained before any permanent stepping-up of the asthma background medication.  
A sensitivity analysis based on LOCF will also be provided to assess the robustness of the 
conclusion from the primary analysis on change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12 against missing data. Details of the sensitivity analyses will be further provided 
in the SAP. 
11.4.2.2.6 Subgroup Analysis  
To assess the consistency in treatment effects across the subgroup levels, subgroup analyses used 
in the primary efficacy endpoint will also be performed for the key secondary efficacy endpoint of 
change from baseline in pre-bronchodilator % predicted FEV1 at Week 12. 
The sensitivity analysis and subgroup analysis (except for the baseline eosinophil levels and 
baseline FeNO levels) for the key secondary endpoint of change from baseline in pre-
bronchodilator % predicted FEV1 at Week 12 will be conducted in the type 2 inflammatory 
phenotype and baseline blood eosinophils ≥300 cells/μL population; and, the subgroup analyses 
for the baseline blood eosinophil level and baseline FeNO level will be performed in the full ITT 
population. 
11.4.2.3 Multiplicity Considerations  
The hypothesis testing on the primary endpoint of annualized severe exacerbation rate will be 
controlled with a two-sided type I error of 0.05 by incorporating a sequential testing procedure as 
below:  
For US and US reference countries: 
 
1st : Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period based on the patients with baseline blood eosinophils ≥300 cells/µL. 
 
2nd : Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period based on the patients with baseline blood eosinophils ≥150 cells/µL. 
 
3rd : Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period based on the patients with type 2 inflammatory phenotype (baseline blood 
eosinophils ≥150 cells/µL or baseline FeNO ≥20 ppb). 
For EU and EU reference countries: 
 
1st: Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period based on the patients with type 2 inflammatory phenotype (baseline blood 
eosinophils ≥150 cells/µL or baseline FeNO ≥20 ppb). 
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 
2nd: Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period based on the patients with baseline blood eosinophils ≥150 cells/µL. 
 
 3rd:  Annualized rate of severe exacerbation events during the 52-week placebo-controlled 
treatment period based on the patients with baseline blood eosinophils ≥300 cells/µL. 
Multiplicity control for any secondary endpoints if considered will be specified in the SAP. 
Otherwise, nominal p-values will be provided. 
11.4.2.4 Handling of Missing Data  
If patients withdraw from the study before Week 52 with severe exacerbation events that may 
occur after study discontinuation (not being observed or without any FEV1 measurements 
available after withdrawal), these patients are considered as patients with missing data on severe 
exacerbation or on FEV1 % predicted. Number, reasons and timing of the missing data will be 
summarized by treatment groups. In the primary analysis for the primary endpoint of severe 
exacerbation, all observed data will be used regardless of treatment adherence or increase of 
asthma background medication. No imputation will be conducted for the missing severe 
exacerbation information after a patient prematurely withdraws from the study up to Week 52. In 
the primary analysis for the key secondary endpoints of change from baseline in FEV1 % 
predicted, all data up to Weeks 12 will be included in MMRM model. No additional imputation 
will be conducted. 
In addition, sensitivity analyses for the primary endpoint and the key secondary endpoints may be 
performed based on a careful examination of the reason and pattern of missing data as described 
in Section 11.4.2.1.1 and Section 11.4.2.2.5. Further details will be specified in the SAP. 
11.4.3 Analyses of Safety Data  
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the safety population according to the following observation period definition. 
The observation period will be divided into 4 epochs: 
 
The screening epoch is defined as the time from the signed informed consent date up to the 
time prior to first administration of the IMP. 
 
The treatment epoch is defined as the time from the first administration of the IMP to the 
last administration of the IMP + 14 days 
 
The residual treatment epoch is defined as the time from the last administration of the 
IMP + 15 days to the last administration of the IMP + 98 days.  
 
The post-treatment epoch is defined as the period of time starting the day after the end of 
the TEAE period up to the end of the study (defined as last protocol planned visit or the 
resolution/stabilization of all serious adverse events and AESIs). 
The TEAE period will include both treatment and residual treatment epochs. 
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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 SAE and AESI. 
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 
study drug. 
 
The following definitions will be applied to laboratory parameters, vital signs and ECG. 
- 
The potentially clinically significant abnormality (PCSA) values are defined as 
abnormal values considered medically important by the Sponsor according to 
predefined criteria/thresholds based on a review of the literature and defined by the 
Sponsor for clinical laboratory tests, vital signs, and ECG.  
- 
The criteria for PCSA will determine which patients had at least 1 PCSA during the 
treatment-emergent 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.  
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. 
The proportion of patients with at least 1 TEAE, serious TEAE, and TEAE leading to 
discontinuation of the study will be tabulated by treatment group. In addition, TEAEs will be 
described according to maximum intensity and relation to the study drug. Serious AEs and AEs 
leading to study discontinuation that occur outside the treatment-emergent period will be 
summarized separately. 
11.4.3.1.1 Adverse Events of Special Interest  
The following summaries will be generated:  
 
Incidence of each AESI will be tabulated by treatment group.  
 
An overview summary of the number (%) of patients with 
- 
any AESI 
- 
any serious AESI (regardless of treatment-emergent status) 
- 
any treatment-emergent serious AESI 
- 
any AESI leading to death 
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- 
any AESI leading to permanent study drug discontinuation 
- 
any AESI 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) 
Definitions of AESIs and the method to identify AESIs will be specified in the SAP. 
11.4.3.1.2 Death  
The following deaths summaries will be generated: 
 
Number (%) of patients who died by study period (treatment emergent period, on-study) 
and reasons for death summarized on the safety population by treatment received 
 
Death in nonrandomized patients or randomized and not treated patients   
 
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. 
11.4.3.2 Clinical 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, SD, median, Q1, Q3, minimum and maximum. 
The descriptive by visit analysis will be conducted from the baseline up to the scheduled 
evaluation visit for all patients disregarding the treatment status of the patients at each visit as 
long as their data is available.   
The proportion of patients who had at least one incidence of PCSA at any time during the 
treatment-emergent 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. 
11.4.3.3 Humoral Immune Response to Vaccines  
For patients who receive vaccination, vaccine response parameters will be summarized by 
treatment groups with descriptive statistics. These parameters will be defined in the SAP. 
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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  
The incidence of positivity in the ADA assay will be assessed as absolute occurrence (n) and 
percent of patients (%), presented by treatment groups. Listing of ADA titer levels will be 
provided for patients positive in the ADA assay. Samples that are positive in the ADA assay will 
be further characterized 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. 
Anti-drug antibodies at baseline will be summarized by: 
 
Number (%) of patients with a baseline sample negative in the ADA assay 
 
Number (%) of patients with a baseline sample positive in the ADA assay 
 
The summary statistics (including number, median, Q1, Q3, minimum, and maximum) of 
the titer for patients positive in the ADA assay at baseline 
Anti-drug antibody incidence and titer will be provided for the following: 
 
Number (%) of patients negative in ADA assay at all times 
 
Number (%) of patients positive in ADA assay at any time 
 
Number (%) of patients with pre-existing positive response 
 
Number (%) of patients with treatment-boosted positive response 
 
Number (%) of patients with treatment-emergent positive response 
 
Number (%) of patients with transient treatment-emergent positive response 
 
Number (%) of patients with persistent treatment-emergent positive response 
 
Number (%) of patients with indeterminate treatment-emergent positive response 
 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for patients with treatment-emergent positive responses 
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The minimum titer for samples positive in the ADA assay is based on the minimum required 
dilution of the assay. It will be classified as  
 
Low (Titer <1000) 
 
Moderate (1000≤Titer ≤10 000) 
 
High (Titer >10 000) 
11.4.4.3 Pharmacodynamics and Phenotyping  
The values to be used as baselines will be those collected at Visit 2 (Day 1). If any of the 
scheduled assessments on Day 1 are technically disqualified (eg, insufficient sample), then values 
determined in any other samples collected prior to the first IMP administration 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 ± SEM) on raw data, absolute changes from baseline and percent changes 
from baseline will be provided by treatment group. 
As part of exploratory analysis, correlations between the baseline values for biomarkers and 
efficacy endpoints will be assessed.  
11.4.5 Analyses of Patient Reported Outcomes (Health-related Quality of Life/Health 
Economics Variables)  
Patient reported outcome variables collected in this study include the ACQ-IA questionnaire 
ACQ-7 score, PAQLQ(S)-IA score, PACQLQ score, and PRQLQ-IA score (in those with history 
of allergic rhinitis). The change from baseline for these endpoints will be analyzed using MMRM 
in the same fashion as for the endpoint of pre-bronchodilator % predicted FEV1. The covariates to 
be included are treatment, age, weight (≤30kg, >30kg), region, baseline eosinophil level 
(<300 cells/μL, ≥300 cells/μL), baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose level 
(medium/high), visit, treatment-by-visit interaction, corresponding baseline value and baseline-
by-visit interaction. Descriptive statistics including number of patients, mean, standard error and 
LS means will be provided for each timepoint. 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 at each timepoint. Note that PRQLQ-IA score (in those with history of 
allergic rhinitis) will only be analyzed for patients with the history of allergic rhinitis. 
11.5 
INTERIM ANALYSIS  
There is no interim analysis planned for this study. 
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11.6 
PLANNED DATABASE LOCK  
The database lock is planned based on the time when all randomized patients reach 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 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Sub-investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) guidelines for good clinical practice (GCP), all applicable laws, rules and 
regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient who is 
≥6 years and his/her parent(s)/caregiver(s)/legal guardian(s) of all pertinent aspects of the clinical 
trial including the written information giving approval/favorable opinion by the Ethics Committee 
(IRB/IEC). All patients/parent(s)/caregiver(s)/legal guardian(s) should be informed to the fullest 
extent possible about the study, in their language and in terms they are able to understand. 
It is the responsibility of the Investigator or designee (if acceptable by local regulations) to obtain 
written informed assent (IA) from each patient ≥6 years of age (or above an age determined by the 
IRB/IEC and in according with the local regulations and requirements), and written ICF from 
each patient’s parent(s)/caregiver(s)/legal guardian(s), prior to the patient’s participation in the 
study, and prior to initiating any screening procedures. The written IAF/ICF should be signed and 
dated by the patient(s) and parent(s)/caregiver(s)/legal guardian(s), respectively. 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required.  
If only 1 parent or guardian signs the consent form, the Investigator must document the reason the 
other parent or guardian did not sign.  The patient may also be required to sign and date the ICF as 
determined by the IRB/IEC and in accordance with the local regulations and requirements.   
 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s) who can write but cannot read will have 
the assent/consent form read to them before writing their name on the form 
 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s) who can understand but who can either 
write nor read will have the informed assent/consent form read to them in presence of an 
impartial witness, who will sign and date the assent/consent form to confirm that informed 
consent was given. 
The original of each completed informed assent/consent form (IAF/ICF) must be retained by the 
Investigator as part of the patient’s study record and a copy of the signed assent/consent form 
must be given to the patient/patient’s parent(s)/caregiver(s)/legal guardian(s). 
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The ICF 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 and on the same date as the Screening Visit 1, and a patients registration in IVRS/IWRS, 
the Investigator or designee must have collected the signed and completed ICF/IAF.  
 
 
 
 
 
 
 
 
 
 
The main study informed consent form, the assent form for girls who have started menstruating, 
 
 
to be used by the Investigator for obtaining the patient's/parent(s)/legal guardian(s) informed 
consent/assent as applicable per national requirements must be reviewed and approved by the 
Sponsor prior to submission to the appropriate Ethics Committee (IRB/IEC) for 
approval/favorable opinion. 
In addition, for Brazil, a country-specific ICF will be issued for the collection of additional blood 
samples for the assessment of pre and post Yellow Fever vaccination titers, dupilumab PK, and 
ADA levels. Refusal to sign the additional ICF will not impact the patient's ability to receive 
Yellow Fever vaccination (Appendix N). 
If the race/ethnic origin of the patients will be collected in the clinical trial, the scientific 
justification should be specified in Section 14.5. 
12.3 
HEALTH AUTHORITIES AND 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 health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure and Investigator’s curriculum vitae 
[CV], etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure will be 
sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING  
13.1 
RESPONSIBILITIES OF THE 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 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The 
Sub-investigators 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 e-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 e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the e-CRFs (eg, patient's medical file, appointment 
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books, original laboratory records). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate e-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 e-CRFs 
should be completed in their entirety 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 Sub-investigator 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 e-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 
EC (IRB/IEC) is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-investigator 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 Sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
 The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
 When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
 The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations 
Subject race or ethnicity will be collected in this study because these data are required by several 
regulatory authorities (eg, on African American population for FDA). 
Analyses of subject genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purposes 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. 
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. 
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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, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. As soon as the Investigator is 
notified of a planned inspection by the authorities, he will inform the Sponsor and authorize the 
Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. Any result and information arising from the inspections by the 
regulatory authorities will be immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
 
The information on the product leads to doubt as to the benefit/risk ratio 
 
Patient enrollment is unsatisfactory 
 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
 
Noncompliance of the Investigator or Sub-investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
 
The total number of patients are included earlier than expected 
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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 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). The 
Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
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8. 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;26:319-38. 
9. 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. 2003;41(5):582–92. 
10. 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. 
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. 
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12. 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. 
13. Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89:46–53. 
 
 
 
 
 
 
  
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17 
APPENDICES  
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Appendix A 
Low, Medium, and High-dose Inhaled Corticosteroids – Children 
(6 to <12 years)  
 
Inhaled Corticosteroid 
Total Daily Dose (mcg) 
Low 
Medium 
High 
Beclometasone dipropionate (CFC) 
100–200 
>200–400 
>400 
Beclometasone dipropionate (HFA) 
50–100 
>100–200 
>200 
Budesonide (DPI) 
100–200 
>200–400 
>400 
Budesonide (HFA) 
100-200 
>200–400 
>400 
Budesonide (nebules) 
250-500 
>500–1000 
>1000 
Ciclesonide (HFA) 
80 
>80–160 
>160 
Flunisolide (HFA) 
160 
>160–<320 
320 
Fluticasone propionate (DPI) 
100–200 
>200–400 
>400 
Fluticasone propionate (HFA) 
100–200 
>200–500 
>500 
Mometasone furoate  
110 
≥220–<440 
≥440 
Triamcinolone acetonide 
400–800 
>800–1200 
>1200 
CFC = chlorofluorocarbon propellant; DPI = dry powder inhaler; HFA = hydrofluoroalkane 
propellant; nebules = nebulized solution 
Source: Adapted from Global Initiative for Asthma (GINA) 2015 guidelines with the addition of 
Budesonide HFA and Flunisolide information 
 
 
 
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Appendix B 
Examples of Commonly Used Asthma Controller Therapies  
 
Controller Group 
Medications 
Inhaled corticosteroids (ICS) 
Beclomethasone dipropionate CFC 
Beclomethasone dipropionate HFA 
Budesonide 
Ciclesonide 
Fluticasone propionate 
Mometasone furoate 
Triamcinolone acetonide 
Fluticasone Furoate  
ICS/long-acting β2 agonist (LABA) combination as metered-dose inhaler (MDI) 
Fluticasone Propionate/Salmeterol 
Fluticasone Propionate/Formoterol 
Fluticasone Furoate/Vilanterol 
Budesonide /Formoterol 
Mometasone Furoate/Formoterol 
Beclometasone Dipropionate and Formoterol 
LABA 
Salmeterol  
Formoterol  
Bambuterol  
Clenbuterol  
Tulobuterol 
Vilanterol 
Olodaterol 
Indacaterol 
Leukotriene receptor antagonists (LTRA) or anti-leukotrienes 
Montelukast  
Pranlukast 
Zafirlukast  
Zileuton 
Long-acting muscarinic antagonist (LAMA) 
Tiotropium 
Glucopyrronium bromide 
Aclidinium bromide 
Umeclidinium 
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Controller Group 
Medications 
Methylxanthines 
Aminophylline 
Theophylline 
Dyphylline  
Oxtryphylline 
Diprophylline 
Acebrophylline 
Bamifylline 
Doxofylline 
Note: This list is indicative and not exhaustive. 
 
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Appendix C List of Prohibited Live Attenuated Vaccines  
Bacillus Calmette-Guérin (BCG) antituberculosis vaccine 
Chickenpox (Varicella) 
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection is 
permitted 
Measles (Rubeola) 
Measles-mumps-rubella (MMR) combination 
Measles-mumps-rubella-varicella (MMRV) combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rotavirus 
Rubella 
Smallpox (Vaccinia) 
Varicella Zoster (shingles) 
Yellow fever 
This list is indicative and not exhaustive. 
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Appendix D Examples of CYP substrates with narrow therapeutic range  
 
CYP ENZYMES 
SUBSTRATES WITH NARROW THERAPEUTIC RANGE(1) 
CYP1A2 
THEOPHYLLINE, TIZANIDINE 
CYP2C8 
PACLITAXEL 
CYP2C9 
WARFARIN, PHENYTOIN 
CYP2C19 
S-MEPHENYTOIN  
CYP3A(2) 
ALFENTANIL, ASTEMIZOLE(3), CISAPRIDE(3), CYCLOSPORINE(4), 
DIHYDROERGOTAMINE, ERGOTAMINE, FENTANYL, PIMOZIDE, 
QUINIDINE, SIROLIMUS, TACROLIMUS(4), TERFENADINE(3) 
CYP2D6 
THIORIDAZINE 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm080499.htm.  
 
(1) CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship 
indicates that small changes in their exposure levels by the concomitant use of CYP inhibitors or inducers 
may lead to either serious safety concerns (eg, Torsades de Pointes) or loss of therapeutic effect.  
(2) Because a number of CYP3A substrates (eg, darunavir, maraviroc) are also substrates of P-gp, the 
observed increase in exposure could be due to inhibition of both CYP3A and P-gp.  
(3) Withdrawn from the United States market because of safety reasons  
(4) Prohibited medication during the study 
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Appendix E Asthma Symptom Score Numerical Rating Scale (NRS)  
 
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Appendix F 
Asthma Control Questionnaire–Interviewer Administered (ACQ-IA) 
for Children 6 to <12 years  
Asthma Control Questionnaire, 7-question version (ACQ-7) 
 
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Appendix G 
Paediatric Asthma Quality of Life Questionnaire With Standardised 
Activities–Interviewer Administered (PAQLQ[S]-IA)  
 
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Appendix H 
Paediatric Asthma Caregiver’s Quality of Life Questionnaire 
(PACQLQ)  
 
 
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Appendix I 
Paediatric Rhinoconjunctivitis Quality of Life Questionnaire–
Interviewer Administered (PRQLQ-IA) – for Children with Comorbid 
Allergic Rhinitis  
 
 
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Appendix J 
Euro Qol (EQ-5D-Y) – for Children  
 
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Appendix K General Guidance for the Follow-up of Laboratory Abnormalities by 
Sanofi  
Neutropenia 
 
Note for PK sampling: For pediatric PK sampling, only 2 mL of blood should be collected to 
freeze 2 serum samples (0.5 mL each) on Day 1. 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met. 
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Note for PK sampling: For pediatric PK sampling, only 2 mL of blood should be collected to 
freeze 2 serum samples (0.5 mL each) on Day 1. 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met. 
Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
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ALT Increase 
 
Monitor LFTs every 72 hours
If baseline ≤ 2 ULN & ALT ≤5 ULN, or 
if baseline > 2 ULN & ALT ≤8 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
If baseline ≤2 ULN & ALT > 5 ULN, or 
if baseline > 2 ULN & ALT > 8 ULN
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
COMPLETE the CRF for «ALT Increase» for any permanent discontinuations due to liver injury (See 
protocol/CRF instructions)
3.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or 
hypotension and/or episode of arrhythmia in the previous 72 hours; rule out muscular injury
4.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
5.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
6.
CONSIDER consulting with hepatologist
7.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
8.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to 
normal/baseline or clinical resolution.
9.
FREEZE serum sample (5ml x 2)
10. In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
Note: 
Normalization is defined as < ULN or baseline value if baseline value is >ULN.
As soon as seriousness criterion is met or the event leads to permanent treatment discontinuation, the monitoring 
team should be notified within 24 hours.
*If unable to retest in 72 hours, use original lab results to decide on further monitoring/ discontinuation . 
Check if special CRF should be 
completed per protocol/CRF 
instructions
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
ALT > 3 ULN
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Note for PK sampling: For pediatric PK sampling, only 2 mL of blood should be collected to 
freeze 2 serum samples (0.5 mL each) on Day 1. 
Acute renal failure is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met. 
Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
ACUTE RENAL FAILURE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
Investigational Medicinal Product by 
renal route
1.
Investigational Medicinal 
Product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
Investigational Medicinal Product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic  
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
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Note for PK sampling: For pediatric PK sampling, only 2 mL of blood should be collected to 
freeze 2 serum samples (0.5 mL each) on Day 1. 
Suspicion of rhabdomyolysis is to be recorded as an AE only if at least 1 of the criteria in the 
general guidelines for reporting adverse events in Section 10.4.3 is met. 
If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
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Appendix L 
Definition of Anaphylaxis  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
Adapted from: 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et al.  Second symposium on the 
definition and management of anaphylaxis: Summary report–Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-397 
Clinical criteria for diagnosing anaphylaxis 
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Appendix M 
List of Opportunistic Infections  
 
Aspergillosis 
 
Blastomyces dermatitidis (pathogenic fungus causing blastomycosis; endemic in the 
south-eastern and south-central states of the US and along Mississippi and Ohio Rivers) 
 
Candidiasis – only systemic or extensive mucosal or cutaneous cases of yeast infection. 
 
Coccidioides immitis (pathogenic fungus causing coccidiosis; endemic south-western US 
and Central and South America) 
 
Cryptococcus 
 
Cytomegalovirus 
 
Herpes Simplex (disseminated) 
 
Herpes Zoster (disseminated, ophthalmic; or involvement of 2 or more dermatomes) 
 
Histoplasmosis (pulmonary or disseminated; most common tropical areas [eg, 
Tennessee-Ohio-Mississippi river basins]) 
 
Listeriosis 
 
Non-tuberculous mycobacteria (NTM), including Mycobacterium avium complex (MAC)  
 
Pneumocystis pneumoniae (pathogenic fungus causing pneumocystis pneumonia) 
NOTE:  This list is indicative and not exhaustive. 
 
 
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Appendix N 
Country specific requirements  
Amendment for Brazil dated 02-Feb-2018 
Section 8.8.1 Prohibited medication (Section 8.8.1) 
In Brazil, due to the Yellow Fever outbreak, any patient who is not previously vaccinated with the 
yellow-fever vaccine (in the outbreak affected area) should be unblinded and should be 
permanently discontinued from treatment with study drug (Section 10.3.3). Patients who 
discontinue IMP must continue to be followed in the study until EOS (Section 10.3.4). 
Section 9.3.1.1.1 Sampling time (Section 9.3.1.1.1) 
Predose blood samples will be collected for determination of functional dupilumab concentration 
in serum and anti-dupilumab antibodies (including neutralizing antibodies) on days designated in 
the Study Flow Chart (see Section 1.2 as well as Section 10.3.4, as needed for Brazil). 
Section 10.3.3 List of criteria for permanent discontinuation (Section 10.3.3) 
 
At the specific request of the Sponsor 
- 
Including some specific circumstances like the Yellow Fever outbreak in Brazil, where 
patients from affected areas who are not previously vaccinated with yellow-fever 
vaccine, are to be permanently discontinued from study drug (see below). 
Section 10.3.4 Handling of patients after permanent treatment discontinuation  
(Section 10.3.4) 
In Brazil, any patient who is permanently discontinued from treatment with study drug due to the 
Yellow Fever outbreak must complete all EOT procedures. These patients should continue to be 
followed in the study until EOS. Specific blood samples for ADA, dupilumab PK, and 
pre-vaccination Yellow Fever antibody titer should be performed, when possible, prior to 
vaccination in patients who received dupilumab. Post-vaccine blood samples for ADA, PK, and 
Yellow Fever antibody titers will also be collected following the appropriate interval (4-6 weeks 
after vaccination and may be extended up to 8 weeks). A specific ICF must be signed prior to 
collection of these samples (See below). 
Brazilian patients who are discontinued early from treatment due to the Yellow Fever outbreak 
will remain eligible for the 1 year long term extension study. 
Section 12.2 Informed consent (Section 12.2) 
For Brazil, a country-specific ICF will be issued for the collection of additional blood samples for 
the assessment of pre and post Yellow Fever vaccination titers, dupilumab PK, and ADA levels. 
Refusal to sign the additional ICF will not impact the patient's ability to receive Yellow Fever 
vaccination. 
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Appendix O 
Protocol amendment history  
 
The Protocol Amendment Summary of Changes Table for the current amended protocol03 is 
located directly before the Table of Contents (TOC). 
Amended protocol 02 dated 18-Jun-2018: 
 
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Table 5 - Summary of changes: amended protocol 02  
Sections  
Initial wording  
Amended or new wording  
Reason/Justification 
for change 
Reasons 
for 
substantial 
amendment 
Sections: Clinical Trial 
Summary and Section 11 
Statistical considerations 
 
 
 
 
 
 
 
 
 
 
 
 
 
The sample size of this study was based on a 
comparison between dupilumab versus placebo with 
regard to the primary endpoints of annualized rate of 
severe exacerbations at Week 52. Assuming the 
number of severe exacerbations follows a negative 
binomial distribution with a dispersion parameter of 
1.5, a placebo annualized rate of exacerbations being 
1.0, a randomization ratio of 2:1, with 294 randomized 
patients (196 for dupilumab and 98 for matching 
placebo group), the study will have approximately 
90% power to detect a 50% relative risk reduction (ie, 
annualized rate of 0.5 for the dupilumab group) in the 
annualized rate of severe exacerbations at the 2-
tailed significance level of α=0.05. This calculation 
assumes a linear discontinuation rate (20% at 1 year), 
thus the average exposure duration for patients is 0.9 
year.  
Patients will be randomized (2:1 ratio) to receive 
dupilumab or matching placebo. After a patient is 
randomly assigned to dupilumab or matching 
placebo, the dosage of dupilumab or matching 
placebo for the patient, 200 or 100 mg SC once q2w, 
will be determined based on bw >30 kg or ≤30 kg, 
respectively. 
Randomization will be stratified by ICS dose 
(medium-dose versus high dose) and eosinophil 
count (<300 cells/μL versus ≥300 cells/μL) at 
Screening, and by region.  
The sample size of this study was based on a 
comparison between dupilumab versus placebo with 
regard to the primary endpoints of annualized rate of 
severe exacerbations at Week 52. 
 
