A Randomized, Double-blind, Placebo-controlled, Parallel-group, 12-week Proof-of-Concept (PoC) Study to Assess the Efficacy, Safety, and Tolerability of SAR440340 and the Coadministration of SAR440340 and Dupilumab in Patients With Moderate-to-Severe Asthma Who Are Not Well Controlled on Inhaled Corticosteroid (ICS) Plus Long-acting β2 Adrenergic Agonist (LABA) Therapy
Phase: PHASE2
Conditions: Asthma
Sponsor: Sanofi

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 
EudraCT  
2017-003289-29 
IND Number(s) 
134401 
Version Number: 
1 
WHO universal trial number: 
Not yet applicable 
Date: 
06-Sep-2018
Total number of pages: 
147 
(electronic 1.0)
COMPOUND: SAR440340/REGN3500 
A randomized, double-blind, placebo-controlled, parallel-group, 12-week Proof-of-
Concept (PoC) study to assess the efficacy, safety, and tolerability of SAR440340, 
and the coadministration of SAR440340 and dupilumab in patients with moderate-
to-severe asthma who are not well controlled on inhaled corticosteroid (ICS) plus 
long-acting β2 adrenergic agonist (LABA) therapy 
STUDY NUMBER: SAR440340-ACT15102 
VERSION DATE / STATUS: 06-Sep-2018 / Approved 
NCT03387852

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Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial protocol 01 
All 
[06 Sep 2018], version 1 (electronic 1.0) 
Original Protocol 
All 
[30 NOV 2017], version 1 (electronic 3.0) 
 
Amended protocol 01 (06-Sep-2018) 
This amended protocol (amendment 01) is considered to be non-substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it neither significantly impacts the safety or physical/mental integrity 
of participants nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for the amendment is to clarify that the responsibilities of the Data Monitoring 
Committee (DMC) are to evaluate the study safety as well as efficacy data, and to allow samples 
collected for pharmacokinetics at earlier timepoints to be used for anti-drug antibody (anti-
SAR440340 antibody or anti dupilumab antibody) analysis, if ADA samples test positive at Week 
12. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Clinical Trial 
Summary and 6.1 
Description of the 
study 
Text added to specify the aim to include half of 
the patients on a medium dose and half on a 
high ICS dose 
While enrolment of patients on either medium or high 
dose ICS therapy is stipulated by the protocol, 
clarification is provided that an about equal proportion 
of patients on medium and high dose ICS is intended 
to have a broad representation of background therapy 
in the study. 
 
Clinical Trial 
Summary and 7.2. 
Exclusion Criteria 
(EO3) 
Exclude patients diagnosed with pulmonary or 
systemic disease associated with elevated 
peripheral eosinophil counts, for eg 
eosinophilic granulomatosis with polyangiitis. 
Eosinophilia associated with clinical symptoms in 
asthma patients has been identified as important 
potential risk with dupilumab treatment. That´s why the 
intention is to exclude patients with pre-existing 
eosinophilic disease since a causal association 
between dupilumab and these underlying conditions 
has not been established. This is also aligned with 
other protocols for the same compound. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Clinical Trial 
Summary and 9.2.1 
Other efficacy 
endpoints 
Time to LOAC post-randomization removed. 
Time to LOAC post-randomization is being considered 
as supportive to the primary analysis of LOAC rather 
than as other efficacy endpoint. 
Clinical Trial 
Summary and 11.3.2 
Safety population 
Defined the safety population as all patients 
who have received at least one dose of the 
IMP, analyzed according to the treatment 
actually received. 
Clarify that the safety population will be analysed 
based on the actual treatment received and not 
treatment group allocated by randomization. 
11.3.3.1 Antidrug 
antibody population 
Definition of the ADA population updated. 
To provide a more specific description of the 
population. 
Clinical Trial 
Summary and 
11.4.2.1 Analysis of 
primary efficacy 
endpoint 
Baseline background ICS dose level and 
number of exacerbation events within 1 year 
prior to screening added as covariates in the 
logistic regression model.  
Both variables were identified as important covariates 
in previous dupilumab studies.  
  
 
 
The following sentence was deleted: “Patients 
discontinued due to lack of efficacy or an AE 
related to asthma worsening will be considered 
as having the primary endpoint. Patients 
discontinued for other reasons will be 
considered as not having the primary 
endpoint.” 
Reason of discontinuation will longer be used to assign 
LOAC event or not. The process of determination of 
LOAC event or not for patients discontinuing treatment 
for a reason other than LOAC will be based on 
documented medical review. 
11.4.2.2 Analyses of 
secondary and other 
efficacy endpoints 
The following sentence was deleted: “For 
patients with an LOAC event or permanently 
discontinued treatment, data collected up to 
EOT visit will be included.” 
The sentence was ambiguous with regards to the 
inclusion or not of the end of treatment value in the 
analysis for patients with LOAC/discontinuation for 
other reason. Furthermore, including data collected at 
EOT for these patients could confound the treatment 
effect due to medications administered after an LOAC 
event or discontinuation for another reason. Thus, this 
sentence is removed and details regarding the 
inclusion of values for analysis depending on 
concurrent events/treatments that could be 
confounded with efficacy will be detailed in the SAP. 
1.1 Graphical Flow 
Design 
Flowchart modified 
Clarify background therapy after the intervention 
period 
1.2 Study Flow Chart,   
9.3.1.1 Sampling time 
Allow samples collected for pharmacokinetics 
at Week 4 to be used for anti-drug antibody 
(anti-SAR440340 antibody or anti dupilumab 
antibody) analysis, if ADA samples test positive 
at Week 12 or at the first post-treatment time 
point analyzed 
As per the FDA request to include additional sampling 
times between Week 0 and Week 12 the sponsor 
proposed that in the event a patient sample is positive 
in the SAR440340 ADA assay at Week 12 or the first 
post-treatment time point analyzed, the Week 4 PK 
sample may be analyzed in the ADA assay.   
1.2 Study Flow Chart,   
9.2.3.4 Clinical 
Laboratory Tests 
HBs Ab (negative) test is removed from 
decision making if to perform HBV DNA testing 
or not 
To fix inconsistency between exclusion criterion E37 
and sections 1.2 and 9.2.3.4 of the protocol. The 
sections mention that HBV DNA testing should only be 
performed if HBsAg negative, HBsAb negative and 
HBcAb positive.  HBs Ab positivity, however, should 
not exclude possibility to perform HBV DNA testing in 
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Section # and 
Name 
Description of Change 
Brief Rationale 
patients who are HBcAb positive. HBs Ab develops in 
patients who recovered from hepatitis B virus infection 
or who have been successfully vaccinated against 
hepatitis B.  
 
6.1 Description of the 
study, 8.2 
Noninvestigational 
medicinal products 
The same inhaler type is required throughout 
study 
Clarification: it was intended that patients use the 
same inhaler type throughout the study, taking into 
account the withdrawal design and the primary 
endpoint of Loss of asthma control (LOAC), but this 
was not specified. 
6.4.1 Data Monitoring 
Committee 
Specify the responsibities of the DMC to 
evaluate all study data (ie.not limited to safety 
data). 
Allow the DMC to review all data (efficacy and safety), 
as per internal DMC charter. 
 
Specify that the DMC members are 
independent of the project/study teams and are 
not involved in the study conduct  
 
7.2. Exclusion 
Criteria (EO9) 
Patients with a history of a systemic 
hypersensitivity reaction to biologic drug is 
changed to “Patients with a history of a 
systemic hypersensitivity reaction to a 
monoclonal antibody”. 
To add clarity and specifity regarding the systemic 
hypersensitivity to a monoclonal antibody, since class 
of biological drugs is very broad and unlikely to be 
predictive of hypersensitivity to either of IMPs. 
Therefore exclusion was narrowed down to past 
hypersensitivity to a monoclonal antibody. 
7.2 Exclusion Criteria 
(E17) 
Exclude patients who  have been treated with 
commercially available dupilumab 
Dupilumab is commercially available in some 
countries. 
7.2 Exclusion Criteria 
(E27) 
Exclude patients with known allergy to 
doxycycline or related compounds, or a known 
allergy to SAR440340 excipients 
Clarify that in addition to patients with a known allergy 
to doxycycline, patients with a known allergy to any 
SAR440340 excipient should be excluded from the 
study. 
8.2 
Noninvestigational 
medicinal products, 
8.8 Concomitant 
Medication 
Specify that the third controller is not allowed 
for an additional 4 weeks prior to screening 
visit (V1). 
To clarify time window required between the third 
controller withdrawal and the screening visit V1. 
8.8 Concomitant 
Medication 
Remove intra-articular steroids from permitted 
concomitant therapy 
Resolve an inconsistency as relevant systemic 
exposure may occur with intra-articular steroids. 
Systemic steroids (except systemic steroids to treat 
asthma exacerbations) are not permitted during the 
screening or treatment phases. 
9.2.2.5 Standardized 
Rhinoconjunctivitis 
Quality of Life 
Questionnaire in 
those patients with 
comorbid allergic 
rhinitis 
Corrected  from Rhinoconjunctivitis Quality of 
Life Questionnaire (RQLQ[S] +12) to RQLQ[S] 
 
 
 
 
To fix discrepancy between the Appendix F and 
section 9.2.2.5. RQLQ [S] is the questionnaire 
intended to be used in the study since only adult 
patients can participate in the study. Section 9.2.2.5 
incorrectly mentions the RQLQ[S] +12 questionnaire 
that is intended for adults and kids of age ≥ 12.   
 
9.3.1.1 Sampling 
time, 10.6.4 Elevated 
liver function tests 
Specify that ADA sampling should only be 
performed for SAEs and AESIs of anaphylaxis, 
hypersensitivity reaction, injection site reaction 
To harmonize with other SAR440340 studies. It is 
anticipated that formation of ADA will likely have 
limited effect on liver function. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
but not in case of liver ALT increase 
 
 
 
9.3.2.1 
Pharmacodynamic 
variables 
Serum (not plasma) will be collected for testing 
Pulmonary and activation-regulated chemokine 
(PARC) 
Serum will be used to assay for PARC 
10.1 Visit Schedule 
Change the order of assessments (ECG 
positioned prior to lung function 
measurements). 
All ECGs should be preferably performed prior to 
FeNO and spirometry measurements in order to 
prevent potential effect of 
albuterol/salbutamol/levalbuterol/levosalbutamol 
administration on ECG tracing. 
10.4.1.3 Adverse 
event of Special 
Interest 
Modify the definition of overdose with NIMP to 
“An overdose (accidental or intentional) with 
any NIMP is an event suspected by the 
Investigator or spontaneously notified by the 
patient and defined as at least twice the 
maximum daily dose as specified in a drug 
label, within the intended therapeutic interval” 
The definition has been modified to better reflect the 
fact that NIMP dose (inhaled steroids, long-acting beta 
agonists, short-acting beta agonists) may increase if 
patients experience a worsening of asthma symptoms. 
This should be considered as therapeutic intervention 
and not overdose. 
Appendix A 
Delete the footnote, “Hormonal contraception 
may be susceptible to interaction with the study 
treatment, which may reduce the efficacy of the 
contraceptive method. In this case TWO highly 
effective methods of contraception should be 
utilized during the treatment period and for at 
least 20 weeks after the last dose of study 
treatment.” 
This footnote is not applicable as the hormonal 
contraception is not expected to interact with study 
treatment. 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: SAR440340 
STUDY No.: ACT15102 
TITLE 
A randomized, double-blind, placebo-controlled, parallel-group, 12-week 
Proof-of-Concept (PoC) study to assess the efficacy, safety, and tolerability 
of SAR440340, and the coadministration of SAR440340 and dupilumab in 
patients with moderate-to-severe asthma who are not well controlled on 
inhaled corticosteroid (ICS) plus long-acting β2 adrenergic agonist (LABA) 
therapy 
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
2a 
STUDY OBJECTIVE(S) 
 
