Clinical trial NCT02134028
Conditions: Asthma
Sponsor: Sanofi
Start date: 2014-08-05; Completion date: 2019-10-11
Enrollment: 2282 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To evaluate the long-term safety and tolerability of dupilumab in participants with asthma who participated in a previous dupilumab asthma study (DRI12544, PDY14192, EFC13579, EFC13691).

Secondary Objectives:

To evaluate the long-term efficacy of dupilumab in participants with asthma who participated in a previous dupilumab asthma clinical study.

To evaluate dupilumab in participants with asthma who participated in a previous dupilumab asthma clinical study, with regards to:

* Systemic exposure
* Anti-drug antibodies
* Biomarkers

Detailed description:
A screening period, up to 3 weeks, applied only for participants who came from DRI12544 study. The total study duration, per participant, was a maximum of 108 weeks (or 111 weeks considering a maximum screening period of 3 weeks for study DRI12544) for the participants enrolled prior to Amendment 04 approval and a maximum of 60 weeks for the participants enrolled after Amendment 04 approval.

Following amendment 04 (dated 31 Oct 2016) the open-label treatment duration was amended to 48 weeks (1 year); and the 16-week post-treatment period was shortened to 12 weeks.

Arms: arm 1: For participants coming from the DRI12544 study: dupilumab loading dose subcutaneous (SC) on Day 1, followed by 1\* Dose every 2 weeks added to current controller medications.

For participants coming from other studies: dupilumab 1 \* Dose SC every 2 weeks added to current controller medications.
Interventions: intervention 1: Dupilumab
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection Routes of administration: Subcutaneous

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 
COMPOUND: SAR231893 
Open-label extension study to evaluate the long-term safety and tolerability of 
dupilumab in patients with asthma who participated in a previous dupilumab 
asthma clinical study 
STUDY NUMBER: LTS12551 
STUDY NAME: LIBERTY ASTHMA TRAVERSE 
VERSION DATE/STATUS: 31-Oct-2016 /Approved 
CLINICAL STUDY DIRECTOR: 
 
Protocol Amendment 04 
Version number 1: (electronic 1.0) 
Date: 31-Oct-2016 
Amended Clinical Trial Protocol 02 
(Japan) 
Version number 1: (electronic 1.0) 
Date: 24-Aug-2016 
Protocol Amendment 03 (Japan) 
Version number 1: (electronic 1.0) 
Date: 24-Aug-2016 
Amended Clinical Trial Protocol 02 
(Germany) 
Version number: 1 (electronic 1.0) 
Date: 22 -Dec-2015 
Protocol Amendment 02 
(Germany) 
Version number: 1 (electronic 1.0) 
Date: 22 -Dec-2015 
Amended Clinical Trial Protocol 01 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Version number: 1 (electronic 1.0) 
Date: 04-Jun-2015 
Date: 04-Jun-2015 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date: 24-Jan-2014 
Version Number:  1 
EudraCT:  
IND Number : 
2013-003856-19/U1111-1117-6745 
105379 
Date:  31-Oct-2016 
Total number of pages:  127 
 
(electronic 4.0)
NCT02134028


Amended Clinical Trial Protocol 02  
31-Oct-2016 
SAR231893-LTS12551 - dupilumab 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
 
(electronic 
 
 
 
4.0)


Amended Clinical Trial Protocol 02  
31-Oct-2016 
SAR231893-LTS12551 - dupilumab 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
 
 
COMPOUND: Dupilumab (SAR231893)  
STUDY No: LTS12551 
TITLE 
Open-label extension study to evaluate the long-term safety and tolerability of
dupilumab in patients with asthma who participated in a previous dupilumab 
asthma clinical study 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
Phase 2b/Phase 3. 
STUDY OBJECTIVES 
Primary objective 
 
• 
To evaluate the long-term safety and tolerability of dupilumab in 
patients with asthma who participated in a previous dupilumab 
asthma clinical study (DRI12544, PDY14192, EFC13579, 
EFC13691).  
 
Secondary objectives 
 
• 
To evaluate the long-term efficacy of dupilumab in patients with 
asthma who participated in a previous dupilumab asthma clinical 
study. 
• 
To evaluate dupilumab in patients with asthma who participated in 
previous dupilumab asthma clinical study, with regard to: 
- 
systemic exposure; 
- 
anti-drug antibodies (ADA); 
- 
biomarkers. 
STUDY DESIGN 
Multinational, multicenter, open-label, extension study evaluating 
dupilumab 300 mg subcutaneously (SC) every 2 weeks (q2w) for 1-year 
(48 weeks) or 2-year (96 weeks) treatment duration.  
Patients enrolled prior to Amendment 04 approval will continue to 
participate in the 2-year treatment duration; patients enrolled after 
Amendment 04 approval will participate in the 1-year treatment duration.  
At enrollment, patients will be on medium or high dose of inhaled 
corticosteroid (ICS) and at least one other asthma controller medication, as 
maintained during the parent study in which they participated (including 
asthma background controller therapy with oral corticosteroids [OCS] only 
for patients from Study EFC13691). 
 
The clinical trial consists of 3 periods: 
• 
Enrollment period: Combined V1/V2 Visit: Eligible patients from 
PDY14192, EFC13579, and EFC13691 studies should rollover into 
LTS12551 the same day as the end-of-treatment visit of the parent 
study.  
- 
Note: A screening period of 0 to 3 weeks was proposed only 
for patients rolling over from DRI12544. Enrollment from Study 
DRI12544 is complete, thus the screening period does not 
apply anymore. 
• 
Treatment period: 48 or 96 weeks open-label treatment.  
(electronic 
 
 
 
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Amended Clinical Trial Protocol 02  
31-Oct-2016 
SAR231893-LTS12551 - dupilumab 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 4 
- 
Patients enrolled prior to Amendment 04 approval will continue 
to participate in the 2-year treatment duration; patients enrolled
after Amendment 04 approval will participate in the 1-year 
treatment duration. During the open-label treatment period, 
patients will continue taking their background controller 
therapy, as maintained during the parent study or as modified 
based on Investigator's judgment. 
• 
Post-treatment period: 12 weeks.  
- 
Upon completion of the open-label treatment period (or 
following early discontinuation of investigational medicinal 
product [IMP]) patients will continue into the post-treatment 
period. During this period, patients will receive their 
background controller regimen, as maintained during the 
open-label treatment period or as modified based on 
Investigator's judgment (eg, taking into account the reduction 
of dupilumab levels over time upon completion of the treatment
period). 
STUDY POPULATION 
 
Main selection criteria 
Main inclusion criteria 
Eligible patients who have completed the treatment period in a previous 
dupilumab asthma study (PDY14192, EFC13579, EFC13691) or patients 
with asthma who completed the treatment and follow-up periods in previous 
dupilumab asthma Study DRI12544 may be enrolled in the LTS12551 
study. 
 
Main exclusion criteria 
Patients who experienced any hypersensitivity reactions to IMP in the 
previous dupilumab asthma study, which, in the opinion of the Investigator, 
could indicate that continued treatment with dupilumab may present an 
unreasonable risk for the patient.  
For the complete list of inclusion/exclusion criteria, please refer to the 
relevant sections of the full protocol.  
Total expected number of patients 
The total number of patients to participate is approximately 2206 (including a 
number of adolescent patients [aged 12 years to less than 18 years] that will
not exceed the sum of adolescent patients enrolled in the parent studies).  
STUDY TREATMENT(s) 
Investigational medicinal 
product(s) (IMP) 
 
 
Formulation 
Dupilumab. 
 
Note: At the time of Amendment 04, all patients have been transitioned to 
prefilled syringes. 
 
Prefilled syringes: Sterile dupilumab will be provided at the concentration of 
150 mg/mL in glass prefilled syringes (2.25 mL total volume) to deliver  
300 mg in the extractable 2 mL volume.  
Route of administration 
SC. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 02  
31-Oct-2016 
SAR231893-LTS12551 - dupilumab 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 5 
Dose regimen 
Eligible patients will receive dupilumab 300 mg (SC) q2w, of open-label 
treatment for 48 weeks (1 year) for patients enrolled after approval of 
Amendment 04 or 96 weeks (2 years) for patients enrolled prior to 
Amendment 04 approval.  
Note: Enrollment from Study DRI12544 is complete; all patients were given 
a 600 mg loading dose on Day 1.  
Noninvestigational medicinal 
product(s) (if applicable) 
 
 
Formulation 
Asthma background controller therapy:  
Inhaled corticosteroid, in combination with a second controller. Patients 
requiring a third controller medication are allowed (eg, long-acting 
beta-agonist [LABA], leukotriene receptor antagonist [LTRA], 
methylxanthines, etc); OCS only for those patients from EFC13691. 
Asthma reliever medication 
Patients may receive salbutamol/albuterol hydrofluoroalkane pressurized 
metered dose inhalers (MDI) or levosalbutamol/levalbuterol 
hydrofluoroalkane pressurized MDI as reliever medication (as needed) during 
the study. Nebulizer solutions with either albuterol/salbutamol or 
levalabuterol/levosalbutamol may be used as an alternative delivery method. 
Route(s) of administration 
Oral inhalation, nebulizers: ICS, ICS combination, albuterol/salbutamol or 
levalbuterol/levosalbutamol; for other background controllers according to 
the label. 
Dose regimen 
Inhaled corticosteroid (medium or high dose); albuterol/salbutamol or 
levalbuterol/levosalbutamol (as needed); other background controllers 
according to the label. 
ENDPOINT(S) 
Primary endpoint 
 
• 
The number (n) and percentage (%) of patients experiencing any 
treatment-emergent adverse events (TEAEs). 
 
Secondary endpoints 
• 
Safety and tolerability 
- 
Vital signs. 
- 
Physical examination. 
- 
Electrocardiogram (ECG). 
- 
Clinical laboratory tests. 
• 
Efficacy 
- 
Forced expiratory volume in 1 second (FEV1). 
- 
Asthma Control Questionnaire–5 question version (ACQ-5). 
- 
Severe asthma exacerbation events, during the treatment 
period. 
- 
Asthma Quality of Life Questionnaire - Standardized 
[AQLQ(S)]. 
- 
EuroQol 5 dimensions questionnaire, 3-level version  
(EQ-5D-3L). 
- 
Health care resource utilization questionnaire. 
- 
Morning and evening peak expiratory flow (PEF). 
- 
Asthma symptom scores. 
- 
Number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 02  
31-Oct-2016 
SAR231893-LTS12551 - dupilumab 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 6 
- 
Nocturnal awakenings due to asthma requiring use of reliever 
medication.  
- 
Prescribed OCS dose for patients from the EFC13691 study. 
 
• 
Dupilumab systemic exposure and anti-drug antibodies 
- 
Serum dupilumab concentrations. 
- 
Anti-drug antibodies. 
 
• 
Biomarkers 
- 
Blood: Eosinophil count. 
- 
Serum: Immunoglobulins (Ig), total IgE. 
 
ASSESSMENT SCHEDULE 
• 
Enrollment period: Combined V1/V2 Visit: Eligible patients from 
PDY14192, EFC13579, and EFC13691 studies should rollover into 
LTS12551 on the same day as the end-of-treatment visit of the 
parent study. 
• 
Treatment period: Open-label treatment for 48 weeks (1 year) for 
patients enrolled after approval of Amendment 04 or 96 weeks 
(2 years) for patients enrolled prior to Amendment 04 approval.  
• 
Post-treatment period: 12 weeks. 
 
Study visits are performed q2w (ie, twice a month / approximately q2w) during 
the first 3 months of study (up to Visit 8), every month during the next 
3 months (up to Visit 11), and every 3 months up to the End-of-Treatment 
(EOT) Visit. In addition, monthly telephone contacts will be performed after 
Week 24/Month 6 (Visit 11).  
 
STATISTICAL CONSIDERATIONS 
 
 
Sample size determination 
The study size is predicated on the overall size of the parent studies; 
hence, the maximum number of patients to participate will correspond 
to the sum of the total number of patients enrolled in the DRI12544, 
PDY14192, EFC13579, and EFC13691 studies.  
 
Analysis population 
Safety population is defined as the patients exposed to dupilumab 
during LTS12551, regardless of the amount of treatment administered.  
The treatment-emergent period is defined as the time from the first 
dose of dupilumab in LTS12551 up to the last dose of dupilumab plus 
2 weeks (one dose interval) plus 12 weeks (follow-up period duration). 
 
Primary analysis 
The primary analysis of this study is the number (n) and percentage (%) of 
patients experiencing any TEAE, which will be summarized using 
descriptive statistics.  
Each adverse event (AE)/TEAE will be coded according to the version of 
the Medical Dictionary for Regulatory Activities (MedDRA) in effect at 
sanofi as of the time of database lock. 
 
Analysis of secondary endpoints 
All analyses will be done descriptively on the safety population. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 02  
31-Oct-2016 
SAR231893-LTS12551 - dupilumab 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 7 
Graphical time course profiles will be provided when appropriate for 
documentation of outcomes. 
DURATION OF STUDY PERIOD (per
patient) 
Enrollment period: 
• 
For patients coming from PDY14192, EFC13579, and EFC13691, 
enrollment should be done at the Combined V1/V2 Visit (ie, on the 
same day as the end-of-treatment visit of the parent study combined 
with Visit 1 and Visit 2 of LTS12551 study).  
- 
Note: A screening period of 0 to 3 weeks was proposed only 
for patients rolling over from DRI12544. Enrollment from Study 
DRI12544 is complete, thus the screening period does not 
apply anymore. 
 
The (open-label) treatment period is:  
• 
48 weeks (1 year) for patients enrolled after Amendment 04 approval
or  
• 
 96 weeks (2 years) for patients enrolled prior to Amendment 04 
approval.  
 
The post-treatment period is 12-weeks. 
 
The total study duration, per patients, is a maximum of 108 weeks (or 
111 weeks considering a maximum screening period of 3 weeks for 
Study DRI12544) for the patients enrolled prior to Amendment 04 
approval and a maximum of 60 weeks for the patients enrolled after 
Amendment 04 approval. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 02  
                                                                      31-Oct-2016 
SAR231893-LTS12551-dupilumab 
 
       Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 8 
1 FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
  
 
  
 
Enrollment
Combined V1/V2 
Visit* 
Open-label treatment period 
 (48 or 96 weeks) 
Post-treatment
period (12 weeks)   
 
*Eligible patients from PDY14192, 
EFC13579 and EFC13691 studies 
should rollover into LTS12551 the 
same day as the end-of-treatment 
visit of the parent study, which will 
be combined with V1 and V2 of 
LTS12551 study.
Start-of-Treatment 
D1  
Dupilumab 300 mg SC 
q2w
End-of-Treatment
V17
 
 
End-of-Study
V18
Background therapy: Medium or high dose ICS and a second controller (LABA, LTRA, etc).  
Third controller is allowed (including daily OCS for patients in Study EFC13691) 
D = Study Day; LABA = long-acting beta agonists; LTRA = leukotriene receptor antagonists OCS = oral corticosteroids; q2w = every 2 
weeks; V = Study Visit
(electronic 
 
 
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Amended Clinical Trial Protocol 02  
                                                                      31-Oct-2016 
SAR231893-LTS12551-dupilumab 
 
       Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 9 
1.2 
STUDY FLOW CHART FOR PATIENTS ENROLLED PRIOR TO AMENDMENT 04 
 
SOTa (D1) 
 
EOTb
EOS 
Study periods 
Enrollment: 
Combined 
V1/V2* 
Open-label treatment period 
(96 weeks) 
Post-treatment period 
(12 weeks) 
Week (W) 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W36 
W48 
W60 
W72 
W84 
W96 
W108 
Month (M) 
 
 
 
M1 
 
M2 
 
M3 
M4 
M5 
M6 
M9 
M12 
M15 
M18 
M21 
M24 
M27 
VISIT 
1c 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Enrollment 
 
Informed consent 
X 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest imaging (MRI was 
already implemented for 
Germanyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
Call IVRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP 
dispense/administratione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection training/technique 
observationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense and download 
electronic diary/PEF meter 
(no longer used following 
amendment 04)g 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
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Amended Clinical Trial Protocol 02  
                                                                      31-Oct-2016 
SAR231893-LTS12551-dupilumab 
 
       Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 10 
 
SOTa (D1) 
 
EOTb
EOS 
Study periods 
Enrollment: 
Combined 
V1/V2* 
Open-label treatment period 
(96 weeks) 
Post-treatment period 
(12 weeks) 
Week (W) 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W36 
W48 
W60 
W72 
W84 
W96 
W108 
Month (M) 
 
 
 
M1 
 
M2 
 
M3 
M4 
M5 
M6 
M9 
M12 
M15 
M18 
M21 
M24 
M27 
VISIT 
1c 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Prior & concomitant 
medication 
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 
 
X 
X 
X 
X 
ACQ-5i 
X** 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
AQLQ(S)i 
X** 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
EQ-5D-3L (no longer 
performed following 
Amendment 04) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resource utilizationj 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
Safety 
 
Vital signsk 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
ECG  
X** 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
X 
Adverse event reporting 
<- ----------------------------------------------------------------------------------------------------------- X ----------------------------------------------------------------------------------------------------------------------------Æ 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratoriesl 
X** 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Pregnancy test: Urinem 
X** 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisn 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
PK samplingo 
X** 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
(electronic 
 
 
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Amended Clinical Trial Protocol 02  
                                                                      31-Oct-2016 
SAR231893-LTS12551-dupilumab 
 
       Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 11 
 
SOTa (D1) 
 
EOTb
EOS 
Study periods 
Enrollment: 
Combined 
V1/V2* 
Open-label treatment period 
(96 weeks) 
Post-treatment period 
(12 weeks) 
Week (W) 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W36 
W48 
W60 
W72 
W84 
W96 
W108 
Month (M) 
 
 
 
M1 
 
M2 
 
M3 
M4 
M5 
M6 
M9 
M12 
M15 
M18 
M21 
M24 
M27 
VISIT 
1c 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
ADAo 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
Serum immunoglobulins 
(no longer performed 
following Amendment 04)o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum total IgE (no longer 
performed following 
Amendment 04)o 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B viral loadq 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Reminder 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICS and controller therapy 
reminderr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medication withhold 
reminderr  
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
Next visit fasting reminderr  
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Safety follow-up: Monthly 
phone contact after 
Week-24s 
 
 
 
<------------------------------------------------------- X -------------------------------------------------Æ 
Abbreviations: ACQ-5 = Asthma Control Questionnaire-5-question version; ADA = anti-drug antibodies; ALT = alanine aminotransferase; ALP = alkaline phosphatase; ANA = anti-nuclear antibody; AST = aspartate 
aminotransferase; AQLQ(S)= Asthma Quality of Life Questionnaire (standardized); BUN = blood urea nitrogen; CPK = creatine phosphokinase; ECG = electrocardiogram; e-CRF = electronic case report form;  
EOS = End-of-Study; EOT = End-of-Treatment; EQ-5D-3L = EuroQol 5 dimensions questionnaire 3-level version; IgE = immunoglobulin E; IMP = Investigational Medicinal Product; IVRS = Interactive Voice Response 
System; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibodies; HIV = Human Immunodeficiency Virus; HRCT = High 
resolution computed tomography; ICS = inhaled corticosteroid; IRB = Institutional Review Board;; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; M = (Study) Month; MRI = Magnetic 
Resonance Imaging; PEF = peak expiratory flow; PK = pharmacokinetic; q2w = every 2 weeks; SOT = Start-of-Treatment; V = (Study) Visit; W = (Study) Week. 
(electronic 
 
 
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Amended Clinical Trial Protocol 02  
                                                                      31-Oct-2016 
SAR231893-LTS12551-dupilumab 
 
       Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 12 
* Eligible patients from PDY14192, EFC13579, and EFC13691 studies should rollover into LTS12551 the same day as the end-of-treatment visit of the parent study (which will be combined with V1 and V2 of 
LTS12551 study).  
** Data for the baseline procedures at D1 will be obtained from the end-of-treatment visit of the PDY14192, EFC13579, and EFC13691 parent studies (see Section 10). 
a Start-of-Treatment/Enrollment (Combined V1/V2) Visit for patients from PDY14192, EFC13579, and EFC13691 studies, after having performed the assessments of end-of-treatment visit in the parent study. Visit windows for 
subsequent visits are ±3 days in the first 12 weeks and ±1 week for the remainder of the study.  
b Patients who discontinue treatment early are scheduled, as soon as possible, for the EOT Visit, followed by the EOS Visit. If LTS12551 is terminated, then the next visit for all involved patients will be the 
EOT Visit, followed by the EOS Visit. 
c Eligible patients in PDY14192, EFC13579, and EFC13691 studies should rollover into LTS12551 the same day as the end-of-treatment visit of the parent study. Visit 1 and Visit 2 of LTS12551 study should be 
combined with the end-of-treatment visit of the PDY14192, EFC13579 or EFC13691 parent studies. 
d Chest imaging: Chest X-ray, MRI or HRCT will be performed only if no chest imaging results obtained within the previous 12 months are available. At the Investigator’s discretion (and based on local regulations) chest 
imaging may be performed during the study (eg, 1 year after the last chest imaging assessment or after a year’s treatment). 
e Every 2 weeks (q2w) the IMP administrations must be separated by at least 11 days. The treatment period visits occur q2w up to Visit 8 (Month 3), every month up to Visit 11 (Month 6), and every 3 months for the 
remaining duration of the study. For IMP administrations coinciding with treatment period visits, patients will be monitored at the study site for a minimum of 30 minutes after injections. If the patient or the 
Investigator decides not to administer IMP at home, the injections can be performed at the study site by way of unscheduled visits. 
f 
The injection training is for patients who are willing to perform self-injection. The Investigator or delegate should review the patient’s self-administration technique at the Combined V1/V2 Visit. 
g Electronic diary / PEF meter will no longer be used in this study due to Amendment 04 (see Section 10.6).  
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 and 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 
ACQ-5 and AQLQ(S) paper forms are completed during clinic visits. Data will be collected into the e-CRF. Note: For patients from PDY14192 study, AQLQ(S) paper form must be completed at the Combined 
V1/V2 Visit as part of the LTS12551 assessments.  
j 
A questionnaire of health care resource utilization (reliever medication, specialist visit, hospitalization, emergency or urgent medical care facility visit, outcome, sick leaves, etc). Data will be collected into the 
e-CRF. 
k 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 (Combined V1/V2) Visit. Vital signs will be measured in the sitting position using the same arm at each visit and will be measured prior to IMP administration at the clinic visits. 
l 
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 non-conjugated bilirubin), ALT, AST, ALP, total protein, albumin, total cholesterol, CPK, glucose, creatinine, 
BUN, uric acid, bicarbonate and electrolytes (sodium, potassium, chloride). At enrollment, clinical laboratory testing results are collected from the parent study for HBsAg, HBsAb, HBcAb, total HBcAb, HCVAb, HIV 
screen (Anti-HIV-1 and HIV-2 antibodies) and ANA (ie, since these tests were scheduled at the visit prior to the end-of-treatment visit of the PDY14192, EFC13579 or EFC13691 parent study). In addition, results 
from hepatitis B virus DNA (HBV DNA) testing and HCV virus RNA (HCV RNA) testing should be collected for those patients who were HBsAg negative and HBcAb positive, and/or HCVAb positive; also anti-
-double-strand DNA antibody results for patients with ANA positive (≥1:160 titer). Note: Japanese patients who have rolled over from DRI12544 study should be retested for hepatitis B (HBsAg, HBsAb, and 
HBcAb), after Visit 1, at any time during the LTS12551 study, via the earliest scheduled study visit, after IRB approval for Local Amendment 03 (Japan). 
m A negative serum pregnancy test was obtained at Visit 1, prior to Start-of-Treatment, for patients coming from DRI12544. Qualifying pregnancy test for patients coming from PDY14192, EFC13579, and EFC13691 
studies will be the urine pregnancy test. 
n Urinalysis: pH, glucose, ketones, leukocyte esterase blood, protein, nitrate, urobilinogen, and bilirubin (by dipstick). 
o Samples will be collected prior to IMP administration, during the treatment period. Note: Serum immunoglobulins (including IgE) will no longer be assayed in LTS12551 study due to Amendment 04.  
 
q This is only applicable for patients in Japan (or other countries/regions if there is a local regulatory requirement) who are HBsAg negative and HBsAb positive at screening during the parent study or at the 
additional test due to Local Amendment 03 (Japan). 
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Page 13 
r 
Remind patient to continue the background therapy of ICS and controller therapies; remind patient to withhold bronchodilators according to their action duration, for example, withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and 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 prior to next visit; remind patient for the next visit in the fasting state. 
s Monthly telephone contact with patient after Week-24 to collect safety information. 
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1.3 
STUDY FLOW CHART FOR PATIENTS ENROLLED AFTER AMENDMENT 04 
 
SOTa (D1) 
 
EOTb
EOS 
Study periods 
Enrollment: 
Combined V1/V2*
Open-label treatment period 
(48 weeks) 
Post-treatment period 
(12 weeks) 
Week (W) 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W36 
W48 
W60 
Month (M) 
 
 
 
M1 
 
M2 
 
M3 
M4 
M5 
M6 
M9 
M12 
M15 
VISIT 
1c 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
17 
18 
Enrollment 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest imaging (MRI was already 
implemented for Germany)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Entry criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
 
Call IVRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP dispense/administratione 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection training / technique 
observationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense and download electronic 
diary/PEF meter (no longer used 
following Amendment t04)g 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy 
 
Spirometryh 
X** 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
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Page 15 
 
SOTa (D1) 
 
EOTb
EOS 
Study periods 
Enrollment: 
Combined V1/V2*
Open-label treatment period 
(48 weeks) 
Post-treatment period 
(12 weeks) 
Week (W) 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W36 
W48 
W60 
Month (M) 
 
 
 
M1 
 
M2 
 
M3 
M4 
M5 
M6 
M9 
M12 
M15 
VISIT 
1c 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
17 
18 
ACQ-5i 
X** 
 
 
 
 
 
 
 
 
X 
 
X 
 
AQLQ(S)i 
X** 
 
 
 
 
 
 
 
 
X 
 
X 
 
EQ-5D-3L (no longer performed 
following Amendment 04) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resource utilizationj 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Safety 
 
Vital signsk 
X** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
ECG  
X** 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Adverse event reporting 
<- ----------------------------------------------------------------------------------------------------------- X -----------------------------------------------------------------------------------------------------------Æ 
Laboratory testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratoriesl 
X** 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
Pregnancy test: Urinem 
X** 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisn 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
PK samplingo 
X** 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
ADAo 
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
Serum immunoglobulins (no longer 
performed following Amendment 04)o 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum total IgE (no longer performed 
following Amendment 04)o 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Page 16 
 
SOTa (D1) 
 
EOTb
EOS 
Study periods 
Enrollment: 
Combined V1/V2*
Open-label treatment period 
(48 weeks) 
Post-treatment period 
(12 weeks) 
Week (W) 
W0 
W2 
W4 
W6 
W8 
W10 
W12 
W16 
W20 
W24 
W36 
W48 
W60 
Month (M) 
 
 
 
M1 
 
M2 
 
M3 
M4 
M5 
M6 
M9 
M12 
M15 
VISIT 
1c 
2c 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
17 
18 
Hepatitis B viral loadq
X** 
 
 
 
 
 
X 
 
 
X 
 
X 
 
Reminder 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICS and controller therapy reminderr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medication withhold reminderr 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
 
Next visit fasting reminderr 
 
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
Safety follow-up: Monthly phone 
contact after Week-24s 
 
 
 
Å--------------------------- X ----------------------------Æ 
Abbreviations: ACQ-5 = Asthma Control Questionnaire 5-question version; ADA = Anti-drug antibodies; ALT = alanine aminotransferase; ALP = alkaline phosphatase; ANA = anti-nuclear antibody; AST = aspartate 
aminotransferase; AQLQ(S)= Asthma Quality of Life Questionnaire (standardized); BUN = blood urea nitrogen; CPK = creatine phosphokinase; ECG = Electrocardiogram; e-CRF = electronic case report form;  
EOS = End-of-Study; EOT = End-of-Treatment; EQ-5D-3L = EuroQol 5 dimensions questionnaire, 3-level version; IgE = immunoglobulin E; IMP = Investigational Medicinal Product; IVRS = Interactive Voice Response 
System; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCV Ab = hepatitis C virus antibodies; HIV = Human Immunodeficiency Virus; HRCT = high 
resolution computed tomography; ICS = inhaled corticosteroid; IRB = Institutional Review Board; LABA = long-acting beta-agonist; LAMA = long-acting muscarinic antagonist; M = (Study) Month; MRI = Magnetic 
Resonance Imaging; PEF = peak expiratory flow; PK = pharmacokinetic; q2w = every 2 weeks; SOT = Start-of-Treatment; V = (Study) Visit; W = (Study) Week. 
* Eligible patients from PDY14192, EFC13579, and EFC13691 studies should rollover into LTS12551 the same day as the end-of-treatment visit of the parent study (which will be combined with V1 and V2 of 
LTS12551 study).  
** Data for the baseline procedures at D1 will be obtained from the end-of-treatment visit of the PDY14192, EFC13579 or EFC13691 parent studies (see Section 10). 
a Start-of-Treatment/Enrollment (Combined V1/V2) Visit for patients from PDY14192, EFC13579, and EFC13691 studies, after having performed the assessments of end-of-treatment visit in the parent study. Visit windows for 
subsequent visits are ±3 days in the first 12 weeks and ±1 week for the remainder of the study.  
b Patients who discontinue treatment early are scheduled, as soon as possible, for the EOT Visit, followed by the EOS Visit. If LTS12551 is terminated, then the next visit for all involved patients will be the EOT 
Visit, followed by the EOS Visit. 
c Eligible patients in PDY14192, EFC13579, and EFC13691 studies should rollover into LTS12551 the same day as the end-of-treatment visit of the parent study. Visit 1 and Visit 2 of LTS12551 study should be 
combined with the end-of-treatment visit of the PDY14192, EFC13579 or EFC13691 parent studies.  
d Chest imaging: Chest X-ray, MRI or HRCT will be performed only if no chest imaging results obtained within the previous 12 months are available. At the Investigator’s discretion (and based on local regulations) chest 
imaging may be performed during the study (eg, 1 year after the last chest imaging assessment or after a year’s treatment). 
e Every 2 weeks (q2w) the IMP administrations must be separated by at least 11 days. The treatment period visits occur q2w up to Visit 8 (Month 3), every month up to Visit 11 (Month 6), and every 3 months for the 
remaining duration of the study. For IMP administrations coinciding with treatment period visits, patients will be monitored at the study site for a minimum of 30 minutes after injections. If the patient or the 
Investigator decides not to administer IMP at home, the injections can be performed at the study site by way of unscheduled visits. 
f 
The injection training is for patients who are willing to perform self-injection. The Investigator or delegate should review the patient’s self-administration technique at the Combined V1/V2 Visit. 
g Electronic diary/PEF meter will no longer be used in this study due to Amendment 04 (see Section 10.6). 
(electronic 
 
 
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       Version number: 1 
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Page 17 
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 and 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 
ACQ-5 and AQLQ(S) paper forms are completed during clinic visits. Data will be collected into the e-CRF. Note: For patients from PDY14192 study, AQLQ(S) paper form will be completed at the Combined V1/V2 
Visit. 
j 
A questionnaire of health care resource utilization (reliever medication, specialist visit, hospitalization, emergency or urgent medical care facility visit, outcome, sick leaves, etc). Data will be collected into the 
e-CRF. 
k 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 (Combined V1/V2) Visit. Vital signs will be measured in the sitting position using the same arm at each visit and will be measured prior to IMP administration at the clinic visits. 
l 
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 non-conjugated bilirubin), ALT, AST, ALP, total protein, albumin, total cholesterol, CPK, glucose, creatinine, 
BUN, uric acid, bicarbonate and electrolytes (sodium, potassium, chloride). At enrollment, clinical laboratory testing results study are collected from the parent study for HBsAg, HBsAb, HBcAb, total HBcAb, 
HCVAb, HIV screen (Anti-HIV-1 and HIV-2 antibodies) and ANA (ie, since these tests were scheduled at the visit prior to the end-of-treatment visit of the PDY14192, EFC13579 or EFC13691 parent studies). In 
addition, results from hepatitis B virus DNA (HBV DNA) testing and HCV virus RNA (HCV RNA) testing should be collected for those patients who were HBsAg negative and HBcAb positive, and/or HCVAb 
positive; also anti-double-strand DNA antibody results for patients with ANA positive (≥1:160 titer). Note: Japanese patients who have rolled over from DRI12544 study should be retested for hepatitis B (HBsAg, 
HBsAb, and HBcAb), after Visit 1, at any time during the LTS12551 study, via the earliest scheduled study visit, after IRB approval for Local Amendment 03 (Japan). 
m A negative serum pregnancy test was obtained at Visit 1, prior to Start-of-Treatment, for patients coming from DRI12544. Qualifying pregnancy test for patients coming from PDY14192, EFC13579, and EFC13691 
studies will be the urine pregnancy test. 
n Urinalysis: pH, glucose, ketones, leukocyte esterase blood, protein, nitrate, urobilinogen, and bilirubin (by dipstick). 
o Samples will be collected prior to IMP administration, during the treatment period. Note: Serum immunoglobulin (including IgE) will no longer be assayed in LTS12551 study due to Amendment 04. 
 
q This is only applicable for patients in Japan (or other countries/regions if there is a local regulatory requirement) who are HBsAg negative and HBsAb positive at screening during the parent study or at the 
additional test due to Local Amendment 03 (Japan). 
r 
Remind patient to continue the background therapy of ICS and controller therapies; remind patient to withhold bronchodilators according to their action duration, for example, withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, and 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 prior to next visit; remind patient for the next visit in the fasting state. 
s Monthly telephone contact with patient after Week-24 to collect safety information.
(electronic 
 
