One Year Study to Evaluate the Long-term Safety and Tolerability of Dupilumab in Pediatric Patients With Asthma Who Participated in a Previous Dupilumab Asthma Clinical Study
Phase: PHASE3
Conditions: Asthma
Sponsor: Sanofi

 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 06      
COMPOUND: DUPILUMAB/SAR231893 
One year study to evaluate the long-term safety and tolerability of dupilumab in 
pediatric patients with asthma who participated in a previous dupilumab asthma 
clinical study 
 
STUDY NUMBER: LTS14424 
STUDY NAME: LIBERTY ASTHMA EXCURSION 
VERSION DATE / STATUS: 21-Dec-2021 / APPROVED 
 
 
 
 
 
 
 
 
 
 
Version Number: 
1  
EudraCT  
2017-003317-25 
IND Number(s) 
105379 
NCT 
NCT03560466 
WHO universal trial number: 
U1111-1200-1757 
Date: 
21-Dec-2021 
Total number of pages: 
158 
 
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Amended Clinical Trial Protocol 06  
21-Dec-2021 
LTS14424 - dupilumab 
Version number: 1 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/countries 
impacted by  
amendment 
Date, version 
Amended Clinical Trial Protocol 06 
Japan only 
21-Dec-2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 05 
Japan only 
01-Feb-2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 04 
All 
15-Apr-2020, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 03 
All 
12-Dec-2019, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 02 
All 
09-Jul-2018, version 1 (electronic 1.0) 
Amended Clinical Trial Protocol 01 (br) 
Brazil only 
14-Mar-2018, version 1 (electronic 1.0) 
Protocol Amendment 01 (br) 
Brazil only 
14-Mar-2018, version 1 (electronic 1.0) 
Original protocol 
 
07-Nov-2017, version 1 (electronic 1.0) 
 
Overall Rationale for the Amendment 
The purpose of this amendment is to remove the DMC and clarify the use of controller medication 
in the substudy of Japanese patients outlined in Section 17.7.2 (Country specific requirements for 
Japan). 
Protocol amendment summary of changes table 
Section # and Name 
Description of change 
Brief Rationale 
Section 17.7.2.7.2.1 Inhaled 
corticosteroids alone or in 
combination with a second 
controller 
Section 17.7.2.9 Study 
procedures / Section 17.7.2.9.1.4 
Open-label treatment period 
(Week 2 to Week 52 [Visits 2-10])  
Change in the management of controller 
medications, to clarify the stability of dose 
and regimen of asthma background 
controller medication during the course of 
the treatment period. 
 
Align the background controller therapy 
with Phase 3 VOYAGE study. 
Decrease the impact of medication 
changes on efficacy outcomes (primary 
endpoint of substudy is efficacy [Week 12 
ppFEV1]). 
Section 17.7.2.5.3 data 
monitoring commitee 
Section 17.7.2.8.3.1 Long-term 
safety and tolerability 
 
 
Removal of the data monitoring committee 
review 
Dupilumab demonstrated an acceptable 
safety profile in global phase 3 program 
and is now approved for asthma in this age 
group in the United States. The open-label 
study will be monitored by the Sponsor 
according to the global safety montoring 
plan. 
17.7.2.9.1.3 Enrollment: Visit 1 
(Week 0, Day 1) 
Change in the visit flow. 
Clarification of listing order to ensure 
appropriate visit flow. 
 
 
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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: 
 
 
 
 
Sanofi-Aventis Research and Development 
1 avenue Pierre Brossolette  
91380 Chilly-Mazarin, France 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: Dupilumab 
STUDY No.: LTS14424 
TITLE 
One year study to evaluate the long-term safety and tolerability of 
dupilumab in pediatric patients with asthma who participated in a 
previous dupilumab asthma clinical study 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVE(S)  
 
Primary objective: 
• 
To evaluate the long-term safety and tolerability of 
dupilumab in pediatric patients with asthma who 
participated in a previous dupilumab asthma clinical study 
(EFC14153). 
Secondary objective(s): 
• 
To evaluate the long-term efficacy of dupilumab in pediatric 
patients with asthma who participated in a previous 
dupilumab asthma clinical study. 
• 
To evaluate dupilumab in pediatric patients with asthma 
who participated in a previous dupilumab asthma clinical 
study with regard to: 
- 
Systemic exposure, 
- 
Anti-drug antibodies (ADAs), 
- 
Biomarkers. 
STUDY DESIGN 
Multinational, multicenter, open-label, single arm, 1-year treatment 
study evaluating dupilumab given subcutaneously (SC) for a period of 
52 weeks. 
The clinical trial consists of 3 periods: 
• 
Enrollment: Eligible patients from EFC14153 will rollover 
into LTS14424 the same day as the end-of-treatment (EOT) 
visit of the parent study. In the specific situation of 
COVID-19 pandemic, for those patients that are not able to 
present to sites for the EOT visit, roll-over into LTS14424 
may also be done at the same day as the end of study 
(EOS) visit of the parent study or up to 12 weeks after EOS 
visit of Study EFC14153. 
• 
Treatment period: 52 weeks open-label treatment. 
• 
Post-treatment period: 12 weeks. 
Upon completion of the treatment period (or following early 
discontinuation of investigational medicinal product [IMP]), patients 
will continue into the post-treatment period. During the post-treatment 
period, patients will receive their background controller regimen 
based on Investigator’s judgement. 
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STUDY POPULATION  
 
Main selection criteria 
Inclusion criteria: 
I 01. 
Pediatric patients with asthma who completed the treatment 
in a dupilumab asthma trial (EFC14153) 
(specifically for Brazil see Section 17.7.1). 
Patients who are not able to complete their treatment in 
Study EFC14153 due to the COVID-19 pandemic will be 
allowed to enroll into Study LTS14424. Patients who enroll 
in LTS14424 after completing the EFC14153 EOS visit 
should have eligibility for LTS14424 reevaluated including 
background medication check and laboratory assessments 
(including CBC with differential and basic chemistry) within 
1 month prior to LTS14424 Visit 1.  
I 02. 
Signed written informed consent/assent.  
 
Main Exclusion criteria: 
E 01. 
Any chronic lung disease other than asthma (for example 
cystic fibrosis, bronchopulmonary dysplasia) which may 
impair lung function. 
E 02. 
Inability to follow the procedures of the study/noncompliance 
(for example due to language problems or psychological 
disorders). 
E 03. 
Patients receiving concomitant treatment or required a new 
concomitant treatment prohibited in the study at Enrollment 
visit. 
E 04. 
Patients who experienced any hypersensitivity reactions to 
IMP in a previous dupilumab study, which, in the opinion of 
the Investigator, could indicate that continued treatment with 
dupilumab may present an unreasonable risk for the patient.  
E 05. 
Any abnormalities or adverse events at enrollment that per 
Investigator’s judgment would adversely affect patient’s 
participation in this study or would require permanent IMP 
discontinuation. Examples: Patients diagnosed with active 
parasitic infection (helminthes), suspected or high risk of 
parasitic infection, active tuberculosis (TB), invasive 
opportunistic infections (eg, histoplasmosis, listeriosis, 
coccidioidiomycosis, pneumocystocis, aspergillosis), despite 
infection resolution’ or unusually frequent, recurrent or 
prolonged infections.  
Total expected number of patients 
Approximately 354   
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
Dupilumab 
Formulation: 
Dupilumab for children ≤30 kg: 150 mg/mL in prefilled syringe to 
deliver a dose of 100 mg q2w in a 0.67 mL SC injection. 
Or 
Dupilumab for children ≤30 kg: 150 mg/mL in prefilled syringe to 
deliver a dose of 300 mg q4w in a 2 mL SC injection. 
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Dupilumab for children >30 kg: 175 mg/mL in prefilled syringe to 
deliver a dose of 200 mg q2w in a 1.14 mL SC injection.  
Route(s) of administration: 
Subcutaneous injection 
Dose regimen: 
Dupilumab 200 mg SC q2w for children with body weight >30 kg and 
100 mg SC q2w or 300mg q4w for children with body weight ≤30 kg.  
For children with body weight ≤30 kg receiving 100 mg q2w, the 
dupilumab dose will be changed to 300 mg q4w at one planned or 
unscheduled site visit only if the visit occurs more than 8 weeks 
before the planned end of the treatment period (switch to q4w dose 
regimen to occur at site visit Week 0 or 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44). Otherwise, they will continue on 100 mg q2w. All newly 
enrolled children with body weight ≤30 kg will take 300 mg q4w.  
At the enrollment visit and subsequent visits, patients whose body 
weight increased from ≤30 kg to >30 kg, can have their dupilumab 
dose adjusted from 100 mg SC q2w or 300 mg SC q4w to 200 mg SC 
q2w and then maintained during the remaining treatment period 
irrespectively of losing weight.  
Patients will receive the first dose of dupilumab in LTS14424 at Visit 1 
which is Week 0 (corresponding to EOT visit at Week 52 of parent 
study or for patients who will not be able to perform EFC14153 EOT 
visit onsite due to COVID-19 pandemic, LTS14424 Visit 1 can occur 
up until 12 weeks after the EFC14153 EOS visit). 
Noninvestigational medicinal product(s)  
 
Formulation: 
Inhaled corticosteroids (ICS) 
Alone or in combination with a second controller. 
Reliever medication 
Patients may receive albuterol/salbutamol or 
levalbuterol/levosalbutamol metered dose inhaler (MDI) as reliever 
medication (as needed) during the study. Nebulizer solutions may be 
used as an alternative delivery method.  
Systemic corticosteroids (SCS) 
Systemic corticosteroids may be given in case of severe asthma 
based on Investigator’s judgement. 
Route(s) of administration: 
Oral inhalation via MDI or dry powder inhaler (DPI; for example ICS, 
ICS combination, albuterol/salbutamol, etc); for other background 
controllers, relievers, and SCS according to label that is applicable to 
pediatric patients. 
Dose regimen: 
 
Inhaled corticosteroid: ICS alone or in combination with a second 
controller, dose to be determined by Investigator based on the 
patient's level of asthma control. 
Reliever medication, as needed. 
Systemic corticosteroid (SCS), as prescribed.  
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ENDPOINT(S) 
 
Primary endpoint: 
• 
The number (n) and percentage (%) of patients 
experiencing any treatment-emergent adverse events 
(TEAEs). 
Secondary endpoints: 
• 
Efficacy 
- 
Annualized rate of severe asthma exacerbation 
events, during the treatment period, 
- 
Change in percentage (%) predicted forced expiratory 
volume in 1 second (FEV1) and other lung function 
parameters (absolute FEV1, forced vital capacity, 
[FVC], forced expiratory flow [FEF] 25% to 75%) from 
baseline and other time points assessed. 
• 
Dupilumab systemic exposure and immunogenicity 
- 
Serum dupilumab concentrations, 
- 
ADAs. 
• 
Biomarkers 
- 
Blood: Eosinophil count, 
- 
Serum: Total IgE. 
ASSESSMENT SCHEDULE 
Study onsite visits are performed q2w up to Visit 3 (Week 4) of the 
study, once every 4 weeks (q4w) up to Visit 8 (Week 24), and 
approximately every 12-16 weeks up to the end-of-study (EOS) visit. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The study size is predicated on the overall size of the parent study; 
hence, the maximum number of patients to participate will be the 
number corresponding to the total randomized in the parent study. 
The expected number of sample size for LTS14424 study is 
approximately 354 patients (that is 87% of 408 patients from parent 
study). 
Analysis population: 
Safety population: defined as all patients exposed to at least 1 dose 
or part of 1 dose of dupilumab during LTS14424 study regardless of 
the amount of treatment administered. Patients will be summarized 
based on patients receiving dupilumab or placebo treatment in parent 
study. 
Primary analysis: 
Incidence of TEAE will be summarized using descriptive statistics. 
Analysis of secondary endpoints: 
For each variable, descriptive summary and/or inferential statistics 
that will include: n, within treatment arm point estimate, and 
confidence intervals will be provided as appropriate. Graphical time 
course profiles will be provided when appropriate for documentation 
of outcomes. 
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DURATION OF STUDY PERIOD (per 
patient)  
• 
Enrollment: Eligible patients from EFC14153 should rollover 
into LTS14424 the same day as the EOT visit of the parent 
study. In the specific situation of COVID-19 pandemic, 
when patients cannot reach onsite EOT visit, enrolment into 
LTS14424 may also be done on a site visit on the same day 
as the EFC14153 end-of-study (EOS) visit or up to 
12 weeks after the EFC14153 EOS visit.  
• 
Treatment period: Open-label treatment for 52 weeks 
(1 year). 
• 
Post-treatment period: 12 weeks. 
The total duration, per patient, is a maximum of approximately 
64 weeks. 
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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN  
Dupilumab 200 mg q2w >30 kg
Dupilumab 100 mg q2w ≤30 kg
Or
Dupilumab 300 mg q4w ≤30 kg
 
* Due to COVID-19 pandemic, patients may enroll in LTS14424 at or up to 12 weeks after the EFC14153 EOS visit. 
Abbreviations: ICS = inhaled corticosteroid; LABA = long acting β2 agonist; LAMA = long acting muscarinic antagonist; LTRA = leukotriene receptor antagonist; q2w = once every 2 weeks; SCS = systemic 
corticosteroid. 
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1.2 
STUDY FLOW CHART  
Study periods 
Open-label treatment period 
(52 weeks)  
Post-treatment period 
(12 weeks) 
Enrollment0 
 
EOT 
 
 
EOS  
SOTb (D1) 
Week (W) 
W0 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28c 
W32c 
W36 
W40c 
W44c 
W48c 
W52 
W56c 
W60c 
W64 
Onsite visit 
1d 
2 
3 
4 
5 
6 
7 
8 
 
 
9 
 
 
 
10 
 
 
11 
Enrollment 
  
Informed consent/assent 
X 
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Patient demography 
X 
  
 
 
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Medical & surgical history 
X 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Entry criteria 
X 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Treatment 
  
Call IVRS/IWRS 
X 
Xf 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
X 
  
  
X 
IMP dispense/ 
administratione 
X 
Xf 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
  
  
  
  
Injection training/technique 
observationg 
X 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
Prior & concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
  
Spirometryh 
X 
X 
  
X 
X 
  
  
X 
 
 
 
  
  
  
X 
  
  
X 
Safety 
  
Vital signs (including height 
and weight)i 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
X 
  
  
X 
Physical examination 
X 
  
  
  
X 
  
  
X 
  
 
 
  
  
  
X 
  
  
X 
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Study periods 
Open-label treatment period 
(52 weeks) 
Post-treatment period 
(12 weeks) 
Enrollment0 
EOT 
EOS 
SOTb (D1)
Week (W) 
W0 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28c 
W32c 
W36 
W40c 
W44c 
W48c 
W52 
W56c 
W60c 
W64 
Onsite visit 
1d 
2 
3 
4 
5 
6 
7 
8 


9 



10 


11 
Menstruation status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
X 
Vaccines record review 
scheduling 
X 
Adverse event reporting 
      <- ------------------------------------------------------------------------------------------------ X --------------------------------------------------------------------------------------------------------------------------→ 
Laboratory Testing 
Clinical laboratoriesj 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test for 
girls that are menstruating 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisk 
X 
X 
X 
X 
X 
PK samplingl 
X 
X 
X 
X 
X 
ADAl
X 
X 
X 
X 
X 
Serum total IgE and 
Ag-specific IgE 
X 
X 
X 
X 
Archival serum samplingm 
X 
X 
Reminder 
Controller and reliever 
therapy reminderc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication withhold 
reminderc 
X 
X 
 X 
X 
X 
X 
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Abbreviations: ADA = anti-drug antibodies; Ag specific IgE = antigen-specific IgE; D1 = Day 1; ECG = electrocardiogram; eCRF = electronic case report form; EOS = end-of-study; EOT = end-of-treatment; 
IgE = immunoglobulin E; IMP = investigational medicinal product; IVRS/IWRS = Interactive Voice Response System/Interactive Web Response System; ICS = inhaled corticosteroid; LABA = long acting β2- 
agonist; LAMA = long acting muscarinic antagonist; PK = pharmacokinetic; q2w = once every 2 weeks; q4w = once every 4 weeks; SOT = start-of-treatment; W = (study) week. 
a Eligible patients from study EFC14153 should rollover into LTS14424 the same day as the EOT visit of the parent study (which will be Visit 1 of LTS14424 study) or for patients who will not be able to perform EOT 
visit onsite due to COVID-19 pandemic, Study LTS14424 Visit 1 can occur at EFC14153 EOS visit, or up until and including 12 weeks after Study EFC14153 EOS visit. Patients who enroll after EOS visit in parent 
study should have laboratory assessments including complete blood count with differential and basic chemistry to evaluate continued eligibility for LTS14424 performed within 1 month prior to LTS14424 Visit 1. 
(Specifically for Brazil see Section 17.7.1).  
b Start-of-treatment/enrollment visit (Visit 1 of present study) for patients after having performed the assessments of EOT or EOS visit in the parent study (due to COVID-19 pandemic). For patients not able to perform EOT 
or EOS visit onsite due to COVID-19 pandemic, LTS14424 Visit 1 may occur up to 12 weeks after EFC14153 EOS visit. Visit windows for subsequent visits are ±3 days during treatment period and ±1 week for the 
remainder of the study 
c Phone contact to collect safety information + reminders for IMP, controller and reliever therapy, if appropriate reminder for withholding medication at the next visit as described in the individual visit schedules 
Safety information and date of phone call will be recorded in eCRF. 
d Eligible patients in parent study should rollover into LTS14424 the same day as the EOT visit of the parent study. All measurements and procedures of EOT visit of parent study should be done before enrollment to 
LTS14424 study. If the data can be obtained from EOT visit of parent study, relative procedures of Visit 1 of LTS14424 study can be waivered. New AEs (including worsening AEs) will be reported only in LTS14424 
eCRF. For patients who will not be able to perform EOT visit onsite due to COVID-19 pandemic, Study LTS14424 Visit 1 can occur up and until 12 weeks after Study EFC14153 EOS. 
e Once every 2 weeks IMP administrations must be separated by at least 11 days. Once every 4 weeks IMP administrations must be separated by at least 25 days. The treatment period visits occur q2w up to Visit 3 
(Week 4) of the study, q4w up to Visit 8 (Week 24), and approximately every 12-16 weeks up to the EOS visit. After each IMP administration, patients should be monitored for a minimum of 30 minutes after 
injections. If the parent(s)/caregiver(s)/legal guardian(s) or the Investigator decides not to administer IMP at home, the injections can be performed at the study site by way of unscheduled visits. The first injection 
of 300 mg dose must be performed onsite. 
f 
For patients receiving 300 mg q4w, no IMP will be dispensed/administered at Week 2 and no IVRS/IWRS call will occur.  
g The injection training is for families who are willing to perform injection administration at home for children receiving q2w doses. The Investigator or delegate should review the patient’s administration technique at 
the Visit 1 (or upcoming onsite visits before permitting IMP administration at home). No IMP administration at home is allowed for patients receiving the 300 mg q4w dose for the first time. Subsequent 
administrations are encouraged to occur at site wherever possible, if not possible can be done by trained care givers or nurses at home. 
h Spirometry should be done at the study site approximately the same time of the day (preferably in the morning, but it could be done at a different time of the day). Spirometry will be performed after a washout period 
of bronchodilators according to their action duration (for example withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at least 
12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours. Also spirometry should be performed prior to IMP administration, as 
applicable.  
i 
Vital signs: blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius), and body weight (kg) will be measured at each visit. Height (cm) will 
only be measured at the enrollment visit (Visit 1 of present study) and EOT visit. Weight will be measured at each onsite visit. Except height and weight, other vital signs will be measured in the sitting position using 
the same arm at each visit. All vital signs will be measured prior to dispensation and/or administration of IMP at the clinic visits. 
j 
Clinical laboratories: Hematology: blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets. Serum 
chemistry: total bilirubin (in case of values above the normal range, differentiation in conjugated and nonconjugated bilirubin), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), total protein, albumin, total cholesterol, creatine phosphokinase (CPK), glucose, creatinine, blood urea nitrogen (BUN), bicarbonate, and electrolytes (sodium, potassium, chloride). 
k Urinalysis: pH, glucose, ketones, leukocyte esterase blood, protein, nitrate, urobilinogen, and bilirubin (by dipstick). 
l 
Samples will be collected prior to IMP administration, during the treatment period. 
m Archival serum sample (optional). 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 06 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
1 
FLOW CHARTS ............................................................................................................................... 9 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................ 9 
1.2 
STUDY FLOW CHART .................................................................................................................. 10 
2 
TABLE OF CONTENTS ................................................................................................................ 13 
2.1 
LIST OF TABLES ........................................................................................................................... 18 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 19 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 21 
4.1 
INTRODUCTION ............................................................................................................................ 21 
4.2 
RATIONALE ................................................................................................................................... 21 
5 
STUDY OBJECTIVES ................................................................................................................... 24 
5.1 
PRIMARY ....................................................................................................................................... 24 
5.2 
SECONDARY ................................................................................................................................ 24 
6 
STUDY DESIGN ............................................................................................................................ 25 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 25 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 25 
6.2.1 
Duration of study participation for each patient ............................................................................. 25 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 25 
6.3 
INTERIM ANALYSIS ...................................................................................................................... 25 
6.4 
DATA MONITORING COMMITTEE .............................................................................................. 26 
7 
SELECTION OF PATIENTS .......................................................................................................... 27 
7.1 
INCLUSION CRITERIA .................................................................................................................. 27 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 27 
7.2.1 
Exclusion criteria related to study methodology ............................................................................ 27 
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7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound ...................................... 27 
8 
STUDY TREATMENT .................................................................................................................... 29 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 29 
8.1.1 
Dupilumab ...................................................................................................................................... 29 
8.1.2 
Preparation of investigational product............................................................................................ 29 
8.1.3 
Dosing schedule ............................................................................................................................. 30 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 31 
8.2.1 
Inhaled corticosteroids alone or in combination with a second controller...................................... 31 
8.2.2 
Reliever medication........................................................................................................................ 32 
8.2.3 
Systemic corticosteroids ................................................................................................................ 33 
8.3 
BLINDING PROCEDURES ............................................................................................................ 33 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 33 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 34 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 34 
8.7 
RESPONSIBILITIES ...................................................................................................................... 35 
8.7.1 
Treatment accountability and compliance...................................................................................... 35 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 36 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 36 
8.8.1 
Prohibited concomitant medication ................................................................................................ 36 
8.8.2 
Cautioned concomitant medication (Cytochrome P450 enzyme substrates) ................................ 36 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 38 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 38 
9.1.1 
Vital signs ....................................................................................................................................... 39 
9.1.2 
Physical examination ..................................................................................................................... 39 
9.1.3 
Electrocardiogram (ECG) ............................................................................................................... 39 
9.1.4 
Clinical laboratory tests .................................................................................................................. 39 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 40 
9.2.1 
Secondary efficacy endpoints ........................................................................................................ 40 
9.2.1.1 
Assessment of severe asthma exacerbation ................................................................................. 41 
9.2.1.2 
Assessment of lung function by spirometry ................................................................................... 41 
9.2.2 
Other secondary endpoints ............................................................................................................ 42 
9.2.2.1 
Dupilumab systemic exposure and immunogenicity ...................................................................... 42 
9.2.2.2 
Pharmacodynamics and phenotyping ............................................................................................ 43 
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9.3 
FUTURE USE OF SAMPLES ........................................................................................................ 44 
9.4 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 44 
10 
STUDY PROCEDURES ................................................................................................................ 45 
10.1 
VISIT SCHEDULE .......................................................................................................................... 46 
10.1.1 
Enrollment: Visit 1 of present study (Start of treatment, Week 0) .................................................. 46 
10.1.2 
Open-label treatment period (Week 0 to Week 52 [Visits 2-10]) ................................................... 48 
10.1.2.1 Visit 2 (Week 2 [±3 days]) .............................................................................................................. 48 
10.1.2.2 Visit 3 (Week 4 [±3 days]) .............................................................................................................. 49 
10.1.2.3 Visit 4 (Week 8 [±3 days]) .............................................................................................................. 50 
10.1.2.4 Visit 5 (Week 12 [±3 days]) ............................................................................................................ 51 
10.1.2.5 Visit 6 (Week 16 [±3 days]) ............................................................................................................ 52 
10.1.2.6 Visit 7 (Week 20 [±3 days]) ............................................................................................................ 53 
10.1.2.7 Visit 8 (Week 24 [±3 days]) ............................................................................................................ 54 
10.1.2.8 Telephone contact at Week 28 and 32 (±3 days) .......................................................................... 55 
10.1.2.9 Visit 9 (Week 36 [±3 days]) ............................................................................................................ 55 
10.1.2.10 Telephone contact at Weeks 40, 44, and 48 (±3 days) ................................................................. 56 
10.1.2.11 Visit 10 (Week 52 [±3 days]), End-of-treatment visit ...................................................................... 56 
10.1.3 
Post-treatment period (12 weeks) .................................................................................................. 57 
10.1.3.1 Telephone contact at Weeks 56 and 60 (±1 week) ....................................................................... 57 
10.1.3.2 Visit 11: (Week 64 [±1 week]), end-of-study visit ........................................................................... 58 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 58 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 59 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 59 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 59 
10.3.3 
List of criteria for permanent treatment discontinuation ................................................................. 60 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 60 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 61 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 62 
10.4.1 
Definitions of adverse events ......................................................................................................... 62 
10.4.1.1 Adverse event ................................................................................................................................ 62 
10.4.1.2 Serious adverse event ................................................................................................................... 62 
10.4.1.3 Adverse event of special interest ................................................................................................... 63 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities ....................................................................................................................................... 64 
10.4.3 
General guidelines for reporting adverse events ........................................................................... 64 
10.4.4 
Instructions for reporting serious adverse events .......................................................................... 65 
10.4.5 
Guidelines for reporting adverse events of special interest ........................................................... 66 
10.4.6 
Guidelines for management of specific laboratory abnormalities .................................................. 66 
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10.5 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 67 
10.6 
SAFETY INSTRUCTIONS ............................................................................................................. 67 
10.6.1 
Hypersensitivity .............................................................................................................................. 67 
10.6.2 
Severe injection site reactions ....................................................................................................... 68 
10.6.3 
Infections ........................................................................................................................................ 68 
10.6.4 
Elevated liver function tests ........................................................................................................... 69 
10.7 
ADVERSE EVENTS MONITORING .............................................................................................. 69 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 70 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 70 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 70 
11.3 
ANALYSIS POPULATIONS ........................................................................................................... 70 
11.3.1 
Efficacy populations ....................................................................................................................... 70 
11.3.2 
Safety population ........................................................................................................................... 70 
11.3.3 
Pharmacokinetics population ......................................................................................................... 70 
11.3.4 
Anti-drug antibody population ........................................................................................................ 71 
11.4 
STATISTICAL METHODS ............................................................................................................. 71 
11.4.1 
Extent of study treatment exposure and compliance ..................................................................... 71 
11.4.1.1 Extent of investigational medicinal product exposure .................................................................... 71 
11.4.1.2 Compliance .................................................................................................................................... 71 
11.4.2 
Analyses of efficacy endpoints ....................................................................................................... 72 
11.4.3 
Analyses of safety data .................................................................................................................. 72 
11.4.3.1 Adverse events .............................................................................................................................. 72 
11.4.4 
Analyses of systemic drug concentration, anti-drug antibodies, and pharmacodynamics 
variables ......................................................................................................................................... 74 
11.4.4.1 Pharmacokinetic analysis .............................................................................................................. 74 
11.4.4.2 Anti-drug antibodies analysis ......................................................................................................... 74 
11.4.4.3 Pharmacodynamics........................................................................................................................ 75 
11.5 
INTERIM ANALYSIS ...................................................................................................................... 75 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 76 
12.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 76 
12.2 
INFORMED CONSENT ................................................................................................................. 76 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE ................................................................................................................... 77 
13 
STUDY MONITORING................................................................................................................... 78 
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13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 78 
13.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 78 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 78 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST ............. 79 
13.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 79 
14 
ADDITIONAL REQUIREMENTS ................................................................................................... 80 
14.1 
CURRICULUM VITAE.................................................................................................................... 80 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................... 80 
14.3 
CONFIDENTIALITY ....................................................................................................................... 80 
14.4 
PROPERTY RIGHTS ..................................................................................................................... 81 
14.5 
DATA PROTECTION ..................................................................................................................... 81 
14.6 
INSURANCE COMPENSATION .................................................................................................... 81 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 82 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 82 
14.8.1 
By the Sponsor ............................................................................................................................... 82 
14.8.2 
By the Investigator ......................................................................................................................... 83 
14.9 
CLINICAL TRIAL RESULTS .......................................................................................................... 83 
14.10 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 83 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS .......................................................................... 84 
16 
BIBLIOGRAPHIC REFERENCES ................................................................................................. 85 
17 
APPENDICES ................................................................................................................................ 88 
17.1 
APPENDIX A: EXAMPLES OF COMMONLY USED ASTHMA CONTROLLER 
THERAPIES ................................................................................................................................... 88 
17.2 
APPENDIX B: LIST OF PROHIBITED LIVE ATTENUATED VACCINES ..................................... 89 
17.3 
APPENDIX C: EXAMPLES OF CYP SUBSTRATES WITH NARROW THERAPEUTIC 
RANGE .......................................................................................................................................... 90 
17.4 
APPENDIX D: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI ...................................................................................................... 91 
17.5 
APPENDIX E: DEFINITION OF ANAPHYLAXIS ........................................................................... 95 
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17.6 
APPENDIX F: LIST OF OPPORTUNISTIC INFECTIONS ............................................................ 95 
17.7 
APPENDIX G: COUNTRY SPECIFIC REQUIREMENTS ............................................................. 96 
17.7.1 
Amended Protocol 01 for Brazil (14 March 2018) .......................................................................... 96 
17.7.2 
Country specific requirements for Japan ....................................................................................... 96 
17.7.2.1 Clinical trial summary ..................................................................................................................... 96 
17.7.2.2 Flow charts ................................................................................................................................... 101 
17.7.2.3 Rationale ...................................................................................................................................... 107 
17.7.2.4 Study objectives ........................................................................................................................... 107 
17.7.2.5 Study design ................................................................................................................................ 107 
17.7.2.6 Selection of patients ..................................................................................................................... 108 
17.7.2.7 Study treatment ............................................................................................................................ 112 
17.7.2.8 Assessment of investigational medicinal product ........................................................................ 118 
17.7.2.9 Study procedures ......................................................................................................................... 125 
17.7.2.10 Statistical considerations ............................................................................................................. 142 
17.7.2.11 Ethical and regulatory considerations .......................................................................................... 144 
17.7.2.12 Study monitoring .......................................................................................................................... 144 
17.7.2.13 Additional requirements ............................................................................................................... 145 
17.7.2.14 Appendix 1: Low, medium, and high-dose inhaled corticosteroids – children aged 6 to <12 
years (Japan) ............................................................................................................................... 145 
17.7.2.15 Appendix 2: Asthma control questionnaire–interviewer administered (ACQ-IA) for children 
6 to <12 years .............................................................................................................................. 145 
17.7.2.16 Appendix 3: Contingency Measures for Japan for a regional or national emergency that is 
declared by a governmental agency ............................................................................................ 151 
17.8 
APPENDIX H: PROTOCOL AMENDMENT HISTORY ................................................................ 152 
 