Primary objective: 
The primary objective of this study is to evaluate the effects of SAR440340 
with or without dupilumab, compared to placebo, on reducing the incidence 
of “loss of asthma control” (LOAC*) events.  
Secondary objectives: 
Evaluate the effects of SAR440340 and coadministration of SAR440340 and 
dupilumab, compared with placebo, on forced expiratory volume in 1 second 
(FEV1). 
Estimate the effects of coadministration of SAR440340 and dupilumab, 
compared with SAR440340 and compared with dupilumab, on FEV1. 
Safety and tolerability of SAR440340 alone and in coadministration with 
dupilumab. 
Other objectives: 
Evaluation of the calibrator (dupilumab) arm performance. 
To evaluate the effects of SAR440340 and the coadministration of both 
compared to placebo on: 
- 
Other spirometric assessments (peak expiratory flow [PEF], 
forced vital capacity [FVC], forced expiratory flow [FEF] 
25-75%). 
- 
Patient reported outcomes. 
- 
Immunogenicity (ie, anti-drug antibodies [ADA]). 
- 
The pharmacokinetic (PK) profile of SAR440340 and 
dupilumab in serum. 
- 
Selected biomarkers of the interleukin (IL)-33 and IL4/IL13 
pathway. 
Furthermore, the effects of the coadministration of SAR440340 and 
dupilumab on relevant endpoints compared to each monotherapy treatment 
arm will be assessed as well. 
* Definition of loss of asthma control (LOAC) 
Loss of asthma control (LOAC) event during the treatment period is a 
deterioration of asthma defined as any of the following: 
A 30% or greater reduction from baseline in morning PEF on 2 consecutive 
days 
≥6 additional reliever puffs of salbutamol/albuterol or 
levosalbutamol/levalbuterol in a 24 hour period (compared to baseline) on 2 
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consecutive days 
Increase in ICS ≥4 times the last prescribed ICS dose (or ≥50% of the 
prescribed ICS dose at V2 if background therapy withdrawal completed) 
Requiring use of systemic (oral and/or parenteral) steroid treatment 
Requiring Hospitalization or emergency room visit. 
STUDY DESIGN 
Multinational, randomized, double-blind, placebo-controlled, parallel-group 
(4 groups), 12-week Proof of Concept (PoC) study that is designed to 
assess the efficacy, safety, and tolerability of SAR440340 (an anti-IL33 
monoclonal antibody), and the coadministration of SAR440340 and 
dupilumab (an anti-IL4-Rα monoclonal antibody that blocks the biologic 
activities of both IL4 and IL13), in patients with moderate-to-severe asthma 
who are not well controlled on inhaled ICS/LABA therapy. Study treatment 
includes IMP (SAR440340 and/or dupilumab and/or placebo) added-on to a 
background therapy of ICS/LABA (fluticasone/salmeterol [noninvestigational 
medicinal product], standardized at screening). Background therapy of 
ICS/LABA will be withdrawn during the 12-week randomized treatment 
period and resumed at the end of the IMP treatment period for the 20-week 
safety follow-up period, as outlined below: 
Screening period (4 weeks ± 3 days)  
Randomized IMP treatment period (12 weeks ± 3 days) 
- 
Background therapy stabilization phase (4 weeks)  
- 
Background therapy withdrawal phase (4-5 weeks)  
- 
No background therapy phase (3-4 weeks) 
Post IMP treatment safety follow-up period (20 weeks ± 5 days) 
At screening, patients must be using medium or high dose ICS therapy 
(≥250 mcg of fluticasone propionate twice daily [BID] or equipotent ICS daily 
dosage to a maximum of 2000 mcg/day of fluticasone propionate or clinically 
comparable) in combination with a LABA for at least 3 months with a stable 
dose ≥1 month prior to Screening Visit 1.  
It is intended that approximately half of the patients included in the study will 
be on medium ICS dose at enrolment. 
After completion of screening procedures, all eligible patients will be 
switched to clinically comparable doses of the study-specific ICS/LABA 
combination therapy with fluticasone/salmeterol, as approved for region: 
Fluticasone/salmeterol – dry powder inhaler (DPI):  
1 puff of 250/50 mcg twice daily (BID) or  
1 puff of 500/50 mcg BID  
    OR 
Fluticasone/salmeterol – metered dose inhaler (MDI):  
2 puffs of 115/21 mcg (230/42 mcg) BID or  
2 puffs of 230/21 mcg (460/42 mcg) BID 
    OR 
Fluticasone/salmeterol – MDI:  
2 puffs of 125/25 mcg (250/50 mcg) BID or  
2 puffs of 250/25 mcg (500/50 mcg) BID 
Patients who satisfy the inclusion and exclusion criteria will be randomized 
(1:1:1:1 ratio) to one of the following IMP treatment groups: 
SAR440340 (300 mg) administered as 2 subcutaneous (SC) injections every 
2 weeks (q2w) for 12 weeks and coadministration of dupilumab placebo as 1 
SC injection q2w for 12 weeks 
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Dupilumab (300 mg) administered as 1 SC injection q2w for 12 weeks and 
coadministration of SAR440340 placebo as 2 SC injections q2w for 
12 weeks 
SAR440340 (300 mg) administered as 2 SC injections q2w for 12 weeks 
and coadministration of dupilumab (300 mg) administered as 1 SC injection 
q2w for 12 weeks 
Coadministration of matching placebos for SAR440340 and dupilumab 
administered as 2 and 1 SC injections, respectively, q2w for 12 weeks  
Visits during the 12-week IMP treatment period will occur every week and 
will be followed by a 20-week observational follow-up period. 
Background therapy (ICS/LABA) withdrawal phase: 
At Week 4 (Visit 6) post-randomization, the LABA component (salmeterol) 
will be withdrawn, and patients will be switched from their BID 
fluticasone/salmeterol combination therapy to a clinically comparable ICS 
dose of fluticasone BID monotherapy, as approved for region: 
- 
Fluticasone (DPI formulation):  
1 puff of 250 mcg BID or 
2 puffs of 250 mcg (500 mcg) BID,  
OR  
- 
Fluticasone (MDI formulation):  
2 puffs of 110 mcg (220 mcg) BID or  
2 puffs of 220 mcg (440 mcg) BID 
OR  
- 
Fluticasone (MDI formulation):  
2 puffs of 125 mcg (250 mcg) BID or  
2 puffs of 250 mcg (500 mcg) BID 
The ICS component (fluticasone) will be withdrawn by a step-wise dose 
reduction starting at Week 6 (Visit 8) and will continue at each Weeks 7, 8, 
and 9 (Visits 9, 10, and 11, respectively), provided that patients do not 
experience a LOAC event. 
Patients that meet the criteria for a LOAC, at any time during the 
randomized IMP treatment phase, will (be): 
- 
Discontinue early from IMP treatment,  
- 
Evaluated and receive treatment by the Investigator with 
standard of care according to standard medical practice, 
- 
Resume their individual prescreening ICS/LABA background 
therapy and,  
- 
Followed for safety during a 20-week Post IMP Treatment 
Period. 
Early treatment discontinuation (ETD) follow-up:  
Patients who discontinue IMP treatment prior to completing the 12-week IMP 
treatment (due to LOAC or due to early treatment discontinuation), will be 
evaluated as soon as possible at the individual patients’ End of Treatment 
(EOT) Visit, using procedures as planned for the EOT Visit at Week 12 
(Visit 14). At their EOT visit, patients will resume their prescreening 
ICS/LABA background therapy and enter the 20-week safety follow-up 
period/Post IMP Treatment Period (Visit 15 to Visit 17). 
 
 
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Post IMP treatment follow-up: 
Patients who complete the 12-week randomized IMP treatment period at 
Week 12 (Visit 14) EOT visit, as per protocol, resume their prescreening 
ICS/LABA therapy and enter the 20-week safety follow-up period/Post IMP 
Treatment Period (Visit 15 to Visit 17).  
Note: For patients who meet the criteria for a LOAC or discontinue IMP 
treatment early (due to other reasons) prior to 12 weeks of treatment, their 
ETD EOT visit and their individual 20-week Post IMP Treatment Period may 
start earlier than at Week 12.  
At any EOT visit, if a patient’s asthma cannot be adequately controlled by 
the prescreening ICS/LABA therapy, additional controller therapies may be 
prescribed based on the Investigator’s clinical judgement. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
I 01. 
Adult patients with a physician diagnosis of asthma for at least 
12 months based on the Global Initiative for Asthma (GINA) 2017 
Guidelines  
I 02. 
Patients with existing treatment with medium to high dose ICS 
(≥250 mcg of fluticasone propionate BID or equipotent ICS daily 
dosage to a maximum of 2000 mcg/day of fluticasone propionate 
or clinically comparable) in combination with a LABA as second 
controller for at least 3 months with a stable dose ≥1 month prior to 
Visit 1. Please note that the lower limit of allowed ICS dose (500 
mcg of fluticasone propionate daily) corresponds to upper limit of 
medium dose defined by GINA guidelines. Patients receiving 
medium ICS dose <500 mcg daily are not eligible. 
I 03. 
Patients with prebronchodilator FEV1 >40% of predicted normal at 
Visit 1/Screening. Prebronchodilator FEV1 ≥50% but ≤85% of 
predicted normal at Visit 2/Baseline.  
I 04. 
Patients with reversibility of at least 12% and 200 mL in FEV1 after 
administration of 2 to 4 puffs (200-400 mcg) of albuterol/salbutamol 
or levalbuterol/levosalbutamol during screening or documented 
history of a reversibility test that meets this criteria within 
12 months prior to Visit 1 or documented positive response to 
methacholine challenge (a decrease in FEV by 20% [PC20] of 
<8mg/mL) within 12 months prior to Visit 1/Screening is considered 
acceptable to meet this inclusion criterion. 
I 05. 
Patients must have experienced, within 1 year prior to Visit 1, any 
of the following events at least once: 
- 
Treatment with a systemic steroid (oral or parenteral) for 
worsening asthma. 
- 
Hospitalization or emergency medical care visit for worsening 
asthma. 
I 06. 
Signed written informed consent. 
Exclusion criteria: 
Patients who have met all the above inclusion criteria will be screened for 
the following key exclusion criteria: 
E 01. 
Patients <18 years or >70 years of age (ie, have reached the age 
of 71 at the screening visit) 
E 02. 
Patients with body mass index (BMI) <16 
E 03. 
Chronic lung disease (for example, chronic obstructive pulmonary 
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disease [COPD], or idiopathic pulmonary fibrosis [IPF]) which may 
impair lung function, or another diagnosed pulmonary or systemic 
disease associated with elevated peripheral eosinophil counts, for 
eg eosinophilic granulomatosis with polyangiitis. 
E 04. 
History of life threatening asthma (ie, severe exacerbation that 
requires intubation). 
E 05. 
Co-morbid disease that might interfere with the evaluation of IMP 
E 06. 
Patients with any of the following events within the 4 weeks prior to 
their Screening Visit 1 or during the screening period: 
- 
Treatment with 1 or more systemic (oral and/or parenteral) 
steroid bursts for worsening asthma 
- 
Hospitalization or emergency medical care visit for worsening 
asthma 
E 07. 
Asthma Control Questionnaire 5-question version (ACQ-5) score 
<1.25 or >3.0 at V2/randomization.  During the screening period an 
ACQ-5 of up to ≤4 is acceptable. 
E 08. 
Anti-immunoglobulin E (IgE) therapy (eg, omalizumab [Xolair®]) 
within 130 days prior to Visit 1 or any other biologic therapy 
(including anti-IL5 monoclonal antibody [mAb]) or systemic 
immunosuppressant (eg, methotrexate) to treat inflammatory 
disease or autoimmune disease (eg, rheumatoid arthritis, 
inflammatory bowel disease, primary biliary cirrhosis, systemic 
lupus erythematosus, multiple sclerosis) and other diseases, within 
2 months or 5 half-lives prior to Visit 1, whichever is longer. 
E 09. 
Patients with a history of a systemic hypersensitivity reaction to a 
monoclonal antibody. 
E 10. 
Patients on or initiation of bronchial thermoplasty within 2 years 
prior to Visit 1 or plan to begin therapy during the screening period 
or the randomized treatment period. 
E 11. 
Current smoker or cessation of smoking within the 6 months prior 
to Visit 1. 
E 12. 
Previous smoker with a smoking history >10 pack-years. 
For a complete list of exclusion criteria, see protocol. 
Total expected number of patients 
Approximately 240 patients, randomized in a 1:1:1:1 ratio to receive 
SAR440340 (60), dupilumab (60), SAR440340 and dupilumab (60), or 
placebo (60). 
Expected number of sites: 
80 
STUDY TREATMENTS 
 
Investigational medicinal products 
SAR440340 and matching placebo  
Dupilumab (SAR231893) and matching placebo 
Formulation: 
SAR440340 for SC administration: 1 vial of lyophilisate drug product 
(287 mg) is reconstituted with 2.5 mL of sterile water for injection resulting in 
2.9 mL of 100 mg/mL SAR440340 DP. A volume of 1.5 mL per injection will 
be withdrawn from the vial. Sterile placebo will be provided in matched glass 
vials. 
Dupilumab for SC administration is supplied as 150 mg/mL in glass prefilled 
syringes to deliver 300 mg in 2.0 mL. Placebo matching dupilumab is 
prepared in the same formulation as dupilumab, without the addition of 
protein. 
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Route of administration: 
SC. All IMP applications will be done as separate injections. 
Dose regimen: 
SAR440340 (300 mg) administered as 2 SC injections q2w for 12 weeks 
and coadministration of dupilumab placebo as 1 SC injection q2w for 
12 weeks 
Dupilumab (300 mg) administered as 1 SC injection q2w for 12 weeks and 
coadministration of SAR440340 placebo as 2 SC injections q2w for 
12 weeks 
SAR440340 (300 mg) administered as 2 SC injections q2w for 12 weeks 
and coadministration of dupilumab (300 mg) administered as 1 SC injection 
q2w for 12 weeks 
Coadministration of matching placebos for SAR440340 and dupilumab 
administered as 2 and 1 SC injections, respectively, q2w for 12 weeks  
Noninvestigational medicinal 
products 
Formulation: 
Background Therapy 
From Screening Visit 1 to Visit 2/randomization (4 weeks), all eligible 
patients will receive fluticasone/salmeterol as study-specific ICS/LABA 
background therapy. This background treatment is maintained for the first 
4 weeks of randomized IMP treatment during the background therapy 
stabilization phase. 
At Week 4 (Visit 6) post-randomization, the LABA component (salmeterol) 
will be withdrawn, and patients will be switched from their BID 
fluticasone/salmeterol combination therapy to a clinically comparable ICS 
dose of fluticasone monotherapy. 
The ICS component (fluticasone) will be withdrawn by a step-wise dose 
reduction starting at Week 6 (Visit 8) and will continue at each  
Weeks 7, 8, and 9 (Visits 9, 10, and 11, respectively), provided that patients 
do not experience a LOAC event (ie, are prematurely withdrawn). 
One inhaler for the combination fluticasone/salmeterol and another inhaler 
for fluticasone alone will be provided while patient is in screening and on 
IMP treatment. Dry Powder Inhaler (DPI)/Metered Dose Inhaler (MDI), as 
applicable. 
Reliever Medication 
Patients may use albuterol/salbutamol or levalbuterol/levosalbutamol MDI as 
reliever medication as needed during the study. Nebulizer solutions may be 
used as an alternative delivery method. 
Route of administration: 
Oral inhalation, nebulizer for albuterol, levalbuterol, fluticasone/salmeterol 
combination therapy, and fluticasone monotherapy. 
Dose regimen: 
 
Background therapy stable phase: From Screening Visit 1 (Week -4) up 
to Visit 6 (Week 4) clinically comparable doses of the study-specific 
ICS/LABA combination therapy with fluticasone/salmeterol, as approved for 
region: 
Fluticasone/salmeterol – DPI:  
1 puff of 250/50 mcg twice daily (BID) or  
1 puff of 500/50 mcg BID 
    OR 
Fluticasone/salmeterol – MDI:  
2 puffs of 115/21 mcg (230/42 mcg) BID or  
2 puffs of 230/21 mcg (460/42 mcg) BID 
    