 
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Page 18 
2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 ..............................................................................................1 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOW CHART FOR PATIENTS ENROLLED PRIOR TO AMENDMENT 04 ....................9 
1.3 
STUDY FLOW CHART FOR PATIENTS ENROLLED AFTER AMENDMENT 04........................14 
2 
TABLE OF CONTENTS ................................................................................................................18 
3 
LIST OF ABBREVIATIONS ..........................................................................................................24 
4 
INTRODUCTION AND RATIONALE.............................................................................................26 
4.1 
INTRODUCTION............................................................................................................................26 
4.2 
RATIONALE...................................................................................................................................26 
5 
STUDY OBJECTIVES ...................................................................................................................29 
5.1 
PRIMARY.......................................................................................................................................29 
5.2 
SECONDARY ................................................................................................................................29 
6 
STUDY DESIGN ............................................................................................................................30 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................30 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................30 
6.2.1 
Duration of study participation for each patient .............................................................................30 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................31 
6.3 
INTERIM ANALYSIS......................................................................................................................31 
6.4 
STUDY COMMITTEES..................................................................................................................31 
6.4.1 
Data monitoring committee ............................................................................................................31 
7 
SELECTION OF PATIENTS..........................................................................................................32 
7.1 
INCLUSION CRITERIA..................................................................................................................32 
7.2 
EXCLUSION CRITERIA ................................................................................................................32 
7.2.1 
Exclusion criteria related to study methodology ............................................................................32 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......33 
7.2.3 
Exclusion criteria related to the current knowledge of sanofi compound.......................................33 
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8 
STUDY TREATMENTS .................................................................................................................35 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................35 
8.1.1 
Dupilumab......................................................................................................................................35 
8.1.2 
Preparation of investigational product............................................................................................35 
8.1.3 
Dose schedule ...............................................................................................................................35 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................36 
8.2.1 
Inhaled corticosteroid and controller therapies ..............................................................................36 
8.2.1.1 
Enrollment V1/V2 visit (combined with the end-of-treatment visit of parent study) .......................36 
8.2.1.2 
Open-label treatment period ..........................................................................................................36 
8.2.1.3 
Post-treatment period.....................................................................................................................36 
8.2.2 
Albuterol or levalbuterol reliever medication..................................................................................37 
8.3 
BLINDING PROCEDURES............................................................................................................37 
8.3.1 
Methods of blinding........................................................................................................................38 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................38 
8.5 
PACKAGING AND LABELING ......................................................................................................38 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................38 
8.7 
RESPONSIBILITIES ......................................................................................................................39 
8.7.1 
Treatment accountability and compliance......................................................................................39 
8.7.2 
Return and/or destruction of treatments ........................................................................................40 
8.8 
CONCOMITANT MEDICATION.....................................................................................................40 
8.8.1 
Prohibited concomitant medication................................................................................................40 
8.8.2 
Permitted concomitant medication.................................................................................................40 
8.8.3 
Cytochrome P450 (CYP) precaution..............................................................................................41 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................42 
9.1 
PRIMARY ENDPOINT ...................................................................................................................42 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................42 
9.2.1 
Safety and tolerability.....................................................................................................................42 
9.2.1.1 
Vital signs.......................................................................................................................................43 
9.2.1.2 
Physical examination .....................................................................................................................43 
9.2.1.3 
Electrocardiogram (ECG) variables ...............................................................................................43 
9.2.1.4 
Clinical laboratory tests..................................................................................................................43 
9.2.2 
Efficacy...........................................................................................................................................44 
9.2.2.1 
Forced expiratory volume in 1 second (FEV1) ...............................................................................45 
9.2.2.2 
ACQ-5 (Asthma Control Questionnaire, 5-question version).........................................................45 
9.2.2.3 
Severe asthma exacerbation events..............................................................................................46 
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9.2.2.4 
Asthma Quality of Life Questionnaire with standardized activities (AQLQ[S]) ..............................46 
9.2.2.5 
EuroQol 5 dimensions questionnaire, 3-level version (EQ-5D-3L)................................................47 
9.2.2.6 
Health care resource utilization......................................................................................................47 
9.2.2.7 
Disease-specific, daily efficacy assessments ................................................................................47 
9.2.2.8 
Prescribed oral corticosteroids (OCS) dose for patients from the EFC13691 study .....................49 
9.3 
OTHER ENDPOINTS.....................................................................................................................49 
9.3.1 
Pharmacokinetics and anti-dupilumab antibodies .........................................................................49 
9.3.1.1 
Sampling time ................................................................................................................................49 
9.3.1.2 
Pharmacokinetics handling procedure...........................................................................................50 
9.3.1.3 
Bioanalytical method......................................................................................................................51 
9.3.1.4 
Pharmacokinetics parameters .......................................................................................................51 
9.3.2 
Pharmacogenetic assessment.......................................................................................................51 
9.3.3 
Pharmacodynamic variables..........................................................................................................51 
9.3.3.1 
Whole blood biomarkers ................................................................................................................51 
9.3.3.2 
Serum biomarkers 
.......................................................................52 
9.3.4 
Quality of life / health economic variables / other endpoints (optional) .........................................52 
10 
STUDY PROCEDURES ................................................................................................................53 
10.1 
VISIT SCHEDULE..........................................................................................................................53 
10.1.1 
For patients enrolled prior to Amendment 04 ................................................................................53 
10.1.1.1 Enrollment: Combined V1/V2 Visit (Start-of-Treatment, Week 0, D1)...........................................53 
10.1.1.2 Visit 3 (Week 2)..............................................................................................................................56 
10.1.1.3 Visit 4 (Month 1, Week 4)...............................................................................................................57 
10.1.1.4 Visit 5 (Week 6)..............................................................................................................................57 
10.1.1.5 Visit 6 (Month 2, Week 8)...............................................................................................................58 
10.1.1.6 Visit 7 (Week 10)............................................................................................................................58 
10.1.1.7 Visit 8 (Month 3, Week 12).............................................................................................................59 
10.1.1.8 Visit 9 (Month 4, Week 16).............................................................................................................59 
10.1.1.9 Visit 10 (Month 5, Week 20);..........................................................................................................60 
10.1.1.10 Visit 11 (Month 6, Week 24)...........................................................................................................60 
10.1.1.11 Visit 12 (Month 9, Week 36)...........................................................................................................61 
10.1.1.12 Visit 13 (Month 12, Week 48).........................................................................................................62 
10.1.1.13 Visit 14 (Month 15, Week 60);........................................................................................................63 
10.1.1.14 Visit 15 (Month 18, Week 72).........................................................................................................64 
10.1.1.15 Visit 16 (Month 21, Week 84).........................................................................................................65 
10.1.1.16 Visit 17 (End-of-Treatment: Month 24, Week 96) ..........................................................................66 
10.1.1.17 Visit 18 (End-of-Study: Month 27, Week 108) ...............................................................................67 
10.1.2 
For patients enrolled after Amendment 04 ....................................................................................67 
10.1.2.1 Enrollment: Combined V1/V2 Visit (Start-of-Treatment, Week 0, D1) ...........................................67 
10.1.2.2 Visit 3 (Week 2)..............................................................................................................................70 
10.1.2.3 Visit 4 (Month 1, Week 4)...............................................................................................................70 
10.1.2.4 Visit 5 (Week 6)..............................................................................................................................71 
10.1.2.5 Visit 6 (Month 2, Week 8)...............................................................................................................71 
10.1.2.6 Visit 7 (Week 10)............................................................................................................................72 
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10.1.2.7 Visit 8 (Month 3, Week 12).............................................................................................................72 
10.1.2.8 Visit 9 (Month 4, Week 16).............................................................................................................73 
10.1.2.9 Visit 10 (Month 5, Week 20)...........................................................................................................74 
10.1.2.10 Visit 11 (Month 6, Week 24)...........................................................................................................74 
10.1.2.11 Visit 12 (Month 9, Week 36)...........................................................................................................75 
10.1.2.12 Visit 17 (End-of-Treatment: Month 12, Week 48) ..........................................................................76 
10.1.2.13 Visit 18 (End-of-Study: Month 15, Week 60) .................................................................................77 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................78 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................78 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................78 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................78 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................79 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................80 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................80 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................80 
10.4.1 
Definitions of adverse events.........................................................................................................80 
10.4.1.1 Adverse event ................................................................................................................................80 
10.4.1.2 Serious adverse event ...................................................................................................................81 
10.4.1.3 Adverse event of special interest...................................................................................................82 
10.4.2 
General guidelines for reporting adverse events ...........................................................................83 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................84 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................85 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................85 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................86 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................86 
10.6.1 
Hypersensitivity..............................................................................................................................86 
10.6.2 
Severe injection site reactions .......................................................................................................87 
10.6.3 
Infections........................................................................................................................................87 
10.6.4 
Elevated liver function tests ...........................................................................................................88 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................88 
11 
STATISTICAL CONSIDERATIONS..............................................................................................89 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................89 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................89 
11.3 
ANALYSIS POPULATIONS...........................................................................................................89 
11.3.1 
Efficacy populations .......................................................................................................................89 
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11.3.2 
Safety population ...........................................................................................................................89 
11.3.3 
Pharmacokinetics population.........................................................................................................89 
11.3.4 
Anti-drug antibody population ........................................................................................................90 
11.4 
STATISTICAL METHODS .............................................................................................................90 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................90 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................90 
11.4.1.2 Compliance ....................................................................................................................................90 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................90 
11.4.3 
Analyses of safety data..................................................................................................................91 
11.4.3.1 Adverse events ..............................................................................................................................91 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................93 
11.4.4.1 Pharmacokinetic analysis - (drug concentration analyses)............................................................93 
11.4.4.2 Anti-drug antibodies analysis .........................................................................................................93 
11.4.4.3 Pharmacodynamics........................................................................................................................93 
11.4.5 
Analyses of patient reported outcomes (health-related quality of life / health economics 
variables)........................................................................................................................................93 
11.5 
INTERIM ANALYSIS......................................................................................................................94 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................95 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................95 
12.2 
INFORMED CONSENT .................................................................................................................95 
12.3 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE.............................96 
13 
STUDY MONITORING...................................................................................................................97 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................97 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................97 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................98 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST .............98 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................98 
14 
ADDITIONAL REQUIREMENTS.................................................................................................100 
14.1 
CURRICULUM VITAE..................................................................................................................100 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................100 
14.3 
CONFIDENTIALITY .....................................................................................................................100 
14.4 
PROPERTY RIGHTS...................................................................................................................101 
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14.5 
DATA PROTECTION...................................................................................................................101 
14.6 
INSURANCE COMPENSATION..................................................................................................101 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................102 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................102 
14.8.1 
By the Sponsor.............................................................................................................................102 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................103 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................103 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................104 
15.1 
BY THE INVESTIGATOR ............................................................................................................104 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................105 
17 
APPENDICES..............................................................................................................................106 
APPENDIX A. 
LIST OF PROHIBITED LIVE, ATTENUATED VACCINES...............................................107 
APPENDIX B. 
EXAMPLES OF COMMONLY USED ASTHMA CONTROLLER THERAPIES................108 
APPENDIX C. 
EXAMPLES(1) OF CYP SUBSTRATES WITH NARROW THERAPEUTIC RANGE........110 
APPENDIX D. 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES    BY SANOFI.................................................................................................111 
APPENDIX E. 
ASTHMA QUALITY OF LIFE QUESTIONNAIRE AQLQ(S).............................................116 
APPENDIX F. ASTHMA CONTROL QUESTIONNAIRE, 5-QUESTION VERSION (ACQ-5) .................122 
APPENDIX G. EUROQUAL QUESTIONNAIRE (EUROQOL 5 DIMENSIONS QUESTIONNAIRE, 
3-LEVEL VERSION [EQ-5D-3L]) .................................................................................................124 
APPENDIX H. 
DEFINITION OF ANAPHYLAXIS .....................................................................................126 
APPENDIX I. LIST OF OPPORTUNISTIC INFECTIONS ........................................................................127 
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3 
LIST OF ABBREVIATIONS 
 
ACQ5: 
Asthma Control Questionnaire-5-question version 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANA: 
anti-nuclear antibody 
AQLQ(S): 
Asthma Quality of Life Questionnaire-Standardized 
AST: 
aspartate aminotransferase 
ATS: 
American Thoracic Society 
BUN: 
blood urea nitrogen 
CPK: 
creatine phosphokinase 
CSR: 
clinical study report 
CYP: 
cytochrome 
DMC: 
Data Monitoring Committee 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EOS: 
End-of-Study 
EOT: 
End-of-Treatment 
EQ-5D-3L: 
EuroQol 5 dimensions questionnaire 3-level version 
FEV1: 
forced expiratory volume in 1 second 
GCP: 
Good Clinical Practice, good clinical practice 
HBcAb: 
hepatitis B core antibody 
HBsAg: 
hepatitis B surface antigen 
HBV DNA: 
hepatitis B virus deoxyribonucleic acid 
HCV Ab: 
hepatitis C virus antibodies 
HCV RNA: 
hepatitis C virus ribonucleic acid 
HIV: 
human immunodeficiency virus 
HLGT: 
high level group term 
HLT: 
high level term 
HRCT: 
high resolution computed tomography 
ICF: 
Informed Consent Form 
ICH: 
International Council on Harmonisation 
ICS: 
inhaled corticosteroids 
IgE: 
immunoglobulin E 
IgM: 
immunoglobulin M 
IL-13: 
interleukin-13 
IL-4: 
interleukin-4 
IL-4Rα: 
interleukin-4 receptor alpha subunit 
IMP: 
Investigational Medicinal Product 
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IRB/IEC: 
Institutional Review Board / Institutional Ethics Committee  
IVRS/IWRS: 
Interactive Voice Response System/Interactive Web Response System 
LABA: 
Long acting beta adrenoceptor agonists 
LAMA: 
long-acting muscarinic antagonist 
LFT: 
liver function test 
LTRA: 
leukotriene receptor antagonists 
MCID: 
Minimal Clinically Important Difference 
MDI: 
metered dose inhalers 
MRI: 
Magnetic Resonance Imaging 
OCS: 
oral cortiocosteroids 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamics 
PEF: 
peak expiratory flow 
PT: 
preferred term 
SAE: 
serious adverse events 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SD: 
standard deviation 
SEM: 
standard error of the mean 
SOC: 
system organ class 
TB: 
tuberculosis 
TEAE: 
treatment-emergent adverse events 
Th2: 
type 2 helper T-cell 
ULN: 
upper limit of normal 
VAS: 
Visual Analogue Scale 
 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyper-responsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. 
The inflammatory component of asthma involves many cell types, including mast cells, 
eosinophils, T-lymphocytes, neutrophils, epithelial cells, and their biological products. For most 
asthma patients, a regimen of controller therapy and reliever therapy provides adequate long-term 
control. However, it is estimated that 5% to 10% of asthma patients have symptomatic disease 
despite maximum recommended treatment with combinations of anti-inflammatory and 
bronchodilator drugs. These patients account for many hospital admissions, use of emergency 
services, and unscheduled physician visits (1). 
Additionally, the long-term adverse effects of systemic and inhaled corticosteroids (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 is loss of asthma control and ultimately, asthma exacerbation and 
medical sequelae of such events. 
The poor response of some patients with asthma may reflect the number of cellular and molecular 
mechanisms operative in asthma. There is increasing interest in distinct phenotypes because 
targeted therapy is more likely to be successful in patients with similar underlying pathobiologic 
features (2). Recent therapeutic approaches in asthma have been focused on trying to control the 
T-helper cell-2 response. Up-regulation of interleukin-4 (IL-4) and interleukin-13 (IL-13) has 
been implicated as an important inflammatory component of asthma disease progression.  
Dupilumab, a fully human monoclonal antibody (mAb) that binds specifically to the shared 
interleukin-4 receptor alpha (IL-4Rα) subunit of the IL-4 and IL-13 receptor complexes, is under 
development as a potential novel treatment for asthma. Dupilumab inhibits IL-4 signaling via the 
Type I receptor, and both IL-4 and IL-13 signaling through the Type II receptor. Dupilumab 
belongs to the pharmacological class of immunomodulators, interleukin inhibitors.  
For complete information regarding the preclinical and clinical evaluation of dupilumab to date, 
including ongoing studies, see the current version of the Investigator’s Brochure. 
4.2 
RATIONALE 
An initial demonstration of the efficacy and safety of dupilumab was provided in the randomized, 
double-blind, placebo-controlled, parallel-group Phase 2a study (ACT11457). This study 
investigated the effects of dupilumab administered subcutaneously (SC) once weekly for 
12 weeks as compared to placebo on the incidence of asthma exacerbations in patients with 
persistent moderate to severe eosinophilic asthma.  
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The primary endpoint was the occurrence of an asthma exacerbation; the secondary endpoints 
included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2) 
associated biomarkers and safety and tolerability are also evaluated (3).The ACT11457 study 
showed an 87% reduction in asthma exacerbations after 12-week 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 Th2-associated biomarkers levels were also 
observed (3).  
The DRI12544 study (phase 2b), a randomized, double-blind, placebo-controlled, dose-ranging 
study, evaluated several dose regimens of dupilumab in patients with moderate to severe 
uncontrolled asthma (300 mg every 2 weeks [q2w] with a 600 mg loading dose, 200 mg q2w with 
a 400 mg loading dose, 300 mg every 4 weeks [q4w] with a 600 mg loading dose, 200 mg q4w 
with a 400 mg loading dose), administered over 24 weeks. The primary efficacy endpoint was the 
change from baseline in FEV1 at Week 12, in patients with baseline blood eosinophil counts of at 
least 300 eosinophils per µL (HEos). Several secondary efficacy endpoints were evaluated 
including: the annualized severe asthma exacerbation rate, percentage change from baseline in 
FEV1, time to severe exacerbation, etc. For the primary endpoint, all dupilumab dose regimens 
(except for the 200 mg q4w) showed a clinically meaningful and statistically significant 
improvement in FEV1 at Week 12 in comparison with placebo in the high blood eosinophil count 
(HEos) population. For the secondary endpoints assessed in the overall population and the 
subgroup with eosinophil counts of fewer than 300 eosinophils per µL, dupilumab q2w (both the 
200 mg and 300 mg) resulted in significant increases in FEV1 (L) compared with placebo at  
Week 12 that were sustained through to week 24. Both doses of dupilumab q2w also resulted in 
significant increases in percentage change in FEV1 compared with placebo through to Week 24 in 
the overall population and in the two subgroups. In addition, both the 200 mg q2w and 300 mg 
q2w dose regimens of dupilumab demonstrated as compared to placebo, a significant reduction in 
the annualized rate of severe asthma exacerbations and a delayed time to first severe asthma 
exacerbation event, during the treatment period.(4) 
LTS12551 is designed as an open-label extension study to evaluate the long-term safety and 
tolerability of dupilumab in patients with asthma who participated in previous dupilumab study. 
The dose of 300 mg q2w, which is the highest dose administered in Study DRI12544 and the 
phase 3 pivotal Study EFC13579, has been selected as the dose to be evaluated in 
Study LTS12551. This dosing regimen is within the range of SC doses administered to healthy 
volunteers in R668-AS-0907 study and a higher dosing regimen of 300 mg qw was tested in the 
ACT11457. Additionally, 300 mg q2w (for 24 weeks) SC is the highest dose-regimen that was 
tested in DRI12544, a randomized, double-blind, placebo controlled dose-ranging efficacy study 
(phase 2b).  Treatment with dupilumab was generally well tolerated in these previous studies. The 
dosing regimen of 300 mg SC q2w is also the higher of the two doses selected for 
Study EFC13579 (QUEST), it is anticipated to saturate the targeted receptors and to allow for the 
attainment of an optimally efficacious concentration. Furthermore, in Study DRI12544, treatment 
effects on lung function and biomarkers of inflammation were similar at 200 mg q2w and 300 mg 
q2w, suggesting a plateauing of the dose-response below exposures achieved at 300 mg qw.  
From a safety perspective, the mean exposure following a dose of 300 mg of dupilumab q2w at 
steady state is 2 to 3 times below the exposure range of SC doses of 300 mg administered every 
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week in the Proof of Concept studies in asthma (ACT11457) and atopic dermatitis 
(R668-AD1117).  
From an efficacy perspective the dosing regimen of 300 mg q2w, added to a medium-to-high dose 
ICS + Long-acting β adrenoceptor agonists (LABA) in adult patients with uncontrolled persistent 
asthma, showed a clinically meaningful and highly statistically significant reduction in the relative 
risk of severe exacerbations, improvement in lung function (FEV1) and asthma symptoms 
(Asthma Control Questionnaire 5-question Version [ACQ5]) (4). 
A loading dose of 600 mg dupilumab was administered on Day 1 for patients enrolling into 
LTS12551 from the DRI12544 study after a 3-month dupilumab-free follow-up period, which 
allow systemic concentrations to reach steady state faster, and potentially reduce the time to 
clinical effect. Loading dose will not apply to patients from other parent studies, as they will 
rollover into LTS12551 the same day as the end-of-treatment (EOT) visit in the parent study and 
thus there will be no interruption in treatment.   
The dose regimens used in the 3 ongoing parent studies were 300 mg q2w and 200 mg q2w versus 
placebo (52 week treatment) in study EFC13579; 300 mg q2w versus placebo (24 week treatment) 
in study EFC13691); and 300 mg q2w versus placebo (12 weeks treatment) in study PDY14192 
(Phase 2). 
The LTS12551 study is intended to provide a long-term safety database to better identify potential 
late onset adverse events (AEs) associated with the use of dupilumab given on top of ICS/LABA 
or ICS and other controller background therapies (LABA, leukotriene receptor antagonists 
(LTRA), long-acting muscarinic antagonist (LAMA), theophylline, etc) including oral 
corticosteroids (OCS). Efficacy, dupilumab concentration and anti-dupilumab antibody and 
associated biomarkers will also be analyzed in the study to deepen the scientific understanding of 
anti-drug antibody (ADA) development and the change of serum biomarkers over the course of 
the study. 
 
 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To evaluate the long-term safety and tolerability of dupilumab in patients with asthma who 
participated in a previous dupilumab asthma clinical study (DRI12544, PDY14192, EFC13579, 
EFC13691).  
5.2 
SECONDARY 
• To assess the long-term efficacy of dupilumab in patients with asthma who participated in 
a previous dupilumab asthma clinical study.  
• To evaluate dupilumab in patients with asthma who participated in a previous dupilumab 
asthma clinical study, with regard to:  
- 
Systemic exposure; 
- 
Anti-drug antibodies; 
- 
Biomarkers. 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
Multinational, multicenter, open-label, extension study evaluating dupilumab 300 mg (SC) q2w 
for 1-year (48 weeks) or 2-year (96 weeks) treatment duration. Patients enrolled prior to 
Amendment 04 approval will continue to participate in the 2-year treatment duration; patients 
enrolled after Amendment 04 approval will participate in the 1-year treatment duration.  
At enrollment, patients will be on medium or high dose of ICS and at least one other asthma 
controller medication, as maintained during the parent study in which they participated (including 
asthma background controller therapy with OCS only for patients from Study EFC13691).  
 For a schematic study design please see Section 1.1. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
LTS12551 study consists of 3 periods (See Section 10):  
Enrollment period: Combined V1/V2 Visit: Eligible patients from PDY14192, EFC13579, and 
EFC13691 studies should rollover into LTS12551 the same day as the end-of-treatment visit of the 
parent study.  
Note: A screening period of 0 to 3 weeks was proposed only for patients rolling over from 
DRI12544. Enrollment from Study DRI12544 is complete, thus the screening period does not 
apply anymore. 
Treatment period: 48 or 96 weeks open-label treatment.  
Patients enrolled prior to Amendment 04 approval, will continue to participate in the 2-year 
treatment duration; patients enrolled after Amendment 04 approval will participate in the 1-year 
treatment duration. During the open-label treatment period, patients will continue taking their 
background controller therapy, as maintained during the parent study or as modified based on 
Investigator's judgment. 
Post-treatment period: 12 weeks.  
Upon completion of the open-label treatment period (or following early discontinuation of 
Investigational Medicinal Product [IMP]) patients will continue into the post-treatment period. 
During this period, patients will continue their background controller therapy, as maintained 
during the open-label treatment period or as modified based on Investigator's judgment (eg, taking 
into account the reduction of dupilumab levels over time upon completion of the treatment 
period). 
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6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial in all participating study sites is reached when the last patient last visit 
is completed as protocol defined.  
6.3 
INTERIM ANALYSIS 
 Interim study 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 clinical study 
report (CSR). 
6.4 
STUDY COMMITTEES 
6.4.1 Data monitoring committee 
A data monitoring committee (DMC) with members’ who are independent from the Sponsor and 
Investigators is commissioned for the dupilumab clinical development program. This committee is 
comprised of externally-based individuals with expertise in the diseases under study, biostatistics, 
or clinical research. The DMC will monitor the safety data of patients at regular intervals and is 
responsible for providing recommendations for protecting the safety and ensuring the welfare of 
these patients and provide sanofi with appropriate recommendations in a timely manner to ensure 
the welfare and safety of the study patients. 
The detailed DMC procedures and safety data to be reviewed 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. Patients with asthma who completed the treatment period in a previous dupilumab asthma 
clinical study (ie, PDY14192, EFC13579 or EFC13691) or patients with asthma who 
completed the treatment and follow-up periods in pervious dupilumab asthma Study 
DRI12544. 
I 02. Patient is on background dose of moderate or high dose ICS, as maintained during the 
parent study in which they participated, in combination with a second controller (and/or 
OCS for those patients from EFC13691). Patients requiring a third controller medication 
are allowed (eg, LABA, LTRA, methylxanthines, etc). 
I 03. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
At enrollment, 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. Deleted. 
E 02. Chronic obstructive pulmonary disease or other lung diseases (eg, emphysema, idiopathic 
pulmonary fibrosis, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis) 
which impair pulmonary function tests. 
E 03. Current smoker or cessation of smoking within 6 months prior to enrollment. 
E 04. Clinically significant comorbidity / lung disease other than asthma. 
E 05. Alcohol abuse or drug abuse.  
E 06. Inability to follow the procedures of the study / noncompliance (eg, due to language 
problems or psychological disorders). 
E 07. Deleted. 
E 08. Deleted. 
E 09. Deleted.  
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E 10. Patient receiving concomitant treatment prohibited in the study (see Section 8.8.1). 
E 11. Deleted. 
E 12. Patient is Investigator or any Subinvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol. 
E 13. Deleted. 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 14. Deleted.  
E 15. Deleted.  
7.2.3 Exclusion criteria related to the current knowledge of sanofi compound  
E 16. Patient who develops: a new medical condition or a change in status of an established 
medical condition; a laboratory abnormality, or requires a new treatment or medication 
prior to enrollment, which (per Investigator’s medical judgment) would adversely affect 
the participation of the patient in this study or would require permanent IMP 
discontinuation. 
E 17. Pregnant or breastfeeding women. 
E 18. Women of childbearing potential (premenopausal female biologically capable of
 becoming pregnant) who: 
• 
Do not have a confirmed negative urine test at enrollment. 
• 
Who are not protected by one of the following acceptable forms of effective contraception 
during the study, including the 12-week follow-up period: 
- 
Established use of oral, injected, implanted or inserted hormonal contraceptive. 
- 
Intrauterine device (IUD) with copper or intrauterine system (IUS) with progestogen. 
- 
Contraceptive barrier (condom, diaphragm, or cervical/vault caps) used with 
spermicide (foam, gel, film, cream, or suppository).  
- 
Female sterilization (eg, tubal occlusion, hysterectomy, or bilateral salpingectomy). 
- 
Male sterilization with post-vasectomy documentation of the absence of sperm in the 
ejaculate; for female patients the study, the vasectomized male partner should be the 
sole partner for that patient. 
- 
True abstinence; periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) is not an acceptable method of contraception. 
- 
Menopausal women (defined as at least 12 consecutive months without menses) are not 
required to use additional contraception. 
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E 19. Diagnosed active parasitic infection; suspected or high risk of parasitic infection, unless 
clinical and (if necessary) laboratory assessments have ruled out active infection before 
enrolment. 
E 20. History of human immunodeficiency virus (HIV) infection or positive HIV screen 
(Anti-HIV-1 and HIV-2 antibodies).  
E 21. Deleted.  
E 22. Deleted.  
E 23. Live, attenuated vaccinations within 12 weeks prior to enrollment or planned live, 
attenuated vaccinations during the study (see Appendix A). 
E 24. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary 
cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) or patients who are 
suspected of having high risk for developing autoimmune disease. 
E 25. Patients with any of the following result at enrolment: 
• 
Positive (or indeterminate) hepatitis B surface antigen (HBsAg); or 
• 
Positive Immunoglobulin M (IgM) hepatitis B core antibody (HBcAb); or 
• 
Positive total HBcAb confirmed by positive hepatitis B virus deoxyribonucleic acid (HBV 
DNA); or 
• 
Positive hepatitis C virus antibodies (HCV Ab) confirmed by positive hepatitis C virus 
ribonucleic acid (HCV RNA) 
E 26. Patients who experienced any hypersensitivity reactions to IMP in the previous dupilumab 
asthma study, which, in the opinion of the Investigator, could indicate that continued 
treatment with dupilumab may present an unreasonable risk for the patient. 
E 27. Deleted.  
E 28. Deleted. 
E 29. Deleted.  
E 30. Deleted. 
E 31. Blood eosinophils >1500 cells/mm3.  
E 32. History of malignancy within 5 years before the screening visit, except completely treated 
in situ carcinoma of the cervix, completely treated and resolved nonmetastatic squamous 
or basal cell carcinoma of the skin. 
 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT 
8.1.1 Dupilumab 
Note: At the time of Amendment 04, all patients have been transitioned to prefilled syringes. 
Dupilumab is supplied as a sterile aqueous solution for SC injection at the concentration of 
150 mg/mL in glass prefilled syringes (2.25 mL total volume) to deliver 300 mg in the extractable 
2 mL volume. 
8.1.2 Preparation of investigational product 
The IMP should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) until use. Instructions for 
IMP preparation are provided in the pharmacy manual and Patient User Instructions for 
self-administration. 
8.1.3 Dose schedule 
The IMP is administered every 14±3 days (q2w). The consecutive doses of the IMP must be 
separated by ≥11 days to avoid an overdose. Reminder: Patients will be monitored for any signs or 
symptoms of hypersensitivity reactions for a minimum of 30 minutes after IMP injection.  
At the Enrollment (Combined V1/V2) Visit, the Investigator or delegate will train the patient 
(and/or caregiver[s]) how to prepare and inject IMP for the first injection or if the patient is 
already self-injecting (in the parent study), the Investigator or delegate will supervise the  
self-injection. 
For subsequent doses, which are not given at the study site, specific pages will be provided to the 
patients to record information related to the injections. The pages will be kept as source data in the 
patient’s study file.  
If the patient (or caregiver) is unable or unwilling to administer IMP, arrangements must be made 
for qualified site personnel and/or healthcare professionals (eg, visiting nurse service) to 
administer IMP for the doses that are not scheduled to be given at the study site. 
If the study visit is not performed at the study site as scheduled, the dose will be administered by 
the patient and/or their caregiver/healthcare professional, or arrangements must be made for a visit 
to the site to administer the IMP.  
When IMP is administered at home, the patients must be advised by the site staff, to self-monitor 
for at least 30 minutes after administration for potential signs and symptoms that may suggest a 
hypersensitivity reaction. 
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Subcutaneous injection sites should be alternated between the 4 quadrants of the abdomen 
(avoiding navel and waist areas), the upper thighs, or upper arms (lateral side), so that the same 
site is not injected twice consecutively. Injection in the upper arms could be done only by a trained 
person (parent/caregiver trained by Investigator or delegate) or health care professional but not the 
patient themselves. For each injection, the anatomic site of administration will be recorded in the 
electronic case report form (e-CRF) and, as applicable, the home dosing diary.  
Detailed instructions for transport, storage, preparation, and administration of IMP are provided to 
the patient. 
Patients will complete a home dosing diary to document compliance with self-injection (or parent 
or caregiver injection) of IMP. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
8.2.1 Inhaled corticosteroid and controller therapies  
Inhaled corticosteroid and other controller therapies (ie, LABA, LTRA, LAMA, theophylline, etc) 
and OCS for patients from EFC13691 will be collected in the e-CRF.  
8.2.1.1 Enrollment V1/V2 visit (combined with the end-of-treatment visit of parent study) 
Patients will be on background asthma therapy of moderate or high-dose ICS as maintained in the 
parent study. Patients will also be using additional asthma controller therapies initiated during the 
parent study. 
Please see Appendix B for a list of commonly used asthma controller medications. 
8.2.1.2 Open-label treatment period 
During the open-label treatment period, patients will continue the background therapy dose 
regimen as maintained in the parent study or as modified based on Investigator's judgment. 
See Appendix B for the most commonly used asthma controller therapies.  
8.2.1.3 Post-treatment period 
Upon completion of the open-label treatment period (or following early discontinuation of IMP) 
patients will continue into the post-treatment period, with their background controller therapy 
dose regimen as maintained over the open-label treatment period or as modified based on 
Investigator's judgment (eg, taking into account the reduction of dupilumab levels over time upon 
completion of the treatment period).  
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8.2.2 Albuterol or levalbuterol reliever medication 
Patients may receive salbutamol/albuterol hydrofluoroalkane pressurized metered dose inhalers 
(MDI) or levosalbutamol/levalbuterol hydrofluoroalkane pressurized MDI as reliever medication 
(as needed) during the study.  
Nebulizer solutions with either albuterol/salbutamol or levalabuterol/levosalbutamol may be used 
as an alternative delivery method. 
Study personnel should convert salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol 
nebulizer use as shown on Table 1 and Table 2: 
Table 1 - Conversion from Salbutamol/Albuterol Nebulizer Solution to Puffs 
Salbutamol/Albuterol Nebulizer Solution – Total 
Daily Dose (mg) 
Number of Puffs* 
1.26 
2 
2.5 
4 
5 
8 
7.5 
12 
10 
16 
*Conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs. 
Example: Patient received 3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 
7 and 11 AM. Total daily = 7.5 mg (12 puffs). 
Table 2 - Conversion from Levosalbutamol/Levalbuterol Nebulizer Solution to Puffs 
Levosalbutamol/Levalbuterol Nebulizer Solution 
– Total Daily Dose (mg) 
Number of Puffs 
1.25 
4 
2.5 
8 
3.75 
12 
5 
16 
Example of levosalbutamol/levalbuterol Nebulizer-to-Puff Conversion: Patient received 3 
levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 and 11 AM. 
Total daily = 3.75 mg (12 puffs).  
All other reliever medications rather than albuterol/salbutamol or levalbuterol/levosalbutamol 
should be avoided. 
8.3 
BLINDING PROCEDURES 
Not applicable. 
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8.3.1 Methods of blinding 
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.  
The patients will be identified by the same identification number used in the parent study. 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. The 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 e-CRF and in the patient’s source documents, and the patient number on the IMP 
label prior to dispensing to the patient. 
The patient 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 
PACKAGING AND LABELING 
Note: At the time of Amendment 04, all patients have been transitioned to prefilled syringes. 
The IMP dupilumab will be packaged in single-use prefilled syringes. One kit box will contain 
one prefilled syringe. When dupilumab administration occurs at home, enough kit boxes will be 
given to the patients for the period of the treatment until the next study visit. 
Each packaging component will be labeled with the project and study number, a medication kit 
number, packaging reference number, Sponsor name, quantity or contents, dispensing instruction, 
caution statement, “use by” date and storage conditions. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
The IMP should be stored at a temperature between 2°C and 8°C (36°F to 46°F) in an appropriate 
and locked room under the responsibility of the Investigator or other authorized persons (eg, 
pharmacists) in accordance with local regulations, labeling specifications, policies, and 
procedures.  
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Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the IMP should be managed 
according to the rules provided by the Sponsor. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained, 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
Measures taken to ensure and document treatment compliance and IMP accountability include: 
• 
Proper recording of treatment kit number as required on appropriate e-CRF page for 
accounting purposes: 
• 
All medication treatment kits (whether empty or unused) are returned by the patient at 
each visit that treatment dispensing is planned. 
- 
The completed patient injection sheet (returned to the site at each visit), returned 
treatment kit boxes, and any unused prefilled syringes will be used for drug 
accountability purposes. 
• 
The Investigator or designee tracks treatment accountability/compliance, either by the 
injection sheet or by counting the number of used treatment kits, and fills in the 
appropriate page of the patient treatment log. 
The monitor in charge of the study then checks the data entered on the IMP administration page 
by comparing them with the IMP that has been retrieved and the patient treatment log form. 
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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 the 
study site. All used prefilled syringes should be kept in a sharp-container by the patients and be 
returned to sites for destroy. The Investigator will not destroy any unused IMP unless the Sponsor 
provides written authorization. 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team.  
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to IMP. 
8.8.1 Prohibited concomitant medication 
The following concomitant treatments are not permitted during the study: 
• 
Anti-immunoglobulin E (IgE) therapy (eg, omalizumab); 
• 
Biologic therapy; 
• 
Systemic immunosuppressants;  
• 
Intravenous immunoglobulin (IVIG) therapy; 
• 
Non-selective beta-adrenergic blockers; 
• 
Other investigational drugs; 
• 
Live/attenuated vaccines (see Appendix A). 
8.8.2 Permitted concomitant medication  
The following asthma-related and other relevant concomitant treatments are permitted:  
• 
Leukotriene antagonists/modifiers; 
• 
Allergen immunotherapy stable dose; 
• 
Antihistamines; 
• 
Systemic (oral or injectable) corticosteroids:  
- 
Oral corticosteroids are allowed as background controller medication for the patients 
from EFC13691 only  
- 
Oral corticosteroids are allowed as treatment for asthma exacerbations and/or AEs as 
per Investigator's decision, for any patient; 
• 
Ocular, intranasal or topical corticosteroids; 
• 
Methylxanthines (eg, theophylline, aminophyllines); 
• 
Lipoxygenase inhibitors (eg, zileuton); 
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• 
Cromones for asthma (eg, cromolyn sodium solution for nebulization, nedocromil DPI); 
• 
Cromones for other reasons (eg, ophthalmic formulations for allergic conjunctivitis, nasal 
formulations for allergic rhinitis); 
• 
Short- and long-acting anti-cholinergic drugs (ipratropium bromide and tiotropium).  
 