2.1 
LIST OF TABLES  
Table 1 - The reliever medication conversion factors ................................................................................... 33 
Table 2 - The reliever medication conversion factors ................................................................................... 33 
Table 3 - Summary of handling procedures for dupilumab ........................................................................... 43 
Table 4 - Summary of bioanalytical methods for dupilumab and anti-dupilumab antibody ........................... 43 
Table 5 - Summary of adverse event reporting instructions .......................................................................... 66 
Table 6 - Eligibility interpretation for hepatitis serology ............................................................................... 123 
  
 
 
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3 
LIST OF ABBREVIATIONS  
 
ACQ-5-IA: 
Asthma Control Questionnaire–Interviewer Administered, 5-question version 
ACQ-7-IA: 
Asthma Control Questionnaire–Interviewer Administer, 7-question version 
ACQ-IA: 
Asthma Control Questionnaire–Interviewer Administered 
AD: 
atopic dermatitis 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATS: 
American Thoracic Society 
CPK: 
creatine phosphokinase  
CSR: 
clinical study report 
CV: 
curriculum vitae  
CYP: 
Cytochrome P450 
DMC: 
Data Monitoring Committee 
DPI: 
dry powder inhaler 
EC: 
Ethics Committee 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
ELISA: 
enzyme-linked immunosorbent assay 
EOS: 
end-of-study 
EOT: 
end-of-treatment 
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 
HIV: 
Human immunodeficiency virus  
HLGT: 
high level group term 
HLT: 
high level term 
IAF: 
informed assent form 
ICF: 
informed consent form 
ICS: 
inhaled corticosteroids 
IEC: 
Independent Ethics Committee 
IgE: 
immunoglobulin E 
IL: 
interleukin 
IL-4Rα: 
interleukin-4 receptor alpha 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
ISR: 
injection site reactions 
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IVRS/IWRS: 
Interactive Voice Response System/ Interactive Web Response System 
K-M: 
Kaplan-Meier 
LABA: 
long acting β2 agonist 
LAMA: 
long acting muscarinic antagonist 
LFT: 
liver function test 
LTRA: 
leukotriene receptor antagonist  
mAb: 
monoclonal antibody 
MDI: 
metered dose inhaler 
NIMP: 
noninvestigational medicinal product 
PD: 
pharmacodynamics 
PK: 
pharmacokinetic 
PT: 
preferred term 
q2w: 
once every 2 weeks 
q4w: 
once every 4 weeks 
qw: 
every week  
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous(ly) 
SD: 
standard deviation 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
TBV: 
total blood volume 
TEAEs: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
V: 
(study) visit 
W: 
(study) week 
 
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4 
INTRODUCTION AND RATIONALE  
4.1 
INTRODUCTION  
Asthma is the most common chronic lung disease of childhood that affects >6.6 million children 
in the United States (US). Asthma is a chronic inflammatory disease of the airways characterized 
by airway hyper-responsiveness, acute and chronic bronchoconstriction, airway edema, and 
mucus plugging. The inflammatory component of asthma involves many cell types, including 
mast cells, eosinophils, T-lymphocytes, neutrophils, 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% to 5% of all asthmatic children have uncontrolled asthma despite maximum 
treatment with conventional medication (1) Children with such severe symptoms are 
heterogeneous with respect to trigger factors, pulmonary function, inflammatory pattern, and 
clinical symptoms (2). 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 
(that is 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 (3). Recent 
therapeutic approaches in asthma have been focused on trying to control type 2 inflammation. 
Dupilumab is a human monoclonal antibody (mAb) directed against the interleukin-4 receptor 
alpha (IL-4Rα) subunit, a component of interleukin (IL)-4 receptors Type I and Type II. The IL-4 
receptors mediate the IL-4 signaling (both Type I and Type II) and IL-13 signaling (Type II). As 
previously mentioned, both IL-4 and IL-13 signaling pathways are thought to play key roles in the 
pathophysiology of inflammatory allergic diseases. Dupilumab has been recently approved in the 
US and European Union (EU) for the treatment of adults with moderate to severe atopic 
dermatitis (AD). 
4.2 
RATIONALE  
An initial demonstration of the efficacy and safety of dupilumab in adults was provided in the 
randomized, double-blind, placebo-controlled, parallel-group Phase 2a study (ACT11457). This 
study investigated the effects of dupilumab administered at a dose of 300 mg subcutaneously (SC) 
once weekly for 12 weeks as compared to placebo on the incidence of asthma exacerbations in 
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adult patients with persistent moderate to severe eosinophilic asthma. During the first 4 weeks 
patients continue taking their background medication, consisting of medium to high dose ICS in 
combination with a long acting β2 agonist (LABA), and then the LABA component was 
withdrawn and finally the ICS component was removed as well leaving patients treated with 
either dupilumab or matching placebo. The primary endpoint was the occurrence of an asthma 
exacerbation; the secondary endpoints included a range of measures of asthma control. The 
ACT11457 study showed an 87% reduction in asthma exacerbations after 12 weeks of treatment 
with dupilumab (5.8%) versus placebo (44.2%). A rapid improvement of lung function, as 
measured by forced expiratory volume in 1 second (FEV1) and reduction of T-helper 2 (Th2) 
associated biomarkers levels were also observed (4). 
In a 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]) 
was evaluated in adult patients with uncontrolled asthma while receiving a stable dose of medium 
to high-dose ICS/LABA in addition to their study treatment (placebo or dupilumab). Dupilumab 
demonstrated dose dependent improvement, compared with placebo, in the change from baseline 
in 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 well tolerated and had an acceptable safety profile 
across all dose regimens examined. Treatment-emergent adverse events (TEAE) 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 (ISR), respiratory 
tract infections and related symptoms, headache, and back pain. There was no apparent dose 
relationship for any particular TEAE except for ISR, majority of which were mild in nature (5).  
Study EFC13579 was a Phase 3 randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of dupilumab in adolescent and adult patients with 
persistent asthma. Dupilumab, when added to standard therapies, reduced severe asthma attacks 
(exacerbations) and improved lung function. At 52 weeks, in the 300 mg dose group, dupilumab 
reduced severe asthma attacks by 46%. At 12 weeks, in the 300 mg dupilumab dose group, mean 
improvement in lung function over placebo as assessed by FEV1 was 130 mL (9%) in the overall 
population, 150 mL (11%) in patients with ≥150 eosinophilic cells/μL, and 240 mL (18%) in 
patients with ≥300 eosinophilic cells/μL (p<0.001 for all groups). The results for the 200 mg and 
300 mg dupilumab dose groups were generally comparable on both exacerbations and FEV1. The 
overall rates of adverse events (AE), deaths, infections, conjunctivitis, herpes, and 
discontinuations were comparable between the dupilumab and placebo groups. Injection site 
reactions were more common in the dupilumab groups occurring in 17% of dupilumab patients 
compared to 8% of placebo patients. 
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As part of the pediatric program, EFC14153 was designed to establish the efficacy and safety of 
dupilumab in comparison to placebo in children 6 to 11 years of age with persistent uncontrolled 
asthma. The dose regimens for this study were selected based on the observed efficacy and safety 
in the dose ranging study in adult asthma patients (Phase 2b study DRI12544), the 
pharmacokinetic (PK) characterization and safety observation in pediatric AD study 
(R668-AD-1412) of 6 to <18 years, as well as the available safety data of EFC13579, the asthma 
pivotal study being conducted in adults and adolescents. As a result of the collective analysis of 
the previously mentioned data, the recommended dosing regimens for the pediatric population 
aged 6 to <12 years were dupilumab 200 mg SC q2w for children >30 kg or 100 mg SC q2w for 
those with a weight ≤30 kg. Subsequent to the start of LTS14424, the pediatric atopic dermatitis 
study R668-AD-1652 was completed. In that study, it was identified that the dose 300 mg q4w for 
patients <30 kg with atopic dermatitis was able to provide acceptable clinical efficacy with an 
acceptable tolerability and safety profile and it was comparable to other regimens. 
Therefore, the Sponsor will introduce this same dose for children with asthma who are ≤30 kg. 
The Sponsor supports harmonizing the PK across indications where possible. This approach is 
supported by the similarity in PK that has been demonstrated across healthy individuals as well as 
patients including those with AD and asthma. Given the high degree of overlap between asthma 
and AD, especially in younger populations, this simplifies the approach for patients. In addition, 
q4w dosing has the potential to reduce patient burden and possibly improve overall compliance. 
In addition to the safety and efficacy data observed in AD patients, the safety and efficacy of the 
300 mg q4w dose is supported by modeling developed from observed data in adults and 
adolescents with asthma. PK modeling incorporating data from the clinical development program 
in asthma populations identifies that 300 mg q4w in children 15 to 30 kg is expected to match the 
adult and adolescent efficacious exposure at 300 mg q2w, within a safe treatment profile and 
within the desired therapeutic window. The predicted Ctrough for 300 mg q4w in pediatric patients 
15 to 30 kg is similar to the adult and adolescent 300 mg q2w Ctrough. The predicted Cmax of 
300 mg q4w in pediatric patients 15 to 30 kg does not exceed the adult 300 mg every week (qw) 
Cmax in asthma Phase 2/3 studies. 
LTS14424 is designed as a 1-year treatment study to evaluate the long-term safety and tolerability 
of dupilumab in pediatric patients with asthma who participated in a previous dupilumab asthma 
study (EFC14153). In addition, this study will collect PK, safety, and clinical response 
information on patients with asthma who weigh ≤30 kg and who are treated with dupilumab 
300 mg q4w. The doses to be used in this study will include dupilumab 200 mg q2w for children 
>30 kg; or, for those with a weight ≤30 kg: 100 mg q2w or 300mg q4w. The dosing regimen will 
be adjusted based on the patient’s weight during the study. In Amended Protocol 04, all 
participants with a weight ≤30 kg who had completed less than 44 weeks of LTS14424 were 
switched from 100 mg q2w to 300mg q4w at onsite visit.  
In Amended Protocol 05, a Japan substudy was added to include pediatric asthma patients aged 
6 to <12 years from Japan.  
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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
The primary objective of this study is to evaluate the long-term safety and tolerability of 
dupilumab in pediatric patients with asthma who participated in a previous dupilumab asthma 
clinical study (EFC14153). 
5.2 
SECONDARY  
The secondary objectives of this study are: 
• To evaluate the long-term efficacy of dupilumab in pediatric patients with asthma who 
participated in a previous dupilumab asthma clinical study. 
• To evaluate dupilumab in pediatric patients with asthma who participated in a previous 
dupilumab asthma clinical study with regard to: 
- 
Systemic exposure, 
- 
Anti-drug antibodies (ADAs), 
- 
Biomarkers. 
 
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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This study is a multinational, multicenter, open-label, single arm, 1-year treatment study 
evaluating dupilumab given SC for a period of 52 weeks. 
Upon completion of the treatment period (or following early discontinuation of investigational 
medicinal product [IMP]), patients will continue into the post-treatment period. During the 
post-treatment period, patients will receive their background controller regimen based on 
Investigator’s judgement. 
For a schematic study design, please refer to Section 1.1. 
6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The total duration, per patient, is a maximum of approximately 64 weeks. 
For each patient, this includes the following 3 periods: 
• Enrollment: Eligible patients from EFC14153 will rollover into LTS14424 the same day 
as the end-of-treatment (EOT) visit of the parent study. In the specific situation of 
COVID-19 pandemic, when patients cannot reach onsite EOT visit, enrolment into 
LTS14424 may also be done on a site visit on the same day as the EFC14153 end-of-study 
(EOS) visit or up to 12 weeks after the EFC14153 EOS visit. 
• Treatment period: 52 weeks open-label treatment (1 year) with last dosing on Week 50. 
• Post-treatment period: 12 weeks. 
6.2.2 Determination of end of clinical trial (all patients)  
The end-of-study (EOS) is defined as the last patient has completed the 12 weeks post-treatment 
period and completed the EOS visit. 
6.3 
INTERIM ANALYSIS  
This is 1-year treatment safety study. Interim analyses/reports may be prepared to support 
regulatory submissions of an indication in the dupilumab project or other purposes. 
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6.4 
DATA MONITORING COMMITTEE  
The data monitoring committee (DMC) that will monitor safety data during the conduct of the 
study is independent from Sponsor. This committee is comprised of externally-based individuals 
with experts in pediatrics, expertise in the diseases under study, biostatistics, or clinical research. 
The primary responsibilities of the DMC are to review and evaluate the safety data during the 
course of the trial and make appropriate recommendations regarding the conduct of the clinical 
trial to the Sponsor. 
The DMC procedures and safety data to be reviewed by the DMC are described in the DMC 
charter. In the above capacities, the DMC is advisory to the Sponsor. The Sponsor is responsible 
for promptly reviewing and for taking into account in a timely manner the recommendations of 
the DMC in terms of trial continuation with or without alterations or of potential trial termination. 
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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. Pediatric patients with asthma who completed the treatment in a dupilumab asthma trial 
(EFC14153) (Specifically for Brazil see Section 17.7.1).  
Patients who are not able to complete their treatment in Study EFC14153 due to the 
COVID-19 pandemic will be allowed to enroll into Study LTS14424. Patients who enroll 
in LTS14424 after completing the EFC14153 EOS visit should have eligibility for 
LTS14424 reevaluated including background medication check and laboratory 
assessments (including CBC with differential and basic chemistry) within 1 month prior to 
LTS14424 Visit 1. 
I 02. Signed written informed consent/assent. 
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. Any chronic lung disease other than asthma (for example cystic fibrosis, 
bronchopulmonary dysplasia) which may impair lung function. 
E 02. Inability to follow the procedures of the study/noncompliance (for example due to 
language problems or psychological disorders). 
E 03. Patients receiving concomitant treatment or required a new concomitant treatment 
prohibited in the study at enrollment visit (see Section 8.8). 
E 04. Patients or his/her parent(s)/caregiver(s)/legal guardian(s) is related to the Investigator or 
any Subinvestigator, research assistant, pharmacist, study coordinator, other staff thereof 
directly involved in the conduct of the study. 
7.2.2 Exclusion criteria related to the current knowledge of Sanofi compound  
E 05. Patients who experienced any hypersensitivity reactions to IMP in a previous dupilumab 
study, which, in the opinion of the Investigator, could indicate that continued treatment 
with dupilumab may present an unreasonable risk for the patient.  
E 06. Any abnormalities or AEs at enrollment that per Investigator’s judgment would adversely 
affect patient’s participation in this study or would require permanent IMP discontinuation. 
Examples: Patients diagnosed with active parasitic infection (helminthes), suspected or 
high risk of parasitic infection, active tuberculosis (TB), invasive opportunistic infections 
(eg, histoplasmosis, listeriosis, coccidioidiomycosis, pneumocystocis, aspergillosis), 
despite infection resolution’ or unusually frequent, recurrent or prolonged infections.  
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E 07. 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 or intrauterine system with progesterone, 
- 
Barrier contraceptive (condom, diaphragm, or cervical/vault caps) used with 
spermicide (foam, gel, film, cream, or suppository). 
E 08. Planned live attenuated vaccinations during the study. 
E 09. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, juvenile idiopathic arthritis, inflammatory bowel disease, 
systemic lupus erythematosus) at enrollment. 
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8 
STUDY TREATMENT  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
8.1.1 Dupilumab  
Route of administration:  
• Dupilumab for children ≤30 kg: 150 mg/mL in prefilled syringe to deliver a dose of 
100 mg q2w in a 0.67 mL SC injection. 
OR 
• Dupilumab for children ≤30 kg: 150 mg/mL in prefilled syringe to deliver a dose of 
300 mg q4w in a 2 mL SC injection. 
• Dupilumab for children >30 kg: 175 mg/mL in prefilled syringe to deliver a dose of 
200 mg q2w in a 1.14 mL SC injection. 
Dose regimen: Dupilumab 200 mg SC q2w for children with body weight >30 kg and 100 mg SC 
q2w or 300mg q4w for children with body weight ≤30 kg. 
For children with body weight ≤30 kg receiving 100 mg q2w, the dupilumab dose will be changed 
to 300 mg q4w at one planned or unscheduled site visit if they are more than 8 weeks out from 
completing the treatment period (switch to q4w dose regimen to occur at site visit at Week 0 or 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44). Otherwise, they will continue on 100 mg q2w. All newly 
enrolled children with body weight ≤30 kg will take 300 mg q4w. 
At enrollment visit and subsequent visits, patients whose body weight increased from ≤30 kg to 
>30 kg, will have their dupilumab dose adjusted from 100 mg SC q2w or 300 mg q4w to 200 mg 
SC q2w and then maintained during the remaining treatment period irrespectively of losing 
weight. 
Patients will receive their first dose of dupilumab in LTS14424 study at the Visit 1 which is 
Week 0 (corresponding to EOT visit at Week 52 of parent study or for patients who will not be 
able to perform EFC14153 EOT visit onsite due to COVID-19 pandemic, Study LTS14424 
Visit 1 can occur at the EFC14153 EOS visit or for up to 12 weeks after the Study EFC14153 
EOS visit).  
8.1.2 Preparation of investigational product  
Dupilumab in glass prefilled syringes will be dispensed to the patients. Additional information 
will be provided in the Pharmacy manual. 
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8.1.3 Dosing schedule  
Dupilumab is administered every 14±3 days q2w or every 28 days ±3 days q4w. The doses of 
investigational product must be separated by ≥11 days for q2w and ≥25 days for q4w to avoid 
overdose.  
For IMP administrations coinciding with scheduled study site visits (q2w up to Visit 3 [Week 4] 
for patients receiving q2w doses, q4w up to Visit 8 [Week 24], and approximately every 
12-16 weeks up to the EOT visit), the IMP administrations can be performed by the Investigator 
or designee at site visits following clinic procedures and blood collection (see Section 1.2).  
Patients should be monitored for a minimum of 30 minutes at the study site after IMP injections, 
to assess any ISR (for example for any signs or symptoms of a hypersensitivity reaction). If the 
parent(s)/caregiver(s)/legal guardian(s) or the Investigator decides not to administrate IMP at 
home, the other injections can be performed at the study site by way of unscheduled visits. In 
order to closely monitor the 300 mg dose administration, the first injection must be performed 
onsite. Subsequent administrations are encouraged to occur at site wherever possible. If this is not 
possible, administration can be done by trained care givers or nurses at home. 
 