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 OR 
Fluticasone/salmeterol – MDI:  
2 puffs of 125/25 mcg (250/50 mcg) BID or  
2 puffs of 250/25 mcg (500/50 mcg) BID. 
Background therapy withdrawal phase: Salmeterol will be withdrawn at 
Week 4 (Visit 6) post-randomization. Patients will be switched from their BID 
fluticasone/salmeterol combination therapy to a clinically comparable ICS 
dose of fluticasone BID monotherapy, as approved for region: 
- 
Fluticasone (DPI formulation):  
1 puff of 250 mcg BID or 
2 puffs of 250 mcg (500 mcg) BID,  
OR  
- 
Fluticasone (MDI formulation):  
2 puffs of 110 mcg (220 mcg) BID or  
2 puffs of 220 mcg (440 mcg) BID 
OR  
- 
Fluticasone (MDI formulation):  
2 puffs of 125 mcg (250 mcg) BID or  
2 puffs of 250 mcg (500 mcg) BID 
The ICS component (fluticasone) will be withdrawn by a step-wise dose 
reduction starting at Week 6/Visit 8 (DPI: 100 mcg BID or 250 mcg BID or 
MDI: 110 or 125 mcg BID or 220 or 250 mcg BID) and will continue at Week 
7 (DPI: 50 mcg BID or 100 mcg BID or MDI: 44 or 50 mcg BID or 110 or  
125 mcg BID), Week 8 (DPI: 0 mcg BID or 50 mcg BID or MDI: 0 mcg BID or 
44 or 50 mcg BID) and Week 9 (DPI: 0 mcg BID or 0 mcg BID or MDI: 0 mcg 
BID or 0 mcg BID), provided that patients do not experience a LOAC event 
(ie, are prematurely withdrawn). 
ENDPOINTS 
 
Primary endpoint: 
The primary endpoint is the proportion of patients with LOAC. 
Secondary endpoint:  
FEV1 change from baseline at Week 12 
(pre- and postbronchodilator).  
Other efficacy endpoints: 
Change from baseline in other lung function measurement (peak expiratory 
flow [PEF], forced vital capacity [FVC], forced expiratory flow [FEF] 25-75%) 
at Week 12 and at each assessment time point. 
ACQ-5 score change from baseline at Week 12 and at each assessment 
time point. 
Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ 
[S]) Self-Administered change from baseline at Week 12 and at each 
assessment time point.  
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score change from 
baseline at Week 12 in patients with a secondary diagnosis of allergic 
rhinitis. 
Change from baseline at Week 12 and change from baseline at each week 
for asthma symptom scores in the morning and evening, and nocturnal 
awakenings. 
Change from baseline at Week 12 and change from baseline at each week 
in number of inhalations/day of albuterol or levalbuterol for symptom relief. 
 
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Safety evaluation: 
Adverse events (AEs)/treatment-emergent adverse events (TEAEs). 
Physical examination and body weight. 
Vital signs and 12-lead electrocardiogram. 
Clinical laboratory tests. 
Tolerability at IMP injection site. 
Systemic drug concentration and Anti-drug antibodies: 
Serum functional SAR440340 concentrations and PK profile. 
Serum functional dupilumab concentrations and PK profile. 
Antidrug antibodies (ADA) against SAR440340.  
ADA against dupilumab. 
Biomarkers and other pharmacodynamics: 
Blood eosinophil and neutrophil counts. 
Fraction of exhaled nitric oxide (FeNO) level compared with baseline. 
Total IL33, soluble IL33 receptor (sST2), periostin. 
Calcitonin.  
Pulmonary and activation-regulated chemokine (PARC) and eotaxin-3.  
Total IgE. 
Optional: Messenger ribonucleic acid (mRNA) sequencing or whole 
transcriptome analysis. 
Optional: Blood sample archival for exploratory research 
Optional: Deoxyribonucleic acid (DNA) for assessment of pharmacogenomic 
effects.  
ASSESSMENT SCHEDULE 
Screening Period (4 weeks [±3 days]). 
Randomized IMP Treatment Period (12 weeks [±3 days]). 
- 
Background (ICS/LABA) therapy stabilization phase 
(4 weeks, [±3 days]).  
- 
Background therapy withdrawal phase (4-5 weeks, 
[±3 days]).  
- 
No background therapy phase (3-4 weeks, [±3 days]). 
Post IMP treatment safety follow-up period (20 weeks [±5 days]). 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Data from a previous study with dupilumab with similar design (ACT11457) 
showed a 44% rate of LOAC in the placebo group in a 12-week study with a 
similar population and background treatment compared to a 6% rate of 
LOAC in the dupilumab group, for an 87% relative reduction with dupilumab. 
Therefore, the placebo incidence of LOAC events is assumed to be 40%, 
and with 50 patients per group the study will have 80% power to detect a 
26% reduction in the rate of LOAC events (to 14% in the SAR440340 group) 
at the 5% significance level (two-sided). Allowing for approximately 15% 
dropouts, a sample size of 60 patients per group has been defined. 
Furthermore, based upon ACT11457 the standard deviation for the absolute 
change in FEV1 after 12 weeks is estimated to be 0.35 L. For the purpose of 
calculation 50 of the 60 randomized patients per group are assumed to have 
Week 12 data (based on ACT11457 where ~80% of patients had this data). 
Therefore at the 5% significance level there will be 80% power to detect 
differences of 0.2 L among the treatment groups. The smallest difference in 
the trial that will still be declared statistically significant at the 5% level is 
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estimated to be 0.14 L. The observed effect of dupilumab versus placebo 
was 0.27 L. 
Randomization will be stratified by Screening Visit 1 eosinophil count and by 
country.  
To ensure enrollment according to intended distribution of baseline 
eosinophil count, alerts will be built into the interactive voice/web response 
system (IVRS/IWRS) to limit enrolling patients in the following 2 stratification 
groups:  
Eosinophil <150/mm3: not more than approximately 25% (60) patients  
Eosinophil ≥300/mm3: at least approximately 45% (108) patients 
 
Analysis population: 
The primary population for efficacy analysis will be all randomized patients 
receiving at least one dose of study drug, analyzed in their assigned group 
(modified intent-to-treat [mITT]). 
The safety population is defined as all patients who have received at least 
one dose of the IMP, analyzed according to the treatment actually received. 
Primary analysis: 
For the primary analysis of proportion of patients experiencing an LOAC 
event, a logistic regression model will be used to compare SAR440340 with 
placebo and the coadministration of SAR440340 and dupilumab with 
placebo. The model will include terms for treatment stratification factors, 
baseline background ICS dose level and number of exacerbation events 
within 1 year prior to screening. The odds ratio and 95% confidence interval 
will be estimated from this model.    
Safety analysis: 
Safety analyses will be descriptive, based on the safety population. The 
safety analysis will focus on the TEAE period. This period is defined as the 
time from the first administration of the IMP to the last administration of the 
IMP plus 22 weeks.  
Interim analyses: 
No formal interim analysis is planned. Analyses will be performed for safety 
monitoring and internal decision making. No formal stopping rules or 
adjustment for multiplicity will be applied. 
DURATION OF STUDY PERIOD (per 
patient)  
The total duration of the study (per patient) is expected to be up to 
36 weeks: 
• 
4 weeks (±3 days) of screening period 
• 
12 weeks (±3 days) of randomized IMP treatment period 
20 weeks (±5 days) of post IMP treatment safety follow-up period 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
 
 
* Depending on regional availability 
 
Abbreviations: SC: subcutaneous, q2w: every 2 weeks, Wk: week, BID: twice daily, DPI: dry powder inhaler, MDI: metered dose inhaler, µg: microgram 
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1.2 
STUDY FLOW CHART 
 
Randomized IMP Treatment Period (± 3 days) 
Including the Following Background ICS/LABA Therapy Phases: 
 
No ICS/LABAb 
Period 
Screening
(± 3 days)
ICS/LABA stabilization 
ICS/LABA withdrawalb,c 
No ICS/LABAc 
Post IMP 
Treatment Period 
(± 5 days) 
VISIT 
V1 
V2 
Randomi 
zation/ 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
EOTd,e
V15 
V16f 
V17 
EOS 
DAYa 
D-28 to D0 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
D141 
D183 D225 
WEEK 
W-4 to W0 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
W20 
W26 
W32 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Previous medical and surgical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualifying Spirometry and Reversibilityg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior & concomitant meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Switch from current ICS/LABA combination to 
Sponsor-supplied fluticasone/salmeterol combination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Call IVRS/IWRS 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study treatment administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP administrationh 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Dispense or download electronic diary/PEF meteri 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xd,e 
 
 
 
Evaluation and LABA (salmeterol) withdrawalj 
 
 
 
 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
Evaluation and ICS (fluticasone) withdrawalk 
 
 
 
 
 
 
 
Xk 
Xk 
Xk 
Xk 
 
 
 
 
 
 
Resume original dose of ICS/LABA therapyd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd,e 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationl 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
Vital signsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Electrocardiogram (12-lead) 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
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Randomized IMP Treatment Period (± 3 days) 
Including the Following Background ICS/LABA Therapy Phases: 
 
No ICS/LABAb 
Period 
Screening
(± 3 days)
ICS/LABA stabilization 
ICS/LABA withdrawalb,c 
No ICS/LABAc 
Post IMP 
Treatment Period 
(± 5 days) 
VISIT 
V1 
V2 
Randomi 
zation/ 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
EOTd,e
V15 
V16f 
V17 
EOS 
DAYa 
D-28 to D0 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
D141 
D183 D225 
WEEK 
W-4 to W0 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
W20 
W26 
W32 
Hematology, biochemistry, urinalysisn 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
Hepatitis and HIV Serology testsn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantiferon gold testingo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (β-hCG blood) testp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy (urine) testp 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Adverse event reporting, including SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetics and Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum sample for SAR440340 concentration 
 
X 
 
X 
 
Xq 
 
 
 
X 
 
 
 
X 
X 
 
X 
Serum sample for dupilumab concentration 
 
X 
 
X 
 
Xq 
 
 
 
X 
 
 
 
X 
X 
 
X 
Anti-SAR440340 antibody and anti-dupilumab 
antibody 
 
X 
 
 
 
Xq 
 
 
 
 
 
 
 
X 
 
 
X 
Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood eosinophils and neutrophils 
X 
X 
 
Xr 
 
X 
 
Xr 
 
X 
 
 
 
X 
X 
 
X 
FeNOs 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
Total IL33 and sST2 (Serum) 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
Calcitonin 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
PARC  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Eotaxin-3  
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Total IgE  
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Periostin  
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
RNA sample (optional) 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Blood sample archival for exploratory research 
(optional) 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
PGx analysis (optional) 
 
X 
 
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Randomized IMP Treatment Period (± 3 days) 
Including the Following Background ICS/LABA Therapy Phases: 
 