8.8.3 Cytochrome P450 (CYP) precaution 
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 up-regulate CYP2E1, 2B6, 3A4 mRNA expression or 
down-regulate CYP1A2 mRNA (12, 13). 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 (14). Since the clinical significance of the limited in vitro findings for IL-4 
and IL-13 involvement in CYP regulation and the impact of dupilumab on CYP enzymes is not 
fully understood, during the study treatment and at least up to the end of follow-up, caution should 
be used for drugs which are metabolized via these CYP isoforms and which have a narrow 
therapeutic index. Close clinical observation and/or laboratory monitoring as applicable are 
required when the investigational product is started or stopped in order to enable early detection 
of toxic manifestations or lack of activity/efficacy of these drugs, followed by dose adjustment or 
their withdrawal if needed. Some examples of CYP450 substrates with narrow therapeutic index 
are provided in Appendix C. 
 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary endpoint of this study is the number (n) and percentage (%) of patients experiencing 
any treatment-emergent adverse events (TEAE). 
Adverse events, serious adverse events (SAEs), adverse events of special interest (AESI), AEs 
leading to IMP discontinuation and death will be collected from the date of the signed informed 
consent form (ICF) for participation in LTS12551 (planned at the Combined V1/V2 Visit). The 
study specific and general safety criteria are detailed in Section 10.4.1. To assure the continuing 
safety of patients in this study, an Independent DMC will be responsible for reviewing the safety 
data on a periodic basis throughout the course of the study as outlined in Section 6.2.  
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.  
Safety Observations 
• 
The Investigator should take all appropriate measures to ensure the safety of the patients. 
Notably, he/she should follow-up the outcome of SAEs/AESIs 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 the case of any SAE/AESI requiring immediate notification, being brought to the 
attention of the Investigator at any time after the end of the study for the patient, and 
considered by him/her to be caused by the investigational product with a reasonable 
possibility, this should be reported to the Sponsor. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Safety and tolerability  
The following parameters will be analyzed (see also Section 11.4.3.1.4 for analysis): 
• 
Vital signs. 
• 
Physical examination. 
• 
Electrocardiogram (ECG) variables. 
• 
Clinical laboratory tests. 
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9.2.1.1 Vital signs 
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 every scheduled treatment visit (see flow charts Section 1.2 and Section 1.3). Height (cm) will 
only be measured at enrollment. 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 study 
visits.  
9.2.1.2 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. All 
deviations from normal will be recorded, including those attributable to the patient’s disease. 
Physical examinations will be performed as per the schedule of assessments (see flow charts 
Section 1.2 and Section 1.3). 
9.2.1.3 Electrocardiogram (ECG) variables 
A 12-lead ECG will be performed as per the schedule of assessments (see flow charts Section 1.2 
and Section 1.3). A minimum of 3 complexes in an appropriate lead (lead II) will be averaged to 
determine the PR-interval, QT/QTc-interval, and QRS-complex (and heart rate will also be 
measured) for each ECG.  
The Investigator should review the ECG and document his interpretation, signed and dated on the 
ECG print out. The original trace is kept as source data. Electrocardiogram tracings are also read 
manually by independent, certified and “centralized” cardiologists, who determine ECG 
parameters and who in addition alert the Investigator and the Sponsor of any clinically significant 
findings or changes. These manually read tracings are the ECG tracing of record for this clinical 
trial. A specific written manual regarding the procedures related to the centralized ECG reading 
are provided to each Investigator. Refer to the ECG manual for further details.  
Notes: Any abnormal ECG parameter should be immediately rechecked for confirmation before 
making a decision of permanent discontinuation of treatment with dupilumab for the concerned 
patient.  
9.2.1.4 Clinical laboratory tests 
The clinical laboratory tests will be conducted by an accredited central laboratory with national 
and regional clinical licenses, as required for diagnostic testing, and must provide evidence of 
participation in proficiency testing, as appropriate. After reviewing the laboratory report and 
evaluating any results that are outside the normal range, the Investigator must sign and date the 
laboratory report. Abnormal laboratory values that are considered to be clinically significant by 
the Investigator must 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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The following laboratory tests will be performed (as per the schedule of assessments, see flow 
charts in Section 1.2 and Section 1.3). Patients will be informed of fasting requirements for 
hematology and serum chemistry assessments. 
• 
Hematology: Blood count (erythrocytes, hemoglobin, hematocrit, leukocytes), differential 
blood count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) and 
platelets. 
• 
Serum chemistry: Total bilirubin (in case of values above the normal range, differentiation 
in conjugated and non-conjugated bilirubin), alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total protein, albumin, total 
cholesterol, creatine phosphokinase (CPK), glucose, creatinine, blood urea nitrogen 
(BUN), uric acid, bicarbonate, and electrolytes (sodium, potassium, and chloride). 
• 
Urine analysis: pH, glucose, ketones, leukocyte esterase blood, protein, nitrate, 
urobilinogen, and bilirubin (by dipstick). If any parameter on the dipstick is abnormal, a 
urine sample should be sent to the central laboratory for testing. If positive for proteins, 
microscopic analysis is performed by central laboratory. 
• 
Serum immunoglobulin, including IgE, are no longer to be assayed due to Amendment 04.  
• 
Clinical laboratory testing: hepatitis screen (HBsAg, HBcAb-IgM), HCVAb, HIV screen 
(anti-HIV-1 and HIV-2 antibodies), and anti-nuclear antibody (ANA). Anti-ds DNA 
antibody will be tested if ANA is positive (≥1:160 titer). Japanese patients who have rolled 
over from DRI12544 study should be retested for hepatitis B (HBsAg, HBsAb, and 
HBcAb), after Visit 1, at any time during the LTS12551 study, via the earliest scheduled 
study visit, after IRB approval for Local Amendment 03 (Japan). 
• 
Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there is 
local regulatory requirement) who were HBsAg negative and HBsAb positive at screening 
during the parent study, or at the additional test due to Local Amendment 03 (Japan). 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D.  
9.2.1.4.1 Pregnancy test 
Qualifying pregnancy test for patients coming from PDY14192, EFC13579, and EFC13691 
studies will be the urine pregnancy test. See the schedule of assessments for details of the timing 
of tests (see flow charts in Section 1.2 and Section 1.3). 
9.2.2 Efficacy  
The following efficacy parameters will be analyzed (see Section 11.4.2 for analysis): 
• Forced expiratory volume in 1 second (FEV1) (see Section 9.2.2.1). 
• Asthma Control Questionnaire – 5 question version (ACQ-5) (see Section 9.2.2.2). 
• Severe asthma exacerbation events during the treatment period (see Section 9.2.2.3). 
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• Asthma Quality of Life Questionnaire - standardized [AQLQ(S)] (see Appendix E). 
• EuroQol 5 dimensions questionnaire 3-level version (EQ-5D-3L) (see Section 9.2.2.5).  
• Health care resource utilization questionnaire (see Section 9.2.2.6). 
• Morning and evening peak expiratory flow (PEF) (see Section 9.2.2.7.1). 
• 
Morning and evening asthma symptom scores (see Section 9.2.2.7.2). 
• Number of inhalations/day of salbutamol/albuterol or levosalbutamol/levalbuterol for 
symptom relief (see Section 9.2.2.7.3). 
• 
Nocturnal awakenings due to asthma requiring the use of reliever medication 
(see Section 9.2.2.7). 
• Prescribed OCS dose for patients from the EFC13691 study (see Section 9.2.2.8). 
9.2.2.1 Forced expiratory volume in 1 second (FEV1) 
The FEV1 is part of the spirometry assessment and will be performed as per the schedule of 
assessments (see flow charts in Section 1.2 and Section 1.3).  
A spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory 
Society (ERS) recommendations will be used. The ATS/ERS Standardization of Spirometry 
should be used as a guideline (5). Spirometry should be done at approximately the same time of 
the day at each visit throughout the study. Pulmonary function tests should be performed in the 
morning if possible, but 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, 
eg, withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 
6 hours and withholding the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol 
should be withheld for at least 24 hours) and withholding the last dose of LAMA for at least 
24 hours. This should be verified before performing the measurements. 
9.2.2.2 ACQ-5 (Asthma Control Questionnaire, 5-question version) 
The ACQ-5 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. 
The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by 
symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath 
and wheeze. Patients are asked to recall how their asthma has been during the previous week and 
to respond to the symptom questions on a 7-point scale (0=no impairment, 6= maximum 
impairment, see Appendix F). 
A global score is calculated: the questions are equally weighted and the ACQ-5 score is the mean 
of the 5 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). 
Higher score indicates lower asthma control. Patients with a score below 1.0 will have adequately 
controlled asthma and above 1.0 their asthma will not be well controlled. On the 7-point scale of 
the ACQ-5, a change or difference in score of 0.5 is the smallest that can be considered clinically 
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important, corresponding to the Minimal Clinically Important Difference (MCID) defined by the 
developer. 
Measurement properties such as reliability, ability to detect change have been documented in the 
literature (6). 
ACQ-5 will be performed as per the schedule of assessments (see flow charts in Section 1.2 and 
Section 1.3). ACQ-5 paper forms are completed and data will be entered into the e-CRF. The 
ACQ-5 will be done in those countries where a validated translation is available. 
9.2.2.3 Severe asthma exacerbation events 
Severe asthma exacerbation events are defined as a deterioration of asthma requiring: 
• 
Use of systemic corticosteroids for ≥3 days: 
- 
For patients from the EFC13691 study who entered the LTS12551 study taking 
systemic corticosteroids: the use of systemic corticosteroids at least double the dose 
currently used for ≥3 days. 
OR 
• 
Hospitalization or emergency room visit because of asthma, requiring systemic 
corticosteroids. 
See Section 10.4.1.1 for asthma exacerbation reporting. 
9.2.2.4 Asthma Quality of Life Questionnaire with standardized activities (AQLQ[S]) 
The AQLQ(S) was designed to measure the functional impairments that are most troublesome to 
patient as a result of their asthma (see Appendix E). The instrument is comprised of 32 items, 
each rated on a 7-point Likert scales from 1 to 7. The AQLQ(S) has 4 domains. The domains and 
the number of items in each domain are as follows: 
• 
Symptoms (12 items); 
• 
Activity limitation (11 items); 
• 
Emotional function (5 items); 
• 
Environmental stimuli (4 items).  
A global score is calculated ranging from 0 to 7 and a score by domain. Higher scores indicate 
better quality of life. The instrument has been used in many clinical trials, and it has been shown 
to be reliable, valid (patient interviews), and sensitive to change. It will be done in those countries 
where a validated translation is available. A MCID is available (7). 
AQLQ(S) will be measured as per the schedule of assessments (see flow charts in Section 1.2 and 
Section 1.3). A paper questionnaire will be used during LTS12551 study and data will be entered 
into the e-CRF.  
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9.2.2.5 EuroQol 5 dimensions questionnaire, 3-level version (EQ-5D-3L) 
The EuroQol 5 dimensions questionnaire, 3-level version (EQ-5D-3L, see Appendix G) is 
validated and reliable self-report health status questionnaire which consists of 6 questions used to 
calculate a health utility score for use in health economic analysis. The EQ-5D-3L essentially 
consists of 2 pages; the EQ-5D-3L descriptive system and the EQ Visual Analogue Scale (VAS). 
The EQ-5D-3L descriptive system comprises 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problem, some 
problems, and severe problems. The EQ-VAS records the respondent’s self-rated health on a 
vertical visual analogue scale. The EQ-VAS "thermometer" has endpoints of 100 (best imaginable 
health state) at the top and 0 (worst imaginable health state) at the bottom.  
Upon approval of Amendment 04, this questionnaire will no longer be performed for any patients. 
9.2.2.6 Health care resource utilization 
A questionnaire of health care resource utilization (reliever medication, specialist visit, 
hospitalization, emergency or urgent medical care facility visit, outcome, sick leaves, etc) will be 
administered as per the schedule of assessments (see flow charts in Section 1.2 and Section 1.3). 
9.2.2.7 Disease-specific, daily efficacy assessments 
All the data detailed in this section will no longer be collected for all patients upon approval 
of Amendment 04. 
Prior to Amendment 04, on a daily basis throughout the study, the patient used an electronic diary 
/ PEF meter to: 
• 
Measure morning and evening PEF; 
• 
Respond to the morning and evening asthma symptom scale questions; 
• 
Indicate the number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief; 
• 
Record the number of inhalations/day of background ICS and controller therapies used. 
9.2.2.7.1 Record the number of nocturnal awakenings and Peak expiratory flow 
Prior to Amendment 04, at Visit 1, patients were issued an electronic PEF meter for recording 
morning (AM) and evening (PM) PEF, daily salbutamol/albuterol or levosalbutamol/levalbuterol, 
morning and evening asthma symptom scores, number of nocturnal awakenings due to asthma 
symptoms and number of night time awakenings due to asthma symptoms that required reliever 
medications. Patients were instructed on the use of the device, and written instructions on the use 
of the electronic PEF meter were provided to the patients. In addition, the Investigator instructed 
the patients on how to record the following variables in the electronic PEF meter: 
• 
AM PEF performed within 15 minutes after arising (between 5:30 AM and 10:00 AM) prior 
to taking any albuterol or levalbuterol. 
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• 
PM PEF performed in the evening (between 5:30 PM and 10:00 PM) prior to taking any 
albuterol or levalbuterol. 
• 
Patients should try to withhold albuterol or levalbuterol for at least 6 hours prior to 
measuring their PEF. 
• 
Three PEF efforts will be performed by the patient; all 3 values were recorded by the 
electronic PEF meter, and the highest value will be used for evaluation. 
Baseline AM PEF will be the mean AM measurement recorded for the 7 days prior to the first 
dose of IMP, and baseline PM PEF will be the mean PM measurement recorded for the 7 days 
prior to the first dose of investigational product or at least 4 days’ measurement for setting up the 
stability limit, prior to dosing in the LTS12551 study. 
9.2.2.7.2 Asthma Symptom Score  
Prior to Amendment 04, patients recorded overall symptom scores twice a day prior to measuring 
PEF. The patient’s overall asthma symptoms experienced during the waking hours were recorded 
in the evening (PM symptom score). Symptoms experienced during the night were recorded upon 
arising (AM symptom score). Baseline symptom scores will be the mean AM and mean PM 
scores recorded for the 7 days prior to the first dose of investigational product. Patients were 
instructed to record the severity of symptoms as follows: 
AM symptom score: 
• 
0 = No asthma symptoms, slept through the night; 
• 
1 = Slept well, but some complaints in the morning. No nighttime awakenings; 
• 
2 = Woke up once because of asthma (including early awakening); 
• 
3 = Woke up several times because of asthma (including early awakening); 
• 
4 = Bad night, awake most of the night because of asthma. 
PM symptom score: 
• 
0 = Very well, no asthma symptoms; 
• 
1 = One episode of wheezing, cough, or breathlessness; 
• 
2 = More than one episode of wheezing, cough, or breathlessness without interference of 
normal activities; 
• 
3 = Wheezing, cough, or breathlessness most of the day, which interfered to some extent 
with normal activities; 
• 
4 = Asthma very bad. Unable to carry out daily activities as usual. 
9.2.2.7.3 Reliever use 
Prior to Amendment 04, the number of salbutamol/albuterol or levosalbutamol/levalbuterol 
inhalations were recorded daily by the patients in the electronic diary / PEF meter. The baseline 
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number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations/day will be based on 
the mean of the 7 days prior to the first dose of investigational product. 
9.2.2.8 Prescribed oral corticosteroids (OCS) dose for patients from the EFC13691 study 
For patients from EFC13691 the prescribed background therapy with OCS will be recorded in the 
e-CRF.  
For the patients from the EFC13691 study only, the following 3 efficacy endpoints will be derived 
using the prescribed dose of the background OCS medications. The baseline OCS dose is the 
original baseline value from the EFC13691 study. 
• 
Percentage change from baseline in OCS dose; 
• 
Proportion of patients achieving a reduction of 50% or greater in their OCS dose compared 
with the original baseline in the parent study; 
• 
Percentage of patients that were able to be tapered off completely of OCS. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics and anti-dupilumab antibodies 
9.3.1.1 Sampling time 
Blood samples collected before the IMP administration are used for the determination of 
functional dupilumab and anti-dupilumab antibodies (also known as ADAs). Samples will be 
collected as per the schedule of assessments (see flow charts in Section 1.2 and Section 1.3). The 
date of collection should be recorded in the patient e-CRF. The date and time will also 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 injection site reaction lasting longer than 
24 hours, samples will be collected near the onset and resolution of the event for any additional 
analysis if required or for archival purposes. An unscheduled systemic drug concentration page 
(“PK page”) in the e-CRF must be completed as well. 
Pre-existing ADAs are defined as:  
• 
An ADA positive response in the assay at baseline with all post-treatment ADA results 
negative, OR 
• 
An ADA positive response at baseline with all post-treatment ADA responses less than 
4-fold over baseline titer levels. 
Treatment-emergent ADAs are defined as:  
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• 
An ADA positive response in the assay post first dose, when baseline results are negative 
or missing. 
Treatment-boosted ADAs are defined as: 
• 
An ADA positive response in the assay post first dose that is greater-than or equal to 
4-fold over baseline titer levels, when baseline results are positive. 
Treatment-emergent ADA responses are further classified as Transient, Persistent or 
Indeterminate: 
a) Persistent Response: defined as a treatment-emergent response with two or more 
consecutive ADA positive sampling time points, separated by more than 12-week period 
(with no ADA negative samples in between). 
b) Indeterminate Response: defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay.  
c) Transient Response: defined as a treatment-emergent response that is not considered 
persistent OR indeterminate. 
Unused samples collected for drug concentration or ADA analyses may be used for research 
purpose. 
9.3.1.2 Pharmacokinetics handling procedure 
It is extremely important to collect all blood samples as close to the protocol-specified time as 
possible. The reasons for any missed or lost blood samples should be documented. 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 drug 
concentration and ADA is provided in Table 3. 
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9.3.1.3 Bioanalytical 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 
Lower limit of quantification 
0.078 mg/L 
Not applicable 
Site of bioanalysis 
Regeneron 
Regeneron 
Abbreviation: ELISA = Enzyme-linked immunosorbent assay. 
9.3.1.4 Pharmacokinetics parameters 
Predose serum samples will be used for functional dupilumab and anti-dupilumab antibodies 
determination as per the schedule of assessments (see flow charts in Section 1.2 and Section 1.3). 
Titer values will be reported for all ADA positive responses.  
Patients will be scheduled for follow-up based on the overall assessment of antibody titers and 
clinical presentation. 
9.3.2 Pharmacogenetic assessment 
No pharmacogenetics samples will be taken during this study. 
9.3.3 Pharmacodynamic variables 
Several biomarkers related to asthmatic inflammation, Th2 polarization and possible IL-4/IL13 
activity will be assessed for their value in predicting therapeutic response and/or in documenting 
the time course of drug response. Sampling will be conducted as per the schedule of assessments 
(see flow charts in Section 1.2 and Section 1.3). More detailed information on the collection, 
handling, transport and preservation of samples (eg, minimum volumes required for blood 
collection and for aliquots for each biomarker assay) will be provided in a separate laboratory 
manual. 
9.3.3.1 Whole blood biomarkers 
Eosinophilia is recognized as a marker for diagnosing and predicting risk of exacerbations in 
asthma. Eosinophils and Th2 cytokines play a central role in the pathophysiology of severe 
asthma. Eosinophil count has been used to guide treatment decisions in severe asthma. In 
LTS12551 study, blood eosinophil count will be measured as part of the standard 5-part white 
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blood cell (WBC) differential cell count on a hematology auto analyzer (as per the schedule of 
assessments for hematology in the flow charts Section 1.2 and Section 1.3).  
9.3.3.2 Serum biomarkers 
 
Serum total IgE: It has been widely recognized and reported that IgE levels correlate with asthma 
severity and bronchial hyper-responsiveness (8). Interleukin-4 regulates IgE synthesis in human 
lung (9). Interleukin-4, in combination with IL-13, induces the class switch–recombination to IgE 
by B-cells (10), (11). Anti-IgE therapy has been reported to decrease asthma exacerbation and the 
requirement for inhaled steroid therapy. In the ACT11457 and DRI12544 studies, IgE  steadily 
declined throughout the treatment periods without reaching a steady state. In DRI12544, total IgE 
and several antigen-specific IgEs declined >50% from baseline during 24 weeks of treatment. 
This suggested that dupilumab may have the function of gradually desensitizing mast cells by 
decreasing surface coating with IgE. The IgE measurement in the LTS12551 study will help us 
better understand how the IgE level changes during the long-term dupilumab treatment.  
Serum total IgE will be measured with a quantitative method (eg, ImmunoCAP) approved for 
diagnostic testing and will no longer be performed in the LTS12551 study, due to Amendment 04. 
Serum immunoglobin assay: IgA, IgG, and IgG1-4, IgM level will no longer be collected in the 
LTS12551 study, due to Amendment 04. 
9.3.4 Quality of life / health economic variables / other endpoints (optional) 
Please see Section 9.2.2 for details of the quality of life and health economic variables that are 
collected as part of this study. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The LTS12551 study consists of 3 periods: 
• 
Enrollment period: Combined V1/V2 Visit: Eligible patients from PDY14192, 
EFC13579 and EFC13691 studies should rollover into LTS12551 the same day as the 
end-of-treatment visit of the parent study. 
- 
Note: A screening period of 0 to 3 weeks was proposed only for patients rolling over 
from DRI12544. Enrollment from study DRI12544 is complete, thus the screening 
period does not apply anymore. 
• 
Treatment period: Open-label treatment for 48 weeks (1 year) for patients enrolled after 
approval of Amendment 04 or 96 weeks (2 years) for patients enrolled prior to 
Amendment 04 approval. 
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 
judgment. 
• 
Post-treatment period: 12 weeks.  
The study visits should be performed on the planned dates (relative to the first injection) and be 
adhered to within the ±3 day visit window with the first 12 weeks and ±1 week for the remaining 
study period. Monthly telephone contact should be done with patient after Week 24 to collect 
safety information. 
It is preferred that all study visits take place in the morning. The results of the evaluation will be 
recorded on the appropriate e-CRF pages. Prior to all screening assessments, after discussion of 
participation in the study, the written consent form must be signed and dated. 
If a patient is prematurely discontinued from treatment, EOT should be scheduled and all 
assessments planned at the EOT Visit should be performed. 
10.1.1  For patients enrolled prior to Amendment 04 
The visit schedule for patients enrolled prior to Amendment 04 are shown in the study flowchart 
in Section 1.2. 
10.1.1.1 Enrollment: Combined V1/V2 Visit (Start-of-Treatment, Week 0, D1) 
Eligible patients from parent studies are considered to be candidates for the LTS12551 study. 
Following a discussion of participation in the clinical trial, the informed consent (and assent in 
case of adolescents) must be obtained before any protocol related investigations. 
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This study is using a central laboratory for blood tests assessments. 
For patients coming from PDY14192, EFC13579, and EFC13691 studies:  
• 
Visit 1 and Visit 2 should be combined with the end-of-treatment visit of the PDY14192, 
EFC13579 or EFC13691 parent studies. The majority of the V1/V2 assessments and 
laboratory procedures for this study correspond to the end-of-treatment visit of the 
PDY14192, EFC13579, and EFC13691 parent studies. 
The following activities are performed at the Enrollment (Combined V1/V2) Visit: 
• 
Obtain signature of informed consent for participation in LTS12551.  
• 
Review inclusion and exclusion criteria to assess eligibility.  
• 
If the patient meets all inclusion and does not meet any exclusion criteria, contact 
IVRS/IWRS to register the visit, confirm the patient’s number and receive the first 
treatment kit number assignment. 
• 
Collect patient’s demographic information, asthma history (including allergy history and 
smoking habits), eligibility module, other medical and surgical history (including 
significant prior and concurrent illnesses), prior and concomitant medications, ICF, 
chest imaging, and IMP administration (via e-CRF pages). 
• 
Commence AE reporting from the time of the signature of the informed consent for 
participation in LTS12551 (anticipated to be at the Combined V1/V2 Visit). 
• 
Record all medication use with start dose in the e-CRF. 
• 
Inquire about background asthma therapy tolerability. 
• 
Instruct the patient to continue the background ICS/LABA or ICS and controller therapy 
stabilized during the parent study. 
• 
Perform chest imaging (X-ray, Magnetic resonance imaging (MRI) or high resolution 
computed tomography (HRCT) scan) if no chest imaging within the previous 12 months is 
available1. 
Dispense and administer IMP (see Section 8.1.3)  
- 
For those patients willing to perform self-injection, the Investigator or delegate will 
train the patient (or parent or caregiver) regarding preparation and injection of IMP 
and may inject the study medication or the patient (or parent or caregiver) may 
perform the injection under the supervision of the Investigator or delegate, if the 
patient is already self-injecting from the parent study.  
- 
Document the training/supervision for IMP self-injection in the patient’s study file. 
                                                 
1 Chest X-ray, MRI or HRCT will be performed only if no chest imaging results within the previous 
12 months are available. At the Investigator’s discretion (and based on local regulations) chest imaging 
may be performed during the study (eg, 1 year after the last chest imaging assessment or after a year’s 
treatment). 
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- 
Patients should be monitored for at least 30 minutes after each administration of IMP 
for any signs or symptoms of a hypersensitivity reaction. 
• 
Schedule appointment for next visit and remind patient to withhold bronchodilators 
according to their action duration, eg, withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA for 
at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and 
withholding the last dose of LAMA for at least 24 hours prior to the next visit. 
• 
Reminder: Sexually active female patients of reproductive potential are required to 
practice an acceptable contraception (as defined in E18 or local protocol amendment in 
case of specific local requirement) during the entire study duration, while taking 
dupilumab and for 12 weeks after the last IMP dose. Study sites should counsel all study 
patients, with special attention towards adolescent patients, regarding the importance of 
practicing responsible and effective contraception during the study and 12 weeks after the 
last dose.  
The following will be obtained from the parent study PDY14192, EFC13579 and EFC13691 
studies and do not have to be repeated in LTS12551:  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, 
weight [kg], height [cm]). 
• 
Perform physical examination including major body systems examination.  
• 
Administer paper ACQ-5, AQLQ(S), and health care resource utilization questionnaire. 
Note: For patients coming from Study PDY14192, AQLQ(S) is not obtained from the 
parent study, so those patients will have to complete the paper questionnaire at the 
Combined V1/V2 Visit in LTS12551 study. 
• 
Spirometry:  
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours, the last dose of LABA for at least 
12 hours (ultra-LABA like vilanterol should be withheld for at least 24 hours) and the 
last dose of LAMA for at least 24 hours, and prior to the administration of IMP. This 
will be verified before performing the measurements. 
• 
Perform 12-lead ECG. 
• 
Collect blood samples for the following (fasting - overnight fast or minimum of 8 hours 
fast): 
- 
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 non-conjugated bilirubin), ALT, AST, ALP, total 
protein, albumin, total cholesterol, CPK, glucose, creatinine, BUN, uric acid, 
bicarbonate, and electrolytes (sodium, potassium, chloride).  
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- 
Serology: HBsAg, hepatitis B surface antibody (HBsAb), HBcAb, total HBcAb, 
HCV Ab, HIV screen (Anti-HIV-1 and HIV-2 antibodies) and ANA; (these tests were 
scheduled at the visit prior to the end-of-treatment visit of the PDY14192, EFC13579 
or EFC13691 parent studies). In addition, results from HBV DNA testing and HCV 
virus RNA (HCV RNA) testing should be collected for those patients who were 
HBsAg negative and HBcAb positive, and/or HCV Ab positive; also anti-double-
strand DNA antibody results for patients with ANA positive (≥1:160 titer). 
• 
Serum sample for PK and ADA (before dose of IMP). 
• 
Eosinophil count (derived from clinical laboratory test). 
• 
 
• 
Urine for urinalysis (dipstick) (see Section 9.2.1.4). 
• 
Urine pregnancy test (for women of childbearing potential). 
10.1.1.2 Visit 3 (Week 2)  
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform spirometry  
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours. This will be 
verified before performing the measurements. 
• 
Call IVRS/IWRS to register visit and obtain next treatment kit number (up to Visit 7, 1 kit 
to be dispensed at each visit).  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind the patient to continue the background ICS/LABA or ICS and controller therapy 
stabilized during the parent study. 
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit.  
• 
Remind patient to come for the next visit in fasting state. 
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10.1.1.3 Visit 4 (Month 1, Week 4) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform spirometry: 
- 
Spirometry will be performed after the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform blood sampling for: 
- 
Clinical laboratories. 
- 
Serum sample (predose) for PK.  
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit.  
10.1.1.4 Visit 5 (Week 6) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
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for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
10.1.1.5 Visit 6 (Month 2, Week 8) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform urine pregnancy test (for women of childbearing potential).  
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
10.1.1.6 Visit 7 (Week 10) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
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• 
Remind patients for the next visit in fasting state. 
10.1.1.7 Visit 8 (Month 3, Week 12) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra- LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick).  
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals.  
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
10.1.1.8 Visit 9 (Month 4, Week 16) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
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• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to  
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
10.1.1.9 Visit 10 (Month 5, Week 20);  
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patients for the next visit in fasting state. 
10.1.1.10 Visit 11 (Month 6, Week 24)  
• 
Record all medication use with start dose in e-CRF including starting dose.  
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• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination.  
• 
Administer paper ACQ-5, AQLQ(S), and health care resource utilization questionnaire. 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.1.11 Visit 12 (Month 9, Week 36) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
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• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patients for the next visit in fasting state. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.1.12 Visit 13 (Month 12, Week 48) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer paper ACQ-5, AQLQ(S), and health care resource utilization questionnaire. 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
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- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit numbers.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.1.13 Visit 14 (Month 15, Week 60); 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability. 
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
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• 
Remind patients for the next visit in fasting state. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.1.14 Visit 15 (Month 18, Week 72)  
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination, including major body systems examination. 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy. 
• 
Schedule appointment for next visit and remind patient to withhold withholding the last 
dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and 
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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 prior to the next visit. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.1.15 Visit 16 (Month 21, Week 84) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patients for the next visit in fasting state. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
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10.1.1.16 Visit 17 (End-of-Treatment: Month 24, Week 96) 
End-of-Treatment Visit is scheduled 2 weeks after the last IMP administration. 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer health care resource utilization utilization questionnaire. 
• 
Perform spirometry 
- Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
  
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick).  
• 
Call IVRS/IWRS to register the EOT date. 
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patient to continue the background therapy.  
• 
Remind patients to arrive for next visit in fasting state. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
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10.1.1.17 Visit 18 (End-of-Study: Month 27, Week 108) 
End-of-Study (EOS) visit is scheduled 12 weeks after EOT. 
• 
Record all medication use with start dose in e-CRF including starting dose. 
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
• 
Call IVRS/IWRS to register the EOS date. 
10.1.2 For patients enrolled after Amendment 04 
The visit schedule for patients enrolled after Amendment 04 are shown in the study flowchart in 
Section 1.3. 
10.1.2.1 Enrollment: Combined V1/V2 Visit (Start-of-Treatment, Week 0, D1) 
Eligible patients from parent studies are considered to be candidates for the LTS12551 study. 
Following a discussion of participation in the clinical trial, the informed consent (and assent in 
case of adolescents) must be obtained before any protocol related investigations. 
This study is using a central laboratory for blood tests assessments. 
For patients coming from PDY14192, EFC13579, and EFC13691 studies:  
• 
Visit 1 and Visit 2 should be combined with the end-of-treatment visit of the PDY14192, 
EFC13579 or EFC13691 parent studies. The majority of the Combined V1/V2 Visit 
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assessments and laboratory procedures for this study correspond to the EOT Visit in the 
PDY14192, EFC13579 and EFC13691 studies. 
The following activities are performed at the Enrollment (Combined V1/V2) Visit: 
• 
Obtain the signature of the informed consent for participation in LTS12551. 
• 
Review inclusion and exclusion criteria to assess eligibility.  
• 
If the patient meets all inclusion and does not meet any exclusion criteria: Contact 
IVRS/IWRS to register the visits, confirm the patient’s number and receive the first 
treatment kit number assignment. 
• 
Collect patient’s demographic information, asthma history (including allergy history and 
smoking habits), eligibility module, other medical and surgical history (including 
significant prior and concurrent illnesses), prior and concomitant medications, ICF, 
chest imaging, and IMP administration (via e-CRF pages). 
• 
Commence AE reporting from the time of the signature of the informed consent for 
participation in LTS12551 (anticipated to be at the Combined V1/V2 Visit). 
• 
Record all medication use with start dose in the e-CRF. 
• 
Inquire about background asthma therapy tolerability. 
• 
Instruct the patient to continue the background ICS/LABA or ICS and controller therapy 
stabilized during the parent study. 
• 
Perform chest imaging (X-ray, MRI, or HRCT scan) if no chest imaging within the 
previous 12 months is available2.  
• 
Dispense and administer IMP (see Section 8.1.3):  
- 
For those patients willing to perform self-injection, the Investigator or delegate will 
train the patient (or parent or caregiver) regarding preparation and injection of IMP 
and may inject the study medication, or the patient (or parent or caregiver) may 
perform the injection under the supervision of the Investigator or delegate if the patient 
is already self-injecting from the parent study. 
- 
Document the training/supervision for IMP self-injection in the patient’s study file. 
- 
Patients should be monitored for at least 30 minutes after each administration of IMP 
for any signs or symptoms of a hypersensitivity reaction. 
• 
Schedule appointment for next visit and remind patient to withhold bronchodilators 
according to their action duration, for example, withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
                                                 