If the parent(s)/caregiver(s)/legal guardian(s) are willing to perform the IMP injection 
administration at home, these parent(s)/caregiver(s)/legal guardian(s) will be trained by the 
Investigator or designee to administer IMP, as well as monitoring of ISR, at the Visit 1 or any 
following visits of present study. After parent(s)/caregiver(s)/legal guardian(s) have successfully 
administered IMP under close supervision or instruction of the Investigator or designee, the 
Investigator approves them to perform home administration of IMP at all further IMP doses. 
Patients should be monitored for 30 minutes after home administration of IMP. 
If the Investigator or designee judges that the parent(s)/caregiver(s)/legal guardian(s)’s injection 
technique is not satisfactory, the further training can be performed in the upcoming 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 
time points 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 or 
IMP doses during the study. For any patient who misses a site visit or IMP dose, the 
parent(s)/caregiver(s)/legal guardian(s) should be reminded to be diligent to avoid missed visits 
and IMP doses thereafter. 
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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 >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 (eCRF) 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. 
Between the protocol-scheduled onsite visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, dupilumab may be supplied from the site to the 
patient/parent(s)/caregiver(s)/legal guardian(s) via a Sponsor-approved courier company where 
allowed by local regulations and approved by the subject. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
8.2.1 Inhaled corticosteroids alone or in combination with a second controller  
The recognized second controller medication for combined use with ICS (dose-levels in children 
7 to 12 years old) as background therapy during this study will include the following classes: 
LABA, LTRA, Long acting muscarinic antagonist (LAMA), or methylxanthines. Please refer to 
Section 17.1 for an indicative (not exhaustive) list of recognized second controller medications 
approved for this study. These controller medications will not be dispensed or supplied by the 
Sponsor. 
Route of administration:  
• Oral inhalation via metered dose inhaler (MDI) or dry powder inhaler (DPI) (for example 
ICS, ICS combination, albuterol/salbutamol, etc); for other background controllers 
according to label that is applicable to pediatric patients. 
Dose regimen:  
• Inhaled corticosteroids: ICS alone or in combination with a second controller as 
prescribed, as per Investigator's judgement. 
For patients experiencing a deterioration of asthma during the study, the ICS with/without second 
controller dose may temporarily be increased, as indicated and upon recommendation of the 
physician and/or Investigator. Treatment may then be changed to systemic corticosteroid (SCS) 
(severe exacerbation event) or reverted back to the original ICS with/without second controller 
dose or modified ICS with/without second controller dose depending on the asthma symptoms 
progression.  
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At enrollment: 
At enrollment, patients must be on background therapy (ICS alone or with a second controller) as 
in EOT visit of parent study. Patients enrolling into Study LTS14424 at a later date due to 
COVID-19 pandemic, must be on background therapy (High ICS dose alone or with a second 
controller or Medium ICS dose with a second controller). 
If patients take 2 different ICS, the total daily dose of ICS should be calculated, to evaluate the 
daily dose of ICS.  
Open-label treatment period: 
During this period, patients will continue to take their controller medication(s). During the course 
of treatment period, the Investigator, based on his/her medical judgement of the patients’ asthma 
control status, may decide to modify the dose regimen of asthma controller medication(s) to 
achieve an adequate control of patient’s asthma. Background controller medication(s) 
continuation per prescription will be reminded throughout the course of study to ensure the good 
compliance of such medication(s). All changes in the background medication regimen should be 
recorded in the eCRF. 
Post-treatment period 
Upon completing the treatment period or following early discontinuation of IMP, patients will 
continue into the post-treatment period. During the post-treatment period, patients will receive 
their background controller regimen based on Investigator’s judgement. 
8.2.2 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. 
The reliever medication (that is albuterol/salbutamol or levalbuterol/levosalbutamol) will not be 
dispensed or supplied by the Sponsor. 
Route of administration:  
• As prescribed. 
Dose regimen:  
• As prescribed. 
The reliever medication will be recorded as number of puffs in eCRF. The conversion factor is 
shown in the Table 1 and Table 2. 
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Table 1 - The reliever medication conversion factors  
Salbutamol/Albuterol nebulizer solution-total daily dose (mg) 
Number of puffsa 
2.5  
4 
5.0 
8 
7.5 
12 
10 
16 
a Conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs 
• Example of salbutamol/albuterol nebulizer-to-puff Conversion: Patient received 
3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. 
Total daily = 7.5 mg or 12 puffs. 
Table 2 - The reliever medication conversion factors  
Levosalbutamol/Levalbuterol nebulizer solution-total daily dose (mg) 
Number of puffsa 
0.63 
2 
1.25  
4 
2.5 
8 
3.75 
12 
5 
16 
a 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. 
8.2.3 Systemic corticosteroids  
Patients may be placed on SCS at any time as clinically indicated based on the presence of 
symptoms consistent with a severe asthma, as per the Investigator’s judgement. Dose and route of 
administration will be as prescribed. 
8.3 
BLINDING PROCEDURES  
Not applicable. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
The study medication will be administered only to patients included in this study following the 
procedures described in the clinical study protocol. The 7-digits serialized treatment kit number 
will be generated centrally by Sanofi clinical supply team. The IMPs are packaged in accordance 
with this list. 
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Patients who meet the entry criteria will receive dupilumab either 200 mg q2w or 300 mg q4w 
SC, based on body weight >30 kg or ≤30 kg at enrollment visit, respectively. Dupilumab dose will 
be adjusted during the treatment period, from 100 mg q2w or 300 mg q4w to 200 q2w mg SC, if 
the body weight increased to >30 kg. Once the dose switched to 200 mg q2w SC, the same dose 
will be maintained during the remaining treatment period. For children with body weight ≤30 kg 
currently in the treatment period receiving 100 mg q2w, the dupilumab dose will be changed at 
one planned or unscheduled site visit to 300 mg q4w if they are more than 8 weeks out from 
completing the treatment period (switch to q4w dose regimen to occur at site visit at Week 0 or 4, 
8, 12, 16, 20, 24, 28, 32, 36, 40, 44). Otherwise, they will continue on 100 mg q2w until EOT. All 
newly enrolled children with body weight ≤30 kg will take 300 mg q4w.  
Patients will be identified with 12-digit patient ID in study LTS14424 whereas 9-digit patient ID 
may be used in parent study. In that case, mapping rules will be applied to adapt parent study 
patient ID to LTS14424 12-digit patient ID. The investigational site will enter the patient tracking 
information for patient identification number, into the Interactive Voice Response System/ 
Interactive Web Response System (IVRS/IWRS) during each scheduled protocol visit. Treatment 
allocation will be performed centrally by IVRS/IWRS. The clinical site coordinator will document 
the patient number and the treatment kit number in the eCRF and in the patient’s source 
documents, and the patient number on the IMP label prior to dispensing to the patient. 
Patients will be considered to be enrolled in the study once a treatment kit number has been 
assigned by the IVRS/IWRS. Therefore, it is important that all inclusion/exclusion criteria are 
confirmed and all required procedures are completed prior to the enrollment contact to the 
IVRS/IWRS. Detailed IVRS/IWRS procedure will be provided in the IVRS/IWRS site manual. 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING  
Dupilumab 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 content of 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 
(for example pharmacists) in accordance with local regulations, policies, and procedures. 
Control of IMP storage conditions, especially control of temperature (for example 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. 
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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) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall 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, and returned by the parent(s)/caregiver(s)/legal guardian(s) of each 
patient. The IMP tracking log and inventory form is to be updated each time investigational 
product is dispensed or returned. Any investigational product not returned (even if considered 
empty) must be accounted for with a comment in the log. 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, any unused prefilled syringes, and the remaining volume of solution in each 
vial or syringe will be used for drug accountability purposes. 
Treatment kit number has to be recorded on the appropriate page of the eCRF and also on the IMP 
tracking log and inventory log form. 
The Monitoring Team in charge of the study will have to check eCRF data comparing them with 
the centralized treatment allocation system information, the IMP kit and IMP tracking log and 
inventory form. 
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A q4w phone contact will be planned after Week 24 to remind the parent(s)/caregiver(s)/legal 
guardian(s) to continue the IMP and the background controller medication (s) of patient as 
instructed by Investigator. 
For noninvestigational 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 (for example 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. 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). 
8.8.1 Prohibited concomitant medication  
The following concomitant treatments are not permitted during the study: 
• Anti-immunoglobulin E (IgE) therapy (for example omalizumab).  
• Biologic therapy.  
• Immunosuppressants.  
• Intravenous immunoglobulin (IVIG) therapy. 
• Live attenuated vaccinations during the study (refer to Section 17.2).  
• Asthma relievers other than salbutamol/albuterol or levosalbutamol/levalbuterol: their use 
is not recommended during the study period. In case of use in exceptional circumstances 
(for example prescribed by a physician not participating in the study), their use will be 
documented in the patient's file and reported in the eCRF. 
• Other investigational drugs.  
8.8.2 Cautioned concomitant medication (Cytochrome P450 enzyme substrates)  
The impact of dupilumab on Cytochrome P450 (CYP) enzyme activity has not been studied and 
the effect of dupilumab on levels of IL-4 and IL-13 has not been fully characterized. However, 
IL-4 was reported to upregulate CYP2E1, 2B6, 3A4 mRNA expression or downregulate CYP1A2 
mRNA (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 (6). 
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The risk of indirect effects of dupilumab, via modulation of IL-4 and IL-13 activities, on the PK 
of selected CYP substrates (midazolam, omeprazole, warfarin, caffeine, and metoprolol) has been 
studied in 14 adult patients with moderate to severe AD. The results of this study showed no 
evidence for a clinically meaningful effect of dupilumab on the activity of CYP3A, CYP2C19, 
CYP2C9, CYP1A2, or CYP2D6. Some examples of CYP450 substrates with narrow therapeutic 
index are provided in Section 17.3. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINT  
The primary endpoint for this study is the number (n) and percentage (%) of patients experiencing 
any TEAE (definition see Section 10.4.1.1) during total study periods. 
Additional analyses will describe the number (n) and percentage (%) of patients experiencing any: 
• Serious adverse events (SAE) (SAE definition refers to Section 10.4.1.2). 
• Adverse events of special interest (AESI) (AESI definition refers to Section 10.4.1.3). 
• Adverse events related to IMP. 
• Adverse events leading to permanent IMP discontinuation. 
• Adverse events other than ISR. 
Adverse events, including SAEs and AESI, will be collected at any time during study starting 
from signed consent form. Any new AEs (including worsening AEs) and ongoing AEs (with onset 
date before the day of enrollment) at enrollment visit (when done on the same day of EOT or EOS 
of parent study) will be reported in present 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. 
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. 
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. 
Adverse events for each patient will be monitored and documented from the time the subject gives 
informed consent/assent at Visit 1 until the EOS visit, except for: 
• Serious adverse events. 
• Adverse events that are ongoing at database lock. 
Adverse events, AESIs, SAEs, AEs leading to IMP discontinuation and deaths will be reported as 
described in Section 10.4.1 and analyzed as in Section 11.4.3.  
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Laboratory tests, vital signs, physical examination, or electrocardiogram (ECG) abnormalities are 
to be recorded as AEs only if they meet the criteria defined in Section 10.4.3, and are assessed as 
described in Section 9.1.1 to Section 9.1.3. Physical examination will also be performed. In 
addition to assessment of primary endpoint, below parameters are used on an ongoing basis 
during the study to monitor safety of participants and will be presented in a descriptive manner.  
9.1.1 Vital signs  
Vital signs including blood pressure (mmHg), heart rate (beats per minute), respiratory rate 
(breaths per minute), and body temperature (degrees Celsius) will be measured at each onsite visit 
except for IMP administration only visits.  
Vital signs will include height (cm) and body weight (kg). Height will be measured at the 
enrollment visit (Visit 1 of present study) and EOT visit, while weight at each onsite visit. 
Vital signs data for the Visit 1 can be obtained from the EOT visit of the parent study. Refer to 
Section 1.2 Study Flow Chart for the schedule of vital signs performed throughout this study. For 
patients not able to perform EOT visit onsite due to COVID-19 pandemic and for whom Visit 1 
can be conducted on the same day as EOS visit of the parent study, vital signs can be obtained 
from EOS. But, in case Visit 1 is done after EOS (up to 12 weeks after EOS), vital signs must be 
repeated. 
9.1.2 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 for girls.  
9.1.3 Electrocardiogram (ECG)  
Electrocardiogram (ECG) variables will be recorded by a standard 12-lead ECG. Enrollment visit 
data will be obtained from EOT visit of parent study. One recording will be performed at EOT 
and EOS (see Section 1.2). For patients not able to perform EOT visit onsite due to COVID-19 
pandemic and for whom Visit 1 can be conducted on the same day as EOS visit of the parent 
study, ECG can be obtained from EOS. But, in case Visit 1 is done after EOS (up to 12 weeks 
after EOS), ECG must be repeated.  
9.1.4 Clinical laboratory tests  
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. 
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Refer to Section 1.2 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 are: 
Hematology:  
To include blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), differential blood 
count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets. 
Serum chemistry:  
To include creatinine, blood urea nitrogen, glucose, total cholesterol, total protein, albumin, total 
bilirubin (in case of values above the normal range, differentiation in conjugated and 
nonconjugated bilirubin), alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), electrolytes (sodium, potassium, chloride), bicarbonate, and creatine 
phosphokinase (CPK). Patients’ fasting or nonfasting status at blood sample collection will be 
recorded on the Central Laboratory Requisition Form. 
Urinalysis: 
Urinalysis will be conducted by dipstick during onsite visit. The parameters include pH, glucose, 
ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen, and bilirubin (by dipstick). If 
any parameter on the dipstick is abnormal, further urine test is under Investigator’s judgement. 
Refer to Section 1.2 Study Flow Chart for the schedule of urinalysis performed throughout this 
study. 
Pregnancy test 
A urine pregnancy test must be negative at Visit 1 of present study for enrolling girls who have 
commenced menstruating, and a urine dipstick pregnancy test will be performed at subsequent 
onsite visits prior to administration of IMP. 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.  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Section 17.4. 
9.2 
SECONDARY ENDPOINTS  
9.2.1 Secondary efficacy endpoints  
The secondary efficacy endpoints of this study are: 
• Annualized rate of severe asthma exacerbation events, during the treatment period. 
• Change in percentage (%) predicted FEV1 (7) and other lung function parameters 
(absolute FEV1, forced vital capacity [FVC], forced expiratory flow [FEF] 25% to 75%) 
from baseline, and other time points assessed. 
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9.2.1.1 Assessment of severe asthma exacerbation  
A severe exacerbation event during the study is defined as a deterioration of asthma requiring:  
• Use of SCS for ≥3 days; or, 
• Hospitalization or emergency room visit because of asthma, requiring SCS. 
Two events will be considered as different if the interval between their start dates is ≥28 days. 
The reasons (for example infections including viral and bacterial, allergen exposure, exercise, and 
others) for any exacerbation event will be recorded in the eCRF. 
9.2.1.2 Assessment of lung function by spirometry  
Lung function parameters will be assessed by centralized spirometry at enrollment visit (Visit 1 of 
present study), Visit 2, Visit 4, Visit 5, Visit 8, EOT, and EOS visits. For Visit 1, spirometry 
parameters prebronchodilators will be obtained directly from EOT of parent study. For those 
patients that enroll in LTS14424 at the EFC14153 EOS visit or after, lung function assessments 
will be conducted at the EOS visit or at Visit 1.  
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 prebronchodilator measured parameters, including FEV1, 
peak expiratory flow (PEF), FVC, and FEF 25% to 75%, spirometry will be performed after a 
wash out period of bronchodilators according to their action duration, for example withholding the 
last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld for at 
least 24 hours), and withholding the last dose of LAMA for at least 24 hours. 
At all related visits, spirometry will be performed either in the AM or PM, but preferably in the 
AM, and 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. 
Pulmonary function tests will be measured in the sitting position; however, if necessary to 
undertake the testing with the subject standing or in another position, this should be noted on the 
spirometry report. For any subject, the position should be consistent throughout the study. 
Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained 
at every visit, if possible. The acceptability criteria must be applied before the repeatability 
criteria. Unacceptable maneuvers must be discarded before applying the repeatability criteria. If a 
subject fails to provide repeatable and/or acceptable maneuvers, an explanation should be 
recorded. 
The largest FEV1 and largest FVC should be recorded after the data are examined from all of the 
acceptable curves, even if they do not come from the same curve. The FEF 25% to 75% should be 
obtained from the single curve that meets the acceptability criteria and gives the largest sum of 
FVC plus FEV1 (best test). 
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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 (that is 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 Other secondary endpoints  
9.2.2.1 Dupilumab systemic exposure and immunogenicity  
Dupilumab systemic exposure and immunogenicity endpoints of this study are the evolution of: 
• Serum dupilumab concentrations. 
• Titers for ADAs. 
9.2.2.1.1 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). The date of collection should be recorded in the patient 
eCRF. 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. 
In the event of any SAE or any AESI of anaphylactic reactions or systemic allergic reactions that 
are related to IMP and require treatment, or severe ISR lasting longer than 24 hours, samples will 
be collected near the onset and resolution of the event for any additional analysis if required or for 
archival purposes. An unscheduled systemic drug concentration page (“PK page”) in the eCRF 
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. 
9.2.2.1.2 Handling procedure  
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and ADA is provided in Table 3. 
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Table 3 - 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 
9.2.2.1.3 Bioanalytic method  
Serum samples will be assayed using validated methods as described in Table 4.  
Table 4 - 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 
Abbreviation: ELISA = enzyme-linked immunosorbent assay. 
9.2.2.2 Pharmacodynamics and phenotyping  
Pharmacodynamics and phenotyping endpoints of this study are the evolution of: 
• Blood: Eosinophil count.  
• Serum: Total IgE. 
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 enrollment, after 24 weeks treatment, at EOT, and at EOS for their association with 
therapeutic response. 
Values of enrollment visit (Visit 1 of present study), will be obtained directly from EOT visit of 
parent study. For those patients that enroll in LTS14424 at the EFC14153 EOS visit or after, these 
assessments will be conducted at the EOS visit or at Visit 1.  
In previous asthma trials in adults and adolescents, treatment with dupilumab significantly 
suppressed the levels of serum total IgE (a product of immunoglobulin class switching driven by 
IL-4) and antigen-specific IgEs enrollment visit 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. These biomarkers have been included in parent study. Therefore, 
these biomarkers are included in the current study to assess their long-term suppression effect. 
Blood eosinophil counts will be captured from hematology assays as describe in Section 1.2. 
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Biomarkers include total IgE which will be measured with a quantitative method (for example 
ImmunoCAP) approved for diagnostic testing and antigen-specific IgE which will be detected 
using panels of antigens appropriate to the location of the clinical site (quantitative ImmunoCAP 
test; Phadia). 
More detailed information on the collection, handling, transport, and preservation of samples (for 
example minimum volumes required for blood collection and for aliquots for each biomarker 
assay) will be provided in a separate laboratory manual. 
9.3 
FUTURE USE OF SAMPLES  
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patient(s)/parent(s)/caregiver(s)/legal guardian(s) who have consented to it, the 
samples that are archived, unused or left over after planned testing may be used for additional 
research purposes. For subjects who have consented to it, archival blood samples will be collected 
at enrollment and at EOT visit of present study. Enrollment visit archival sampling will be 
waivered for patients who have been performed archival serum sampling at EOT visit of parent 
study. 
Archival blood samples will be collected into red-topped tubes with clot activator (5 mL draw), 
kept at room temperature for 30 minutes and then centrifuged at approximately 1500 g for 
10 minutes at room temperature. The serum will then be transferred, in equal portions, into 
2 storage tubes, which will be immediately capped and frozen in an upright position at -20°C or 
colder. 
These archived serum samples, and any residual or leftover serum, plasma or blood remaining 
from planned laboratory work, may be used for research purposes related to asthma (for example 
exploratory biomarkers of disease or drug effect), additional drug safety assessments or 
development and validation of bioassay methods beyond those defined in the present protocol. 
These samples will remain labeled with the same identifiers as the ones used during the study 
(that is subject ID, sample ID). They will be transferred to a Sanofi site (or a subcontractor site) 
which can be located outside of the country where the study is conducted. The Sponsor has 
included safeguards for protecting subject confidentiality and personal data (see Section 13.4 and 
Section 14.5). Any unused samples will be discarded by 5 years after completion of the last visit 
for the last patient enrolled in this trial. 
Globally, guidelines for blood collection volume limits for pediatric studies range between 
1% and 5% of total blood volume (TBV) for a single draw (or during a 24-hour period) and up to 
10% of TBV over 8 weeks (9). Scheduled collections in the current protocol, for the smallest 
possible patient (16 kg), remain within this limit for every 3 months. For all scheduled blood 
collection visits, the total volume does not exceed 1.5 mL/kg for the smallest possible patient. 
9.4 
APPROPRIATENESS OF MEASUREMENTS  
The safety and efficacy 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 3 periods, using an add-on therapy approach to conventional 
background asthma controller medications: 
• Enrollment (Visit 1 of present study).  
• Open-label treatment period (52 weeks; Visits 1-10). 
During the open-label treatment period, patients will continue their background therapy 
dose regimen, as maintained in the parent study or as modified based on Investigator's 
judgement. 
• Post-treatment period (12 weeks; Visit 11). 
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 in the treatment period and ±1 week for the 
remaining study period. 
Spirometry should be done at the study site approximately the same time of the day (preferably in 
the morning, but it could be done at a different time of the day). Spirometry should be performed 
at visits as detailed in Section 9.2.1.2. 
Once every 2 weeks IMP administration must be separated by at least 11 days. Once every 
4 weeks IMP administration must be separated by at least 25 days. The treatment period visits 
occur q2w up to Visit 3 (Week 4), q4w up to Visit 8 (Week 24), and approximately every 
12-16 weeks up to the EOS visit as detailed in Section 8.1.3. 
Investigational medicinal product can be administrated at home from Visit 2 (Week 2) after 
approval of Investigator. Patients should be monitored for a minimum of 30 minutes after 
injections at home. Observations should be recorded in a support document by injection giver and 
provided to Investigator or delegated during onsite visit. However, if the 
parent(s)/caregiver(s)/legal guardian(s) or the Investigator decides not to administer IMP at home, 
the injections can be performed at the study site by way of unscheduled visits. Patients should be 
monitored at the study site for a minimum of 30 minutes after injections.  
At the time of permanent treatment discontinuation, patients will perform the early treatment 
discontinuation (ETD) visits including early EOT visit and early EOS visit. Early EOT will be 
performed 2 weeks (with a ±3 days window) after last IMP injection whenever possible. If the 
time of decision taken for permanent IMP discontinuation is >2 weeks after last IMP injection, 
this early EOT visit should be scheduled as early as possible from permanent discontinuation of 
IMP decision. 
All the assessments defined for the EOT Visit 10 will be performed during this early EOT. Early 
EOS visit will be performed 12 weeks after early EOT visit with a ±1 week window. All the 
assessment defined for the EOS Visit 11 will be performed during this early EOS visit. 
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Patients should be reminded that sexually active 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. Procedures: 
a) Electrocardiogram 
b) Spirometry 
2. Safety and laboratory assessments. 
3. Investigational medicinal product administration, if planned, IMP dispensation and return. 
4. Controller therapy and medication withhold for next spirometry reminder. 
10.1 
VISIT SCHEDULE  
10.1.1 Enrollment: Visit 1 of present study (Start of treatment, Week 0)  
Eligible patients from parent study are considered to be candidates for the LTS14424 study. 
Patients who enroll in LTS14424 after completing the EFC14153 EOS visit should have 
laboratory assessments including complete blood count with differential and basic chemistry 
within 1 month prior to LTS14424 Visit 1 to evaluate continued eligibility. Prior to any discussion 
of participation of LTS14424 study, all the procedures related to EOT visit of parent study should 
be performed. Then following a discussion of participation in the present clinical trial, the patient 
and the parent(s)/caregiver(s)/legal guardian(s) must sign and date the Ethics Committee (EC) 
approved informed consent form (ICF)/informed assent form (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. These steps precede any study procedures. 
The below assessments are conducted at Visit 1. These assessments do not need to be repeated if 
Visit 1 is performed on the same day as EFC14153 EOT or EOS visit. 
The following activities are performed at the enrollment visit (Visit 1): 
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height); (waiver if data can be obtained from EOT or EOS visit of Study EFC14153 when 
it is done on the same day as Visit 1 of present study, except for body weight). 
• Call IVRS/IWRS to assign patient number and register enrollment visit. 
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• Interview to collect patient demographic information, medical history, asthma-specific 
medical history (that is family history of atopy and IgE mediated disease [particularly 
maternal], premature birth and/or, low birth weight, exposure to tobacco smoke, recurring 
viral infections in early childhood), surgical history. Data can be obtained from the parent 
study, if applicable. 
• Inquire prior and concomitant medications, including asthma controller and reliever 
medications. 
• Commence AE reporting from the time of the signature of the informed consent/assent for 
participation in LTS14424 (anticipated to be at the Visit 1). 
• Interview to collect vaccination information and vaccination plan during the treatment 
period. Remind live vaccines are not authorized. 
• Review entry criteria to assess eligibility. 
• Perform 12-lead ECG (data may be obtained from EOT or EOS visit of parent study when 
it is done at the same day as Visit 1 of present study). 
• Perform physical examination; (waiver if data can be obtained from EOT or EOS visit of 
parent study when it is done on the same day as Visit 1 of present study). 
• Perform spirometry (waiver if data can be obtained from EOT or EOS visit of parent study 
when it is done on the same day as Visit 1 of present study). 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours. 
• Menstruation status for female patients of childbearing potential. (Waiver if data can be 
obtained from EOT or EOS visit of parent study when it is done on the same day as Visit 1 
of present study). 
• Obtain blood samples for clinical laboratory parameters; (waiver if data can be obtained 
from EOT or EOS visit of parent study when it is done on the same day as Visit 1 of 
present study): 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating); (waiver if data can be obtained from EOT or EOS visit of 
parent study when it is done on the same day as Visit 1 of present study). 
• Obtain urinalysis test (dipstick); (waiver if data can be obtained from EOT or EOS visit of 
parent study when it is done on the same day as Visit 1 of present study). 
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• Systemic drug concentration and ADA; (waiver if data can be obtained from EOT or EOS 
visit of parent study when it is done on the same day as Visit 1 of present study). 
• Total IgE and antigen-specific IgE (refer to Section 9.2.2.2); (waiver if data can be 
obtained from EOT visit of parent study when it is done on the same day as Visit 1 of 
present study. For patients enrolling into Study LTS14424 at EOS visit of Study 
EFC14153 or up to 12 weeks after EOS, an additional blood draw will be done for total 
and antigen-specific IgE. 
• Archival serum for those patients who have signed a specific Future Use of Specimens 
informed consent/assent of present LTS14424 study (refer to Section 9.3); (waiver if 
sample is obtained from EOT visit of parent study). 
• Note: For patients not able to perform EOT or EOS visit of parent study onsite due to 
COVID-19 pandemic, all the assessments above must be performed during Visit 1. 
• Dispense and administer IMP. Patient whose body weight increased from ≤30 kg to 
>30 kg during the parent study, their dupilumab dose will be adjusted from 100 mg SC 
q2w or 300 mg SC q4w to 200 mg SC q2w at the time of enrollment visit (Visit 1 of 
present study and during treatment period: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection, 
- 
The injection training is for families who are willing to perform injection 
administration at home for children receiving q2w doses. The Investigator or delegate 
will review the patient’s administration technique at the Visit 1 (or upcoming onsite 
visits before permitting IMP administration at home).  
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to continue their dose of 
ICS alone or in combination with a second controller. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours. 
• Schedule a site visit 2 weeks later (Week 2 ±3 days) at approximately the same time of this 
visit. 
10.1.2 Open-label treatment period (Week 0 to Week 52 [Visits 2-10])  
10.1.2.1 Visit 2 (Week 2 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
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• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours.  
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP for children receiving q2w doses: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if IMP administrated on site. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Schedule a site visit 2 weeks later (Week 4 ±3 days) at approximately the same time of this 
visit. 
10.1.2.2 Visit 3 (Week 4 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Obtain blood samples for screening clinical laboratory determinations: 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
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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 if patients receive IMP on site, 
- 
Record observation of at least 30 minutes after the injection monitored by IMP giver if 
patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours. 
• Schedule a site visit 4 weeks later (Week 8 ±3 days) at approximately the same time of this 
visit. 
10.1.2.3 Visit 4 (Week 8 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform spirometry 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours. 
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
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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 if patients receive IMP on site, 
- 
Record observation of at least 30 minutes after the injection monitored by IMP giver if 
patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold the IMP 
dosing to secure an interval of 14 ±3 days prior to next onsite visit (Visit 5) for patients 
receiving IMP administration at home. 
• Schedule a site visit 4 weeks later (Week 12 ±3 days) at approximately the same time of 
this visit.  
10.1.2.4 Visit 5 (Week 12 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours. 
• Perform physical examination. 
• Assess menstruation status. 
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• Obtain blood samples for: 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1.1 for details). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Urinalysis (dipstick). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of at least 30 minutes after the injection monitored by IMP giver if 
patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Schedule a site visit 4 weeks later (Week 16 ±3 days) at approximately the same time of 
this visit. 
10.1.2.5 Visit 6 (Week 16 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of a minimum of 30 minutes after the injections monitored by IMP 
giver if patients receive IMP at home. 
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• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Schedule a site visit 4 weeks later (Week 20±3 days) at approximately the same time of 
this visit. 
10.1.2.6 Visit 7 (Week 20 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of a minimum of 30 minutes after the injection monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours.  
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold the IMP 
dosing to secure an interval of 14 ±3 days prior to next onsite visit (Visit 8) for patients 
receiving IMP administration at home. 
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• Schedule a site visit 4 weeks later (Week 24±3 days) at approximately the same time of 
this visit.  
10.1.2.7 Visit 8 (Week 24 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform physical examination. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours. 
• Assess menstruation status. 
• Obtain blood samples for: 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1 for details). 
• Total IgE and antigen-specific IgE (refer to Section 9.2.2.2).  
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Urinalysis (dipstick). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of a minimum of 30 minutes after the injection monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
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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 or as adjusted per 
Investigator's decision. 
• Schedule a site visit 12 weeks later (Week 36 ±3 days) at approximately the same time of 
this visit. 
10.1.2.8 Telephone contact at Week 28 and 32 (±3 days)  
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs; and report in eCRF along with 
date of phone call. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
10.1.2.9 Visit 9 (Week 36 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Obtain blood samples for: 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of a minimum of 30 minutes after the injection monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
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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 or as adjusted per 
Investigator's decision. 
• Schedule a site visit 16 weeks later (Week 52 ±3 days) at approximately the same time of 
this visit. 
10.1.2.10 
Telephone contact at Weeks 40, 44, and 48 (±3 days)  
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs; and report in eCRF along with 
date of phone call. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
For Week 48 only 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold the IMP 
dosing to secure an interval of 14 ±3 days prior to next onsite visit (EOT visit) for patients 
receiving IMP administration q2w at home or 28 ±3 days prior to next onsite visit (EOT 
visit) for patients receiving IMP administration q4w. 
10.1.2.11 
Visit 10 (Week 52 [±3 days]), End-of-treatment visit  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height). 
• Call IVRS/IWRS to register EOT visit. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform spirometry: 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 
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levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours. 
• Perform physical examination. 
• Assess menstruation status. 
• Perform 12-lead ECG. 
• Obtain blood samples for: 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1 for details). 
• Total IgE and antigen-specific IgE (refer to Section 9.2.2.2) . 
• Archival serum for those patients who have signed a specific Future Use of Specimens 
informed consent/assent (refer to Section 9.3).  
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Urinalysis (dipstick). 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
• Schedule a site visit 12 weeks later (Week 64 ±1 week) at approximately the same time of 
this visit. 
10.1.3 Post-treatment period (12 weeks)  
10.1.3.1 Telephone contact at Weeks 56 and 60 (±1 week)  
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs; and report in eCRF along with 
date of phone call. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol or levosalbutamol/levalbuterol as reliever medication as instructed by 
Investigator. 
• 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 or as adjusted per 
Investigator's decision. 
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For Week 60 only: 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours. 
10.1.3.2 Visit 11: (Week 64 [±1 week]), end-of-study visit  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register EOS visit. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform physical examination. 
• Perform spirometry: 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
Spirometry will be performed after a wash out period of bronchodilators according to 
their action duration, for example withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) 
and withholding the last dose of LAMA for at least 24 hours. 
• Assess menstruation status. 
• Perform 12-lead ECG. 
• Obtain blood samples for: 
- 
Hematology (see Section 9.1.4 for details), 
- 
Serum chemistry (see Section 9.1.4 for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1 for details). 
• Total IgE and antigen-specific IgE (refer to Section 9.2.2.2).  
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Obtain urinalysis test (dipstick). 
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 
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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 eCRF should be transcribed directly from source documents. Data 
downloaded from the study-associated central laboratories, and spirometry 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 must be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)  
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Re-initiation 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 judgement 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 will be causes 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 
Section 17.4 on Guidelines for management of specific laboratory abnormalities. 
• Any administration of live attenuated vaccines (refer to Section 17.2) during the study 
period. 
Temporary discontinuation may lead to permanent discontinuation after Sponsor’s review on a 
case by case basis. 
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 not to re-expose the patient to the IMP at any time during 
the study, or from the patient not to be re-exposed to the IMP whatever the reason. 
In case of permanent treatment discontinuation, the patient follow-up and visits are detailed in 
Section 10.3.4.  
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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 eCRF. 
Patients must be withdrawn from the study treatment (that is 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. 
• In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor. 
• Pregnancy (Note: dupilumab should be stopped but patient should be followed up until the 
outcome has been determined). 
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment. 
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin. 
• Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (see Section 17.6). 
• Serum ALT >3 upper limit of normal (ULN) and total bilirubin >2 ULN (see Section 17.4) 
• Serum ALT >5 ULN if enrollment visit ALT is <2 ULN or ALT >8 ULN if enrollment 
visit ALT is >2 ULN (Section 17.4). 
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 
judgement. 
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Patients who prematurely discontinue the study medication, at the time of permanent treatment 
discontinuation, patients will perform: 
• Early EOT visit: 2 weeks (with a ±3 days window) after last IMP injection. If the time of 
decision taken for permanent IMP discontinuation is >2 weeks +3 days after last IMP 
injection, this early EOT visit should be scheduled as early as possible from permanent 
discontinuation of IMP decision. All the assessments defined for the EOT Visit 10 will be 
performed during this early EOT,  
• Early EOS visit: 12 weeks after early EOT visit with a ±1 week window. All the 
assessment defined for the EOS Visit 11 will be performed during this visit. 
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 
eCRF when considered as confirmed. 
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 without any 
effect on their care. However, if patients no longer wish to take the IMP, they will be encouraged 
to remain in the study and perform the procedures planned for the EOT/EOS visit, including 
spirometry. 
The Investigators should discuss with parent(s)/caregiver(s)/legal guardian(s) key visits the patient 
to attend. The value of all their study data collected during their continued involvement will be 
emphasized as important to the public health value of the study. 
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision and any AE information elicited must be documented. 
All study withdrawals must be recorded by the Investigator in the appropriate screens of the eCRF 
and in the patient’s medical records. In the medical record, at least the date of the withdrawal and 
the reason should be documented. 
In addition, a patient may withdraw his/her consent to stop participating in the study. Withdrawal 
of consent for treatment should be distinguished from withdrawal of consent for follow-up visits 
and from withdrawal of consent for nonpatient contact follow-up, for example medical record 
checks. The site should document any case of withdrawal of consent. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must make the best effort to recontact the patient (for example contact patient’s 
family or private physician, review available registries or health care databases), and to determine 
his/her health status, including at least his/her vital status. Attempts to contact such patients must 
be documented in the patient’s records (for example times and dates of attempted telephone 
contact, receipt for sending a registered letter). 
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Patients who have withdrawn from the study cannot be re-enrolled (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. 
Protocol-defined severe asthma exacerbation events (for detailed definitions see 
Section 9.2.1.1) are collected as efficacy endpoints on the e-CRF. Only asthma exacerbations 
which fulfill a seriousness criterion should be reported as an AE (SAE) (as per Section 10.4.1.2). 
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 judgement 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 (that is 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 (that is agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc.) 
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- 
Development of drug dependence or drug abuse, 
- 
Alanine aminotransferase (ALT) >3 x ULN + total bilirubin >2 x ULN or 
asymptomatic ALT increase >10 x ULN, 
- 
New psychosis, 
- 
Suicide attempt or any event suggestive of suicidality, 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling), 
- 
Bullous cutaneous eruptions, 
- 
Bullous cutaneous eruptions requiring treatment, 
- 
Cancers diagnosed during the study, 
- 
Chronic neurodegenerative diseases (newly diagnosed). 
10.4.1.3 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or 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 Section 17.5 for the definition of anaphylaxis). 
• Serious ISRs or severe ISRs that last longer than 24 hours. 
Note: A severe ISR (for AE reporting) is any event that meets one of the following 
criteria: 
- 
With a diameter of at least 10 cm, 
- 
Impacting daily activities, 
- 
With ulceration or necrosis, 
- 
For which operative intervention is required. 
• An infection that meets at least one of the following criteria: 
- 
Any severe or serious infection (that meet any of the SAE criteria), 
- 
Is a parasitic infection, 
- 
Is an opportunistic infection (see list in Section 17.6). 
• Significant elevation of ALT (Section 17.4): 
- 
Alanine aminotransferase (ALT) >3 x the ULN associated with total 
bilirubin >2 x ULN; or, 
- 
Alanine aminotransferase (ALT) >5 × ULN in patients with enrollment visit 
ALT ≤2 × ULN; or, 
- 
Alanine aminotransferase (ALT) >8 × ULN if enrollment visit ALT >2 × ULN. 
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• 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 nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice the intended dose during an interval of <11 days 
for q2w or <25 days for q4w. The circumstances (that is accidental or intentional) 
should be clearly specified in the verbatim and symptoms, if any, entered on separate 
AE forms, 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice of the 
intended dose within the intended therapeutic interval. The circumstances (that is 
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/assent 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 eCRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and, his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). In studies that require the use of 
combined/multiple IMPs/NIMPs, the Global Safety Officer (GSO) with input from other 
appropriate study team members must determine if the causal relationship will either be 
assessed for the combined product as a regimen or as distinct entities. The GSO must 
communicate this decision to the study team for inclusion in the protocol and AE eCRF. 
• Causality will be assessed separately for IMP and NIMP. 
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• 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. 
At the prespecified study end-date, patients who experience an ongoing SAE or an AESI 
should be followed until resolution, stabilization, or death and related data will be 
collected. 
• 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, 
- 
Requiring either corrective treatment or consultation, and/or, 
- 
Leading to IMP discontinuation or modification of dosing, and/or, 
- 
Fulfilling a seriousness criterion, and/or, 
- 
Defined as an AESI. 
Instructions for AE reporting are summarized in Table 5. 
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 eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges.  
• All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper case report form [CRF] process) is available and should be 
used when the eCRF system does not work. 
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• 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 (that is within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the screens in the eCRF. 
Instructions for AE reporting are summarized in Table 5. 
10.4.6 Guidelines for management of specific laboratory abnormalities  
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Section 17.4.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices. 
• 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. 
Table 5 - 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 enrollment visit ALT is ≤2 ULN 
Within 24 hours 
 