No ICS/LABAb 
Period 
Screening
(± 3 days)
ICS/LABA stabilization 
ICS/LABA withdrawalb,c 
No ICS/LABAc 
Post IMP 
Treatment Period 
(± 5 days) 
VISIT 
V1 
V2 
Randomi 
zation/ 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
EOTd,e
V15 
V16f 
V17 
EOS 
DAYa 
D-28 to D0 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
D141 
D183 D225 
WEEK 
W-4 to W0 
W0 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
W20 
W26 
W32 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOAC event reporting 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Spirometry (FEV1) (pre-BD)t 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Spirometry (FEV1) (post-BD)t 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
ACQ-5u 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
AQLQ(S)u 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
RQLQ (patients with history of allergic rhinitis only)u 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
Abbreviations:ACQ-5 = asthma control questionnaire-5; AQLQ(S) = asthma quality of life questionnaire;β-hCG = beta human chorionic gonadotropin, D = day; DNA  =  deoxyribonucleic acid; EDTA = ethylene-diamine-
tetra-acetic acid; EOT = End of Treatment; FEF = forced expiratory flow; FeNO = fraction of exhaled nitric oxide; FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; IgE = Immunoglobulin E; 
IMP = investigational medicinal product, IL33  = interleukin-33; IVRS/IWRS = Interactive Voice/Web Response System; LABA = long-acting β2 adrenergic agonist; LOAC = loss of asthma control;  BD = bronchodilator; 
PARC = pulmonary and activation-regulated chemokine; PEF = peak expiratory flow; PGx = pharmacogenomics; PK = pharmacokinetic; RNA = ribonucleic acid; RQLQ = rhinoconjunctivitis quality of life questionnaire; 
SAE = serious adverse event; sST2 = soluble IL33 receptor; V = visit; W = week. 
a The study visits occur on the planned dates (relative to the first injection), as scheduled. The visit schedule should be adhered to within ±3 days for the screening period and randomized IMP treatment period, and 
±5 days for the visits during the post IMP treatment safety follow-up period. 
b After 5 weeks of ICS/LABA withdrawal phase, patients with high dose ICS (fluticasone) backgound at Visit 2/baseline will be on IMP treatment without background therapy for 3 weeks.  
c After 4 weeks of ICS/LABA withdrawal phase, patients with medium dose fluticasone backgound at Visit 2/baseline will be on IMP treatment without background therapy for 4 weeks. 
d End of IMP treatment (EOT) visit: Patients who discontinue prematurely from the study (ie, early treatment discontinuation [ETD]), prior to completing the 12-week IMP treatment (eg, due to a LOAC event or due to 
other reasons), will be evaluated as soon as possible at the individual patients’ EOT Visit, using procedures as planned for the EOT Visit at Week 12 (Visit 14). At their EOT visit, all patients will resume their 
prescreening ICS/LABA background therapy and enter the 20-week Post IMP Treatment Period (V15 to V17). If a patient’s asthma cannot be adequately controlled by the prescreening ICS/LABA therapy, 
additional controller therapies may be prescribed based on the Investigator’s clinical judgement. 
e The Post IMP Treatment Period will start at Week 12 for patients who complete the IMP treatment period, and may start earlier than Week 12 for patients who meet the criteria for a LOAC or discontinue IMP 
treatment early (due to other reasons) prior to completing the 12-week IMP treatment. 
f 
Visit 16 visit can be either an on-site visit or a phone-call. 
g Patients with reversibility of at least 12% and 200 mL in FEV1 after administration of 2 to 4 puffs (200-400 mcg) of albuterol/salbutamol or levalbuterol/levosalbutamol during screening or documented history of a 
reversibility test that meets this criteria within 12 months prior to Visit 1 or documented positive response to methacholine challenge (a decrease in FEV by 20% [PC20] of <8mg/mL) within 12 months prior to Visit 
1/Screening is considered acceptable to meet this inclusion criterion. If the subject does not meet the qualifying criteria for reversibility at Visit 1/Screening, up to 2 additional attempts during the screening period, 
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each on a different day prior to Visit 2/Baseline, may be performed. When reversibility assessment is repeated during the screening period, the prebronchodilator FEV1 should again meet the inclusion criterion (I 
03) of >40% of predicted normal. 
h Patients should be monitored by site personnel for at least 30 minutes after administration of all IMP injections. Monitoring period may be extended as per country specific requirements. 
i 
Electronic diary/PEF meter is a handheld device used for daily recording of salbutamol/albuterol or levosalbutamol/levalbuterol use, asthma controller drug use, asthma symptom score Numerical Rating Scale 
(NRS), nocturnal awakenings due to asthma symptoms and AM and PM PEF, and recording of patient’s answers to the ACQ-5, AQLQ(S), and RQLQ questionnaires during the scheduled visits. This handheld 
device is dispensed at Visit 1 (including instructions for use) and recorded information is downloaded from this device on the other indicated days. If not already done so, patient will return electronic devices to the 
site at EOS. Electronic devices will be returned to the sponsor at EOS as the latest. 
j 
After evaluation for LOAC events, all patients that do not meet the criteria for LOAC at Week 4/V6, will have the LABA (salmeterol) withdrawn from their background therapy and will be switched from 
fluticasone/salmeterol combination therapy to clinically comparable ICS dose of fluticasone monotherapy. 
k After evaluation for LOAC events, all patients that do not meet the criteria for LOAC at V8, V9, V10 (and V11), will have ICS (fluticasone) withdrawn by 3 or 4 steps of dose reduction depending on their medium or 
high dose ICS (fluticasone) background treatment at Visit 2/baseline, respectively.  
l 
Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
m Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), and respiratory rate (breaths per minute) will be measured at all visits detailed in the flowchart. Height (cm) will be 
measured at screening (Visit 1) only. Body weight (kg) will be measured at Visit 1/Screening, Visit 2/Baseline and Visit 14/EOT. 
n Hematology will include hemoglobin, hematocrit, platelet count, total white blood cell count, differential count, and total red blood cell count. Serum chemistry will include include creatinine, blood urea nitrogen, 
glucose, uric acid, total cholesterol, total protein, albumin, total bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, electrolytes (sodium, potassium, chloride), bicarbonate, and 
creatine phosphokinase. Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, leukocyte esterase, urobilinogen, and bilirubin. If any parameter on the dipstick is abnormal, a urine 
sample should be sent to the central laboratory for quantitative measurement. If positive for protein and/or red blood cells, microscopic analysis will be performed by the central laboratory. Clinical laboratory testing 
at Screening Visit 1 will include hepatitis screen covering hepatitis B surface antigen (HBs Ag), hepatitis B surface antibody (HBs Ab), hepatitis B core antibody (HBc Ab), hepatitis C virus antibodies (HCV Ab), 
human immunodeficiency virus (HIV) screen (Anti-HIV-1 and HIV-2 antibodies) and anti-nuclear antibody (ANA). In case of results showing HBs Ag (negative), and HBc Ab (positive), an HBV DNA testing may be 
performed prior to randomization to rule out a false positivity if the Investigator believes the patient is a false positive, or to clarify the serological status if the investigator finds it unclear to interpret in absence of 
known HBV infection. In case of results showing HCV Ab (positive), an HCV RNA testing may be performed to rule out a false positivity, if the Investigator believes the patient is a false positive. Note: Anti-ds DNA 
antibody will be tested if ANA is positive (≥1:160 titer). The blood sample for serum chemistry must be taken with the patient in fasting state which means no intake of any food or drink except for water for at least 
8 hours (if the visit can only be done at a different time of the day and the patient is not fasting, then he/she should be advised to eat light food and the site should document that serum chemistry was not obtained 
under fasting conditions). 
o Quantiferon gold should be collected for all patients at the Screening Visit 1. If the result is confirmed positive, the patient should be referred to an Infectious Disease specialist.  Please refer to the central 
laboratory manual for additional details. 
p Only for women of childbearing potential: serum pregnancy test at Screening/V1 and urine pregnancy tests at V2, V6, V10, V14/EOT, and V17/EOS. A negative result must be obtained at V1 and at V2 prior to 
randomization. In case of positive urine test the study treatment will be withheld and a serum pregnancy test to confirm the pregnancy should be performed as soon as possible. Pregnancy will lead to definitive 
treatment discontinuation in all cases.   
q If ADA assessment at week 12 (or the first post-treatment time point analyzed) is positive, additional measurements may be performed from PK samples collected at Week 4. 
r 
Hematology sample will be drawn for eosinophils and neutrophils (with other critical values reported per lab manual). 
s Exhaled nitric oxide assessment will be conducted prior to spirometry and following a fast of at least 1 hour. 
t 
Spirometry (pre-BD FEV1, post-BD FEV1, and PEF, FVC, FEF) should be performed not earlier than 6 hours after last dose of albuterol or levalbuterol (if any) and withholding the last dose of LABA for at least 
12 hours, and prior to administration of investigational product. The postbronchodilator spirometry may be repeated several times within 30 minutes after administration of bronchodilator. 
u The ACQ-5, AQLQ(S), and RQLQ are to be completed on the patient’s handheld device during clinic visits. 
 
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2 
TABLE OF CONTENTS 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................3 
DOCUMENT HISTORY...................................................................................................................................3 
OVERALL RATIONALE FOR THE AMENDMENT........................................................................................3 
1 
FLOW CHARTS.............................................................................................................................16 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................16 
1.2 
STUDY FLOW CHART ..................................................................................................................17 
2 
TABLE OF CONTENTS ................................................................................................................21 
2.1 
LIST OF TABLES...........................................................................................................................27 
3 
LIST OF ABBREVIATIONS ..........................................................................................................28 
4 
INTRODUCTION AND RATIONALE.............................................................................................30 
4.1 
ASTHMA ........................................................................................................................................30 
4.2 
SAR440340 ANTI-IL33 MONOCLONAL ANTIBODY....................................................................31 
4.3 
DUPILUMAB ANTI-IL4R ALPHA MONOCLONAL ANTIBODY.....................................................32 
4.4 
COADMINISTRATION OF SAR440340 WITH DUPILUMAB........................................................32 
4.5 
RISK/BENEFIT...............................................................................................................................33 
4.6 
RATIONALE FOR SELECTING THE DOSE .................................................................................34 
4.7 
STUDY DESIGN ............................................................................................................................34 
5 
STUDY OBJECTIVES ...................................................................................................................36 
5.1 
PRIMARY OBJECTIVE..................................................................................................................36 
5.2 
SECONDARY OBJECTIVES.........................................................................................................36 
5.3 
OTHER OBJECTIVES ...................................................................................................................36 
6 
STUDY DESIGN ............................................................................................................................37 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................37 
6.1.1 
Background therapy (ICS/LABA) withdrawal phase ......................................................................38 
6.1.2 
Early treatment discontinuation (ETD) follow-up ...........................................................................39 
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6.1.3 
Post IMP treatment follow-up.........................................................................................................39 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................40 
6.2.1 
Duration of study participation for each patient .............................................................................40 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................40 
6.3 
INTERIM ANALYSIS......................................................................................................................40 
6.4 
STUDY COMMITTEES..................................................................................................................40 
6.4.1 
Data monitoring committee ............................................................................................................40 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS .............................40 
7 
SELECTION OF PATIENTS..........................................................................................................42 
7.1 
INCLUSION CRITERIA..................................................................................................................42 
7.2 
EXCLUSION CRITERIA ................................................................................................................43 
7.2.1 
Exclusion criteria related to study methodology ............................................................................43 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......44 
7.2.3 
Exclusion criteria related to the current knowledge of SAR440340...............................................45 
7.2.4 
Additional exclusion criteria during or at the end of the screening period .....................................47 
8 
STUDY TREATMENTS .................................................................................................................48 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................48 
8.1.1 
SAR440340....................................................................................................................................48 
8.1.2 
SAR440340 matching placebo ......................................................................................................48 
8.1.3 
Dupilumab......................................................................................................................................48 
8.1.4 
Placebo matching dupilumab.........................................................................................................48 
8.1.5 
Preparation of investigational product............................................................................................48 
8.1.6 
Dosing schedule.............................................................................................................................48 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................49 
8.2.1 
Background therapy (ICS/LABA) withdrawal phase ......................................................................50 
8.2.2 
Reliever medication........................................................................................................................51 
8.3 
BLINDING PROCEDURES............................................................................................................53 
8.3.1 
Methods of blinding........................................................................................................................53 
8.3.2 
Randomization code breaking during the study.............................................................................53 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................53 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................54 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................55 
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8.7 
RESPONSIBILITIES ......................................................................................................................55 
8.7.1 
Treatment accountability and compliance......................................................................................55 
8.7.2 
Return and/or destruction of treatments ........................................................................................56 
8.8 
CONCOMITANT MEDICATION.....................................................................................................56 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................58 
9.1 
PRIMARY ENDPOINT ...................................................................................................................58 
9.2 
SECONDARY AND OTHER EFFICACY ENDPOINTS.................................................................58 
9.2.1 
Other efficacy endpoints ................................................................................................................58 
9.2.2 
Disease-specific efficacy measures...............................................................................................58 
9.2.2.1 
Spirometry......................................................................................................................................58 
9.2.2.2 
Disease-specific, daily efficacy assessments ................................................................................59 
9.2.2.3 
ACQ (Asthma Control Questionnaire)............................................................................................60 
9.2.2.4 
Asthma Quality Of Life Questionnaire with Standardized Activities Self-Administered.................61 
9.2.2.5 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire in those patients with 
comorbid allergic rhinitis ................................................................................................................61 
9.2.2.6 
Asthma Symptom Score Numerical Rating Scale (NRS) ..............................................................62 
9.2.3 
Safety and tolerability endpoints ....................................................................................................62 
9.2.3.1 
Adverse events ..............................................................................................................................62 
9.2.3.2 
Vital signs.......................................................................................................................................63 
9.2.3.3 
Electrocardiogram..........................................................................................................................63 
9.2.3.4 
Clinical laboratory tests..................................................................................................................63 
9.2.3.5 
Pregnancy test ...............................................................................................................................64 
9.3 
OTHER ENDPOINTS.....................................................................................................................65 
9.3.1 
Systemic drug concentration and anti-drug antibodies..................................................................65 
9.3.1.1 
Sampling time ................................................................................................................................65 
9.3.1.2 
Handling procedures......................................................................................................................65 
9.3.1.3 
Bioanalytical method......................................................................................................................66 
9.3.2 
Pharmacodynamics and phenotyping............................................................................................66 
9.3.2.1 
Pharmacodynamic variables..........................................................................................................66 
9.3.2.2 
Whole blood biomarkers ................................................................................................................67 
9.3.2.3 
Exhaled nitric oxide........................................................................................................................67 
9.3.2.4 
Plasma/serum biomarkers .............................................................................................................67 
9.3.3 
Pharmacogenetics .........................................................................................................................68 
9.3.3.1 
Stored DNA (optional) and RNA (optional) samples......................................................................68 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................68 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................69 
10 
STUDY PROCEDURES ................................................................................................................70 
10.1 
VISIT SCHEDULE..........................................................................................................................70 
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10.1.1 
Visit 1/Screening (Week -4 to Week 0 [zero], Day -28 to Day 0) – Screening Visit ......................71 
10.1.2 
Randomized IMP Treatment Phase – Week 0 to Week 12 ...........................................................74 
10.1.2.1 Background therapy stabilization phase – Week 0 to Week 3 (Visits 2 to 5) ................................74 
10.1.2.2 Background therapy withdrawal phase – Week 4 to Week 9 (Visits 6 to 11): LABA 
withdrawal at Week 4, ICS step-wise withdrawal starting at Week 6 ............................................78 
10.1.2.3 No ICS/LABA background therapy phase – Week 9 to Week 12 (Visits 11 to 14)........................83 
10.1.2.4 Week 12 (Visit 14) – End of Treatment – End of Randomized IMP Treatment Period .................86 
10.1.2.5 Post IMP treatment observation period (Visits 15 and 17) ............................................................87 
10.1.2.6 Visit 17, Day 225 (Week 32) – End of Study Visit..........................................................................88 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................89 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................90 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................90 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................90 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................90 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................91 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................92 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................93 
10.4.1 
Definitions of adverse events.........................................................................................................93 
10.4.1.1 Adverse event ................................................................................................................................93 
10.4.1.2 Serious adverse event ...................................................................................................................93 
10.4.1.3 Adverse event of special interest...................................................................................................94 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................95 
10.4.3 
General guidelines for reporting adverse events ...........................................................................95 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................97 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................98 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................98 
10.4.7 
Guidelines for reporting product complaints (IMP/NIMP) ..............................................................98 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................98 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................99 
10.6.1 
Hypersensitivity..............................................................................................................................99 
10.6.2 
Severe injection site reactions .....................................................................................................100 
10.6.3 
Infections, including parasitic infections.......................................................................................100 
10.6.4 
Elevated liver function tests .........................................................................................................101 
10.6.5 
Malignancy...................................................................................................................................102 
10.7 
ADVERSE EVENTS MONITORING............................................................................................102 
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11 
STATISTICAL CONSIDERATIONS............................................................................................103 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................103 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................103 
11.3 
ANALYSIS POPULATIONS.........................................................................................................104 
11.3.1 
Efficacy populations .....................................................................................................................104 
11.3.1.1 Modified intent-to-treat population ...............................................................................................104 
11.3.2 
Safety population .........................................................................................................................104 
11.3.3 
Pharmacokinetic analysis population...........................................................................................104 
11.3.3.1 Antidrug antibody population .......................................................................................................104 
11.4 
STATISTICAL METHODS ...........................................................................................................104 
11.4.1 
Extent of study treatment exposure and compliance...................................................................104 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................104 
11.4.1.2 Compliance ..................................................................................................................................105 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................105 
11.4.2.1 Analysis of primary efficacy endpoint...........................................................................................105 
11.4.2.2 Analyses of secondary and other efficacy endpoints...................................................................105 
11.4.2.3 Multiplicity considerations ............................................................................................................106 
11.4.2.4 Handling of missing data..............................................................................................................106 
11.4.3 
Analyses of safety data................................................................................................................106 
11.4.3.1 Adverse events ............................................................................................................................106 
11.4.4 
Pharmacokinetics, pharmacodynamics, and analyses of antidrug antibodies ............................108 
11.4.4.1 Pharmacokinetic analysis ............................................................................................................108 
11.4.4.2 Anti-drug antibodies analysis .......................................................................................................108 
11.4.4.3 Pharmacodynamics......................................................................................................................108 
11.4.5 
Analyses of patient reported outcomes (health-related quality of life/health economics 
variables)......................................................................................................................................108 
11.5 
INTERIM ANALYSIS....................................................................................................................108 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................109 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................109 
12.2 
INFORMED CONSENT ...............................................................................................................109 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC).................................................................................................110 
13 
STUDY MONITORING.................................................................................................................111 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................111 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................111 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................111 
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13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................112 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................112 
14 
ADDITIONAL REQUIREMENTS.................................................................................................113 
14.1 
CURRICULUM VITAE..................................................................................................................113 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................113 
14.3 
CONFIDENTIALITY .....................................................................................................................113 
14.4 
PROPERTY RIGHTS...................................................................................................................114 
14.5 
DATA PROTECTION...................................................................................................................114 
14.6 
INSURANCE COMPENSATION..................................................................................................114 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................115 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................115 
14.8.1 
By the Sponsor.............................................................................................................................115 
14.8.2 
By the Investigator .......................................................................................................................116 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................116 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................116 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................117 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................118 
17 
APPENDICES..............................................................................................................................121 
APPENDIX A 
HIGHLY EFFECTIVE CONTRACEPTIVE METHODS......................................................122 
APPENDIX B 
LIST OF PROHIBITED LIVE ATTENUATED VACCINES.................................................123 
APPENDIX C LOW, MEDIUM, AND HIGH DOSE INHALED CORTICOSTEROIDS..............................124 
APPENDIX D ASTHMA CONTROL QUESTIONNAIRE (ACQ)...............................................................125 
APPENDIX E 
ASTHMA QUALITY OF LIFE QUESTIONNAIRE..............................................................127 
APPENDIX F STANDARDIZED RHINOCONJUNCTIVITIS QUALITY OF LIFE QUESTIONNAIRE   
RQLQ(S) ......................................................................................................................................133 
APPENDIX G 
ASTHMA SYMPTOM SCORE NUMERICAL RATING SCALE (NRS) .............................138 
APPENDIX H GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY  SANOFI...................................................................................................139 
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APPENDIX I 
LIST OF OPPORTUNISTIC INFECTIONS.........................................................................144 
APPENDIX J 
DEFINITION OF ANAPHYLAXIS.......................................................................................145 
APPENDIX K 
COUNTRY-SPECIFIC REQUIREMENTS.........................................................................146 
APPENDIX L PROTOCOL AMENDMENT HISTORY..............................................................................147 
 