2 Chest X-ray, MRI or HRCT will be performed only if no chest imaging results within the previous  
12 months are available. At the Investigator’s discretion (and based on local regulations) chest imaging 
may be performed during the study (eg, 1 year after the last chest imaging assessment or after a year’s 
treatment). 
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for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Reminder: Sexually active female patients of reproductive potential are required to 
practice an acceptable contraception (as defined in E18 or local protocol amendment in 
case of specific local requirement) during the entire study duration, while taking 
dupilumab and for 12 weeks after the last IMP dose. Study sites should counsel all study 
patients, with special attention towards adolescent patients, regarding the importance of 
practicing responsible and effective contraception during the study and 12 weeks after the 
last dose.  
The following will be obtained from the end-of-treatment visit in the parent study (PDY14192, 
EFC13579, and EFC13691 studies) and do not have to be repeated in LTS12551:  
• 
Measure vital signs [blood pressure, heart rate, respiration rate, body temperature, 
weight (kg), height (cm)].  
• 
Perform physical examination including major body systems exam, Administer paper 
ACQ-5, AQLQ(S) and health care resource utilization questionnaire. Note: For patients 
coming from Study PDY14192, AQLQ(S) is not obtained from the parent study so 
patients from the PDY14192 study will have to complete the questionnaire at the 
Combined V1/V2 Visit in the LTS12551 study. 
• 
Spirometry:  
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours and prior to 
administration of investigational product. This will be verified before performing the 
measurements.  
• 
Perform 12-lead ECG. 
• 
Collect blood samples for the following (fasting - overnight fast or minimum of 8 hours 
fast): 
- 
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 non-conjugated bilirubin), ALT, AST, ALP, total 
protein, albumin, total cholesterol, CPK, glucose, creatinine, BUN, uric acid, 
bicarbonate and electrolytes (sodium, potassium, chloride). 
- 
Serology: HBsAg, hepatitis B surface antibody (HBsAb), HBcAb, total HBcAb, 
HCV Ab, HIV screen (Anti-HIV-1 and HIV-2 antibodies) and ANA; (these tests were 
scheduled at the visit prior to the end-of-treatment visit of parent study). In addition, 
results from hepatitis B virus DNA (HBV DNA) testing and HCV RNA testing should 
be collected for those patients who were HBsAg negative and HBcAb positive, and/or 
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HCV Ab positive; also anti-double-strand DNA antibody results for patients with 
ANA positive (≥1:160 titer). 
• 
Serum sample for PK and ADA (before dose of IMP). 
• 
Eosinophil count (derived from clinical laboratory test). 
• 
 
• 
Urine for urinalysis (dipstick) (see Section 9.2.1.4). 
• 
Urine pregnancy test (for women of childbearing potential). 
• 
Schedule appointment for next visit. 
10.1.2.2 Visit 3 (Week 2)  
• 
Record all medication use with start dose in e-CRF including starting dose. 
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform spirometry:  
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours. This will be 
verified before performing the measurements. 
• 
Call IVRS/IWRS to register visit and obtain next treatment kit number (up to Visit 7, 1 kit 
to be dispensed at each visit).   
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind the patient to continue the background ICS/LABA or ICS and controller therapy 
stabilized during the parent study.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patient to come for the next visit in fasting state. 
10.1.2.3 Visit 4 (Month 1, Week 4) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
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• 
Perform spirometry: 
- 
Spirometry will be performed after the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements.  
• 
Perform blood sampling for: 
- 
Clinical laboratories. 
- 
Serum sample (predose) for PK.  
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit.  
10.1.2.4 Visit 5 (Week 6) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
10.1.2.5 Visit 6 (Month 2, Week 8) 
• 
Record all medication use with start dose in e-CRF including starting dose. 
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
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• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least  
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
10.1.2.6 Visit 7 (Week 10) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kit number.  
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. This will be verified before performing the measurements. 
• 
Remind patients for the next visit in fasting state. 
10.1.2.7 Visit 8 (Month 3, Week 12) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
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• 
Perform physical examination. 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick).  
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers.  
• 
Dispense and administer IMP 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals.  
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
10.1.2.8 Visit 9 (Month 4, Week 16) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
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- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
10.1.2.9 Visit 10 (Month 5, Week 20) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patients for the next visit in fasting state. 
10.1.2.10 Visit 11 (Month 6, Week 24)  
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination.  
• 
Administer paper ACQ-5, AQLQ(S), and health care resource utilization questionnaire. 
• 
Perform spirometry: 
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- 
Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy and schedule appointment for next 
visit. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.2.11 Visit 12 (Month 9, Week 36) 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Call IVRS/IWRS to register visit and obtain treatment kits' numbers. 
• 
Dispense and administer IMP: 
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- 
Patients will be monitored at the study site for a minimum of 30 minutes after the 
injection. 
- 
After Week 12, for patients (or parents caregivers) unable or unwilling to 
self-administer IMP, arrangements must be made for the patient to receive IMP 
injections at the study site as unscheduled visits, or for qualified site personnel and/or a 
professional caregiver to administer IMP at home at q2w intervals. 
• 
Remind patient to continue the background therapy.  
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patients for the next visit in fasting state. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
Note: Patient’s next visit will be Visit 17 (EOT: Month 12, Week 48) 
10.1.2.12 Visit 17 (End-of-Treatment: Month 12, Week 48)  
End-of-Treatment visit is scheduled 2 weeks after the last IMP administration. 
• 
Record all medication use with start dose in e-CRF including starting dose. 
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer paper ACQ-5 and AQLQ(S). 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
- Hepatitis B viral load testing: For patients in Japan (or other countries/regions if there 
is local regulatory requirement) who were HBsAg negative and HBsAb positive at 
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screening during the parent study, or at the additional test due to Local Amendment 03 
(Japan). 
• 
 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick).  
• 
Call IVRS/IWRS to register the EOT date. 
• 
Schedule appointment for next visit and remind patient to withhold the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours and withholding 
the last dose of LABA for at least 12 hours (ultra-LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
the next visit. 
• 
Remind patient to continue the background therapy.  
• 
Remind patients to arrive for next visit in fasting state. 
• 
Perform monthly telephone contact with patient after Week 24 (Visit 11) to collect safety 
information. 
10.1.2.13 Visit 18 (End-of-Study: Month 15, Week 60) 
End-of-Study Visit is scheduled 12 weeks after EOT. 
• 
Record all medication use with start dose in e-CRF including starting dose.  
• 
Inquire about AEs/SAEs and background asthma therapy tolerability.  
• 
Measure vital signs (blood pressure, heart rate, respiration rate, body temperature, weight). 
• 
Perform physical examination. 
• 
Administer health care resource utilization questionnaire. 
• 
Perform spirometry: 
- Spirometry will be performed after withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA 
for at least 12 hours (ultra-LABA like vilanterol should be withheld for at least 
24 hours) and withholding the last dose of LAMA for at least 24 hours prior to 
administration of investigational product. This will be verified before performing the 
measurements. 
• 
Perform 12-lead ECG. 
• 
Perform blood sampling for: 
- Clinical laboratories. 
- Serum sample (predose) for PK and anti-dupilumab antibody analysis. 
• 
Perform urine pregnancy test (for women of childbearing potential). 
• 
Obtain urine for urinalysis (dipstick). 
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• 
Call IVRS/IWRS to register the EOS date. 
10.2 
DEFINITION OF SOURCE DATA 
Source data is all information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and 
evaluation of the trial. Source data are contained in source documents. Source documents are 
original documents, data and records such as hospital records, clinic and office charts, laboratory 
notes, memoranda, pharmacy dispensing records, recorded data from automated instruments, etc. 
All the data collected in the e-CRF should be transcribed directly from source documents. Data 
downloaded from the study-associated central laboratories, spirometry, ECG, and patient 
electronic diary.  
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
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 
Appendix D. 
In addition, 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 judgment) that the AE is sufficiently resolved and unlikely to recur after 
resuming therapy with IMP, that the responsibility of the IMP in the occurrence of the concerned 
event was unlikely, and that the selection criteria for the study are still met (see Section 7.1 and 
Section 7.2). 
For all temporary treatment discontinuations, the Investigator should record injections that are 
missed in the e-CRF IMP pages. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
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In case permanent treatment discontinuation, the patient should be scheduled for the EOT Visit 
and procedures and continue the 12-week follow-up period for safety evaluation. 
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 e-CRF. 
Any abnormal laboratory value or ECG parameter should be immediately rechecked for 
confirmation (within 24 hours) before making a decision of permanent discontinuation of the IMP 
for the concerned patient. Threshold values for the discontinuation of IMP are defined in 
collaboration with Global Pharmacovigilance and Epidemiology (see Appendix D). 
The following criteria will lead to permanent treatment discontinuation:  
• 
At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research).  
• 
If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being (see also safety Section 10.6). 
• 
At the specific request of the Sponsor. 
• 
In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor. 
• 
Pregnancy (Note: dupilumab should be stopped but patient should be followed up until 
delivery). 
• 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment. 
• 
Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin. 
• 
Any opportunistic infection, such as tuberculosis (TB) or other infections whose nature or 
course may suggest an immunocompromised status (See Appendix I). 
• 
Serum ALT >3 Upper Limit of Normal (ULN) concurrent with Total Bilirubin >2 ULN 
(see Appendix D). 
• 
Serum ALT >5 ULN if baseline ALT < 2 ULN or ALT >8 ULN if baseline  
ALT >2 ULN (Appendix D). 
Note: Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient. 
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10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol. 
After the permanent discontinuation of dupilumab, the patients will be assessed using the 
procedure normally planned for the EOT Visit. After 12 weeks follow-up time, the patients will 
be asked to return for the EOS assessments.  
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study  
 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. 
For patients who fail to return to the study site, the Investigator should make the best effort to re-
contact the patient (eg, contacting patient’s family or private physician, reviewing available 
registries or health care databases), and to determine his/her health status, including at least 
his/her vital status. Attempts to contact such patients must be documented in the patient’s 
records (eg, times and dates of attempted telephone contact, receipt for sending a registered letter). 
If possible, the patients are assessed using the procedures normally planned for the EOT Visit, 
including a PK sample, if appropriate. 
 
A patient should only be designated as lost to follow-up if the site is unable to establish 
contact with the patient after 3 documented attempts via 2 different methods (phone, text, e-mail, 
certified letter, etc). 
Patients who have withdrawn from the study cannot be re-enrolled (treated) in the study. Their 
inclusion and treatment numbers must not be reused. The statistical analysis plan (SAP) will 
specify how these patients lost to follow-up for their primary endpoints will be analyzed. The 
patients may withdraw from the study before study completion if they decide to do so, at any time 
and irrespective of the reason.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
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Asthma exacerbation events are collected as secondary efficacy endpoints via the “Asthma 
Exacerbation Event Form”. These events should not be reported as AEs unless they fulfill a 
seriousness criterion.  
For this study, asthma exacerbations should be managed by the Investigators based on their 
medical judgment and applicable national / international asthma management guidelines. 
10.4.1.2 Serious adverse event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
 
the patient was at risk of death at the time of the event; it does not refer to an event which 
 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect, or 
• 
Is a medically important event. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or may require 
medical or surgical intervention (ie, specific measures or corrective treatment) to prevent one of 
the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is not 
intended to be exhaustive: 
• 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm, Anaphylaxis. See Appendix H for the Definition of 
Anaphylaxis. 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc).  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• 
Development of drug dependence or drug abuse. 
• 
ALT >3 x ULN + total bilirubin >2 x ULN or ALT increase >10 x ULN. 
• 
Suicide attempt or any event suggestive of suicidality. 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
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• 
Bullous cutaneous eruptions. 
• 
Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies). 
• 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically the 
effect of a study drug on these diseases). 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. AESIs may be added or removed during a study by protocol 
amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described in Section 10.4.3, even if not fulfilling a seriousness criterion, using the 
corresponding pages/screens in the e-CRF.  
• 
Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Appendix H for Definition of Anaphylaxis). 
• 
Severe injection site reactions that last longer than 24 hours. 
• 
Any infection meeting at least one of the following criteria (see Section 10.6.3): 
- 
Any serious infection (SAE). 
- 
Requires parenteral (intravenous, intramuscular, SC) antimicrobial therapy. 
- 
Requires oral antimicrobial therapy for longer than 2 weeks. 
- 
Is a parasitic infection. 
- 
Is an opportunistic infection (see Appendix I). 
Note: Antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents. 
• 
Significant ALT elevation:  
- ALT >5 x the ULN in patients with baseline ALT ≤2 x ULN; or 
- ALT >8 x ULN if baseline ALT >2 x ULN.  
• 
Pregnancy: 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued. 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Section 9.2.1.4.1). 
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• 
Symptomatic overdose with IMP/Non-IMP: 
- 
An accidental or intentional overdose with the IMP/Non-IMP is an event suspected by 
the Investigator or spontaneously notified by the patient and defined as at least twice 
the planned dose during an interval of less than 11 days. The circumstances (ie, 
accidental or intentional) should be clearly specified in the verbatim and symptoms, if 
any, entered on separate AE forms. 
- 
An accidental or intentional overdose with any Non-IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice of the 
intended dose within the intended therapeutic interval. The circumstances (ie, 
accidental or intentional) should be clearly specified in the verbatim and symptoms, if 
any, entered on separate AE forms. 
10.4.2 General guidelines for reporting adverse events 
• 
All AEs, regardless of seriousness or relationship to IMP/Non-IMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF. 
• 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). 
• 
The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• 
Patients who experience an ongoing SAE or an AESI with immediate notification, at the 
pre-specified study end-date, 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. 
Table 5 summarizes the reporting timelines. 
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Table 5 - Adverse event/laboratory abnormality reporting timelines 
Adverse event / laboratory abnormality 
Reporting timeline 
Serious adverse event (SAE) 
 
Within 24 hours 
Adverse event (non-SAE, non-AESI) 
 
Routine 
Pregnancy 
 
Within 24 hours 
Overdose 
Symptomatic 
Within 24 hours 
 
Asymptomatic 
Routine 
ALT elevation 
 
 
ALT >5 ULN if baseline ALT is ≤2 ULN 
 
Within 24 hours 
ALT >8 ULN if baseline ALT is >2 ULN 
 
Within 24 hours 
ALT >3 ULN plus total bilirubin >2 ULN                      
 
Within 24 hours 
Anaphylactic reactions or acute allergic reactions that require immediate treatment 
Within 24 hours 
Severe injection site reactions that last longer than 24 hours 
Within 24 hours 
Infections, as defined in Section 10.4.1.3 
Within 24 hours 
Abbreviations: AESI = Adverse event of special interest; ALT= Alanine Aminotransferase; SAE = serious adverse event; ULT= Upper limit of 
normal. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge. In addition, every effort should be made to further 
document any SAE that is fatal or life threatening within a week (7 days) of the initial 
notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
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10.4.4 Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages/screens in the e-CRF. Instructions for AE reporting are 
summarized in Table 6.  
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by sanofi are provided in 
Appendix D. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices:  
• 
Neutropenia; 
• 
Thrombocytopenia; 
• 
Increase in ALT; 
• 
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.  
NOTE: Increase in ALT is considered as an AESI (see Section 10.4.1.3). 
Appropriate reporting according to categories will appear in the CRF instructions/completion 
guide.  
Table 6 - Summary of adverse event reporting instructions 
CASE REPORT FORM COMPLETION 
EVENT 
CATEGORY 
REPORTING 
TIMEFRAME 
SPECIFIC EVENTS IN THIS 
CATEGORY 
AE 
form 
Safety Comple-
mentary Form 
Other specific 
forms 
AE (non-SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
SAE (non-AESI or AESI) 
Expedited (within 24 
hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
 
 
 
 
 
 
Adverse Event of Special 
Interest  
Expedited (within 24 
hours) 
As per Section 10.4.1.3 
Yes 
Yes 
No 
Abbreviations: AE = Adverse event; AESI = Adverse event of special interest; SAE = Serious adverse event 
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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 (ie, a Serious 
Unexpected Serious Adverse Reaction [SUSAR]), to the regulatory authorities, 
Institutional Review Boards / Institutional Ethics Committees (IRBs/IECs) 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 exacerbations of asthma, as pre-existing condition, will be considered expected for 
purposes of regulatory reporting, unless the event is life-threatening or with fatal outcome (see the 
Investigator’s Brochure). 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the 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 e-CRF pages for local injection reactions 
recording. 
10.6.1 Hypersensitivity  
Allergic reaction is a potential risk associated with the administration of most therapeutic 
monoclonal antibodies. 
Allergic reactions may be defined as an immunologically mediated response to a pharmaceutical 
and/or formulation agent in a sensitized person. Signs and symptoms are often experienced during 
or shortly after therapeutic administration. Anaphylaxis may represent the most severe form of 
allergic reactions; see Appendix H “Definition of Anaphylaxis”, which describes the clinical 
criteria for the diagnosis of anaphylaxis. 
Patients should be monitored for at least 30 minutes after each study-site administered 
investigational product administration for any signs or symptoms of a hypersensitivity reaction. 
Trained personnel and medications should be available to treat anaphylaxis or any severe allergic 
reaction if it occurs. Furthermore, the patients will be advised, when the IMP is administered at 
home, to self-monitor for potential signs and symptoms that may suggest a hypersensitive reaction 
for 30 minutes after administration.  
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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. ADA and PK samples 
will be collected near the onset and resolution of the AESI for any additional analysis. 
10.6.2  Severe injection site reactions 
Based on the SC mode of administration of high doses of protein and on a higher incidence of 
local injection site reactions observed at the highest dose level (300 mg weekly) severe injection 
site reactions are considered as a potential risk. Patients who experience an injection site reaction 
must be closely monitored for the possibility of a more intense injection site reaction with a future 
injection. Any severe injection reaction that lasts over 24 hours will be reported as an AESI with 
immediate notification. ADA and PK samples will be collected near the onset and resolution of 
the AESI for any additional analysis. 
Prophylactic treatment/premedication for an injection site reaction is not permitted. 
10.6.3 Infections 
Some biologic therapies have been associated with an increased risk of infection, including 
opportunistic infection. As a precautionary measure, the Investigator is required to carefully 
monitor for any signs or symptoms of infection such as, but not limited to, increased body 
temperature, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, or serious febrile 
systemic illness. 
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 
could be associated with a parasitic infection should be carefully evaluated; especially if there is a 
history of parasitic exposure through recent travel to/or residence in endemic areas, particularly 
when conditions are conducive to infection (eg, extended stay, rural or slum areas, lack of running 
water, consumption of uncooked, undercooked, or otherwise potentially contaminated food, close 
contact with carriers and vectors, etc). Subsequent medical assessments (eg, stool exam, blood 
tests, etc) must be performed in order to rule out parasitic infection/infestation. Patients with 
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confirmed parasitic infections during the study should be reported as AESI with immediate 
notification. 
Infections defined in Section 10.4.1.3 should be reported as AESIs within 24 hours. 
A complete diagnostic work-up should be performed (ie, cultures, histopathological or cytological 
evaluation, antigen detection and serum antibody titers). Patients should be referred to an 
infectious disease specialist, if deemed necessary, for diagnostic work up and appropriate 
treatment: 
• 
Infections or infestations that do not respond to medical treatment should have study IMP 
discontinued until the infection is resolved. 
• 
For any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (See Appendix I), 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. Clinical 
laboratory testing also includes a hepatitis screen for HBsAg, HBcAb-IgM, HCVAb. Patients who 
are total-HBcAb positive and HBsAg negative must undergo HBV DNA testing to determine 
eligibility. Furthermore, it is recommended that patients who are receiving potentially 
immunosuppressive therapy and are HBcAb positive and HBV DNA negative undergo 
surveillance HBV DNA every 1 to 3 months depending upon the individual potential therapeutic 
risk and comorbidities. If necessary, a hepatologist should be consulted on a case-by-case basis.  
Note: Japanese patients who have rolled over from DRI12544 study should be retested for 
hepatitis B (HBsAg, HBsAb, and HBcAb) after Visit 1, at any time during the LTS12551 study 
via the earliest scheduled study visit, after IRB approval for Local Amendment 03 (Japan). 
Japanese patients with HBsAg negative and HBsAb positive at any time during the parent study 
or at the additional test due to Local Amendment 03 (Japan) do not need to discontinue the study. 
In Japan (or other countries/regions if there is local regulatory requirement), hepatitis B viral load 
(HBV DNA) will be tested for patients who are HBsAg negative and HBsAb positive at screening 
during the parent study or at the additional test due to Local Amendment 03 (Japan).  
Guidance for the investigation of elevated LFTs is provided in Appendix D. 
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 trials. 
Hence, the maximal number of patients to participate in this extension study will be the number 
corresponding to the total randomized in those studies. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patients who signed the informed consent form. 
Enrolled patients consist of all the patients who signed informed consent 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 LTS12551 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 who have 
actually received at least one dose or part of a dose of dupilumab in the LTS12551 study.  
The treatment-emergent period is defined as the time from the first dose of dupilumab in 
LTS12551 up to the last dose of dupilumab plus 2 weeks (corresponding to one dose interval) plus 
12 weeks (follow-up period duration). The pre-treatment period is defined as the time from the 
starting of AE reporting in LTS12551 study up to the first dose of dupilumab in LTS12551. 
11.3.3 Pharmacokinetics population 
The PK population (the systemic drug concentration population) will consist of all the patients in 
the safety population with at least one non-missing and evaluable predose serum concentration 
value after the first dose of dupilumab in the LTS12551 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 
predose sample that was assayed successfully using the ADA assay after the first dose of 
dupilumab in the LTS12551 study.  
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
Extent of study treatment exposure and compliance will be summarized on the safety population. 
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 (number, mean, SD, median, minimum 
and maximum). The percentage of patients with compliance <80% will be summarized. 
11.4.2 Analyses of efficacy endpoints 
There will be no confirmatory analysis for the efficacy variables. All analyses will be done 
descriptively on the safety population in observed case, as appropriate. The baseline value for the 
applicable efficacy parameters is the original baseline from the parent studies. 
For the continuous efficacy variables, descriptive statistics (number, mean, SD, median, minimum 
and maximum) will be presented for the parameter and its change from baseline over visits. In 
addition, a 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 
all patients who have data available at that time point.  
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For severe exacerbation events, the 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 and maximum) during the 
treatment period will be summarized. 
More details about the efficacy analysis can be found in the SAP. 
11.4.3 Analyses of safety data 
All safety analysis will be performed on the safety population. The baseline value for the 
applicable safety parameters is the original baseline from the parent studies. 
11.4.3.1 Adverse events 
Adverse event reported in this study will be coded using the version of 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 TEAE. 
11.4.3.1.1  Treatment-emergent adverse events  
Treatment-emergent AE 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.  
The proportion of patients with at least one TEAE, serious TEAE and TEAE leading to 
discontinuation of the study will be tabulated. In addition TEAEs will be described according to 
maximum intensity and relation to the study drug. Adverse events that are not treatment-emergent 
will be summarized separately. 
11.4.3.1.2  Adverse Events 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 methods and displayed as  
Kaplan-Meier plots (cumulative incidence [%] versus time based on Kaplan-Meier 
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). 
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- 
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 (Kaplan-Meier estimates) up to specified time points. 
AESI definitions and the method to identify AESIs will be specified in the SAP. 
11.4.3.1.3  Death 
The following summaries of deaths will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population.  
• 
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
Patient data listings will be provided for all AEs, TEAEs, SAE, 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, lower and upper quartiles, minimum and 
maximum. 
The proportion of patients who had at least one incidence of potentially clinically significant 
abnormality (PCSA) at any time during the TEAE period will be summarized by biological 
category. Shift tables showing changes with respect to baseline and Week 0 (predose) status will 
be provided. 
Listings will be provided with flags indicating clinically out-of range values, as well as PCSA 
values. 
The following definitions will be applied to laboratory parameters, vital signs, and ECG: 
• 
The PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG.  
• 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
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including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables 
11.4.4.1 Pharmacokinetic analysis - (drug concentration analyses) 
The PK analyses will be performed on the PK (systemic drug concentration) population. The 
baseline value of each applicable PK variable is the original baseline from the parent studies. 
Serum concentrations of functional dupilumab will be summarized using arithmetic and geometric 
means, SD, standard error of the mean (SEM), coefficient of variation, median, minimum and 
maximum per visit.  
11.4.4.2 Anti-drug antibodies analysis 
The ADA analyses will be performed on the ADA population. The baseline value of each 
applicable ADA variable is the original baseline from the parent studies. 
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. 
11.4.4.3 Pharmacodynamics 
The biomarker analyses will be applied to the safety population. The baseline value for the 
applicable pharmacodynamic (PD) variables is the original baseline from the parent studies. For 
all PD parameters, the descriptive statistics (number, mean, median, SD, lower and upper 
quartiles, 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.  
11.4.5 Analyses of patient reported outcomes (health-related quality of life / health 
economics variables) 
Change from baseline in the following variables: global measure of AQLQ(S) and the four 
domains, the quantitative variables of the EQ-5D-3L (single index utility) will be summarized in 
the same way as described previously for the continuous efficacy variables. 
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11.5 
INTERIM ANALYSIS 
Interim study 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, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the International Council on Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 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 Institutional Review Board / Institutional Ethics Committee (IRB/IEC). All 
participants should be informed to the fullest extent possible about the study, in language and 
terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent 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 discussion.  
A copy of the signed and dated written informed consent form will be provided to the patient (for 
adult patients) or patient’s parent(s) or patient's legally accepted representative for pediatric 
patients. Local law must be observed in deciding whether 1 or both parents/guardians consent is 
required for pediatric patients.  If only 1 parent or guardian signs the consent form, the 
Investigator must document the reason for only 1 parent or guardian’s signature. 
In addition, participants will assent as detailed below or will follow the IRB/IEC approved 
standard practice for pediatric participants at each participating center (age of assent to be 
determined by the IRB/IEC or be consistent with the local requirements): 
• 
Pediatric participants who can read the assent form will do so before writing their name 
and dating or signing and dating the form. 
• 
Pediatric participants who can write but cannot read will have the assent form read to them 
before writing their name on the form. 
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If informed consent is obtained under special circumstances (emergency, from a guardian, minor, 
etc), the method should be specified following the ICH requirements.  
12.3 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title, and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae, etc) and the date of the review should be clearly stated on the written IRB/IEC 
approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator(s) and delegated Investigator staff undertake(s) to perform the clinical trial in 
accordance with this clinical trial protocol, ICH guidelines for GCP and the applicable regulatory 
requirements. 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the study site will be contacted, through monitoring 
visits, letters or telephone calls, by a representative of the monitoring team to review study 
progress, Investigator and patient compliance with clinical trial protocol requirements and any 
emergent problems. These monitoring visits will include but not be limited to review of the 
following aspects: patient informed consent, patient recruitment and follow-up, SAE 
documentation and reporting, AESI documentation and reporting, AE documentation, IMP 
allocation, patient compliance with the IMP regimen, IMP accountability, concomitant therapy 
use and quality of data. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the IRB/IEC, and the regulatory authorities to have direct access to original medical 
records, which support the data on the CRFs (eg, patient's medical file, appointment books, 
original laboratory records, etc). These personnel, bound by professional secrecy, must maintain 
the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
Computerized systems planned to be used during the different steps of the study are: 
• 
For screening and enrollment activities, IVRS/IWRS. 
• 
For data management activities, Medidata Rave. 
• 
For statistical activities, SAS, query Advisor 6.01. 
• 
For pharmacovigilance activities, AWARE. 
• 
For investigational product ordering/tracking, SmartSupplies PMD. 
• 
For monitoring activities, IMPACT, POLARIS, CTI, I/J review, SmartSupplies RAR. 
• 
For medical writing activities, DOMASYS. 
• 
CT-fast for IMP forecasts. 
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External data loading is planned for this clinical trial. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
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The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
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. 
• 
Patient’s race or ethnicity will be collected in this study because these data are required by 
several regulatory authorities. 
• 
The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/risk ratio, efficacy and safety of the product(s). 
They may be further processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
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The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IRBs/IECs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual study 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. 
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• 
The total number of patients are included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.9 
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 study 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 study 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). 
Sanofi is free to publish, and to communicate the recommendations made by the DMC, using all 
existing or future means of communication with an agreement between both parties. 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 
15.1 
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 study site, for 
any reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
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16 
BIBLIOGRAPHIC REFERENCES  
1. Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are correlated with 
severity: A 1-yr prospective study. Eur Respir J 2002;9(1):61-7. 
2. Levine SJ and Wenzel SE. Narrative review: the role of Th2 immune pathway modulation in 
the treatment of severe asthma and its phenotypes. Ann Intern Med. 2010;152:232–7. 
3. Wenzel S, 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. 
4. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab eﬃcacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose 
inhaled corticosteroids plus a long-acting β 2  agonist: a randomised double-blind placebo-
controlled pivotal Phase 2b dose-ranging trial. Lancet. 2016,388:31-44. 
5. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F. Standardization of the 
measurement of lung volumes. Series “ATS/ERS TASK FORCE: Standardization of Lung 
Function Testing” Edited by Brusasco V, Crapo R, and Viegi G. Eur Respir J. 
2005;26(3):511-52. 
6. Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties an interpretation of three 
shortened versions of the asthma control questionnaire.  Respir Med. 2005;99(5):553-8. 
7. Juniper EF, Guyatt GH, Willan A. Griffith LE. Determing a minimal important change in a 
disease-specific quality of life questionnaire. J Clin Epidemiol. 1994;47(1):81-7. 
8. Czech W, Krutmann J, Schöpf E, Kapp A. Serum eosinophil cationic protein (ECP) is a 
sensitive measure for disease activity in atopic dermatitis. Br. J. Dermatol. 1992;126(4):351-5. 
9. Oettgen HC, Geha RS. IgE regulation and roles in asthma pathogenesis. J Allergy Clin 
Immunol. 2001;107(4):429-40. 
10. Gain F, Senna G, Piglia P, Grosso B, Mezzelani P, Pozzi E. Cytokines and asthma.  Recenti 
Prog Med. 1998; 89(10):520-8. 
11. Bottaro A, Lansford R, Xu L, Zhang J, Rothman P, Alt FW. S region transcription per se 
promotes basal IgE class switch recombination but additional factors regulate the  efficiency 
of the process.  EMBO J. 1994;13(3): 665-74. 
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17 
APPENDICES 
 
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Appendix A. 
List of prohibited live, attenuated vaccines 
• 
Bacillus Calmette-Guérin (BCG) antituberculosis vaccine. 
• 
Chickenpox (Varicella). 
• 
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection. 
is permitted. 
• 
Measles (Rubeola). 
• 
Measles-mumps-rubella (MMR) combination. 
• 
Measles-mumps-rubella-varicella (MMRV) combination. 
• 
Mumps. 
• 
Oral polio (Sabin). 
• 
Oral typhoid. 
• 
Rotavirus. 
• 
Rubella. 
• 
Smallpox (Vaccinia). 
• 
Varicella Zoster (shingles). 
• 
Yellow fever. 
 
This list is indicative and not exhaustive. 
 