ALT >8 ULN if enrollment visit 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 ISR 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 
Abbreviations: AESI = adverse event of special interest; ALT = alanine aminotransferase; ISR = injection site reaction; ULN = upper limit of 
normal.  
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10.5 
OBLIGATIONS OF THE SPONSOR  
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (Suspected 
Unexpected Serious Adverse Reaction [SUSAR]), to the regulatory authorities, 
Independent Ethics Committee (IEC)/Institutional Review Boards (IRB) 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 (for example wheezing related to asthma). 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health 
Authority of any SUSAR and reasonably associated with the use of the IMP according to either 
the judgement 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 (CSR). 
10.6 
SAFETY INSTRUCTIONS  
During the study, all patients will be closely monitored.  
In addition, any problems related to dupilumab injection administration should be documented in 
the patient’s home dosing diary and in the specific eCRF pages for local injection reactions 
recording. 
10.6.1 Hypersensitivity  
Allergic reaction is a potential risk associated with the administration of most therapeutic mAb. 
Allergic reactions may be defined as an immunologically mediated response to a pharmaceutical 
and/or formulation agent in a sensitized person. Signs and symptoms are often experienced during 
or shortly after therapeutic administration. Anaphylaxis may represent the most severe form of 
allergic reactions; refer to Section 17.5 “Definition of Anaphylaxis”, which describes the clinical 
criteria for the diagnosis of anaphylaxis. 
Patients should be monitored for at least 30 minutes after each study-site administered 
investigational product administration for any signs or symptoms of a hypersensitivity reaction. 
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Trained personnel and medications should be available to treat anaphylaxis or any severe allergic 
reaction if it occurs. Furthermore, the patients will be advised, when the IMP is administered at 
home, to self-monitor for potential signs and symptoms that may suggest a hypersensitive reaction 
for 30 minutes after administration. 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require treatment 
must be reported as an AESI (within 24 hours, for further details, see AESI definition in 
Section 10.4.1.3) and study medication must be permanently discontinued. Anti-drug antibodies 
and PK samples will be collected near the onset and resolution of the AESI for any additional 
analysis. 
In case of suspected anaphylaxis or systemic hypersensitivity reaction, sample for ADA should be 
obtained as close to the time of the event as possible. 
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 ISR observed at the highest dose level (300 mg weekly) severe ISR are considered as a 
potential risk. Patients who experience an ISR must be closely monitored for the possibility of a 
more intense ISR with a future injection. Any severe ISR that lasts over 24 hours will be reported 
as an AESI with immediate notification. Anti-drug antibodies and PK samples will be collected 
near the onset and resolution of the AESI for any additional analysis. 
Prophylactic treatment/premedication for an ISR is not permitted. 
10.6.3 Infections  
Some biologic therapies have been associated with an increased risk of infection, including 
opportunistic infection. As a precautionary measure, the Investigator is required to carefully 
monitor for any signs or symptoms of infection such as, but not limited to, increased body 
temperature, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, or serious febrile 
systemic illness. 
Infections with a diversity of helminthic parasites elicit eosinophilia via stimulation of Th2-like 
lymphocyte responses. The Th2 response is characterized by production of IL-4, IL-13, and IL-5, 
subsequently generating IgG1 and IgE-secreting cells, and eliciting eosinophilia. The eosinophilic 
response to helminths is determined both by the host's immune response and by the parasite, 
including its distribution, migration, and development within the infected host. Since dupilumab 
binds to IL-4Rα, preventing IL-4 and IL-13 binding, and activation of their respective receptors, it 
inhibits Th2 cytokine production. Therefore, patients treated with dupilumab may potentially have 
an increased risk of parasitic infection. 
In order to minimize this risk, any patient with an active parasitic infection should be excluded 
from the study. Similarly, patients with suspected parasitic infection, or those at high risk of 
parasitic infection are also excluded, unless clinical and (if necessary) laboratory assessments 
have ruled out active infection before enrollment. During the study, appearance of signs or 
symptoms (such as abdominal pain, cough, diarrhea, fever, fatigue, hepatosplenomegaly) that 
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could be associated with a parasitic infection should be carefully evaluated; especially if there is a 
history of parasitic exposure through recent travel to/or residence in endemic areas, particularly 
when conditions are conducive to infection (for example extended stay, rural or slum areas, lack 
of running water, consumption of uncooked, undercooked, or otherwise potentially contaminated 
food, close contact with carriers, and vectors, etc). Subsequent medical assessments (for example 
stool exam, blood tests, etc) must be performed in order to rule out parasitic infection/infestation. 
Patients with confirmed parasitic infections during the study should be reported as AESI with 
immediate notification. 
Infections defined in Section 10.4.1.3 should be reported as AESIs within 24 hours. 
A complete diagnostic work-up should be performed (that is cultures, histopathological or 
cytological evaluation, antigen detection, and serum antibody titers). Patients should be referred to 
an infectious disease specialist, if deemed necessary, for diagnostic work up, and appropriate 
treatment: 
• Infections or infestations that do not respond to medical treatment should have study IMP 
discontinued until the infection is resolved. 
• For any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (see Section 17.6), patients must be permanently 
discontinued from IMP. 
10.6.4 Elevated liver function tests  
No preclinical or clinical data have suggested any hepatic toxicity of dupilumab; however, as 
general consideration of clinical development, the administration of immunosuppressant or 
immunomodulating agents may represent an additional risk factor for hepatotoxicity. 
In order to closely follow liver function tests (LFT), assessment of total protein, albumin, total 
bilirubin, ALT, AST, and ALP are measured as part of the clinical laboratory testing. 
Guidance for the investigation of elevated LFTs is provided in Section 17.4. 
10.7 
ADVERSE EVENTS MONITORING  
All events will be managed and reported in compliance with all applicable regulations and 
included in the final CSR. 
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11 
STATISTICAL CONSIDERATIONS  
11.1 
DETERMINATION OF SAMPLE SIZE  
The primary objective of the study is to evaluate the long-term safety and tolerability of 
dupilumab in patients with asthma who participated in previous dupilumab asthma clinical trial. 
Hence, the maximal number of patients to participate in this 1-year treatment safety study will be 
the number corresponding to the total randomized in previous dupilumab asthma clinical study.  
Based on the observed enrolment rate of 87% from parent study to this study, the expected 
number of sample size for LTS14424 study is approximately 354 patients (that is around 87% of 
408 patients from parent study). 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patients who signed the informed consent/assent.  
Enrolled patients consist of all the patients who signed informed consent/assent and had a 
treatment kit number allocated and recorded in IVRS/IWRS database, and regardless of whether 
the treatment kit was used or not.   
The safety population consists of the patients who actually received at least one dose or part of a 
dose of dupilumab in the LTS14424 study. 
11.3 
ANALYSIS POPULATIONS  
11.3.1 Efficacy populations  
Efficacy population is the same as the safety population.  
11.3.2 Safety population  
The primary analysis population is the safety population, which is defined as all patients exposed 
to at least 1 dose or part of 1 dose of dupilumab during LTS14424 study regardless of the amount 
of treatment administered. 
11.3.3 Pharmacokinetics population  
The PK population will consist of all the patients in the safety population with at least one 
nonmissing and evaluable predose serum concentration value after the first dose of dupilumab in 
the LTS14424 study.  
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11.3.4  Anti-drug antibody population  
The ADA population will consist of all the patients in the safety population with at least one 
non-missing ADA result following the first dose of dupilumab in the LTS14424 study. 
11.4 
STATISTICAL METHODS  
For each analysis population defined in Section 11.3, the planned analyses will be conducted in 
the following two analysis sets, respectively.  
The full analysis set for each analysis population will include all data observed in the study.  
The modified analysis set for each analysis population will censor the data observed on or after 
the first dose of 300 mg q4w for the patients in this analysis population who were exposed to the 
300 mg q4w regimen. Particularly, the patients who will initiate the treatment on 300 mg q4w 
regimen since Week 0 of LTS14424 study will be excluded from the modified analysis set.  
For each analysis set, the planned analyses will be presented by the group of patients according to 
their actual treatment groups in the parent study EFC14153, specifically, ‘Placebo-Dupilumab’, 
‘Dupilumab-Dupilumab’, and ‘All’. 
11.4.1 Extent of study treatment exposure and compliance  
The extent of study treatment exposure and compliance will be summarized in the two analysis 
sets for safety population as defined in Section 11.4. 
11.4.1.1 Extent of investigational medicinal product exposure  
Duration of exposure to IMP is defined as: last dose date – first dose date of dupilumab + dose 
interval, regardless of unplanned intermittent discontinuations. Duration of exposure will be 
summarized using descriptive statistics such as mean, standard deviation (SD), median, minimum, 
and maximum. 
11.4.1.2 Compliance  
A given administration of IMP will be considered "noncompliant" if the patient did not take the 
planned dose of treatment as required by the protocol. No imputation will be made for patients 
with missing or incomplete data. 
Percentage of compliance for a patient will be defined as 100 x (the number of administrations the 
patient was compliant divided by the total number of administrations the patient was planned to 
take during the treatment period). 
Treatment compliance will be summarized descriptively (N, mean, SD, median, minimum, and 
maximum). The percentage of patients with compliance <80% will be summarized. 
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11.4.2 Analyses of efficacy endpoints  
All analyses will be done descriptively in the two analysis sets for safety population as defined in 
Section 11.4 in observed case, as appropriate. 
The baseline value for the applicable efficacy parameters is the original baseline from the parent 
study. 
For the continuous efficacy variables, descriptive statistics (mean, SD, median, minimum, and 
maximum) will be presented for the parameter and its change from baseline over visits. In 
addition, figure of mean change from baseline (with corresponding standard error) will be 
presented for the continuous efficacy parameter over visits. The baseline for the primary analyses 
for change from baseline for continuous efficacy variables will be the baseline in parent study. 
Supplemental analyses for change from current study baseline will also be provided for selected 
efficacy variables. The list of these selected variables will be further detailed in Statistical 
Analysis Plan (SAP). 
For the categorical efficacy variables, the number and percentage will be presented over time for 
all patients who have data available at that time point. 
For severe exacerbation events, total number of severe exacerbation events, total patient-years, 
unadjusted annualized severe exacerbation event rate, and individual patient annualized severe 
exacerbation event rate (number, mean, SD, median, minimum, maximum) during the treatment 
period will be summarized. In the modified analysis set, for the patients whose dose regimen 
switch from 100 mg q2w to 300 mg q4w, the events observed on or after the first injection day of 
300 mg q4w regimen will be excluded and the observational period will be censored at the day 
before the first dose of 300 mg q4w. The time point window for the efficacy analyses will be the 
same as that defined for safety analyses. More details about the efficacy analysis methods and the 
time point window can be found in the SAP. 
11.4.3 Analyses of safety data  
All safety analysis will be performed in two analysis sets for the safety population as defined in 
Section 11.4. The baseline value for the applicable safety parameters is the original baseline from 
the parent study. 
11.4.3.1 Adverse events  
The treatment-emergent period is defined for the two analysis sets separately as follows. 
For the full analysis set, the treatment emergent period is from the date of first IMP injection to 
the date of the last IMP injection +14 weeks for the patients who end the dupilumab treatment on 
either 100 mg q2w or 200 mg q2w regimen; and, the treatment emergent period is from the date 
of first IMP injection to the date of the last IMP injection +16 weeks for the patients who end the 
dupilumab treatment on 300 mg q4w regimen. 
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For the modified analysis set, the treatment emergent period is from the date of first IMP injection 
to the date of the last IMP injection +14 weeks for the patients who never expose to the 300 mg 
q4w regimen; and, the treatment emergent period is from the date of first injection of 100 mg q2w 
regimen to the date before the first injection of the 300 mg q4w regimen for the patients who 
uptitrate the dosage from 100 mg q2w to 300 mg q4w during the study. 
Adverse event reported in this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) in effect at Sanofi at the time of database lock. Adverse events occurred 
during the treatment-emergent period will be considered as TEAEs. 
11.4.3.1.1  Treatment-emergent adverse events  
Treatment-emergent adverse event incidence tables will be presented 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, the number (n) and percentage (%) of 
patients experiencing a TEAE. Multiple occurrences of the same event in the same patient will be 
counted only once in the tables. The denominator is based on the total number of patients in the 
safety population. 
Proportion of patients with at least one TEAE, serious TEAE, and TEAE leading to 
discontinuation of the study will be tabulated. TEAEs will also be described according to 
maximum intensity and relation to the study drug. Adverse events that are not treatment-emergent 
will be summarized separately. 
11.4.3.1.2 Adverse event of special interest  
The following summaries will be generated: 
• Incidence of each AESI will be tabulated. 
• The time-to-first event analyzed using Kaplan-Meier (K-M) methods and displayed as 
K-M plots (cumulative incidence (%) versus time based on K-M estimates) will be 
provided to depict the course of onset over time. Number of treatment-emergent AESIs per 
100 patient-years (total number of events adjusted for the total duration of exposure) will 
be presented by decreasing incidence of PT. 
• An overview summary of the number (%) of patients with: 
- 
Any TEAE, 
- 
Any serious AE (regardless of treatment-emergent status), 
- 
Any treatment-emergent SAE, 
- 
Any AE leading to death, 
- 
Any TEAE leading to permanent study drug discontinuation, 
- 
Any TEAE by maximum intensity, corrective treatment, and final outcome, 
- 
Cumulative incidence (K-M estimates) up to specified time points. 
Adverse event of special interest (AESI) definitions and the method to identify AESIs will be 
specified in the SAP. 
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11.4.3.1.3  Death  
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population. 
• Treatment-emergent adverse event (TEAE) leading to death (death as an outcome on the 
AE eCRF page as reported by the Investigator) by primary SOC, HLGT, HLT, and PT 
showing number (%) of patients sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT. 
Patient data listings will be provided for all AEs, TEAEs, SAE, and AEs leading to study 
discontinuation, AESIs, and deaths. 
11.4.3.1.4 Clinical laboratory evaluation, vital signs, and electrocardiogram data  
Results and change from baseline for the parameters will be summarized for baseline and each 
post baseline time point, endpoint, minimum, and maximum value. Summary statistics will 
include number of patients, mean, SD, median, first quartile (Q1), the third quartile (Q3), 
minimum, and maximum. 
Listings will be provided with flags indicating clinically out of range values, as well as potentially 
clinically significant abnormalities (PCSA) values. 
11.4.4 Analyses of systemic drug concentration, anti-drug antibodies, and 
pharmacodynamics variables  
11.4.4.1 Pharmacokinetic analysis  
The PK analyses will be performed in the two analysis sets for PK population as defined in 
Section 11.4 by the dose regimen. The baseline value of each applicable PK variable is the 
original baseline from the parent study. Serum concentrations of functional dupilumab will be 
summarized using arithmetic and geometric means, SD, standard error of the mean (SEM), 
coefficient of variation, minimum, maximum, and median. 
11.4.4.2 Anti-drug antibodies analysis  
The ADA analyses will be performed in the two analysis sets for ADA population as defined in 
Section 11.4. The baseline value of each applicable ADA variable is the original baseline from the 
parent study. The incidence of positivity in the ADA assay will be assessed as absolute occurrence 
(n) and percent of patients (%). 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, if applicable. Assessment of the potential 
impact of ADA on safety, efficacy, and PK may be provided. The ADA analyses will be detailed 
in SAP. 
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11.4.4.3 Pharmacodynamics  
The biomarker analyses will be applied in the two analysis sets for safety population. The baseline 
value for the applicable pharmacodynamics (PD) variables is the original baseline from the parent 
study. For all PD parameters, the descriptive statistics (number, mean, median, SD, Q1, Q3, 
minimum and maximum) will be summarized over time for the raw measurements, the change 
from baseline, and percentage change from baseline. Summary plots (mean ±SEM) over time on 
the raw measurements, change from baseline, and percentage change from the baseline will be 
presented for the PD parameters. 
All parameters will be summarized in descriptive statistics. 
11.5 
INTERIM ANALYSIS  
This is 1 year treatment safety study. Interim analyses/reports may be prepared to support 
regulatory submissions of an indication in the dupilumab project or other purposes. No alpha 
adjustment is needed for the final CSR. 
 