2.1 
LIST OF TABLES 
Table 1 - Withdrawal of fluticasone - downward titration doses (administered twice a day).........................51 
Table 2 - Summary of handling procedures for samples ..............................................................................66 
Table 3 - Summary of bioanalytical methods for pharmacokinetics and antidrug antibody..........................66 
Table 4 - Adverse event reporting.................................................................................................................97 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
ACQ-5: 
Asthma Control Questionnaire-5 
ADA: 
Anti-drug antibodies 
AEs: 
Adverse events 
AESI: 
Adverse events of special interest 
ALT: 
Alanine transaminase 
AQLQ[S]: 
Asthma Quality of Life Questionnaire with Standardized Activities 
AST: 
Aspartate transaminase 
BID: 
Twice daily 
COPD: 
Chronic obstructive pulmonary disease 
DMC: 
Data monitoring committee 
DNA: 
Deoxyribonucleic acid 
DPI: 
Dry powder inhaler 
ECG: 
Electrocardiogram 
eCRF: 
Electronic case report form 
EOS: 
End of study 
FEV1: 
Forced expiratory volume in 1 second 
FIH: 
First-in-human  
FVC: 
Forced vital capacity 
GSO: 
Global Safety Officer 
HBc Ab: 
Hepatitis B core antibody 
HBs Ag: 
Hepatitis B surface antigen 
HDM: 
House dust mite 
HIV: 
Human immunodeficiency virus 
IB: 
Investigator's brochure 
ICF: 
Informed consent form 
ICH: 
International Conference on Harmonisation 
ICS: 
Inhaled corticosteroids 
IEC: 
Independent Ethics Committee 
Ig: 
Immunoglobulin 
IL: 
Interleukin 
ILC2: 
Innate lymphoid cells type 2 
IMP: 
Investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
Interactive Response Technology 
ISR: 
Injection site reaction 
IV: 
Intravenous 
IVRS: 
Interactive Voice Response System 
IWRS: 
Interactive Web Response System 
LABA: 
Long-acting β2 adrenergic agonist 
LOAC: 
Loss of asthma control 
LS: 
Least square 
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mAb: 
Monoclonal antibody 
MCID: 
Minimal Clinically Important Difference 
MDI: 
Metered dose inhaler 
mITT: 
Modified intent-to-treat 
NIMP: 
Noninvestigational medicinal product 
NRS: 
Numerical Rating Scale 
OCS: 
Oral corticosteroid 
PARC: 
Pulmonary and activation-regulated chemokine 
PCSA: 
Potentially clinically significant abnormality 
PEF: 
Peak expiratory flow 
PK: 
Pharmacokinetics 
ppb: 
Parts per billion 
q2w: 
Every 2 weeks 
RNA: 
Ribonucleic acid 
RQLQ: 
Rhinoconjunctivitis Quality of Life Questionnaire 
SAEs: 
Serious adverse events 
SC: 
Subcutaneous 
TB: 
Tuberculosis 
TEAE: 
Treatment-emergent adverse event 
Th2: 
T-helper 2 
ULN: 
Upper limit of normal range 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
ASTHMA 
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyperresponsiveness, acute and chronic bronchoconstriction, airway edema and mucus plugging. 
The inflammation component of asthma is thought to involve many cell types including epithelial 
cells, T lymphocytes, eosinophils, mast cells, neutrophils, innate lymphoid cells type 2 (ILC2) and 
their biological products. Patients with asthma most often present with symptoms of wheezing, 
shortness of breath, cough, and chest tightness.  
Despite current treatment options, uncontrolled asthma continues to carry a significant burden, 
with more than 1 million moderate-to-severe asthmatic adolescent and adults in the US having 
uncontrolled symptoms on inhaled corticosteroids (ICS) combined with a second controller or 
systemic corticosteroid therapy (1,2). These patients are prone to severe exacerbations, and 
contribute disproportionately to the overall morbidity in this condition, including more hospital 
days, emergency room visits, and lost work/school days than matched controls with good asthma 
control. Additionally, they are likely to experience co-morbidities such as anxiety, depression, and 
insomnia (3,4). Furthermore, systemic corticosteroids, while clinically effective, are associated 
with significant side effects, such as fluid retention and swelling, glaucoma, increased blood 
pressure, increased risk of infections, diabetes, osteoporosis, and impaired growth in children (5).  
Due to the limitations of the standard of care therapy, there are a number of biologics in 
development for moderate-to-severe asthma (5,6,7,8,9, and 10). For severe uncontrolled asthma 
patients, there are four currently approved biologics. In the severe, corticosteroid-refractory 
allergy-induced asthma population, the anti-immunoglobulin E (IgE) agent omalizumab 
(XOLAIR®) has shown efficacy. Xolair is associated with a black box warning of potential for 
anaphylaxis. In the severe population with an eosinophilic phenotype, the two currently approved 
anti-interleukin (IL)-5 agents, mepolizumab (NUCALA®) and reslizumab (CINQAIR®), and the 
most recently approved anti-IL5 receptor benralizumab (Fasenra™)  have shown efficacy as well. 
These anti-IL5 agents now provide an additional therapeutic option with important limitations 
though. Even in the high eosinophilic group, 36% of patients on mepolizumab had no decrease in 
oral corticosteroid (OCS) dose or had a lack of asthma control (11), suggesting that targeting a 
single cytokine in a heterogenous disease such as asthma is not sufficient. In this context, there is 
a need for identification of novel therapeutic targets and development of more efficacious and 
well tolerated treatments for severe asthma. 
To address these limitations, dupilumab, an anti-IL4-Rα antibody that blocks the biologic 
activities of both IL4 and IL13, is currently being investigated in a Phase 3 program in 
moderate-to-severe asthma. In the pivotal Phase 2b study (10), it was demonstrated that in patients 
with moderate-to-severe uncontrolled asthma, treatment with dupilumab 200 mg or 300 mg every 
2 weeks (q2w) as an add-on to ICS/long-acting β2 adrenergic agonist (LABA) combination 
therapy produced a clinically meaningful and statistically significant increase from baseline in 
forced expiratory volume in 1 second (FEV1) at Week 12 and Week 24 and a significant 
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reduction in the annualized rate of severe asthma exacerbations in both the high eosinophil 
population (≥300 cells/µL) (71.2% to 80.7% reductions in severe asthma exacerbations) and the 
overall population (70% to 70.5% reductions in severe asthma exacerbations) (10). A second 
pivotal study to evaluate the efficacy and safety of dupilumab in patients with persistent asthma is 
ongoing. Results from completed studies indicate that dupilumab is generally well-tolerated. 
The main objective for new biologics is to further improve asthma symptoms, lung function, and 
prevent exacerbations, while optimizing adherence to the treatment. One of the reasons for the 
poor response to medication in some patients with severe asthma may be the heterogeneity of the 
disease, namely the mixed eosinophilic and neutrophilic inflammation, only partly responding to 
the current targeted therapies. Also, asthma exacerbations are associated with upper respiratory 
viral infections, mostly rhinoviruses, with frequency estimates of 85% and 60% for childhood and 
adult asthma, respectively. Underlying deficiencies in innate immunity and evidence of a 
synergism between viral infection and allergic mechanisms in increasing risk of exacerbations are 
all important mechanisms to target with novel treatments (12). 
4.2 
SAR440340 ANTI-IL33 MONOCLONAL ANTIBODY 
SAR440340 is a human monoclonal antibody (mAb) that targets IL33 and is under development 
as a potential novel treatment for asthma and chronic obstructive pulmonary disease (COPD). 
IL33 is a proinflammatory cytokine that initiates and amplifies innate and adaptive inflammatory 
cascades (13), in response to epithelial cell stress or damage due to exposure to airborne allergens, 
viruses, cigarette smoke, and air pollutants. Human genetic susceptibility data as well as 
preclinical data suggest that SAR440340 may be efficacious in asthma via targeting of 
inflammatory pathways including T-helper 2 (Th2)/eosinophilic, neutrophilic, and ILC2 
mediators.  
The role of IL33 in asthma is supported by genetic association in humans and by preclinical 
studies in animal models. In humans, gene variants of IL33 and its receptor ST2 are associated 
with increased levels of peripheral eosinophils and greater risk for asthma (14), and increased 
levels of IL33 have been reported in bronchial cells of asthma patients (15). In mice, genetic 
deletion or blockade of IL33 or ST2 suppressed lung inflammation (16,17). IL33 has also been 
described as a potent suppressor of innate antiviral immunity, contributing to synergistic 
associations between frequent lower respiratory infections in early life and asthma onset in later 
childhood (18). In a House Dust Mite (HDM) extract-induced model of chronic airway 
inflammation in humanized IL33 mice (Il33hu/hu mice), SAR440340 blocked several pathologic 
markers of type 1 and type 2 immune responses. Chronic HDM exposure in mice induces severe 
lung inflammation of mixed type 1 and type 2 phenotypes such as tissue infiltration by type 1 
inflammatory cells (neutrophils), induction of type 2 cytokines, severe lung remodeling, and type 
2-characteristic increases in serum IgE and HDM-specific IgG1. Mice treated with SAR440340 
had significantly reduced lung weights and lung consolidation, reduced pulmonary neutrophilic 
infiltration, decreased IL5 protein levels and IL13 messenger ribonucleic acid (mRNA) levels, and 
decreased serum amyloid A. 
The first-in-human (FIH) study (R3500-HV-1551) to investigate safety and pharmacokinetics 
(PK) of a single intravenous (IV) infusion of 0.3, 1, 3, or 10 mg/kg or a single subcutaneous (SC) 
injection of 150 mg of SAR440340 in normal healthy volunteers was completed. Treatment with 
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SAR440340 was generally well-tolerated. No deaths and no serious adverse events (SAEs) were 
reported. 
The first-in-patient study (R3500-AS-1619) to investigate safety, tolerability, PK, and 
pharmacodynamic (PD) effects of a repeated SC administration of SAR440340 at 2 dose levels 
(75 and 150 mg), every week for 4 weeks, in adult patients with moderate asthma is ongoing. 
A PD study (R3500-AS-1633) to assess the effects of a single IV dose of 10 mg/kg SAR440340, 
2 repeated q2w SC doses of dupilumab (600 mg loading dose then 300 mg dose), and the 
coadministration of SAR440340 with dupilumab on markers of inflammation after Bronchial 
Allergen Challenge in patients with mild allergic asthma is ongoing. 
At the time of writing this protocol, acceptable safety and tolerability was observed from the 
blinded assessments in both these ongoing studies for asthma patients. 
4.3 
DUPILUMAB ANTI-IL4R ALPHA MONOCLONAL ANTIBODY 
In the ACT15102 study, dupilumab will be used as an active calibrator since it was successfully 
tested in a similar ICS/LABA withdrawal design targeting high eosinophilic patients 
(ACT11457) (19) and also demonstrated a satisfactory efficacy profile in a broader spectrum of 
asthma patients in Phase 2b, with 70% reduction of annual exacerbation and 160 to 200 mL FEV1 
improvement versus placebo (DRI12544) (10). 
Based on the results of DRI12544 study, the 2 q2w dupilumab regimens (200 mg and 300 mg) are 
currently being evaluated in the ongoing Phase 3 pivotal study (EFC13579).  EFC13579 is a study 
of dupilumab in a broad population of adult and adolescent patients with uncontrolled, persistent 
asthma.  In September 2017, topline results showed this study met the 2 primary endpoints.  
Dupilumab, when added to standard therapies, reduced severe asthma attacks (exacerbations) and 
improved lung function.  At 52 weeks, in the 300 mg dose group, dupilumab reduced severe 
asthma attacks by 46% in the overall population, 60% in patients with ≥150 eosinophilic cells/µL, 
and 67% in patients with ≥300 eosinophilic cells/µL (p<0.001 for all groups).  At 12 weeks, in the 
300 mg dupilumab dose group, mean improvement in lung function over placebo as assessed by 
FEV1 was 130 mL (9%) in the overall population, 150 mL (11%) in patients with 
≥150 eosinophilic cells/µL, and 240 mL (18%) in patients with ≥300 eosinophilic cells/µL 
(p<0.001 for all groups).  The results for the 200 mg and 300 mg dupilumab dose groups were 
generally comparable on both LOACs and FEV1.  The extent of patient response correlated with 
allergic or atopic status as reflected by blood eosinophils and other markers.  Less activity was 
observed in patients with < 150 eosinophilic cells/µL. 
4.4 
COADMINISTRATION OF SAR440340 WITH DUPILUMAB 
Increasingly it is appreciated that severe asthma is a complex and heterogeneous condition. While 
OCS are often required in this condition due to their broad anti-inflammatory effects, the side 
effects of these agents are unacceptable for long term use. Targeted mAb approaches which block 
single pathways may not be sufficient to treat the most severe patients and hence it is suggested 
that combination of mAbs which target separate yet complementary pathways and which are safe 
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and efficacious may be a successful and safe approach to treat the most severe, complex asthma 
phenotypes. The mechanism of action of SAR440340 and dupilumab as well as preclinical data in 
a mouse model of chronic HDM allergic inflammation suggest that the coadministration of 
SAR440340 with dupilumab may have additive anti-inflammatory effects compared to either 
SAR440340 or dupilumab alone, due to both distinct and overlapping effects of each mAb. 
Humanized mice expressing human IL33, IL4, and IL4Rα (Il33hu/hu, Il4hu/hu, Il4rahu/hu mice) 
exposed to HDM extract thrice-weekly for 19 weeks were treated twice-weekly from Week 12 to 
Week 19 with SAR440340, dupilumab, coadministration of SAR440340 and dupilumab, or an 
isotype control antibody. Gross lung pathology type 1 and/or type 2 immune response markers 
were assessed. The combination of SAR440340 and dupilumab showed improved efficacy 
compared to either treatment alone at preventing HDM-induced increases in lung weight, at 
reducing HDM-induced lung inflammation, with statistical significance for lung hIL4, IL-6, tumor 
necrosis factor (TNFα), growth related oncogene (GROα), monocyte chemoattractant protein-1 
(MCP-1) and myeloperoxidase (MPO) relative to control IgG4P, and at reducing serum IgE and 
serum amyloid A protein (SAA). In addition, a recent publication has demonstrated in two well 
established murine models of asthma that dual inhibition of both IL33 and IL13 was more 
efficacious than inhibiting each cytokine alone in reducing airway eosinophilia, levels of IL5 in 
bronchoalveolar lavage as well as ILC2 cells in the lung (20).  
Thus, it may be hypothesized that the coadministration of SAR440340 and dupilumab may offer 
additive effects on the prevention of LOAC events and improvement of FEV1 in patients with 
moderate-to-severe asthma. Based on the results of the combination toxicology study of 
REGN646 the surrogate antibody for dupilumab, with SAR440340 in cynomolgus monkey and 
the lack of additive or synergistic safety findings with the combination, the existing data are 
deemed adequate to support FIH combination studies of these 2 agents. 
4.5 
RISK/BENEFIT 
As outlined above, results of preclinical studies and Phase 1 studies suggest that SAR440340 is 
well-tolerated at doses up to 10 mg/kg administered IV as a single dose. A repeated dose study of 
SAR440340 at 75 and 150 mg administered every week for 4 weeks in adult patients with 
moderate asthma is ongoing. SAR440340 is expected to inhibit the proinflammatory activity of 
IL33, which is elevated in asthma patients. Thus, the benefit/risk profile for SAR440340 in this 
study supports its evaluation as a potential agent for treatment of asthma. 
Dupilumab, at the proposed dose of 300 mg q2w administered SC, has been shown to be 
well-tolerated, has an acceptable safety profile, and was associated with significant improvements 
in clinical outcomes and markers of asthma control in 2 Phase 2 studies, with Phase 3 studies 
currently ongoing (10,19). 
In summary, SAR440340 or dupilumab, individually, have either been demonstrated to or 
predicted (based on genetic and preclinical data) to provide high benefit for asthma patients along 
with a low safety risk, and combining SAR440340 and dupilumab has potentially additive 
benefits for the treatment of severe asthma. As outlined in Section 4.4, there is a compelling 
rationale for evaluating the combination of SAR440340 and dupilumab for treatment of asthma, 
as compared with SAR440340 or dupilumab, alone.  
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There is a theoretical risk of infection associated with blocking of host defense pathways by the 
combination of SAR440340 plus dupilumab. The preliminary safety data from the FIH study of 
SAR440340 have revealed no safety signals. Dupilumab has been found in clinical studies to be 
generally well-tolerated with a favorable safety profile and was not associated with an increased 
risk of infections other than oral Herpes infections in patients with atopic dermatitis.  
The combination toxicology study supports the use of the combination at doses above those 
proposed for the proof of concept (PoC) study. There are no preclinical safety findings or signs of 
overlapping toxicity that would preclude the combination of SAR440340 and dupilumab. 
Furthermore, no drug-drug interactions affecting drug metabolism or excretion are expected for 
2 mAbs. Therefore, the anticipated safety of the combination SAR440340 plus dupilumab is 
considered reasonable, with close monitoring of adverse events (AEs) and laboratory results 
throughout the study and follow-up period. The safety data for SAR440340 and dupilumab are 
summarized in the Investigator's brochure (IB) for each of these agents. 
4.6 
RATIONALE FOR SELECTING THE DOSE 
The proposed dose regimen of SAR440340 is 300 mg SC q2w. It has been chosen based on safety 
data from the first-in-human (FIH) study in healthy subjects (R3500-HV-1551) and modeling of 
300 mg q2w using PK data from the FIH study showing coverage at steady state of 5-fold the 
plasma level concentration of 17 mg/L shown to be required for optimal in vivo efficacy in a 
chronic exposure to HDM asthma model in mice. 
The regimen of dupilumab that will be used in this study, consisting of 300 mg SC dose q2w, is 
based upon doses that have been shown in pivotal studies to reduce the rate of exacerbations and 
demonstrated a satisfactory safety profile in patients with severe asthma (10) (See Section 4.3 for 
additional details). 
The doses of SAR440340 and dupilumab within the coadministration arm are supported by the 
justification above as well. Maintaining these levels without dose adjustment is supported by the 
absence of signs of overlapping toxicity from the combination toxicology study and the fact that 
for these biological drugs no drug-drug interactions affecting drug metabolism or excretion are 
expected. 
4.7 
STUDY DESIGN 
ACT15102 study will evaluate the efficacy and safety of SAR440340, and the coadministration of 
both SAR440340 and dupilumab, in the treatment of patients with moderate-to-severe asthma. 
SAR440340 and dupilumab will be administered as 2 and 1 SC injection, respectively, q2w over a 
12-week randomized investigational medicinal product (IMP) treatment period. This 12-week 
randomized IMP treatment period consists of a 4-week standardized ICS/LABA background 
therapy stabilization phase, a 4-5 week background therapy withdrawal phase and a 3-4 week no 
background therapy phase, followed by a 20-week post IMP treatment safety follow-up period. 
This study design has been successfully deployed in a previous Phase 2a investigation of 
dupilumab (19). 
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This study will be a multinational, randomized, double-blind, placebo-controlled, parallel-group 
(4 groups), 12-week Proof of Concept (PoC) study conducted in adult patients aged of 18 to 70 
years, suffering from asthma based on the Global Initiative for Asthma (GINA) 2017 Guidelines, 
and whose asthma is partially controlled or uncontrolled on ICS/LABA background therapy with 
medium to high dose ICS (≥250 mcg of fluticasone propionate BID or equipotent ICS daily 
dosage to a maximum of 2000 mcg/day of fluticasone propionate or clinically comparable) in 
combination with a LABA as second controller for at least 3 months with a stable dose ≥1 month 
prior to Visit 1.  
To ensure enrollment according to intended distribution of baseline eosinophil count, alerts will 
be built into the Interactive Voice Response System (IVRS)/Interactive Web Response System 
(IWRS) to limit enrolling patients in the following 2 stratification subgroups: 
• Eosinophil <150/mm3 not more than approximately 25% (60) patients  
• Eosinophil ≥300/mm3 at least approximately 45% (108) patients 
The 12-week treatment duration is based on published data from ACT11457 dupilumab study 
with similar design, and should allow the observation of a reduction of the LOAC (primary 
efficacy variable) with SAR440340, and the coadministration of SAR440340 with dupilumab, as 
compared to placebo, considering the severity of the target population, under medium to high dose 
ICS/LABA therapy. In addition, 12-weeks are deemed sufficient to demonstrate treatment-
induced changes on reversibility of airflow limitation as measured by FEV1 (secondary efficacy 
variable). 
Upon completing 12 weeks of treatment with the IMP (or following early discontinuation of 
investigational products), patients enter the 20-week safety follow-up period/Post IMP Treatment 
Period. The 20-week follow-up period post IMP treatment, which covers approximately to 
5 half-lives of SAR440340, will allow safety follow-up and efficacy recording.  
The safety analysis will focus on the IMP treatment-emergent adverse event (TEAE) period, from 
the first administration of the IMP to 22 weeks after the last administration of the IMP. 
After the end of IMP treatment (or following early discontinuation of IMP), patients will resume 
their original ICS/LABA (ie, prior to screening) background therapy and enter the 20-week safety 
follow-up period. If a patient’s asthma cannot be consistently controlled on his/her original 
ICS/LABA therapy, and there is a safety concern, additional controller therapies may be 
prescribed based on the Investigator’s clinical judgement. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to evaluate the effects of SAR440340 with or without 
dupilumab, compared to placebo, on reducing the incidence of “loss of asthma control” (LOAC*) 
events. 
5.2 
SECONDARY OBJECTIVES 
• Evaluate the effects of SAR440340 and coadministration of SAR440340 and dupilumab, 
compared with placebo, on FEV1. 
• Estimate the effects of coadministration of SAR440340 and dupilumab, compared with 
SAR440340 and compared with dupilumab, on FEV1. 
• Safety and tolerability of SAR440340 alone and in coadministration with dupilumab. 
5.3 
OTHER OBJECTIVES 
• Evaluation of the calibrator (dupilumab) arm performance. 
• To evaluate the effects of SAR440340 and the coadministration of both compared to 
placebo on: 
- 
Other spirometric assessments (peak expiratory flow [PEF], forced vital capacity 
[FVC], forced expiratory flow [FEF] 25-75%). 
- 
Patient reported outcomes.  
- 
Immunogenicity (ie, anti-drug antibodies [ADA]).  
- 
The PK profile of SAR440340 and dupilumab in serum.  
- 
Selected biomarkers of the IL33 and IL4/IL13 pathway. 
• Furthermore, the effects of the coadministration of SAR440340 and dupilumab on relevant 
endpoints compared to each monotherapy treatment arm will be assessed as well. 
* Definition of Loss of Asthma Control 
Loss of asthma control (LOAC) event during the treatment period is a deterioration of asthma 
defined as any of the following: 
• A 30% or greater reduction from baseline in morning PEF on 2 consecutive days 
• ≥6 additional reliever puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24 
hour period (compared to baseline) on 2 consecutive days 
• Increase in ICS ≥4 times the last prescribed ICS dose (or ≥50% of the prescribed ICS dose 
at V2 if background therapy withdrawal completed) 
• Requiring use of systemic (oral and/or parenteral) steroid treatment 
• Requiring hospitalization or emergency room visit. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
The multinational, randomized, double-blind, placebo-controlled, parallel-group (4 groups), 
12-week PoC study that is designed to assess the efficacy, safety, and tolerability of SAR440340 
(an anti-IL33 monoclonal antibody), and the coadministration of SAR440340 and dupilumab (an 
anti-IL4-Rα monoclonal antibody that blocks the biologic activities of both IL4 and IL13) in 
patients with moderate-to-severe asthma who are not well controlled on ICS/LABA therapy. 
Study treatment includes IMP (SAR440340 and/or dupilumab and/or placebo) added-on to a 
background therapy of ICS/LABA (fluticasone/salmeterol [Noninvestigational medicinal product 
{NIMP}], standardized at screening). Background therapy of ICS/LABA is to be withdrawn 
during the 12-week randomized treatment period and resumed at the end of the IMP treatment 
period for the 20-week safety follow-up period (Section 1.1 and Section 1.2), as outlined below: 
• Screening period (4 weeks ± 3 days) 
• Randomized IMP Treatment Period (12 weeks ± 3 days) 
- 
Background therapy stabilization phase (4 weeks)  
- 
Background therapy withdrawal phase (4-5 weeks, see Section 6.1.1 and for more 
details see Section 8.2.1)  
- 
No background therapy phase (3-4 weeks, see Section 1.2) 
• Post IMP treatment safety follow-up period (20 weeks ± 5 days)  
At the Screening Visit 1, all patients must be on a stable therapy for their asthma which must 