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Appendix B. 
Examples of commonly used asthma controller therapies 
Controller groups 
Medications 
ICS 
Beclomethasone dipropionate CFC 
ICS 
Beclomethasone dipropionate HFA 
ICS 
Budesonide 
ICS 
Ciclesonide 
ICS 
Fluticasone propionate 
ICS 
Mometasone furoate 
ICS 
Triamcinolone acetonide 
ICS 
Fluticasone furoate  
ICS/LABA 
Fluticasone Propionate / Salmeterol 
ICS/LABA 
Fluticasone Propionate / Formoterol 
ICS/LABA 
Fluticasone Furoate / Vilanterol 
ICS/LABA 
Budesonide /Formoterol 
ICS/LABA 
Mometasone Furoate / Formoterol 
ICS/LABA 
Beclometasone Dipropionate/ Formoterol 
LABA 
Salmeterol  
LABA 
Formoterol  
LABA 
Bambuterol  
LABA 
Clenbuterol  
LABA 
Tulobuterol 
LABA 
Vilanterol 
LABA 
Olodaterol 
LABA 
Indacaterol 
LAMA 
Tiotropium 
LAMA 
Glucopyrronium bromide 
LAMA 
Aclidinium bromide 
LAMA 
Umeclidinium 
Anti-Leukotrienes 
Montelukast  
Anti-Leukotrienes 
Pranlukast 
Anti-Leukotrienes 
Zafirlukast  
Anti-Leukotrienes 
Zileuton 
Methylxanthines 
Aminophylline 
Methylxanthines 
Theophylline 
Methylxanthines 
Dyphylline  
Methylxanthines 
Oxtriphylline 
Methylxanthines 
Diprophylline 
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Controller groups 
Medications 
Methylxanthines 
Acebrophylline 
Methylxanthines 
Bamifylline 
Methylxanthines 
Doxofylline 
This list is indicative and not exhaustive. 
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Appendix C. 
Examples(1) of CYP substrates with narrow therapeutic range 
 
CYP enzymes 
Substrates  
with narrow therapeutic range(2) 
CYP1A2 
Theophylline, tizanidine 
CYP2C8 
Paclitaxel 
CYP2C9 
Warfarin, phenytoin 
CYP2C19 
S-mephenytoin  
CYP3A(3) 
Alfentanil, astemizole(4) cisapride, (4) cyclosporine (5), dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus (5), 
terfenadine(4) 
CYP2D6 
Thioridazine 
 
1) Note that this is not an exhaustive list. For an updated list, see the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm  
(2) CYP substrates with narrow therapeutic range refers to drugs whose exposure-response 
relationship indicates that small changes in their exposure levels by the concomitant use of CYP 
inhibitors or inducers may lead to either serious safety concerns (eg, Torsades de Pointes) or loss 
of therapeutic effect.  
(3) Because a number of CYP3A substrates (eg, darunavir, maraviroc) are also substrates of P-gp, 
the observed increase in exposure could be due to inhibition of both CYP3A and P-gp.  
(4) Withdrawn from the United States market because of safety reasons  
(5) Prohibited medication during the study 
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Appendix D. 
General guidance for the follow-up of laboratory abnormalities  
 
 
by sanofi  
 
Neutropenia is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting AEs in Section 10.4.2 is met. 
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Thrombocytopenia is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting AEs in Section 10.4.2 is met. 
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ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 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.
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
3.
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)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances 
suggesting hepatic encephalopathy
7.
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.
8.
FREEZE serum sample (5ml x 2)
9.
In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
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
INCREASE IN ALT
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening. 
• See Section 10.4 for guidance on safety reporting. 
• Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
 
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Acute renal failure is to be recorded as AE only if at least one of the criteria listed in the General 
guidelines for reporting AEs in Section 10.4.2 is met. 
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie: stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE Investigational 
Medicinal Product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK ≤10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
SUSPICION OF RHABDOMYOLYSIS
 
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria in the 
General guidelines for reporting AEs in Section 10.4.2 is met. 
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Appendix E. 
Asthma Quality of Life Questionnaire AQLQ(S) 
 
 
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Appendix F. 
Asthma Control Questionnaire, 5-question Version (ACQ-5) 
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Appendix G. 
EuroQUAL Questionnaire (EuroQol 5 dimensions questionnaire, 
3-Level Version [EQ-5D-3L]) 
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Appendix H. 
Definition of Anaphylaxis  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et al.  Second 
symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol  2006; 117: 391-
397) 
Clinical criteria for diagnosing anaphylaxis: 
 
 
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Appendix I. List of opportunistic infections 
 
• 
Aspergillosis 
• 
Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, along 
Mississippi and Ohio Rivers) 
• Candidiasis – only systemic or extensive mucosal or cutaneous candidiasis  
• Coccidioides immitis (endemic south-western US and Central and South America) 
• 
Cryptococcus 
• 
Cytomegalovirus 
• 
Herpes Simplex (disseminated) 
• 
Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
• 
Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
• 
Listeriosis 
Mycobacterium avium 
• 
Nontuberculosis mycobacteria 
• 
Pneumocystis pneumonia (PCP). 
This list is indicative and not exhaustive.  
 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
lts12551-amended-protocol02
Regulatory Approval
Clinical Approval
Clinical Approval

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1
STATISTICAL ANALYSIS PLAN 
An open-label extension study to evaluate the long-term safety and 
tolerability of dupilumab in patients with asthma who participated in a 
previous dupilumab asthma clinical study  
SAR231893-LTS12551 
STATISTICIAN: 
  
DATE OF ISSUE: 20-Jul-2017 
Total number of pages: 
94 
(electronic 3.0)
NCT02134028


Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................9 
1.2.1 
Primary objectives............................................................................................................................9 
1.2.2 
Secondary objectives .......................................................................................................................9 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................9 
1.4 
STUDY PLAN.................................................................................................................................10 
1.4.1 
Graphical Study Design..................................................................................................................11 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................12 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN......................13 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................17 
2.1 
ANALYSIS ENDPOINTS................................................................................................................17 
2.1.1 
Demographic and baseline characteristics ....................................................................................17 
2.1.2 
Prior or concomitant medications...................................................................................................19 
2.1.2.1 
Salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication.......................................20 
2.1.3 
Efficacy endpoints ..........................................................................................................................21 
2.1.3.1 
Severe Exacerbation Events..........................................................................................................22 
2.1.3.2 
Forced expiratory volume in one second (FEV1) and other spirometry assessments...................23 
2.1.3.3 
Asthma control questionnaire, 5-question version (ACQ-5)...........................................................23 
2.1.3.4 
Asthma quality of life questionnaire (AQLQ)..................................................................................24 
2.1.3.5 
EuroQoL questionnaire (EQ-5D-3L)...............................................................................................25 
2.1.3.6 
Daily efficacy assessments ............................................................................................................26 
2.1.3.7 
Endpoints linked to the prescribed OCS dose ...............................................................................28 
2.1.4 
Safety endpoints.............................................................................................................................29 
2.1.4.1 
Adverse events variables ...............................................................................................................29 
2.1.4.2 
Deaths............................................................................................................................................31 
2.1.4.3 
Laboratory safety variables ............................................................................................................31 
2.1.4.4 
Vital signs variables........................................................................................................................33 
2.1.4.5 
Electrocardiogram variables...........................................................................................................33 
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2.1.5 
Pharmacokinetic variables .............................................................................................................33 
2.1.6 
Anti-drug antibody (ADA) variables ................................................................................................33 
2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................35 
2.1.7.1 
Whole blood biomarkers ................................................................................................................35 
2.1.7.2 
Serum biomarkers..........................................................................................................................35 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................35 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................36 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................37 
2.3.1 
OCS dependent and Non-OCS dependent populations ................................................................37 
2.3.2 
Safety population............................................................................................................................37 
2.3.3 
Efficacy populations .......................................................................................................................38 
2.3.4 
Pharmacokinetics (PK) population.................................................................................................38 
2.3.5 
Anti-drug antibody (ADA) population..............................................................................................38 
2.4 
STATISTICAL METHODS .............................................................................................................38 
2.4.1 
Demographics and baseline characteristics ..................................................................................38 
2.4.2 
Prior or concomitant medications...................................................................................................39 
2.4.2.1 
ICS in combination with allowable controller medication(s) ...........................................................39 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................40 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................40 
2.4.3.2 
Compliance ....................................................................................................................................41 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................42 
2.4.4.1 
Subgroup analyses.........................................................................................................................43 
2.4.4.2 
Multiplicity issues............................................................................................................................43 
2.4.5 
Analyses of safety data ..................................................................................................................43 
2.4.5.1 
Analyses of adverse events ...........................................................................................................44 
2.4.5.2 
Deaths............................................................................................................................................48 
2.4.5.3 
Analyses of laboratory variables ....................................................................................................48 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................49 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................50 
2.4.5.6 
Subgroup analyses.........................................................................................................................51 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................51 
2.4.6.1 
Pharmacokinetic analysis...............................................................................................................51 
2.4.6.2 
Pharmacodynamics........................................................................................................................51 
2.4.7 
Analyses of ADA variables.............................................................................................................52 
2.4.7.1 
Status in the ADA assay at baseline of the parent study ...............................................................52 
2.4.7.2 
Status in the ADA assay in the current study.................................................................................52 
2.4.7.3 
Impact of ADA on clinical safety.....................................................................................................53 
2.4.7.4 
Impact of ADA on clinical efficacy..................................................................................................53 
2.4.7.5 
Impact of ADA on PK .....................................................................................................................54 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................54 
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2.5.1 
General conventions ......................................................................................................................54 
2.5.2 
Data handling conventions for secondary efficacy variables..........................................................55 
2.5.3 
Missing data ...................................................................................................................................56 
2.5.4 
Windows for time points.................................................................................................................58 
2.5.5 
Unscheduled visits .........................................................................................................................64 
2.5.6 
Pooling of centers for statistical analyses ......................................................................................65 
2.5.7 
Statistical technical issues .............................................................................................................65 
3 
INTERIM ANALYSIS .....................................................................................................................66 
4 
DATABASE LOCK ........................................................................................................................67 
5 
SOFTWARE DOCUMENTATION..................................................................................................68 
6 
REFERENCES...............................................................................................................................69 
7 
LIST OF APPENDICES .................................................................................................................70 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITY CRITERIA FOR 
INCLUDED LABORATORY PARAMETERS: COMBINED ADULT (≥ 18) AND 
ADOLESCENT (≥ 12 TO < 18) CRITERIA ABSTRACTED FROM BTD-009536 V3.0 WITH 
APPROVED MODIFICATIONS......................................................................................................71 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES.........................................................................78 
APPENDIX C 
LOW, MEDIUM AND HIGH DOSE INHALED CORTICOSTEROIDS- ADULTS AND 
ADOLESCENTS (≥12 YEARS)......................................................................................................80 
APPENDIX D 
DEFINITION OF ANAPHYLAXIS ........................................................................................82 
APPENDIX E 
LIST OF OPPORTUNISTIC INFECTIONS..........................................................................83 
APPENDIX F 
ASTHMA CONTROL QUESTIONNAIRE, 5-QUESTION VERSION ...................................84 
APPENDIX G 
ASTHMA QUALITY OF LIFE QUESTIONNAIRE................................................................86 
APPENDIX H 
EUROQOL QUESTIONNAIRE (EQ-5D-3L).........................................................................92 
APPENDIX I 
SAS CODE FOR EQ-5D INDEX UTILITY SCORING...........................................................94 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACQ-5 
Asthma Control Questionnaire 5-item scale 
ADA 
Anti-drug Antibodies  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest  
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ATS 
American Thoracic Society  
COPD 
Chronic Obstructive Pulmonary Disease 
CRFs 
Case Report Forms (CRFs) 
CV 
Curriculum Vitae 
CV% 
CYP 
Coefficient of Variation 
Cytochrome P 
DMC 
Data Monitoring Committee  
DNA 
Deoxyribonucleic acid 
DRF 
Discrepancy Resolution Form 
ECG 
EOS 
EOT 
Electrocardiogram/Electrocardiography  
End-of-Study 
End-of-treatment 
e-CRF  
Electronic Case Report Form 
ELISA 
Enzyme-Linked Immunosorbent Assay  
EQ 
EuroQual  
FEV1 
Forced Expiratory Volume in one second 
GCP 
Good Clinical Practice 
HBcAb-IgM 
Hepatitis B IgM Core Antibody  
HBsAg 
Hepatitis B Surface Antigen 
HCAb 
Hepatitis C Core Antibody 
HLGT 
High-Level Group Term  
HLT 
High Level Term 
HIV 
Human Immunodeficiency Virus  
ICH 
International Conference on Harmonization 
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ICS 
Inhaled Corticosteroid  
LABA 
Long-Acting Beta Agonist 
LAMA 
Long-Acting Muscarinic Antagonist 
LTRA 
Leukotriene Receptor Antagonist 
IgE 
Immunoglobulin E 
IL-4 
Interleukin 4 
IL-4Rα 
Interleukin 4 Receptor Alpha Subunit 
IL-13 
Interleukin 13 
IMP 
Investigational Medicinal Product 
IRB/IEC 
Institutional Review Board / Institutional Ethics Committee  
IVRS/IWRS 
Interactive Voice Response System/Interactive Web Response System  
LFT 
Liver Function Test 
MDI 
Metered Dose Inhaler 
MMR 
Measles, Mumps, Rubella 
MMRV 
Measles, Mumps, Rubella, Varicella 
Non-IMP 
Non-investigational Medicinal Product 
PCSA 
PEF 
Potentially Clinically Significant Abnormalities   
Peak expiratory flow 
PK 
Pharmacokinetics  
q2w 
Once every 2 weeks 
PT 
Preferred Term  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SEM 
Standard Error of the Mean  
SC 
Subcutaneously 
SD 
Standard Deviation 
SOC 
System Organ Class  
TEAE 
Treatment-Emergent Adverse Event 
Th2 
T-helper 2 
ULN 
Upper Limit of Normal  
VAS 
Visual Analogue Scale  
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
LTS12551 is a multinational, multicenter, 1-year (48 weeks) or 2-year (96 weeks) single arm 
extension study to evaluate the long-term safety and tolerability of dupilumab in patients with 
asthma, who completed the treatment and follow-up period in the DRI12544 study, or who 
completed the treatment period in the EFC13579, EFC13691 or PDY14192 studies.  
In the LTS12551 study, dupilumab 300 mg is administered subcutaneously (SC) every 2 weeks 
(q2w), as an add-on therapy to a variety of allowable combinations between inhaled corticosteroid 
(ICS) and other controller medications as maintained during the parent study, including the oral 
corticosteroids (OCS) medication for the patients from the EFC13691 study. The LTS12551 
consists of three periods: 
• 
Screening Period (0-3 weeks, if applicable) 
• 
Treatment Period (48 weeks open-label period for the patients enrolled after the protocol 
amendment 4, or 96 weeks open-label period for the patients enrolled before the protocol 
amendment 4) 
• 
Post-treatment Period (12 weeks, dupilumab-free follow-up period) 
The 4 parent studies are described briefly as follows: 
DRI12544: A phase 2b, randomized, double-blind, placebo-controlled, dose ranging, parallel 
group study comparing different doses and regimens of dupilumab SC for 24 weeks in patients 
with moderate to severe, uncontrolled asthma. Patients were randomized in ratio of 1:1:1:1:1 into 
5 arms, dupilumab 200 mg every 4 weeks (q4w), dupilumab 300 mg q4w, dupilumab 200 mg 
q2w, dupilumab 300 mg q2w, and placebo. Patients were allowed to administer moderate- or 
high-dose inhaled corticosteroid (ICS) in combination with long-acting beta agonist (LABA) as 
follows: mometasone furoate / formoterol, budesonide / formoterol, and fluticasone propionate / 
salmeterol in the treatment period, and continued with the stable dosage of controller medications 
in the 16-week post-treatment follow-up period. There were 776 patients enrolled in DRI12544. 
EFC13579: A phase 3, randomized, double blind, placebo-controlled, parallel group study to 
evaluate the efficacy and safety of dupilumab SC for 52 weeks in patients with persistent asthma. 
Patients were randomized in ratio of 2:2:1:1 into the following regimens, dupilumab 200 mg q2w, 
dupilumab 300 mg q2w, placebo matching 200mg q2w and placebo matching 300 mg q2w. In the 
treatment period, patients are allowed to administer a stable background therapy of medium to 
high dose of inhaled corticosteroid (ICS) in combination with a second controller medication (for 
example, long-acting beta agonist [LABA], leukotriene receptor antagonist [LTRA], theophylline, 
and etc.), and potentially plus a third controller medication. There were in total 1902 patients 
randomized for EFC13579. 
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EFC13691: A phase 3, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of dupilumab 300 mg q2w SC for 24 weeks in patients with severe oral 
corticosteroid dependent asthma. Patients are randomized in a ratio of 1:1 to dupilumab 300 mg 
q2w and matching placebo, which will be given on top of standard of care and of oral 
corticosteroids. During the course of the study, the oral corticosteroid (OCS) 
[prednisone/prednisolone] doses will be adjusted to the dose required for the maintenance of 
asthma control. In the screening period, patients experience an OCS dose optimization process. In 
the treatment period, patients continue with the optimized OCS doses in the first 4 weeks, then 
have the OCS dose down-titrated till Week 20, and at last maintain on the Week 20 OCS dose for 
the rest 4 weeks. In the meantime, patients are also allowed to be on a stable dose of high dose 
ICS with a second controller medication (LABA, LTRA, theophylline, etc), and potentially plus a 
third controller medication per requested by patients. There were in total 210 patients randomized 
for EFC13691. 
PDY14192: A phase 2a, exploratory, randomized, double-blind, placebo-controlled study of the 
effects of dupilumab 300 mg q2w SC for 12 weeks on airway inflammation of adults with 
persistent asthma. Patients are randomized in a ratio of 1:1 to dupilumab 300 mg q2w and placebo 
q2w. Patients undergo two bronchoscopy procedures respectively before treatment and at the end 
of treatment period, each of which is followed with an oral prednisone 40 mg daily treatment for 3 
(up to 5) days. Patients are allowed to administer a background therapy of medium to high dose 
ICS in combination with a second controller medication (LABA), and potentially plus a third 
controller medication (eg, LAMA, LTRA). There are in total 42 patients planned for PDY14192. 
 
Parent study 
Sample size 
Treatment arms 
Treatment duration 
DRI12544 
776 
Dupilumab 300 mg q2w,  
Dupilumab 200 mg q2w,  
Dupilumab 300 mg q4w,  
Dupilumab 200 mg q4w,  
Placebo q2w (2 mL in matched 5 mL vials) 
24 weeks 
EFC13579 
1902 
Dupilumab 300 mg q2w,  
Placebo q2w matching 300 mg q2w (2 mL in 
matched pre-filled syringe),  
Dupilumab 200 mg q2w, 
Placebo q2w matching 200 mg q2w (1.14 mL 
in matched pre-filled syringe) 
52 weeks 
EFC13691 
210 
Dupilumab 300 mg q2w, Placebo q2w (2 mL 
in matched pre-filled syringe) 
24 weeks 
PDY14192 
42 
Dupilumab 300 mg q2w, Placebo q2w (2 mL 
in matched pre-filled syringe) 
12 weeks 
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Patients from DRI12544 who completed the 24-week treatment period and 16-week follow-up 
period might be eligible for enrolling into LTS12551 at the end of study (EOS) visit of DRI12544 
or thereafter. The screening period (Visit 1 and Visit 2) of LTS12551, and a 600 mg loading dose 
on Day 1 were only applicable for patients coming from DRI12544, as those patients experienced 
a gap in dosing for at least 16 weeks. According to the original protocol of LTS12551, patients 
coming from DRI12544 (non-US) could combine the EOS visit of DRI12544 with Visit 1/Visit 2 
of LTS12551; according to the amended protocol 1, Visit 1 and Visit 2 of LTS12551 should be 
independent from the EOS visit of DRI12544. Thus, after the protocol amendment 1 became 
effective in LTS12551, patients from DRI12544 should be screened starting at Visit 1 (for 7 to 21 
days) in LTS12551 before dosing started at Visit 2. 
Patients from EFC13579, EFC13691 or PDY14192 who complete the entire planned treatment 
period may be eligible for enrolling into LTS12551 immediately at the end of treatment (EOT) 
visit of the parent study. In other words, for patients coming from these 3 studies, the end of 
treatment visit of parent study should be combined with Visit 1 and Visit 2 of LTS12551, so there 
is no gap in dosing, and screening and loading dose at Day 1 are not applicable. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to evaluate the long-term safety and tolerability of 
dupilumab in patients with asthma who participated in a previous dupilumab asthma clinical study 
(DRI12544, EFC13579, EFC13691 or PDY14192). 
1.2.2 Secondary objectives 
To evaluate the long-term efficacy of dupilumab in patients with asthma who participated in a 
previous dupilumab asthma clinical study (DRI12544, EFC13579, EFC13691 or PDY14192). 
To evaluate dupilumab in patients with asthma who participated in a previous dupilumab asthma 
clinical study (DRI12544, EFC13579, EFC13691 or PDY14192), with regards to: 
• 
Systemic exposure 
• 
Anti-drug antibodies 
• 
Biomarkers 
1.3 
DETERMINATION OF SAMPLE SIZE 
The study size is predicated on the overall size of the parent studies; hence, the maximum number 
of patients to participate will be the number corresponding to the sum of the total enrolled in 
DRI12544, PDY14192, EFC13579, and EFC13691 studies. Based on the actual patient number of 
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Page 10 
DRI12544 study and the planned patient numbers of EFC13579, EFC13691 and PDY14192 
studies, the maximum number of patients of LTS12551 can be estimated as 2930. 
1.4 
STUDY PLAN 
LTS12551 study consists of three periods, using an add-on therapy approach to inhaled 
corticosteroid (ICS) in combination with other acceptable controller medications maintained 
during the parent study, including the oral corticosteroids for the patients from the EFC13691 
study.  
Screening Period (0-3 weeks) 
Patients are to be stabilized on their background dose of moderate or high-dose ICS for ≥1 month 
prior to Visit 1 and continue the stable dose during the screening period.  
• 
The screening period is applicable for the patients from the DRI12544 study only.  
• 
Eligible patients in PDY14192, EFC13579 or EFC13691 studies are to rollover into 
LTS12551 on the same day as the end of treatment visit in the parent study. Visit 1 and 
Visit 2 of LTS12551 study are combined with the end of treatment visit in the parent study 
for the patients enrolled from PDY14192, EFC13579 or EFC13691 studies, who start 
directly with the treatment period in the LTS12551 study. 
Open-label Treatment Period (48 or 96 weeks) 
During the open-label treatment period, patients continue their background controller therapy as 
maintained during the parent study or as modified based on investigator’s judgment, including the 
oral corticosteroids for the patients from the EFC13691 study.  
Post-treatment Period (12 weeks) 
Upon completion of the open-label treatment period (or following early discontinuation of IMP) 
patients continue into the post-treatment period. During this period, patients continue with the 
background controller therapies as maintained during the open-label treatment period or as 
modified based on investigator’s judgment. 
Reliever Medications 
Over the course of LTS12551 study, patients may receive salbutamol / albuterol 
hydrofluoroalkane pressurized MDI or levosalbutamol / levalbuterol hydrofluoroalkane 
pressurized MDI as reliever medication as needed. Nebulizer solutions with either albuterol / 
salbutamol or levalabuterol / levosalbutamol may be used as an alternative delivery method. 
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1.4.1 Graphical Study Design 
 
 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 
4 
31-Oct-
2016 
Based on the data defining 
the safety profile of 
dupilumab to date (as 
determined in multiple 
clinical trials performed 
across the AD, Asthma and 
NP indications), data from 
a 1 year asthma OLE study 
is anticipated to be 
sufficient to support the 
asthma program. 
The open-label treatment duration 
is amended to 48 weeks (1 year), 
for patients providing consents 
after the implementation of the 
protocol amendment 4. 
4 
31-Oct-
2016 
The DRI12544 study 
showed that the median 
dupilumab concentration at 
12 weeks post-last-dose (at 
PK steady-state) was below 
the limit of quantitation (78 
ng/mL) for the group of 
patients on 300 mg every 2 
weeks (q2w). Given this, 
the duration of study 
participation can be 
minimized by reducing the 
post-treatment period by 
1 month. The follow-up 
duration for all the ongoing 
dupilumab asthma studies 
has been harmonized as 12 
weeks. 
The post-treatment period is 
shortened to 12 weeks for all 
patients in the LTS12551 study. 
4 
31-Oct-
2016 
The patient population 
from study EFC13691 is a 
different population from 
the patient population from 
the other parent studies. 
The patients from 
Three efficacy endpoints linked to 
the prescribed oral corticosteroids 
(OCS) dose and corresponding 
analyses have been added only for 
the patients from the EFC13691. 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 
EFC13691 are more severe 
at the baseline of the parent 
study and are using a 
different background 
controller medication. The 
endpoints linked to the 
reduction of the OCS dose 
are only used in 
EFC13691, in addition to 
the other efficacy 
endpoints shared in 
common with the patients 
from the other parent 
studies. 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
This statistical analysis plan (SAP) version 3.0 is based on the LTS12551 amended protocol 2 
(protocol amendment 4) dated October 31st, 2016, and is the third version of SAP for LTS12551. 
Table 2 - Statistical analysis plan statistical changes 
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
23-Nov-2016 Protocol amendment 4 
shortens the open-label 
treatment period to 48 
weeks. 
The open-label treatment duration 
is amended to 48 weeks for patients 
providing consents after the 
implementation of the protocol 
amendment 4.  
2 
23-Nov-2016 Protocol amendment 4 drops 
the electronic diary, PEF 
meter, EQ-5D-3L, serum 
immunoglobulins, and 
serum total IgE for all the 
patients in LTS12551 study. 
Before the protocol 
amendment 4 becomes 
effective, the patients from 
The analyses for AM/PM PEF, 
AM/PM asthma symptom score, 
number of reliever uses, number of 
nocturnal awakenings, EQ-5D-3L 
score, serum immunoglobulins and 
serum total IgE in LTS12551 study 
will be restricted to the patients 
from the DRI12544 study and 
performed to the data observed up 
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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
DRI12544 study have data 
collection for the 
aforementioned endpoints 
for more than one year, 
while only a few of patients 
from EFC13579, EFC13691 
or PDY14192 studies have 
limited amount of data 
collected for those 
endpoints. 
to the end of their collection. The 
compliance for background 
controller medications will be 
calculated using the data observed 
up to the end of the electronic diary 
collection. 
2 
23-Nov-2016 Protocol amendment 4 adds 
three efficacy endpoints 
linked to the prescribed OCS 
dose for the patients from 
the EFC13691 study only. 
They are the percentage 
change from baseline in the 
OCS dose, the proportion of 
patients achieving a 
reduction of 50% or greater 
in the OCS dose compared 
with the baseline, and the 
proportion of patients whose 
background OCS are 
completely tapered off. The 
baseline OCS dose is 
defined as the original 
baseline value of the parent 
study. 
The proportion of patients whose 
background OCS are completely 
tapered off and its analysis have 
been added to this version of SAP, 
and the other two endpoints linked 
to the OCS dose and their 
corresponding analyses have 
already existed in the SAP 1.0. 
2 
23-Nov-2016 Protocol amendment 4 
reduces the frequency of 
assessments for the ACQ-5, 
AQLQ, clinical laboratories, 
ECG and ADA variables for 
all patients in the LTS12551 
study. 
The scheduled visits and 
corresponding analysis windows for 
the endpoints of ACQ-5, AQLQ, 
clinical laboratories, ECG and 
ADA are adjusted accordingly per 
the reduced scheduled visits in the 
protocol amendment 4. 
2 
23-Nov-2016 The patient population from 
study EFC13691 is expected 
to be different from the 
All the planned analyses in 
LTS12551 study will be performed 
and presented separately for the 
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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
patient population from the 
DRI12544, EFC13579 or 
PDY14192 studies. The 
patients from EFC13691 are 
more severe at the baseline 
of the parent study and are 
using a different background 
controller medication, and 
thus potentially have 
different safety profiles in 
general from the patient 
population from the other 
parent studies.  
patients from EFC13691 study and 
the patients from DRI12544, 
EFC13579 or PDY14192 studies, 
except for the endpoints that are 
particularly collected for the 
patients from EFC13691 study 
only. 
 