 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS  
12.1 
ETHICAL AND REGULATORY STANDARDS  
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Council for Harmonisation (ICH) guidelines for Good Clinical Practice (GCP), all applicable 
laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the EC (IRB/IEC). All participants should be informed to the fullest extent possible 
about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent/assent form 
should be signed, name filled in and personally dated by the patient or by the patient’s legally 
acceptable representative, and by the person who conducted the informed consent/assent 
discussion. A copy of the signed and dated written informed consent/assent form will be provided 
to the patient. 
The informed consent/assent form used by the Investigator for obtaining the patient's informed 
consent/assent must be reviewed and approved by the Sponsor prior to submission to the 
appropriate EC (IRB/IEC) for approval/favorable opinion. 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, should fully inform the patient (and the parent[s] or guardian[s]) of all pertinent 
aspects of the clinical trial including the written information given approval/favorable opinion by 
the EC (IRB/IEC). All participants should be informed to the fullest extent possible about the 
study in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the informed consent/assent form should be 
signed, name filled in and personally dated by the patient’s parent(s) or by the patient’s legally 
acceptable representative, and by the person who conducted the informed consent/assent 
discussion. Local law must be observed in deciding whether 1 or both parents/guardians consent 
is required. If only 1 parent or guardian signs the consent form, the Investigator must document 
the reason for only 1 parent or guardian’s signature. 
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In addition, participants will assent as detailed below or will follow the EC (IRB/IEC) approved 
standard practice for pediatric participants at each participating center (age of assent to be 
determined by the IRB’s/IEC’s or be consistent with the local requirements): 
• Participants who can read the assent form will do so before writing their name and dating 
or signing and dating the form. 
• Participants who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Participants who can understand but who can neither write nor read will have the assent 
form read to them in presence of an impartial witness, who will sign and date the assent 
form to confirm that assent was given. 
The informed consent/assent form and the assent form used by the Investigator for obtaining the 
Patient’s Informed Consent/assent must be reviewed and approved by the Sponsor prior to 
submission to the appropriate EC (IRB/IEC) for approval/favorable opinion. 
In relation with the population of patients exposed in the trial that is pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical, and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title, and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s 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 eCRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements, and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent/assent, patient recruitment and follow-up, SAE documentation 
and reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use, and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the preidentified source data directly recorded in the eCRF. The informed 
consent/assent form will include a statement by which the patient allows the Sponsor’s duly 
authorized personnel, the EC (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (for example patient's medical file, 
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appointment books, original laboratory records, etc.). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS  
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 
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14 
ADDITIONAL REQUIREMENTS  
14.1 
CURRICULUM VITAE  
A current copy of the CV describing the experience, qualification, and training of each 
Investigator and Subinvestigator will be signed, dated, and provided to the Sponsor prior to the 
beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES  
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents for 25 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 eCRFs, the Investigator's, 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 Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Subject race or ethnicity will be collected in this study because these data are required by several 
regulatory authorities (for example on African American population for Food and Drug 
Administration [FDA]). 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION  
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IRBs/IECs or regulatory authorities in countries requiring this document. 
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES  
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE  
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio. 
• Patient enrollment is unsatisfactory. 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator  
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent/assent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent/assent form prior to implementation of the change and patient signature should be 
recollected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES  
1. Nordlund B, Melen E, Schultz ES, Grönlund H, Hedlin G, Kull I. Prevalence of severe 
childhood asthma according to the WHO. Respir Med. 2014;108(8):1234-7. 
2. Hedlin G, Bush A, Lodrup Carlsen K, Wennergren G, De Benedictis FM, Melen E, et al. 
Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur 
Respir J. 2010;36(1):196-201. 
3. Levine SJ, Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the 
treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152(4):232-7. 
4. Wenzel SE, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in 
persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-66. 
5. Wenzel SE, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-
controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388(10039):31-44. 
6. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, et al. The impact of cytokines 
on the expression of drug transporters, cytochrome P 450 enzymes and chemokine receptors in 
human PBMC. Br J Pharmacol. 2009;156(3):497-508. 
7. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-
regulate expression of major cytochrome p-450 enzymes in adult human hepatocytes in 
primary culture. Mol. Pharmacol. 1993;44(4):707-15 
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(2):319-38. 
9. Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89(1):46–53 
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. Hedlin G, Bush A, Lodrup Carlsen K, Wennergren G, De Benedictis FM, Melen E, et al. 
Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur 
Respir J. 2010;36(1):196-201. 
12. Levine SJ, Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the 
treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152(4):232-7. 
13. Wenzel SE, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in 
persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-66. 
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14. Wenzel SE, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-
controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388(10039):31-44. 
15. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, et al. The impact of cytokines 
on the expression of drug transporters, cytochrome P 450 enzymes and chemokine receptors in 
human PBMC. Br J Pharmacol. 2009;156(3):497-508. 
16. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-
regulate expression of major cytochrome p-450 enzymes in adult human hepatocytes in 
primary culture. Mol. Pharmacol. 1993;44(4):707-15 
17. 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(2):319-38. 
18. Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89(1):46–53 
19. 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. 
20. Hedlin G, Bush A, Lodrup Carlsen K, Wennergren G, De Benedictis FM, Melen E, et al. 
Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur 
Respir J. 2010;36(1):196-201. 
21. Levine SJ, Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the 
treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152(4):232-7. 
22. Wenzel SE, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in 
persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-66. 
23. Wenzel SE, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-
controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388(10039):31-44. 
24. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, et al. The impact of cytokines 
on the expression of drug transporters, cytochrome P 450 enzymes and chemokine receptors in 
human PBMC. Br J Pharmacol. 2009;156(3):497-508. 
25. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-
regulate expression of major cytochrome p-450 enzymes in adult human hepatocytes in 
primary culture. Mol. Pharmacol. 1993;44(4):707-15 
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26. 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(2):319-38. 
27. Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89(1):46–53 
28. 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. 
29. Hedlin G, Bush A, Lodrup Carlsen K, Wennergren G, De Benedictis FM, Melen E, et al. 
Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur 
Respir J. 2010;36(1):196-201. 
30. Levine SJ, Wenzel SE. Narrative review: The role of Th2 immune pathway modulation in the 
treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152(4):232-7. 
31. Wenzel SE, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in 
persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368(26):2455-66. 
32. Wenzel SE, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β2 agonist: a randomized double-blind placebo-
controlled pivotal phase 2b dose-ranging trial. Lancet 2016;388(10039):31-44. 
33. Liptrott NJ, Penny M, Bray PG, Sathish J, Khoo SH, Back DJ, et al. The impact of cytokines 
on the expression of drug transporters, cytochrome P 450 enzymes and chemokine receptors in 
human PBMC. Br J Pharmacol. 2009;156(3):497-508. 
34. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier JC, Corcos L, Turlin B, et al. Cytokines down-
regulate expression of major cytochrome p-450 enzymes in adult human hepatocytes in 
primary culture. Mol. Pharmacol. 1993;44(4):707-15 
35. 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(2):319-38. 
36. Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ. 2011;89(1):46–53 
37. 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. 
 
 
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17 
APPENDICES  
17.1 
APPENDIX A: 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 
Long acting β2 agonist (LABA) 
 
Salmeterol 
 
Formoterol  
 
Bambuterol  
 
Clenbuterol  
 
Tulobuterol 
 
Vilanterol 
 
Olodaterol 
 
Indacaterol 
Leukotriene receptor antagonists (LTRA) or anti-leukotrienes 
 
Montelukast  
 
Pranlukast 
 
Zafirlukast  
 
Zileuton 
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Controller group 
Medications 
Long acting muscarinic antagonist (LAMA) 
 
Tiotropium 
 
Glucopyrronium bromide 
 
Aclidinium bromide 
 
Umeclidinium 
Methylxanthines 
 
Aminophylline 
 
Theophylline 
 
Dyphylline  
 
Oxtryphylline 
 
Diprophylline 
 
Acebrophylline 
 
Bamifylline 
 
Doxofylline 
Abbreviations: CFC = chlorofluorocarbon propellant; HFA = hydrofluoroalkane propellant; MDI = metered dose inhaler. 
Note: This list is indicative and not exhaustive. 
17.2 
APPENDIX B: 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 
Note: This list is indicative and not exhaustive. 
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17.3 
APPENDIX C: 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 
Abbreviation: CYP = Cytochromes P450. 
Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm. 
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 (for 
example Torsades de Pointes) or loss of therapeutic effect.  
2. 
Because a number of CYP3A substrates (for example 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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17.4 
APPENDIX D: GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI  
 
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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Applies to Phase 2, 3, and 4 studies where inclusion is limited to patients with baseline ALT 
≤2 x ULN (excluding patients with clinically-relevant hepatic disease) 
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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17.5 
APPENDIX E: DEFINITION OF ANAPHYLAXIS  
 
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
 
Adapted from: 
 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et al. Second symposium on the 
 
definition and management of anaphylaxis: Summary report–Second National Institute of Allergy and Infectious 
 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117:391-7 
 
Clinical criteria for diagnosing anaphylaxis 
 
17.6 
APPENDIX F: 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 [for example 
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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17.7 
APPENDIX G: COUNTRY SPECIFIC REQUIREMENTS  
17.7.1 Amended Protocol 01 for Brazil (14 March 2018)  
The following text is applicable to Brazil: 
Sections: Tabulated Clinical Trial Summary (see I 01) and 7.1 Inclusion Criteria (see I 01, 
Section 7.1), respectively 
I 01. 
Pediatric patients with asthma who completed the treatment in a dupilumab asthma trial 
(EFC14153).  
Specific for Brazil: EFC14153 patients from Brazil, who prematurely discontinued IMP to 
receive Yellow Fever vaccine (a live attenuated vaccine) during Yellow Fever outbreak, 
are allowed to be enrolled in LTS14424 after completing the required procedures in 
EFC14153 (completion of remaining visits and procedures until EOT V28, considered as 
V1 for LTS14424). 
17.7.2 Country specific requirements for Japan  
Japan substudy. 
17.7.2.1 Clinical trial summary  
 
COMPOUND: Dupilumab 
STUDY No.: LTS14424 
INVESTIGATOR/TRIAL LOCATION 
Japan 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVE(S)  
 
Primary objective: 
• 
To evaluate the efficacy of dupilumab in children of 6 to <12 
years of age with uncontrolled persistent asthma in the 
Japan substudy. 
Secondary objective(s): 
• 
To evaluate the safety and tolerability of dupilumab in 
pediatric patients with asthma in the Japan substudy. 
• 
To evaluate dupilumab in pediatric patients with asthma in 
the Japan substudy with regard to: 
- 
Systemic exposure, 
- 
Anti-drug antibodies (ADAs), 
- 
Biomarkers. 
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STUDY DESIGN 
The substudy consists of 3 periods: 
• 
Screening period:4 [±1] weeks. 
- 
Prior to and during the screening period, patients must 
be on stable-dose background therapy of medium-
dose inhaled corticosteroids (ICS) with a second 
controller medication (ie, long acting β2 agonists 
[LABA], long acting muscarinic antagonists [LAMA], 
leukotriene receptor antagonists [LTRA], or 
methylxanthines) or high-dose ICS alone, or high-dose 
ICS with a second controller medication, for at least 3 
months with a stable dose ≥1 month prior to the 
screening visit (Visit 0).  
• 
Treatment period: 52 weeks open-label treatment. 
• 
Post-treatment period: 12 weeks. 
Upon completion of the treatment period (or following early 
discontinuation of the investigational medicinal product (IMP]), 
patients will continue into the post-treatment period. During the 
post-treatment period, patients will receive their background controller 
regimen based on Investigator’s judgement. 
STUDY POPULATION  
 
 
Main Inclusion criteria: 
I 01. 
Signed written inform consent/assent. 
I 02. 
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 
a second controller medication (ie, LABA, LTRA, 
LAMA, or methylxanthines) or high-dose ICS alone or 
high-dose ICS with a second controller, for at least 
3 months with a stable dose ≥1 month prior to the 
screening visit (Visit  0). Fluticasone propionate must 
be ≥200 mcg daily. 
- 
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 visit (Visit 0) and baseline visit 
(Visit 1). 
- 
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 
salbutamol reliever medication before enrollment (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 between the 
screening visit (Visit 0) and up to the day of the actual 
baseline visit (Visit 1). Patients can have the last 
attempt of reversibility testing (for eligibility) at the 
baseline visit (Visit 1) before enrollment. 
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Note: Documented reversibility or positive airway 
hyperresponsiveness to methacholine within 
12 months prior to screening visit (Visit 0) is 
considered acceptable. 
- 
Must have experienced, within 1 year prior to the 
screening visit (Visit 0), 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 Asthma Control 
Questionnaire–Interviewer Administered (ACQ-IA) 
ACQ-5 score ≥1.5 at the screening visit (Visit 0) and 
baseline visit (Visit 1), prior to enrollment. 
I 03. 
Blood eosinophil count ≥150 cells/μL or fractional exhaled 
nitric oxide (FeNO)  ≥20 parts per billion (ppb) at screening 
visit (Visit 0). 
 
Main Exclusion criteria: 
E 01. 
Any chronic lung disease other than asthma (eg, cystic 
fibrosis, bronchopulmonary dysplasia) which may impair 
lung function. 
E 02. 
Inability to follow the procedures of the study/noncompliance 
(eg, due to language problems or psychological disorders). 
E 03. 
Patients receiving concomitant treatment or required a new 
concomitant treatment prohibited in the study at the 
screening and enrollment visits. 
E 13. 
Patients who previously have been treated with dupilumab 
E 14. 
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 15. 
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.  
Total expected number of patients 
Approximately 16 patients 
STUDY TREATMENT(s) 
Investigational medicinal product(s) 
Dupilumab 
Formulation: 
Dupilumab for children ≥15kg and ≤30 kg: 150 mg/mL in prefilled 
syringe to deliver a dose of 100 mg once every 2 weeks (q2w) in a 
0.67 mL subcutaneous (SC) injection. 
Or 
Dupilumab for children ≥15kg and≤30 kg: 150 mg/mL in prefilled 
syringe to deliver a dose of 300 mg once every 4 weeks (q4w) in a 
2 mL SC injection. 
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Dupilumab for children >30 kg: 175 mg/mL in prefilled syringe to 
deliver a dose of 200 mg q2w in a 1.14 mL SC injection.  
Route(s) of administration: 
SC injection 
Dose regimen: 
Dupilumab 200 mg SC q2w for children with body weight >30 kg and 
100 mg SC q2w or 300mg q4w for children with body weight ≥15kg 
and ≤30 kg.  
Patients with body weight ≤30 kg will receive dupilumab 100 mg q2w 
or 300 mg q4w in 1:1 ratio at randomization. The same dose regimen 
determined at baseline will be maintained and will not be adjusted 
upon weight gain or loss during the treatment period. A minimum of 
3 patients assigned to treatment with each of the 3 dose regimens is 
targeted. 
Noninvestigational medicinal product(s)  
 
Formulation: 
Inhaled corticosteroids (ICS) 
Alone or in combination with a second controller. 
Reliever medication 
Patients may receive salbutamol MDI as reliever medication (as 
needed) during the study. Nebulizer solutions may be used as an 
alternative delivery method.  
Systemic corticosteroids (SCS) 
Systemic corticosteroids may be given in case of severe asthma 
based on Investigator’s judgement. 
Route(s) of administration: 
Oral inhalation via MDI or dry powder inhaler (DPI; for example ICS, 
ICS combination, salbutamol, etc.); for background controllers, 
relievers, and SCS according to label that is applicable to pediatric 
patients. 
Dose regimen: 
 
Inhaled corticosteroid: ICS alone or in combination with a second 
controller. 
Reliever medication, as needed. 
SCS, as prescribed.  
ENDPOINT(S) 
 
Primary endpoint: 
• 
Change from baseline in pre-bronchodilator percentage (%) 
predicted FEV1 at Week 12. 
Secondary endpoints: 
• 
Efficacy 
- 
Annualized rate of severe asthma exacerbation 
events, during the treatment period. 
- 
Change from baseline in pre-bronchodilator % 
predicted FEV1 at Weeks 2, 4, 8, 24, 52, and 64. 
- 
Change from baseline in other lung function 
measurements (absolute FEV1, FVC, FEF 25-75%) at 
Weeks 2, 4, 8, 12, 24, 52, and 64. 
- 
Change from baseline at Week 2, 4, 8, 12, 24, 36, 52, 
and 64 in ACQ-IA. 
• 
Safety 
- 
The number (n) and percentage (%) of patients 
experiencing any treatment-emergent adverse events 
(TEAEs). 
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• 
Dupilumab systemic exposure and immunogenicity 
- 
Serum dupilumab concentrations. 
- 
ADAs. 
• 
Biomarkers 
- 
Serum: Total immunoglobulin E (IgE). 
- 
FeNO. 
ASSESSMENT SCHEDULE 
Study onsite visits are performed q2w up to Visit 3 (Week 4) of the 
study, q4w up to Visit 8 (Week 24), and approximately every 
12-16 weeks up to the end-of-study (EOS) visit. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
For the Japan substudy, the primary objective is to evaluate the 
efficacy of dupilumab in children 6 to <12 years of age with 
uncontrolled persistent asthma. Assuming the change from baseline 
in % predicted FEV1 at Week 12 among the Japan substudy follows a 
normal distribution with mean of 10.74% and standard deviation of 
14.12%, a sample size of 16 for the Japan sub-study will lead to a 
half-width of the 95% confidence interval being 7.5%. A minimum of 3 
patients assigned to treatment with each of the 3 dose regimens is 
targeted. 
The sample size calculations were performed using nQuery Advisor. 
Analysis population: 
Efficacy population: same as safety population, which is defined as all 
patients exposed to at least 1 dose or part of 1 dose of dupilumab 
during LTS14424 study regardless of the amount of treatment 
administered.  
Primary analysis: 
Change from baseline in percentage (%) predicted FEV1 at Week 12 
will be summarized using descriptive statistics. 
Analysis of secondary endpoints: 
For each variable, descriptive summary will include: n, point estimate, 
and confidence intervals will be provided as appropriate. Graphical 
time course profiles will be provided when appropriate for 
documentation of outcomes. 
Incidence of TEAE will be summarized using descriptive statistics. 
DURATION OF STUDY PERIOD (per 
patient)  
• 
Screening period:  4 [±1] weeks. 
• 
Treatment period: Open-label treatment for 52 weeks 
(1 year). 
• 
Post-treatment period: 12 weeks. 
The total duration, per patient, is approximately 68 weeks. 
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17.7.2.2 Flow charts  
17.7.2.2.1 Graphical study design  
 
 
Abbreviations: E = enrollment; ICS = inhaled corticosteroid; LABA = long acting β2 agonist; LAMA = long acting muscarinic antagonist; LTRA = leukotriene receptor antagonist; q2w = once every 
2 weeks; q4w=once every 4 weeks; SCS = systemic corticosteroid.  
 