include any medium or high dose ICS therapy (≥250 mcg of fluticasone propionate twice daily 
[BID] or equipotent ICS daily dosage to a maximum of 2000 mcg/day of fluticasone propionate or 
clinically comparable) in combination with a LABA as second controller for at least 3 months 
with a stable dose ≥1 month prior to Screening Visit 1. 
It is intended that approximately half of the patients included in the study will be on medium ICS 
dose at enrolment.  
After completion of screening procedures, all eligible patients will be switched to clinically 
comparable doses of the study-specific ICS/LABA background therapy with 
fluticasone/salmeterol, as approved for region: 
• Fluticasone/salmeterol - dry powder inhaler (DPI):  
1 puff of 250/50 mcg twice daily (BID) or  
1 puff of 500/50 mcg BID 
OR  
• Fluticasone/salmeterol - metered dose inhaler (MDI):  
2 puffs of 115/21 mcg (230/42 mcg) BID or  
2 puffs of 230/21 mcg (460/42 mcg) BID 
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OR  
• Fluticasone/salmeterol - MDI:  
2 puffs of 125/25 mcg (250/50 mcg) BID or  
2 puffs of 250/25 mcg (500/50 mcg) BID 
Please note that patients should use the same inhaler type (either DPI or MDI) throughout the 
study. 
Patients who satisfy the inclusion and exclusion criteria will be randomized (1:1:1:1 ratio) to one 
of the following treatment groups: 
• SAR440340 (300 mg) administered as 2 SC injections q2w for 12 weeks and 
coadministration of dupilumab placebo as 1 SC injection q2w for 12 weeks. 
• Dupilumab (300 mg) administered as 1 SC injection q2w for 12 weeks and 
coadministration of SAR440340 placebo as 2 SC injections q2w for 12 weeks. 
• SAR440340 (300 mg) administered as 2 SC injections q2w for 12 weeks and 
coadministration of dupilumab (300 mg) administered as 1 SC injection q2w for 12 weeks. 
• Coadministration of matching placebos for SAR440340 and dupilumab administered as  
2 and 1 SC injections, respectively, q2w for 12 weeks.  
Visits during the 12-week IMP treatment period will occur every week and will be followed by a 
20-week observational follow-up period. 
6.1.1 Background therapy (ICS/LABA) withdrawal phase 
Withdrawal of background therapy with the ICS fluticasone and the LABA salmeterol, during the 
12-week IMP treatment period, will be performed as described in Section 8.2.1, and summarized 
below (for overview please refer to Section 1.1 and Section 1.2). 
At Week 4 (Visit 6) post-randomization, the LABA component (salmeterol) will be withdrawn, 
and patients will be switched from their BID fluticasone/salmeterol combination therapy to a 
clinically comparable ICS dose of fluticasone BID monotherapy, as approved for region: 
• Fluticasone (DPI formulation):  
1 puff of 250 mcg BID or 
2 puffs of 250 mcg (500 mcg) BID,  
OR 
• Fluticasone (MDI formulation):  
2 puffs of 110 mcg (220 mcg) BID or  
2 puffs of 220 mcg (440 mcg) BID 
OR 
• Fluticasone (MDI formulation):  
2 puffs of 125 mcg (250 mcg) BID or  
2 puffs of 250 mcg (500 mcg) BID 
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The ICS component (fluticasone) will be withdrawn by a step-wise dose reduction starting at 
Week 6 (Visit 8) and will continue at each Weeks 7, 8, and 9 (Visits 9, 10, and 11, respectively), 
provided that patients do not experience a LOAC event.  
An appropriate inhaler for each required ICS dose while patient is in screening and on IMP 
treatment will be provided by the Sponsor per local regulation.  
Patients that meet the criteria for a LOAC, at any time during the randomized IMP treatment 
phase, will (be): 
• Discontinue early from IMP treatment,  
• Evaluated and receive treatment by the Investigator with standard of care according to 
standard medical practice, 
• Resume their individual prescreening ICS/LABA background therapy and  
• Followed for safety during the 20-week Post IMP Treatment Period. 
6.1.2 Early treatment discontinuation (ETD) follow-up  
Patients who discontinue IMP treatment prior to completing the 12-week IMP treatment (due to 
LOAC or due to early treatment discontinuation [ETD]), will be evaluated as soon as possible at 
the individual patients’ End of Treatment (EOT) Visit, using procedures as planned for the EOT 
Visit at Week 12 (Visit 14). At their EOT visit, patients will resume their prescreening ICS/LABA 
background therapy and enter the 20-week safety follow-up period/Post IMP Treatment Period 
(Visit 15 to Visit 17). 
6.1.3 Post IMP treatment follow-up 
Patients who complete the 12-week randomized IMP treatment period at Week 12 (Visit 14) EOT 
visit, as per protocol, resume their prescreening ICS/LABA therapy and enter the 20-week safety 
follow-up period/Post IMP Treatment Period (Visit 15 to Visit 17).  
Note: For patients who meet the criteria for a LOAC or discontinue IMP treatment early (due to 
other reasons) prior to 12 weeks of treatment, their ETD EOT visit and their individual 20-week 
Post IMP Treatment Period may start earlier than at Week 12.  
At any EOT visit, if a patient’s asthma cannot be adequately controlled by the prescreening 
ICS/LABA therapy, additional controller therapies may be prescribed based on the Investigator’s 
clinical judgement. 
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6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Study participation for each patient will be a total of 252 days (approximately 36 weeks) 
including 28 days screening, 84 days IMP treatment period, and 140 days post IMP treatment 
safety follow-up period. 
6.2.2 Determination of end of clinical trial (all patients) 
The last patient last visit (the End of Study (EOS) Visit at Week 32, Day 225) will occur at the 
end of a 20-week safety follow-up period for those patients who complete the study as per 
protocol.  
Patients who discontinue prematurely from the study (prior to completing the 12-week IMP 
treatment) will be evaluated as soon as possible using the procedure normally planned for the 
EOT Visit at Week 12 (Visit 14), and return to the study site for the post IMP treatment safety 
follow-up period (Visit 15 to Visit 17).  
6.3 
INTERIM ANALYSIS 
No formal interim analysis is planned. Analyses will be performed for safety monitoring and 
internal decision making. No formal stopping rules or adjustment for multiplicity will be applied. 
6.4 
STUDY COMMITTEES 
6.4.1 Data monitoring committee 
An internal data monitoring committee (DMC) will be unblinded and comprised of individuals 
with expertise in the diseases under study, biostatistics, or clinical research. The DMC members 
are independent of the project/study teams and are not involved in the study conduct. The primary 
responsibilities of the DMC are to review and evaluate the study data during the course of the trial 
and make appropriate recommendations regarding the conduct of the clinical trial to the 
project/study team. 
The DMC procedures and data to be reviewed by the DMC are described in the DMC charter. 
6.5 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUPS 
ACT15102 study will evaluate the efficacy and safety of SAR440340, and the coadministration of 
the same dose level of both SAR440340 and dupilumab (for more details please refer to  
Section 4.4), administered SC q2w over a 12-week treatment period for the treatment of patients 
with moderate-to-severe asthma. This study design has been successfully deployed in a previous 
Phase 2a investigation of dupilumab (19). 
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The 12-week treatment duration is based on published data from ACT11457 dupilumab study 
with similar design, and should allow the observation of a reduction of the LOAC (primary 
efficacy variable) with SAR440340, and the coadministration of SAR440340 with dupilumab, as 
compared to placebo, considering the severity of the target population, under medium to high dose 
ICS/LABA therapy. In addition, 12-weeks are deemed sufficient to demonstrate treatment-
induced changes on reversibility of airflow limitation as measured by FEV1 (secondary efficacy 
variable).  
A follow-up period of 20 weeks, which covers approximately to 5 half-lives of SAR440340, will 
allow safety and efficacy recording after the end of the intervention period. The safety analysis 
will focus on the TEAE period, from the first administration of the IMP to 22 weeks after the last 
administration of the IMP. 
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7 
SELECTION OF PATIENTS 
A total of up to approximately 240 subjects (up to approximately 60 subjects per treatment arm) 
are expected to be randomized and treated in up to approximately 80 sites worldwide.  
The Screening Visit blood eosinophils count will be assessed at baseline and it is planned that at 
least approximately 45% of patients will have blood eosinophil counts of  ≥300/mm3 and no more 
than approximately 25% of patients will have blood eosinophil counts <150/mm3 (stratified 
randomization).  
7.1 
INCLUSION CRITERIA 
I 01. Adult patients with a physician diagnosis of asthma for at least 12 months based on the 
Global Initiative for Asthma (GINA) 2017 Guidelines (1).  
I 02. Patients with existing treatment with medium to high dose ICS (≥250 mcg of fluticasone 
propionate BID or equipotent ICS daily dosage to a maximum of 2000 mcg/day of 
fluticasone propionate or clinically comparable) in combination with a LABA as second 
controller for at least 3 months with a stable dose ≥1 month prior to Visit 1. Please note 
that the lower limit of allowed ICS dose (500 mcg of fluticasone propionate daily) 
corresponds to upper limit of medium dose defined by GINA guidelines. Patients receiving 
medium ICS dose <500 mcg daily are not eligible. 
I 03. Patients with prebronchodilator forced expiratory volume (FEV1) >40% of predicted 
normal at Visit 1/Screening. Prebronchodilator FEV1 ≥50% but ≤85% of predicted normal 
at Visit 2/Baseline.  
I 04. Patients with reversibility of at least 12% and 200 mL in FEV1 after administration of 2 to 
4 puffs (200-400 mcg) of albuterol/salbutamol or levalbuterol/levosalbutamol during 
screening or documented history of a reversibility test that meets this criteria within 12 
months prior to Visit 1 or documented positive response to methacholine challenge (a 
decrease in FEV by 20% [PC20] of < 8mg/mL) within 12 months prior to Visit 1/Screening 
is considered acceptable to meet this inclusion criterion. 
I 05. Patients must have experienced, within 1 year prior to Visit 1, any of the following events 
at least once: 
- 
Treatment with a systemic steroid (oral or parenteral) for worsening asthma. 
- 
Hospitalization or emergency medical care visit for worsening asthma. 
I 06. Signed written informed consent. 
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7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Patients less than 18 years or >70 years of age (ie, have reached the age of 71 at the 
screening visit). 
E 02. Patients with body mass index (BMI) <16. 
E 03. Chronic lung disease (for example, chronic obstructive pulmonary disease [COPD], or 
idiopathic pulmonary fibrosis [IPF]), which may impair lung function, or another 
diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil 
counts, for eg eosinophilic granulomatosis with polyangiitis. 
E 04. History of life threatening asthma (ie, severe exacerbation that requires intubation). 
E 05. Co-morbid disease that might interfere with the evaluation of IMP. 
E 06. Patients with any of the following events within the 4 weeks prior to their 
Screening Visit 1 or during the screening period: 
- 
Treatment with 1 or more systemic steroid (oral or parenteral) bursts for worsening 
asthma. 
- 
Hospitalization or an emergency medical care visit for worsening asthma. 
E 07. Asthma Control Questionnaire 5-question version (ACQ-5) score <1.25 or >3.0 at 
V2/randomization. During the screening period an ACQ-5 of up to ≤4 is acceptable.   
E 08. Anti-IgE therapy (eg, omalizumab [Xolair®]) within 130 days prior to Visit 1 or any other 
biologic therapy (including anti-IL5 mAb) or systemic immunosuppressant  
(eg, methotrexate, any anti-TNF mAbs, B and/or T cell targeted immunosuppressive 
therapies) to treat inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, 
inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, 
multiple sclerosis) and other diseases, within 2 months or 5 half-lives prior to Visit 1, 
whichever is longer. 
E 09. Patients with a history of a systemic hypersensitivity reaction to a monoclonal antibody. 
E 10. Patients on or initiation of bronchial thermoplasty within 2 years prior to Visit 1 or plan to 
begin therapy during the screening period or the randomized IMP treatment period. 
E 11. Current smoker or cessation of smoking within the 6 months prior to Visit 1. 
E 12. Previous smoker with a smoking history >10 pack-years. 
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E 13. Current history of substance and/or alcohol abuse. 
E 14. Inability to follow the procedures of the study (eg, due to language problems, 
psychological disorders) or unable to read, understand and fill a questionnaire or use an 
electronic diary without any help. 
E 15. Exposure to another investigative drug (small molecules as well as monoclonal antibodies) 
within a time period prior to Visit 1 that is <5 PK half-lives of the antibody. In case the 
half-life is not known, then the minimum interval since the exposure to the prior 
investigative antibody is 6 months. The minimum interval since exposure to any other 
(non-antibody) investigative study medication is 30 days prior to Visit 1. 
E 16. Clinically relevant abnormal laboratory values suggesting an unknown disease and 
requiring further evaluation. 
E 17. Patients who have previously been treated in any clinical trial of SAR440340 or 
dupilumab, or have been treated with commercially available dupilumab. 
E 18. Patient is the Investigator, or any Subinvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the study.  
E 19. Prisoners and patients who are legally institutionalized. 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 20. Clinically significant abnormal electrocardiogram (ECG) at Visit 1 that may affect the 
conduct of the study in the judgment of the Investigator. 
E 21. Concomitant severe diseases or diseases for which the use of ICS (eg, active and inactive 
pulmonary tuberculosis) or LABA based on judgment of Investigator are contraindicated. 
E 22. Use of injectable glucocorticosteroids or oral systemic glucocorticosteroids within 1 month 
prior to Visit 1/Screening or more than 4 courses of IV glucocorticosteroids within the 
6 months prior to Visit 1. 
E 23. Patients during the screening period that require medications or therapy that are prohibited 
as concomitant medications (see Section 8.8). 
E 24. A patient with a history of clinically significant renal, hepatic, cardiovascular, metabolic, 
neurologic, hematologic, ophthalmologic, respiratory, gastrointestinal, cerebrovascular or 
other significant medical illness or disorder which, in the judgment of the Investigator, 
could interfere with the study or require treatment that might interfere with the study. 
Specific examples include but are not limited to uncontrolled diabetes, severe 
hypertension, severe ischemic heart disease, unstable angina in the last 6 months, unstable 
cardiac arrhythmias, and Class IV heart failure.  
E 25. Exclusion related to tuberculosis (TB): 
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• Active TB or a history of incompletely treated TB. 
• Confirmed Quantiferon-positive patients (no active disease) are excluded from the 
study unless all of the following conditions are met: 
- 
Patients with a history of prior documented completed chemoprophylaxis for latent 
tuberculosis infection (TBI) (with a treatment regimen as per local guidelines) or 
treatment of active TBI, and 
- 
Has obtained consultation with a specialist to rule out or treat active TBI, and  
- 
Review and approval from Sponsor has been granted. 
• Suspected extrapulmonary TB infection. 
• Patients at high risk of contracting TB, such as close contact with individuals with 
active or latent TB. 
• Patient who received Bacille Calmette Guerin (BCG)-vaccination within 12 months 
prior to Screening Visit 1. 
E 26. Patients on DPI controller within 1 month prior to visit 1 in those countries where the 
study specified doses of controllers are not available in the DPI formulation 
7.2.3 Exclusion criteria related to the current knowledge of SAR440340  
E 27. Known allergy to doxycycline or related compounds or known allergy to SAR440340 
excipients. 
E 28. Females who are lactating, breastfeeding or who are pregnant. 
E 29. Women of childbearing potential (premenopausal female biologically capable of becoming 
pregnant) who: 
- 
Do not have: 
• A confirmed negative serum β-human chorionic gonadotropin (β-hCG) test at 
Visit 1. 
• Negative urine pregnancy test prior to Visit 2/Randomization. 
- 
Who are not protected by one of the acceptable forms of effective contraception (See 
Appendix A) during the protocol-defined time frame (Section 6.2.1).  
Postmenopausal women (defined as at least 12 consecutive months without menses) are 
not required to use additional contraception. 
For men in the study: 
- 
Male participants with female partners of childbearing potential are not eligible to 
participate unless they agree to ONE of the following (during the protocol-defined 
time frame [Section 6.2.1]): 
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• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
• Agree to use a male condom plus partner use of a contraceptive method with a 
failure rate of <1% per year (see Appendix A) when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently pregnant. 
- 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration (during the protocol-defined time frame [Section 6.2.1]). 
E 30. Diagnosed active parasitic infection (helminthes), suspected or high risk of parasitic 
infection, unless clinical and (if necessary) laboratory assessments have ruled out active 
infection before randomization. 
E 31. History of human immunodeficiency virus (HIV) infection or positive HIV 1/2 serology at 
Visit 1. 
E 32. Known or suspected history of immunosuppression, including history of invasive 
opportunistic infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, 
penumocystosis, aspergillosis), despite infection resolution; or unusually frequent, 
recurrent or prolonged infections, per Investigator's judgment.  
E 33. Evidence of acute or chronic infection requiring treatment with antibacterials, antivirals, 
antifungals, antiparasitics, or antiprotozoals within 4 weeks before Visit 1, significant viral 
infections within 4 weeks before Visit 1 that may not have received antiviral treatment (eg, 
influenza receiving only symptomatic treatment). 
E 34. Live attenuated vaccinations within 12 weeks prior to Visit 1 or planned live, attenuated 
vaccinations during the study; see Appendix B for list of prohibited live, attenuated 
vaccines. 
E 35. Patients with autoimmune disease or patients using systemic immunosuppressive therapy 
for autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary 
biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) or patients with 
high titer autoantibodies at screening who are suspected of having high risk for developing 
autoimmune disease at the discretion of the Investigator or the Sponsor. 
E 36. Patients requiring maintenance treatment with non-selective β-1 adrenergic receptor 
blockers. 
E 37. Active hepatitis or patients with positive or indeterminate hepatitis B surface antigen (HBs 
Ag), hepatitis B core antibody (HBc Ab) (Confirmed with presence of hepatitis B virus 
[HBV] deoxyribonucleic acid [DNA]) or positive hepatitis C virus antibody (HCV Ab) 
(Confirmed with presence of HCV RNA [RNA]) at Screening Visit 1. 
E 38. Any prior history of malignancy or active malignancy, including lymphoproliferative 
diseases (except successfully treated carcinoma in-situ of the cervix, non-metastatic 
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squamous cell or basal cell carcinoma of the skin) within 5 years prior to Screening 
Visit 1. 
E 39. Clinically significant laboratory tests at Visit 1: 
- 
Alanine transaminase (ALT) or aspartate transaminase (AST) >3 times upper limit of 
normal range (ULN), 
- 
Hemoglobin <10 g/dL for male and <9 g/dL for female, 
- 
Neutrophils <1.5 K/mm3 (except <1.0 /mm3 for those of African descent), 
- 
Platelets <100 K/mm3, 
- 
Creatinine ≥150 µmol/L. 
7.2.4 Additional exclusion criteria during or at the end of the screening period 
E 40. Patient who has withdrawn consent before enrollment/randomization. 
E 41. Despite screening of the patient, enrollment/randomization is stopped at the study level. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
8.1.1 SAR440340 
Sterile SAR440340 will be provided in one 20 mL vial containing 287 mg of lyophilisate drug 
product. 
8.1.2 SAR440340 matching placebo 
Sterile placebo for SAR440340 will be provided in matched 20 mL vial containing lyophilisate 
placebo. 
8.1.3 Dupilumab 
Sterile dupilumab (ie, SAR231893) will be provided as 150 mg/mL in glass prefilled syringe to 
deliver 300 mg in 2.0 mL. 
8.1.4 Placebo matching dupilumab 
Sterile placebo for dupilumab will be provided in matched glass prefilled syringe to deliver 
2.0 mL.  
8.1.5 Preparation of investigational product 
SAR440340 or matching placebo lyophilisate will be reconstituted by an unmasked site 
pharmacist or designee (not involved with study) as per instruction provided in study pharmacy 
manual.  
Administration will be performed by blinded nurse or designee as per instruction provided in 
study pharmacy manual. 
Dupilumab or matching placebo in glass prefilled syringes will be dispensed to the Investigator or 
designee for administration to the respective patient. Additional information will be provided in 
the pharmacy manual. 
8.1.6 Dosing schedule 
The IMP is administered every 14±3 days (q2w) by the Investigator or designee during visits to 
the study site.  
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Investigational medicinal product will be administered by the Investigator or designee following 
clinic procedures and blood collection. Patients should be monitored for any signs or symptoms of 
a hypersensitivity reaction for at least 30 minutes after all IMP injections are administered. The 
monitoring period may be extended up to 2 hours as per country specific requirements. Trained 
personnel and medications should be available to treat anaphylaxis or any severe allergic reaction 
if it occurs. 
Subcutaneous injection sites should alternate between the upper thighs, 4 quadrants of the 
abdomen or the upper arms, so that the same site is not injected twice during 2 consecutive visits. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Noninvestigational medicinal product (Asthma Control Therapy) during screening and treatment 
will be locally sourced at site level. In the case site will not be able to locally manage the 
provision of the product, the clinical study unit or local depot will assist the site by providing the 
products to the sites or voucher to the patients. 
At the Screening Visit 1, all patients must be on a stable therapy for their asthma which must 
include any medium or high dose ICS therapy (see Appendix C) in combination with a LABA as 
second controller for at least 3 months with a stable dose ≥1 month prior to screening. Please note 
that eligible medium ICS dose of 250 mcg of fluticasone propionate BID or equipotent ICS daily 
dosage corresponds to upper limit of medium dose defined by GINA guidelines in Appendix C. 
Please note that doses may be country-specific depending on labelling requirements. 
The third controller is not allowed during the screening and treatment phase of the study, and may 
not be used for an additional 4 weeks prior to screening visit (V1). After completion of screening 
procedures, all eligible patients will be switched to a clinically comparable dose of the study-
specific ICS/LABA background therapy with fluticasone/salmeterol, as approved for region: 
• Fluticasone/salmeterol – dry powder inhaler (DPI):  
1 puff of 250/50 mcg twice daily (BID) or  
1 puff of 500/50 mcg BID 
OR  
• Fluticasone/salmeterol – metered dose inhaler (MDI):  
2 puffs of 115/21 mcg (230/42 mcg) BID or  
2 puffs of 230/21 mcg (460/42 mcg) BID 
OR  
• Fluticasone/salmeterol – metered dose inhaler (MDI):  
2 puffs of 125/25 mcg (250/50 mcg) BID or  
2 puffs of 250/25 mcg (500/50 mcg) BID 
Please note that patients should use the same inhaler type (either DPI or MDI) throughout the 
study. 
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From Screening Visit 1 to Visit 2/randomization (4 weeks), all eligible patients will receive 
fluticasone/salmeterol as study-specific ICS/LABA background therapy. This background 
treatment is maintained for the first 4 weeks of randomized IMP treatment during the background 
therapy stabilization phase. 
8.2.1 Background therapy (ICS/LABA) withdrawal phase 
Withdrawal of background therapy with the ICS fluticasone and the LABA salmeterol, during the 
12-week IMP treatment period, will be performed as described below in detail for each visit from 
Week 4 through Week 9 (for overview please refer to Section 1.1 and Section 1.2). 
Week 4 (Visit 6) – LABA withdrawal: 
At Week 4 (Visit 6) post-randomization, the LABA component (salmeterol) will be withdrawn, 
and patients will be switched from their BID fluticasone/salmeterol combination therapy to a 
clinically comparable ICS dose of fluticasone BID monotherapy, as approved for region: 
• Fluticasone (DPI formulation):  
1 puff of 250 mcg BID or 
2 puffs of 250 mcg (500 mcg) BID,  
OR  
• Fluticasone (MDI formulation):  
2 puffs of 110 mcg (220 mcg) BID or  
2 puffs of 220 mcg (440 mcg) BID 
OR  
• Fluticasone (MDI formulation):  
2 puffs of 125 mcg (250 mcg) BID or  
2 puffs of 250 mcg (500 mcg) BID 
 