 
 
 
 
 
 
 
 
 This calculation also 
assumes a linear discontinuation rate (20% at 1 year), 
thus the average exposure duration for patients is 0.9 
year.  
Patients will be randomized (2:1 ratio) to receive 
dupilumab or matching placebo. After a patient is 
randomly assigned to dupilumab or matching placebo, 
the dosage of dupilumab or matching placebo for the 
patient, 200 or 100 mg SC once q2w, will be 
determined based on bw >30 kg or ≤30 kg, 
respectively.  
Randomization will be stratified by ICS dose (medium-
dose versus high-dose) and eosinophil count (<300 
cells/μL versus ≥300 cells/μL) at Screening, and by 
region. 
Change: Increase in study 
sample size. 
Reason for change: Due to 
an update on the 
assumptions used to perform 
the sample size calculation. 
The original effective size 
assumption was based on 
the observed risk reduction in 
the dupilumab Phase 2b 
study in adult patients with 
uncontrolled persistent 
asthma. This assumption is 
being updated based on the 
effect size observed in the 
recently concluded Phase 3 
dupilumab clinical trial in 
adult and adolescent patients 
with uncontrolled persistent 
asthma. The sample size is 
adjusted to maintain 90% 
power based on a more 
accurate estimation of 
treatment effect from a larger 
clinical study. 
 
Change in 
sample size 
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Sections  
Initial wording  
Amended or new wording  
Reason/Justification 
for change 
Reasons 
for 
substantial 
amendment 
To ensure scientific validity, alerts will be built into the 
interactive voice response system (IVRS) system to 
limit enrolling patients in the following stratification 
subgroups: 
1. Background therapy with medium-dose ICS not to 
exceed 50%, or 146 patients, 
2. Eosinophil <150 cells/μL not to exceed 20%, or 58 
patients 
 
To ensure scientific validity, alerts will be built into the 
interactive voice response system (IVRS) system to 
limit enrolling patients in the following stratification 
subgroups: 
1. Background therapy with medium-dose ICS not to 
exceed 50%
 
2. Eosinophil <150 cells/μL not to exceed 20%
 
 
Sections: Clinical Trial 
Summary and Section 
7.1   Inclusion criteria 
 
 
Reversibility of at least 10% in FEV1 after the 
administration of 200 to 400 mcg (2 to 4 puff 
inhalations with metered-dose inhaler [MDI]) of 
albuterol/salbutamol or 45 to 90 mcg (2 to 4 puffs with 
MDI) of levoalbuterol/levosalbutamol reliever 
medication before randomization (up to 3 
opportunities during the same visit are allowed with a 
maximum of 12 puffs of reliever medication if 
tolerated by the patient). Documented reversibility or 
positive airway hyperresponsiveness to methacholine 
within 12 months prior to Screening V1 is considered 
acceptable 
 
 
Reversibility of at least 10% in FEV1 after the 
administration of 200 to 400 mcg (2 to 4 puff 
inhalations with metered-dose inhaler [MDI]) of 
albuterol/salbutamol or 45 to 90 mcg (2 to 4 puffs with 
MDI) of levoalbuterol/levosalbutamol reliever 
medication before randomization (up to 3 opportunities 
during the same visit are allowed with a maximum of 
12 puffs of reliever medication if tolerated by the 
patient).  
Note: A maximum of 3 visits to meet the qualifying 
criterion of reversibility may be made during the 
screening period and prior to the patient's 
randomization. 
Note: Documented reversibility or positive airway 
hyperresponsiveness to methacholine within 12 
months prior to Screening V1 is considered acceptable 
 
Change: Reversibility 
attempts definition during the 
screening period  
Reason for change: To 
clarify that for patients that 
will have an additional and 
last attempt of reversibility 
testing (for eligibility) at the 
Baseline Visit 2 before 
patient’s randomization using 
the IRT (Interactive 
Response Technology), the 
post-bronchodilator FEV1 will 
come from the result of this 
reversibility test.    
Clarification of 
an inclusion 
criterion 
Section 11.1 
Determination of sample 
size 
Randomization will be stratified by ICS dose 
(medium-dose versus high-dose) and eosinophil 
count (<300 cells/μL versus ≥300 cells/μL) at 
Screening, and by region (Latin America: Argentina, 
Randomization will be stratified by ICS dose (medium-
dose versus high-dose) and eosinophil count (<300 
cells/μL versus ≥300 cells/μL) at Screening, and by 
Change: To include Russia 
and Ukraine among Eastern 
Europe region 
Inclusion of 
new 
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Sections  
Initial wording  
Amended or new wording  
Reason/Justification 
for change 
Reasons 
for 
substantial 
amendment 
Brazil, Colombia, Chile and Mexico; Eastern Europe: 
Poland, Hungary, Romania, Lithuania and Turkey; 
Western Countries: Australia, Canada, Italy, South 
Africa, Spain, and USA). The final definition of region 
may be updated in the SAP, if additional countries are 
included in the study. If during the study, additional 
countries are included, necessary changes will be 
made to the randomization algorithm. These changes 
will be documented in the SAP. 
region (Latin America: Argentina, Brazil, Colombia, 
Chile and Mexico; Eastern Europe: Poland, Hungary, 
Romania, Lithuania, Turkey, Russia and Ukraine; 
Western Countries: Australia, Canada, Italy, South 
Africa, Spain, and USA). The final definition of region 
may be updated in the SAP, if additional countries are 
included in the study. If during the study, additional 
countries are included, necessary changes will be 
made to the randomization algorithm. These changes 
will be documented in the SAP. 
Reason for change: to add 
new countries in the study  
 
countries/sites 
in the trial 
Sections: Flowchart and 
9.3.1.2 Humoral Immune 
Response to Vaccines  
 
Scheduled blood sample collection for pre- and post-
vaccine antibody titers (ie, for IgG response 
assessment), for both vaccinations (ie, any tetanus, 
diphtheria and pertussis and/or seasonal 
trivalent/quadrivalent influenza) should be drawn 
within 8 weeks prior to vaccination and at 3-4 weeks 
(up to 6 weeks) after the respective vaccination(s); 
however, all blood titer samples must be drawn 
between Week 6 and Week 48 (ie, Visit 5 and Visit 
26, respectively).  
 
 
Scheduled blood sample collection for pre- and post-
vaccine antibody titers (ie, for IgG response 
assessment), for both vaccinations (ie, any tetanus, 
diphtheria and pertussis and/or seasonal 
trivalent/quadrivalent influenza) should be drawn within 
8 weeks prior to vaccination and at 3-4 weeks (up to 6 
weeks) after the respective vaccination(s); however, all 
blood titer samples must be drawn between Week 6 
and Week 50 (ie, Visit 5 and Visit 27, respectively).  
 
Change: To change last 
possible date for post 
vaccination sample collection 
from W48 to W50 
Reason for change: To 
correct last possible date for 
post vaccination sample 
collection to W50 considering 
it can be drawn up to 6 
weeks after vaccination 
Change in 
schedule of 
samples 
Section 8.8.1 Prohibited 
Concomitant Medication 
and 8.8.2 Permitted 
Concomitant Medication 
 
8.8.1 Prohibited Concomitant Medication 
The following concomitant treatments are not 
permitted during the Screening Period or during the 
Randomized Treatment Period: 
 
SCS for diagnoses other than severe 
exacerbation of asthma and/or high-potency 
topical, ocular, or intra-nasal steroids within 
30 days before Screening Visit 1, during the 
Screening Period, and/or during the 
Randomized Treatment Phase of this study. 
8.8.1 Prohibited Concomitant Medication 
The following concomitant treatments are not 
permitted during the Screening Period or during the 
Randomized Treatment Period: 
 
SCS for diagnoses other than severe 
exacerbation of asthma and/or high-potency 
topical steroids within 30 days before 
Screening Visit 1, during the Screening 
Period, and/or during the Randomized 
Treatment Phase of this study. Intra-articular 
Change: Clarification on 
topical corticosteroids to be 
avoided during study 
Reason for change: To 
clarify that potent 
dermatological topical 
corticosteroids are to be 
avoided during the study. 
This definition of potency 
does not apply to ocular and 
intranasal corticosteroids  
Clarification of 
prohibited 
concomitant 
medication 
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Sections  
Initial wording  
Amended or new wording  
Reason/Justification 
for change 
Reasons 
for 
substantial 
amendment 
Intra-articular steroids are not allowed to be 
used in the above mentioned period. 
 
8.8.2 Permitted Concomitant Medication 
 
Antihistamines 
 
Topical, ocular or intranasal corticosteroids 
(except for high-potency) 
 
steroids are not allowed to be used in the 
above mentioned period. 
 
8.8.2 Permitted Concomitant Medication 
 
Dermatological, ocular or intranasal 
corticosteroids (except for high-potency 
dermatological corticosteroids) 
 
  
Section 10.1.1  Screening 
Period (Week -5 to Week 
0, maximum 35 days 
prior Day 0) 
Patients that fail the initial screening for exclusion 
criteria, eg, concomitant medications, may be 
re-screened for study eligibility one additional time (as 
described in Section 8.4). For patients re-screened a 
new ICF/IAF, as applicable, must be signed by 
patient/parent(s)/caregiver(s)/legal guardian(s), and a 
new patient number will be allocated. All of the Visit 1 
procedures must be repeated (refer to Section 8.4 for 
further instructions related to re-screening) unless a 
prior assessment is performed within the time frame 
permitted prior to study entry.  
 
Patients that fail the initial screening for exclusion 
criteria, eg, concomitant medications, may be 
re-screened for study eligibility one additional time (as 
described in Section 8.4). For patients re-screened a 
new ICF/IAF, as applicable, must be signed by 
patient/parent(s)/caregiver(s)/legal guardian(s), and a 
new patient number will be allocated. All of the Visit 1 
procedures must be repeated (refer to Section 8.4 for 
further instructions related to re-screening).  
 
Change: removal of using 
prior assessments for re-
screening 
Reasons for change: 
Values  from previous 
assessments cannot be re-
used for the purpose of re-
screening 
Change in re-
screening  
Section 9.2.2.2.1 
Electronic Diary/PEF 
meter 
 
Baseline reliever use will be the mean number of 
reliever use 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 for both 
measurements. 
Reason for change: To 
include reliever medication 
baseline definition 
 
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Sections  
Initial wording  
Amended or new wording  
Reason/Justification 
for change 
Reasons 
for 
substantial 
amendment 
Appendix K 
General Guidance for the 
follow up of laboratory 
abnormalities by Sanofi 
 
•Neutrophils value 
Neutrophils <1500/mm3 or according to ethnic group  
 
 
•Neutrophils value 
Neutrophils <1000/mm3 according to ethnic group 
Change: neutrophils value 
for Sanofi follow up of 
abnormalities 
Reasons for change:  To 
adjust the neutrophil count 
defining neutropenia in the 
study population age group 
(pediatric trial) 
  
Change of  
safety 
monitoring 
parameter 
 
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Amendment protocol 01 dated 10-Mar-2017 
 
FeNO results  
In section: 9.4.2.2  
Rationale: 
- 
Blinding of FeNO results as described in Section 9.4.2.2 was determined to be 
operationally not feasible. Therefore, the FeNO value will not be blinded to 
investigators or site personnel, as well as patient(s)/parent(s)/caregiver(s)/legal 
guardian(s).  
 
 
Live attenuated vaccines  
In section(s): Sections 7.2.3 and 8.8.1  
Rationale: 
- 
In order to clearly define the interval between live (attenuated) vaccines administration 
and IMP administration and be consistent with other dupilumab trials, an Exclusion 
Criterion E27 will be added to clarify that live (attenuated) vaccines are not allowed 
within 4 weeks before the baseline visit. Section 8.8.1 Prohibited Concomitant 
medication will be rewritten to clarify that live (attenuated) vaccines are allowed in the 
screening period if taken at least 4 weeks prior to baseline visit.  
 
 
PAQLQ Domains  
In section: 9.2.2.4.2  
Rationale: 
- 
The number of domains was incorrectly described as 4, instead of 3. 
 
 
PAQLQ (S)-IA Periodicity  
In section(s): Clinical Trial Summary (Secondary Endpoints Efficacy) and Section 11.4.2   
Rationale: 
- 
The periodicity of PAQLQ(S)-IA was incorrectly marked as Weeks 2, 4, 8, 12, 24, 36, 
52. Its correct periodicity is at Weeks 12, 24, 36, 52, 64. 
 
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 
Inhaled Corticosteroids Doses 
In section: Appendix A  
Rationale: 
- 
Medium and high doses of beclometasone dipropionate (CFC and HFA) and 
budesonide (DPI) are inconsistent with GINA Guidelines 2015. Therefore, the table 
will be updated with the correct values for medium and high dose of beclometasone 
dipropionate (CFC and HFA) and budesonide (DPI). 
 
 
PEF meter 
In Section: 9.2.2.2.1  
Rationale: 
- 
AM and PM time frames were extended by 2 hours, ie, to end at 11:59 AM and 
11:59 PM, respectively.  
- 
Albuterol/salbutamol or levoalbuterol/levosalbutamol reliever medication are the only 
medications to be withheld for at least 6 hours before PEF measurement, if possible. 
 
 
IMP compliance check 
In section: 10.1.10 
Rationale: 
- 
IMP compliance must be verified at these visits. This information is missing in the 
protocol. 
 
 
Informed Assent Form (IAF) for girls who started menstruating 
In section: 1.2 and 12.2 
Rationale: 
- 
Clarified that as soon as the investigator is notified that the first menses of a female 
patient have occurred (at any time during this study) a separate IAF must be obtained 
from such female patients at the earliest visit to the site. This information is missing in 
the protocol. 
 
 
Patient monitoring 
In section: 8.1.4 
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Rationale: 
- 
To avoid confusion and make it clear that patients should be monitored after home 
administration of IMP.  
 
 
Country list/Region 
In section: 11.1 
Rationale: 
- 
New Zealand is not a part of the study and should be removed. 
 
 
Template 
In section: Appendix K 
Rationale:  
- 
Instructions from the protocol template, which should be removed were left in the final 
version of the protocol in error. 
- 
Added clarification of PK sample blood volume for pediatric study. 
 
 
Vaccination Response 
In section: 10.1.2 
Rationale: 
- 
Vaccination information and vaccination plan during the treatment period should be 
collected for all patients at screening, because the vaccination response is not an 
optional assessment. 
 
 
Adverse Event of Special Interest 
In section: 10.4.1.3 
Rationale: 
- 
An error was noted in the asthma pediatric study EFC14153 study where “suicidal 
behavior” was noted as AESI.  Suicidal behavior was an AESI for atopic dermatitis 
(AD) trials; however, there was no signal of these events in patients treated with 
dupilumab. Therefore, suicidal behavior was removed from the AESI. 
 
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 
Term ‘Slum areas’  
In section: 10.6.3 
Rationale: 
- 
An alternative terminology, "heavily populated informal settlements" will be used for 
the term ‘slum areas’. 
 
 
Typographical Errors 
In section: 1.1 (Overview of Study Design) schematic picture 
Rationale: 
- 
To correct a typographical error in subject number ‘195’ (correct number ‘196’) in the 
schematic picture of the overall study design in the original final protocol. 
- 
To add footnote about background therapy with inhaled corticosteroids. 
 
In section: 1.2 (Study flowchart) footnote U 
Rationale: 
- 
Although correctly found in the study flowchart at Week 6, in footnote ‘U’ it is written 
that DNA sampling collection is to be performed at Week 0. 
- 
Blood DNA can be collected any time during the protocol, taking into consideration 
blood collection volume limitation, if any, at the time. 
In section: 7.2.3 
Rationale: 
- 
Deleted E23 (about previous history of malignancy), because it is a duplicate of E6 
(about history of malignancy). 
- 
Clarified E25 Liver injury related criteria 
- 
Corrected E26 Abnormal lab values at Screening 
 
In addition, other minor changes were implemented. 
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According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A randomized, double-blind, placebo-controlled, parallel group study to evaluate 
the efficacy and safety of dupilumab in children 6 to <12 years of age with 
uncontrolled persistent asthma 
SAR231893 – EFC14153 
STATISTICIAN: 
  
DATE OF ISSUE: 14-Sep-2020 
Total number of pages: 
125 
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Statistical Analysis Plan  
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Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.2.3 
Exploratory objectives ...................................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.4.1 
Graphical Overview of Study Design ................................................................................................ 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 8 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN...................... 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 14 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 14 
2.1.1 
Demographic and baseline characteristics .................................................................................... 14 
2.1.2 
Prior or concomitant medications ................................................................................................... 16 
2.1.2.1 
Inhaled corticosteroid in combination with one or two other controllers ......................................... 17 
2.1.2.2 
Reliever medication ........................................................................................................................ 17 
2.1.3 
Efficacy endpoints .......................................................................................................................... 18 
2.1.3.1 
Primary efficacy endpoint(s) ........................................................................................................... 18 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 19 
2.1.3.3 
Disease-specific Efficacy Measures............................................................................................... 20 
2.1.3.4 
Disease-specific, Daily Efficacy Assessments ............................................................................... 21 
2.1.3.5 
Patient Reported Outcomes, Including Health Related Quality of Life (Secondary 
Endpoints) ...................................................................................................................................... 22 
2.1.4 
Safety endpoints ............................................................................................................................. 26 
2.1.4.1 
Adverse events variables ............................................................................................................... 27 
2.1.4.2 
Deaths ............................................................................................................................................ 28 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 28 
2.1.4.4 
Vital signs variables ........................................................................................................................ 29 
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2.1.4.5 
Electrocardiogram variables ........................................................................................................... 30 
2.1.4.6 
Physical Examination ..................................................................................................................... 30 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 30 
2.1.6 
Anti-drug antibody (ADA) variables ................................................................................................ 30 
2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 31 
2.1.8 
Humoral immune response to vaccines ......................................................................................... 32 
2.1.9 
Health economic endpoints ............................................................................................................ 32 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 32 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 33 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 34 
2.3.1 
Efficacy populations ....................................................................................................................... 34 
2.3.2 
Safety population ............................................................................................................................ 35 
2.3.3 
Population for pharmacokinetics, immunogenicity, and pharmacodynamics analyses ................. 36 
2.4 
STATISTICAL METHODS ............................................................................................................. 36 
2.4.1 
Demographics and baseline characteristics .................................................................................. 36 
2.4.2 
Prior or concomitant medications ................................................................................................... 37 
2.4.2.1 
ICS in combination with other controllers ....................................................................................... 37 
2.4.3 
Extent of investigational medicinal product exposure and compliance .......................................... 39 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 39 
2.4.3.2 
Compliance .................................................................................................................................... 39 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 40 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 40 
2.4.4.2 
Analyses of key secondary efficacy endpoints ............................................................................... 48 
2.4.4.3 
Analyses of secondary efficacy endpoints ..................................................................................... 54 
2.4.4.4 
Multiplicity issues ............................................................................................................................ 58 
2.4.4.5 
Additional efficacy analysis(es) ...................................................................................................... 61 
2.4.5 
Analyses of safety data .................................................................................................................. 62 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 63 
2.4.5.2 
Deaths ............................................................................................................................................ 67 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 67 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 69 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 69 
2.4.6 
Analyses of pharmacokinetic, immunogenicity, and pharmacodynamic variables ........................ 69 
2.4.6.2 
Pharmacodynamics/genomics analyses ........................................................................................ 71 
2.4.7 
Analyses of vaccine response ........................................................................................................ 72 
2.4.8 
Analyses of health economics variables ........................................................................................ 72 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 72 
2.5.1 
General conventions ...................................................................................................................... 72 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 73 
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2.5.3 
Missing data handling for safety analysis ....................................................................................... 74 
2.5.4 
Windows for time points ................................................................................................................. 76 
2.5.5 
Unscheduled visits ......................................................................................................................... 80 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 80 
2.5.7 
Statistical technical issues ............................................................................................................. 80 
3 
INTERIM ANALYSIS ..................................................................................................................... 81 
4 
DATABASE LOCK ........................................................................................................................ 82 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 83 
6 
REFERENCES ............................................................................................................................... 84 
7 
LIST OF APPENDICES ................................................................................................................. 85 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA (BTD-
009536 VERSION 3.0 21-MAY-2014) ............................................................................................ 86 
APPENDIX B 
LIST OF COMMONLY USED ASTHMA CONTROLLER THERAPIES ............................... 97 
APPENDIX C 
LOW, MEDIUM AND HIGH DOSE INHALED CORTICOSTEROIDS- CHILDREN  (6-
11 YEARS) ..................................................................................................................................... 98 
APPENDIX D 
HANDLING OF MISSING DATA ......................................................................................... 99 
APPENDIX E 
ASTHMA CONTROL QUESTIONNAIRE-INTERVIEWER ADMINISTERED (ACQ-IA) 
FOR CHILDREN 6 TO <12 YEARS ............................................................................................. 104 
APPENDIX F 
ASTHMA SYMPTOM SCORE NUMERICAL RATING SCALE (NRS) .............................. 107 
APPENDIX G 
PAEDIATRIC ASTHMA QUALITY OF LIFE QUESTIONNAIRE WITH 
STANDARDISED ACTIVITIES(PAQLQ[S]) ................................................................................. 108 
APPENDIX H 
EUROQUAL QUESTIONNAIRE (EQ-5D-5Y) – FOR CHILDREN ..................................... 112 
APPENDIX I 
PEDIATRIC RHINOCONJUNCTIVITIS QUALITY OF LIFE QUESTIONNAIRE–
INTERVIEWER ADMINISTERED (PRQLQ-IA) – FOR CHILDREN WITH COMORBID 
ALLERGIC RHINITIS ................................................................................................................... 114 
APPENDIX J 
PEDIATRIC ASTHMA CAREGIVER’S QUALITY OF LIFE QUESTIONNAIRE 
(PACQLQ) .................................................................................................................................... 120 
APPENDIX K 
DEFINITION OF ANAPHYLAXIS....................................................................................... 123 
APPENDIX L 
LIST OF OPPORTUNISTIC INFECTIONS ........................................................................ 124 
APPENDIX M 
SUMMARY OF THE PLANNED ANALYSES BY POPULATION ...................................... 125 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACQ-7 IA: 
Asthma Control Questionnaire–Interviewer Administered, 7-question version 
ATS: 
American Thoracic Society 
ECG: 
electrocardiogram 
ERS: 
European Respiratory Society 
FEF: 
Forced expiratorf flow 
HCRU: 
healthcare resource utilization 
MCID: 
minimal clinically important difference 
MID: 
minimally important difference 
NRS: 
Numerical Rating Scale 
PEF: 
peak expiratory flow 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
EFC14153 is a multinational, multicenter, randomized, double blind, placebo-controlled, parallel 
group study assessing the effect of dupilumab administered subcutaneously (SC) for 52 weeks in 
children 6 to <12 years of age with uncontrolled persistent asthma. Patients with baseline body 
weight of <=30 kg will be assigned dupilumab 100mg Q2W/matching placebo, and patients with 
weight >30kg at baseline will be assigned dupilumab 200 mg Q2W/matching placebo. Both 
investigator and patients are unblinded to the dose level of dupilumab 200 mg/matching placebo 
or dupilumab 100 mg/matching placebo due to different volume (1.14 mL vs. 0.67 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 2:1 randomization ratio for dupilumab and placebo. Randomization will be 
stratified by ICS dose level (medium, high) at screening, eosinophil count (<0.3 Giga/L versus 
≥0.3 Giga/L) at screening and regions (Latin America: Argentina, Brazil, Colombia, Chile and 
Mexico; Eastern Europe: Poland, Hungary, Romania, Lithuania, Russia, Ukraine and Turkey; 
Western Countries: Australia, Canada, Italy, South Africa, Spain, and USA). 
Approximately 402 patients will be randomized in this study with approximately 345 patients 
having either baseline eosinophil ≥0.15 Giga/L or baseline FeNO ≥20 ppb, and approximately  
255 patients having baseline eosinophil ≥0.3 Giga/L. 
 