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17.7.2.2.2 Study flow chart  
Study periods 
Screening 
period 
(4±1 weeks)a 
Open-label treatment period 
(52 weeks)  
Post-treatment period 
(12 weeks) 
Enrollment 
 
EOTb 
 
 
EOS  
SOT (D1) 
Week (W) 
W-4 
W0 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28c 
W32c 
W36 
W40c 
W44c 
W48c 
W52 
W56c 
W60c 
W64 
Onsite visitd 
0 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
9 
 
 
 
10 
 
 
11 
Enrollment 
 
  
Informed 
consent/assente 
X 
 
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Inclusion /Exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
demographics 
X 
 
  
 
 
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Medical & surgical 
historyf, and 
reversibilityg 
X 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Treatment 
 
  
Call IVRS/IWRS 
X 
X 
Xh 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
X 
  
  
X 
IMP dispense/ 
administrationi 
 
X 
Xh 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
  
  
  
  
Injection 
training/technique 
observationj 
 
   <- ---------------------------------------------------------------------------- X ------------------------------------------------------------------------------→ 
  
  
  
Prior & concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Study periods 
Screening 
period 
(4±1 weeks)a 
Open-label treatment period 
(52 weeks)  
Post-treatment period 
(12 weeks) 
Enrollment 
 
EOTb 
 
 
EOS  
SOT (D1) 
Week (W) 
W-4 
W0 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28c 
W32c 
W36 
W40c 
W44c 
W48c 
W52 
W56c 
W60c 
W64 
Onsite visitd 
0 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
9 
 
 
 
10 
 
 
11 
Patient reported 
outcome(s) 
 
  
ACQ-IAk 
X 
X 
X 
 X 
X 
X 
 
  
X 
 
 
X 
  
  
  
X 
  
  
X 
Efficacy 
 
  
Spirometryl 
X 
X 
X 
 X 
X 
X 
  
  
X 
 
 
 
  
  
  
X 
  
  
X 
Safety 
 
  
Vital signs 
(including height 
and weight)m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
X 
  
  
X 
Physical 
examination 
X 
 
  
  
  
X 
  
  
X 
  
 
 
  
  
  
X 
  
  
X 
Menstruation status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
X 
  
  
X 
Dispense or check 
diaryn 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG  
X 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
X 
  
  
X 
Vaccines record 
review scheduling 
X 
 
  
  
 
 
 
  
 
  
 
 
 
  
 
  
 
  
  
Adverse event 
reporting 
   <- ------------------------------------------------------------------------------------------------ X --------------------------------------------------------------------------------------------------------------------------→ 
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Study periods 
Screening 
period 
(4±1 weeks)a 
Open-label treatment period 
(52 weeks)  
Post-treatment period 
(12 weeks) 
Enrollment 
 
EOTb 
 
 
EOS  
SOT (D1) 
Week (W) 
W-4 
W0 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28c 
W32c 
W36 
W40c 
W44c 
W48c 
W52 
W56c 
W60c 
W64 
Onsite visitd 
0 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
9 
 
 
 
10 
 
 
11 
Laboratory 
Testing 
 
  
 
 
  
 
  
  
  
  
 
 
  
  
  
  
  
  
  
Clinical 
laboratorieso 
X 
X 
  
X 
 
X 
  
  
X 
 
 
X 
  
  
  
X 
  
  
X 
Urine pregnancy 
test for girls that are 
menstruatingp,r 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
  
  
  
X 
  
  
X 
Urinalysisq,r 
X 
 
  
  
  
X 
  
  
X 
  
 
 
  
  
  
X 
  
  
X 
PK samplingr 
 
X 
  
  
 
X 
  
  
X 
  
 
 
  
  
  
X 
  
  
X 
ADAr 
 
X 
  
  
 
X 
  
  
X 
  
 
 
  
  
  
X 
  
  
X 
Serum total IgE and 
Ag-specific IgEr 
 
X 
 
  
  
 
 
  
X 
  
 
 
  
  
  
X 
  
  
X 
FeNOs 
X 
X 
X 
X  
X 
X 
  
  
X 
 
 
 
  
  
  
X 
  
  
X 
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Study periods 
Screening 
period 
(4±1 weeks)a 
Open-label treatment period 
(52 weeks)  
Post-treatment period 
(12 weeks) 
Enrollment 
 
EOTb 
 
 
EOS  
SOT (D1) 
Week (W) 
W-4 
W0 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W28c 
W32c 
W36 
W40c 
W44c 
W48c 
W52 
W56c 
W60c 
W64 
Onsite visitd 
0 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
9 
 
 
 
10 
 
 
11 
Reminder 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
Controller and 
reliever therapy 
reminderc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Medication withhold 
reminderc 
X 
X 
X 
X  
 X 
 
  
X 
 
 
 
 
 
 
X 
 
 
X 
  
Abbreviations: ADA = anti-drug antibody; ACQ = Asthma Control Questionnaire; Ag specific IgE = antigen-specific IgE; D = (study) day; ECG = electrocardiogram; eCRF = electronic case report form; EOS = end-of-
study; EOT = end-of-treatment; FeNO = fractional exhaled nitric oxide; IgE = immunoglobulin E; IMP = investigational medicinal product; IVRS/IWRS = Interactive Voice Response System/Interactive Web Response 
System; ICS = inhaled corticosteroid; LABA = long acting β2-agonist; LAMA = long acting muscarinic antagonist; PK = pharmacokinetic; q2w = once every 2 weeks; q4w = once every 4 weeks; SOT = start-of-treatment; 
W = (study) week. 
a The screening period is 4±1 weeks (21-35 days) in duration to 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 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 the screening visit (Visit 0). 
b Patients who permanently discontinue IMP 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 ±1 week window or 
up to recovery or stabilization of any adverse event. At the time of permanent treatment discontinuation, patients will perform the ETD visit with all the assessments defined for the EOT Visit 10. 
c Phone contact to collect safety information + reminders for IMP, controller, and reliever therapy, if appropriate reminder for withholding medication at the next visit as described in the individual visit schedules 
Safety information and date of phone call will be recorded in eCRF. 
d The visit windows for all subsequent visits post-enrollment on Day 1 will be ±3 days during the treatment period and ±1 week during the post-treatment period.  
e 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.  
f 
Medical history, asthma- history, atopic and food allergy medical history, surgical history. 
g Reversibility of at least 10% in FEV1 after the administration of 200 to 400 mcg (2 to 4 puff inhalations with MDI) of salbutamol reliever medication before enrolment (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 V0 is 
considered acceptable. If the patient does not meet this reversibility criterion at the screening visit (Visit 0), up to 2 additional assessment attempts can be performed at any time between the screening (Visit 0) and 
baseline (Visit 1) visits. 
h For patients receiving 300 mg q4w, no IMP will be dispensed/administered at Week 2 and no IVRS/IWRS call will occur. 
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i 
Once every 2 weeks IMP administrations must be separated by at least 11 days. Once every 4 weeks IMP administrations must be separated by at least 25 days.  After each IMP administration, patients should be 
monitored for a minimum of 30 minutes after injections. If the parent(s)/caregiver(s)/legal guardian(s) or the Investigator decides not to administer IMP at home, the injections can be performed at the study site 
by way of unscheduled visits. 
j 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to perform injection administration at home.  It is possible to start home administration 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 injections (eg, at Week 0, Week 2 and Week 4 for q2w doses and at Week 0, Week 4 and Week 
8 for q4w doses) followed by a successful IMP administration under close supervision of the investigator or designee at not less than 3 injections (eg, at Week 6, Week 8, Week 10, and Week 12 for q2w doses and 
Week 12, Week 16 and Week 20 for q4w doses). Subsequent administrations are encouraged to occur at site wherever possible, 
k Asthma Control Questionnaire–Interviewer Administered (ACQ-IA, for children 6 to <12 years), ACQ-7 and ACQ-5 scores 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 V0 and Baseline V1 for all patients. 
l 
Spirometry should be done at the study site approximately the same time of the day (preferably in the morning, but it could be done at a different time of the day). Spirometry will be performed after a washout period 
of bronchodilators according to their action duration (for example withholding the last dose of salbutamol for at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be 
withheld for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours. Also spirometry should be performed prior to IMP administration, as applicable.  
m Vital signs, including blood pressure (mmHg), heart rate (beats per minute), respiratory rate (breaths per minute), body temperature (degrees Celsius), and body weight (kg) will be measured at each on site visit 
except for IMP administration only visit. Height will be measured at each onsite visit except for the IMP administration only visit and Visit 9 (Week 36).Except for height and weight, other vital signs will be measured 
in the sitting position using the same arm at each visit, and will be measured prior to receiving investigational product at the clinic visits. 
n Paper diary is used for daily recording of asthma controller drug use during the screening period to calculate controller treatment compliance. The diary is dispensed at Visit 0. 
o Clinical laboratories: Hematology: blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets. Serum 
chemistry: total bilirubin (in case of values above the normal range, differentiation in conjugated and nonconjugated bilirubin), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), total protein, albumin, total cholesterol, creatine phosphokinase (CPK), glucose, creatinine, blood urea nitrogen (BUN), bicarbonate, and electrolytes (sodium, potassium, chloride). Clinical 
laboratory testing only at Visit 0 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). For details, please refer to Section 17.7.2.8.3.5. 
p 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 (Visit 0) with negative result obtained prior to 
enrolment at Visit 1 (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. In case of positive urine test, the study treatment will be withheld and a serum pregnancy test to confirm the pregnancy should be performed as soon as possible. 
q Urinalysis: pH, glucose, ketones, leukocyte esterase blood, protein, nitrate, urobilinogen, and bilirubin (by dipstick). For details, please refer to Section 17.7.2.8.3.5. 
r 
Samples will be collected prior to IMP administration.  
s FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
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17.7.2.3 Rationale  
Patients in Japan were not included in Study EFC14153. A substudy is added with Japanese 
patients aged 6 to <12 years with uncontrolled persistent asthma. The primary objective of the 
substudy is to evaluate efficacy of dupilumab in this population, which will be evaluated in a 
separate analysis. The details of the substudy including patient characteristics, evaluations, 
statistical analysis, and database lock are outlined below. 
17.7.2.4 Study objectives  
17.7.2.4.1 Primary  
The primary objective of this Japan substudy is to evaluate the efficacy of dupilumab in children 
from Japan who are 6 to <12 years of age with uncontrolled, persistent asthma. 
17.7.2.4.2 Secondary  
The secondary objectives of this study are: 
• To evaluate the safety and tolerability of dupilumab in Japanese pediatric patients with 
asthma. 
• To evaluate dupilumab in Japanese pediatric patients with asthma with regard to: 
- 
Systemic exposure, 
- 
ADAs, 
- 
Biomarkers. 
17.7.2.5 Study design  
17.7.2.5.1 Description of the study  
This substudy is a multicenter, open-label, single arm, 1-year treatment study evaluating 
dupilumab given SC for a period of 52 weeks among pediatric patients in Japan. Dose regimen 
will be 200 mg q2w for patients with body weight >30 kg, 100 mg q2w or 300 mg q4w in 1:1 
ratio for patients with body weight ≥15 kg and ≤30 kg. 
Upon completion of the treatment period (or following early discontinuation of IMP), patients will 
continue into the post-treatment period. During the post-treatment period, patients will receive 
their background controller regimen based on Investigator’s judgement. 
For a schematic study design, please refer to Section 17.7.2.2.1. 
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17.7.2.5.2 Duration of study participation  
17.7.2.5.2.1 
Duration of study participation for each patient  
The total duration, per patient, is of approximately 68 weeks. 
For each patient, this includes the following 3 periods: 
• Screening period: 4 ±1 weeks. 
• Treatment period: 52 weeks open-label treatment (1 year) with last dosing at Week 50 
for q2w and at Week 48 for q4w. 
• Post-treatment period: 12 weeks. 
17.7.2.5.2.2 
Determination of end of clinical trial (all patients)  
See Section 6.2.2. 
17.7.2.5.3 Data monitoring committee  
Not applicable. 
17.7.2.6 Selection of patients  
17.7.2.6.1 Inclusion criteria  
I 01. Signed written inform consent/assent. 
I 02. 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 GINA 2015 Guidelines, and the following criteria: 
- 
Existing 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 ≥1 month prior to 
screening visit (Visit 0) (dose levels as per Section 17.7.2.14). Fluticasone propionate 
must be ≥200 mcg daily, 
- 
Pre-bronchodilator FEV1 ≤95% of predicted normal or pre bronchodilator FEV1/FVC 
ratio <0.85 at screening visit (Visit 0) and baseline visit (Visit 1), 
- 
Reversibility of at least 10% in FEV1 after the administration of 200 to 400 mcg 
(2 to 4 puffs with MDI) of salbutamol reliever medication before enrollment (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 between the screening visit (Visit 0) and up to the day of the actual baseline visit 
(Visit 1). Patients can have the last attempt of reversibility testing (for eligibility) at the 
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baseline visit (Visit 1) before enrollment. 
Note: Documented reversibility or positive airway hyper-responsiveness to 
methacholine within 12 months prior to screening visit (Visit 0) is considered 
acceptable. 
- 
Must have experienced, within 1 year prior to screening visit (Visit 0), defined as any 
of the following events: 
a) Treatment with a 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 Asthma Control Questionnaire–Interviewer 
Administered (ACQ-IA) ACQ-5 score ≥1.5 at the screening visit (Visit 0) and the 
baseline visit (Visit 1), prior to enrollment. 
I 03. Blood eosinophil count ≥150 cells/μL or FeNO ≥20 parts per billion (ppb) at screening 
visit (Visit 0). 
I 04. Willing and able to comply with clinic visits and study-related procedures. 
I 05. With parent(s)/caregiver(s)/legal guardian(s) able to understand the study requirements. 
I 06. Patients/parent(s)/caregiver(s)/legal guardian(s), as appropriate, must be able to understand 
and complete study-related questionnaires. 
17.7.2.6.2 Exclusion criteria  
Exclusion criteria related to study methodology 
E 01. Any chronic lung disease other than asthma (eg, cystic fibrosis, bronchopulmonary 
dysplasia) which may impair lung function. 
E 02. Inability to follow the procedures of the study/noncompliance (eg, due to language 
problems or psychological disorders). 
E 03. Patients receiving concomitant treatment or required a new concomitant treatment 
prohibited in the study at the screening and enrollment visits (see Section 17.7.2.7.8). 
E 04. Patients or his/her parent(s)/caregiver(s)/legal guardian(s) is related to the Investigator or 
any Subinvestigator, research assistant, pharmacist, study coordinator, other staff thereof 
directly involved in the conduct of the study. 
E 05. Patients <6 or ≥12 years of age. 
E 06. Patients <15 kg body weight at baseline. 
E 07. A patient with any history of life-threatening asthma (eg, requiring intubation). 
E 08. Co-morbid disease that might interfere with the evaluation of IMP. 
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E 09. History of malignancy of any kind. 
E 10. Anti-immunoglobulin E therapy (omalizumab) within 130 days or interleukin-5 antagonist 
(mepolizumab) within 110 days prior to Visit 0, or any other biologic 
therapy/immunosuppressant to treat inflammatory disease or autoimmune disease (eg, 
rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus as well as 
other diseases) within 2 months or 5 half-lives prior to Visit 0, whichever is longer. 
E 11. Initiation of allergen immunotherapy within 3 months prior to Visit 0 or dose change from 
1 month prior to Visit 0 or a plan to begin allergen immunotherapy or to change its dose 
during the screening period or the open-label treatment period. 
E 12. Exposure to another investigative antibody within a time period prior to Visit 0 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 0. 
E 13. Patients who previously have been treated with dupilumab. 
Exclusion criteria related to the current knowledge of Sanofi compound 
E 14. 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 15. 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 16. For female patients who have commenced menstruating at any time during the study and 
are either: 
• Found to have a positive urine pregnancy test, confirmed by a serum pregnancy test in 
case of a positive urine test, or 
• Sexually active, not using an established acceptable contraceptive method: 
- 
Oral, injected, inserted, or implanted hormonal contraceptive. 
- 
Intrauterine device or intrauterine system with progesterone. 
- 
Barrier contraceptive (condom, diaphragm, or cervical/vault caps) used with 
spermicide (foam, gel, film, cream, or suppository). 
E 17. Planned live (attenuated) vaccinations during the study and receiving live (attenuated) 
vaccines within 4 weeks before the enrollment visit (Visit 1). 
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E 18. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, juvenile idiopathic arthritis, inflammatory bowel disease, 
systemic lupus erythematosus). Those 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. 
Exclusion criteria related to the current knowledge of Sanofi compound 
E 19. History of human immunodeficiency virus (HIV) infection or positive HIV serology at 
Visit 0. 
E 20. Evidence of acute or chronic infection requiring systemic treatment with antibacterials, 
antivirals, antifungals, antiparasitics, or antiprotozoals within 4 weeks before Visit 0 or 
during the screening period, significant viral infections within 4 weeks before Visit 0 or 
during the screening period that may not have received antiviral treatment (eg, influenza 
receiving only symptomatic treatment). 
E 21. Patient with a history of a systemic hypersensitivity reaction, other than localized injection 
site reaction, to any biologic drug. 
E 22. At the screening: Patients with positive (or indeterminate) test for hepatitis B surface 
antigen (HBs-Ag) or positive immunoglobulin M (IgM) hepatitis B core antibody or 
positive total hepatitis B core antibody (HBc-Ab) confirmed by positive hepatitis B virus 
DNA (HBV DNA) or positive hepatitis C virus antibody (HCV-Ab) confirmed by positive 
hepatitis C virus RNA (HCV RNA). 
E 23. Liver injury related criteria: 
- 
Clinically significant/active hepatobiliary disease, or, 
- 
Elevated transaminases (ALT and/or AST) >3 ULN at screening. 
E 24. Abnormal lab values at Screening: 
- 
CPK >3 ULN, or, 
- 
Platelets <100 000 cells/mm3, or, 
- 
Eosinophils >1500 cells/mm3. 
Exclusion Criteria Related to the Active Comparator and/or Mandatory Background 
Therapies  
E 25. 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 a 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 diary during the screening period. 
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E 26. Patient treated with SCS for diagnoses other than severe exacerbation of asthma, and/or 
high-potency topical steroids within 30 days before screening visit (Visit 0), during the 
screening period, and/or during the treatment phase of this study. 
E 27. 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 
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. 
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 ICF/IAF). 
E 29. Despite screening of the patient, enrollment/randomization is stopped at the study level. 
17.7.2.6.3 Criteria for temporarily delaying screening, enrollment, and administration of the study 
treatment  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix 3 (see Section 17.7.2.16) should be considered for screening, enrollment, and 
administration of the study treatment. 
17.7.2.7 Study treatment  
17.7.2.7.1 Investigational medicinal product(s)  
17.7.2.7.1.1 
Dupilumab  
Route of administration:  
• Dupilumab for children ≥15 kg and ≤30 kg: 150 mg/mL in prefilled syringe to deliver a 
dose of 100 mg q2w in a 0.67 mL SC injection. 
OR 
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• Dupilumab for children ≥15 kg and ≤30 kg: 150 mg/mL in prefilled syringe to deliver a 
dose of 300 mg q4w in a 2 mL SC injection. 
• Dupilumab for children >30 kg: 175 mg/mL in prefilled syringe to deliver a dose of 
200 mg q2w in a 1.14 mL SC injection. 
Dose regimen: Dupilumab 200 mg SC q2w for children with body weight >30 kg and 100 mg SC 
q2w or 300 mg q4w for children with body weight ≥15 kg and ≤30 kg. 
Patients with body weight ≥15 kg and ≤30 kg will receive dupilumab 100 mg q2w or 300 mg q4w 
in 1:1 ratio at randomization. The same dose regimen determined at baseline will be maintained 
and will not be adjusted upon weight gain or loss during the treatment period. A minimum of 
3 patients assigned to treatment with each of the 3 dose regimens is targeted. 
17.7.2.7.1.2 
Preparation of investigational product  
See Section 8.1.2. 
17.7.2.7.1.3 
Dosing schedule  
Dupilumab is administered every 14±3 days q2w or every 28 days ±3 days q4w. The doses of 
investigational product must be separated by ≥11 days for q2w and ≥25 days for q4w to avoid 
overdose.  
For IMP administrations coinciding with scheduled study site visits (q2w up to Visit 3 [Week 4] 
for patients receiving q2w doses, q4w up to Visit 8 [Week 24], and approximately every 
12-16 weeks up to the EOT visit), the IMP administrations can be performed by the Investigator 
or designee at site visits following clinic procedures and blood collection (see Section 17.7.2.2.2).  
Patients should be monitored for a minimum of 30 minutes at the study site after IMP injections, 
to assess any ISR (for example for any signs or symptoms of a hypersensitivity reaction). If the 
parent(s)/caregiver(s)/legal guardian(s) or the Investigator decides not to administrate IMP at 
home, the other injections can be performed at the study site by way of unscheduled visits. 
Administrations are encouraged to occur at site wherever possible. If this is not possible, 
administration can be done by trained care givers or nurses at home. 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to perform 
injection administration at home. It is possible to start home administration provided 
parent(s)/caregiver(s)/legal guardian(s) who have been trained to administer IMP by 
demonstration of at least 3 injections by the Investigator or designee followed by at least 3 
successful IMP administration under close supervision of the Investigator or designee. 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 eg, at Visit 1 (Week 0), Visit 2 (Week 2), and Visit 3 (Week 4) 
for q2w doses and Visit 1 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8) for q4w doses 
(injections performed by Investigator or designee). After parent(s)/caregiver(s)/legal guardian(s) 
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have successfully administered IMP under close supervision of the Investigator or designee eg, at 
Week 6, Visit 4 (Week 8), Week 10, and Visit 5 (Week 12) for q2w doses and Visit 5 (Week 12), 
Visit 6 (Week 16), and Visit 7 (Week 20) for q4w doses, the Investigator may approve them to 
perform home administration of IMP.  
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 the injections can be 
performed at the study site by way of unscheduled visits or to administer IMP at these time points 
at the patient's home by qualified site personnel and/or healthcare professionals (for example 
visiting nurse service). 
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 or 
IMP doses during the study. For any patient who misses a site visit or IMP dose, the 
parent(s)/caregiver(s)/legal guardian(s) should be reminded to be diligent to avoid missed visits 
and IMP doses 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 17.7.2.2.2) even if >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 (eCRF) 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. 
Between the protocol-scheduled onsite visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, dupilumab may be supplied from the site to the 
patient/parent(s)/caregiver(s)/legal guardian(s) via a Sponsor-approved courier company where 
allowed by local regulations and approved by the patient. 
17.7.2.7.2 Noninvestigational medicinal product(s)  
17.7.2.7.2.1 
Inhaled corticosteroids alone or in combination with a second controller  
The recognized second controller medication for combined use with ICS (dose-levels in children 
6 to <12 years old) as background therapy during this study will include the following classes: 
LABA, LTRA, LAMA, or methylxanthines. Please refer to Appendix A (see Section 17.1) for an 
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indicative (not exhaustive) list of recognized second controller medications approved for this 
study. Fluticasone propionate must be ≥200 mcg daily. These controller medications will not be 
dispensed or supplied by the Sponsor. 
Route of administration:  
• Oral inhalation via MDI or DPI (for example ICS, ICS combination, albuterol/salbutamol, 
etc.); for other background controllers according to label that is applicable to pediatric 
patients. 
Dose regimen:  
• Inhaled corticosteroids: ICS alone or in combination with a second controller as 
prescribed. 
For patients experiencing a deterioration of asthma during the study, the ICS with/without second 
controller dose may temporarily be increased, up to 4-fold for a maximum of 10 days, as indicated 
and upon recommendation of the physician or Investigator. Treatment may then be changed to 
SCS (severe exacerbation event) or reverted back to the original ICS with/without second 
controller 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 Section 17.1 Appendix A and Section 17.7.2.14 
Appendix 1) 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 the screening 
visit (Visit 0).  
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 Section 17.7.2.14. 
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 (Visit 0), any 
changes in ongoing asthma medications must occur more than 1 month in advance of the 
screening visit (Visit 0) Day 1, in order to maintain a stable dose for at least 1 month prior to 
Day 1 (Section 17.7.2.6). 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 17.7.2.6). 
 