3 
This version 
The layouts of all outputs are 
changed to avoid potential 
confounding introduced by 
between-study variation. 
The treatment category (Naïve, Re-
treated, Interrupted treatment, and 
Continuously treated) is removed. 
The layouts of all outputs are 
changed to: 
For the patients from EFC13691 
study, results of each planned 
analysis will be presented by 
“Placebo/Dupilumab, 
Dupilumab/Dupilumab, and All” 
(see Section 2.3.2). 
For the patients from 
DRI12544/EFC13579/PDY14192 
studies, results of each planned 
analysis will be presented by the 
parent study and “All”, and by 
“Placebo/Dupilumab and 
Dupilumab/Dupilumab” within 
each parent study (see Section 
2.3.2). 
3 
This version 
To be consistent with ISS 
SAP 
The definition of AESI and other 
selected AE groupings are updated 
in Section 2.1.4.1 
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SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
3 
This version 
To be consistent with ISS 
SAP by including the 
combined PCSA criteria for 
adult and adolescents 
PCSA criteria in Appendix A are 
updated 
3 
This version 
To be consistent with the 
amended protocol #2 of 
LTS12551 study 
The lab test parameters lactate 
dehydrogenase, low-density 
lipoprotein, high-density 
lipoprotein, and triglycerides are 
removed according to the amended 
protocol #2 of LTS12551 study   
3 
This version 
To be consistent with 
EFC13579 / EFC13691 
studies 
The definition of persistent ADA 
response is updated in Section 2.1.6 
3 
This version 
To be consistent with 
EFC13579 / EFC13691 
studies 
The definitions of Comorbidity 
history and Atopic Medical History 
are updated in Section 2.1.1 
3 
This version 
Add additional subgroup 
analyses 
The subgroup defined by the 
eosinophil count at baseline of 
parent study is added to the 
subgroup analysis for key efficacy 
endpoints in Section 2.4.4.1. 
The subgroup defined by the 
Ethnicity at baseline of parent study 
is added to the subgroup analysis 
for key safety endpoints in Section 
2.4.5.6. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
In general, the baseline values of endpoints in LTS12551 are correspondingly defined as the 
original baselines of the parent studies, unless otherwise specified. In addition to the baselines, the 
pre-dose measurements at Week 0 of LTS12551 are defined as follows. For patients enrolled from 
DRI12544, the measurements at Week 0 are obtained from the EOS visit of DRI12544 if 
available, regardless of whether the EOS visit in DRI12544 was combined with Visit 1/Visit 2 in 
LTS12551; otherwise, Week 0 value will be the last available measurement prior to the first IMP 
dose in LTS12551 study. For patients enrolled from EFC13579, EFC13691 or PDY14192, the 
measurements at Week 0 are obtained from the EOT visit of the parent studies if available; 
otherwise, Week 0 value will be the last available measurement prior to the first IMP dose in 
LTS12551 study. 
2.1.1 Demographic and baseline characteristics 
Demographic characteristics 
The following demographic characteristics will be summarized: 
Age (years) 
Age group (age <18, 18≤ age <65, 65≤ age <75, 75≤ age < 85, age ≥85 years) 
Gender (Male, Female) 
Region (Asia, Latin America, East Europe, Western Countries) following the classification 
in the parent study 
Territory (North America: Canada and USA; European Union: France, Germany, Hungary, 
Italy, Poland, Spain and United Kingdom; Rest of World: Argentina, Australia, Brazil, 
Colombia, Chile, Japan, Mexico, Russia, South Africa, South Korea, Taiwan, Turkey and 
Ukraine) 
Race (Caucasian/White, Black, Asian/Oriental, American Indian or Alaska native, Native 
Hawaiian or other Pacific Islander, Other) 
Ethnicity (Hispanic, Not Hispanic) 
Height (cm) 
Weight (kg) 
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Weight group (weight <50, 50≤ weight <100, weight ≥100 kg) 
BMI (kg/m2) 
BMI group (BMI<25, 25≤ BMI <30, BMI≥30 kg/m2) 
Alcohol drinking frequency (Never, At least monthly, At least weekly and At least daily) 
and number of standard alcohol drinks on a typical day when drinking (1 or 2, >2) 
The data for demographic characteristics will be obtained from the original baselines of the parent 
studies. 
Medical or surgical history 
Medical or surgical history includes all the relevant medical (or surgical) history during the 
lifetime of the patient. This information will be coded to a “Lower Level Term (LLT)”, “Preferred 
Term (PT)”, “High Level Term (HLT)”, “High Level Group Term (HLGT)”, and associated 
primary “System Organ Class (SOC)” using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Sanofi at the time of database locks. 
Comorbidity history will be summarized separately. The following comorbid diseases will be 
summarized. 
Atopic dermatitis history (Yes, Ongoing condition) 
Allergic conjunctivitis history (Yes, Ongoing condition) 
Allergic rhinitis history (Yes, Ongoing condition) 
Allergic conjunctivitis history and/or allergic rhinitis history (Yes, Ongoing condition) 
Chronic rhinosinusitis history (Yes, Ongoing condition) 
Nasal polyposis history (Yes, Ongoing condition) 
Eosinophillic esophagitis history (Yes, Ongoing condition) 
Food allergy history (Yes, Ongoing condition) 
Hives history (Yes, Ongoing condition) 
A patient will be considered to have an atopic medical condition if the patient has any of the 
following: atopic dermatitis, allergic conjunctivitis or allergic rhinitis, eosinophilic esophagitis, 
food allergy, hives; or has baseline (parent study) total IgE ≥100 IU/mL and at least one 
aeroantigen specific IgE is positive (≥0.35 IU/mL) at baseline of parent study. 
The data of medical or surgical history will be obtained from the original baselines of the parent 
studies. 
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Disease characteristics at baseline   
The following baseline disease characteristics will be summarized: 
• 
Prior ICS (medium, high as defined in Appendix C) in combination with allowable 
controller therapy  
• 
Age of asthma onset 
• 
Time since first diagnosis of asthma (years) 
(Year of randomization in parent study – Year of first diagnosis of asthma) + (month of 
randomization in parent study – month of first diagnosis of asthma)/12 
• 
Smoking history (Never, Former)  
- 
For former smokers, 
- 
Time since cessation of smoking for former smokers (months) to be derived as  
(Year of randomization in parent study – Year of cessation)×12 + (month of 
randomization in parent study – month of cessation) 
- 
Smoking quantity (Pack-year) 
• 
Time since last asthma exacerbation (months)  
(Year of randomization in parent study – Year of last asthma exacerbation)×12 + (month 
of randomization in parent study – month of last asthma exacerbation) 
• Number of asthma exacerbations experienced 1 year before Visit 1 of the parent study 
• Number of asthma exacerbations required hospitalization or urgent medical care 1 year 
before Visit 1 of the parent study  
• FEV1 (L) 
• ACQ-5 score 
The data of baseline disease characteristics will be obtained from the original baselines of the 
parent studies, unless otherwise specified. Any technical detail related to computation, dates, and 
imputation for missing dates is described in Section 2.5.   
2.1.2 Prior or concomitant medications  
• 
Prior medications are any treatments taken by patient prior to the first IMP administration 
in the parent study. Prior medications can be discontinued before the first IMP 
administration in parent study or can be maintained during treatment phase in parent study.  
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• 
Concomitant medications in parent study are any treatments received by patient 
concomitantly to the IMP in the parent studies, from (on/after) the first administration of 
IMP to the end of post-treatment follow-up period. 
• 
Concomitant medications are any treatments received by patient concomitantly to the IMP 
in the LTS12551 study, from (on/after) the first administration of IMP to the end of post-
treatment follow-up period. A given medication can be classified both as a prior 
medication and as a concomitant medication. 
All medications taken at any time either prior to the first IMP administration or on/after the first 
IMP dose till the end of follow-up period in the parent study are reported in the case report form 
and obtained from the parent studies. All medications obtained from the parent studies will be 
coded using the World Health Organization-Drug Dictionary (WHO-DD) using the version 
currently in effect at Sanofi at the time of database locks. 
All medications taken at any time during the LTS12551 study, from the time of first IMP 
administration to the end of follow-up period, including inhaled corticosteroid (ICS) in 
combination with other allowable controller therapies (LABA, LTRA, LAMA, theophylline, etc.), 
albuterol or levalbuterol reliever medications, and the background oral corticosteroids medication 
(for patients from the EFC13691 study only) are to be reported in the case report form.  
All medications collected during the LTS12551 will be coded using the World Health 
Organization-Drug Dictionary (WHO-DD) using the version currently in effect at Sanofi at the 
time of database locks. 
2.1.2.1 Salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication 
Patients may administer salbutamol/albuterol hydrofluoroalkane pressurized MDI or 
levosalbutamol/levalbuterol hydrofluoroalkane pressurized MDI as reliever medication as needed 
during the study. Nebulizer solutions with either albuterol / salbutamol or levalabuterol / 
levosalbutamol may be used as an alternative delivery method.  
Study personnel are to convert salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol 
nebulizer use as shown by the following table: 
Salbutamol/Albuterol Nebulizer Solution -Total Daily Dose (mg)  
Number of Puffs* 
2.5 
4 
5.0 
8 
7.5 
12 
10 
16 
*Conversion factor: salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs 
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- 
Example of salbutamol/albuterol nebulizer-to-puff conversion: patient received 3 
salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM.   
Total = 7.5 mg → 12 puffs. 
Levosalbutamol/Levalbuterol Nebulizer Solution -Total Daily Dose 
(mg) 
Number of Puffs* 
1.25 
4 
2.5 
8 
3.75 
12 
5 
16 
*Conversion factor: salbutamol/albuterol nebulizer solution (2.5 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 = 3.75 mg → 12 puffs. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Efficacy endpoints are secondary endpoints of this study. The following efficacy endpoints will be 
analyzed: 
• 
Number and Annualized rate of severe exacerbation events during the treatment period 
• 
Forced expiratory volume in one second (FEV1) 
• 
Other spirometry endpoints: Percent Predicted FEV1, Forced Vital Capacity (FVC), 
Forced Expiratory Flow (FEF) 25-75% 
• 
Asthma control questionnaire 5-question version (ACQ-5) score and responder status 
• 
Asthma quality of life questionnaire (AQLQ) score and responder status 
• 
EuroQoL questionnaire (EQ-5D-3L) score 
• 
Morning and evening peak expiratory flow (PEF) 
• 
Morning evening asthma symptom scores 
• 
Number of inhalations / day of salbutamol / albuterol or levosalbutamol / levalbuterol for 
symptom relief 
• 
Number of Nocturnal awakenings due to asthma symptoms 
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• 
Endpoints linked to the prescribed oral corticosteroids (OCS) dose for the patients from 
the EFC13691 study: 
- 
Percentage change from baseline in OCS dose, where the baseline OCS dose is the 
original baseline from EFC13691 
- 
Proportion of patients achieving a reduction of 50% or greater in OCS dose compared 
with the original baseline in the parent study 
- 
Proportion of patients whose background OCS are completely tapered off  
For the above efficacy endpoints, except for the number of severe exacerbations, ACQ-5/AQLQ 
responder, and the three endpoints particularly for the patients from EFC13691, the change from 
baseline over time will also be analyzed. The baseline values are the original baselines from the 
parent study. 
2.1.3.1 Severe Exacerbation Events 
A severe exacerbation event during the study is defined as any of the following: 
• 
Use of systemic corticosteroids for ≥ 3 days. 
- 
At least double the dose of systemic corticosteroids for patients enrolling from 
EFC13691 who are currently on systemic corticosteroids. 
• 
Or, hospitalization or emergency room visit because of asthma, requiring a systemic 
corticosteroid treatment. 
The severe exacerbation events are collected on eCRF page “Asthma exacerbations event”. Only 
events confirmed on eCRF page will be used in the analysis. 
Both number and annualized rate of severe exacerbation events will be analyzed. The annualized 
event rate is defined as the number of severe exacerbation events per patient-year. Number and 
annualized rate will also be analyzed for severe exacerbation with use of systemic corticosteroids 
for ≥3 days only, and that with hospitalization or with emergency room visit only. The mean 
duration of a severe exacerbation will also be summarized. 
For the treatment period, total number of events and standardized on-treatment duration will be 
calculated for each patient: 
• 
The total number of events is defined as the number of events that are onset between the 
date of first IMP dose in LTS12551 study and the date of last IMP dose in LTS12551 study 
+ 14 days;  
The standardized on-treatment duration (in years) is calculated by (the date of last IMP dose in 
LTS12551 study – the date of first IMP dose in LTS12551 study + 14 days)/365.25. 
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2.1.3.2 Forced expiratory volume in one second (FEV1) and other spirometry 
assessments 
The forced expiratory volume in one second (FEV1) is part of the spirometry assessment that will 
be performed at Visit 1, Visit 3 (Week 2), Visit 4 (Week 4), Visit 6 (Week 8), Visit 8 (Week 12), 
Visit 11 (Week 24), Visit 13 (Week 48; if applicable), Visit 15 (Week 72; if applicable), Visit 16 
(Week 84; if applicable), Visit 17 (End-of-Treatment) and Visit 18 (End-of-Study). The other 
parts of the spirometry assessment, including the percent predicted FEV1, Forced Vital Capacity 
(FVC) and Forced Expiratory Flow (FEF) 25-75%, will be performed at the same visits as above. 
A spirometer that meets the 2005 American Thoracic Society (ATS) / European Respiratory 
Society (ERS) recommendations will be used. The ATS/ ERS Standardization of Spirometry 
should be used as a guideline (1).  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 and 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. 
Pulmonary function tests will be measured in the sitting position and the highest measure will be 
recorded in liters for FEV1.  
2.1.3.3 Asthma control questionnaire, 5-question version (ACQ-5) 
The ACQ-5 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.  
The ACQ-5 has 5 questions, reflecting the top-scoring five asthma symptoms: woken at night by 
symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath 
and wheeze. Patients are asked to recall how their asthma has been during the previous week and 
to respond to the symptom questions on a 7-point scale (0=no impairment, 6= maximum 
impairment) (see Appendix F). 
A global score is calculated: the questions are equally weighted and the ACQ-5 score is the mean 
of the 5 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). 
Higher score indicates lower asthma control. On the 7-point scale of the ACQ-5, a change or 
difference in score of 0.5 is the smallest that can be considered clinically important, corresponding 
to the Minimal Clinically Important Difference (MCID) defined by the developer.  
In addition, the minimal clinically important difference at patient level (pMCID) is the smallest 
treatment efficacy that would lead to a change in a patient’s management; and, the minimal 
clinically important difference at group mean level (gMCID) is the smallest treatment efficacy that 
would lead to a change in a group’s management. The threshold of gMCID is usually published or 
calculated based on the Cohen’s rule (2). Based on the gMCID and the condition that absolute 
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value of pMCID is greater than or equal to the absolute value of gMCID, the value of pMCID is 
derived out. The pMCID for ACQ-5 is derived as -0.5. 
• 
Definition of ACQ-5 responder (based on pMCID): a patient is considered to be a 
“responder” if his/her change in ACQ-5 score from the baseline in parent study is equal to 
or greater than the minimal clinically important difference at patient level (pMCID): 
Responder = Yes, if change from baseline in ACQ-5 score ≤ pMCID; 
Responder = No, if change from baseline in ACQ-5 score > pMCID. 
Measurement properties such as reliability, ability to detect change have been documented in the 
literature (3). 
Based on the manual of ACQ (4), any more than one missing value is not acceptable. If more than 
one of the questions have missing value, the global score is invalid and will be considered as 
missing. If only one question has missing value, it will be interpolated (pro-rated) using the 
completed questionnaires from the previous visit. For instance, answer to question 5 is missing at 
Visit 2, and all questions are completed at Visit 1. Then the question 5 score at Visit 2 is 
interpolated as: (total score at Visit 2/sum of scores of question 1 to question 4 at Visit 1) × score 
of question 5 at Visit 1.  If the questionnaire from the previous visit is not complete either, the 
missing value will be imputed as the average of the completed questions within the current visit. 
2.1.3.4 Asthma quality of life questionnaire (AQLQ) 
The AQLQ was designed to measure the functional impairments that are most troublesome to 
adults (17 to 70 years) as a result of their asthma (see Appendix G). The instrument is comprised 
of 32 items, each rated on a 7-point scale from 1 (severely impaired) to 7 (not impaired). The 
AQLQ has 4 domains. The domains and the number of items in each domain are as follows: 
• Symptoms (12 items) 
• Activity limitation (11 items) 
• Emotional function (5 items) 
• Environmental Stimuli (4 items) 
The instrument has been used in many clinical trials, and it has been shown to be reliable, valid 
(patient interviews), and sensitive to change.  
Individual items are equally weighted. The overall score is the mean of response to each of the 32 
questions. The score of each domain is the mean of response to each question in that domain. 
Higher scores indicate better quality of life. An MCID is available: the pMCID is approximated to 
be 0.5 (5). 
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• 
Definition of AQLQ responder (based on pMCID): a patient is considered to be a 
“responder” if his/her change in AQLQ overall score from the baseline in parent study is 
equal to or greater than the minimal clinically important difference at patient level 
(pMCID): 
Responder = Yes, if change from baseline in AQLQ overall score ≥ pMCID; 
Responder = No, if change from baseline in AQLQ overall score < pMCID. 
To have a valid overall score, it is not acceptable to have more than three missing responses or 
more than one missing response per domain.  For the symptoms and activity limitation domain 
score, only one missing value per domain is acceptable. For the emotional function and 
environmental stimuli domain scores, no missing value is acceptable. For responses with 
intolerable amount of missing value(s), the overall or the domain score will be considered as 
missing. For the other case, the missing score will be interpolated using the previous completions 
of the questionnaire following the similar algorithm used for ACQ-5.  
The analysis for AQLQ in LTS12551 study will exclude the patients enrolled from the PDY14192 
study, as the AQLQ is not assessed in the PDY14192 study. 
2.1.3.5 EuroQoL questionnaire (EQ-5D-3L) 
EQ-5D-3L is a standardized health-related quality of life questionnaire developed by the EuroQol 
Group in order to provide a simple, generic measure of health for clinical and economic appraisal 
(6). EQ-5D-3L is designed for self-completion by patients. 
The EQ-5D essentially consists of 2 pages – the EQ-5D descriptive system and the EQ VAS (See 
Appendix H). The EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problem, some 
problems, and severe problems.  
The 5 dimensional 3-level systems are converted into a single index utility score. Values for the 
243 theoretically possible health states defined by the EuroQol classification are calculated using a 
regression model and weighted according to the social preferences of the UK population (7). The 
minimum value for the single index utility score is -0.594, which corresponds to a level 3 (severe 
problems) for mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 
maximum value for this index is 1.0, which corresponds to a full health (level 1 (no problem) for 
mobility, self-care, usual activities, pain/discomfort and anxiety/depression). 
The EQ Visual Analogue Scale (VAS) records the respondent’s self-rated health on a vertical 
visual analogue scale. The EQ VAS ‘thermometer’ has endpoints of 100 (Best imaginable health 
state) at the top and 0 (Worst imaginable health state) at the bottom. Appendix I provides the SAS 
code to derive the index utility score using UK based population. 
The collection of the EQ-5D-3L will be stopped after the approval of protocol amendment 4. The 
analyses for the EQ-5D-3L endpoints in LTS12551 study will be restricted to the patients from 
DRI12544 study and performed to the data observed up to the end of collection. 
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2.1.3.6 Daily efficacy assessments 
On a daily basis before the approval of protocol amendment 4, the patient uses an electronic diary 
/ PEF meter to: 
• Measure morning and evening PEF 
• Respond to the morning and evening asthma symptom scale questions 
• Indicate the number of inhalations / day of salbutamol / albuterol or levosalbutamol / 
levalbuterol for symptom relief 
• Record the number of nocturnal awakenings 
The use of the electronic diary/PEF meter will be stopped after the approval of protocol 
amendment 4. The analyses in LTS12551 study for the above four daily efficacy endpoints in this 
section will be restricted to the patients from DRI12544 study and performed to the data observed 
up to the end of collection. 
2.1.3.6.1 Peak expiratory flow  
At Visit 1, patients are issued an electronic PEF meter to record morning (AM) and evening (PM) 
PEF, daily salbutamol/albuterol or levosalbutamol/levalbuterol, morning and evening asthma 
symptom scores, and number of nighttime awakenings due to asthma symptoms that require 
reliever medications. Patients are instructed on the use of the device, and written instructions on 
the use of the electronic PEF meter are provided to the patients. In addition, the investigator 
instructs the patients on how to record the following variables in the electronic PEF meter: 
• AM PEF performed within 15 minutes after arising (between 5:30 AM and 10 AM) prior 
to taking any salbutamol/albuterol or levosalbutamol/levalbuterol 
• PM PEF performed in the evening (between 5:30 PM and 10 PM) prior to taking any 
salbutamol/albuterol or levosalbutamol/levalbuterol 
• Patients should try to withhold salbutamol/albuterol or levosalbutamol/levalbuterol for at 
least 6 hours prior to measuring their PEF 
• Three PEF efforts are performed by the patient; all 3 values will be recorded by the 
electronic PEF meter, and the highest value will be used for evaluation and it is called PEF 
maximum (MAX). If more than 3 PEF readings are captured, the highest value of 3 
readings closest to the Diary start date and time is the PEF MAX. If only 2 PEF readings 
are captured, the maximum of the 2 PEF readings captured is the PEF MAX. If only 1 PEF 
readings is captured, the PEF MAX is treated as missing. 
Baseline AM/PM PEF is calculated based on the original baseline values from the parent studies. 
Baseline AM PEF is the mean AM PEF MAX measurements from the 7 morning diaries 
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(minimum of 4) prior to randomization in parent study, including the morning diary completed on 
the randomization day prior to the first dose of IMP. Out of the 7 diaries, if less than 4 have 
missing PEF value, the baseline AM PEF is the mean of the completed AM PEF MAX within the 
7 diaries. If 4 or more diaries have missing AM PEF MAX value, the baseline AM PEF is the 
mean of the 4 AM PEF MAX prior to and closest to randomization during the whole screening 
period in parent study. 
Baseline PM PEF is the mean PM PEF maximum (MAX) measurement from the 7 evening diaries 
(minimum of 4) prior to randomization in parent study. Out of the 7 diaries, if less than 4 have 
missing PEF value, the baseline PM PEF is the mean of the completed PM PEF MAX within the 7 
diaries. If 4 or more diaries have missing PM PEF MAX value, the baseline PM PEF is the mean 
of 4 PM PEF MAX prior to and closest to randomization during the whole screening period in 
parent study. 
In addition to the original baselines from parent study, the pre-dose AM/PM PEF at Week 0 of 
LTS12551 study is to be presented separately, and is calculated in the same way as for the original 
baseline AM/PM PEF of parent studies.  
2.1.3.6.2 Asthma Symptom Score  
Patients record overall symptom scores twice a day prior to measuring PEF. The patient’s overall 
asthma symptoms experienced during the waking hours will be recorded in the evening (PM 
symptom score). Symptoms experienced during the night will be recorded upon arising (AM 
symptom score). Patients will be instructed to record the severity of symptoms as follows: 
AM symptom score: 
• 0 = No asthma symptoms, slept through the night, 
• 1 = Slept well, but some complaints in the morning. No nighttime awakenings, 
• 2 = Woke up once because of asthma (including early awakening), 
• 3 = Woke up several times because of asthma (including early awakening), 
• 4 = Bad night, awake most of the night because of asthma, 
PM symptom score: 
• 0 = Very well, no asthma symptoms, 
• 1 = One episode of wheezing, cough, or breathlessness, 
• 2 = More than one episode of wheezing, cough, or breathlessness without interference of 
normal activities, 
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• 3 = Wheezing, cough, or breathlessness most of the day, which interfered to some extent 
with normal activities, 
• 4 = Asthma very bad. Unable to carry out daily activities as usual 
The baseline AM/PM symptom score is from the original baselines of parent study, and will be 
computed following the same algorithm used for baseline AM/PM PEF. An MCID of 0.35 is 
being used (8). 
2.1.3.6.3 Reliever use 
The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations is recorded daily 
by the patients in an electronic diary/PEF meter. In the case that Nebulizer solutions are used as an 
alternative delivery method, the nebulizer dose is converted to number of puffs according to 
Section 2.1.2.1. Each patient should be reminded that salbutamol/albuterol or 
levosalbutamol/levalbuterol should be used only as needed for symptoms, not on a regular basis or 
prophylactically.  
A diary day is defined as the period beginning with an Evening diary, and ending with the 
following day’s Morning Diary. The baseline reliever med use is obtained from the original 
baselines of parent studies, and will be calculated as follows:  
The mean of reliever puffs taken in each of the 7 diary days (minimum 4 diary days) prior to 
randomization, including the diary day that ends with the morning diary completed on the 
randomization day.  
A diary day cannot be included in the calculation if it is not complete, meaning if an evening or 
morning diary is missing for that diary day. Out of the 7 diary days, if less than 4 are incomplete, 
the baseline reliever use is the mean of reliever puffs in each of the complete dairy days. If 4 or 
more diary days are incomplete, the baseline reliever use is the mean of reliever puffs taken in the 
closest 4 diary days with complete reliever use information prior to randomization. 
2.1.3.6.4 Nocturnal awakenings 
The number of nocturnal awakening because of asthma symptoms is recorded every morning by 
the patients in an electronic diary. The baseline number of nocturnal awakenings is obtained from 
the original baselines of parent studies, and is computed following the same algorithm used for 
AM PEF. 
2.1.3.7 Endpoints linked to the prescribed OCS dose 
For the patients from the EFC13691 study only, the following three efficacy endpoints are derived 
using the prescribed dose of the background oral corticosteroids (OCS) medications. The baseline 
OCS dose is the original baseline value from the EFC13691 study. 
• 
Percentage change from baseline in the OCS dose 
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• 
Proportion of patients achieving a reduction of 50% or greater in the OCS dose compared 
with the baseline 
• 
Proportion of patients whose background OCS are completely tapered off 
2.1.4 Safety endpoints 
The primary endpoint of this study is the number (n) and percentage (%) of patients experiencing 
any treatment-emergent adverse events (TEAE). Adverse Events (AEs), Serious Adverse Events 
(SAEs), Adverse Events of Special Interest (AESI), adverse events leading to treatment 
discontinuation are collected at each visit from the time of informed consent signature to the end 
of study. The safety analysis will be based on the reported adverse events and other safety 
information, such as clinical laboratory data, vital signs, and ECG. 
Observation period 
The observation period will be divided into 4 epochs: 
• 
The screening epoch is defined as the time period prior to the date/time of the first dose of 
IMP in LTS12551. 
• 
The treatment epoch is defined as the time period from the date/time of the first dose of 
IMP to the date/time of the last dose of IMP + 14 days. 
• 
The follow-up epoch is defined as the time period from the date/time of the last dose of 
IMP + 15 days to the end date of 12-week post-treatment follow-up period. 
• 
The post-study epoch is defined as the time period from the end date of 12-week post-
treatment follow-up period + 1 day. 
The treatment - emergent adverse event period will include both the treatment epoch and 
follow-up epoch. If applicable, the post-treatment-emergent adverse event period will be the 
post-study epoch. 
The pre-treatment adverse event period will be from starting time of AE reporting up to the first 
dose of IMP in the LTS12551 study. For all the periods aforementioned, both date and time shall 
be used in the determination of the periods, as long as they will be available.  
2.1.4.1 Adverse events variables 
Adverse event observation period  
• 
Pre-treatment adverse events are adverse events that develop or worsen or become serious 
during the pre-treatment adverse event period.  
• 
Treatment-emergent adverse events are adverse events that develop or worsen or become 
serious during the treatment-emergent adverse event period. 
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• 
Post-treatment-emergent adverse events are adverse events that develop or worsen or 
become serious during the post-treatment-emergent adverse event period. 
All adverse events (including serious adverse events and adverse events of special interest) will be 
coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), high-level group 
term (HLGT), and associated primary system organ class (SOC) using the version of Medical 
Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time of 
database lock. 
The occurrence of all adverse events (regardless of seriousness or relationship to IMP/NIMP) is 
recorded from the time of signed informed consent for patients from DRI12544 and from the time 
of the first IMP dose in LTS12551 study for patients from EFC13579, EFC13691 and PDY14192, 
until the end of the study as defined by the protocol for that patient.  
Adverse events of special interest (AESI) and other selected AE groupings will be searched 
based on the criteria in Table 3  
Table 3 - Criteria for adverse events of special interest and other selected AE groupings 
AE Grouping 
Criteria 
AESI 
 
Anaphylactic reaction 
Anaphylactic reaction algorithmic approach (Introductory Guide for 
Standardised MedDRA Queries (SMQs) Version 18.1): includes 
anaphylactic reaction narrow SMQ (20000021) terms; for selection 
based on occurrence of multiple symptoms, the symptoms must have 
occurred within 24 hours of each other 
Hypersensitivity 
(medically reviewed) 
Hypersensitivity narrow SMQ (20000214) and [AE corrective 
treatment/therapy=’Y’ or Action taken with IMP=’Drug withdrawn’ 
or Action taken with IMP=’Drug interrupted’] followed by medical 
review (documented process) for selection of relevant systemic 
hypersensitivity events 
Severe injection site 
reactions that last longer 
than 24 hours or serious 
injection site reaction 
HLT = ‘Injection site reaction’ and either with serious status, or with 
severe status and (AE end date/time –AE start date/time) ≥ 24 hours 
or ongoing 
Severe or serious infection Primary SOC = ‘infections and infestations’ and with severe or 
serious status 
Parasitic infection 
The Infection Type ‘Parasitic’ was checked on the eCRF page 
“Infection Defined as AESI Complementary Form” 
Opportunistic infection 
The Infection Type ‘Opportunistic’ was checked on the eCRF page 
“Infection Defined as AESI Complementary Form” 
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AE Grouping 
Criteria 
Drug-related hepatic 
disorder 
Drug-related hepatic disorders - Comprehensive search narrow SMQ 
(20000006) 
Pregnancy 
Primary SOC = ‘Pregnancy, puerperium and perinatal conditions’, or 
PT in (Aborted pregnancy, False negative pregnancy test, Pregnancy 
test positive, Pregnancy test urine positive, Ectopic pregnancy 
termination) 
Symptomatic overdose 
with IMP 
The question “Is the event a Symptomatic Overdose with IMP?” is 
answered “Yes” on the eCRF page “Adverse Event” 
Symptomatic overdose 
with non-IMP 
The question “Is the event a Symptomatic Overdose with non-IMP?” 
is answered “Yes” on the eCRF page “Adverse Event” 
Other selected AE 
grouping 
 