 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
• To evaluate the efficacy of dupilumab in children 6 to <12 years of age with uncontrolled 
persistent asthma. 
1.2.2 Secondary objectives 
• 
To assess the safety and tolerability of dupilumab 
• 
To evaluate the effect of dupilumab in improving patient reported outcomes (PROs) 
including health related quality of life (HRQoL). 
• 
To evaluate dupilumab systemic exposure and incidence of anti-drug antibodies 
• 
To evaluate the association between dupilumab treatment and pediatric immune responses 
to vaccines: any vaccination for tetanus, diphtheria, pertussis and/or seasonal 
trivalent/quadrivalent influenza vaccine 
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1.2.3 Exploratory objectives 
• 
To explore baseline and on-treatment levels of biomarkers for their potential to predict and 
to associate with a treatment response 
 
 
 
• 
To evaluate the proportion of patients requiring increased dose of inhaled corticosteroids 
(ICS) or step up in the second controller medication regimen 
• 
To evaluate the effect of dupilumab on additional PROs 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size of this study was based on a comparison between dupilumab versus placebo with 
regard to the primary endpoint of annualized rate of severe exacerbations over 52 weeks of 
treatment for the 3 populations of interest: patients with baseline blood eosinophils ≥0.3 Giga/L, 
patients with baseline blood eosinophils ≥0.15 Giga/L, and Type 2 inflammatory asthma 
phenotype populations (as defined in Section 2.3.1), with assuming the number of severe 
exacerbations follows a negative binomial distribution and a randomization ratio of 2:1.  
The sample size calculation assumes a linear discontinuation rate (20% at 1 year), thus the average 
exposure duration for patients is 0.9 year. The assumed relative risk reductions are based on the 
results in the Phase 3 asthma study EFC13579 (QUEST). 
To achieve target sample size for each of the populations stated above, at least a total of  
402 patients in the overall population (268 for dupilumab and 134 for placebo) need to be 
randomized assuming approximately 86% of the randomized patients have the Type 2 
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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 to 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 who choose not to participate in the 1-year long-term extension 
study 
1.4.1 Graphical Overview of Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Background medication:  medium dose ICS + second controller or high dose ICS alone or  + second controller 
D: day; EOT: end of treatment; EOS: end of study; ICS: inhaled corticosteroids; q2w: every 2 week; R: randomization; 
SC: subcutaneous 
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) but before the study is unblinded. 
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section. 
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Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
2 
31-May-2018 
The following text: 
 
The sample size of this study was based on a 
comparison between dupilumab versus 
placebo with regard to the primary endpoints of 
annualized rate of severe exacerbations at 
Week 52. Assuming the number of severe 
exacerbations follows a negative binomial 
distribution with a dispersion parameter of 1.5, 
a placebo annualized rate of exacerbations 
being 1.0, a randomization ratio of 2:1, with 
294 randomized patients (196 for dupilumab 
and 98 for matching placebo group), the study 
will have approximately 90% power to detect a 
50% relative risk reduction (ie, annualized rate 
of 0.5 for the dupilumab group) in the 
annualized rate of severe exacerbations at the 
2-tailed significance level of α=0.05. This 
calculation assumes a linear discontinuation 
rate (20% at 1 year), thus the average 
exposure duration for patients is 0.9 year. 
 
Was replaced with: 
 
The sample size of this study was based on a 
comparison between dupilumab versus 
placebo with regard to the primary endpoints of 
annualized rate of severe exacerbations at 
Week 52. 
 
 
 
 
 
 
 
 
 
 
 
 
 This calculation 
also assumes a linear discontinuation rate 
(20% at 1 year), thus the average exposure 
duration for patients is 0.9 year. 
3 
18-October-
2019 
The following text was added: 
The sample size of this study was based on a 
comparison between dupilumab versus placebo 
with regard to the primary endpoints of 
annualized rate of severe exacerbations at 
Week 52. 
 
 
 
 
 
 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
 
 
 
 
 
 This 
calculation also assumes a linear 
discontinuation rate (20% at 1 year), thus the 
average exposure duration for patients is 0.9 
year. 
 
Was replaced by: 
The sample size of this study was based on a 
comparison between dupilumab versus placebo 
with regard to the primary endpoint of 
annualized rate of severe exacerbations over 
52 weeks of treatment for the 3 populations of 
interest: patients with baseline blood 
eosinophils ≥0.3 Giga/L, patients with baseline 
blood eosinophils ≥0.15 Giga/L, and patients 
with Type 2 inflammatory asthma phenotype 
(baseline blood eosinophils ≥0.15 Giga/L or 
baseline FeNO ≥20 ppb), with assuming the 
number of severe exacerbations follows a 
negative binomial distribution and a 
randomization ratio of 2:1. 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
The sample size calculation assumes a linear 
discontinuation rate (20% at 1 year), thus the 
average exposure duration for patients is 0.9 
year. The assumed relative risk reductions are 
based on the results in the QUEST study. 
To achieve target sample size for each of the 
population stated above, at least 402 patients in 
total (268 for dupilumab and 134 for placebo) 
need to be randomized assuming approximately 
86% of the randomized patients have baseline 
blood eosinophils ≥0.15 Giga/L or baseline 
FeNO ≥20 ppb, assuming approximately 81% 
of the randomized patients have baseline blood 
eosinophils ≥0.15 Giga/L, and approximately 
64% of the randomized patients have baseline 
blood eosinophils  
≥0.3 Giga/L. 
3 
18-October-
2019 
The hypothesis testing on the primary endpoint 
of annualized severe exacerbation rate will be 
controlled with a two-sided Type I error of 0.05. 
Only nominal p-values are provided for 
secondary endpoints. 
 
Was replaced by: 
 
The hypothesis testing on the primary endpoint 
of annualized severe exacerbation rate will be 
controlled with a two-sided Type I error of 0.05 
by incorporating a sequential testing procedure 
as below: 
For US and US reference countries: 
1st: Annualized rate of severe exacerbation 
events during the 52-week placebo-controlled 
treatment period in patients with baseline blood 
eosinophils ≥0.3 Giga/L. 
2nd: Annualized rate of severe exacerbation 
events during the 52-week placebo-controlled 
treatment period in patients with baseline blood 
eosinophils ≥0.15 Giga/L. 
3rd: Annualized rate of severe exacerbation 
events during the 52-week placebo-controlled 
treatment period based on patients withtype 2 
inflammatory asthma phenotype (baseline 
blood eosinophils ≥0.15 Giga/L or baseline 
FeNO ≥20 ppb). 
 
For EU and EU reference countries: 
1st: Annualized rate of severe exacerbation 
events during the 52-week placebo-controlled 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
treatment period based on patients with Type 2 
inflammatory asthma phenotype (baseline 
blood eosinophils ≥0.15 Giga/L or baseline 
FeNO ≥20 ppb). 
2nd: Annualized rate of severe exacerbation 
events during the 52-week placebo-controlled 
treatment period in patients with baseline blood 
eosinophils ≥0.15 Giga/L population. 
 3rd:  Annualized rate of severe exacerbation 
events during the 52-week placebo-controlled 
treatment period in patients with baseline blood 
eosinophils ≥0.3 Giga/L population. 
Multiplicity control for any secondary endpoints 
if considered will be specified in the SAP. 
Otherwise, nominal p-values will be provided. 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
This Statistical Analysis Plan (SAP) for study EFC14153 is based on the protocol dated 18 
October 2019. This section summarizes major changes to the statistical analysis features in the 
SAP.   
Table 2 - Major changes in statistical analysis plan 
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
1.0 
23-OCT-2019 
Not Applicable  
Original version 
2.0 
Current version 
Elaboration of Estimand 
Clarification per FDA’s 
recommendation. 
 
 
Analysis of systemic corticosteroid exposure 
To evaluate efficacy of 
Dupilumab in reducing exposure 
to systemic corticosteroids  
 
 
Addition of the analysis of the annualized rate of loss of asthma 
control (LOAC)  
To evaluate efficacy of 
Dupilumab in reducing Loss of 
Asthma Control (LOAC) events 
 
 
COVID19 pandemic relevant analysis: 
To evaluate the impact of 
COVID19 pandemic on study 
conduct.  
 
 
Subgroup analysis, treatment exposure adjusted analysis for key 
adverse event endpoints  
 
To further evaluate the safety of 
Dupilumab in subgroups of 
interest; 
To evaluate the safety of 
Dupilumab taking the duration of 
exposure into consideration. 
 
 
 
For analysis of Pre-bronchodilator % predicted FEV1, covariates of 
age, sex, and baseline height are removed from the model 
The effect of age, sex, and 
height on the predicted FEV1 
have already been accounted for 
in the predicted FEV1 
calculation equation. 
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SAP 
Version 
Approval 
Date 
Changes 
Rationale 
 
 
Add treatment-by-biomarker analysis for annualized severe 
exacerbation rate during the 52 week treatment period to explore 
FeNO's independent predictability of Dupilumab's treatment effect 
Per FDA recommendation. 
 
 
Add treatment-by-biomarker analysis for Pre-bronchodilator % 
predicted FEV1 change from baseline at Week to explore FeNO's 
independent predictability of Dupilumab's treatment effect 
Per FDA recommendation. 
 
 
Add quadrant analysis using different FeNO cutoff values 
Per FDA recommendation. 
 
 
Remove subgroup analysis by baseline age group (6-8, 9-11 
years) 
Not a meaningful subgroup 
analysis. 
 
 
Remove subgroup analysis by Elevated IgE (Yes/No) 
This is already a subgroup to 
evaluate the baseline IgE level, 
ie, Total IgE  
((<100 IU/mL, ≥100 IU/mL) 
Table 3 - Changes to the planned analysis approach in the protocol 
SAP 
Version 
Approval 
Date 
Planned analysis in the 
protocol 
Analysis in the statistical 
analysis plan 
Rationale 
2.0 
Current 
version 
When performing the key secondary 
endpoint analysis in the Type 2 
inflammatory asthma phenotype, 
baseline blood eosinophils ≥0.15 
Giga/L, and full ITT populations, the 
model will include change from 
baseline in % predicted FEV1 values 
up to Week 12 as response variables, 
and treatment, age, baseline weight, 
region, sex, ethnicity, baseline height, 
baseline eosinophil level, baseline 
FeNO level, baseline ICS dose level, 
visit, treatment by-visit interaction, 
baseline % predicted FEV1 value and 
baseline-by-visit interaction as 
covariates. 
The model covariates are updated by 
removing age, sex, and baseline 
height: 
 
When performing the key secondary 
endpoint analysis in the Type 2 
inflammatory asthma phenotype, 
baseline blood eosinophils ≥0.15 
Giga/L, and full ITT populations, the 
model will include change from 
baseline in % predicted FEV1 values 
up to Week 12 as response variables, 
and treatment, baseline weight, region, 
ethnicity, baseline eosinophil level, 
baseline FeNO level, baseline ICS 
dose level, visit, treatment by-visit 
interaction, baseline % predicted FEV1 
value and baseline-by-visit interaction 
as covariates. 
The effect of 
age, sex, and 
height on the 
predicted FEV1 
have already 
been accounted 
in the predicted 
FEV1 calculation 
equation. 
 
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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 2.5 and 
Section 2.4.4). 
Demographic characteristics 
Demographic variables are  
• Gender (Male, Female) 
• Race (Caucasian/White, Black/of African descent, Asian/Oriental, American Indian or 
Alaska native, Native Hawaiian or other Pacific Islander, Other) 
• Age in years 
• Ethnicity (Hispanic, non-Hispanic) 
• Region (Latin America: Argentina, Brazil, Colombia, Chile and Mexico; Eastern Europe: 
Poland, Hungary, Romania, Lithuania, Russia, Ukraine and Turkey; Western Countries: 
Australia, Canada, Italy, South Africa, Spain, and USA) 
• Weight in kg (quantitative and qualitative variable: ≤30, >30 kg) 
• BMI in kg/m2 (quantitative and qualitative variable: <20, ≥20 kg/m2) 
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. 
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Comorbidity history will be summarized separately. The following comorbid diseases will be 
summarized. 
• Atopic dermatitis history (Yes, Ongoing condition) 
• Allergic conjunctivitis history (Yes, Ongoing condition) 
• Allergic rhinitis history (Yes, Ongoing condition) 
• Allergic conjunctivitis and/or rhinitis history (Yes, Ongoing condition) 
• Chronic rhinitis history (Yes, Ongoing condition) 
• Chronic sinusitis history (Yes, Ongoing condition) 
• Nasal polyposis history (Yes, Ongoing condition) 
• Chronic rhinitis and sinusitis with nasal polyposis 
• Chronic rhinitis and sinusitis without nasal polyposis 
• Eosinophilic esophagitis history (Yes, Ongoing condition) 
• Food allergy history (Yes, Ongoing condition) 
• Hives history (Yes, Ongoing condition) 
A patient is considered to have an ongoing 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 positive aeroantigen specific 
IgE (≥0.35 IU/mL) at baseline.  
A patient is considered to have elevated IgE if he/she has baseline total IgE ≥100 IU/mL and at 
least one aeroantigen specific IgE is positive (≥0.35 IU/mL). 
Disease characteristics at baseline 
The following baseline disease characteristics will be summarized by treatment group separately: 
• ICS dose level (medium, high as defined in Appendix C)  
• Age at asthma onset 
• Time since first diagnosis of asthma (years)  
• Time since last severe asthma exacerbation (months) 
• Number of severe asthma exacerbation experienced within 1 year before Visit 1 
(quantitative variable and qualitative variable: 0, 1, 2, 3, ≥4) 
• Baseline eosinophil count (Giga/L) 
• Baseline eosinophil count category (<0.15,  ≥0.15 and <0.3, ≥0.3 Giga/L ) 
• Baseline FeNO (ppb) 
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• Baseline FeNO category (<20, ≥20 ppb and ≤35 ppb, >35) 
• Baseline serum total IgE (IU/mL) 
• Baseline serum TARC (pg/mL) 
• Baseline spirometry data including pre-bronchodilator FEV1 (L), percent predicted FEV1, 
post-bronchodilator FEV1 (L) and FEV1 reversibility (%). 
• 
AM and PM PEF (L/min) 
• 
AM and PM symptom scores 
• 
Number of nocturnal awakenings/day 
• 
ACQ-5 score (ACQ-IA) 
• 
ACQ-7 score (ACQ-IA) 
• 
PAQLQ-IA global score 
• Number of inhalations of salbutamol/albuterol and levosalbutamol/levabuterol per day 
• Hypersensitivity to aspirin/NSAID (Yes, Ongoing condition) 
Severe asthma exacerbation prior to the study is defined as any of the following events: 
a) Treatment with a systemic steroid (oral or parenteral) for worsening asthma at least once.  
b) Hospitalization or an emergency/urgent medical care visit for worsening asthma.  
The aforementioned baseline values for the daily efficacy assessments are defined in  
Section 2.1.3.4. 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 and 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. 
• Prior medications are those the patient used prior to first IMP injection.  Prior medications 
can be discontinued before first administration or can be ongoing during treatment phase. 
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the first administration of IMP to the last administration of IMP + 98 days or 
till rollover to the LTS14424 study. A given medication can be classified as a prior 
medication, concomitant medication, and posttreatment medication at the same time. 
• Posttreatment medications are those the patient took in the period from the last 
administration of IMP + 99 days to the end of the study 
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2.1.2.1 Inhaled corticosteroid in combination with one or two other controllers 
On a daily basis throughout the study, the patient(s)/parent(s)/caregiver(s)/legal guardian(s)  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 dose of ICS (total 
daily dose >200 mcg to 400 mcg of fluticasone propionate (DPI) or equipotent ICS daily dosage) 
in combination with a second controller medication (eg, long-acting beta agonist [LABA], 
leukotriene receptor antagonist [LTRA], theophylline, etc.) to high dose of ICS (total daily dose 
>400 mcg of fluticasone propionate (DPI) or equipotent ICS daily dosage) alone or in combination 
with a second controller medication for at least 3 months with a stable dose ≥1 month prior to 
Visit 1. Patients requiring a third controller are not allowed to participate in this study. 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. A list of recognized controller medications is 
provided in Appendix B and the conversion Table 5. 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, patients will continue to take their controller 
medication(s) used during the screening period. The dose and regimen should not be changed 
unless being stepped up as instructed by the protocol after at least two severe asthma exacerbation 
events. Other change such as 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 randomized treatment period, patients not continuing with the long-term, 
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 regarding of the patients’ asthma control status.  
2.1.2.2 Reliever medication 
The reliever medication (ie, albuterol/salbutamol or levalbuterol/levosalbutamol) will not be 
dispensed or supplied by the Sponsor. All other reliever medications other than 
albuterol/salbutamol or levalbuterol/levosalbutamol should be avoided. 
Patient(s)/parent(s)/caregiver(s)/legal guardian(s) may administer albuterol/salbutamol or 
levalbuterol/levosalbutamol reliever medication by MDI as needed during the study. Nebulizer 
solutions may be used as an alternative delivery method.  
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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 
 
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 
2.1.3.1 Primary efficacy endpoint(s) 
The primary endpoint for this study is the annualized rate of severe exacerbation events during the 
52-week placebo-controlled treatment period.  
A severe exacerbation event during the study is defined as a deterioration of asthma requiring: 
• 
Use of systemic corticosteroids for ≥3 days; or 
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• 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids 
Two events will be considered as different if the interval between their start dates is equal or 
greater than 28 days. 
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 28(Week 52) will be included.  
2.1.3.2 Secondary efficacy endpoint(s) 
The key secondary endpoint of this study is the change from baseline in pre-bronchodilator % 
predicted FEV1 at Week 12. 
The other secondary efficacy endpoints include: 
• Change from baseline in pre-bronchodilator % predicted FEV1 at Weeks 2, 4, 8, 24, 36, 
and 52 and other time points assessed 
• Time to first severe exacerbation event during 52-week treatment period 
• Time to first LOAC Event during 52-week treatment period 
• Change from baseline in other lung function measurements (absolute and relative FEV1, 
AM/PM peak expiratory flow, FVC, forced expiratory flow (FEF) 25-75%, 
post-bronchodilator % predicted FEV1) at Weeks 2, 4, 8, 12, 24, 36, 52, and other time 
points assessed 
• The effect of dupilumab on healthcare resource utilization (HCRU) 
• Change from Baseline at Weeks 2, 4, 8, 12, 24, 36, and 52 and other timepoints in: 
- 
Morning/evening asthma symptom score (electronic diary) 
- 
PRO: 
- 
ACQ-IA, for children 6 to <12 years old,  
- 
Use of reliever medication 
- 
Number of nocturnal awakenings due to asthma symptoms requiring the use of 
reliever medication 
• Change from Baseline at Weeks 12, 24, 36, 52, 64 in: 
- 
PRO: 
- 
Paediatric Asthma Quality of Life Questionnaire with Standardised Activities–
Interviewer Administered (PAQLQ(S) IA) score, for children ≥7 to <12 years 
old at Randomization Visit 2 
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LOAC event during the study is defined as any of the following: 
• ≥6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 
24 hour period (compared to baseline) on 2 consecutive days or 
• 
Increase in ICS dose ≥4 times than the dose at Visit 2 or 
• 
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 
(Day 1); or 
• 
Severe exacerbation event 
Two events will be considered as different if the interval between their start dates is equal or 
greater than 28 days. 
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 28/Week 52, then the patient will be considered as free of event till the date of visit at  
Visit 28/Week 52 or the last contact date, whichever happens earlier. 
2.1.3.3 Disease-specific Efficacy Measures  
2.1.3.3.1 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). 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.  
For pre-bronchodilator measured parameters, including FEV1, peak expiratory flow (PEF), FVC 
and FEF 25-75%, will be assessed at Visit 1 (Screening), Visit 2 (randomization), and every 
subsequent visit. Reversibility/Post-bronchodilator FEV1 
Reversibility is defined as an increase in absolute FEV1 of 10% over the baseline value, 
demonstrated within 30 minutes of bronchodilator administration.  
Post-bronchodilator FEV1 is assessed at Visit 1 (Screening), Visit 2 (randomization), Visit 3 
(Week 2), Visit 4 (Week 4), Visit 6 (Week 8), Visit 8 (Week 12), Visit 14 (Week 24), Visit 20 
(Week 36), Visit 28 (Week 52/EOT), and Visit 31 (Week 64/EOS). 
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2.1.3.4 Disease-specific, Daily Efficacy Assessments 
2.1.3.4.1 Electronic Diary/PEF meter  
On a daily basis throughout the study, the patient uses an electronic diary/PEF meter to: 
• Measure morning and evening PEF 
• Respond to the morning and evening asthma symptom scale questions 
• Indicate the number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief 
• Record the number of inhalations/day of background product used 
• Record the number of nocturnal awakenings due to asthma symptoms requiring the use of 
reliever medication 
• Record oral steroids use for exacerbation event 
At Screening (Visit 1), patients and parent(s)/caregiver(s)/legal guardian(s) will be issued an 
electronic diary/PEF meter. Parent(s)/caregiver(s)/legal guardian(s) 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 
parent(s)/caregiver(s)/legal guardian(s). In addition, the Investigator will instruct the 
parent(s)/caregiver(s)/legal guardian(s) on how to record the following variables in the electronic 
PEF meter: 
• AM PEF performed within 15 minutes after arising (between 5:30 AM and 11:59 AM) prior 
to taking any albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication  
• PM PEF performed in the evening (between 5:30 PM and 11:59 PM) prior to taking any 
albuterol/salbutamol or levalbuterol/levosalbutamol reliever medication 
• Patient/Parent(s)/caregiver(s)/legal guardian(s) should try to withhold albuterol/salbutamol 
or levalbuterol/levosalbutamol reliever medication for at least 6 hours before performing 
the PEF measurements  
• 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 Day 1. 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. 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. 
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2.1.3.4.2 Asthma Symptom Numerical Rating Scale (NRS) Score 
Parent(s)/caregiver(s)/legal guardian(s) 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). 
Symptoms experienced during the night will be recorded upon arising (AM 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. A Minimal clinically important difference (MCID) of 0.35 is being used (2).  
2.1.3.4.3 Use of Reliever Medicine 
The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations will be recorded 
daily by the parent(s)/caregiver(s)/legal guardian(s) 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 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. 
2.1.3.5 Patient Reported Outcomes, Including Health Related Quality of Life (Secondary 
Endpoints) 
Patients will be administered the following PRO questionnaires by their 
parent(s)/caregiver(s)/legal guardian(s) or with their help. The interviewer administered versions 
are only for children: ACQ-IA, pediatric asthma quality of life questionnaire (PAQLQ) and will be 
administered by an interviewer (clinic staff designated by Investigator).  
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2.1.3.5.1 Asthma Control Questionnaire–Interviewer Administered  
The ACQ-IA 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, and will be used for children 
6 years to <12 years old at Screening.  
2.1.3.5.1.1 ACQ-7-IA (Asthma Control Questionnaire–Interviewer Administered, 7-question 
version) 
The Asthma Control Questionnaire–Interviewer Administered, 7-question version (ACQ-7-IA) 
has 7 questions, with the first 5 items of ACQ-7 (ACQ-5-IA score) addressing 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. And with 2 questions on overall reliever medication use 
6) short-acting bronchodilator use, and – after spirometry assessment – current asthma status: 
7) predicted bronchodilator use of FEV1 (pre-bronchodilator use, % and % predicted use).  
Patients and/or parent(s)/caregiver(s)/legal guardian(s) are asked to recall how their asthma and/or 
their child’s asthma, has been during the previous week and to respond to the symptom and 
bronchodilator use questions on a 7-point scale (0 = no impairment, 6 = maximum impairment). 
Clinic staff scores the % predicted FEV1 on a 7-point scale based on the pre-central reading 
spirometry result displayed immediately after the testing. Then, the questions are equally weighted 
and the global ACQ-7 score is the mean of the 7 questions and therefore between 0 (totally 
controlled) and 6 (severely uncontrolled).  
After spirometry assessment, patients and/or parent(s)/caregiver(s)/legal guardian(s) are asked to 
recall how their asthma and/or their child’s asthma Clinic staff scores the % predicted FEV1 on a 
7-point scale (see Appendix E).  
For statistical analysis, ACQ-7 global score is calculated by the sponsor using the BMS post 
central reading value of the %predicted FEV1 for the question 7 of the questionnaire. 
A global score is calculated: the questions are equally weighted and the ACQ-7-IA 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-IA, a change or difference in score of 0.5 is the 
smallest change that can be considered clinically important, corresponding to the MCID defined 
by the developer. 
Based on the manual of ACQ (3), 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 
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 
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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. 
Measurement properties such as reliability and ability to detect change have been documented in 
the literature. 
2.1.3.5.1.2 ACQ-5-IA (Asthma Control Questionnaire–Interviewer Administered, 5-question 
version) 
The ACQ-5-IA will be deduced from the responses to the first 5 questions of ACQ-7-IA and will 
be used for children ≥6 years to <12 years old at Screening.  
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-IA, a change or difference in score of 0.5 is the smallest change 
that can be considered clinically important, corresponding to the MCID defined by the developer. 
Missing scores will be handled in the same way as for ACQ-7 score. 
Measurement properties such as reliability and ability to detect change have been documented in 
the literature. 
2.1.3.5.2 Pediatric Asthma Quality of Life Questionnaire with Standardized Activities–Interviewer 
Administered 
The PAQLQ(S)–IA was designed as an interviewer-administered PRO to measure the functional 
impairments that are most troublesome to children ≥7 years old at Randomization Visit 2, as a 
result of their asthma (see Appendix G). The instrument is comprised of 23 items, each rated on a 
7-point Likert scales from 1 to 7.  
The PAQLQ(S)-IA has 3 domains. The domains and the number of items in each domain are as 
follows: 
• Symptoms (10 items: 4, 6, 8, 10, 12, 14, 16, 18, 20, and 23) 
• Activity limitation (5 items: 1, 2, 3, 19, and 22) 
• Emotional function (8 items: 5, 7, 9, 11, 13, 15, 17, and 21) 
A global score is calculated ranging from 1 to 7 and a score by domain. 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 domain score, only one missing 
value is acceptable. For the activity limitation and emotional function 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. 
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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 PAQLQ(S)-IA is 0.5. 
2.1.3.5.3 Paediatric Asthma Caregiver's Quality of Life Questionnaire 
The PACQLQ was designed as a 13-item questionnaire for the parent(s)/caregiver(s)/legal 
guardian(s) of children ≥7 years old and <12 years of age at Randomization Visit 2, and each item 
is rated on a 7-point scales ranging from 1 to 7, higher scores indicating better quality of life, in 
order to capture the impact of the child’s asthma on their quality of life and which aspects were 
most troublesome to the parent(s)/caregiver(s)/legal guardian(s) during the time prior to this 
assessment (see Appendix J). 
The PACQLQ has 2 domains. The domains and the number of items in each domain are as 
follows: 
• Activity limitation (4 items: 2, 4, 6, and 8) 
• Emotional function (8 items: 1, 3, 5, 7, 9, 10, 11, 12, and 13) 
A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate 
better quality of life. 
2.1.3.5.4 Pediatric Rhinoconjunctivitis Quality Of Life Questionnaire–Interviewer Administered in 
patients with comorbid allergic rhinitis. 
PRQLQ-IA (see Appendix I) is an interviewer-administered questionnaire developed to measure 
HRQoL signs and symptoms that are most problematic in children ≥6 years to <12 years old, as a 
result of perennial or seasonal allergic rhinitis. The 23-item PRQLQ-IA 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 takes approximately 7 minutes to complete. The minimally important difference (MID) 
of 0.5 has been established as the minimal important difference indicative of a clinically 
meaningful change (4).  
The PRQLQ-IA has 5 domains. The domains and the number of items in each domain are as 
follows: 
• Activity limitations (4 items: 16, 21, 22, and 23) 
• Eye symptoms (4 items: 5, 6, 7, and 8) 
• Nose symptoms (4 items: 1, 2, 3, and 4) 
• Practical problems (5 items: 9, 10, 11, 12, and 20) 
• Other symptoms (6 items: 13, 14, 15, 17, 18, and 19) 
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. 
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2.1.3.5.5 Euro Qol (EQ-5D-Y) – for Children  
The EQ-5D-Y will be completed by children (relates to the quality of life to the child). Those who 
can read are encouraged to fill the questionnaire by themselves. Those who cannot read, fill it with 
the help of their adult caregiver (parent/caregiver). 
The EQ-5D-Y consists of 2 pages, the EQ-5D-Y descriptive system and the EQ visual analogue 
scale (VAS; see Appendix H). The descriptive system assesses 5 dimensions but using a 
child-friendly wording (mobility, looking after myself, doing usual activities, having pain or 
discomfort, feeling worried, sad or unhappy). Each dimension has 3 levels: no problems, some 
problems, a lot of problems. The respondent is asked to indicate his/her health state by ticking (or 
placing a cross) in the box against the most appropriate statement in each of the 5 dimensions. The 
EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale where the 
endpoints are labelled ‘The best health you can imagine’ and ‘The worst health you can imagine’. 
This information can be used as a quantitative measure of health outcome as judged by the 
individual respondents. Also, previously published studies by EuroQol Group members showed 
preliminary evidence of the instrument’s feasibility, reliability and validity. 
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 exam.  
Observation period  
The observation period will be divided into 4 epochs: 
The screening epoch is defined as the time from the signed informed consent date up to the first 
IMP administration.  
The treatment epoch is defined as the time from the first administration of the IMP to the last 
administration of IMP + 14 days or till rollover to the LTS14424 study whichever is earlier.  
The residual treatment epoch is defined as the time from the last administration of the IMP + 15 
days to the last administration of IMP + 98 days or till rollover to the LTS14424 study whichever 
is earlier.  
The treatment-emergent adverse event period will consist of the treatment and residual 
treatment epochs. 
The post-treatment 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 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  
• 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 
• Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period 
• Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period 
All adverse events (including serious adverse events and adverse events with pre-specified 
monitoring/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 OR specify version if already known from project 
specifics. 
Adverse events of special interests (AESI) and other selected AE groupings will be searched 
based on the criteria in Table 4.  
Table 4 - 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 symptoms, the 
symptoms must have occurred within 24 hours of each other, which are related to IMP 
and requires treatments 
Hypersensitivity  
(medically reviewed) 
SMQ hypersensitivity (20000214) narrow search) and [AE corrective 
treatment/therapy=’Y’ or Action taken with IMP=’Drug withdrawn’ or Action taken with 
IMP=’Drug interrupted’] followed by blinded medical review (documented process) for 
selection of relevant systemic hypersensitivity events  
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 (Intensity=’Severe’ or Serious=’Y’) 
Parasitic infection 
The Infection Type ‘Parasitic’ was checked on eCRF page “Infection Defined as AESI 
Complementary Form” 
Opportunistic infection 
The Infection Type ‘Opportunistic’ was checked on eCRF page “Infection Defined as 
AESI Complementary Form” 
Potentially drug-related liver disorder 
Drug-related hepatic disorders-Comprehensive search narrow SMQ (20000006) 
Pregnancy 
Primary SOC ‘Pregnancy, puerperium and perinatal conditions’ or PT in (Aborted 
pregnancy, False negative pregnancy test, Pregnancy test positive, Pregnancy test 
urine positive, Ectopic pregnancy termination) 
Symptomatic overdose with IMP 
The question “Is the event a Symptomatic Overdose with IMP?” is answered “Yes” on 
the eCRF page “Adverse Event”. 
Symptomatic overdose with NIMP 
The question “Is the event a Symptomatic Overdose with NIMP?” is answered “Yes” on 
the eCRF page “Adverse Event”. 
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AE Grouping 
Criteria 
Other selected AE grouping 
 