Week 6 (Visit 8) – ICS withdrawal  
The ICS component (fluticasone) will be withdrawn by a step-wise dose reduction (see Table 1) 
starting at Week 6 (Visit 8) and will continue at each Weeks 7, 8, and 9 (Visits 9, 10, and 11, 
respectively), provided that patients do not experience a LOAC event (see description below 
Table 1). 
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Table 1 - Withdrawal of fluticasone - downward titration doses (administered twice a day) 
 
Week 4/ 
Visit 6 
Week 6/ 
Visit 8 
Week 7/ 
Visit 9 
Week 8/ 
Visit 10 
Week 9/ 
Visit 11 
250 
100 
50 
0 
0 
Fluticasone DPI Dose (mcg) 
administered BID 
500 
250 
100 
50 
0 
220 
110 
44 
0 
0 
440 
220 
110 
44 
0 
250 
125 
50 
0 
0 
Fluticasone MDI Dose (mcg) 
administered BID 
500 
250 
125 
50 
0 
BID = Twice daily; DPI = Dry powder inhaler; MDI = Metered dose inhaler. 
If a patient meets the criteria for a LOAC at any time during this ICS/LABA withdrawal phase 
(and randomized treatment period), he/she will be withdrawn from IMP and treated by the 
Investigator with standard of care according to standard medical practice. The patient will resume 
his/her original ICS/LABA (ie, prior to screening) background therapy and will be followed for 
safety, if possible, for the subsequent 20-week Post IMP Treatment Period as planned per 
protocol. 
End of IMP Treatment Visit 14 (Week 12) – prescreening ICS/LABA is resumed 
Upon completing the 12-week randomized IMP treatment (or following early discontinuation of 
investigational products), patients will resume their original ICS/LABA (ie, prior to screening) 
background therapy and enter the 20-week safety follow-up period. If a patient’s asthma cannot be 
consistently controlled on his/her original ICS/LABA therapy, and there is a safety concern, 
additional controller therapies may be prescribed based on the Investigator’s clinical judgement. 
8.2.2 Reliever medication 
The reliever medication will not be dispensed or supplied by the Sponsor. 
Patients may administer albuterol/salbutamol or levalbuterol/levosalbutamol MDI as reliever 
medication as needed during the study. Nebulizer solutions may be used as an alternative delivery 
method.  
The description of the criterion for qualifying an asthma exacerbation event based on nebulizer 
using, will use the nebulizer-to-puff conversion factor for application to loss of asthma control 
(LOAC) definition. 
Salbutamol/albuterol nebulizer and levosalbutamol/levalbuterol nebulizer use will be converted as 
shown on the following tables:  
 