Injection site reaction  
HLT = ‘Injection site reaction’ 
Malignancy 
Sub-SMQ (20000091) – Malignant or unspecified tumors 
Suicidal behavior 
PT in (Completed suicide, Suicidal ideation, Depression suicidal, 
Suicidal behavior, Suicide attempt) 
Partner pregnancy 
PT in (Pregnancy of partner, Miscarriage of partner) 
Conjunctivitis (narrow) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, 
Conjunctivitis viral, Atopic keratoconjunctivitis) 
Conjunctivitis (broad) 
PT in (Conjunctivitis, Conjunctivitis allergic, Conjunctivitis bacterial, 
Conjunctivitis viral, Atopic keratoconjunctivitis, Blepharitis, Dry eye, 
Eye irritation, Eye pruritus, Lacrimation increased, Eye discharge, 
Foreign body sensation in eyes, Photophobia, Xerophthalmia, Ocular 
hyperaemia, Conjunctival hyperaemia) 
Hypereosinophilia 
HLT = ‘Eosinophilic disorders’ or PT = ‘Eosinophil count increased’ 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.   
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values will be converted to standard international units and analyzed 
in standard international units; international units will be used in all listings and tables. Baseline 
values for clinical laboratory variables will be the original baseline from the parent study. 
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Blood samples for clinical laboratories will be collected at Visit1, Visit 4 (Week 4), Visit 8 (Week 
12), Visit 11 (Week 24), Visit 13 (Week 48; if applicable), Visit 15 (Week 72; if applicable), 17 
(End-of-Treatment), 18 (End-of-Study) and/or early termination, unless otherwise specified. The 
laboratory parameters will be classified as follows: 
• 
Hematology:  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, platelet 
count and total red blood cell count. 
- 
White blood cells: total white blood cell count, with five-part differential count 
(neutrophils, lymphocytes, monocytes, basophils, eosinophils). 
• 
Clinical chemistry 
- 
Metabolism: glucose, total cholesterol, total protein, creatine phosphokinase. 
- 
Electrolytes: sodium, potassium, chloride, bicarbonate 
- 
Renal function: creatinine, creatinine clearance, blood urea nitrogen, uric acid 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total bilirubin, albumin 
- 
Pregnancy test: A serum pregnancy test (β-human chorionic gonadotrophin) 
performed at screening (Visit 1) in women of childbearing potential will be applicable 
to patients coming from DRI12544.  
- 
Hepatitis screen: A hepatitis screen (hepatitis B surface antigen [HBsAg], Hepatitis B 
IgM core antibody [HBcAb-IgM], hepatitis C antibodies [HC Ab]) will be performed 
at Visit 1. 
- 
HIV screen: HIV screen (Anti-HIV-1 and HIV-2 antibodies) will be performed at 
Visit 1. 
- 
Antibody: anti-nuclear antibody (ANA) at Visit 1. Note: Anti-double-strand DNA 
antibody will be tested if ANA is positive (≥1:160 titer). 
• 
Serum immunoglobulin quantitative immunoassays (IEP) (IgG, IgG subclasses 1-4 
subtypes, IgM, and IgA). The collection for serum immunoglobulin will be stopped after 
the approval of protocol amendment 4. The analyses for IgG, IgG subclasses 1-4 subtypes, 
IgM, and IgA in LTS12551 study will be restricted to the patients from DRI12544 study 
and performed to the data observed up to the end of collection.  
Urine samples will be collected as follows: 
• 
Urinalysis - Quantitative analyses: pH, glucose, ketones, leukocyte esterase, blood, 
protein, nitrate, urobilinogen and bilirubin (by dipstick). If any parameter on the dipstick is 
abnormal, a urine sample should be sent to the central laboratory for testing. If positive for 
proteins, microscopic analysis is performed by central laboratory. Testing is performed at 
Visit 1, Visit 8 (Week 12), Visit 11 (Week 24), Visit 13 (Week 48; if applicable), Visit 15 
(Week 72; if applicable), Visit 16 (Week 84; if applicable), Visit 17 (End-of-Treatment) 
and Visit 18 (End-of-Study). 
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• 
Pregnancy test: Qualifying pregnancy test for patients coming from EFC13579, 
EFC13691 and PDY14192 studies will be the urine pregnancy test performed at the 
combined EOT/V1/V2 visit. The urine pregnancy test will be performed at visit 2 (Day 1) 
and every scheduled visit from Visit 4 (Week 4) to Visit 18 (End-of-Study). 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
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 every scheduled visit. Height (cm) will be measured at Visit 1 only. 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 study visits. Baseline values for vital signs will be the 
original baseline from the parent studies. 
2.1.4.5 Electrocardiogram variables 
ECG results will be from an independent central lab. Baseline values for ECG will be the original 
baseline from the parent study. 
One recording of a standard 12-lead ECG will be performed at Visit 1,  Visit 11 (Week 24), Visit 
13 (Week 48; if applicable), Visit 17 (End-of-Treatment) and Visit 18 (End-of-Study). A 
minimum of 3 complexes in an appropriate lead (lead II) will be averaged to determine the PR-
interval, QT/QTcF/QTcB interval, QRS-complex and heart rate will be measured for each ECG. 
At the post-enrollment visits, ECGs will be performed prior to investigational product 
administration. All ECGs will be performed with the subject in a reclined position.  
2.1.5 Pharmacokinetic variables 
Blood samples of serum functional dupilumab are collected at Visit 1, Visit 4 (Week 4), Visit 8 
(Week 12), Visit 11 (Week 24), Visit 13 (Week 48; if applicable), Visit 15 (Week 72; if 
applicable), Visit 17 (End-of-Treatment), Visit 18 (End-of-Study) and/or early termination, and 
before the IMP administration at corresponding scheduled visits that are specified in the protocol. 
The pre-dose serum dupilumab concentration will be collected at the scheduled visits in 
LTS12551 study. The baseline values for PK variables are the original baselines from the parent 
studies. 
2.1.6 Anti-drug antibody (ADA) variables 
Samples for anti-drug antibodies (ADAs) are collected at various time points throughout the study. 
ADA samples collected at Visit 1, Visit 8 (Week 12), Visit 11 (Week 24), Visit 13 (Week 48; if 
applicable), Visit 15 (Week 72; if applicable), Visit 17 (End-of-Treatment), Visit 18 (End-of-
Study) and/or early termination will be analyzed for ADA. The baseline used to define ADA 
variables refers to the baseline value in the parent study. 
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In response to AE’s of special interest like anaphylaxis or hypersensitivity additional ADA 
samples closer to the event may be analyzed, based on the judgment of the medical investigator 
and/or medical monitor. 
The ADA variables include ADA status (positive or negative) and titer as follows: 
• 
Number of patients with pre-existing immunoreactivity  
Pre-existing immunoreactivity is defined as either an ADA positive response in the assay 
at baseline of the parent study with all post first dose ADA results negative in the current 
study, or an ADA positive response at baseline of the parent study with all post first dose 
ADA results in the current study less than 4-fold of the baseline titer levels of the parent 
study. 
• 
Number of patients with treatment-emergent response in the ADA assay 
Treatment-emergent response is defined as a positive response in the ADA assay post first 
dose in the current study, when baseline status in the parent study is negative or missing. 
The treatment-emergent response is further characterized as: 
- 
Persistent response - defined as a treatment-emergent ADA positive response with two 
or more consecutive ADA positive sampling time points separated by greater than 12-
week period (greater than 84 days), with no ADA negative sample in between. 
- 
Indeterminate response - defined as a treatment-emergent response with only the last 
collected sample positive in the ADA assay.  
- 
Transient response – defined as a treatment-emergent ADA positive response that is 
not considered persistent or indeterminate. 
• 
Number of patients with treatment-boosted response in the ADA assay 
Treatment-boosted response is defined as a positive response in the ADA assay post first 
dose in the current study that is greater than or equal to 4-fold of the baseline titer levels of 
the parent studies, when baseline status of the parent studies are positive.  
• 
Titer values (titer value category)  
- 
Low (titer <1,000)  
- 
Moderate (1,000 ≤ titer ≤10,000) 
- 
High (titer >10,000). 
• 
ADA positive samples will be further characterized for the presence of neutralizing 
antibody (NAb) response 
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2.1.7 Pharmacodynamic/genomics endpoints 
2.1.7.1 Whole blood biomarkers 
Blood eosinophil count will be measured as part of the standard 5-part white blood cell (WBC) 
differential cell count on a hematology auto analyzer. 
2.1.7.2 Serum biomarkers 
Serum total IgE will be measured with a quantitative method (eg, ImmunoCAP) approved for 
diagnostic testing at Visit 1, Visit 13 (Week 48), Visit 16 (Week 84), and Visit 17 (End-of-
Treatment). 
Serum IgM, IgA, IgG and IgG subtypes will be measured with immunoassays at Visit 1, Visit 11 
(Week 24), Visit 13 (Week 48), Visit 16 (Week 84), and Visit 17 (End-of-Treatment). 
The collection for serum immunoglobulin and serum total IgE will be stopped after the approval 
of protocol amendment 4. The analyses for the total IgE in LTS12551 study will be restricted to 
the patients from DRI12544 study and performed to the data observed up to the end of collection. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations for LTS12551 only, unless otherwise specified. 
• 
Screened patients are defined as the patients who signed the informed consent. 
• 
Enrolled patients are defined as the patients who signed the informed consent and had a 
treatment kit number allocated and recorded in the IVRS/IWRS database, regardless of 
whether the treatment kit was used. 
• 
The safety population consists of the patients who actually received at least one dose or 
part of a dose of the LTS12551 study medication. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report via using a summary table: 
• 
Screened patients 
• 
Screen failure patients and reasons for screen failure 
• 
Non-enrolled but treated patients 
• 
Enrolled patients (Overall and by parent study) 
• 
Enrolled but not treated patients 
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Enrolled and treated patients (by the treatment category and overall, defined in Section 2.3.2) 
• 
Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
• 
Status at last study contact  
For all categories of patients (except for the screened and non-enrolled categories), percentages 
will be calculated using the total number of all enrolled patients as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages.  This 
summary will be provided by the treatment category (see Section 2.3.2) and may also by 
region/pooled countries. 
A patient is considered as lost to follow-up at the end of study if he/she is not assessed at the last 
protocol planned visit. 
All critical or major deviations potentially impacting safety evaluation, drug-dispensing 
irregularities, and other major or critical deviations will be summarized in tables giving numbers 
and percentages of deviations by treatment category.  
Additionally, the analysis populations for safety, efficacy, PK and Anti-drug antibody will be 
summarized in a table by number of patients in the enrolled population. 
• 
Safety population (for both safety and efficacy analyses) 
• 
Pharmacokinetics population 
• 
Anti-drug antibody population  
2.2.1 Randomization and drug dispensing irregularities 
There is no randomization procedure in LTS12551. Drug-dispensing irregularities occur 
whenever: 
• 
A patient is dispensed an IMP kit not allocated by the IVRS, such as, a) a patient at any 
time in the study is dispensed a different treatment kit than as assigned, or b) a non-
screened patient is treated with IMP reserved for enrolled patients. 
Drug-dispensing irregularities will be monitored throughout the study and reviewed on an ongoing 
basis.  
All drug-dispensing irregularities will be documented in the clinical study report.  If the number of 
irregularities is large enough to make a tabular summary useful, the irregularities will be 
categorized and summarized among enrolled patients (number and percentages).  Non-enrolled 
and treated patients will be described separately.  
Drug-dispensing irregularities to be prospectively identified include but are not limited to:  
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Randomization and drug allocation irregularities 
Kit dispensation without IVRS transaction 
Erroneous kit dispensation 
Kit not available 
Subject enrolled twice 
Subject switched to another site 
2.3 
ANALYSIS POPULATIONS 
The primary analysis population is the safety population. All safety and efficacy analyses will be 
performed based on the safety population. 
2.3.1 OCS dependent and Non-OCS dependent populations 
The OCS dependent population is defined as the patients who participated in EFC13691 study and 
then subsequently enrolled in the LTS12551 study. 
The non-OCS dependent population is defined as the patients who were not on daily chronic OCS 
therapy and participated in DRI12544, EFC13579 or PDY14192 studies and then enrolled in the 
LTS12551 study. 
The patients from the EFC13691 study are considered as a different patient population from the 
patients from the DRI12544, EFC13579 or PDY14192 studies. This is because the patients from 
the EFC13691 study are more severe at the baseline of parent study, are using a different 
background controller medication, and potentially could have different safety profiles and 
different efficacy effect from the patients enrolled from the DRI12544, EFC13579 or PDY14192 
studies. In addition, for the patients from the EFC13691 study only, LTS12551 study will assess 
the efficacy endpoints linked to the reduction of the OCS dose. 
Furthermore, all analyses planned in LTS12551 will be performed and presented separately for the 
patients from the EFC13691 study and the patients from the DRI12544, EFC13579 or PDY14192 
studies, except for the endpoints (see Section 2.1.3.7) that are collected for the patients from 
EFC13691 study only. 
2.3.2 Safety population 
The safety population is defined as the patients who have actually received at least 1 dose or part 
of a dose of the IMP in LTS12551.  
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Enrolled patients for whom it is unclear whether they took the IMP or not will be included in the 
safety population as enrolled. 
The treatment category “Placebo/Dupilumab” is defined as the patients who have been in the 
actual placebo arms of the parent studies and exposed to Dupilumab in LTS12551. The treatment 
category “Dupilumab/Dupilumab” is defined as the patients who have been in the actual 
Dupilumab arms of the parent studies and exposed to Dupilumab in LTS12551. 
For the OCS dependent patients, results of each planned analysis will be presented by 
“Placebo/Dupilumab”, “Dupilumab/Dupilumab” and “All”.  
For the non-OCS dependent patients, results of each planned analysis will be presented by the 
parent study and “All”, and further by “Placebo/Dupilumab” and “Dupilumab/Dupilumab” within 
each parent study. 
2.3.3 Efficacy populations 
The efficacy analysis population is the same as the safety population. 
2.3.4 Pharmacokinetics (PK) population 
The PK population will consist of all the patients in the safety population who had at least one 
non-missing functional dupilumab concentration value after the 1st dose of study drug in the 
current study. 
2.3.5 Anti-drug antibody (ADA) population 
ADA Population will consist of all the patients in the safety population who had at least one non-
missing ADA result in the ADA assay after the 1st dose of study drug in the current study. 
2.4 
STATISTICAL METHODS 
2.4.1 Demographics and baseline characteristics 
The demographics and baseline characteristics will be summarized for the safety population. The 
data for demographics and baseline characteristics will be obtained from the original baselines of 
the parent studies. Continuous data will be summarized by the treatment category and overall (see 
Section 2.3.2), using the number of available data, mean, standard deviation (SD), median, 
minimum, and maximum. Categorical and ordinal data will be summarized by the treatment 
category and overall (see Section 2.3.2), using the number and percentage of patients.  
Parameters described in Section 2.1.1 will be summarized for the safety population by the 
treatment category and overall (see Section 2.3.2) using descriptive statistics.  
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Medical and surgical history will be summarized by the treatment category and overall (see 
Section 2.3.2), by system organ class (SOC) and preferred term (PT) sorted by internationally 
agreed order of SOC and by the decreasing frequency of PT within SOC based on the overall 
group. Comorbidity history and atopic medical history will be summarized separately.  
No specific description of the safety/efficacy parameters will be provided at baseline. If relevant, 
the baseline values will be described along with each safety/efficacy analysis.  
2.4.2 Prior or concomitant medications 
The prior medications, concomitant medications in parent study, and concomitant medications 
will be presented for the safety population by the treatment category and overall (see 
Section 2.3.2). The prior medications are those the patients used prior to the first IMP dose in the 
parent study. The data of prior medications are obtained from the parent study. Medications will 
be summarized according to the WHO-DD dictionary, considering the first digit of the ATC class 
(anatomic category) and the first 3 digits of the ATC class (therapeutic category).  All ATC codes 
corresponding to a medication will be summarized. Patients will be counted once in each ATC 
category (anatomic or therapeutic) linked to the medication, and therefore patients may be counted 
several times for the same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence.  In case of equal frequency regarding 
ATC (anatomic or therapeutic), alphabetical order will be used. 
The tables for concomitant medications in parent study will be sorted by decreasing frequency of 
ATC followed by all other therapeutic classes based on the overall incidence. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the overall incidence. In case of equal frequency 
regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
In addition, the ICS in combination with allowable controller medication(s), the 
salbutamol/albuterol or levosalbutamol/levalbuterol reliever medication, and the OCS medication 
(for patients from EFC13691 only) will be summarized separately.  
2.4.2.1 ICS in combination with allowable controller medication(s) 
ICS in combination with allowable controller medications and the OCS medication (for patients 
from EFC13691 only) taken within 30 days prior to screening of parent study will be summarized 
by the treatment category and overall (see Section 2.3.2), and will be sorted by decreasing 
frequency of medication name in the overall category. The data of prior ICS and controller 
medications and the OCS medication (for patients from EFC13691 only) are sourced from the 
parent studies.  
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The prescription of ICS in combination with allowable controller medication(s) at enrollment of 
LTS12551 will be summarized by the treatment category and overall (see Section 2.3.2). Number 
(%) of patients will be presented by medication names and also by ICS dose level (medium/high 
as defined in Appendix C) according to the classification specified in (9). The descriptive 
summary for the percentage change from baseline in OCS dose will be presented in the efficacy 
evaluations for patients from EFC13691. 
2.4.2.1.1 Compliance for ICS and controller medications 
During the LTS12551 study, the prescription of background asthma controller medications is 
reported on the eCRF, and the daily intake is recorded on the electronic diary by patients. The use 
of electronic diary will be stopped after the approval of protocol amendment 4 in LTS12551. The 
compliance for the controller medications with ICS component will be calculated for each patient, 
based on the data observed up to the end of electronic diary collection. 
For a patient from DRI12544 study, a morning/evening dairy is compliant if the number of puffs 
administered is the same as or greater than what is prescribed. Percentage of Compliance is 
defined as the total number of controller medication puffs taken divided by the total number of 
expected puffs of controller medication during the treatment period (ie, from the evening dairy of 
the first IMP dose date in LTS12551 study to the morning dairy of the last IMP dose in LTS12551 
study + 14 days). The total number of controller medication puff taken is the sum of the controller 
medication puffs captured in each morning and evening diary during the treatment period, with 
each diary being capped at the number of puffs expected per diary, according to the patient’s 
prescribed controller medication dosing regimen. 
For a patient from EFC13579, EFC13691 or PDY14192 studies, due to changes in the design of 
electronic diary logpad, the daily intake of each prescribed asthma controller medication is 
recorded on the electronic diary every evening. An evening diary is considered as compliant to the 
prescribed controller medication with ICS component if the actual dose of each controller 
medication with ICS component is same as or greater than the prescribed dose. Percentage of 
Compliance is defined as the number of days when the patient is compliant to the prescribed 
controller medication(s) with ICS component divided by the number of days the patient stays in 
the treatment period (from first dose to last dose + 14 days).  
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by the treatment 
category and overall on the safety population (Section 2.3.2).  
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure in LTS12551 study. 
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Duration of investigational product exposure is defined as:  the last IMP dose date in LTS12551 
study – the first IMP dose date in LTS12551 study + 14 days, regardless of unplanned intermittent 
discontinuations (see Section 2.5.3 for calculation in case of missing or incomplete data).   
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum). In addition, duration of treatment exposure will 
also be summarized categorically by counts and percentages for each of the following categories 
and cumulatively according to these categories (the categories exceeding Week 48 may apply to 
only the patients on the 96-week treatment period who signed the informed consent form before 
the approval of protocol amendment 4):  
≤ 4 week 
> 4 and ≤ 12 weeks 
> 12 and ≤ 24 weeks 
> 24 and ≤ 48 weeks 
> 48 and ≤ 72 weeks 
> 72 and ≤ 96 weeks 
> 96 weeks 
Additionally, the cumulative duration of treatment exposure, will be provided in patient years by 
treatment category and overall (see Section 2.3.2). 
Number and percentage of patients will be summarized by total number of injections they received 
during the LTS12551 study. The number and percentage of patients who receive injection will be 
summarized by type of administrator (site staff, patient or non-professional care giver, 
professional care giver at home), by dosing week, and maybe by IMP packaging way (vial or pre-
filled syringe). 
2.4.3.2 Compliance 
A given IMP administration will be considered noncompliant if the patient did not take the 
planned dose of treatment as required by the protocol. No imputation will be made for patients 
with missing or incomplete data. An administration is considered compliant if an injection is 
performed, regardless the actual amount of solution injected.  
The loading dose will be considered as two administrations, and the administration of loading 
dose will be considered compliant if both the two injections are performed. The loading dose on 
Day 1 of LTS12551 is applied to patients from DRI12544 only, and is not applicable to patients 
from EFC13579, EFC13691 or PDY14192. 
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Percentage of compliance for a patient will be defined as the number of administrations that the 
patient was compliant divided by the total number of administrations that the patient was planned 
to take during the treatment epoch defined in Section 2.1.4.  
Treatment compliance percentages will be summarized descriptively as quantitative variables 
(number, mean, SD, median, minimum, and maximum). The percentage of patients whose 
compliance is < 80% will be summarized. 
Cases of overdose (at least twice the dose during an interval of less than 11 days) will constitute 
serious adverse events and will be listed as such. More generally, dosing irregularities will be 
listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints 
There will be no confirmatory analysis for the efficacy variables. All analyses will be done 
descriptively on the safety population in observed case, as appropriate. The baseline value for 
efficacy parameters is the original baselines from the parent studies.  
For severe exacerbation events, the number of patients with one or more severe exacerbation 
events (number and qualitative variable: Yes/No), number of severe exacerbation events 
(qualitative variable: 0, 1, 2, 3, ≥4), 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) will be presented by 
the treatment category and overall (see Section 2.3.2) during the treatment period. Number and 
annualized rate will also be analyzed for severe exacerbation with use of systemic corticosteroids 
for ≥3 days only, and that with hospitalization or with emergency room visit only. The mean 
duration of a severe exacerbation will also be summarized. 
For the continuous efficacy variables listed in Section 2.1.3, descriptive statistics (mean, SD, 
median, minimum and maximum) will be presented for the parameter and its change from 
baseline over visits and by the treatment category and overall (see Section 2.3.2). In addition, 
figure of mean change from baseline (with corresponding standard error) will be presented for the 
continuous efficacy parameter over visits and by the treatment category and overall (see Section 
2.3.2). 
For the categorical efficacy variables listed in Section 2.1.3, the number and percentage will be 
presented over time for all patients who have data available at that time point by the treatment 
category and overall (see Section 2.3.2). 
In addition, particularly for the patients coming from the EFC13691 study, the descriptive 
statistics (mean, SD, median, minimum and maximum) for the percentage change from baseline in 
oral corticosteroids (OCS) dose will be presented over time by the treatment category and overall 
(see Section 2.3.2); and, the proportion of patients achieving a reduction of 50% or greater in their 
OCS dose compared with the original baseline in parent study, and the proportion of patients 
whose background OCS are completely tapered off will be presented over time by the treatment 
category and overall (see Section 2.3.2). 
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2.4.4.1 Subgroup analyses 
Subgroup analyses will be performed for several key efficacy variables (severe exacerbation 
events, FEV1, ACQ5, and AQLQ) by: 
• 
ICS dose group: patients on the medium or high ICS dose at the original baseline in the 
parent studies 
• 
Blood eosinophil (Giga/L) groups at baseline of the parent study: ≥0.3, <0.3, ≥0.15, 
<0.15, ≥0.15 - <0.3, ≥0.3 - <0.5, and  ≥0.5 
2.4.4.2 Multiplicity issues 
Not applicable.   
2.4.5 Analyses of safety data 
The summary of safety endpoints will be presented by the treatment category and overall (see 
Section 2.3.2). 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
The baseline value for safety parameters is defined as the original baseline from the parent 
studies. 
• 
In addition to the baseline values, the pre-dose measurements at Week 0 in LTS12551 will 
be presented in the by-visit summary/figure for laboratory, vital signs or ECG parameters. 
The pre-dose measurements at Week 0 of LTS12551 are defined as follows: for patients 
enrolled from DRI12544, the measurements at Week 0 are obtained from the EOS visit of 
DRI12544 if available, regardless whether the EOS visit in DRI12544 was combined with 
Visit 1/Visit 2 in LTS12551; otherwise, Week 0 value will be the last available 
measurement prior to the first IMP dose in LTS12551 study. For patients enrolled from 
EFC13579, EFC13691 and PDY14192, the measurements at Week 0 are obtained from the 
EOT visit of parent studies if available; otherwise, Week 0 value will be the last available 
measurement prior to the first IMP dose in LTS12551 study.  
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the sponsor according to predefined 
criteria/thresholds based on literature review and defined by the sponsor for clinical 
laboratory tests, vital signs, and ECG (Appendix A). 
• 
PCSA criteria will determine which patients had at least one PCSA during the treatment-
emergent adverse event period, taking into account all evaluations performed during the 
treatment-emergent adverse event period, including non-scheduled or repeated evaluations.  
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The number of all such patients will be the numerator for the on-treatment PCSA 
percentage. 
• 
The treatment-emergent PCSA denominator for a given parameter will be based on the 
number of patients assessed for that given parameter in the treatment-emergent adverse 
event period by the treatment category and overall (see Section 2.3.2) on the safety 
population. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment category and overall (see Section 2.3.2).  Summaries will include the 
endpoint value and/or the worst on-treatment value. The endpoint value is commonly 
defined as the value collected at the date of last IMP dose + 14 days or the end of treatment 
visit. If this value is missing, this endpoint value will be the closest value prior to the last 
administration of IMP + 14 days. The worst value is defined as the nadir and /or the peak 
post-baseline (up to last administration of IMP + 14 days) according to the direction 
(minimum or maximum) of the abnormality as defined in the PCSA list. 
• 
All of the values including unscheduled measurements will be assigned to the appropriate 
safety analysis visit window. The safety analysis visit window is defined in Section 2.5.4. 
• 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary endpoint of this study is the number (n) and percentage (%) of patients experiencing 
any treatment-emergent adverse events (TEAE). Pre-treatment (if applicable) adverse events will 
be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pre-treatment or treatment-
emergent adverse event. The algorithm for imputing date/time of onset will be conservative and 
will classify an adverse event as treatment-emergent, unless there is definitive information to 
determine it is pre-treatment.  Details on classification of adverse events with missing or partial 
onset dates are provided in Section 2.5. 
Adverse event incidence tables will be presented by system organ class (SOC), high level group 
term (HLGT), high level term (HLT) and preferred term (PT) sorted in alphabetical order, to 
summarize the number (n) and percentage (%) of patients experiencing at least an AE by the 
treatment category and overall (see Section 2.3.2). Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment category. The denominator 
for computation of percentages is the safety population within each treatment category. In all AE 
incidence tables, the total patient years (in the unit of 100 patient-years) for each treatment 
category and overall (see Section 2.3.2) will be presented in the corresponding column headers. 
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The number of events per 100 patient-years (adjusted for the total duration of exposure) by the 
treatment category and overall (see Section 2.3.2) will be presented for each AESI during the 
treatment-emergent period. 
The table of all treatment-emergent adverse events presented by SOC and PT will be sorted by the 
internationally agreed SOC order (from MedDRA) and decreasing frequency of PTs within SOCs. 
Sorting will be based on the results for the overall patients across treatment categories, unless 
otherwise specified.  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries by the treatment category and overall 
patients (see Section 2.3.2) will be generated for the safety population. Sorting will be based on 
the results for the overall patients across treatment categories, unless otherwise specified. 
• 
Overview of treatment-emergent adverse events, summarizing number (%) of patients 
(including total patient years in column headers) with any 
- 
Treatment-emergent adverse event 
- 
Treatment-emergent serious adverse event 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
• 
All treatment-emergent adverse events by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients (including total patient years in column headers) with at least one 
treatment-emergent adverse event sorted by the SOC internationally agreed order. The 
other levels (HLGT, HLT, PT) will be sorted in alphabetical order. 
• 
All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients (including total patient years in column headers) with at least one treatment-
emergent adverse event, will be presented by the internationally agreed SOC order and by 
decreasing incidence of PTs within each SOC. 
• 
All treatment-emergent adverse events by primary SOC, showing the number (%) of 
patients (including total patient years in column headers) with at least one treatment-
emergent adverse event, will be presented by the internationally agreed SOC order. 
• 
All possibly drug-related TEAEs by primary SOC and PT, showing number (%) of patients 
(including total patient years in column headers) with at least one TEAE, will be presented 
by SOC internationally agreed order and by decreasing incidence of PTs within each SOC. 
• 
All TEAEs by maximal severity, presented by primary SOC and PT, showing the number 
(%) of patients (including total patient years in column headers) with at least one TEAE by 
severity (ie, mild, moderate, or severe), sorted by the order defined above.  
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• 
Number (%) of patients (including total patient years in column headers) experiencing 
TEAE(s) presented by primary and secondary SOC, HLGT, HLT, and PT sorted by SOC 
internationally agreed order. The other level (HLGT, HLT, PT) will be presented in an 
alphabetic order. 
Analysis of all treatment emergent serious adverse event(s) 
• 
All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients (including total patient years in column headers) with 
at least one treatment-emergent serious adverse event, will be presented by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
• 
All treatment-emergent serious adverse events by primary SOC and PT, showing number 
(%) of patients (including total patient years in column headers) with at least one TEAE, 
will be presented by SOC internationally agreed order and decreasing incidence of PTs 
within SOC. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients (including total patient years in column headers) will 
be presented by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order. 
• 
All TEAEs leading to treatment discontinuation, by primary SOC and PT, showing number 
(%) of patients (including total patient years in column headers) with at least one TEAE, 
will be presented by SOC internationally agreed order and by decreasing incidence of PTs 
within each SOC. 
Analysis of adverse events of special interest (AESI) and other selected AE groupings 
Summaries of AESI defined by the search criteria: 
• 
All treatment emergent AESIs and other selected AE groupings identifiable by MedDRA 
terms or by laboratory values (as in ALT elevation), by AESI category and PT, showing 
the number (%) of patients (including total patient years in column headers), will be 
presented by decreasing incidence of PT within each AESI category. 
• 
An overview summary within each treatment-emergent AESI and other selected AE 
groupings will include:  
- 
Number (%) of patients with any TEAE 
- 
Number  (%) of patients with any SAE (regardless of treatment-emergent status) 
- 
Number (%) of patients with any treatment-emergent SAE 
- 
Number (%) of patients with any AE leading to death 
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- 
Number (%) of patients with any TEAE leading to permanent treatment 
discontinuation 
- 
Number (%) of patients with any TEAE by maximum intensity, corrective treatment, 
and final outcome 
- 
Number (%) of patients with any possibly related TEAE 
- 
Kaplan-Meier plot (cumulative incidence (%) versus time up to Week 60 based on K-
M estimate) for time-to-onset of the first TEAE 
- 
Cumulative incidence (K-M estimates) up to specified time points (Week 4, Week 12, 
Week 24, Week 48, Week 60) 
Notes for the last two bullets: when TEAE start date or worsening date is partially 
available, the maximum of the earliest possible TEAE start date and the treatment start 
date will be used. When TEAE start date or worsening date is completely missing, the 
treatment start date will be used. 
• 
Number of treatment-emergent AESIs and other selected AE groupings per 100 patient-
years (total number of events adjusted for the total duration of exposure) will be presented 
by decreasing incidence of PT within each AESI and other selected AE groupings 
category. 
Analysis of pre-treatment adverse events 
• All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients 
(including total patient years in column headers) with at least one pre-treatment AE, will 
be presented by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC. 
• All pre-treatment SAEs by primary SOC and PT, showing the number (%) of patients 
(including total patient years in column headers) with at least one pre-treatment SAE, will 
be presented by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC. 
• All pre-treatment adverse events leading to study discontinuation by primary SOC and PT, 
showing the number (%) of patients (including total patient years in column headers), will 
be presented by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC. 
Analysis of adverse events 
• 
All pre-treatment, treatment-emergent, or post-treatment-emergent AEs by primary SOC 
and PT, showing the number (%) of patients (including total patient years in column 
headers) with at least one AE, will be presented by the internationally agreed SOC order 
and by decreasing incidence of PTs within each SOC. 
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2.4.5.2 Deaths 
The following death summaries will be generated on the safety population, unless otherwise 
specified. 
• 
Number (%) of patients (including total patient years in column headers) who died by 
primary SOC and PT for death  
• 
Deaths in non-enrolled patients or enrolled but not treated patients   
• 
TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC and PT showing number (%) of patients (including total 
patient years in column headers) sorted by internationally agreed SOC order, and by 
alphabetical order of PT within each SOC. 
• 
All pre-treatment AE leading to death by primary SOC and PT, showing the number (%) 
of patients (including total patient years in column headers), sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC.  
• 
Listing of deaths showing parent study, treatment category, patient identifier, gender, race, 
age, duration of exposure, date of death (if relevant), reason of death. 
2.4.5.3 Analyses of laboratory variables  
The baseline value of all laboratory variables is the original baseline from the parent studies. The 
pre-dose measurement at Week 0 of LTS12551 will be separately presented in the summaries or 
plots over time. This section will be organized by biological function as in Section 2.1.4.3. 
The summary statistics (including number, mean, median, standard deviation, Q1, Q3, minimum 
and maximum) of all laboratory variables (central laboratory values and changes from baseline) 
will be calculated for each visit or study assessment (baseline, each post-baseline time point, and 
endpoint) by the treatment category and overall (see Section 2.3.2).  
For all laboratory variables, the mean change from baseline with corresponding standard error at 
each visit will be plotted by the treatment category and overall (see Section 2.3.2).  
For all laboratory variables, the summary statistics over visits for either measurements or mean 
change from baseline, and the plot of mean change from baseline over visits should use the 
centralized data only, and should include the measurements obtained at either scheduled or 
unscheduled visits. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function, and by the treatment category and 
overall (see Section 2.3.2), regardless of the baseline level and/or according to the following status 
at baseline of parent study and at Week 0 of LTS12551 study, respectively:  
• 
Normal/missing 
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• 
Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criterion is defined, similar table(s) using the normal range 
will be provided. 
For PCSA analyses, the laboratory measurements obtained at either scheduled or unscheduled 
visits should be used; and, both the centralized and local test results should be used, as long as 
their available dates/time is different from each other’s. Centralized data will be used 
preferentially to the local measures in the PCSA analyses when measurements are performed on 
the same date and at the same time for a given laboratory test.  
A listing of patients with at least one post-baseline PCSA will be provided and will display the 
whole profile over time of all parameters of the corresponding biological function. In this listing, 
baseline, endpoint value and individual values will be flagged when lower or higher than the lower 
or upper laboratory limits and/or when reaching the absolute limit of abnormality criteria.  
Drug-induced liver injury 
Additional analysis of liver-related adverse events will be performed if necessary. 
2.4.5.4 Analyses of vital sign variables 
The baseline value of all vital sign variables is the original baseline from the parent studies. The 
pre-dose measurement at Week 0 of LTS12551 will be separately presented in the summaries or 
plots over time. 
The summary statistics (including number, mean, median, standard deviation, Q1, Q3, minimum 
and maximum) of all vital signs variables (measurements and changes from baseline) will be 
calculated for each visit or study assessment (baseline, each post-baseline time point, and 
endpoint) by the treatment category and overall (see Section 2.3.2).   
For all vital sign variables, the mean change from baseline with corresponding standard error at 
each visit will be plotted by the treatment category and overall (see Section 2.3.2). 
For all vital sign variables, the summary statistics over visits for either measurements or mean 
change from baseline, and the plot of mean change from baseline over visits should include the 
measurements obtained at either scheduled or unscheduled visits. 
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The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by the treatment category and overall (see Section 2.3.2), irrespective of the baseline 
level and/or according to the following status at baseline of parent study and at Week 0 of 
LTS12551 study, respectively:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
For PCSA analyses, the vital sign measurements obtained at either scheduled or unscheduled 
visits should be used. 
2.4.5.5 Analyses of electrocardiogram variables 
The baseline value of all ECG variables is the original baseline from the parent studies. The pre-
dose measurement at Week 0 of LTS12551 will be separately presented in the summaries or plots 
over time. 
The summary statistics (including number, mean, median, standard deviation, Q1, Q3, minimum 
and maximum) of all ECG variables (measurements and changes from baseline) will be calculated 
for each visit or study assessment (baseline and each post-baseline time point, and endpoint) by 
the treatment category and overall (see Section 2.3.2). 
For all ECG parameters, the mean change from baseline with corresponding standard error at each 
visit will be plotted by the treatment category and overall (see Section 2.3.2). 
For all ECG variables, the summary statistics over visits for either measurements or mean change 
from baseline, and the plot of mean change from baseline over visits should use the centralized 
data only, and should include the measurements obtained at either scheduled or unscheduled 
visits. 
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by treatment category and overall (see Section 2.3.2) irrespective of the baseline level 
and/or according to the following status at baseline of parent study and at Week 0 of LTS12551 
study, respectively:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
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For PCSA analyses, the ECG measurements obtained at either scheduled or unscheduled visits 
should be used; and, both the centralized and local ECG results should be used, as long as their 
available dates/time is different from each other’s. Centralized data will be used preferentially to 
the local measures in the PCSA analyses when measurements are performed on the same date and 
at the same time.  
2.4.5.6 Subgroup analyses 
Subgroup analyses will be performed for several key safety variables (treatment-emergent 
AE/SAE/AESI/AE leading to permanent treatment discontinuation) by: 
• 
ICS dose group: patients on the medium or high ICS dose at the original baseline in parent 
studies 
• 
Age group (< 18, 18-64, ≥ 65 years) 
• 
Race (Caucasian/White, Black/of African descent, Asian/Oriental, all the other) 
• 
Sex (Female, Male) 
• 
Ethnicity (Hispanic, Not Hispanic) 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
The baseline value of PK and PD variables is the original baseline from the parent studies. 
2.4.6.1 Pharmacokinetic analysis 
The PK analyses will be performed on the PK population (Section 2.3.4). Serum concentrations of 
dupilumab will be summarized using arithmetic and geometric means, SD, standard error of the 
mean (SEM), coefficient of variation (CV), minimum, median and maximum by visit. If date 
and/or time of the drug intake and/or sampling are missing, then the concentration will not be 
taken into account. For the patients from the Dupilumab arms of EFC13579, EFC13691 or 
PDY14192 studies,, if the pre-dose concentration values at Week 0 of LTS12551 are below the 
lower limit of quantitation (LLOQ = 78 ng/ml), one-half of LLOQ will be used; for the patients 
from the Dupilumab arms of DRI12544 study, the pre-dose concentration value at Week 0 of 
LTS12551 should use 0; for the patients from the Placebo arms of parent studies, the pre-dose 
concentration value at Week 0 of LTS12551 should use 0. Values will be expressed in the tables 
with no more than three significant figures.  
2.4.6.2 Pharmacodynamics   
For all biomarkers noted in the Pharmacodynamics (PD) section of the protocol, the biomarker 
analyses will be applied to the safety population. The collection for serum immunoglobulin and 
serum total IgE will be stopped after the approval of protocol amendment 4. The analyses for 
serum immunoglobulin and serum total IgE in LTS12551 study will be restricted to the patients 
from DRI12544 study and performed to the data observed up to the end of collection. 
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For eosinophil count and serum total IgE, IgM, IgA, IgG and IgG subtypes, descriptive statistics 
(including number, mean, median, standard deviation, Q1, Q3, minimum and maximum), change 
from baseline and percentage change from baseline over visits will be presented by the treatment 
category and overall (see Section 2.3.2). In addition, the mean, mean change from baseline, mean 
percentage change from baseline with corresponding standard error will be plotted across visits by 
the treatment category and overall (see Section 2.3.2). For biomarkers showing substantial 
skewness, the geometric means will also be presented. 
For eosinophil count, with subgrouping the patients into original baseline EOS ≤0.5 Giga/L and 
>0.5 Giga/L, the mean change from baseline will be plotted over visits for each of the two 
subgroups and overall. And table showing number (%) of patients who have peak post-baseline 
EOS count  ≥1 Giga/L, ≥3 Giga/L and ≥5 Giga/L will be presented for each of the two subgroups 
and overall. 
2.4.7 Analyses of ADA variables 
The baseline value used to define ADA variables is the original baseline from the parent studies. 
The ADA analyses will be performed on the ADA population (Section 2.3.5). The ADA variables 
described in Section 2.1.6 will be summarized using descriptive statistics in the ADA analysis set. 
Frequency tables of the proportion of patients developing ADA positivity in the ADA assay, 
neutralizing antibody status in the NAb assay, pre-existing immunoreactivity, treatment-emergent, 
treatment-boosted, persistent, indeterminate, transient ADA responses and titers will be presented. 
Listing of all ADA peak titer levels and neutralizing antibody status will be provided for ADA 
positive patients. 
2.4.7.1 Status in the ADA assay at baseline of the parent study 
The following summary will be provided based on the ADA population (Section 2.3.5): 
• 
Number (%) of patients negative in the ADA assay at baseline of parent study 
• 
Number (%) of patients positive in the ADA assay at baseline of parent study 
- 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) 
of the titer for the patients positive in the ADA assay at baseline of the parent study 
- 
Number (%) of patients with neutralizing antibody status (negative or positive in the 
NAb assay) 
2.4.7.2 Status in the ADA assay in the current study 
The following summary will be provided based on ADA population (Section 2.3.5): 
• 
Number (%) of patients with ADA status (negative or positive in the ADA assay) at time 
points analyzed 
- 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) 
of the peak post-baseline titer for ADA positive patients 
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- 
ADA titers using descriptive statistics (median, Q1, Q3, minimum and maximum) at 
ADA time points analyzed 
- 
Number (%) of patients with neutralizing antibody status (negative or positive in the 
NAb assay) for the ADA positive patients 
• 
Number (%) of patients with pre-existing immunoreactivity 
• 
Number (%) of patients with treatment-boosted anti-drug antibodies.  
- 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) 
of the peak post-baseline titer for treatment-boosted ADA patients 
• 
Number (%) of patients with treatment-emergent ADA.  
- 
The summary statistics (including number, median, Q1, Q3, minimum and maximum) 
of the peak post-baseline titer for treatment-emergent positive patients 
- 
Number (%) of patients in the low, moderate or high titer category with treatment-
emergent positive response  
- 
Number (%) of patients with transient, indeterminate, or persistent treatment-emergent 
ADA response 
• 
Number (%) of patients with neutralizing antibody results (negative or positive in the NAb 
assay).  
2.4.7.3 Impact of ADA on clinical safety 
The safety assessment will focus on the following events: 
• 
Severe injection site reactions last longer than 24 hours or serious injection site reactions 
• 
Hypersensitivity reactions (SMQ hypersensitivity narrow search and confirmed by medical 
review) 
• 
Anaphylactic reactions (SMQ anaphylactic reaction narrow search) 
In response to AE’s of special interest like anaphylaxis or hypersensitivity additional ADA 
samples closer to the event may be analyzed, based on the judgment of the medical investigator 
and/or medical monitor.  
Correlations between ADA variables (eg, ADA peak titers, neutralizing antibody status, treatment-
emergent, treatment-boosted, transient, indeterminate and persistent ADA responses) and safety 
may be explored. 
2.4.7.4 Impact of ADA on clinical efficacy 
Correlations between ADA variables (eg, ADA peak titers, neutralizing antibody status, treatment-
emergent, treatment-boosted, transient, indeterminate and persistent ADA responses) and efficacy 
endpoints may be explored for each treatment category and overall (see Section 2.3.2):  
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• 
Annualized rate of severe exacerbation events 
• 
Change from baseline in FEV1 
2.4.7.5 Impact of ADA on PK 
Correlations between ADA variables (eg, ADA peak titers, neutralizing antibody status) and 
descriptive summary of serum concentration of dupilumab may be explored for each treatment 
category and overall (see Section 2.3.2). Plot of individual serum concentration of functional 
dupilumab over visits may also be provided by ADA classifications (negative at all time, pre-
existing immunoreactivity, treatment-boosted anti-drug antibodies, and treatment-emergent anti-
drug antibodies [further separated by NAb status and peak titer category]) for each treatment 
category and overall (see Section 2.3.2). 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
Age is calculated as following: 
Age = integer part of (informed consent date – birth date)/365.25 
Age of onset of asthma is calculated as following: 
Age = integer part of (asthma onset date – birth date)/365.25 
BMI is calculated as following: 
BMI = Weight in kg / (height2 in meters) 
Smoking quantity (pack-year) is calculated as following: 
Number of pack-year= (packs smoked per day) × (years as a smoker) 
Renal function formulas  
Creatinine clearance (CLcr) value will be derived using the equation of Cockroft and Gault: 
CLcr (ml/min) = (140 - age) * weight (kg) * (1 - 0.15*sex (0-M, 1-F)) /(0.814*creatinine (µmol/l)) 
CLcr will be calculated using weight assessed at the same visit that creatinine was assessed and 
age at the lab sampling date. Here age is calculated as following: 
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Age = integer part of (lab sampling date – birth date)/365.25 
2.5.2 Data handling conventions for secondary efficacy variables 
Calculation of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations/day: 
A diary day is defined as the period beginning with an Evening diary, and ending with the 
following day’s Morning Diary.  The number of salbutamol/albuterol or 
levosalbutamol/levalbuterol inhalations per day is the sum of number of inhalations recorded in 
one diary day including the evening diary and the following day’s morning diary. 
Periodical average of daily efficacy endpoints at designated study days: 
For the daily efficacy endpoints, the time period used to calculate the periodical average at each 
designated study day is summarized in Table 4. The day of the first IMP administration in 
LTS12551 study is used as the reference start day (day 1). The use of electronic diary and PEF 
meter will be stopped after the approval of protocol amendment 4, the periodical average 
calculation will be performed to the data observed within each interval up to the end of using 
electronic diary/PEF meter in LTS12551. 
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Table 4 - Periodical average of daily efficacy assessment 
  
  
Day 15 
Day 29 
Day 57 
Day 85 
Day 169 Day 337 Day 505 
  
Endpoint 
Days used to compute average 
morning PEF, asthma 
symptom score, number of 
awakenings 
 2-15 
 16-29 
30-57 
58-85 
86-169 
170-337 
338-505 
evening PEF, asthma symptom 
score 
 1-14 
 15-28 
29-56 
57-84 
85-168 
169-336 
337-504 
Days 
used to 
compute 
average 
Number of inhalations/day of 
salbutamol/albuterol or 
levosalbutamol/levalbuterol for 
symptom relief 
Diary 
daya    
1-14 
Diary 
day 
15-28 
Diary 
day 
29-56 
Dairy 
day 
57-84 
Diary 
day   
85-168 
Diary 
day 
169-336 
Diary 
day 
337-504 
a Note: A diary day is defined as the period beginning with an Evening diary, and ending with the following day’s Morning Diary. For example, 
diary day 14 includes the evening dairy on day 14 and the morning dairy on day 15 
 
 
  
  
Day 589 
Day 673 
 
 
 
 
 
  
Endpoint 
Days used to compute average 
morning PEF, asthma 
symptom score, number of 
awakenings 
 506-589 
 590-673 
 
 
 
 
 
evening PEF, asthma symptom 
score 
 505-588 
 589-672 
 
 
 
 
 
Days 
used to 
compute 
average 
Number of inhalations/day of 
salbutamol/albuterol or 
levosalbutamol/levalbuterol for 
symptom relief 
Diary daya  
505-588 
Diary day 
589-672 
 
 
 