Injection site reaction  
HLT = ‘Injection site reaction’  
Malignancy 
Sub-SMQ (20000091)– Malignant or unspecified tumors 
 
Partner pregnancy 
PT in (Pregnancy of partner, Miscarriage of partner) 
 
Conjunctivitis (narrow company medical 
query) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, Conjunctivitis viral, 
Atopic keratoconjunctivitis) 
Conjunctivitis (broad company medical 
query) 
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) 
Eosinophilia 
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 periods are per the observation periods defined above  
• Death on-study:  deaths occurring during the on-study observation period 
• Death on-treatment:  deaths occurring during the treatment-emergent adverse event period  
• Death poststudy:  deaths occurring after the end of the study  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables.  
Blood samples for clinical laboratories will be taken at Visit 1(Week -4±1), Visit 2 (Week 0), 
Visit 8 (Week 12), Visit 14 (Week 24), Visit 20 (Week 36), Visit 28 (Week 52), Visit 31 
(Week 64) and early termination unless otherwise specified.  The laboratory parameters will be 
classified as follows:   
• 
Hematology  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, red blood 
cell count, platelet count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• 
Clinical chemistry  
- 
Metabolism:  glucose, total cholesterol, total protein, creatine phosphokinase 
- 
Electrolytes:  sodium, potassium, chloride, bicarbonate 
- 
Renal function:  creatinine, blood urea nitrogen, uric acid 
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- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, total bilirubin (in case of values above the normal 
range, differentiation in conjugated and non-conjugated bilirubin), albumin 
- 
Hepatitis screen: Hepatitis virus tests will be performed at Screening Visit 1, 
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 
- 
HIV screen: anti-HIV-1 and HIV-2 antibodies will be tested at Visit 1 
- 
Anti-nuclear antibody (ANA) will be tested at Visit 1 
• 
Serum immunoglobulins: quantitative immunoassays for total IgG, IgG subclasses 1-4, 
IgM, and IgA will be tested at Visit 2, Visit 14 (Week 24), and Visit 28 (Week 52) 
Urine samples will be collected as follows:  
• 
Urinalysis (limited to Visit 1(Week -4±1), Visit 8 (Week 12), Visit 14 (Week 24), Visit 20 
(Week 36), Visit 28 (Week 52), and Visit 31 (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 
• 
Pregnancy test: A urine pregnancy test will be performed at Screening (Visit 1) in female 
patients of childbearing potential who have commenced menstruating, and a urine dipstick 
pregnancy test will be performed at Visit 2 prior to randomization, Visit 4 (Week 4),  
Visit 6 (Week 8), Visit 8 (Week 12), Visit 10 (Week 16), Visit 12 (Week 20), Visit 14 
(Week 24), Visit 16 (Week 28), Visit 18 (Week 32), Visit 20 (Week 36), Visit 22  
(Week 40), Visit 24 (Week 44), Visit 26 (Week 48), Visit 28 (Week 52), and Visit 31 
(Week 64). Those female patients who commence initial menstruation during the study 
will be similarly monitored with urine dipstick pregnancy tests and contraception 
consulting for the duration of the study 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per 
minute), body temperature (degrees Celsius), and will include height (cm) and body weight (kg), 
measured at the Screening and Randomization Visits (Visits 1 and 2) and every subsequent visit. 
Height will be measured with a proper stadiometer at every visit. Stadiometer measurements will 
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be made without patient wearing shoes. Vital signs will be measured at clinic visits, in sitting 
position, using the same arm at each visit, and prior to administration of investigational product. 
2.1.4.5 Electrocardiogram variables 
One recording of a standard 12-lead electrocardiogram (ECG) will be performed at Screening, 
Visit 28 (Week 52/EOT), and Visit 31 (Week 64/EOS). ECGs were recorded automatically by the 
device at the Investigator site.   
2.1.4.6 Physical Examination 
Physical examinations will be performed at Screening, Visit 14 (Week 24), Visit 28 
(Week 52/EOT), and Visit 31 (Week 64/EOS) and will include an assessment of general 
appearance, skin, eyes, ear/nose/throat, heart, chest, abdomen, reflexes, lymph nodes, spine, and 
extremities, including menstruation status. All deviations from normal will be recorded, including 
those attributable to the patient’s disease.  
2.1.5 Pharmacokinetic variables  
Predose blood samples will be collected for determination of functional dupilumab concentration 
in serum on Visit 2 (Week 0), Visit 5 (Week 6), Visit 8(Week 12), Visit 14 (Week 24), Visit 28 
(Week 52) and Visit 31 (Week 64).  
2.1.6 Anti-drug antibody (ADA) variables 
Anti-dupilumab antibody (ADA) (including neutralizing antibodies) status (negative or titer value, 
if positive in the ADA assay) at Visit 2 (Day 1), Visit 8(Week 12), Visit 14 (Week 24), Visit 28 
(Week 52) and Visit 31 (Week 64) will be provided. Patients who discontinue early from 
treatment or patients who choose not to participate in the LTS 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.  
ADA incidence will be classified as the following: 
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. 
Treatment-emergent response is defined as:  
A positive response in the ADA assay post first dose, when baseline results are negative or 
missing. 
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Treatment-emergent ADA responses are further classified as Persistent, Indeterminate or Transient 
a) Persistent Response - defined as a treatment-emergent ADA response with two or more 
consecutive ADA positive sampling time points, separated by greater than (>) 12-week 
period (84 days), with no ADA negative samples in between. 
b) Indeterminate Response - defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay  
c) Transient Response - defined as a treatment-emergent response that is not considered 
persistent OR indeterminate 
Treatment-boosted response is defined as: 
A positive response in the ADA assay post first dose that is greater-than or equal to 4-fold over 
baseline titer levels, when baseline results are positive. 
Titer values (Titer value category) 
• 
Low (Titer <1000) 
• 
Moderate (1,000 ≤ Titer ≤10,000) 
• 
High (Titer >10,000) 
Samples that are positive in the ADA assay will be further characterized for the presence of anti-
dupilumab neutralizing antibodies (NAb). 
ADA negative is defined as ADA assay is negative at all times or exhibit a pre-existing 
immunoreactivity. 
ADA positive is defined as either treatment-boosted or treatment-emergent response in the ADA 
assay. 
2.1.7 Pharmacodynamic/genomics endpoints  
Serum total IgE, antigen-specific IgE, antigen-specific IgG4 panel, and Thymus and Activation-
Regulated Chemokine (TARC) will all be assayed at Visit 2(Week 0), (TARC only Visit 8 
(Week 12)), Visit 14 (Week 28), and EOT (Week 52). 
Fractional exhaled nitric oxide (FeNO) will be analyzed using a NIOX instrument (Aerocrine AB, 
Solna, Sweden), or similar analyzer using a flow rate of 50 mL/s, and reported in parts per billion 
(ppb). This assessment should be conducted prior to spirometry and following a fast of at least 1 
hour at Visit 1(Week -4±1), Visit 2 (Week 0), Visit 3 (Week 2),Visit 4 (Week 4), Visit 5 (Week 6) 
, Visit 6 (Week 8) , Visit 7 (Week 10), Visit 8 (Week 12), Visit 10 (Week 16), Visit 12  
(Week 20), Visit 14 (Week 24), Visit 16 (Week 28), Visit 18 (Week 32) , Visit 20 (Week 36) , 
Visit 22 (Week 40) , Visit 24 (Week 44), Visit 26 (Week 48), Visit 28 (Week 52), Visit 29 
(Week 56), Visit 30(Week 60), Visit 31(Week 64). 
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Blood eosinophil counts from hematology assays will be collected at Visit 1(Week -4±1), Visit 2 
(Week 0), Visit 8 (Week 12), Visit 14 (Week 24), Visit 20 (Week 36), Visit 28 (Week 52),  
Visit 31(Week 64) and early termination. 
 
 
 
 
 
2.1.8 Humoral immune response to vaccines  
Humoral immune responses to standard vaccines (in this study: any vaccination for tetanus, 
diphtheria, pertussis and/or seasonal trivalent/quadrivalent influenza vaccine) occurring during 
dupilumab treatment will be evaluated for those patients eligible for these vaccinations. 
Any patient who will receive planned vaccination for tetanus, diphtheria, pertussis and/or seasonal 
trivalent/quadrivalent influenza during the study, will be scheduled to receive the respective 
vaccination(s) and to have blood samples for antibody titers drawn before and after the respective 
vaccination(s), as detailed below. 
Scheduled blood sample collection for pre- and post-vaccine antibody titers, for both vaccinations 
(ie, any tetanus, diphtheria and pertussis and/or seasonal trivalent/quadrivalent influenza) should 
be drawn within 8 weeks prior to vaccination and at 3-4 weeks (up to 6 weeks) after the respective 
vaccination(s); however, all blood titer samples must be drawn between Week 6 and Week 50 (ie, 
Visit 5 and Visit 27, respectively).  
2.1.9 Health economic endpoints  
The Health Care Resource Utilization (HCRU) questionnaire (questions on use of reliever 
medication, specialist visit, hospitalization, emergency or urgent medical care facility visit, 
outcome, school days’ loss, etc), as integrated part of the e-CRF, will be administered at Visit 2, 
Visit 8, Visit 14, Visit 20, Visit 26, Visit 28 and Visit 31, and will additionally be used to asses 
HCRU in the event of any asthma exacerbation: severe asthma exacerbation event or evidence of 
LOAC (for detailed definitions see Section 2.1.3.1). 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for patient study status. 
Screened patients are defined as any patients that have 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. 
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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: 
• Screened patients 
• Screen failure patients and reasons for screen failure 
• Nonrandomized but treated patients 
• Randomized patients 
• Randomized but not treated patients 
• Randomized and treated patients 
• Patients who did not complete the 52-week treatment as per protocol 
• Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
• Patients who withdraw from study prior to Week 52 
• Patients who withdraw from study prior to Week 52 by main reason for study 
discontinuation. 
• Patients who withdraw from study 
• Patients who rolled over to the LTS14424 study 
• 
Patients who withdraw from study by main reason for study discontinuation 
• Death 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, including due to the COVID-19 pandemic, 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. 
All critical or major deviations will be summarized in tables giving numbers and percentages of 
deviations by deviation category for each treatment group. Critical or major deviations that are 
related to the COVID-19 pandemic will be summarized in a similar manner. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error.  
 
OR 
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2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are not 
limited to:  
Randomization and drug allocation irregularities 
Kit dispensation without IRT transaction 
Erroneous kit dispensation 
Kit not available 
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 full intent-to-treat (ITT) population is defined as all randomized patients.  
Type 2 inflammatory asthma phenotype population is defined as the randomized patients with 
baseline blood eosinophils ≥0.15 Giga/L or baseline FeNO ≥20 ppb.  
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Baseline blood eosinophils ≥0.3 Giga/L population is defined as the randomized patients with 
baseline blood eosinophils ≥0.3 Giga/L.  
Baseline blood eosinophils ≥0.15 Giga/L population is defined as the randomized patients with 
baseline blood eosinophils ≥0.15 Giga/L.  
Baseline FeNO ≥20 ppb population is defined as the randomized patients with baseline FeNO  
≥20 ppb.  
All efficacy endpoints will be analyzed based on both the population with a Type 2 inflammatory 
asthma phenotype and the population with baseline blood eosinophils ≥0.3 Giga/L. For selected 
efficacy endpoints, the analysis will be done for all four efficacy populations. For detailed analysis 
plan, refer to Appendix M. For the analysis of primary efficacy endpoint, the testing hierarchy will 
start with the patients with baseline blood eosinophils ≥0.3 Giga/L population for the US and US 
reference countries; For EU and EU reference countries, the testing hierarchy will start with the 
Type 2 inflammatory asthma phenotype population (patients with baseline blood eosinophils 
≥0.15 Giga/L or baseline FeNO ≥20 ppb). For more details about multiplicity consideration, refer 
to Section 2.4.4.4. 
Patients will be analyzed in the treatment group to which they are randomized. 
For PRO endpoints which are only valid on specific subpopulations of patients, only patients 
within the subpopulation will be analyzed according to their randomized treatment group. Such 
subpopulations include patients of age ≥7 years old at randomization for PACQLQ(S) and patients 
with history of allergic rhinitis for PRQLQ-IA. 
If a patient is unblinded during the study, only data obtained before the unblinding will be 
included in the efficacy analyses.  
2.3.2 Safety population 
The safety population is defined as:  
• 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:  
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 
• 
For patients on placebo but accidentally exposed to dupilumab, the treatment group 
allocation for as-treated analysis will be dupilumab group. 
• 
If a patient is unblinded during the study, all safety data from the patient regardless of 
before or after unblinding will be included in the safety analyses according to the treatment 
patients actually received before the unblinding. 
All analyses will be provided by treatment regimens as Dupilumab vs placebo. No planned 
analysis based on the subcategory of dose level will be provided. 
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2.3.3 Population for pharmacokinetics, immunogenicity, and pharmacodynamics 
analyses 
The PK population will consist of all patients in the safety population with at least one non-
missing serum concentration data. Patients will be analyzed according to the treatment actually 
received. 
The ADA population will consist of all patients in the safety population who had at least one non-
missing ADA results (either ‘ADA negative’ or ‘ADA positive’) after first dose of the study 
treatment. Patients will be analyzed according to the treatment actually received. 
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 
The demographics, baseline characteristics and medical history will be presented for the 
population with Type 2 inflammatory asthma phenotype, population with baseline blood 
eosinophils ≥0.3 Giga/L, population with baseline blood eosinophils ≥0.15 Giga/L, population 
with baseline FeNO ≥20 ppb and full ITT population. 
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 full ITT 
population in the primary analysis 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. P-values 
will not be calculated. 
No specific description of either efficacy or safety parameters will be provided at baseline.  If 
relevant, the baseline values will be described along with each efficacy or safety analysis. 
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2.4.2 Prior or concomitant medications 
The general prior and concomitant medications, and controller medications will be presented for 
the population with Type 2 inflammatory asthma phenotype, and population with baseline blood 
eosinophils ≥0.3 Giga/L, and full ITT 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 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. Number of patients who have their controller medications 
permanently stepped-up during the study according to protocol will also be summarized and the 
time to first permanent step-up will also be summarized with descriptive statistics. 
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 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 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 5 - Equivalent dose for inhaled corticosteroids for children (≥6-11 years) 
Inhaled corticosteroid 
Conversion Factor to Fluticasone propionate 
(DPI) 
Low 
Medium 
High 
BECLOMETASONE DIPROPIONATE (CFC) 
1 
1 
1 
BECLOMETASONE DIPROPIONATE (HFA) 
2 
2 
2 
BUDESONIDE (DPI) 
1 
1 
1 
BUDESONIDE (HFA) 
1 
1 
1 
BUDESONIDE (nebules) 
0.4 
0.4 
0.4 
CICLESONIDE (HFA) 
2.5 
2.5 
2.5 
FLUNISOLIDE (HFA) 
1.25 
1.25 
1.25 
FLUTICASONE PROPIONATE(HFA) 
1 
(200+x*2)/3 
0.8 
MOMETASONE FUROATE 
10/11 
10/11 
10/11 
TRIAMCINOLONE ACETONIDE 
0.25 
-200+x/2 
1/3 
HFA=hydrofluoroalkane, DPI= Dry Powder Inhaler 
x: the actual dose level of the corresponding inhaled corticosteroid 
Example:  
1): when the dose of FP(HFA) is 500 mcg, the corresponding dose of FP(DPI) will be 200/3 + 500*2/3=400 mcg. 
2): when the dose of TRIAMCINOLONE ACETONIDE is 1200 mcg, the corresponding dose of FP(DPI) will be (-200 + 1200/2) = 400 mcg. 
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 to 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 to all controller medication if the actual dose of each controller medication is same as 
or greater than the prescribed dose.  Note that if the prescribed dose has been stepped-up based on 
protocol specified criteria, the compliance post dose increase will be calculated based on the 
updated prescribed controller medication dose.  
Compliance for controller medication(s) with ICS component is defined as the number of 
days when the patient is compliant to 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 to all prescribed controller medication divided by the number of 
days the patient stays in the treatment period. Since it is required by the protocol that a 12 hours 
washout is required before spirometry tests, the calculation of overall controller medication 
compliance for patients with prescribed LABA will exclude the data from the spirometry test days. 
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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 
for Safety population, population with Type 2 inflammatory asthma phenotype, and population 
with baseline blood eosinophils ≥0.3 Giga/L (Section 2.3.1). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
Duration of IMP exposure is defined as last dose date – first dose date + 14 days, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data).  
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum).  In addition, duration of treatment exposure will 
also be summarized categorically by numbers and percentages for each of the following categories 
and cumulatively according to these categories:  
>0 and ≤2 weeks 
>2 and ≤4 weeks 
>4 and ≤8 weeks 
>8 and ≤12 weeks 
>12 and ≤16 weeks 
… 
…. 
>48 and ≤52 weeks 
>52 weeks 
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. 
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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 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% underplanned dose administrations. 
Cases of overdose of IMP (defined as at least twice the intended dose during an interval of less 
than 11 days) will be summarized by numbers and percentages of patients with at least 1 over dose 
by treatment group. Different overdose intense by dose interval, ie, 1 day, 2 days, etc., will also be 
summarized.  More generally, dosing irregularities will be listed as being described in 
Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints 
All efficacy endpoints will be analyzed based on both the population with Type 2 inflammatory 
asthma phenotype and patients with baseline blood eosinophils ≥0.3 Giga/L populations.  
Some selected efficacy endpoints will be also analyzed for full ITT population, as well as the 
Patients with baseline blood eosinophils ≥0.15 Giga/L population, and the patients with baseline 
FeNO ≥20 ppb. For more details, refer to Appendix M. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
Primary statistical model 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 this primary 
approach, for the patients who prematurely discontinue treatment, their off-treatment 
measurements up to Week 52 or the study withdrawal whichever comes earlier will be included 
for the analysis. Patients who permanently discontinue the study medication will be asked and 
encouraged to return to the clinic for all remaining study visits. If a patient stays in study until the 
end of the 52-week treatment period, all severe exacerbation events that happen up to Visit 28 will 
be included in the primary analysis, regardless whether the patient is on-treatment or not, and the 
observation duration is defined as from randomization to Visit 28. If a patient withdraws from the 
study prior to the end of the 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 
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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. 
The annualized rate of severe exacerbation events as defined in Section 2.1.3.1 will be analyzed 
using a negative binomial regression model. The analysis for the annualized severe exacerbation 
rate will be performed in the Type 2 inflammatory asthma phenotype, baseline blood eosinophils 
≥0.3 Giga/L, baseline blood eosinophils ≥0.15 Giga/L, baseline FeNO ≥20 ppb and full ITT 
populations. 
When performing the analysis for the annualized severe exacerbation rate in the Type 2 
inflammatory asthma phenotype, baseline blood eosinophils ≥0.15 Giga/L or full ITT population, 
the model will include the total number of events that occur during the observation period defined 
above as the response variable, with the treatment arm, age, baseline weight (≤30kg, >30kg), 
region, baseline eosinophil level (<0.3 Giga/L, ≥0.3 Giga/L), baseline FeNO level (<20 ppb,  
≥20 ppb), baseline ICS dose level (medium/high) and number of severe exacerbation events 
within 1 year prior to the study as covariates. When performing the primary endpoint analysis in 
the baseline blood eosinophils ≥0.3 Giga/L population, the baseline eosinophil level will be 
removed from the model covariates. When performing the primary endpoint analysis in the 
baseline FeNO ≥20 ppb population, the baseline FeNO level will be removed from the model 
covariates. 
Treatment groups, baseline weight, region, baseline eosinophil level, baseline FeNO level, and 
baseline ICS dose level will be treated as categorical variables. Age and number of severe 
exacerbation events within 1 year prior to the study will be treated as continuous variables. Log 
transformed observation duration will be the offset variable.  In the case where the negative 
binomial regression model may not converge, a categorical variable for the number of severe 
exacerbation events within 1 year prior to study (1, 2, more than 2) will replace the corresponding 
continuous variable in the model. A similar approach will also be applied to other analyses for 
severe exacerbation endpoint if applicable. 
Comparisons of the annualized event rates between dupilumab and placebo will be derived by 
testing dupilumab group versus placebo. The estimated annualized event rate for each treatment 
group and its two-sided 95% confidence intervals will be derived from the negative binominal 
model.  
Sample SAS code can be found below: 
proc glimmix data=event; 
  class weight eosblgpn1 fenoblgrn ics trt01pn cntygr1n; 
  model numevents=trt01pn age weight eosblgpn1 fenoblgrn ics cntygr1n asmanum       
                  /offset=logdur dist=negbin link=log solution;                               
run; 
 
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If the model fails to achieve convergence, different estimation algorithms will be applied 
following the order: default→LAPLACE→QUAD; if the non-convergence issue still exists, other 
handling may be considered. The adjustment will be added to the footnote of the corresponding 
outputs. 
The gross estimated annualized event rates will also be presented by each treatment group. Mean 
cumulative function plot will be provided for descriptive purpose. 
The primary estimand for the primary endpoint used in the aforementioned statistical analysis 
method is the treatment policy estimand. Details about the intercurrent events strategy and missing 
data handling in this primary estimand are presented in as below Table 6. 
Table 6 - Protocol amendment statistical changes 
Endpoint 
Category 
(estimand) 
Estimand 
Endpoint 
Population 
Intercurrent event(s) 
strategy and missing data 
handling 
Population-level summary 
 
Primary objective: The primary objective is to evaluate the efficacy of dupilumab in children 6 to <12 years of age with uncontrolled 
persistent asthma 
Primary 
endpointa  
(treatment 
policy) 
Annualized rate 
of severe 
exacerbation 
events during 
the 52-week 
placebo-
controlled 
treatment 
period. 
Patients with 
Type 2 
inflammatory 
asthma 
phenotype for 
EU and EU 
reference 
countries 
 
 
Patients with 
baseline blood 
eosinophils ≥
0.3 Giga/L for 
US and US 
reference 
countries 
 
The intercurrent events will be 
handled as follows: 
Discontinuation of study treatment 
before Week 52: Off-study treatment 
data up to Week 52 will be included 
in the analysis (treatment policy 
strategy).  
 