 
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Open-label treatment period 
During this period, patients will continue to take their controller medication(s) used during the 
screening period. The dose and baseline regimen of controller medications 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).  
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 treatment period or following early discontinuation of IMP, patients will 
continue into the post-treatment period. During the post-treatment period, patients will receive 
their background controller regimen based on Investigator’s judgement. 
17.7.2.7.2.2 
Reliever medication  
See Section 8.2.2. 
17.7.2.7.2.3 
Systemic corticosteroids  
See Section 8.2.3. 
17.7.2.7.3 Blinding procedures  
See Section 8.3. 
17.7.2.7.4 Method of assigning patients to treatment group  
The study medication will be administered only to patients included in this study following the 
procedures described in the clinical study protocol. The 7-digit serialized treatment kit number 
will be generated centrally by the Sanofi clinical supply team. The IMPs are packaged in 
accordance with this list. 
Dose regimen will be 200 mg q2w for patients with body weight >30 kg, 100 mg q2w or 300 mg 
q4w in 1:1 ratio for patients with body weight ≥15 kg to ≤30 kg. The same dose regimen 
determined at baseline will be maintained and will not be adjusted upon weight gain or loss during 
the treatment period. A minimum of 3 patients assigned to treatment with each of the 3 dose 
regimens is targeted.   
Patients will be identified with a 12-digit patient ID. The investigational site will enter the patient 
tracking information for patient identification number, into the Interactive Voice Response 
System/ Interactive Web Response System (IVRS/IWRS) during each scheduled protocol visit. 
Treatment allocation will be performed centrally by IVRS/IWRS. The clinical site coordinator 
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will document the patient number and the treatment kit number in the eCRF and in the patient’s 
source documents, and the patient number on the IMP label prior to dispensing to the patient. 
Patients will be considered to be enrolled in the study once a treatment kit number has been 
assigned by the IVRS/IWRS. Therefore, it is important that all inclusion/exclusion criteria are 
confirmed and all required procedures are completed prior to the enrollment contact to the 
IVRS/IWRS. Detailed IVRS/IWRS procedure will be provided in the IVRS/IWRS site manual. 
17.7.2.7.5 Investigational medicinal product packaging and labeling  
See Section 8.5. 
17.7.2.7.6 Storage conditions and shelf life  
See Section 8.6. 
17.7.2.7.7 Responsibilities  
See Section 8.7. 
17.7.2.7.8 Concomitant medication  
See Section 8.8. 
17.7.2.7.8.1 
Prohibited concomitant medication  
The following concomitant treatments are not permitted during the Screening Period or during the 
Treatment Period: 
• SCS for treatment other than severe exacerbation of asthma and/or high-potency topical 
steroids within 30 days before the screening visit (Visit 0), during the screening period, 
and/or during the 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 or interleukin-5 antagonist (e.g. 
mepolizumab) within 110 days prior to screening visit (Visit 0), or any other biologic 
therapy/immunosuppressant to treat inflammatory disease or autoimmune disease within 2 
months prior to screening visit (Visit 0). 
• Allergen immunotherapy (except if initiated more than 3 months prior to Visit 0 and dose 
stable 1 month prior to Visit 0). 
• IVIG therapy. 
• Live Attenuated Vaccines: refer to Appendix B. 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 visit 1). 
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• Asthma relievers other than salbutamol/albuterol: 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 0 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 0.  
• Any investigational treatment and procedure. 
17.7.2.7.9 Cautioned concomitant medication (Cytochrome P450 enzyme substrates)  
See Section 8.8.2. 
17.7.2.8 Assessment of investigational medicinal product  
17.7.2.8.1 Primary endpoint  
The primary endpoint in the Japan substudy is change from baseline in % predicted FEV1 at 
Week 12. 
17.7.2.8.2 Secondary endpoints  
The secondary efficacy endpoints of this study are: 
• Annualized rate of severe asthma exacerbation events, during the treatment period. 
• Change from baseline in pre-bronchodilator % predicted FEV1 at Weeks 2, 4, 8, 24, 52, 
and 64. 
• Change from baseline in other lung function measurements (absolute FEV1, FVC, FEF 
25-75%) at Weeks 2, 4, 8, 12, 24, 52, and 64. 
• Change from baseline at Week 2, 4, 8, 12, 24, 36, 52, and 64 in ACQ-IA. 
See Section 9.2.1.1 on assessment of severe asthma exacerbation. 
17.7.2.8.2.1 
Assessment of lung function by spirometry  
Lung function parameters will be assessed by centralized spirometry at screening visit (Visit 0), 
Visit 1 (Week 0), Visit 2 (Week 2), Visit 3 (Week 4), Visit 4 (Week 8), Visit 5 (Week 12), Visit 8 
(Week 24), EOT (Week 52), and EOS visits (Week 64). 
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 prebronchodilator measured parameters, including FEV1, 
peak expiratory flow (PEF), FVC, and FEF 25% to 75%, spirometry will be performed after a 
wash out period of bronchodilators according to their action duration, for example withholding the 
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last dose of salbutamol/albuterol for at least 6 hours, withholding the last dose of LABA for at 
least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours), and 
withholding the last dose of LAMA for at least 24 hours. 
At all related visits, spirometry will be performed either in the AM or PM, but preferably in the 
AM, and 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. 
Pulmonary function tests will be measured in the sitting position; however, if necessary to 
undertake the testing with the patient standing or in another position, this should be noted on the 
spirometry report. For any patient, 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 
patient 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% to 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 patient is seen and spirometry is carried out. The calibration records should be kept in 
a reviewable log. It is preferred that the calibration equipment (that is 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. 
17.7.2.8.2.2 
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. 
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 
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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 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 spirometry 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 Section 17.7.2.15). 
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 (10). 
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 and baseline for eligibility evaluation. 
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. 
17.7.2.8.3 Other secondary endpoints  
17.7.2.8.3.1 
Long-term safety and tolerability  
Long-term safety and tolerability for this study is the number (n) and percentage (%) of patients 
experiencing any TEAE during total study periods (definition see Section 10.4.1.1). 
Additional analyses will describe the number (n) and percentage (%) of patients experiencing any: 
• Serious adverse events (SAE definition refers to Section 10.4.1.2). 
• Adverse events of special interest (AESI definition refers to Section 10.4.1.3). 
• Adverse events related to IMP. 
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• Adverse events leading to permanent IMP discontinuation. 
• Adverse events other than ISR. 
Adverse events, including SAEs and AESI, will be collected at any time during study starting 
from signed consent form. The Investigator will ask the patient and parents how he/she has felt 
since the last study visit. 
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. 
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. 
Adverse events for each patient will be monitored and documented from the time the patient gives 
informed consent/assent at Visit 0 until the EOS visit, except for: 
• Serious adverse events. 
• Adverse events that are ongoing at database lock. 
Adverse events, AESIs, SAEs, AEs leading to IMP discontinuation and deaths will be reported as 
described in Section 10.4.1 and analyzed as in Section 17.7.2.10.4.3.  
Laboratory tests, vital signs, physical examination, or electrocardiogram (ECG) abnormalities are 
to be recorded as AEs only if they meet the criteria defined in Section 10.4.3, and are assessed as 
described in Section 17.7.2.8.3.5, Section 17.7.2.8.3.2, Section 9.1.2 and Section 17.7.2.8.3.4. In 
addition to assessment of primary endpoint, below parameters are used on an ongoing basis 
during the study to monitor safety of participants and will be presented in a descriptive manner.  
17.7.2.8.3.2 
Vital signs  
Vital signs including blood pressure (mmHg), heart rate (beats per minute), respiratory rate 
(breaths per minute), and body temperature (degrees Celsius) will be measured at each onsite visit 
except for IMP administration only visits.  
Vital signs will include height (cm) and body weight (kg). Height will be measured at each onsite 
visit except for the IMP administration only visit and Visit 9 (Week 36). Weight will be measured 
at each onsite visit except for the IMP administration only visit. 
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17.7.2.8.3.3 
Physical examinations  
See Section 9.1.2. 
17.7.2.8.3.4 
Electrocardiograms  
Electrocardiogram (ECG) variables will be recorded by a standard 12-lead ECG. ECGs will be 
performed at screening, EOT, and EOS (see Section 17.7.2.2.2). 
17.7.2.8.3.5 
Clinical laboratory values  
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. 
Globally, guidelines for blood collection volume limits for pediatric studies range between 1% 
and 5% of total blood volume (TBV) for a single draw (or during a 24-hour period) and up to 10% 
of TBV over 8 weeks (9). Scheduled collections in the current protocol, for the smallest possible 
patient (15 kg), remain within this limit for every 3 months. For all scheduled blood collection 
visits, the total volume does not exceed 1.5 mL/kg for the smallest possible patient. 
Refer to Section 17.7.2.2.2 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 are: 
Hematology:  
To include blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), differential blood 
count (neutrophils, lymphocytes, monocytes, eosinophils, basophils), and platelets. 
Serum chemistry:  
To include creatinine, blood urea nitrogen, glucose, total cholesterol, total protein, albumin, total 
bilirubin (in case of values above the normal range, differentiation in conjugated and 
nonconjugated bilirubin), ALT, AST, ALP, electrolytes (sodium, potassium, chloride), 
bicarbonate, and CPK. Patients’ fasting or nonfasting 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. 
Urinalysis: 
Urinalysis will be conducted by dipstick during onsite visit. The parameters include pH, glucose, 
ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen, and bilirubin (by dipstick). If 
any parameter on the dipstick is abnormal, further urine test is under Investigator’s judgement. 
Refer to Section 17.7.2.2.2 (Study Flow Chart) for the schedule of urinalysis performed 
throughout this study.  
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Pregnancy test 
A urine pregnancy test must be negative at Visit 0 and Visit 1 for enrolling girls who have 
commenced menstruating, and a urine dipstick pregnancy test will be performed at subsequent 
onsite visits prior to administration of IMP. In case of a positive urine test, a serum pregnancy test 
should be performed to confirm. Patients found to have a positive urine pregnancy test, confirmed 
by a positive serum pregnancy test will be excluded from the study. Patients with a false positive 
urine pregnancy test manifested as a positive urine pregnancy test but a negative serum pregnancy 
test will be allowed to be enrolled. Refer to Section 17.7.2.2.2 (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. 
Clinical laboratory testing at screening visit (Visit 0) 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). For eligibility interpretation for hepatitis serology, refer to Table 6. 
Table 6 - 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. 
Abbreviations: 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 
Section 17.4. 
17.7.2.8.3.6 
Dupilumab systemic exposure and immunogenicity  
See Section 9.2.2.1. 
17.7.2.8.3.6.1 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 17.7.2.2.2). The date of collection should be recorded in the 
patient eCRF. 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. 
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In the event of any SAE or any AESI of anaphylactic reactions or systemic allergic reactions that 
are related to IMP and require treatment, or severe ISR lasting longer than 24 hours, samples will 
be collected near the onset and resolution of the event for any additional analysis if required or for 
archival purposes. An unscheduled systemic drug concentration page (“PK page”) in the eCRF 
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. 
17.7.2.8.3.6.2 Handling procedure  
See Section 9.2.2.1.2. 
17.7.2.8.3.6.3 Bioanalytic method  
See Section 9.2.2.1.3. 
17.7.2.8.3.7 
Pharmacodynamics  
Pharmacodynamics are the evolution of: 
• Serum: Total IgE. 
• FeNO. 
Refer to Section 17.7.2.2.2 Study Flow Chart for the schedule of sample collection throughout this 
study.  
Biomarkers include total IgE which will be measured with a quantitative method (for example 
ImmunoCAP) approved for diagnostic testing and antigen-specific IgE, which will be detected 
using panels of antigens appropriate to the location of the clinical site (quantitative ImmunoCAP 
test; Phadia). 
FeNO assessment 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. 
More detailed information on the collection, handling, transport, and preservation of samples (for 
example minimum volumes required for blood collection and for aliquots for each biomarker 
assay) will be provided in a separate laboratory manual. 
17.7.2.8.4 Appropriateness of measurements  
See Section 9.4.  
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17.7.2.9 Study procedures  
The substudy consists of 3 periods: 
• Screening period (Visit 0). 
• Open-label treatment period (52 weeks; Visits 1-10). 
During the open-label treatment period, patients will continue their background therapy 
dose regimen used during screening period. 
• Post-treatment period (12 weeks; Visit 11). 
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 in the treatment period and ±1 week for the 
remaining study period. 
Spirometry should be done at the study site approximately the same time of the day (preferably in 
the morning, but it could be done at a different time of the day). Spirometry should be performed 
at visits as detailed in Section 17.7.2.8.2.1. 
Once every 2 weeks IMP administration must be separated by at least 11 days. Once every 
4 weeks IMP administration must be separated by at least 25 days. The treatment period visits 
occur q2w up to Visit 3 (Week 4), q4w up to Visit 8 (Week 24), and approximately every 
12-16 weeks up to the EOS visit as detailed in Section 17.7.2.7.1.3. 
See Section 17.7.2.7.1.3 for Investigational medicinal product administration.  
At the time of permanent treatment discontinuation, patients will perform the ETD visits including 
early EOT visit and early EOS visit. Early EOT will be performed 2 weeks (with a ±3 days 
window) after last IMP injection whenever possible. If the time of decision taken for permanent 
IMP discontinuation is >2 weeks after last IMP injection, this early EOT visit should be scheduled 
as early as possible from permanent discontinuation of IMP decision. 
All the assessments defined for the EOT Visit 10 will be performed during this early EOT. Early 
EOS visit will be performed 12 weeks after early EOT visit with a ±1 week window. All the 
assessment defined for the EOS Visit 11 will be performed during this early EOS visit. 
Patients should be reminded that sexually active 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. Procedures: 
a) ECG 
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b) FeNO levels 
c) Spirometry 
2. Safety and laboratory assessments. 
3. Investigational medicinal product administration, if planned, IMP dispensation and return. 
4. Controller therapy and medication withhold for next spirometry reminder. 
17.7.2.9.1 Visit schedule  
17.7.2.9.1.1 
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 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 17.7.2.2.2), 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 enrollment (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 
21-35 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. 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 0 procedures must be repeated, for further instructions 
related to re-screening) unless a prior assessment is performed within the time frame permitted 
prior to study entry.  
17.7.2.9.1.2 
Screening visit (Visit 0; 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. 
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• Interview to collect patient demographic information, medical history, asthma history, 
atopic and food allergy medical history, surgical history, prior and concomitant 
medications and menstruation status for female patients of childbearing potential. 
• Review entry criteria to assess eligibility, with special attention to assess the following:  
- 
Prescribed treatment dosage meets the definition of medium to high-dose ICS (see 
Section 17.7.2.14) 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 (Visit 0).  
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 0) 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. 
• Interview to collect vaccination information and vaccination plan during the treatment 
period. Remind live vaccines are not authorized. 
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height).  
• Perform physical examination. 
• Administer ACQ-5-IA for children (6 to <12 years old).  
- 
Verify if ACQ-5-IA score is ≥1.5. 
• Perform 12 lead ECG. 
•  Measure FeNO.  
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
- 
Entry criteria at Visit 0 include blood eosinophil count ≥150 cells/μL or FeNO 
≥20 ppb. 
• Perform spirometry: 
- 
Entry criteria at Visit 0 include the requirement of a specific FEV1 and demonstration 
of reversibility as specified in Section 17.7.2.6.1. See below for additional directions, 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 for 
at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose 
of LAMA for at least 24 hours, 
- 
Pre-bronchodilator FEV1 must be ≤95% of predicted normal or pre-bronchodilator 
FEV1/FVC ratio <0.85. 
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• Establish reversibility: 
- 
Reversibility must be at least 10% in FEV1 after 200 to 400 mcg (2 to 4 puffs with 
MDI) of salbutamol 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 (Visit 0) and up to the day of the actual baseline visit 
(Visit 1).  
Note: Documented reversibility or positive airway hyperresponsiveness to 
methacholine within 12 months prior to Screening V0 is considered acceptable. 
• Menstruation status for female patients of childbearing potential.  
• Obtain blood samples for screening clinical laboratory determinations: 
- 
Hematology (see Section 17.7.2.8.3.5 for details), 
- 
Entry criteria at Visit 0 include blood eosinophil count ≥150 cells/μL or FeNO 
≥20 ppb, 
- 
Serum chemistry (see Section 17.7.2.8.3.5 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. 
• Dispense paper diary, provide instructions for daily use, and remind patient and their 
parent(s)/caregiver(s)/legal guardian(s) to bring it to the next visit. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication throughout the study.  
• 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 paper 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 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.  
• Schedule a site visit within a maximum of 35 days (Visit 1, Week 0) and request patient 
and their parent(s)/caregiver(s)/legal guardian(s) to come at approximately the same time 
of this visit. 
17.7.2.9.1.3 
Enrollment: Visit 1 (Week 0, Day 1)  
• Reconfirm eligibility based on review of inclusion/exclusion criteria. 
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
and height). 
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• Record all medication use with start date and dose in eCRF; 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. 
• 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 diary during the screening period. 
• Measure FeNO: 
- 
FeNO 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 17.7.2.6.1. 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 duration of action, for example, 
withholding the last dose of salbutamol/albuterol 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 prior to administration of investigational product, 
- 
Pre-bronchodilator FEV1 must be ≤95% of predicted normal or pre-bronchodilator 
FEV1/FVC ratio <0.85, 
- 
Patients must meet the inclusion criteria for spirometry at Visit 1 prior to enrollment. If 
a patient’s FEV1 does not qualify, then the patient will not be enrolled. 
If the patient meets all inclusion and does not meet any exclusion criteria: 
• Call IVRS/IWRS to register visit: Enroll the patient and receive the first assignment for 
1 treatment kit number. Refer to Section 17.7.2.7.1.1. 
- 
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 17.7.2.8.3.5), 
- 
Systemic drug concentration and ADA (refer to Section 9.2.2.1), 
- 
Biomarker set, total IgE, and antigen-specific IgE (refer to Section 17.7.2.8.3.7). 
• Dispense and administer IMP: 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home. For those parent(s)/caregiver(s)/legal 
guardian(s) who wish to learn and train to home-administer the IMP injection (see 
Section 17.7.2.7.1.3 for details):  
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- 
They will be trained by the Investigator or designee to administer IMP, by 
demonstration eg, at V1, V2, and V3 for q2w doses and V1, V3, and V4 for q4w doses 
(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. 
- 
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 as reliever medication throughout the study.  
• 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. 
• 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 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.  
• Schedule a site visit 2 weeks later (Week 2 ± 3 days) at approximately the same time of 
this visit. 
17.7.2.9.1.4 
Open-label treatment period (Week 2 to Week 52 [Visits 2-10])  
17.7.2.9.1.4.1 Visit 2 (Week 2 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 for 
at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose 
of LAMA for at least 24 hours.  
• Assess menstruation status. 
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• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP for children receiving q2w doses: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if IMP administrated on site. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home. If parent(s)/caregiver(s)/legal guardian(s) 
wish to learn and train to home administer the IMP injection (see Section 17.7.2.7.1.3 
for details), they will continue to be trained by the Investigator or designee to 
administer IMP, by demonstration eg, at Visit 1, Visit 2, and Visit 3 for q2w doses and 
V1, V3, and V4 for q4w doses (injections performed by Investigator or designee). 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 as reliever medication as instructed by Investigator. 
• 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. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol for at least 
6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA like 
vilanterol should be withheld for at least 24 hours) and withholding the last dose of 
LAMA for at least 24 hours. 
• Schedule a site visit 2 weeks later (Week 4 ±3 days) at approximately the same time of this 
visit. 
17.7.2.9.1.4.2 Visit 3 (Week 4 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height). 
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO 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 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. 
• Obtain blood samples for: 
- 
Hematology (refer to Section 17.7.2.8.3.5), 
- 
Serum chemistry (refer to Section 17.7.2.8.3.5). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of at least 30 minutes after the injection monitored by IMP giver if 
patients receive IMP at home. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home. If parent(s)/caregiver(s)/legal guardian(s) 
wish to learn and train to home administer the IMP injection (see Section 17.7.2.7.1.3 
for details), they will continue to be trained by the Investigator or designee to 
administer IMP, by demonstration eg, at Visit 1, Visit 2, and Visit 3 for q2w doses and 
V1, V3, and V4 for q4w doses (injections performed by Investigator or designee). 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 as reliever medication 
as instructed by Investigator. 
• 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. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol for at least 
6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA like 
vilanterol should be withheld for at least 24 hours) and withholding the last dose of 
LAMA for at least 24 hours. 
• Schedule a site visit 4 weeks later (Week 8 ±3 days) at approximately the same time of this 
visit. 
17.7.2.9.1.4.3 Visit 4 (Week 8 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height). 
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• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 for 
at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose 
of LAMA for at least 24 hours. 
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site, 
- 
Record observation of at least 30 minutes after the injection monitored by IMP giver if 
patients receive IMP at home. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home(see Section 17.7.2.7.1.3 for details). If 
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, 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. 
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 as reliever medication as instructed by Investigator. 
• 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. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol for at least 
6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA like 
vilanterol should be withheld for at least 24 hours) and withholding the last dose of 
LAMA for at least 24 hours. 
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• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold the IMP 
dosing to secure an interval of 14 ±3 days prior to next onsite visit (Visit 5) for patients 
receiving IMP administration at home. 
• Schedule a site visit 4 weeks later (Week 12 ±3 days) at approximately the same time of 
this visit.  
17.7.2.9.1.4.4 Visit 5 (Week 12 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 for 
at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose 
of LAMA for at least 24 hours. 
• Perform physical examination. 
• Assess menstruation status. 
• Obtain blood samples for: 
- 
Hematology (refer to Section 17.7.2.8.3.5), 
- 
Serum chemistry (refer to Section 17.7.2.8.3.5). 
• Systemic drug concentration and ADA (see Section 9.2.2.1.1 for details). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Urinalysis (dipstick). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site. 
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- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home (see Section 17.7.2.7.1.3 for details). If 
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, 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. 
The training should be documented in the patient’s medical records.  
- 
Record observation of at least 30 minutes after the injection monitored by IMP giver if 
patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication as instructed by Investigator. 
• 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. 
• Schedule a site visit 4 weeks later (Week 16 ±3 days) at approximately the same time of 
this visit. 
17.7.2.9.1.4.5 Visit 6 (Week 16 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height). 
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home (see Section 17.7.2.7.1.3 for details). If 
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, 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. 
The training should be documented in the patient’s medical records.  
- 
Record observation of a minimum of 30 minutes after the injections monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication as instructed by Investigator. 
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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. 
• Schedule a site visit 4 weeks later (Week 20±3 days) at approximately the same time of 
this visit. 
17.7.2.9.1.4.6 Visit 7 (Week 20 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Assess menstruation status. 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home (see Section 17.7.2.7.1.3 for details). If 
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, 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. 
The training should be documented in the patient’s medical records.  
- 
Record observation of a minimum of 30 minutes after the injection monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication as instructed by Investigator. 
• 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. 
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold 
bronchodilators prior to next study visit when spirometry is scheduled according to their 
action duration, for example withholding the last dose of salbutamol/albuterol for at least 
6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA like 
vilanterol should be withheld for at least 24 hours) and withholding the last dose of 
LAMA for at least 24 hours.  
• Remind patient and their parent(s)/caregiver(s)/legal guardian(s) to withhold the IMP 
dosing to secure an interval of 14 ±3 days prior to next onsite visit (Visit 8) for patients 
receiving IMP administration at home. 
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• Schedule a site visit 4 weeks later (Week 24±3 days) at approximately the same time of 
this visit.  
17.7.2.9.1.4.7 Visit 8 (Week 24 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform physical examination. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 for 
at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose 
of LAMA for at least 24 hours. 
• Assess menstruation status. 
• Obtain blood samples for: 
- 
Hematology (see Section 17.7.2.8.3.5 for details), 
- 
Serum chemistry (see Section 17.7.2.8.3.5  for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1 for details). 
• Total IgE and antigen-specific IgE (refer to Section 17.7.2.8.3.7).  
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Urinalysis (dipstick). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home (see Section 17.7.2.7.1.3 for details). If 
parent(s)/caregiver(s)/legal guardian(s) have been trained by the Investigator or 
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designee to administer IMP by demonstration at not less than 3 visits, 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. 
The training should be documented in the patient’s medical records.  
- 
Record observation of a minimum of 30 minutes after the injection monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication as instructed by Investigator. 
• 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. 
• Schedule a site visit 12 weeks later (Week 36 ±3 days) at approximately the same time of 
this visit. 
17.7.2.9.1.4.8 Telephone contact at Week 28 and 32 (±3 days)  
See Section 10.1.2.8. 
17.7.2.9.1.4.9 Visit 9 (Week 36 [±3 days])  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight).  
• Call IVRS/IWRS to register visit and obtain treatment kits number. 
Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Administer ACQ-7. 
• Assess menstruation status. 
• Obtain blood samples for: 
- 
Hematology (see Section 17.7.2.8.3.5 for details), 
- 
Serum chemistry (see Section 17.7.2.8.3.5 for details). 
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection if patients receive IMP on site. 
- 
The injection training is for parent(s)/caregiver(s)/legal guardian(s) who are willing to 
perform injection administration at home (see Section 17.7.2.7.1.3 for details). If 
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, under the close 
supervision of the Investigator or delegate, parent(s)/caregiver(s)/legal guardian(s) will 
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perform the injection, including feedback on technique by the Investigator or delegate. 
The training should be documented in the patient’s medical records.  
- 
Record observation of a minimum of 30 minutes after the injection monitored by IMP 
giver if patients receive IMP at home. 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication as instructed by Investigator. 
• 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. 
• Schedule a site visit 16 weeks later (Week 52 ±3 days) at approximately the same time of 
this visit. 
17.7.2.9.1.4.10 Telephone contact at Weeks 40, 44, and 48 (±3 days)  
See Section 10.1.2.10. 
17.7.2.9.1.4.11 Visit 10 (Week 52 [±3 days]), End-of-treatment visit  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, 
height). 
• Call IVRS/IWRS to register EOT visit. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
• Perform spirometry: 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 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 for at least 6 hours, 
withholding the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should 
be withheld for at least 24 hours) and withholding the last dose of LAMA for at least 
24 hours. 
• Perform physical examination. 
• Assess menstruation status. 
• Perform 12-lead ECG. 
• Obtain blood samples for: 
- 
Hematology (see Section 17.7.2.8.3.5 for details), 
- 
Serum chemistry (see Section 17.7.2.8.3.5 for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1 for details). 
• Total IgE and antigen-specific IgE (refer to Section 17.7.2.8.3.7). 
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• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Urinalysis (dipstick). 
• Remind patients and their parent(s)/caregiver(s)/legal guardian(s) to use 
salbutamol/albuterol as reliever medication as instructed by Investigator. 
• 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. 
• Schedule a site visit 12 weeks later (Week 64 ±1 week) at approximately the same time of 
this visit. 
17.7.2.9.1.5 
Post-treatment period (12 weeks)  
17.7.2.9.1.5.1 Telephone contact at Weeks 56 and 60 (±1 week)  
See Section 10.1.3.1. 
17.7.2.9.1.5.2 Visit 11: (Week 64 [±1 week]), end-of-study visit  
• Measure vital signs (blood pressure, heart rate, respiratory rate, body temperature, and 
weight and height).  
• Call IVRS/IWRS to register EOS visit. 
• Record all concomitant medication use (including but not limited to asthma background 
controller, reliever, and vaccine); inquire about AEs/SAEs. 
• Perform physical examination. 
• Administer ACQ-7. 
• Measure FeNO: 
- 
FeNO assessment is conducted prior to spirometry and following a fast of ≥1 hour. 
• Perform spirometry: 
- 
Spirometry must be done at the study site approximately the same time of the day 
(preferably in the morning, but it could be done at a different time of the day). 
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 for 
at least 6 hours, withholding the last dose of LABA for at least 12 hours (ultra-LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose 
of LAMA for at least 24 hours. 
• Assess menstruation status. 
• Perform 12-lead ECG. 
• Obtain blood samples for: 
- 
Hematology (see Section 17.7.2.8.3.5 for details), 
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- 
Serum chemistry (see Section 17.7.2.8.3.5 for details). 
• Systemic drug concentration and ADA (see Section 9.2.2.1 for details). 
• Total IgE and antigen-specific IgE (refer to Section 17.7.2.8.3.7).  
• Obtain urine pregnancy test (dipstick) if female patients are of childbearing potential (who 
have commenced menstruating). 
• Obtain urinalysis test (dipstick). 
17.7.2.9.2 Definition of source data  
See Section 10.2. 
17.7.2.9.3 Handling of patient temporary or permanent treatment discontinuation and of patient 
study discontinuation  
See Section 10.3. 
17.7.2.9.3.1 
Temporary treatment discontinuation with investigational medicinal product(s)  
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Re-initiation 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 judgement 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 17.7.2.6.1 and 
Section 17.7.2.6.2), AE is sufficiently resolved and unlikely to recur after resuming therapy with 
IMP. 
In addition, the following conditions will be causes 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 
Section 17.4 on Guidelines for management of specific laboratory abnormalities. 
• Any administration of live attenuated vaccines (refer to Appendix B, Section 17.2) during 
the study period. 
Temporary discontinuation may lead to permanent discontinuation after Sponsor’s review on a 
case by case basis. 
17.7.2.9.3.2 
Permanent treatment discontinuation with investigational medicinal product(s)  
See Section 10.3.2. 
17.7.2.9.3.3 
List of criteria for permanent treatment discontinuation  
See Section 10.3.3. 
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17.7.2.9.3.4 
Handling of patients after permanent treatment discontinuation  
See Section 10.3.4. 
17.7.2.9.3.5 
Procedure and consequence for patient withdrawal from study  
See Section 10.3.5. 
17.7.2.9.4 Obligation of the investigator regarding safety reporting  
See Section 10.4. 
17.7.2.9.5 Obligations of the sponsor  
See Section 10.5. 
17.7.2.9.6 Safety instructions  
See Section 10.6. 
17.7.2.9.7 Adverse events monitoring  
See Section 10.7. 
17.7.2.10 
Statistical considerations  
17.7.2.10.1 
Determination of sample size  
For the Japan substudy, the primary objective is to evaluate the efficacy of dupilumab in children 
6 to <12 years of age with uncontrolled persistent asthma. Assuming the change from baseline 
in % predicted FEV1 at Week 12 among the Japan substudy follows a normal distribution with 
mean of 10.74% and standard deviation of 14.12%, a sample size of 16 for the Japan sub-study 
will lead to a half-width of the 95% confidence interval being 7.5%. A minimum of 3 patients 
assigned to treatment in each of the 3 dose regimens is targeted. 
The sample size calculations were performed using nQuery Advisor. 
17.7.2.10.2 
Disposition of patients  
See Section 11.2. 
17.7.2.10.3 
Analysis population  
See Section 11.3 for the definition of analysis populations. 
The primary analysis population for the Japan substudy is the efficacy population. 
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17.7.2.10.4 
Statistical methods  
All analyses on analysis populations defined in Section 11.3 will be implemented for non-Japan 
study and Japan substudy separately.  
For Japan substudy, the planned analyses will be performed on the observed data from the Japan 
substudy in each analysis population from the substudy. More details about the specific analysis 
for Japan substudy will be specified in the SAP. 
17.7.2.10.4.1 Extent of study treatment exposure and compliance  
The extent of study treatment exposure and compliance will be summarized for the Japan 
substudy in the safety population using the same analysis approach as defined for the full analysis 
set of the non-Japan study in Section 11.4.1.1 and Section 11.4.1.2. 
17.7.2.10.4.2 Analyses of efficacy endpoint  
The efficacy analyses will be done descriptively on the observed data for the Japan substudy in 
the substudy efficacy population.  The baseline value for the applicable efficacy parameters is the 
baseline from LTS14424 study, which is defined as the last available measurement prior to the 
first IMP dose in LTS14424 study. 
For the continuous efficacy variables, descriptive statistics (mean, SD, median, minimum, and 
maximum) will be presented for the parameter and its change from baseline over visits, 
confidence interval will be presented as appropriate. In addition, figure of mean change from 
baseline (with corresponding standard error) will be presented for the continuous efficacy 
parameter over visits.  
For the categorical efficacy variables, the number and percentage will be presented over time for 
the patients who have data available at that time point. 
For severe exacerbation events, total number of severe exacerbation events, total patient-years, 
unadjusted annualized severe exacerbation event rate, and individual patient annualized severe 
exacerbation event rate (number, mean, SD, median, minimum, maximum) during the treatment 
period will be summarized. 
17.7.2.10.4.3 Analyses of safety data  
The safety analyses will be performed descriptively on the observed data in the safety population. 
The baseline value for the applicable safety parameters is the baseline from LTS14424 study, 
which is defined as the last available measurements prior to the first IMP dose in LTS14424 
study. 
The treatment-emergent period is from the date of first IMP injection to the date of the last IMP 
injection + 14 weeks for the patients who end the dupilumab treatment on either 100 mg q2w or 
200 mg q2w regimen; and, the treatment emergent period is from the date of first IMP injection to 
the date of the last IMP injection +16 weeks for the patients who end the dupilumab treatment on 
300 mg q4w regimen. 
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Same analysis approach as defined for the full analysis set of the non-Japan study in 
Section 11.4.3.1.1 to Section 11.4.3.1.4 will be used for the safety analysis for Japan substudy. 
17.7.2.10.4.4 Analyses of systemic drug concentration, anti-drug antibodies, and 
pharmacodynamics variables  
Pharmacokinetic analysis 
The PK analyses will be performed by dose regimen for the Japan substudy in the PK population 
using the same descriptive analysis method as defined for the full analysis set of the non-Japan 
study in Section 11.4.4.1. The baseline value of each applicable PK variable is the baseline from 
LTS14424 study, which is defined as the last available measurements prior to the first IMP dose 
in LTS14424 study. 
Anti-drug antibodies analysis  
The ADA analyses will be performed for the Japan substudy in the ADA population using the 
same analysis approach as defined for the full analysis set of the non-Japan study in 
Section 11.4.4.2. The baseline value of each applicable ADA variable is the baseline from 
LTS14424 study, which is defined as the last available measurements prior to the first IMP dose 
in LTS14424 study. 
17.7.2.10.4.5 Pharmacodynamics  
The biomarker analyses will be applied descriptively on the observed data for the Japan substudy 
in safety population using the same descriptive analysis method as defined for the full analysis set 
of the non-Japan study in Section 11.4.4.3. The baseline value for the applicable 
pharmacodynamics (PD) variables is the baseline from LTS14424 study, which is defined as the 
last available measurements prior to the first IMP dose in LTS14424 study. 
17.7.2.10.5 
Interim analysis  
There is no interim analysis planned for the Japan substudy. 
17.7.2.10.6 
Planned database lock  
There will be a separate database lock for the Japan substudy to occur after the last patient has 
completed the last visit from Japan. 
17.7.2.11 
Ethical and regulatory considerations  
See Section 12. 
17.7.2.12 
Study monitoring  
See Section 13. 
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17.7.2.13 
Additional requirements  
See Section 14. 
17.7.2.14 
Appendix 1: Low, medium, and high-dose inhaled corticosteroids – children 
aged 6 to <12 years (Japan)  
Inhaled Corticosteroid 
Total Daily Dose (mcg) 
Low 
Medium 
High 
Fluticasone propionate   
-100 
-200 
-400 
Beclomethasone dipropionate  
-100 
-200 
-400 
Ciclesonide 
-100 
-200 
-400 
Budesonide  
-200 
-400 
-800 
Budesonide inhalation solution 
-250 
-500 
-1000 
Source: Adapted from Japanese Guidelines for Childhood Asthma 2020. 
17.7.2.15 
Appendix 2: Asthma control questionnaire–interviewer administered (ACQ-
IA) for children 6 to <12 years  
Asthma Control Questionnaire, 7-question version (ACQ-7) 
Of note, ACQ-IA version in Japanese will be used for the Japan substudy. North American 
English version has been added in this Amended Protocol as an example only. 
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17.7.2.16  
Appendix 3: Contingency Measures for Japan for a regional or national 
emergency that is declared by a governmental agency 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in  
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the  
implementation of these procedures for the duration of the emergency; this agreement must be 
provided in writing by the sponsor and will be kept in the Investigator file. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as  
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods,  
responsibilities and requirements, including handling of noncompliance issues and monitoring  
techniques (central, remote or on-site monitoring) are provided in separate study documents. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, screening and enrollment may be temporarily delayed/halted. 
Attempts should be made to perform all assessments in accordance with the approved protocol to the 
extent possible. In case this is not possible due to a temporary disruption caused by an  
emergency, focus should be given to assessments necessary to ensure the safety of participants and 
those important to preserving the main scientific value of the study. 
 