 
 
a Note: A diary day is defined as the period beginning with an Evening diary, and ending with the following day’s Morning Diary. For example, 
diary day 14 includes the evening dairy on day 14 and the morning dairy on day 15 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
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Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the end-of-treatment case report form page.  If this date is missing, 
the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior and concomitant medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial adverse 
event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be classified 
as treatment-emergent.  No imputation of adverse event end dates/times will be performed.  These 
data imputations are for categorization purpose only and will not be used in listings.  No 
imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of randomization should be considered as treatment-emergent adverse events.  
The exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity/grades of adverse events 
If the severity/grade is missing for 1 of the treatment-emergent occurrences of an adverse event, 
the maximal severity on the remaining occurrences will be considered.  If the severity is missing 
for all the occurrences, a “missing” category will be added in the summary table. 
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Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points 
For the safety assessment, the reference date for the derivation of relative days of events or 
findings will be the date of first IMP dose injection in LTS12551 study. Selected safety variables 
will be summarized by the analysis window defined in Table 5 for the by-visit descriptive 
analysis. For all laboratory/vital sign/ECG variables, the summary statistics over visits for either 
measurements or mean change from baseline, and the plot of mean change from baseline over 
visits should use the centralized data only (if applicable), and should include the measurements 
obtained at either scheduled or unscheduled visits. For PCSA analyses, the measurements of 
laboratory/vital sign/ECG variables obtained at either scheduled visits or unscheduled visits 
should be used; and, both the centralized and local test results should be used (if applicable), as 
long as their available dates/time are different from each other’s. All available safety 
measurements (from either scheduled or unscheduled visit) will be assigned to the appropriate 
visit window. In the event of multiple measurements of the same test in the same window, the one 
closest to the targeted visit date will be used for the by-visit summary. If they are at the same 
distance to the target day, the latest one will be used.  
The pre-dose measurements at Week 0 of LTS12551 are defined as follows: for patients enrolled 
from DRI12544, the measurements at Week 0 are obtained from the EOS visit of DRI12544 if 
available, regardless whether the EOS visit in DRI12544 was combined with Visit 1/Visit 2 in 
LTS12551; otherwise, Week 0 value will be the last available measurement prior to the first IMP 
dose in LTS12551 study. For patients enrolled from EFC13579, EFC13691 and PDY14192, the 
measurements at Week 0 are obtained from the EOT visit of parent studies if available; otherwise, 
Week 0 value will be the last available measurement prior to the first IMP dose in LTS12551 
study. 
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Table 5 - Time window for safety variables 
Vital Signs 
ECG 
Physical Examination,  
Urine Analysis 
Hematology, Serum 
Chemistry 
Visit 
Week 
Target 
day 
Minimum 
days 
Maximum 
days 
Minimum 
days 
Maximum 
days 
Minimum 
days 
Maximum 
days 
Minimum 
days 
Maximum 
days 
1 & 2 
0 
Derived 
 
Up to 1st 
IMP dose 
date/time 
 
Up to 1st 
IMP dose 
date/time 
 
Up to 1st 
IMP dose 
date/time 
 
Up to 1st 
IMP dose 
date/time 
3 
2 
15 
After 1st 
IMP dose 
date/time 
21 
 
 
 
 
 
 
4 
4 
29 
22 
35 
 
 
 
 
After 1st 
IMP dose 
date/time 
56 
5 
6 
43 
36 
49 
 
 
 
 
 
 
6 
8 
57 
50 
63 
 
 
 
 
 
 
7 
10 
71 
64 
77 
 
 
 
 
 
 
8 
12 
85 
78 
98 
 
 
After 1st 
IMP dose 
date/time 
126 
57 
126 
9 
16 
113 
99 
126 
 
 
 
 
 
 
10 
20 
141 
127 
154 
 
 
 
 
 
 
11 
24 
169 
155 
210 
After 1st 
IMP dose 
date/time  
252 
127 
252 
127 
252 
12 
36 
253 
211 
294 
 
 
 
 
 
 
13 
48 
337 
295 
378 
253 
504 
253 
420 
253 
420 
14 
60 
421 
379 
462 
 
 
 
 
 
 
15 
72 
505 
463 
546 
 
 
421 
546 
421 
588 
16 
84 
589 
547 
630 
 
 
547 
630 
 
 
17 (EOT) 
96 
673 
631 
d* 
505 
d* 
631 
d* 
589 
d* 
18 (EOS) 
108 
757 
d*+1 
 
d*+1 
 
d*+1 
 
d*+1 
 
*Note: d= max (last IMP dose +14 days, EOT date) 
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Pregnancy Test 
Serum Immunoglobulin 
Visit 
Week 
Target day 
Minimum days 
Maximum days 
Minimum days 
Maximum days 
1 & 2 
0 
Derived 
 
Up to 1st IMP 
dose date/time 
 
Up to 1st IMP 
dose date/time 
3 
2 
15 
 
 
 
 
4 
4 
29 
After 1st IMP 
dose date/time 
35 
 
 
5 
6 
43 
36 
49 
 
 
6 
8 
57 
50 
63 
 
 
7 
10 
71 
64 
77 
 
 
8 
12 
85 
78 
98 
 
 
9 
16 
113 
99 
126 
 
 
10 
20 
141 
127 
154 
 
 
11 
24 
169 
155 
210 
After 1st IMP 
dose date/time 
252 
12 
36 
253 
211 
294 
 
 
13 
48 
337 
295 
378 
253 
462 
14 
60 
421 
379 
462 
 
 
15 
72 
505 
463 
546 
 
 
16 
84 
589 
547 
630 
463 
630 
17 (EOT) 
96 
673 
631 
d* 
631 
 
18 (EOS) 
108 
757 
d*+1 
 
 
 
*Note: d= max (last IMP dose +14 days, EOT date) 
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For the efficacy assessment, the reference date for the derivation of relative days of events or 
findings will be the day of the first IMP injection in LTS12551 study. And for the endpoints not 
measured daily, all available values of scheduled measurements will be assigned to the appropriate 
visit window according to Table 6. In the event of multiple measurements of the same test in the 
same window, the one closest to the targeted visit date will be used for the by-visit summary. If 
they are at the same distance to the target day, the latest one will be used. The pre-dose 
measurements at Week 0 of LTS12551 are defined in the same way as in the paragraph prior to 
Table 5. 
Table 6 - Time window for efficacy variables 
Spirometry 
ACQ-5, AQLQ 
Visit 
Week 
Target day 
Minimum days 
Maximum days 
Minimum days 
Maximum days 
1 & 2 
0 
Derived 
 
1st IMP dose date/time (Day 1) 
 
1st IMP dose date/time 
(Day 1) 
3 
2 
15 
2 
21 
 
 
4 
4 
29 
22 
42 
 
 
5 
6 
43 
 
 
 
 
6 
8 
57 
43 
70 
 
 
7 
10 
71 
 
 
 
 
8 
12 
85 
71 
126 
 
 
9 
16 
113 
 
 
 
 
10 
20 
141 
 
 
 
 
11 
24 
169 
127 
252 
2 
252 
12 
36 
253 
 
 
 
 
13 
48 
337 
253 
420 
253 
 
14 
60 
421 
 
 
 
 
15 
72 
505 
421 
546 
 
 
16 
84 
589 
547 
630 
 
 
17 (EOT) 
96 
673 
631 
d* 
 
 
18 (EOS) 
108 
757 
d*+1 
 
 
 
*Note: d= max (last dose +14 days, EOT date) 
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EQ-5D, Resource Utilization 
Prescribed OCS dose 
Visit 
Week 
Target day 
Minimum days 
Maximum days 
Minimum days 
Maximum days 
1 & 2 
0 
Derived 
 
1st IMP dose date/time 
(Day 1) 
 
1st IMP dose 
date/time (Day 1) 
3 
2 
15 
 
 
2 
21 
4 
4 
29 
 
 
22 
35 
5 
6 
43 
 
 
36 
49 
6 
8 
57 
 
 
50 
63 
7 
10 
71 
 
 
64 
77 
8 
12 
85 
2 
126 
78 
98 
9 
16 
113 
 
 
99 
126 
10 
20 
141 
 
 
127 
154 
11 
24 
169 
127 
252 
155 
210 
12 
36 
253 
 
 
211 
294 
13 
48 
337 
253 
420 
295 
378 
14 
60 
421 
 
 
379 
462 
15 
72 
505 
421 
546 
463 
546 
16 
84 
589 
547 
630 
547 
630 
17 (EOT) 
96 
673 
631 
d* 
631 
d* 
18 (EOS) 
108 
757 
d*+1 
 
d*+1 
 
*Note: d= max (last dose +14 days, EOT date) 
For the pharmacokinetics/pharmacodynamics variables summary, the reference date for the 
derivation of relative days of measurements will be the date of first IMP dose injection in 
LTS12551 study. Pharmacodynamics variables will be summarized by the analysis window 
defined in Table 7 for the by visit descriptive analyses. All available values of scheduled 
measurements will be assigned to the appropriate visit window. In the event of multiple 
measurements of the same test in the same window, the one closest to the targeted visit date will 
be used for the by-visit summary. If they are at the same distance to the target day, the latest one 
will be used. The pre-dose measurements at Week 0 of LTS12551 are defined in the same way as 
in the paragraph prior to Table 5. 
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Table 7 - Time window for pharmacokinetics and pharmacodynamics variables 
PK sampling, dupilumab concentration 
Anti-drug antibodies 
Visit 
Week 
Target 
day 
Minimum days 
Maximum days 
Minimum days 
Maximum days 
1 & 2 
0 
Derived 
 
Up to 1st IMP dose 
date/time 
 
Up to 1st IMP 
dose date/time 
3 
2 
15 
 
 
 
 
4 
4 
29 
After 1st IMP dose 
date/time 
56 
 
 
5 
6 
43 
 
 
 
 
6 
8 
57 
 
 
 
 
7 
10 
71 
 
 
 
 
8 
12 
85 
57 
126 
After 1st IMP dose 
date/time 
126 
9 
16 
113 
 
 
 
 
10 
20 
141 
 
 
 
 
11 
24 
169 
127 
252 
127 
252 
12 
36 
253 
 
 
 
 
13 
48 
337 
253 
420 
253 
420 
14 
60 
421 
 
 
 
 
15 
72 
505 
421 
588 
421 
588 
16 
84 
589 
 
 
 
 
17 (EOT) 
96 
673 
589 
d* 
589 
d* 
18 (EOS) 
108 
757 
d*+1 
 
d*+1 
 
*Note: d= max (last dose +14 days, EOT date) 
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Total IgE 
Visit 
Week 
Target 
day 
Minimum days 
Maximum days 
1 & 2 
0 
Derived 
 
Up to 1st IMP 
dose date/time 
3 
2 
15 
 
 
4 
4 
29 
 
 
5 
6 
43 
 
 
6 
8 
57 
 
 
7 
10 
71 
 
 
8 
12 
85 
 
 
9 
16 
113 
 
 
10 
20 
141 
 
 
11 
24 
169 
 
 
12 
36 
253 
 
 
13 
48 
337 
After 1st IMP dose 
date/time 
462 
14 
60 
421 
 
 
15 
72 
505 
 
 
16 
84 
589 
463 
630 
17 (EOT) 
96 
673 
631 
 
18 (EOS) 
108 
757 
 
 
*Note: d= max (last dose +14 days, EOT date) 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be included in the 
by-visit summaries and figures, as well as the computation of baseline, worst values, and PCSAs. 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Property of the Sanofi Group - strictly confidential 
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2.5.6 Pooling of centers for statistical analyses 
Not applicable 
2.5.7 Statistical technical issues 
None 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 66 
3 
INTERIM ANALYSIS 
This is an open-label extension study. Interim analyses/reports may be prepared to support 
regulatory submission of an indication in the dupilumab project or other purpose. 
Interim analysis for non-asthma submission 
In general, the analyses for this report will focus on the safety evaluations on the accumulative 
data in LTS12551 as of the cut-off date. Specifically, the report shall include all safety analyses, 
demographics, baseline characteristics, patient disposition, exposure to IMP, as well as the prior 
and concomitant medications. 
Interim analysis for asthma submission 
All planned analyses in this SAP shall be performed for this report. 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 67 
4 
DATABASE LOCK 
At the time of the initial dupilumab marketing authorization application for the treatment of 
Asthma, an interim database lock will be performed. Additional database snapshots may be 
performed to support regulatory submission of an indication in dupilumab project, or prior to 
subsequent marketing authorization applications in major markets, eg, EU. The final database lock 
is planned to occur 4 weeks after last patient last visit. 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 68 
5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 69 
6 
REFERENCES 
 
1. 
Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F. Standardization of 
the measurement of lung volumes. Series "ATS/ERS TASK FORCE: Standardization of lung 
function testing" Edited by Brusasco V, Crapo R, and Viegi G. Eur Respir J. 2005;26(3):511-522. 
2. 
Cohen J. Statistical power analysis for the behavioral sciences (2nd edition). Lawrence 
Erlbaum Associates; Hillsdale, NJ. 1988. 
3. 
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir med. 2005;99(5):553-8. 
4. 
Juniper E. Asthma control questionnaire - background, administration and analysis. 2012; 
QOL Technologies, West Sussex, UK. 
5. 
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change 
in a disease-specific quality of life questionnaire. J Clin Epidemiol. 1994;47(1):81-7. 
6. 
EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16:199-208. 
7. 
Dolan P. Modeling valuations for EuroQol health states. Medical Care. 1997;35(11):1095-
1108. 
8. 
Norman GR, Sloan JA, Wyrwich KW. Point/Counterpoint, Interpretation of Changes in 
Health-related Quality of life: the remarkable university of half a standard deviation. Medical 
Care. 2003;41(5):582-592. 
9. 
Global Initiative for Asthma (GINA). Global strategy for asthma management and 
prevention. 2014; available at www.ginasthma.org. 
 
 
 
 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 70 
7 
LIST OF APPENDICES 
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Summary of statistical analyses 
Appendix C: 
Low, medium and high dose inhaled corticosteroids- Adults and adolescents (≥12 
years) 
Appendix D: 
Definition of Anaphylaxis 
Appendix E:  
List of opportunistic infections 
Appendix F: 
Asthma Control Questionnaire, 5-question Version 
Appendix G: 
Asthma Quality of Life Questionnaire 
Appendix H: 
EuroQol Questionnaire (EQ-5D-3L) 
Appendix I: 
SAS code for EQ-5D index utility scoring 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Property of the Sanofi Group - strictly confidential 
Page 71 
Appendix A 
Potentially clinically significant abnormality criteria for included 
laboratory parameters: Combined Adult (≥ 18) and Adolescent (≥ 12 
to < 18) criteria abstracted from BTD-009536 V3.0 with approved 
modifications  
 
Where adolescent criteria (age ≥12 to <18) are different than adult criteria (≥18), the adolescent criteria are 
provided in parentheses in the combined column. 
Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
Vitals 
 
 
 
SBP (mmHg) 
≤95 mmHg and decrease 
from baseline ≥20mmHg 
≥160 mmHg and increase 
from baseline ≥20 mmHg 
≤90 mmHg and decrease from 
baseline ≥20 mmHg 
≥119mmHg and increase from 
baseline ≥20 mmHg 
≤95 (≤90) mmHg and 
decrease from baseline ≥20 
mmHg 
≥160 (≥119) mmHg and 
increase from baseline ≥20 
mmHg 
DBP (mmHg) 
≤45 mmHg and decrease 
from baseline ≥10 mmHg 
≥110 mmHg and increase 
from baseline ≥10 mmHg 
≤54 mmHg and decrease from 
baseline ≥10 mmHg 
≥78mHg and increase from 
baseline ≥10 mmHg 
≤45 (≤54) mmHg and 
decrease from baseline ≥10 
mmHg 
≥110 (≥78) mmHg and 
increase from baseline ≥10 
mmHg 
HR (bpm) 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase 
from baseline≥20 bpm 
NONE 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
Respiratory 
rate 
(breaths/min) 
NONE 
<12 breaths/min 
>20 breaths/min 
<12 breaths/min 
>20 breaths/min 
Temperature 
(◦C) 
NONE 
Rectal, ear or temporal artery: 
≥100.4°F/38.0 °C 
Oral or pacifier: ≥99.5 °F/37.5 
°C 
Axillary or skin infrared: 
≥99°F/37.2 °C 
≥38.0 °C rectal/ear/temporal 
≥37.5 °C oral 
≥37.2 °C axillary 
Weight (kg) 
≥5% increase from baseline 
≥5% weight loss from baseline 
≥5% increase from baseline 
(adults only) 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
≥5% decrease from 
baseline 
≥5% decrease from baseline 
ECG 
 
 
 
Heart rate 
(bpm) 
<50 bpm 
<50 bpm and decrease from 
baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from 
baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from 
baseline ≥20 bpm 
>90 bpm 
>90 bpm and increase from 
baseline ≥20bpm 
>100 bpm 
>100 bpm and increase 
from baseline ≥20bpm 
>120 bpm 
>120 bpm and increase 
from baseline ≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
<50 bpm  
<50 bpm and decrease from 
baseline ≥20 bpm 
<40 bpm  
<40 bpm and decrease from 
baseline ≥20 bpm 
<30 bpm  
<30 bpm and decrease from 
baseline ≥20 bpm 
>90 bpm  
>90 bpm and increase from 
baseline ≥20 bpm 
>100 bpm  
>100 bpm and increase from 
baseline ≥20 bpm 
>120 bpm  
>120 bpm and increase from 
baseline ≥20 bpm 
PR interval 
(ms) 
>200 ms 
>200 ms and increase from 
baseline ≥25% 
> 220 ms 
>220 ms and increase from 
baseline ≥25% 
> 240 ms 
> 240 ms and increase from 
≥180 ms 
>200 (≥180) ms  
>200 (≥180) ms and increase 
from baseline ≥25% 
>220 ms  
>220 ms and increase from 
baseline ≥25% 
>240 ms  
>240 ms and increase from 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
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Property of the Sanofi Group - strictly confidential 
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Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
baseline ≥25% 
baseline ≥25% 
QRS interval 
(ms) 
>110 ms 
>110 msec and increase 
from baseline ≥25% 
>120 ms 
>120 ms and increase from 
baseline ≥25% 
≥110 ms 
>110 ms  
>110 ms and increase from 
baseline ≥25% 
>120 ms  
>120 ms and increase from 
baseline ≥25% 
QT interval 
(ms) 
>500 ms 
NONE 
>500 ms 
QTc (ms) 
>450 ms 
>480 ms 
>500 ms 
 
AND 
 
Increase from baseline ]30-
60] ms 
Increase from baseline >60 
ms 
Borderline: 431-450 ms 
(Boys); 451-470 ms (Girls) 
Prolonged*: >450 ms (Boys); 
>470 ms (Girls) 
Additional: ≥500 ms 
 
AND 
 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged*: Increase from 
baseline >60 ms 
Borderline: 451- 480 ms 
(431- 450 ms boys; 451- 470 
ms girls) 
Prolonged: >480 ms (>450 
ms boys; >470 ms girls) 
Additional: > 500 ms 
 
AND 
 
>30 to ≤60 ms increase from 
baseline 
>60 ms increase from 
baseline 
Hematology 
 
 
 
Hemoglobin 
(g/L) 
≤115 g/L (Male); ≤95 g/L 
(Female) 
≥185 g/L (Male); ≥165 g/L 
(Female) 
Decrease from Baseline 
≥20 g/L 
<6.2 mmol/L or 10 g/dL or 
any decrease ≥1.2 mmol/L or 
2 g/dL 
Decrease from baseline ≥20 
g/L 
≤115 g/L males; ≤95 g/L 
females (<100 g/L 
adolescents) 
≥185 g/L males; ≥165 g/L 
females (≥185 g/L 
adolescents) 
Hematocrit  
≤0.37 v/v (Male) ; ≤0.32 
<0.32 l/l or 32 % 
≤0.37 v/v males; ≤0.32 v/v 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 74 
Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
(v/v) 
v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v 
(Female) 
>0.47 l/l or 47 % 
females (<0.32 v/v) 
≥0.55 v/v males; ≥0.5 v/v 
females (>0.47 v/v) 
RBC (Tera/L) 
≥6 Tera/L 
NONE 
≥6 Tera/L 
Platelets 
(Giga/L) 
<100 Giga/L 
≥700 Giga/L 
<100 GIGA/L or 100,000 
/mm3 
>700 GIGA/L or 700,000 
/mm3 
<100 Giga/L 
≥700 Giga/L 
WBC (Giga/L) 
<3.0 Giga/L (Non-Black); 
<2.0 Giga/L (Black) 
≥16.0 Giga/L 
<4,5 GIGA/L or 5,000 /mm3 
>13.5 GIGA/L or 17,000 
/mm3 
<3.0 Giga/L non-Black; <2.0 
Giga/L Black (<4.5 Giga/L) 
≥16 (>13.5) Giga/L  
Lymphocytes 
(Giga/L) 
>4.0 Giga/L 
<0.6 GIGA/L or 600 /mm3 
>6.0 GIGA/L or 6,000 /mm3 
<0.6 Giga/L (adolescents 
only) 
>4.0 (>6.0) Giga/L 
Neutrophils 
(Giga/L) 
<1.5 Giga/L (Non-
Black);<1.0 Giga/L (Black) 
<1.2 GIGA/L or 1,200 /mm3 
> 1 ULN 
<1.5 Giga/L non-Black; <1.0 
Giga/L Black (<1.2 Giga/L) 
>1xULN (adolescents only) 
Monocytes 
(Giga/L) 
>0.7 Giga/L 
NONE 
>0.7 Giga/L (adults only) 
Basophils 
(Giga/L) 
>0.1 Giga/L 
NONE 
>0.1 Giga/L (adults only) 
Eosinophils 
(Giga/L) 
>0.5 Giga/L or >ULN (if 
ULN≥0.5 Giga/L) 
>0.5 GIGA/L or 500 /mm3 
Or >ULN if ULN >0.5 
GIGA/L or 500/mm3 
>0.5 Giga/L or > ULN if 
ULN >0.5 Giga/L 
Clinical 
Chemistry 
 
 
 
Glucose 
(mmol/L) 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); 
≥7 mmol/L (fasted) 
Hypoglycaemia <2.7 mmol/L  
Hyperglycaemia ≥7 mmol/L  
(fasted after >12 hours of 
fast); ≥10.0 mmol/L (unfasted) 
≤3.9 mmol/L and < LLN 
(<2.7 mmol/L) 
≥11.1 (≥10) mmol/L 
unfasted; ≥7 mmol/L fasted 
Glucose 
(mg/dL) 
NONE 
Hypoglycaemia <50 mg/dL 
≤70 mg/dL and < LLN (<50 
mg/dL) 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 75 
Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
Hyperglycaemia ≥120 mg/dL 
(fasted after >12 hours of 
fast); ≥180 mg/dL (unfasted) 
≥200 (≥180) mg/dL unfasted; 
126 (≥120) mg/dL fasted 
Total 
cholesterol 
(mmol/L) 
≥7.74 mmol/L 
≥6.20 mmol/L 
≥7.74 (≥6.20) mmol/L 
Total 
cholesterol 
(mg/dL) 
NONE 
≥240 mg/dL 
≥300 (≥240) mg/dL 
Creatine 
phosphokinase 
(ULN) 
>3 ULN 
>10 ULN 
≥3 ULN 
>3 ULN  
>10 ULN 
Albumin (g/L) 
≤25 g/L 
NONE 
≤25 g/L (adults only) 
Sodium 
(mmol/L) 
≤129 mmol/L 
≥160 mmol/L 
≤129 mmol/L or 129 mEq/L 
≥150 mmol/L or 150 mEq/L 
≤129 mmol/L 
≥160 (≥150) mmol/L 
Potassium 
(mmol/L) 
<3 mmol/L 
≥5.5 mmol/L 
≤3.5 mmol/L or 3.5 mEq/L 
≥5.5 mmol/L or 5.5 mEq/L 
<3.0 (≤3.5) mmol/L 
≥5.5  mmol/L 
Bicarbonate 
(mmol/L) 
NONE 
≤16 mmol/L or 16 mEq/L 
≥30 mmol/L or 30 mEq/L 
≤16 mmol/L 
≥30 mmol/L 
Chloride 
(mmol/L) 
<80 mmol/L 
>115 mmol/L 
≤80 mmol/L or 80 mEq/L 
≥115 mmol/L or 115 mEq/L 
<80 mmol/L 
>115  mmol/L 
Creatinine 
(µmol/L) 
≥150 µmol/L (Adults) 
≥30% change from baseline 
≥100% change from 
baseline 
≥132µmol/L 
≥150 (≥132) µmol/L 
≥30% change from baseline 
≥100% change from baseline 
Creatinine 
(mg/dL) 
NONE 
≥1.5mg/dL 
≥1.7 (≥1.5) mg/dL 
≥30% change from baseline 
≥100% change from baseline 
Creatinine 
clearance 
<15 (end stage renal 
disease) 
<15 (end stage renal disease) 
<15 mL/min (end stage renal 
disease) 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 76 
Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
(mL/min) 
≥15 - <30 (severe decrease 
in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild decrease in 
GFR) 
≥ 90 (normal GFR) 
≥15 - <30 (severe decrease in 
GFR) 
≥30 - < 60 (moderate decrease 
in GFR) 
≥60 - <90 (mild decrease in 
GFR) 
≥ 90 (normal GFR) 
≥15 - <30 mL/min (severe 
decrease in GFR) 
≥30 - <60 mL/min (moderate 
decrease in GFR) 
≥60 - <90 mL/min (mild 
decrease in GFR) 
BUN 
(mmol/L) 
≥17 mmol/L 
≥6.4 mmol/L 
≥17 (≥6.4) mmol/L 
BUN (mg/dL) 
≥48 mg/dL 
≥18 mg/dl 
≥48 (≥18) mg/dL 
Uric acid 
(µmol/L) 
<120 µmol/L  
>408 µmol/L 
≤119 µmol/L 
≥476 µmol/L 
<120 µmol/L  
>408 (≥476) µmol/L 
Uric acid 
(mg/dL) 
NONE 
≤2.0 mg/dL  
≥8.0 mg/dL 
≤2 mg/dL  
≥7 (≥8) mg/dL 
ALT (ULN) 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
≥3 ULN 
≥5 ULN 
≥10 ULN 
≥20 ULN 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
AST (ULN) 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
≥3 ULN 
≥5 ULN 
≥10 ULN 
≥20 ULN 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
ALP (ULN) 
>1.5 ULN 
≥1.5 ULN 
>1.5 ULN 
Total bilirubin 
(ULN) 
>1.5 ULN 
>2 ULN 
≥1.3 ULN 
>1.5 (≥1.3) ULN 
>2 ULN 
ALT and total 
bilirubin 
(ULN) 
ALT>3 ULN and TBILI>2 
ULN 
ALT ≥ 3 ULN and Total 
Bilirubin ≥ 2 ULN 
ALT >3 ULN and TBILI >2 
ULN 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
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Version number: 3 
Property of the Sanofi Group - strictly confidential 
Page 77 
Parameter 
Adults (≥ 18) 
Adolescents (≥12 to <18) 
Combined 
Conjugated 
and total 
bilirubin 
(ULN) 
Conjugated Bilirubin >35% 
Total Bilirubin and 
TBILI>1.5 ULN 
>35% Total Bilirubin and 
TBILI≥1.3 ULN 
Conjugated bilirubin > 35% 
total bilirubin and total 
bilirubin >1.5 (≥1.3) ULN 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 78 
Appendix B 
Summary of statistical analyses 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Statistical  
Method 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
FEV1, % Predicted 
FEV1, FVC and FEF 
25-75% 
Safety 
Measurement and change from baseline at all 
visits 
Descriptive statistics 
  No 
Yes (Baseline ICS dose 
and EOS count 
subgroups) 
No 
Severe exacerbation: 
number of 
events/annualized event 
rate during the 
treatment period 
Safety 
Summary of number/annualized rate of severe 
exacerbation events during the treatment period  Descriptive statistics 
No 
Yes (Baseline ICS 
dose and EOS count 
subgroups) 
No 
Morning asthma 
symptom score 
Safety  
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No 
No 
No 
Evening asthma 
symptom score 
Safety  
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No 
No 
No 
ACQ-5 score 
Safety 
Measurement, change from baseline, and 
responder status at all visits 
Descriptive statistics 
No 
Yes (Baseline ICS 
dose and EOS count 
subgroups) 
No 
AQLQ overall score 
Safety 
Measurement, change from baseline, and 
responder status at all visits, excluding patients 
from the PDY14192 study 
Descriptive statistics 
No  
Yes (Baseline ICS 
dose and EOS count 
subgroups) 
No 
AM PEF 
Safety 
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No  
No 
No 
PM PEF 
Safety 
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No  
No 
No 
Number of 
inhalations/day of 
Safety 
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No  
No 
No 
(electronic 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 79 
Endpoint 
Analysis 
population 
Primary 
analysis 
Statistical  
Method 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
reliever medication 
Number of nocturnal 
awakenings 
Safety 
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No  
No 
No 
EQ-5D-3L single utility 
score and VAS 
Safety 
Measurement and change from baseline at all 
visits, for patients from the DRI12544 study only 
Descriptive statistics 
No  
No 
No 
Percentage change 
from baseline in OCS 
dose 
Safety 
Summary statistics for percentage change from 
baseline in oral corticosteroids (OCS) dose over 
visits, for patients from the EFC13691 study 
only 
Descriptive statistics 
No  
No 
No 
Proportion of patients 
achieving a reduction of 
50% or greater in their 
OCS dose compared 
with baseline in the 
parent study 
Safety 
Proportion of patients achieving a reduction of 
50% or greater in their OCS dose compared 
with the baseline in the parent study over visits, 
for patients from the EFC13691 study only  
Descriptive statistics 
No  
No 
No 
Proportion of patients 
whose background OCS 
are completely tapered 
off 
Safety 
Proportion of patients whose background OCS 
are completely tapered off over visits, for 
patients from the EFC13691 study only 
Descriptive statistics 
No  
No 
No 
 
SAFETY ANALYSES 
Endpoint 
Analysis 
population 
Primary analysis 
Statistical  
Method 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Adverse events 
Safety 
Follow safety guidelines 
Descriptive statistics 
No 
Yes (Baseline ICS dose, 
Age, Race, Sex and 
Ethnicity subgroups) 
No 
Lab/vital signs/ECGs 
Safety 
Follow safety guidelines; PCSA analysis; Descriptive 
Descriptive statistics 
No 
No 
No 
 
(electronic 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 80 
Appendix C 
Low, medium and high dose inhaled corticosteroids- Adults and 
adolescents (≥12 years) 
INHALED CORTICOSTEROID 
TOTAL DAILY DOSE (MCG) 
 
LOW 
MEDIUM 
HIGH 
BECLOMETASONE DIPROPIONATE (CFC) 
200–500 
>500–1000 
>1000 
BECLOMETASONE DIPROPIONATE (HFA) 
100–200 
>200–400 
>400 
BUDESONIDE (DPI) 
200–400 
>400–800 
>800 
CICLESONIDE (HFA) 
80–160 
>160–320 
>320 
FLUTICASONE PROPIONATE (DPI OR 
HFA) 
100–250 
>250–500 
>500 
MOMETASONE FUROATE  
110–220 
>220–440 
>440 
TRIAMCINOLONE ACETONIDE 
400–1000 
>1000–2000 
>2000 
( ADAPTED FROM GINA 2014 GUIDELINES) 
Low, medium and high dose inhaled corticosteroids  
Adults (Japan) 
Agent Treatment 
Low daily dose (mcg) 
Medium daily dose 
(mcg) 
High daily dose 
(mcg) 
BDP-HFA 
100-200 
400 
800 
FP-HFA 
100-200 
400 
800 
CIC-HFA 
100-200 
400 
800 
FP-DPI 
100-200 
400 
800 
BUD-DPI 
200-400 
800 
1600 
BIS 
0.5 mg/day 
1.0 mg/day 
2.0 mg/day 
MF-DPI 
100-200 
400 
800 
BDP= Beclomethasone dipropionate, FP= Fluticasone propionate, CIC= Ciclesonide, BIS= Budesonide inhalation suspension, HFA= 
hydrofluoroalkane, DPI= Dry Powder Inhaler 
(Adapted from Japanese Guideline for Adult Asthma 2014) 
(electronic 
 
 
 
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Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 81 
Low, medium and high dose inhaled corticosteroids  
Children (Japan) 
Agent Treatment 
Low daily dose (mcg) 
Medium daily dose 
(mcg) 
High daily dose 
(mcg) 
Fluticasone (FP) 
100 
200 
400 
Beclomethasone (BDP) 
100 
200 
400 
Ciclesonide (CIC) 
100 
200 
400 
Budesonide(BUD-DPI) 
200 
400 
800 
Budesonide inhalation 
solution(BIS) 
250 
500 
1000 
(Adapted from Japanese Guideline for Childhood Asthma 2014) 
The above lists are indicative and not exhaustive. 
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Statistical Analysis Plan  
 
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Property of the Sanofi Group - strictly confidential                                                                       Page 82 
Appendix D 
Definition of Anaphylaxis 
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , 
Branum A, et al.  Second symposium on the definition and management of anaphylaxis: 
Summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy 
and Anaphylaxis Network symposium. J Allergy Clin Immunol  2006; 117: 391-397)  
Clinical criteria for diagnosing anaphylaxis 
 
 
 
 
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Statistical Analysis Plan  
 
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Property of the Sanofi Group - strictly confidential                                                                       Page 83 
Appendix E 
List of opportunistic infections 
• 
Aspergillosis 
• 
Blastomyces dermatitidis (endemic in the south-eastern and south-central states US, 
along Mississippi and Ohio Rivers) 
• 
Candidiasis – only systemic or extensive mucosal or cutaneous candidiasis 
• 
Coccidioides immitis (endemic south-western US and Central and South America) 
• 
Cryptococcus 
• 
Cytomegalovirus 
• 
Herpes Simplex (disseminated) 
• 
Herpes Zoster (disseminated; ophthalmic; involvement of 2 or more dermatomes) 
• 
Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
• 
Listeriosis 
• 
Mycobacterium avium 
• 
Nontuberculosis mycobacteria 
• 
Pneumocystis pneumonia (PCP) 
 
This list is indicative and not exhaustive. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 84 
Appendix F 
Asthma Control Questionnaire, 5-question Version 
(electronic 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 85 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 86 
Appendix G 
Asthma Quality of Life Questionnaire 
 
 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 87 
 
 
 
 
(electronic 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 88 
 
 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 89 
 
 
 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 90 
 
 
 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
SAR231893-LTS12551 - dupilumab 
Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 91 
 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 92 
Appendix H 
EuroQol Questionnaire (EQ-5D-3L) 
 
 
 
 
(electronic 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 93 
 
 
 
 
 
 
 
 
 
 
 
 
 
(electronic 
 
 
 
3.0)


Statistical Analysis Plan  
 
20-Jul-2017 
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Version number: 3 
Property of the Sanofi Group - strictly confidential                                                                       Page 94 
Appendix I 
SAS code for EQ-5D index utility scoring 
 
(electronic 
 
 
 
3.0)