In addition, the missing data 
imputation rules are as follows: 
Discontinuing the study follow-up 
before Week 52: Analyses will be 
censored at the time of study 
discontinuation. 
 
 
 
In patients with Type 2 
inflammatory asthma phenotype, 
the primary endpoint will be 
analyzed using negative binomial 
regression model, with the 
treatment group, age, weight 
(≤30kg, >30kg), region, baseline 
eosinophil level (<0.3 Giga/L,  
≥0.3 Giga/L), baseline FeNO level 
(<20 ppb, ≥20 ppb), baseline ICS 
dose level (medium/high) and 
number of severe asthma 
exacerbation events prior to the 
study as covariates, and log-
transformed exposure will be used 
as the offset. The adjusted 
annualized severe exacerbation 
rate of each arm, relative risk 
between treatment and placebo 
arms, 95% confidence interval 
and P value will be reported. 
 
In patients with baseline blood 
eosinophils ≥0.3 Giga/L, the 
analysis will remain same as 
above except that the covariate of 
baseline eosinophil level will be 
removed. 
 
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Estimand of clinical efficacy of dupilumab versus placebo with treatment adherence 
An analysis to assess the efficacy of dupilumab if patients adhere to the treatment as directed is 
also specified. In this approach, the severe exacerbation events reported after the premature 
treatment discontinuation will be excluded from the analysis. Any exacerbation obtained after the 
first permanent stepping-up of background asthma medication (following at least two severe 
exacerbation per protocol) will also be excluded from the analysis. The supportive analysis for the 
primary endpoint will be performed in the Type 2 inflammatory asthma phenotype and baseline 
blood eosinophils ≥0.3 Giga/L populations. A negative binomial model with the same set of 
covariates as specified for the primary endpoint analysis in each of the Type 2 inflammatory 
asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L populations will be used. This 
model will include severe exacerbation events occurring during the treatment epoch before any 
permanent treatment regimen change (including permanent IMP discontinuation and/or step-up of 
controller medication) as the response variable and the log transformed duration of the treatment 
epoch or from randomization to first permanent treatment regimen change whichever is shorter 
will be the offset variable. This approach defines the estimand to be the efficacy of dupilumab 
with treatment adherence. 
Handling of missing data 
If patients withdraw from the study before Visit 28 (Week 52), severe exacerbation events that 
may occur after study discontinuation will not be observed. These patients are considered as 
patients with missing data for the severe exacerbation endpoint. 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, the following sensitivity analyses will be conducted to 
assess the robustness of the conclusion drawn based on the main model for the primary analysis to 
the missing data: 
• 
Pattern mixture model (PMM-MI with logistic regression model) 
For each patient with partial missing data of severe exacerbation events, the unobserved 
number of events after study discontinuation up to Week 52 will be imputed on monthly basis. 
Since the definition of severe exacerbation in Section 2.1.3.1 requires the start dates of 
2 consecutive severe exacerbation events experienced by one patient to depart at least 28 days 
from each other, each patient is possible to have a maximum of one event per month that is 
defined as 28 days. A logistic regression model therefore can be used to impute whether a 
patient has an event or not for each of the corresponding unobservable months. This 
imputation will be repeated multiple times. A final statistical inference will be obtained by 
using Rubins’ formula to combine the binomial regression results based on each of the 
imputed datasets. Details of the PMM model are described in Appendix D.  
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• Control-based PMM 
Similar to aforementioned PMM model except that the individual monthly mean probability 
will be calculated based on observations in placebo arm only in the logistic regression, with 
adjustment of missing observation duration. 
• 
Tipping point analysis 
Similar to aforementioned PMM model except that if a patient with missing data is on 
dupilumab, the odds in the logistic model for each unobservable month will be increased, and 
vice versa if the patient is on placebo, the odds will be decreased. This adjustment will 
artificially lower the predicted event rates in placebo group and increase the predicted event 
rates in Dupilumab group.  For each increasing/decreasing ratio, a p-value can be obtained 
based on the imputed dataset with this specific ratio. A sequence of different ratios will be 
explored until p-value becomes >0.05.  
The missing data sensitivity analyses for the primary endpoint analysis will be performed in the 
Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L populations. 
For each of the above methods, a negative binomial model will be fitted using the complete 
dataset composed of observed and imputed data, including the total number of observed and 
imputed events during the 52 weeks as the response variable. When performing the sensitivity 
analyses in the population with Type 2 inflammatory asthma phenotype, the model will include 
the treatment group, age, baseline weight (≤30kg, >30kg), region (pooled country), baseline 
eosinophil level, baseline FeNO level, baseline ICS dose level and number of severe exacerbation 
events within 1 year prior to the study as covariates. When performing the sensitivity analyses in 
the population with baseline blood eosinophils ≥0.3 Giga/L, the baseline eosinophil level will be 
removed from the model covariates. Log transformed observation duration will be the offset 
variable.  
More details of the imputation and analyses methods are provided in Appendix D. 
Sensitivity analysis related to COVID-19 Pandemic 
To assess missing data due to COVID-19 pandemic, missing data from patients who were 
discontinued from the study before Week 52 due to COVID-19 will be imputed using a manner 
similar to pattern mixture model as mentioned above except breaking down the ‘Other’ 
discontinuation reason into ‘Due to COVID-19 or not’ when defining the missing patterns. 
Subgroup analyses  
To assess the 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: 
• Gender (Male, Female) 
• Region (Latin America, Eastern Europe, and Western Countries)  
• Race (Caucasian/White, Black/of African descent, Asian/Oriental, all the other) 
• Background ICS dose levels at randomization (medium, high) 
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• Baseline blood eosinophil level (<0.3 Giga/L, ≥0.3 Giga/L; <0.15 Giga/L, ≥0.15 Giga/L; 
<0.15 Giga/L, ≥0.15 - <0.3 Giga/L, ≥0.3 - <0.5 cells/μL, ≥0.5 cells/μL) 
• Baseline FeNO level (<20 ppb, ≥20 – <35 ppb, ≥35 ppb) 
• Eos-FeNO Quadrant (0.15-20) 1 (H-H): Baseline blood eosinophil level ≥0.15 Giga/L and 
Baseline FeNO ≥20 ppb 
• Eos-FeNO Quadrant (0.15-20) 2 (H-L): Baseline blood eosinophil level ≥0.15 Giga/L and 
Baseline FeNO <20 ppb 
• Eos-FeNO Quadrant (0.15-20) 3 (L-H): Baseline blood eosinophil level <0.15 Giga/L and 
Baseline FeNO >=20 ppb 
• Eos-FeNO Quadrant (0.15-20) 4 (L-L): Baseline blood eosinophil level <0.15 Giga/L and 
Baseline FeNO <20 ppb 
• Eos-FeNO Quadrant (0.3-20) 1 (H-H): Baseline blood eosinophil level ≥0.3 Giga/L and 
Baseline FeNO ≥20 ppb 
• Eos-FeNO Quadrant (0.3-20) 2 (H-L): Baseline blood eosinophil level ≥0.3 Giga/L and 
Baseline FeNO <20 ppb 
• Eos-FeNO Quadrant (0.3-20) 3 (L-H): Baseline blood eosinophil level <0.3 Giga/L and 
Baseline FeNO >=20 ppb 
• Eos-FeNO Quadrant (0.3-20) 4 (L-L): Baseline blood eosinophil level <0.3 Giga/L and 
Baseline FeNO <20 ppb 
• Background controller type at randomization (ICS only, ICS + LABA) 
• Baseline predicted FEV1% (<80%, ≥80%) 
• Baseline predicted FEV1% (<median, ≥median) 
• Baseline ACQ-7-IA (≤2, >2) 
• Baseline weight (≤30, >30 kg) 
• Atopic medical condition (Yes, No) 
• Baseline Total IgE (<median, ≥median) 
• Baseline Total IgE (<100 IU/mL, ≥100 IU/mL) 
• Age at onset of asthma (0 - <2, 2-<6, >=6) 
• Number of severe asthma exacerbation prior to the study as defined in Section 2.1.1  
(<=1, =2, >2) 
Additional EOS-FeNO Quadrant analysis will be performed using alternative cut-off value for the 
baseline FeNO: 
• Eos-FeNO Quadrant (0.15-35) 1 (H-H): Baseline blood eosinophil level ≥0.15 Giga/L and 
Baseline FeNO ≥35 ppb 
• Eos-FeNO Quadrant (0.15-35) 2 (H-L): Baseline blood eosinophil level ≥0.15 Giga/L and 
Baseline FeNO <35 ppb 
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• Eos-FeNO Quadrant (0.15-35) 3 (L-H): Baseline blood eosinophil level <0.15 Giga/L and 
Baseline FeNO >=35 ppb 
• Eos-FeNO Quadrant (0.15-35) 4 (L-L): Baseline blood eosinophil level <0.15 Giga/L and 
Baseline FeNO <35 ppb 
A patient is considered to have ongoing 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 serum total IgE ≥100 IU/mL and at least one positive aeroantigen 
specific IgE (≥0.35 IU/mL) at baseline.  
The aforementioned subgroup analyses (except for the baseline eosinophil levels and baseline 
FeNO levels) will be performed in the Type 2 inflammatory asthma phenotype population and 
baseline blood eosinophils ≥0.3 Giga/L population; and, the subgroup analyses concerning the 
baseline blood eosinophil level and baseline FeNO level will be performed in the full ITT 
population. The annualized rate of severe exacerbation events as defined in Section 2.1.3.1 will be 
analyzed using a negative binomial regression model.  
When performing the subgroup analysis in the Type 2 inflammatory asthma phenotype population 
or the full ITT population, the model will include the total number of events that occur during the 
observation period defined above as the response variable, with the treatment arm, age, baseline 
weight (≤30kg, >30kg), region, baseline blood eosinophil level (<0.3 Giga/L, ≥0.3 Giga/L), 
baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS dose level (medium/high) and number of 
severe exacerbation events within 1 year prior to the study as covariates. When performing the 
subgroup analysis in the baseline blood eosinophils ≥0.3 Giga/L population, the baseline 
eosinophil level will be removed from the model covariates. Furthermore, in the Type 2 
inflammatory asthma phenotype, baseline blood eosinophils ≥0.3 Giga/L, or full ITT population, 
when performing the subgroup analysis that is defined by age, baseline weight, region, baseline 
blood eosinophil level, baseline FeNO level, baseline ICS dose level, or number of severe 
exacerbation events within 1 year prior to the study, the covariate that defines the subgroup will be 
removed from the model covariates.  
Treatment groups, baseline weight, region, baseline eosinophil level, baseline FeNO level, and 
baseline ICS dose level will be treated as categorical variables. Age and number of severe 
exacerbation events within 1 year prior to the study will be treated as continuous variables. Log 
transformed observation duration will be the offset variable.  In the case where the negative 
binomial regression model may not converge, a categorical variable for the number of severe 
exacerbation events within 1 year prior to study (1, 2, more than 2) will replace the corresponding 
continuous variable in the model. 
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 treatment groups, age, baseline weight, region, baseline 
eosinophil level, baseline FeNO level, 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 
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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 dupilumab vs. placebo for the subgroups will be provided. 
Treatment-by-Type 2 biomarker interaction 
To examine the ability of FeNO to predict the treatment effect of dupilumab independent of blood 
eosinophil levels for the primary endpoint, treatment-by-biomarker interactions will be tested 
using negative binomial regression models that include the total number of severe exacerbation 
events during 52-week treatment period as the response variable, and with the following different 
sets of model covariates, respectively. A threshold value of 0.15 will be utilized for the nominal p 
value of interaction test. 
 
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2.4.4.2 Analyses of key secondary efficacy endpoints 
Statistical analysis methods for the key secondary endpoints are presented below.  
2.4.4.2.1 Change from baseline in percentage predicted pre-bronchodilator (pre-BD) FEV1 at 
Week 12 
Primary statistical model and adjustment for covariates 
The analysis of change from baseline in % predicted pre-BD FEV1 at Week 12 is to assess the 
efficacy of dupilumab regardless of treatment adherence. The absolute change from baseline in % 
predicted FEV1 at Week 12 will be analyzed using a mixed-effect model with repeated measures 
(MMRM) approach. The analysis for change from baseline in % predicted pre-BD FEV1 will be 
performed in the Type 2 inflammatory asthma phenotype, baseline blood eosinophils ≥0.3 Giga/L, 
baseline blood eosinophils ≥0.15 Giga/L, baseline FeNO ≥20 ppb and full ITT populations.  
When performing the key secondary endpoint analysis in the Type 2 inflammatory asthma 
phenotype, baseline blood eosinophils ≥0.15 Giga/L, and full ITT populations, the model will 
include change from baseline in % predicted FEV1 values up to Week 12 as response variables, 
and treatment, baseline weight, region, ethnicity, baseline eosinophil level, baseline FeNO level, 
baseline ICS dose level, visit, treatment by-visit interaction, baseline % predicted FEV1 value and 
baseline-by-visit interaction as covariates. When performing the key secondary endpoint analysis 
in the baseline blood eosinophils ≥0.3 Giga/L population, the baseline eosinophil level will be 
removed from the model covariates. When performing the key secondary endpoint analysis in the 
baseline FeNO ≥20 ppb population, the baseline FeNO level will be removed from the model 
covariates. 
Treatment group, baseline weight, region, baseline eosinophil level, baseline FeNO level, 
ethnicity, baseline ICS dose level, and visit will be treated as categorical variables. 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-treatment % predicted FEV1 values 
measured up to Week 12 will be included in the primary analysis. For patients who withdraw from 
the study before Week 12, % predicted FEV1 values will be missing after study discontinuation. 
No imputation will be performed for missing values in the primary analysis. This estimand 
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compares the change from baseline in % predicted 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. 
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 % predicted 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 dupilumab against placebo. In addition, descriptive statistics including number of 
patients, mean, standard error and LS mean of change from baseline will be provided.  
A sample SAS code can be found below: 
proc mixed data=adsd.adre method=reml; 
 
where paramcd='FEV1PP'and ATPT='PRE-BRONCHODILATOR' and avisitn ge 3 and 
avisitn le 8 and ittfl='Y'; 
 
class subjid weight eosblgpn1 fenoblgpn ics trt01pn avisitn cntygr1n ethnicity; 
 
model chg = trt01pn weight ics eosblgpn1 fenoblgpn cntygr1n ethnicity avisitn 
trt01p*avisitn base base*avisitn/ddfm=kr residual; 
 
repeated avisitn/type=un subject=subjid; 
 
lsmeans trt01pn*avisitn /pdiff cl; 
     estimate 'dupilumab vs Placebo at Week 12 Visit 8'  
     trt01pn -1 1 trt01pn*avisitn   0 0 0 0 0 -1 0 0 0 0 0 1/cl; 
  run; 
The primary estimand for the key secondary endpoint is summarized as in below Table 7.  
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Table 7 - Summary of primary estimand for key secondary endpoint 
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
strategy and missing 
data handling 
Population-level summary 
 
Primary objective: The primary objective is to evaluate the efficacy of dupilumab in children 6 to <12 years of age with uncontrolled 
persistent asthma 
Key 
secondary 
endpoint 
(treatment 
policy) 
Change from 
baseline in pre-
bronchodilator 
% predicted 
forced 
expiratory 
volume in 1 
second (FEV1) 
at Week 12 
Type 2 
inflammation 
phenotype; 
 
Patients with 
baseline blood 
eosinophils ≥
0.3 Giga/L 
population 
 
The intercurrent events will be 
handled as follows: 
Discontinuation of study 
treatment before Week 12: Off-
study treatment data up to 
Week 12 will be included in the 
analysis (treatment policy 
strategy).  
 
 
In addition, the missing data 
imputation rules are as follows: 
In addition, missing data will be 
imputed latently by MMRM 
based on missing at random 
assumption  
 
In patients with Type 2 inflammatory 
asthma phenotype, the key secondary 
endpoint will be will be analyzed using 
MMRM with change from baseline in % 
predicted FEV1 values up to Week 12 as 
response variable, and treatment, age, 
baseline weight, region, sex, ethnicity, 
baseline height, baseline eosinophil 
level, baseline FeNO level, baseline ICS 
dose level, visit, treatment by-visit 
interaction, baseline % predicted FEV1 
value and baseline-by-visit interaction as 
covariates. The LS mean of each group, 
difference of LS means between 
treatment and placebo arms, 95% 
confidence internal and P value will be 
reported. 
 
In patients with baseline blood 
eosinophils ≥0.3 Giga/L, the analysis 
will remain same as above except that 
the covariate of baseline eosinophil level 
will be removed. 
 
Estimand of clinical efficacy of dupilumab versus placebo with treatment adherence  
To assess the treatment effect when the patients adhere to the study treatment as directed, 
on-treatment % predicted pre-BD FEV1 measurements will be analyzed using the similar MMRM 
model as for the key secondary endpoint analyses, using the same estimation algorithm. The 
model will include on-treatment change from baseline in % predicted pre-BD FEV1 values up to 
Visit 8 (Week 12) as response variables. A % predicted pre-BD FEV1 value is considered as on-
treatment if it’s measured before or on the last dose date + 14 days. The on-treatment analyses for 
the key secondary endpoint will be performed in the Type 2 inflammatory asthma phenotype and 
baseline blood eosinophils ≥0.3 Giga/L populations. The same set of covariates as specified for 
the key secondary endpoint analyses in each of the Type 2 inflammatory asthma phenotype and 
baseline blood eosinophils ≥0.3 Giga/L populations will be used in the MMRM model for the 
on-treatment analyses. Measurements obtained during off treatment period will be considered as 
missing. 
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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 % predicted pre-
BD FEV1 measurements confounded by the systemic corticosteroid use will be performed: 
• 
Censoring method 1: The % predicted 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 
• 
Censoring method 2: All % predicted 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 the key secondary endpoint analyses and the 
on-treatment analysis for the key secondary endpoint.  
Handling of missing data 
If a patient misses scheduled % predicted 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 % 
predicted pre-BD FEV1 data from these time points up to Week 12. Descriptive statistics of % 
predicted 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 % predicted pre-BD FEV1, reasons and timing for missing % predicted pre-BD FEV1 
will be summarized by treatment groups. In addition, the following sensitivity analyses will be 
conducted to assess the robustness of the conclusion drawn based on the main model for the key 
secondary endpoint analyses to the missing data: 
• 
Pattern mixture model-multiple imputation (PMM-MI) 
Missing % predicted pre-BD FEV1 values will be imputed multiple times with adjustment for 
covariates including treatment, region, ethnicity, baseline eosinophil level, baseline FeNO 
level, baseline ICS dose level, baseline % predicted FEV1 value and reason of treatment 
discontinuation. Each of the complete datasets will be analyzed using the ANCOVA model 
with change from baseline in % predicted pre-BD FEV1 at Week 12 as the response variable, 
treatment, baseline weight, region, ethnicity, baseline eosinophil level, baseline FeNO level, 
baseline ICS dose level, and baseline % predicted 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. 
• 
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 % predicted pre-BD FEV1 as patients on the placebo who were not 
exposed to dupilumab. 
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• 
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 % predicted pre-BD FEV1 at Week 12 and the corresponding p-values will be 
provided for each combination of shift parameters. 
The missing data sensitivity analyses for the key secondary endpoint analysis will be performed in 
the Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L 
populations. When performing the sensitivity analyses in the population with Type 2 inflammatory 
asthma phenotype, the model will include treatment, baseline weight, region, ethnicity, baseline 
eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit interaction, 
baseline % predicted FEV1 value and baseline-by-visit interaction as covariates. When performing 
the sensitivity analyses in the population with baseline blood eosinophils ≥0.3 Giga/L, the baseline 
eosinophil level will be removed from the model covariates. 
More details of the imputation and analyses methods are included in Appendix D. 
Subgroup analysis 
To assess the consistency of treatment effects across the subgroup levels, subgroup analyses will 
be conducted for the change from baseline in % predicted pre-BD FEV1 at Week 12 in the same 
set of subgroups as defined for the primary endpoint of annualized rate of severe exacerbation 
events. The subgroup analyses (except for the baseline eosinophil levels and baseline FeNO 
levels) will be performed in the Type 2 inflammatory asthma phenotype population and baseline 
blood eosinophils ≥0.3 Giga/L population; and, the subgroup analyses for the baseline blood 
eosinophil level and baseline FeNO level will be performed in the full ITT population. The same 
MMRM model for the key secondary endpoint will be applied for the subgroup analyses.  
When performing the subgroup analysis in the Type 2 inflammatory asthma phenotype population 
or the full ITT population, the model will include change from baseline in % predicted FEV1 
values up to Week 12 as response variables, and treatment, baseline weight, region, ethnicity, 
baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment by-visit 
interaction, baseline % predicted FEV1 value and baseline-by-visit interaction as covariates. 
When performing the subgroup analysis in the baseline blood eosinophils ≥0.3 Giga/L population, 
the baseline eosinophil level will be removed from the model covariates. Furthermore, in the  
Type 2 inflammatory asthma phenotype, baseline blood eosinophils ≥0.3 Giga/L, or full ITT 
population, when performing the subgroup analysis that is defined by age, baseline weight, region, 
gender, baseline blood eosinophil level, baseline FeNO level, baseline ICS dose level, or baseline 
% predicted FEV1, the covariate that defines the subgroup will be removed from the model 
covariates. 
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Treatment-by-subgroup interaction at Week 12 and its p-value will be derived from an MMRM 
model. 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 % predicted pre-bronchodilator FEV1 
will be provided within each subgroup. Forest plot of LS mean difference and corresponding CIs 
comparing dupilumab vs placebo for the subgroups will be provided. 
Distribution of change from baseline in percent predicted pre-BD FEV1 
Water fall plots of change from baseline in % predicted FEV1 at Week 12 and Week 52 will be 
presented in the Type 2 inflammatory asthma phenotype population and baseline blood 
eosinophils ≥0.3 Giga/L population. 
Treatment-by-Type 2 biomarker interaction 
To examine the ability of FeNO to predict the treatment effect of dupilumab independent of blood 
eosinophil levels for the key secondary endpoint, the treatment-by-biomarker interactions will be 
tested with MMRM model, which includes change from baseline in % predicted FEV1 values up 
to Week 12 as response variables, and with the following different sets of model covariates, 
respectively. A threshold value of 0.15 will be utilized for the nominal p value of interaction test. 
 