17.7.2.16.1    Study procedures 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
1.  New screenings during a regional or national emergency declared by a governmental  
 
agency can be performed only if allowed by local competent authorities and after  
 
Sponsor’s agreement is obtained. Rescreening will be permitted when the situation  
 
normalizes and only if allowed by local competent authorities and after Sponsor’s  
 
agreement is obtained. 
2.  If onsite visits or alternative location (out of patient’s home) are not possible, all visits 
from Week 2 (including those planned to be done onsite) will be performed at home by a 
trained healthcare professional and if allowed by local competent authorities for: 
- 
Treatment administration 
- 
Monitoring of injection site reactions, AEs and SAEs 
- 
Collect study samples for safety, and pregnancy test (if applicable) 
- 
Perform study examinations (eg, Measuring vital signs) 
 
 
 
 
 
 
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3.  IMP Injection Training: In case of emergency (eg, natural disaster, pandemic) different 
training ways (eg, training remotely with instruction provided by phone) can be performed 
(and will be documented in the participant’s study file). 
4.  After Sponsor agreement is obtained, the IMP may be supplied from the site to the 
participant via a Sponsor-approved courier company where allowed by local regulations 
and agreed upon by the patients. 
The use of a local laboratory may be allowed for safety follow up in case the central lab cannot be  
used. 
If onsite or home visits are not possible, the Investigator or delegate will perform a phone-call  
visit at each onsite planned visit to collect safety data and concomitant treatment. All data  
collected remotely will be properly documented in the patient’s medical record and the study  
CRF. 
For all assessments which will not be performed remotely, the assessment windows will be 
extended until patients may access the site. 
If onsite visit and home visit are not possible, a temporary treatment discontinuation may be 
considered. The Investigator or delegate will perform a phone-call visit at each onsite planned 
visit to collect safety data and concomitant treatment. 
Contingencies implemented due to emergency will be documented in the participant’s medical  
record. 
 
17.8   APPENDIX H: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Clinical Trial Summary. 
AMENDED PROTOCOL 05 (01 February 2021) 
Overall Rationale for the Amendment 
The purpose of this amendment is to add a substudy of pediatric asthma patients from Japan 
within Study LTS14424 in order to evaluate efficacy, PK, and safety in this population. Patients in  
Japan were not included in the parent Study EFC14153, and this amendment adds a substudy of  
Japanese patients aged 6 to <12 years with uncontrolled persistent asthma. The primary objective  
of the substudy of Japanese patients aged 6 to <12 years with asthma is to evaluate the efficacy of  
dupilumab. 
The description of the substudy of Japanese patients is outlined in Section 17.7.2 (Country 
specific requirements for Japan). 
 
 
 
 
 
 
 
 
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Protocol amendment summary of changes table 
Section # and Name 
Description of change 
Brief Rationale 
Section 3 List of abbreviations 
New abbreviations added. 
Update 
Section 4.2 Rationale 
Japan specific wording added. 
Clarifying text provided in 
order to highlight 
information that is 
specific to patients from  
Japan 
Section 16 Bibliographic references 
New references added and internal cross 
Update 
references updated throughout the 
document. 
Section 17.7.2 Country specific requirements for 
Sections added under appendix G. 
Japan specific wording 
Japan & all 17.7.2 subsections 
Numerical numbering newly inserted for all 
appendices under section 17 (appendix A  
changed to section 17.1 -appendix A, etc.). 
 
Section 17.8 Appendix H: Protocol amendment 
Protocol amendment history updated. 
Update 
history 
Throughout the document 
New sections added. 
Update 
Table of contents updated. 
In-text references updated in relation to the 
update of sections. 
 
 
AMENDED PROTOCOL 04 (15 April 2020) 
This amended protocol 04 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 
This amendment is in response to the current COVID-19 pandemic, which has made it 
challenging for patients to reach onsite visits or may interrupt access to IMP. The current 
eligibility criteria for LTS14424 requires that patients complete study treatment in parent study  
EFC14153, and that they roll-over to LTS14424 at the EFC14153 end-of-treatment (EOT) visit.  
In order to ensure that otherwise eligible patients are able to enter Study LTS14424, Visit 1 will  
be allowed to occur at the EFC14153 EOT visit, the EFC14153 end-of-study (EOS) visit, or for  
up to 12 weeks after completion of EFC14153 EOS visit, and patients that do not complete all  
study treatments in EFC14153 due to the COVID-19 pandemic will still be eligible for 
LTS14424. 
 
 
 
 
 
 
 
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Protocol amendment summary of changes table 
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical trial summary 
1.1 Graphical Study design 
1.2 Study flow chart 
(footnotes) 
6.2.1 Duration of study 
participation for each patient 
7.1 Inclusion criteria 
8.1 Investigational medicinal 
product 
9 Assessment of 
Investigational medicinal 
Product 
10.1.1 Enrollment: Visit 1 of 
present study 
(Start-of-treatment, Week 0) 
To allow later entrance in 
LTS14424 for EFC14153 
patients who are not able to 
perform the EFC14153 EOT 
visit onsite to rollover at 
V28/EOT, or to receive last 
IMP doses in parent study 
EFC14153 due to the 
COVID19 pandemic. 
The LTS14424 Study is an Open Label Extension study to 
evaluate the long-term safety and tolerability of dupilumab in 
pediatric patients who participated in Study EFC14153. The 
sponsor’s intent was to allow all eligible patients to continue 
to the open label extension study. However, due to the 
current restrictions in place related to the COVID-19 
pandemic, many patients may not be able to complete their 
treatment or go to sites for the combined Study EFC14153 
EOT visit/Study LTS14424 Visit1. Therefore to allow these 
patients to remain eligible for LTS14424, the sponsor is 
providing more flexibility. Patients who did not receive last 
IMP doses or could not enroll at LTS14424 at V28/EOT of 
parent study EFC14153 due to COVID-19 pandemic will be 
allowed to enroll in Study LTS14424 at either EFC14153 EOS 
Visit or until 12 weeks afterEFC14153 EOS Visit. 
11.4 Statistical methods 
11.4.2 Analyses of efficacy 
endpoints 
11.4.3.1.3. Death 
To remove the monthly 
300 mg dose specific 
analysis set 
The current protocol requires that patients who are ≤30kg 
start or switch to 300 mg q4w dosing at an onsite visit. 
However, due to the current COVID-19 situation, many 
patients have not been able or will not be able to present to 
sites. As this will result in a smaller total number of patients 
exposed to 300 mg q4w, the sponsor will evaluate the safety 
and efficacy of patients exposed to 300 mg q4w regimen 
together with the other dose regimens in the full analysis set. 
1.2 Study Flowchart 
footnote g 
8.1.3 Dosing schedule 
10.1.1 Enrollment: Visit 1 of 
present study 
(Start-of-treatment, Week 0) 
To allow at home 
administration of 300 mg 
monthly doses from the 
second administration 
onwards (following first 300 
mg administered onsite) 
Due to COVID-19 pandemic, some patients may not be able 
to return monthly to sites for onsite administration of IMP 
300 mg. This amendment will still require that patients switch/ 
initiate 300 mg dose onsite, but will allow patients to receive 
subsequent doses at home. Previous experience with this 
dose, including 122 children age 6 to <12 years old exposed 
to 300 mg q4w in the pivotal phase III Atopic dermatitis study 
(R668-AD-1652) supports the acceptability of at home 
administration for this dose. 
AMENDED PROTOCOL 03 (12 December 2019) 
This amended protocol 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 
The purpose of this amendment is to modify the dupilumab dose for children with body weight  
≤30 kg from 100 mg every 2 weeks (q2w) to 300 mg every 4 weeks (q4w). This update provides  
data to support harmonization of dosing across indications and decreases overall burden by  
shifting from q2w to q4w dosing in children ≤30 kg. Pharmacokinetic (PK) modeling supports  
that this dose achieves a concentration that is within the therapeutic window for dupilumab in 
 
 
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asthma. This dose was recently demonstrated to have a favorable safety profile and to be effective  
for atopic dermatitis (AD) patients age 6-11 years with body weight <30kg, including patients  
with comorbid asthma. Therefore, given the similar PK that have been observed across healthy  
volunteers as well as patients with AD and asthma, the Sponsor anticipates a similar profile in  
children with asthma. 
Protocol amendment summary of changes table 
 
Section # and 
Name 
Description of 
Change 
Brief Rationale 
Clinical trial summary 
1.1 Graphical flow chart 
1.2 Study flow chart 
4.2 Rationale 
8.1 Investigational 
medicinal product 
8.4 Method of assigning 
patients to treatment 
group 
10.1.1 Enrollment: Visit 
1 of present study (Start 
of treatment, Week 0) 
10.1.2 Open-label 
treatment period (Week 
0 to Week 52 [Visits 2- 
10]) 
To change dupilumab 
dose for children with 
body weight ≤30 kg 
from 100 mg q2w to 
300 mg q4w 
The PK profile for dupilumab has been demonstrated to be similar 
across healthy patients as well as across indications including AD and 
asthma. Wherever possible, the sponsor would like to enable 
harmonization of dosing posology across patients of similar age and 
weight. The recent AD 6-11 years clinical trial (R668­AD-1652) 
demonstrated that the dose 300 mg q4w was efficacious and has an 
acceptable safety profile for patients age 6-11 with body weight 15 to 
<30 kg. Therefore, the Sponsor proposes to introduce this same dose 
regimen in to LTS14424 in order to collect safety and clinical data in 
asthma patients of a similar age and body weight. This harmonization of 
dosing posology is intended to reduce overall patient burden through 
less frequent dosing with an anticipated exposure range similar to that 
demonstrating an efficacious dose with an acceptable safety profile in 
the AD patients aged 6-11 years of age and 15 to <30 kg. 
Subsequent to the start of LTS14424, the AD study evaluating the 
efficacy and safety of dupilumab for the treatment of children age 6-11 
years old with severe atopic dermatitis (R668­AD-1652) was completed. 
Two doses for children with baseline weight <30kg were evaluated: 100 
mg q2w and 300 mg q4w. In that study, the 300 mg q4w dose was found 
to be effective and had an acceptable safety profile. Of note, 46.7% of 
the patients enrolled in R668-AD-1652 had comorbid asthma. 
In addition, modeling data supports that the 300 mg q4w dose 
approximates the therapeutic concentration in adults. PK modeling 
incorporating data from the clinical development program in asthma 
populations identifies that 300 mg q4w in children 15 to 30 kg is 
expected to match adult and adolescent efficacious exposure at 300 mg 
q2w, within a safe treatment profile within the desired therapeutic 
window. The predicted Ctrough for 300 mg q4w in pediatric patients 15 to 
30 kg is similar to the adult and adolescent 300 mg q2w Ctrough. The 
predicted Cmax of 300 mg q4w in pediatric patients 15 to 30 kg does not 
exceed the adult 300 mg every week (qw) Cmax in asthma Phase 2/3 
studies. 
Therefore, based on the observed data in AD as well as modeling data 
in asthma populations, the 300 mg q4w dose is anticipated to be 
efficacious with a favorable safety profile in the same age and weight 
class for asthma. 
All newly enrolled children with body weight ≤30 kg will take 300 mg q4w 
and children ≤30 kg receiving 100 mg q2w will be switched to 300 mg 
q4w if they have more than 8 weeks before the planned end of the 
treatment period. Safety, PK and clinical data will be monitored in this 
population. 
 
 
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Section # and 
Name 
Description of 
Change 
Brief Rationale 
Clinical trial summary 
9.2.2.2 
Pharmacodynamics and 
phenotyping 
To remove 
Immunoglobulins (Igs) 
as Other secondary 
endpoints 
Immunoglobulins other than IgE are not being collected in this 
LTS14424. 
10.4.1.1 Adverse event 
Clarification on when an 
asthma exacerbation is 
to be reported as 
adverse event 
Protocol-defined severe asthma exacerbation events are collected as 
efficacy endpoints. Only asthma exacerbations which fulfill a 
seriousness criterion should be reported as an AE (SAE). 
10.4.1.3 Adverse event 
of special interest 
Addition of relatedness 
to IMP in the 
AESI Anaphylactic 
reaction and systemic 
allergic reaction 
To match dupilumab program AESI definition (Anaphylactic reaction and 
systemic allergic reaction related to IMP that require treatment). 
10.6.4 Elevated liver 
function tests 
To clarify that hepatitis 
serologies are not 
repeated for 
determining patients’ 
eligibility in LTS14424 
Hepatitis serologies are performed as part of the parent study 
(EFC14153) eligibility and not repeated before rolling over to LTS14424. 
Clinical trial summary 
11.1 Determination of 
Sample Size 
Change in study sample 
size 
The sample size for the parent study EFC14153 was reduced with a shift 
in focus to patients with type 2 inflammation as well as updated power 
calculations for this population, and at the same time, there has been a 
higher than anticipated roll-over rate from this study to LTS14424. 
Therefore, the Sponsor will update the anticipated sample size for 
LTS14424. 
11.4 Statistical methods 
To update analysis 
populations according 
to the dose regimen. 
There will be two analysis sets of each analysis population. The full 
analysis set will include all data collected during LTS14424 study 
regardless of the dose regimen (including 300 mg q4w dose). The 
modified analysis set will censor the data observed on or after the first 
injection date of 300 mg q4w for the patients ever exposed to the 300 
mg q4w regimen. 
14.2 Record retention in 
study sites 
To update retention of 
study documents in 
study sites from 15 to 
25 years 
The record retention in study sites was updated according to dupilumab 
program and to be consistent with the information provided in Informed 
consent form (ICF)/written patient information (WSI). 
AMENDED PROTOCOL 02 (09 July 2018) 
This amended protocol (amendment 02) 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 increase study sample size due to increase in number of participants in EFC14153 (parent 
study of LTS14424). 
 
 
 
 
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Protocol amendment summary of changes table 
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary; 
11.1 Determination of 
Sample Size 
Change in study sample size 
Due to the increase in the sample size of EFC14153 (parent 
study of LTS14424), the number of participants in LTS14424 
will also increase 
Clinical Trial Summary; 
9.2.1 Secondary safety and 
tolerability endpoints 
Removal of secondary safety 
endpoint 
The secondary endpoint "Safety and tolerability" is described 
in the Primary endpoint under of the name of TEAEs. Vital 
signs, physical examination, ECG and laboratory tests are 
measurements of safety and will be presented in a descriptive 
manner 
9.3 Future Use of Samples; 
12.2 Informed Consent; 
14.5 Data Protection 
Removal of Optional 
pharmacogenetic informed 
consent/assent form mention 
No pharmacogenetics analysis is planned in this study 
10.3.3 List of criteria for 
permanent treatment 
discontinuation 
Pregnancy outcome follow-up 
period 
To correct the information on when the follow-up shall end in 
case of pregnancy 
1.2 Study Flow Chart; 
9.2.2.2 Assessment of lung 
function by spirometry; 
10.1.1 Enrollment: Visit 1 of 
present study (Start of 
treatment, Week 0); 
10.1.2 Open-label treatment 
period (Week 0 to Week 52 
[Visits 2-10]) and 
10.1.3 Post-treatment period 
(12 weeks) 
LAMA and Ultra LABA 
(vilanterol) withdrawal period 
before spirometry 
To harmonize LAMA and Ultra LABA (vilanterol) 24h 
withdrawal period before spirometry information along the 
protocol 
9.3 Future Use of Samples 
Total volume of blood 
collected in a single visit 
To correct the information that maximum volume of blood 
collected at Visit 10 (24 mL) represents 1.5 mL/kg for the 
smallest patient (16 kg) 
1.2 Study Flow Chart 
LTS14424 Visit 1 data 
To correct the information that data for LTS14424 Visit 1 
coming from EOT Visit from parent study will not be reported 
in LTS14424 eCRF 
1.2 Study Flow Chart 
10 Study procedures 
(10.1.2.1; 10.1.2.3; 10.1.2.6; 
10.1.2.8; 10.1.2.10; 10.1.3.1; 
Fasting condition 
To remove the need of fasting condition before blood samples 
collection 
 
AMENDED CLINICAL TRIAL PROTOCOL 01 (BRAZIL) BASED ON PROTOCOL 
AMENDMENT 01 (BRAZIL) (14 March 2018) 
This amended protocol (amendment 01) is considered to be non-substantial based on the criteria  
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of  
the European Union. 
 
 
 
 
 
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Overall rationale for the amendment: 
To allow Brazilian patients who were prematurely discontinued from IMP in EFC14153 due to 
the need of Yellow Fever vaccination during Yellow Fever outbreak, to be included in LTS14424. 
Protocol amendment summary of changes table 
 
Section # and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary; 
7.1 Inclusion Criteria 
To allow Brazilian patients 
who were prematurely 
discontinued from IMP in 
EFC14153 due to the need of 
Yellow Fever vaccination 
during Yellow Fever 
outbreak, to be included in 
LTS14424. 
The LTS14424 study includes pediatric patients with asthma 
who completed the treatment in a Dupilumab asthma trial 
(EFC14153). Any Brazilian patient who was prematurely 
discontinued from the IMP (in Study EFC14153) due to the 
need of Yellow Fever Vaccination during the Yellow Fever 
outbreak will be allowed to be enrolled in LTS14424 provided 
that the required follow-up procedures are completed in study 
EFC14153. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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