Biomarker covariate and 
treatment -by-biomarker 
interaction 
Model covariates 
Baseline biomarker as categorical variable: 
Baseline FeNO group (<20 ppb, 
>=20 ppb), and treatment-by-
baseline FeNO group interaction 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity,  baseline FeNO 
level (<20 ppb, ≥20 ppb), baseline ICS dose level (medium/high), visit, treatment by-visit interaction, 
baseline % predicted FEV1 value and baseline % predicted FEV1 value -by-visit interaction, and 
treatment-by-baseline FeNO group interaction as covariates. 
Baseline eosinophil group (<0.15 
Giga/L, >=0.15 Giga/L), and 
treatment-by- baseline eosinophil 
group interaction 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity,  baseline 
eosinophil level (<0.15 Giga/L, ≥0.15 Giga/L), baseline ICS dose level (medium/high), visit, treatment 
by-visit interaction, baseline % predicted FEV1 value and baseline % predicted FEV1 value -by-visit 
interaction, and treatment-by- baseline eosinophil group interaction as covariates. 
Baseline FeNO group (<20 ppb, 
>=20 ppb), baseline eosinophil 
group (<0.15 Giga/L, >=0.15 
Giga/L), and treatment-by-
baseline FeNO group interaction 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity,  baseline 
eosinophil level (<0.15 Giga/L, ≥0.15 Giga/L), baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS 
dose level (medium/high), visit, treatment by-visit interaction, baseline % predicted FEV1 value and 
baseline % predicted FEV1 value -by-visit interaction, and treatment-by-baseline FeNO group 
interaction as covariates. 
Baseline FeNO group (<20 ppb, 
>=20 ppb), baseline eosinophil 
group (<0.15 Giga/L, >=0.15 
Giga/L), treatment-by-baseline 
FeNO group interaction, and 
treatment-by- baseline eosinophil 
group interaction 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity,  baseline 
eosinophil level (<0.15 Giga/L, ≥0.15 Giga/L), baseline FeNO level (<20 ppb, ≥20 ppb), baseline ICS 
dose level (medium/high), visit, treatment by-visit interaction, baseline % predicted FEV1 value and 
baseline % predicted FEV1 value -by-visit interaction, and treatment-by- baseline eosinophil group 
interaction, and treatment-by-baseline FeNO group interaction as covariates. 
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Baseline biomarker as continuous variable: 
Baseline FeNO value, and 
treatment-by-baseline FeNO 
value interaction 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity,  baseline FeNO 
value, baseline ICS dose level (medium/high), visit, treatment by-visit interaction, baseline % 
predicted FEV1 value and baseline % predicted FEV1 value -by-visit interaction, and treatment-by-
baseline FeNO value interaction as covariates. 
Baseline eosinophil value, and 
treatment-by- baseline eosinophil 
value interaction 
 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity,  baseline 
eosinophil value, baseline ICS dose level (medium/high), visit, treatment by-visit interaction, baseline 
% predicted FEV1 value and baseline % predicted FEV1 value -by-visit interaction, and treatment-
by- baseline eosinophil value interaction as covariates. 
Baseline FeNO value, baseline 
eosinophil value, and treatment-
by-baseline FeNO value 
interaction 
 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity, baseline ICS dose 
level (medium/high), visit, treatment by-visit interaction, baseline % predicted FEV1 value and 
baseline % predicted FEV1 value -by-visit interaction, baseline eosinophil value, baseline FeNO 
value, and treatment-by-baseline FeNO value interaction as covariates. 
Baseline FeNO value, baseline 
eosinophil value, treatment-by-
baseline FeNO value interaction, 
and treatment-by- baseline 
eosinophil value interaction 
 
MMRM with the treatment arm, baseline weight (≤30kg, >30kg), region, ethnicity, baseline ICS dose 
level (medium/high), visit, treatment by-visit interaction, baseline % predicted FEV1 value and 
baseline % predicted FEV1 value -by-visit interaction, baseline eosinophil value, baseline FeNO 
value, treatment-by- baseline eosinophil value interaction, and treatment-by-baseline FeNO value 
interaction as covariates. 
Slope analysis of post-bronchodilator % predicted FEV1 
For post-bronchodilator % predicted FEV1, the rate of change in post-bronchodilator % predicted 
FEV1% (termed as % predicted FEV1 slope) will be compared between dupilumab and placebo in 
the Type 2 inflammatory asthma phenotype population and baseline blood eosinophils  
≥0.3 Giga/L population. Change from baseline in post-bronchodilator % predicted FEV1 after 
Week 4 and after Week 8 will be analyzed correspondingly using linear mixed-effects model with 
treatment, baseline weight, region, ethnicity, baseline eosinophil level, baseline FeNO level, 
baseline ICS dose level, time since randomization, and treatment-by-time interaction, baseline 
post-bronchodilator % predicted FEV1 value as covariates in the Type 2 inflammatory asthma 
phenotype population; when performing the slope analysis in the baseline blood eosinophils  
≥0.3 Giga/L population, the baseline eosinophil level will be removed from the model covariates 
Intercept and time since randomization will be treated as random effects in this mixed-effects 
model.  
2.4.4.3 Analyses of secondary efficacy endpoints 
2.4.4.3.1 Change from baseline for continuous endpoints 
Change from baseline in ACQ-7-IA Week 24 will be analyzed using MMRM model 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. Change from baseline in FeNO at Week 12 will be 
analyzed using MMRM including change from baseline up to Week 12 as response variables, 
regardless if the patient is on treatment or not when the endpoint is measured. The analyses for the 
secondary endpoints of ACQ-7-IA and FeNO will be performed in the Type 2 inflammatory 
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asthma phenotype, baseline blood eosinophils ≥0.3 Giga/L, baseline blood eosinophils 
≥0.15 Giga/L, baseline FeNO ≥20 ppb and full ITT populations. When performing these analyses 
in the Type 2 inflammatory asthma phenotype, baseline blood eosinophils ≥0.15 Giga/L or full 
ITT population, the MMRM models will include treatment, age, baseline weight, region (pooled 
country), baseline eosinophil level, baseline FeNO level, baseline ICS dose level, visit, treatment 
by-visit interaction, baseline endpoint value, and baseline-by-visit interaction as covariates. When 
performing these analyses in the baseline blood eosinophils ≥0.3 Giga/L population, the baseline 
eosinophil level will be removed from the model covariates. When performing these analyses in 
the baseline FeNO ≥20 ppb population, the baseline FeNO level will be removed from the model 
covariates. An MMRM model including measurements up to Week 52 will also be used to derive 
LS mean change at all time-points in the Type 2 inflammatory asthma phenotype and baseline 
blood eosinophils ≥0.3 Giga/L populations, with including the same set of model covariates as 
specified for the secondary endpoint analyses. Differences in LS means, the corresponding 95% CI 
and the p-value will be provided for comparison between dupilumab and placebo along with 
descriptive statistics. 
In the Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L 
populations, change from baseline for other continuous endpoints at all time-points will be 
analyzed using MMRM model including measurements up to Week 52. The model will include 
change from baseline of these endpoints from all available planned time points up to Week 52 as 
response variables, regardless if the patient is on treatment or not when the endpoint is measured. 
When performing these analyses in the Type 2 inflammatory asthma phenotype population, 
treatment, age, baseline weight, region (pooled country), baseline eosinophil level, baseline FeNO 
level, baseline ICS dose level, visit, treatment by-visit interaction, baseline endpoint value and 
baseline-by-visit interaction will be the model covariates. When performing these analyses in the 
baseline blood eosinophils ≥0.3 Giga/L population, the baseline eosinophil level will be removed 
from the model covariates. Ethnicity will be included as the covariate only in the models for 
spirometry parameters, specifically. Differences in LS means, the corresponding 95% CI and the 
p-value will be provided for comparison between dupilumab and placebo along with descriptive 
statistics. 
In addition to the MMRM analyses for change from baseline in ACQ-7, ACQ-5, and AQLQ total 
score a responder analysis will also be performed for these endpoints at Week 12, 24, 36 and 52, 
in the Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L 
populations. For ACQ-7 score, a logistic regression model will be used to compare percentage of 
patients who reached MCID (responders) in dupilumab and placebo group at the time points 
aforementioned correspondingly. Patients with change from baseline in ACQ-7 ≤ -0.5 will be 
considered as responders. Patients with change from baseline in ACQ-7 > -0.5 or with missing 
value will be considered as non-responders. When performing the analyses in the Type 2 
inflammatory asthma phenotype population, the logistic model will include treatment, age, 
baseline weight, region (pooled country), baseline eosinophil level, baseline FeNO level, baseline 
ICS dose level, and baseline ACQ-7 score as covariates. When performing the analyses in the 
baseline blood eosinophils ≥0.3 Giga/L population, the baseline eosinophil level will be removed 
from the model covariates. Odds ratio of being a responder comparing dupilumab and placebo 
group will be provided along with the corresponding 95% CI and p-value. Descriptive statistics 
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including number and percentage of responders will also be provided. Responder analysis for 
ACQ-5 and AQLQ global score will be performed in the same way. For ACQ-5, a patient is 
considered as a responder if change from baseline in ACQ-5 score ≤ -0.5, or as a nonresponder if 
change from baseline in ACQ-5 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. 
2.4.4.3.2 Time to event variables 
A Cox regression model and Kaplan-Meier method will be used to assess treatment differences in 
time to events (defined in Section 2.1.3.2) in the Type 2 inflammatory asthma phenotype and 
baseline blood eosinophils ≥0.3 Giga/L populations. 
When performing the time-to-event analyses in the Type 2 inflammatory asthma phenotype 
population, the model will include the time to the first event as the dependent variable, and 
treatment groups, age, baseline weight (≤30kg, >30kg), region, baseline eosinophil level, baseline 
FeNO level, baseline ICS dose level and number of severe exacerbation events within 1 year prior 
to the study as covariates. When performing the time-to-event analyses in the baseline blood 
eosinophils ≥0.3 Giga/L population, the baseline eosinophil level will be removed from the model 
covariates. Hazard ratio will be estimated for the comparison between dupilumab and 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 weight eosblgpn eosblgpn1 fenoblgpn ics trt01pn cntygr1n /param=GLM; 
model aval*CNSR(1) =trt01pn weight age eosblgpn1 fenoblgpn ics cntygr1n asmanum; 
contrast ‘dupilumab vs Placebo rate ratio’ trt01pn –1 1  
run; 
For these secondary endpoints, the primary estimand and details about the intercurrent events 
strategy and missing data handling are presented in  
Table 8 as below. Additional secondary objectives/endpoints are not included in this table but 
would be handled with a similar strategy as the endpoint type (ie, count, continuous, proportion, 
time-to-event). 
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Table 8 - Summary of primary estimand for secondary endpoints 
 
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
strategy and missing data 
handling 
Population-level summary 
 
Primary objective: The primary objective is to evaluate the efficacy of dupilumab in children 6 to <12 years of age with uncontrolled 
persistent asthma 
Secondary 
endpoint 
(treatment 
policy) 
Time to first 
severe 
exacerbation 
event during 
52-week 
treatment 
period 
Type 2 
inflammation 
phenotype; 
 
Patients with 
baseline 
blood 
eosinophils  
≥0.3 Giga/L 
population 
 
 
The intercurrent events will be 
handled as follows: 
Discontinuation of study treatment 
before Week 52: Off-study treatment 
data up to Week 52 will be included 
in the analysis (treatment policy 
strategy). 
 
In addition, the missing data 
imputation rules are as follows: 
Discontinuing the study follow-up 
before Week 52: Analyses will be 
censored at the time of study 
discontinuation. 
In patients with Type 2 inflammatory 
asthma phenotype, this time-to-event 
endpoint will be analyzed using the Cox 
proportional hazards model, include the 
time to the first event as the dependent 
variable, and treatment groups, age, 
baseline weight, region, baseline 
eosinophil level, baseline FeNO level, 
baseline ICS dose level and number of 
severe exacerbation events within 1 
year prior to the study as covariates. 
The hazards ratio, its 95% confidence 
interval and p-value will be reported. 
 
Kaplan-Meier curves will be also 
provided. 
 
In patients with baseline blood 
eosinophils ≥0.3 Giga/L, the analysis 
will remain same as above except that 
the covariate of baseline eosinophil level 
will be removed. 
Secondary 
endpoint 
(treatment 
policy) 
Proportion of 
participants 
who reached 
MCID 
(responders) 
defined as 
change from 
baseline in 
ACQ-7 ≤ -
0.5 at Week 
12, 24, 36 or 
52. 
Type 2 
inflammation 
phenotype; 
 
Patients with 
baseline 
blood 
eosinophils 
≥0.3 Giga/L 
population 
 
The intercurrent events will be 
handled as follows: 
Discontinuation of study treatment 
before the visit to be analyzed: Off-
study treatment data wil be included 
in the analysis (treatment policy 
strategy). 
 
In addition, the missing data 
imputation rules are as follows: 
In addition, having missing data at 
the visit to be analyzed, patients will 
be considered as non-responders  
 
In patients with Type 2 inflammatory 
asthma phenotype, this endpoint will be 
analyzed using logistic regression with 
treatment, age, baseline 
weight, region (pooled country), 
baseline eosinophil level, baseline 
FeNO level, baseline ICS dose, level, 
and baseline ACQ-7 score as 
covariates. The number (n) and 
percentage (%) of responders of each 
arm, odds ratio between treatment and 
placebo arms, 95% confidence internal 
and P value will be reported. 
 
In patients with baseline blood 
eosinophils ≥0.3 Giga/L, the analysis 
will remain same as above except that 
the covariate of baseline eosinophil level 
will be removed. 
 
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2.4.4.4 Multiplicity issues 
To control the type-I error rate for the analysis of efficacy endpoint, 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 2-sided 5% level.  
To match the approved indication in adults and adolescents, for the US and US reference 
countries, the testing hierarchy will start with baseline blood eosinophils ≥0.3 Giga/L population. 
For EU and EU reference countries, the testing hierarchy will start with Type 2 inflammatory 
asthma phenotype population. The complete list of the endpoints with their testing order is 
specified in Table 9 (For US and US reference countries) and Table 10 (for EU and EU reference 
countries). 
For US and US reference countries: 
Table 9 - Hierarchical testing order for US and US reference countries: 
Endpoints 
Population 
Test 
Order 
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
1st  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
2nd  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
3rd  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
4th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
5th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
6th  
Change in ACQ-7-IA at Week 24 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
7th  
Change in ACQ-7-IA at Week 24 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
8th  
Change in ACQ-7-IA at Week 24 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
9th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Baseline FeNO ≥20 ppb 
10th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12 
Baseline FeNO ≥20 ppb 
11th  
Change in ACQ-7-IA at Week 24 
Baseline FeNO ≥20 ppb 
12th  
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Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Full ITT 
13th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Full ITT 
14th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.3 Giga/L and 
High ICS at baseline 
15th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.15 Giga/L and 
High ICS at baseline 
16th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) with 
High ICS at baseline 
17th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Baseline FeNO ≥20 ppb with High ICS at baseline 
18th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Full ITT with High ICS at baseline 
19th  
Change from baseline in FeNO at Week 12 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
20th  
Change from baseline in FeNO at Week 12 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
21st  
Change from baseline in FeNO at Week 12 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
22nd  
Change from baseline in FeNO at Week 12 
Baseline FeNO ≥20 ppb 
23rd  
Change from baseline in FeNO at Week 12 
Full ITT 
24th  
For EU and EU reference countries:  
Table 10 - Hierarchical testing order for EU and EU reference countries 
Endpoints 
Population 
Test 
Order 
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
1st  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
2nd  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
3rd  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
4th  
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Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
5th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
6th  
Change in ACQ-7-IA at Week 24 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
7th  
Change in ACQ-7-IA at Week 24 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
8th  
Change in ACQ-7-IA at Week 24 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
9th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Baseline FeNO ≥20 ppb 
10th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12 
Baseline FeNO ≥20 ppb 
11th  
Change in ACQ-7-IA at Week 24 
Baseline FeNO ≥20 ppb 
12th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Full ITT 
13th  
Change from baseline in pre-bronchodilator % predicted 
FEV1 at Week 12. 
Full ITT 
14th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) with 
High ICS at baseline  
15th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.15 Giga/L and 
High ICS at baseline 
16th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Patients with baseline blood eosinophils ≥0.3 Giga/L and 
High ICS at baseline 
17th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Baseline FeNO ≥20 ppb and High ICS at baseline 
18th  
Annualized rate of severe exacerbation events during 
the 52-week placebo-controlled treatment period 
Full ITT and High ICS at baseline 
19th  
Change from baseline in FeNO at Week 12 
Type 2 inflammatory asthma phenotype (Baseline blood 
eosinophils ≥0.15 Giga/L or Baseline FeNO ≥20 ppb) 
20th  
Change from baseline in FeNO at Week 12 
Patients with baseline blood eosinophils ≥0.15 Giga/L 
21st  
Change from baseline in FeNO at Week 12 
Patients with baseline blood eosinophils ≥0.3 Giga/L 
22nd  
Change from baseline in FeNO at Week 12 
Baseline FeNO ≥20 ppb 
23rd  
Change from baseline in FeNO at Week 12 
Full ITT 
24th  
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2.4.4.5 Additional efficacy analysis(es) 
2.4.4.5.1 Analysis of additional PROs 
Change from baseline in additional PRO endpoints listed in Section 2.1.3.5 will be analyzed using 
the same MMRM model for the key secondary endpoint analysis as described in Section 2.4.4.2.1 
in the Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L 
populations defined in Section 2.3.1. Differences in LS means, the corresponding 95% CI and the 
p-value will be provided for comparison between dupilumab and placebo along with descriptive 
statistics. 
2.4.4.5.2 Analysis of systemic corticosteroid (SCS)  
SCS exposure in the dupilumab versus placebo exposed groups will be evaluated by total SCS 
intake in days, number of courses of SCS, and time to first SCS use. This will be evaluated in the 
population with the Type 2 inflammatory asthma phenotype and the population with baseline 
blood eosinophils >/= 0.3 Giga/L. Total SCS intake in days, and number of courses during the 
treatment period, will be summarized by treatment groups of Dupilumab and placebo with the 
treatment duration defined as in Section 2.4.4.1. A course of SCS is considered continuous if 
treatment is separated by less than 7 days.  
For patients who discontinue treatment, data collected during the off- treatment period will also be 
used. 
Descriptive statistics including number of subjects, mean, standard deviation, min, and max will 
be provided together with annualized number of courses or annualized total dose. The annualized 
number of courses of SCS intake during the treatment period will be analyzed using a negative 
binomial regression model. The model will include the number of courses of SCS intake during 
the treatment period as the response variable, and same set of covariates as defined in 
Section 2.4.4.1. 
Time to the first use of SCS during the 52-week placebo-controlled treatment period will be 
analyzed as time to event variable using same method as stated in Section 2.4.4.3.2 in both the 
Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L population. 
2.4.4.5.3 Annualized rate of Loss of asthma control (LOAC) 
 
 If a patient stays in the study until the end of the 52-week treatment period, all LOAC events that 
happen up to Week 52 visit will be included in the analysis, regardless whether the patient is on-
treatment or not, and the observation duration is defined as from randomization to Week 52 visit. 
If a patient withdraws from the study prior to the end of the 52-week treatment period, all 
observed LOAC 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. Patients who 
prematurely discontinue treatment will have off-treatment measurements included in the analysis 
up to either Week 52 or study withdrawal, whichever comes earlier. 
 
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The annualized rate of LOAC events will be analyzed using negative binomial regression model in 
the Type 2 inflammatory asthma phenotype and baseline blood eosinophils ≥0.3 Giga/L 
populations. This model includes the total number of events that occur during the observation 
period defined above as the response variable, with the treatment arm, age, baseline weight 
(≤30kg, >30kg), region, baseline eosinophil level (<0.3 Giga/L, ≥0.3 Giga/L), baseline FeNO level 
(<20 ppb, ≥20 ppb), baseline ICS dose level (medium/high) and number of severe exacerbation 
events within 1 year prior to the study as covariates. When performing the analysis in the baseline 
blood eosinophils ≥0.3 Giga/L population, the baseline eosinophil level will be removed from the 
model covariates. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group actually received.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2.  
• Analysis of TEAE as defined in Section 2.4.5.1 
- 
Analysis of all treatment-emergent adverse events 
- 
Analysis of all treatment-emergent serious adverse event(s) 
- 
Analysis of all treatment-emergent adverse event(s) leading to permanent treatment 
discontinuation or drug interruption 
- 
Analysis of adverse events of special interest (AESI) and other selected AE 
groupings 
- 
Death 
• Change in blood eosinophil as defined in Section 2.4.5.3 
Unless otherwise specified, following common rules will be applied: 
• The baseline value is defined as the last available value before the first dose of IMP 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG for this age group (PCSA version dated May 2014 
[Appendix A]) 
• PCSA criteria will determine which patients had at least 1 PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including nonscheduled or repeated evaluations.  
The number of all such patients will be the numerator for the on-treatment PCSA 
percentage 
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. Number (%) of patients 
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with at least 1 PCSA will be summarized regardless of baseline PCSA status and also by 
baseline PCSA status 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the endpoint value and/or the worst on-
treatment value.  The endpoint value is commonly defined as the value collected at the end 
of treatment.  If this value is missing, this endpoint value will be the closest value prior to 
the end of treatment epoch.  The worst value is defined as the nadir and /or the peak post-
baseline (up to the end of treatment epoch or EOT) according to the direction (minimum or 
maximum) of the abnormality as defined in the PCSA list 
• 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned  
• 
All safety values including unscheduled measurements will be assigned to the appropriate 
safety analysis visit window defined in Section 2.5.4 
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. 
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 group. 
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• Overview of treatment-emergent adverse events, summarizing number (%) of patients with 
any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
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- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
• Overview of exposure adjusted incidence rate of treatment-emergent adverse events, 
summarizing number of patients with an event per 100 patient years with any: 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
• All treatment-emergent adverse 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  
• All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the SOC 
internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
• Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT  
• All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC.  
• Exposure adjusted incidence rate of all treatment-emergent adverse events by primary SOC 
and PT, showing the number of patients with at least 1 treatment-emergent adverse event 
per 100 patient-years 
• All treatment-emergent adverse events regardless of relationship and related by primary 
SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 1 treatment-
emergent adverse event, sorted by the internationally agreed SOC order.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order 
• All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC  
• 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 
• Incidence rate of all common TEAEs (PT >= 2%) with >= 1% higher incidence in one of 
the groups compared to any other by primary SOC and PT. The relative risk ratio of 
qualifying TEAEs along its 95% confidence interval will be presented. 
• A listing of all treatment-emergent adverse events will be presented 
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Analysis of all treatment-emergent serious adverse event(s) 
• All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order 
• All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order 
• All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 treatment-emergent serious adverse event, sorted by 
the internationally agreed SOC order and by decreasing incidence of PTs within each SOC   
• Exposure adjusted incidence rate of serious treatment-emergent adverse events by primary 
SOC and PT, showing the number of patients with at least 1 serious treatment-emergent 
adverse event per 100 patient-years 
• 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 
• 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 
• 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 
• Exposure adjusted incidence rate of treatment-emergent adverse events leading to 
permanent treatment discontinuation by primary SOC and PT, showing the number of 
patients with at least 1 treatment-emergent adverse event leading to permanent treatment 
discontinuation per 100 patient-years  
Analysis of adverse events of special interest (AESI) and other selected AE groupings 
• All treatment-emergent adverse events, by selected standardized MedDRA query (SMQ) 
and PT or by laboratory values (as in ALT elevation), showing the number (%) of patients 
with at least 1 PT, sorted by decreasing incidence of PTs within each SMQ 
• For each AESI,  
- 
Number (%) of patients with any specific treatment emergent AESI  
- 
Number (%) of patients with any specific serious AESI (regardless of treatment 
emergent status) 
- 
Number (%) of patients with any specific treatment emergent serious AESI 
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- 
Number (%) of patients with any specific AESI leading to death 
- 
Number (%) of patients with any specific treatment emergent AESI leading to 
permanent study drug discontinuation 
- 
Number (%) of patients with any specific treatment emergent AESI by maximum 
intensity, corrective treatment, and final outcome 
- 
Number of specific treatment emergent AESI adjusted by the exposure duration 
- 
Number of patients with any specific treatment emergent AESI adjusted by the 
exposure duration 
• 
Number of patients with any specific treatment emergent AESI adjusted by the exposure 
duration at risk. For each AESI, Kaplan-Meier estimates of cumulative incidence at  
Week 12, 24, 36 and 52 and K-M plot may be provided to depict the course of onset over 
time if the number of events is large enough 
• 
Number (%) of patients with injection site reactions by the related injection 
• 
Number (%) of patients with different number of injection site reactions 
Analysis of pretreatment adverse events  
• All pretreatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC 
• All serious pretreatment adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 pretreatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC 
• All pretreatment adverse events leading to permanent treatment discontinuation by primary 
SOC and PT, showing the number (%) of patients, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs within each SOC 
• All pretreatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
If only a few patients have pretreatment adverse events leading to permanent treatment 
discontinuation, a listing will be presented instead of the summary table above. 
Subgroup analysis for adverse events 
Analysis of adverse events will be performed for below subgroups of interest based on safety 
population: 
• 
Race (Caucasian/White, Black/of African descent, Asian/Oriental, all the other). 
• 
Sex (Female, Male) 
• 
Ethnicity (Hispanic, Not Hispanic) 
• 
Baseline weight group (≤30, >30 kg) 
• 
Baseline ICS level (Medium, High) 
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The subgroup analysis of adverse events includes: 
• 
Overview of treatment emergent AE 
• 
Treatment emergent AE by primary SOC and PT 
• 
Treatment emergent SAE by primary SOC and PT 
• 
Treatment emergent AE leading to permanent treatment discontinuation by primary SOC 
and PT 
• 
AESI by category 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the safety population. 
• Number (%) of patients who died by study period (on-study, on-treatment, poststudy)  
• Deaths in nonrandomized patients or randomized but not treated patients 
• Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC  
• All pretreatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC 
A listing of deaths will be provided. 
2.4.5.3 Analyses of laboratory variables  
The analyses of laboratory data will be performed in the safety population. The summary statistics 
(including number, mean, median, Q1, Q3, standard deviation, minimum and maximum) of all 
laboratory variables (central laboratory values and changes from baseline) will be calculated for 
each visit or study assessment (baseline, each postbaseline time point, last on-treatment and/or 
worst on-treatment value) by treatment group.  For each continuous parameters listed in  
Section 2.1.4.3, mean changes from baseline with the corresponding standard error will be plotted 
over time in each treatment group. This section will be organized by biological function as 
specified in Section 2.1.4.3. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
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For PCSA analyses, the laboratory measurements obtained at either scheduled or unscheduled 
visits should be used; and, both the centralized and local test results should be used, as long as 
their available dates/time is different from each other’s. Centralized data will be used 
preferentially to the local measures in the PCSA analyses when measurements are performed on 
the same date and at the same time for a given laboratory test. 
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 
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 and median 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). 
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2.4.5.4 Analyses of vital sign variables 
The analyses of vital sign data will be performed in the safety population. 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:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
2.4.5.5 Analyses of electrocardiogram variables 
The analyses of electrocardiogram (ECG) data will be performed in the safety population. The 
summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum and 
maximum) of all ECG variables (values and changes from baseline) will be calculated for each 
visit or study assessment (baseline, V28 (EOT) and V31(EOS) and ETD, last on-treatment and/or 
worst on-treatment value) by treatment group.  
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment group irrespective of the baseline level and/or according to the following 
baseline status categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
2.4.6 Analyses of pharmacokinetic, immunogenicity, and pharmacodynamic variables 
The PK/ADA analyses will be based on the PK/ADA population as defined in Section 2.3.3. 
2.4.6.1.1 Analyses of serum concentrations of SAR231893 (REGN668) 
Serum concentrations of SAR231893 (REGN668) will be summarized using arithmetic and 
geometric means, SD, standard error of the mean (SEM), coefficient of variation (CV), minimum, 
median and maximum per sampling time by each dose regimen group and overall treatment group. 
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, 
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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 by each dose regimen group and overall treatment group: 
• 
Number (%) of patients negative in ADA assay at all times 
• 
Number (%) of patients with pre-existing ADA 
• 
Number (%) of patients with treatment-emergent ADA 
• 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for patients with treatment-emergent ADA, and patients with 
persistent, indeterminate and transient ADA response 
• 
Number (%) of patient with transient treatment-emergent ADA  
• 
Number (%) of patients with persistent treatment-emergent ADA 
• 
Number (%) of patients with indeterminate treatment-emergent ADA 
• 
Number (%) of patients with treatment-boosted ADA. 
• 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) of 
the peak post-baseline titer for  patients with treatment-boosted ADA 
• 
The summary statistics (including number, mean, SD, median, Q1, Q3, minimum and 
maximum) of the ratio of peak post-baseline titer to baseline titer for patients with 
treatment-boosted ADA 
• 
Listing of ADA peak titer levels and neutralizing antibody status (y/n) for the positive 
ADA samples 
• 
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 and overall treatment group. 
Plot of percentage of patients with ADA treatment-emergent ADA positive response at each visit 
will be provided by each dose regimen group and overall treatment group. 
 
Impact of ADA on PK  
Associations between ADA variables (eg, ADA peak titers, neutralizing antibody status, 
treatment-emergent, persistent, indeterminate and transient response, treatment-boosted) and 
serum concentration of dupilumab may be explored for each dupilumab dose group. Plot of serum 
concentration of functional SAR231893 (REGN668) versus visit will be provided by ADA 
classifications for each dupilumab dose group. 
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Impact of ADA on clinical efficacy 
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: 
• 
Annualized rate of severe exacerbation events 
• 
Change from baseline in % predicted Pre-BD FEV1 
 
Impact of ADA on clinical safety 
Association of safety versus ADA status may be analyzed in the ADA population. The safety 
assessment may focus on the following events: 
• 
Severe injection site reactions last longer than 24 hours or serious injection site reactions 
• 
Hypersensitivity reactions (SMQ hypersensitivity narrow search and confirmed by medical 
review) 
• 
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 2.1.7 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.  
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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.
 
2.4.7 Analyses of vaccine response 
For patients who receive vaccination, vaccine IgG titers in serum prior and after vaccination will 
be summarized by treatment groups with descriptive statistics by treatment group and vaccine 
types. 
Number of patients who receive vaccination and number of patients who are eligible to receive 
vaccination and the type of vaccination received will also be summarized by 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 Outcomes Research (HEOR) department of Sanofi. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
Age is calculated as: 
Integer part of (informed consent date -birth date)/365.25 
Age of onset of 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 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) 
 
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Renal function formulas  
For patients ≥6 and <12 years old, CLcr value will be derived using the equation of GFR Bedside 
Schwartz  
GFR (mL/min/1.73 m2) = k  height (cm) / sCr (mg/dL), 
where the coefficient k=0.55. 
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 11. Randomization day is used as the reference day 
(Day 1). 
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2.5.3 Missing data handling for safety analysis 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the 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. 
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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. 
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.   
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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 12 for the by visit descriptive analysis. All available 
values from central lab will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. For procedures planned on Visit 2, if it is done on the same date as the first IMP 
injection but the performance time is missing, it will belong to Visit 2 time window. 
Table 12 - Time window for safety endpoints 
 
Target 
Day 
 
Time windows for 
Visit 
Vital 
signs 
ECG 
endpoints 
Clinical 
lab 
testing 
(serum) 
Urinalysis 
Urine 
Pregnancy 
test 
Serum 
immunoglobulins 
Hepatitis 
screen, 
HIV 
screen, 
ANA and 
Anti-ds 
DNA 
antibogy 
Visit 1 
(Week -4±1) 
-28±7 
<-14 
1- 
<-14 
1- 
<-14 
1- 
1- 
Visit 2 
(Week 0) 
1 
-14-1- 
 
-14-1- 
 
-14-1- 
 
 
Visit 3 
(Week 2) 
15 
1+-21 
 
 
 
 
 
 
Visit 4 
(Week 4) 
29 
22-35 
 
 
 
1+-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 
 
1+-126 
1+-126 
71-98 
 
 
Visit 10 
(Week 16) 
113 
99-126 
 
 
 
99-126 
 
 
Visit 12 
(Week 20) 
141 
127-154 
 
 
 
127-154 
 
 
Visit 14 
(Week 24) 
169 
155-182 
 
127-210 
127-210 
155-182 
1+-266 
 
Visit 16 
(Week 28) 
197 
183-210 
 
 
 
183-210 
 
 
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Target 
Day 
 
Time windows for 
Visit 
Vital 
signs 
ECG 
endpoints 
Clinical 
lab 
testing 
(serum) 
Urinalysis 
Urine 
Pregnancy 
test 
Serum 
immunoglobulins 
Hepatitis 
screen, 
HIV 
screen, 
ANA and 
Anti-ds 
DNA 
antibogy 
Visit 18 
(Week 32) 
225 
211-238 
 
 
 
211-238 
 
 
Visit 20 
(Week 36) 
253 
239-266 
 
211-308 
211-308 
239-266 
 
 
Visit 22 
(Week 40) 
281 
267-294 
 
 
 
267-294 
 
 
Visit 24 
(Week 44) 
309 
295-322 
 
 
 
295-322 
 
 
Visit 26 
(Week 48) 
337 
323-350 
 
 
 
323-350 
 
 
Visit 28 
(Week 52) 
365 
351-378 
1+-406 
309-406 
309-406 
351-378 
267-406 
 
Visit 29 
(Week 56) 
393 
379-406 
 
 
 
379-406 
 
 
Visit 30 
(Week 60) 
421 
407-434 
 
 
 
407-434 
 
 
Visit 31 
(Week 64) 
449 
>434- 
>406 
>406 
>406 
>434- 
>406 
 
 
1-: up to 1st dose date/time; 1+: after 1st dose date/time; 
 
For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the randomization day. If a patient receives IMP prior to the randomization by 
mistake, the reference date of efficacy assessment will be the date of the first IMP administration 
for that patient. For the primary analyses, all available values of scheduled measurements will be 
assigned to the appropriate visit window according to Table 13. 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.  
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Table 13 - Time window for efficacy variables 
Visit 
Target 
Day 
Time windows for  
 
 
 
Pre-bronchodilator 
Spirometry, ACQ-IA  
Post-
bronchodilator 
spirometry 
PAQLQ(S)-IA, 
PACQLQ(S)-IA 
PRQLQ-IA 
EQ-5D-Y 
Visit 1 (Week -
4±1) 
-28±7 
<-14 
 
 
 
Visit 2 (Week 0) 
1 
-14-1- 
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 10 (Week 16) 
113 
99-126 
 
 
 
Visit 12 (Week 20) 
141 
127-154 
 
 
 
Visit 14 (Week 24) 
169 
155-182 
127-210 
127-210 
1+-266 
Visit 16 (Week 28) 
197 
183-210 
 
 
 
Visit 18 (Week 32) 
225 
211-238 
 
 
 
Visit 20 (Week 36) 
253 
239-266 
211-308 
211-308 
 
Visit 22 (Week 40) 
281 
267-294 
 
 
 
Visit 24 (Week 44) 
309 
295-322 
 
 
 
Visit 26 (Week 48) 
337 
323-350 
 
 
 
Visit 28 (Week 52) 
365 
351-378(spirometry) 
351-406(ACQ-IA) 
309-406 
309-406 
267-406 
Visit 29 (Week 56) 
393 
379-406(spirometry only) 
 
 
 
Visit 30 (Week 60) 
421 
407-434(spirometry only) 
 
 
 
Visit 31 (Week 64) 
449 
>434(spirometry) 
>406(ACQ-IA)  
>406 
>406 
>406 
1-: up to randomization and before 1st dose date/time; 1+: after randomization or 1st dose date/time   
 
For the pharmacokinetics, immunogenicity, and 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 14 for the by visit descriptive analyses. All available values of 
measurements will be assigned to the appropriate visit window. In the event of multiple 
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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 14 - Time window for pharmacokinetics/pharmacodynamics variables 
 
 
Time windows for 
Visit 
Target 
day 
TARC 
Exhaled 
NO 
Systemic 
drug 
concentration 
Anti-drug 
antibodies 
Total 
IgE/Antigen-
specific 
IgE/IgG 4 
panel 
Visit 1 (Week -4±1) 
-28±7 
 
 
 
 
 
Visit 2 (Week 0) 
1 
1- 
1- 
1- 
1- 
1- 
Visit 3 (Week 2) 
15 
 
1+-21 
 
 
 
Visit 4 (Week 4) 
29 
 
22-35 
 
 
 
Visit 5 (Week 6) 
43 
 
36-49 
1+-63 
 
 
Visit 6 (Week 8) 
57 
 
50-63 
 
 
 
Visit 7 (Week 10) 
71 
 
64-77 
 
 
 
Visit 8 (Week 12) 
85 
1+-126 
78-98 
64-126 
1+-126 
 
Visit 10 (Week 16) 
113 
 
99-126 
 
 
 
Visit 12 (Week 20) 
141 
 
127-154 
 
 
 
Visit 14 (Week 24) 
169 
127-266 
155-182 
127-266 
127-266 
1+-266 
Visit 16 (Week 28) 
197 
 
183-210 
 
 
 
Visit 18 (Week 32) 
225 
 
211-238 
 
 
 
Visit 20 (Week 36) 
253 
 
239-266 
 
 
 
Visit 22 (Week 40) 
281 
 
267-294 
 
 
 
Visit 24 (Week 44) 
309 
 
295-322 
 
 
 
Visit 26 (Week 48) 
337 
 
323-350 
 
 
 
Visit 28 (Week 52) 
365 
267-406 
351-378 
267-406 
267-406 
>267 
Visit 29 (Week 56) 
393 
 
379-406 
 
 
 
Visit 30 (Week 60) 
421 
 
407-434 
 
 
 
Visit 31 (Week 64) 
449 
>406 
>434 
>406 
>406 
 
1-: up to 1st dose date/time or randomization if patient is not treated; 1+: after 1st dose date/time or randomization date if patient is 
not treated; 
 
 
 
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2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will not be included in 
the by-visit summaries, but will be used for computation of baseline, worst value 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: 
• 
East Europe: Poland, Hungary, Romania, Lithuania, Turkey, Russia and Ukraine 
• 
Western Countries: Australia, Canada, Italy, South Africa, Spain, and USA  
• 
Latin America: Argentina, Brazil, Colombia, Chile and Mexico  
2.5.7 Statistical technical issues 
All statistical technical issues have been described in each associated sections.  
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3 
INTERIM ANALYSIS 
No interim analysis is planned. 
 
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4 
DATABASE LOCK 
The database lock is planned based on the time when all randomized patients 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. In reality, because all patients have completed the follow-up visits shortly after the 
Week 52 visit of the last patient, the originally planned two DBLs will be integrated into one 
single final DBL. In this case, there will be one clinical study report, which will summarize all the 
data in the integrated DBL, instead of the originally planned one CSR plus one CSR addendum. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
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6 
REFERENCES 
1. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, 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;26:319-38. 
2. Juniper E. Asthma control questionnaire: Background, administration and analysis. 2012; 
QOL Technologies, West Sussex, UK. 
3. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference 
values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur 
Respir J. 2012;40:1324-43. 
4. 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. 
 
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7 
LIST OF APPENDICES 
 
Appendix A 
Potentially clinically significant abnormalities criteria (BTD-009536 Version 3.0 
21-MAY-2014) 
 
Appendix B 
List of commonly used asthma controller therapies 
 
Appendix C 
Low, medium and high dose inhaled corticosteroids- Children  
(6-11 years) 
 
Appendix D 
Handling of missing data 
 
Appendix E 
Asthma Control Questionnaire-Interviewer Administered (ACQ-IA) for Children 
6 to <12 years 
 
Appendix F 
Asthma Symptom Score Numerical Rating Scale (NRS) 
 
Appendix G 
Paediatric Asthma Quality of Life Questionnaire With Standardised 
Activities(PAQLQ[S]) 
 
Appendix H 
EuroQual Questionnaire (EQ-5D-5Y) – for Children 
 
Appendix I 
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire–Interviewer 
Administered (PRQLQ-IA) – for Children with Comorbid Allergic Rhinitis 
 
Appendix J 
Pediatric Asthma Caregiver’s Quality of Life Questionnaire (PACQLQ) 
 
Appendix K 
Definition of Anaphylaxis 
 
Appendix L 
List of opportunistic infections 
 
Appendix M  
Summary of the planned analyses by population 
 
 
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Appendix A 
Potentially clinically significant abnormalities criteria (BTD-009536 Version 3.0 21-MAY-2014) 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
ECG parameters 
Ref. : Rijnbeek P.R. et al., Eur Heart J 2001; 
Davignon A. et al., Ped Cardiol 1979/1980; Semizel 
E.et al., Cardiol Young 2008; Mulberg AE et al. 
Pediatric Drug Development Concepts and 
applications. John Wiley & sons, Inc. 2009 
HR 
Birth/0 to 27 days old (Neonates) 
90 bpm and decrease from baseline 20 bpm 
190 bpm and increase from baseline 20 bpm 
 
28 days/1 month to 23 months old (Infants) 
80 bpm and decrease from baseline 20 bpm 
175 bpm and increase from baseline 20 bpm 
24 months/2 years to <6 years old (Children) 
75 bpm and decrease from baseline 20 bpm 
140 bpm and increase from baseline 20 bpm 
6 to <12 years old (Children) 
50 bpm and decrease from baseline 20 bpm 
120 bpm and increase from baseline 20 bpm 
12 to 16/18 years old (Adolescents) 
50 bpm and decrease from baseline 20 bpm  
120 bpm and increase from baseline 20 bpm  
PR 
Birth/0 to 27 days old (Neonates) 
120 ms 
 
28 days/1 month to 23 months old (Infants) 
140 ms 
24 months/2 years to <6 years old (Children) 
160 ms 
6 to <12 years old (Children) 
170 ms 
12 to 16/18 years old (Adolescents) 
180 ms 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
QRS 
Birth/0 to 27 days old (Neonates) 
85 ms 
 
28 days/1 month to 23 months old (Infants) 
85 ms 
2 to <6 years old (Children) 
95 ms 
6 to <12 years old (Children) 
100 ms 
12 to 16/18 years old (Adolescents) 
110 ms 
QTc  
Birth/0 to <12 years old  
(Neonates, Infants, Children) 
 
 
 
 
 
 
 
Absolute values (ms)  
Borderline: 431-450 ms  
Prolonged*: >450 ms  
Additional: ≥500 ms 
 
AND 
 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms 
To be applied to QTcF 
 
*QTc prolonged and QTc>60 ms are the PCSA to 
be identified in individual subjects/patients listings. 
 
12 to 16/18 years old (Adolescents) 
 
Borderline: 431-450 ms (Boys); 451-470 ms (Girls) 
Prolonged*: >450 ms (Boys); >470 ms (Girls) 
Additional: ≥500 ms 
 
AND 
 
Increase from baseline  
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms  
Vital Signs 
Ref. : Kidney Disease Outcomes Quality Initiatives 
(KDOQI) Guideline 13; 1996; The fourth report on the 
diagnosis, evaluation, and treatment of high blood 
pressure in children and adolescents, Pediatrics 
2004; Bowman E & Fraser S Neonatal Handbook 
2012;  Mulberg AE et al. Pediatric Drug Development 
Concepts and applications. John Wiley & sons, Inc. 
2009; Pediatric respiratory rates 
http://www.health.ny.gov/ 
SBP  
 
Birth/0 to 27 days old (Neonates) 
60 mmHg and decrease from baseline 20 mmHg  
85mHg and increase from baseline 20 mmHg 
Based on definition of Hypertension as 
average SBP or DBP ≥95th percentile for 
gender, age, and height on ≥3 occasions 
28 days/1 month to 23 months old (Infants) 
70 mmHg and decrease from baseline 20 mmHg  
98 mmHg and increase from baseline 20 mmHg 
24 months/2 years to <6 years old (Children) 
70 mmHg and decrease from baseline 20 mmHg  
101mHg and increase from baseline 20 mmHg 
6 to <12 years old (Children) 
80 mmHg and decrease from baseline 20 mmHg  
108 mmHg and increase from baseline 20 mmHg 
12 to 16/18 years old (Adolescents) 
90 mmHg and decrease from baseline 20 mmHg  
119mmHg and increase from baseline 20 mmHg 
DBP 
  
 
Birth/0 to 27 days old (Neonates) 
34 mmHg and decrease from baseline 10 mmHg  
50mHg and increase from baseline 10 mmHg 
 
28 days/1 month to 23 months old (Infants) 
34 mmHg and decrease from baseline 10 mmHg  
54mHg and increase from baseline 10 mmHg 
24 months/2 years to <6 years old (Children) 
34 mmHg and decrease from baseline 10 mmHg  
59mHg and increase from baseline 10 mmHg  
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
6 to <12 years old (Children) 
48 mmHg and decrease from baseline 10 mmHg  
72mHg and increase from baseline 10 mmHg  
12 to 16/18 years old (Adolescents) 
54 mmHg and decrease from baseline 10 mmHg  
78mHg and increase from baseline 10 mmHg  
Orthostatic 
hypotension 
All age ranges 
SBP : St — Su ≤ - 20 mmHg  
DBP : St — Su ≤ - 10 mmHg  
 
Temperature 
All age ranges 
Rectal, ear or temporal artery: >100.4 °F/38.0 °C 
Oral or pacifier: >99.5 °F/37.5 °C 
Axillary or skin infrared: >99 °F/37.2 °C 
Ear temperature not accurate below 6 months of age 
Respiratory rate 
Birth/0 to 27 days old (Neonates) 
<30 per minutes  
>60 per minutes 
Based on normal range 
 
28 days/1 month to 23 months old (Infants) 
<24 per minutes  
>40 per minutes 
24 months/2 years to <6 years old (Children) 
<22 per minutes  
>34 per minutes 
6 to <12 years old (Children) 
<18 per minutes  
>30 per minutes 
12 to 16/18 years old (Adolescents) 
<12 per minutes  
>20 per minutes 
Sa02 
All age ranges 
<95 % 
 
Weight 
All ranges 
>5 % weight loss from baseline 
 
Based on identification of trends in the child’s growth 
with a series of visits 
WHO Multicentre Reference Study Group, 2006; 
Center for Disease Control. Growth chart 2007 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Clinical Chemistry  
Ref Molleston JP et al. JPGN 2011; Moritz et al., 
Pediatrics 1999; Moritz et al., Pediatr Nephrol 2005 ; 
Sedlacek et al., Seminars in Dialysis 2006) Gong G 
et al. Clinical Biochemistry 2009; Masilamani et al. 
Arch Dis Children 2012; Mulberg AE et al. Pediatric 
Drug Development Concepts and applications. John 
Wiley & sons, Inc. 2009 
ALT/SGPT 
All age ranges 
>3 ULN 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Based on normal ranges: 6 to 50 U/L (0-5 days), 5 to 
45 U/L (1-19 years)  
AST/SGOT 
All age ranges 
>3 ULN 
By distribution analysis: 
>3 ULN    
>5 ULN   
>10 ULN  
>20 ULN 
Based on normal ranges: 35 to 140 U/L (0-5 days), 
15 to 55 U/L (1-9 years), 5 to 45 U/L (10-19 years) 
Alkaline Phosphatase 
All age ranges 
≥1.5 ULN 
Based on normal ranges: 145 to 420 U/L (1-9 years), 
130 to 560 U/L (10-11 years), 200 to 495 U/L (Boys 
12-13 years), 105 to 420 U/L (Girls 12-13 years), 130 
to 525 U/L (Boys 14-15 years), 70 to 130 U/L (Girls 
14-15 years), 65 to 260 U/L (Boys 16-19 years), 50 
to 130 U/L (Girls 16-19 years) 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Total Bilirubin 
All age ranges 
≥1.3 ULN 
CF = mg x 1.7 = µmol 
Based on normal ranges: <6 mg/dL (Term 0-1 day), 
<8 mg/dL (Term 1-2 days), <12 mg/dL (Term 3-5 
days), <1 mg/dL (Term >5 days) 
Conjugated Bilirubin 
All age ranges 
>35% Total Bilirubin and TBILI≥1.3 ULN 
CF = mg x 1.7 = µmol 
Based on normal range: 0 to 0.4 mg/dL  
ALT and Total 
Bilirubin 
All age ranges  
ALT ≥3 ULN and Total Bilirubin ≥2 ULN 
 
CPK 
All age ranges 
≥3 ULN 
 
Creatinine 
Birth/0 to <6 years old (Neonates, Infants, Children) 
>53 µmol/L or 0.6 mg/dL   
CF = mg x 8.8 = µmol 
Based on normal ranges: <0.6 mg/dL (0-1 year), 
0.5 to 1.5 mg/dL (1 to 16/18 years) 
6 years to <12 years old (Children) 
>90 µmol/L or 1.1mg/dL 
12 years to 16/18 years old (Adolescents) 
>132µmol/L or 1.5mg/dL 
Creatinine Clearance 
All age ranges 
50 % of normal  
<60 ml/min/1.73m2 (After 1 year old) 
Based on GFR Bedside Schwartz Formula 
Based on normal ranges: 20 to 50 (<8 days), 25 to 
80 (8 days to 1 month), 30 to 90 (1-6 months), 40 to 
115 (6-12 months), 60 to 190 (12-23 months), 90 to 
165 (2-12 years), 80-120 (After 12 years)  
Uric Acid  
All age ranges 
<2.0 mg/dL or 119 µmol/L 
>8.0 mg/dL or 476 µmol/L  
CF = mg x 5.95 = µmol 
Based on normal ranges: 2.4 to 6.4 mg/dL  
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Blood Urea Nitrogen 
(BUN) 
Birth/0 to 27 days old (Neonates) 
≥4.3 mmol/L or 12 mg/dl 
CF = g x 16.66 = mmol 
Based on normal ranges: 3 to 12 mg/dL (NN; 5 to 18 
mg/dL (other classes of age) 
28 days/1 month to 16/18 years old (Infants, Children, 
Adolescents) 
≥6.4 mmol/L or 18 mg/dl 
Chloride 
All age ranges 
≤80 mmol/L or 80 mEq/L 
≥115 mmol/L or 115 mEq/L 
CF = 1 
Based on normal range: 98 to 106 
Sodium 
All age ranges 
≤129 mmol/L or 129 mEq/L 
≥150 mmol/L or 150 mEq/L 
CF = 1 
Based on normal range : 134 to 146 
Potassium 
Birth/0 to 27 days old (Neonates) 
≤3.0 mmol/L or 3.0 mEq/L 
≥7.0 mmol/L or 7.0 mEq/L 
CF = 1 
Based on normal ranges: 3.0 to 7.0 (NN); 3.5 to 6.0 
(Infants); 3.5 to 5.0 (>Infants) 
28 days/1 month to 23 months old (Infants) 
≤3.5 mmol/L or 3.5 mEq/L 
≥6.0 mmol/L or 6.0 mEq/L 
24 months/2 years to 16/18 years old (Children, 
Adolescents) 
≤3.5 mmol/L or 3.5 mEq/L 
≥5.5 mmol/L or 5.5 mEq/L 
Bicarbonate 
All age ranges 
≤16 mmol/L or 16 mEq/L 
≥30 mmol/L or 30 mEq/L 
CF = 1 
Based on normal range: 18 to 26 
Calcium total 
All age ranges 
≤2.0 mmol/L or 8.0 mg/dL 
≥2.9 mmol/L or 11.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 8.4 to 10.9 mg/dL 
Calcium ionized 
All age ranges 
≤1.0 mmol/L or 4.0 mg/dL 
≥1.4 mmol/L or 5.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 4.0 to 5.1 mg/dL 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Total Cholesterol 
All age ranges  
>6.20 mmol/L or 240 mg/dL 
CF = g x 2.58 = mmol 
Based on normal ranges: 45 to 182 mg/dL  
(1-3 years), 109 to 189 mg/dL (4-6 years), 126 to  
191 mg/dL (Boys 6-9 years), 122 to 209 mg/dL  
(Girls 6-9 years), 130 to 204 mg/dL (Boys 10-14 
years), 124-217 mg/dL (Girls 10-14 years), 114 to 
198 mg/dL (Boys 15-19 years), 125 to 212 mg/dL 
(Girls 14-19 years) 
Triglycerides 
All age ranges 
>4.0 mmol/L or 350 mg/dL 
After >12 hours of fast) 
CF = g x 1.14 = mmol 
Based on normal ranges: 30 to 86 mg/dL  
(Boys 0-5 years), 32 to 99 mg/dL (Girls 0-5 years), 
31-108 mg/dL (Boys 6-11 years), 35 to 114 mg/dL 
(Girls 6-11 years), 36 to 138 mg/dL  
(Boys 12-15 years), 43 to 138 mg/dL  
(Girls 12-15 years), 40 to 163 mg/dL (Boys 16-19 
years), 40-128 mg/dL (Girls 16-19 years) 
Lipasemia 
All age ranges 
>2 ULN 
Based on normal ranges: 3 to32 U/L (1-18 years) 
Amylasemia 
All age ranges 
>2 ULN 
Based on normal ranges: 10 to 30 U/L (NN), 10 to 45 
U/L (1-18 years) 
Glucose 
All age ranges 
Hypoglycaemia <2.7 mmol/L or 50 mg/dL 
Hyperglycaemia >7 mmol/L or 120 mg/dL (fasted after 
>12 hours of fast); >10.0 mmol/L or 180 mg/dL 
(unfasted) 
CF = g x 5.55 = mmol 
Based on normal ranges: 50 to 90 mg/dL (NN), 60 to 
100 mg/dL (Child) 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
CRP 
All age ranges 
>2 ULN or 
>10 mg/L (if ULN not provided) 
Based on normal ranges: <6 mg/L 
Hematology 
Common Terminology Criteria for Adverse Events 
v3.0 (CTCAE), 2006 ; Division of Microbiology and 
Infections Diseases Pediatric Toxicity Tables, 2007 ; 
Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, 2004; Mulberg 
AE et al. Pediatric Drug Development Concepts and 
applications. John Wiley & sons, Inc. 2009; Family 
Practice Notebook, LLC, 2012; Tietz NW et al. 
Clinical Guide to Laboratory Testing, 3rd edition 1995 
WBC 
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L or 4,000 /mm3 
>25.0 GIGA/L or 25,000 /mm3 
To be used if no differential count available 
Based on normal ranges: 9,000 to 30,000 /mm3 
(birth), 9,400 to 38,000 /mm3 (0-1 day), 5,000 to 
21,000 /mm3 (1 day-1 month), 6,000 to 17,500 /mm3 
(1 month-2 years), 5,000 to 17,000 /mm3 (2-6 years), 
4,500 to 15,500 /mm3 (6-11 years), 4,500 to 13,500 
/mm3 (11-18 years) 
28 days/1 month to 23 months old (Infants) 
<4.0 GIGA/L or 4,000 /mm3 
>20.0 GIGA/L or 20,000 /mm3 
24 months/2 years to <6 years old (Children) 
<3.0 GIGA/L or 3,000 /mm3 
>16.0 GIGA/L or 16,000 /mm3 
6 to <12 years old (Children) 
<5.0 GIGA/L or 5,000 /mm3 
>17.0 GIGA/L or 17,000 /mm3 
12 to 16/18 years old (Adolescents) 
<4,5 GIGA/L or 5,000 /mm3 
>13.5 GIGA/L or 17,000 /mm3 
Lymphocytes (ALC) 
Birth/0 to 27 days old (Neonates) 
<1.2 GIGA/L or 1,200 /mm3 
>17.0 GIGA/L or 17,000 /mm3 
Based on normal ranges: 2,000 to 11,500 /mm3 (0-1 
days), 2,000 to 17,000 /mm3 (2 days-1 month), 3,000 
to 13,500 /mm3 (1 month-2 years), 1,500 to 9,500 
/mm3 (2-6 years), 1,500 to 8,000 /mm3 (6-10 years), 
1,200 to 5,200 /mm3 (10-18 years) 
28 days/1 month to 23 months old (Infants) 
<2.0 GIGA/L or 2,000 /mm3 
>13.5 GIGA/L or 13,500 /mm3 
24 months/2 years to <6 years old (Children) 
<1.0 GIGA/L or 1,000 /mm3 
>9.5 GIGA/L or 9,500 /mm3 
6 to <12 years old (Children) 
<1.0 GIGA/L or 1,000 /mm3 
>8.0 GIGA/L or 8,000 /mm3 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
12 to 16/18 years old (Adolescents) 
<0.6 GIGA/L or 600 /mm3 
>6.0 GIGA/L or 6,000 /mm3 
Absolute Neutrophil 
Count (ANC) 
Birth/0 to 27 days old (Neonates) 
<4.0 GIGA/L or 4,000 /mm3 (1 day old) 
<1.5 GIGA/L or 1,500 /mm3 (2-7 days old) 
<1.25 GIGA/L or 1,250 /mm3 (>7 day-1 month old) 
>1 ULN 
Based on normal ranges: 5,000 to 28,000 /mm3 (0-1 
day), 1,000 to 10,000 (1 day-1 month), 1,000 to 
8,500 (1-12 months), 1,500 to 8,500 (1 to 6 years), 
1,500 to 8,000 (6 to 10 years), 1;800 to 8,000 (10 to 
18 years)  
28 days/1 month to 23 months old (Infants) 
<1.0 GIGA/L or 1,000/mm3 (1-3 months) 
<1.2 GIGA/L or 1,200 /mm3 (3-24 months) 
>1 ULN 
24 months/2 years to <6 years old (Children) 
<1.2 GIGA/L or 1,200 /mm3 
>1 ULN 
6 to <12 years old (Children) 
<1.2 GIGA/L or 1,200 /mm3 
>1 ULN 
12 to 16/18 years old (Adolescents)  
<1.2 GIGA/L or 1,200 /mm3 
>1 ULN 
Eosinophils 
All age ranges 
>0.5 GIGA/L or 500 /mm3  
Or >ULN if ULN >0.5 GIGA/L or  
500 /mm3 
Based on normal ranges: 0 to 500 /mm3 (0-1 month), 
0 to 300 /mm3 (1 month-18 years) 
Hemoglobin 
Birth/0 to 27 days old (Neonates) 
<86 mmol/L or 12.0 g/dL or any decrease >0.31 
mmol/L or 2 g/dL 
CF = g x 1.55 = mmol 
Based on normal ranges: 15 to 20 g/dL (0-3 days), 
12.5 to 18.5 g/dL (1-2 weeks), 10.0 to 13.0 g/dL  
(1-6 months), 10.5 to 13.0 g/dL (7 months-2 years), 
11.5 to 13.0 g/dL (2-5 years), 11.5 to 14.5 (5-8 
years), 12.0 to 15.2 g/dL (13-18 years)   
28 days/1 month to 23 months old (Infants) 
<1.40 mmol/L or 9.0 g/dL or any decrease >0.31 
mmol/L or 2 g/dL 
24 months/2 years to <16/18 years old (Children, 
Adolescents) 
<1.55 mmol/L or10.0 g/dL or any decrease >0.31 
mmol/L or 2 g/dL 
Hematocrit 
Birth/0 to 27 days old (Neonates) 
<0.39 l/l or 40 % 
>0.61 l/l or 47 % 
CF = % x 0.01 = l/l 
Based on normal ranges: 45 to 61 % (0-3 days),  
39 to 57 % (1-2 weeks), 29 to 42 % (1-6 months), 33 
to 38 % (7 months-2 years), 34 to 39 % (2-5 years), 
35 to 42 % (5-8 years); 36 to 47 % (13-18 years) 
28 days/1 month to 23 months old (Infants) 
<0.29 l/l or 29 % 
>0.42 l/l or 42 % 
24 months/2 years to <16/18 years old (Adolescents) 
<0.32 l/l or 32 % 
>0.47 l/l or 47 % 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For Studies in Children 
Parameter 
Age range 
PCSA 
Comments 
Platelets 
All age ranges 
<100 GIGA/L or 100,000 /mm3 
>700 GIGA/L or 700,000 /mm3 
Based on normal ranges: 250,000 to 450,000 /mm3 
(NN); 300,000 to 700,000 /mm3 (1-6 months), 
250,000 to 600,00 /mm3 (7 months-2 years), 
250,000 to 550,000 /mm3 (2-12 years), 150,000 to 
450,000 /mm3 (13-18 years) 
Urinalysis 
Patel HP, Pediatr Clin N Am, 2006 
Ketonuria 
All age ranges 
Presence 
Semi-quantitative methods 
Glycosuria 
All age ranges 
Presence 
Semi-quantitative methods 
Hematuria 
All age ranges 
>1+ 
Semi-quantitative methods 
Proteinuria 
All age ranges 
>1+ 
Semi-quantitative methods 
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Appendix B 
List of commonly used asthma controller therapies 
 
ICS 
ICS/LABA 
LABA 
Anti-leukotrienes 
Long-acting 
muscarinic 
antagonist (LAMA) 
Methylanthines 
Beclomethasone dipropionate 
CFC 
Beclomethasone dipropionate 
HFA 
Budesonide DPI 
Budesonide HFA 
Budesonide nebules 
Ciclesonide HFA 
Flunisolide HFA 
Fluticasone propionate HFA 
Fluticasone propionate DPI 
Mometasone furoate 
Triamcinolone acetonide 
Fluticasone furoate 
Fluticasone Propionate 
/ Salmeterol 
 Fluticasone Propionate 
/ Formoterol 
 Fluticasone Furoate / 
Vilanterol 
Budesonide /Formoterol 
Mometasone Furoate / 
Formoterol 
Beclometasone 
Dipropionate and 
Formoterol 
 
 
Salmeterol  
Formoterol  
Bambuterol  
Clenbuterol  
Tulobuterol 
Vilanterol 
Olodaterol 
Indacaterol 
Montelukast  
Pranlukast 
Zafirlukast  
Zileuton 
Tiotropium 
Glucopyrronium bromide 
Aclidinium bromide 
Umeclidinium 
Aminophylline 
Theophylline 
Dyphylline  
Oxtryphylline 
Diprophylline 
Acebrophylline 
Bamifylline 
Doxofylline 
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Appendix C 
Low, medium and high dose inhaled corticosteroids- Children  
(6-11 years) 
 
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Appendix D 
Handling of missing data 
Annualized severe exacerbation events during the 52-Week period  
• 
Pattern mixture model (PMM) 
Step 1. The 52-week observation period is partitioned into monthly (4-week) segments. In 
the analysis, for each patient, in each month, an imputation flag (imputefl) will indicate 
whether the patient needs imputation in that month. 
Step 2. Calculation of observed monthly mean of event count 
 
Within each month, the logistic regression model will be fitted to the observed data to 
model coefficient estimates and the estimated variance-covariance matrix, with adjusting 
for the planned treatment group, age, baseline weight (≤30kg, >30kg), region (pooled 
country), baseline eosinophil level (removed for the baseline eosinophils ≥0.3 Giga/L 
population), baseline FeNO level, baseline ICS dose level, and number of severe 
exacerbation events within 1 year prior to the study. From the posterior distribution of the 
model coefficients, we randomly draw 40 sets of iid samples. As a result, for each patient 
and in each month, 40 estimated probabilities can be obtained by using the 40 samples of 
coefficients and the patient’s covariates values. 
Step 3. Imputation of event count after study withdrawal 
 
If a patient withdraws from the study at the kth (1≤k<28) day of Month i prior to Week 52, 
and experienced a severe exacerbation within the first k days, this patient will be 
considered as “observed” (imputefl=0) up to Month i and will need imputations 
(imputefl=1) from Month i+1 to Month 13 (Week 52).  
 
If a patient withdraws from the study at the kth (1≤k<28) day of Month i prior to Week 52, 
and has no severe exacerbation in Month i, this patient will be considered as “observed” 
(imputefl=0) up to Month i-1 and will need imputations (imputefl=1) from Month i to 
Month 13 (Week 52).  
 
For a patient who needs imputation from Month i+1 to Month 13, in each month, 40 
independent random samples will be respectively drawn from 40 estimated Bernoulli 
distributions, whose probabilities are obtained in Step 2. For each patient who early 
withdraws from the study, 40 sets of complete event count data can be obtained by 
summing the observed event count prior to withdrawal and each series of imputed binary 
events after withdrawal up to Week 52. 
 
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Step 2 and 3 can be realized by using PROC MI in SAS. Sample code can be found below: 
 
proc mi data=dd seed=9816388 nimpute=40 out=outdata; 
by month; 
class outcome trt01pn weight eosbgp1n cntygr1 icsgrp fenoblgrn ; 
monotone reg (asmanum/details) 
logistic (outcome=trt01pn age weight eosbgp1n cntygr1 icsgrp fenoblgrn asmanum/details 
DESCENDING); 
var eosbgp1n cntygr1 age icsgrp trt01pn fenoblgrn asmanum outcome; 
run; 
Step 4. A negative binomial model with the same set of covariates as in the primary 
endpoint analysis will be fitted with 40 sets of complete datasets obtained in Step 3, so as 
to obtain 40 sets of treatment effect estimates and p-values accordingly. Log transformed 
observation duration will be the offset variable for patients who complete the 52-Week 
treatment/study period, and log transformed 52 weeks will be the offset variable for 
patients who discontinue the study before Visit 18 (Week 52). At last, the SAS 
MIANALYZE procedure will be used to generate statistical inferences by combining 
results from the 40 analyses using Rubin’s formula. 
 
Step 4 can be realized by using PROC MIANALYZE in SAS. Sample code can be found 
below 
proc mianalyze data=rr_conv; 
by Label; 
modeleffects Estimate; 
stderr StdErr; 
ods output ParameterEstimates=rr_pooled; 
run; 
proc mianalyze data=aer_conv; 
by TRT01PN; 
modeleffects Estimate; 
stderr; 
ods output ParameterEstimates=aer_pooled; 
run; 
• 
Control-based PMM 
All steps are the same as the aforementioned approach except in Step 2:  the individual 
monthly mean probability will be calculated based on observations in placebo arm only, 
with adjustment of missing observation duration. 
• 
Tipping point analysis 
The tipping point analysis for severe exacerbation events will use the similar approach as 
PMM-MI with tipping values for the odds 
 
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Step 1.  Estimation for the monthly binary event probability using observed data 
 
Within each month up to Week 52, the logistic regression model will be fitted to the 
observed data to obtain the model coefficient estimates and the estimated variance 
covariance matrix, with adjusting for the planned treatment group, age, baseline weight 
(≤30kg, >30kg), region (pooled country), baseline eosinophil level (removed for the 
baseline eosinophils ≥0.3 Giga/L population), baseline FeNO level, baseline ICS dose 
level, and number of severe exacerbation events within 1 year prior to the study. From the 
posterior distribution for the model coefficients, we randomly draw 40 sets of iid samples. 
As a result, for each patient and in each month, 40 estimated binary event probabilities can 
be obtained by using the 40 samples of coefficients and the patient’s covariate values. 
 
Step 2. Tip on the monthly binary odds (the probability of have an event in the month 
over the probability of being event-free in the month) 
 
Within each month, for the patients from the placebo group(s) and need imputation in that 
month, the estimated odds for binary event will be deflated by decreasing a positive 
amount; for the patients from the treatment group(s) and need imputation in that month, 
the estimated odds for binary event will be inflated by increasing a positive amount. After 
the deflation/inflation, 40 sets of binary event probabilities can be obtained for the placebo 
and treatment groups, respectively. 
 
Step 3. Multiple Imputation of binary event by month after study withdrawal 
 
For a patient who needs imputation from Month i+1 to Month 13, in each month, 40 
independent random samples will be respectively drawn from 40 estimated Bernoulli 
distributions, whose probabilities are obtained in Step 2.  
 
For each patient who early withdraws from the study, 40 sets of complete event count data 
can be obtained by summing the observed event count prior to withdrawal and each series 
of imputed binary events after withdrawal up to Week 52. 
 
Step 4. A negative binomial model with the same set of covariates as in the primary 
analysis will be fitted to the 40 sets of complete datasets obtained in Step 3, so as to obtain 
40 sets of treatment effect estimates and p-values accordingly. Log transformed 
observation duration will be the offset variable for patients who complete the 52-Week 
treatment/study period, and log transformed 52 weeks will be the offset variable for 
patients who discontinue the study before Visit 18 (Week 52). Then, the SAS 
MIANALYZE procedure will be used to generate statistical inferences by combining 
results from the 40 analyses using Rubin’s formula. 
 
Step 2, 3 and 4 will be repeated iteratively until the p-value for combined treatment effect 
of dupilumab compared to placebo estimated in Step 4 is >0.05. 
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Change from baseline in % predicted pre-BD FEV1 at Week 12 
Pattern mixture model-multiple imputation (PMM-MI) 
Step 1. Monotone missing pattern was induced by Markov Chain Monte Carlo (MCMC) 
method using PROC MI: for patients who have missing values at intermediate visits, but have 
value at subsequent visits, the intermediate missing values were imputed assuming a 
multivariate normal distribution over observations from all visits. 40 datasets with a monotone 
missing pattern will be obtained using this method. 
Step2. For each of the imputed dataset with monotone missing pattern obtained in Step 1, the 
remaining missing data will be imputed using the regression method for the monotone pattern 
with adjustment for covariates including response variable, treatment groups, baseline weight 
(≤30kg, >30kg), region (pooled country), ethnicity, baseline eosinophil level (removed for the 
baseline eosinophils ≥0.3 Giga/L population), baseline FeNO level, baseline ICS dose level, 
and baseline % predicted pre-BD FEV1 and missing pattern defined by reason of treatment 
discontinuation. All available data in the monotone missing pattern data will be used. 40 fully 
imputed datasets are obtained. 
Step 3. Each of the 40 complete datasets will be analyzed using an ANCOVA model with 
change from baseline in % predicted pre-BD FEV1 at Week 12 as the response variable,  
treatment, baseline weight (≤30kg, >30kg), region (pooled country), ethnicity, baseline 
eosinophil level (removed for the baseline eosinophils ≥0.3 Giga/L population), baseline 
FeNO level, baseline ICS dose level, and baseline % predicted pre-BD FEV1 value as 
covariates. Then the SAS MIANALYZE procedure will be used to generate statistical 
inferences by combining results from the 40 analyses using Rubin’s formula. 
Control based PMM-MI 
The analysis is similar as the standard PMM-MI described above, except Step 2. To 
implement control-based imputation, we broke the imputation process into a sequence of 
PROC MI, where each call is to impute missing values at one time-point only. The steps are as 
follows: 
Step 2.1 Call PROC MI to impute values for the first time-point t with missing values. The 
input dataset include data up to time-point t for all Placebo patients and patients on 
Dupilumab with missing values at time-point t. 
Step 2.2 Repeat Step 2.1 for all the following time-points sequentially. Data imputed in the 
previous step will be included for imputation of missing values at time-point t+1.  
Tipping point analysis 
Step 1. 40 imputations will be performed to generate 40 completed data sets following Step 1 
and 2 for PMM-MI. 
Step 2. The imputed % predicted FEV1 values in Dupilumab group are subtracted by a 
positive amount d for each imputed data sets. 
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Step 3. The imputed % predicted FEV1 values in placebo group are added by a positive 
amount p for each imputed data sets. 
Step 4. Change from baseline in % predicted pre-BD FEV1 will be analyzed using the 
ANCOVA model as described in the PMM-MI for each of the 40 complete datasets. Then the 
SAS MIANALYZE procedure will be used to generate statistical inferences by combining 
results from the 40 analyses using Rubin’s formula. 
Step 2 and Step 3 will be repeated iteratively until the p-value for treatment effect of 
dupilumab compared to placebo estimated in Step 4 is >0.05. 
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Appendix E 
Asthma Control Questionnaire-Interviewer Administered (ACQ-IA) 
for Children 6 to <12 years 
Asthma Control Questionnaire, 7-question version (ACQ-7) 
 
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Appendix F 
Asthma Symptom Score Numerical Rating Scale (NRS) 
 
 
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Appendix G 
Paediatric Asthma Quality of Life Questionnaire With Standardised 
Activities(PAQLQ[S]) 
 
 
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Appendix H 
EuroQual Questionnaire (EQ-5D-5Y) – for Children 
 
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Appendix I 
Pediatric Rhinoconjunctivitis Quality of Life Questionnaire–
Interviewer Administered (PRQLQ-IA) – for Children with Comorbid 
Allergic Rhinitis 
 
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Statistical Analysis Plan  
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Page 120 
Appendix J 
Pediatric Asthma Caregiver’s Quality of Life Questionnaire 
(PACQLQ) 
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Statistical Analysis Plan  
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Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 121 
VV-CLIN-0551071 2.0


Statistical Analysis Plan  
14-Sep-2020 
SAR231893-EFC14153 - dupilumab 
Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 122 
VV-CLIN-0551071 2.0


Statistical Analysis Plan  
14-Sep-2020 
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Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 123 
Appendix K 
Definition of Anaphylaxis 
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et al.  Second 
symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol  2006; 117: 391-
397)  
Clinical criteria for diagnosing anaphylaxis 
 
 
 
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Statistical Analysis Plan  
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Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 124 
Appendix L 
List of opportunistic infections 
• 
Aspergillosis 
• 
Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
• 
Candidiasis – Note that all cases should be collected as AEs (or SAEs if requirements 
met), however, only cases which are NOT cutaneous (systemic or mucous membranes 
involved) unless involvement is extensive, will be considered as AE with pre-specified 
monitoring. 
• 
Coccidioides immitis (endemic south-western US and Central and South America) 
• 
Cryptococcus 
• 
Cytomegalovirus 
• 
Herpes Simplex (severe/disseminated) 
• 
Herpes Zoster 
• 
Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-Ohio-
Mississippi river basins) 
• 
Listeriosis 
• 
Mycobacterium avium 
• 
Nontuberculosis mycobacteria 
• 
Pneumocystis pneumonia (PCP) 
This list is indicative and not exhaustive 
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Statistical Analysis Plan  
14-Sep-2020 
SAR231893-EFC14153 - dupilumab 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 125 
Appendix M 
Summary of the planned analyses by population 
Section 
Analyses 
Type 2 
inflammatory 
asthma 
phenotype 
Baseline 
Eosinophils 
≥0.3 Giga/L 
Baseline 
Eosinophils 
≥0.15 
Giga/L 
Baseline 
FeNO  
≥20 ppb 
Full 
ITT 
Safety 
PK 
/ADA 
Disposition 
Patient disposition 
Y 
Y 
 
 
Y 
 
 
Demographics 
and baseline 
characteristics 
Demographics, baseline characteristics, baseline biomarkers, 
atopic medical history 
Y 
Y 
Y 
Y 
Y 
 
 
Others 
 
 
 
 
Y 
 
 
Medication 
Prior, concomitant and controller medications 
Y 
Y 
 
 
Y 
 
 
IMP Exposure 
IMP compliance and dosing 
Y 
Y 
 
 
 
Y 
 
Efficacy 
Annualized severe exacerbation rate during 52-week treatment 
period 
Y 
Y 
Y 
Y 
Y 
 
 
Change from baseline in % predicted FEV1 at Week 12 
Y 
Y 
Y 
Y 
Y 
 
 
Change from baseline in % predicted FEV1 up to Week 52 
Y 
Y 
Y 
Y 
Y 
 
 
Change from baseline in ACQ-7-IA at Week 24 
Y 
Y 
Y 
Y 
Y 
 
 
Annualized severe exacerbation rate during 52-week treatment 
period in patients with baseline high ICS dose 
Y 
Y 
Y 
Y 
Y 
 
 
Change from baseline in FeNO at Week 12 
Y 
Y 
Y 
Y 
Y 
 
 
On-treatment analysis, missing data sensitivity analyses, and 
subgroup analyses (except for EOS/FeNO) for endpoints of severe 
exacerbation and % predicted FEV1 at Week 12 
Y 
Y 
 
 
 
 
 
Baseline EOS/FeNO subgroup analyses, and EOS-FeNO quadrant 
analyses for endpoints of severe exacerbation and % predicted 
FEV1 at Week 12 
 
 
 
 
Y 
 
 
LOAC, severe exacerbation leading to hospitalization/ER, time-to-
event, other spirometry endpoints, PRO, change from baseline for 
continuous endpoints at all time points, and other efficacy 
endpoints 
Y 
Y 
 
 
 
 
 
Systemic corticosteroid exposure 
Y 
Y 
Y 
Y 
 
 
 
Safety / 
Biomarker 
The endpoints of AE, Laboratory, Vital sign, ECG, Eosinophils, 
and Biomarkers 
 
 
 
 
 
Y 
 
PK/ADA 
Endpoints of PK, ADA and NAb 
 
 
 
 
 
 
Y 
 
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