 
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Salbutamol/Albuterol Nebulizer Solution -Total Daily Dose (mg) 
Number of Puffs* 
2.5  
4 
5.0 
8 
7.5 
12 
10 
16 
*Conversion factor:  salbutamol/albuterol nebulizer solution (2.5 mg) corresponds to 4 puffs 
• Example of salbutamol/albuterol nebulizer-to-puff Conversion: Patient received 
3 salbutamol/albuterol nebulizer treatments (2.5 mg/treatment) between 7 and 11 AM. 
Total daily = 7.5 mg or 12 puffs 
 
Levosalbutamol/Levalbuterol Nebulizer Solution  -Total Daily Dose (mg) 
Number of Puffs* 
0.63  
2 
1.25/1.26 
4 
1.89 
6 
2.5/2.52 
8 
3.15 
10 
3.75/3.78 
12 
5/5.04 
16 
*Conversion factor:  levosalbutamol/levalbuterol nebulizer solution (1.25 mg) corresponds to 4 puffs 
• Example of levosalbutamol/levalbuterol nebulizer-to-puff Conversion: Patient received 
3 levosalbutamol/levalbuterol nebulizer treatments (1.25 mg/treatment) between 7 and 
11 AM. Total daily = 3.75 mg or 12 puffs.  
After conversion of nebulizer-to-puff, and for every instance, where the number of puffs is 
≥6 additional puffs of salbutamol/albuterol or levosalbutamol/levalbuterol in a 24-hour period 
(compared to Baseline) on 2 consecutive days in any week, a LOAC event should be documented. 
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8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
SAR440340 and placebo will be provided in treatment kits indistinguishable in appearance and 
will be labeled with a treatment kit number. The randomized treatment kit number list will be 
generated by Sanofi. 
In accordance with the double-blind design, study patients, Investigators, and study site personnel 
(except the personnel who conduct the reconstitution of the IMP and preparation of syringes for 
injection) will remain blinded except under circumstances described in Section 8.3.2. 
To maintain blinding, the personnel involved with dose preparation will be required to agree not 
to reveal to other study personnel the type of IMP solution (SAR440340 or dupilumab versus 
placebo) in the vials/syringes. 
Dupilumab and placebo will be provided in identically matched prefilled syringes. To protect the 
blind, each treatment kit of glass prefilled syringes (dupilumab/placebo) will be prepared such that 
the treatments (dupilumab and its matching placebo) are identical and indistinguishable and will 
be labeled with a treatment kit number. The randomized treatment kit number list will be 
generated by Sanofi. 
Patients, Investigators, and study site personnel will not have access to the randomization 
(treatment codes) except under circumstances described in Section 8.3.2. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the code must only be broken in circumstances when knowledge of the IMP is 
required for treating the patient.  
Code breaking can be performed at any time by using the proper module of the Interactive 
Response Technology (IRT) and/or by calling any other phone number provided by the Sponsor 
for that purpose. If the blind is broken, the Investigator must document the date, time of day, and 
reason for code breaking.  
Subject withdrawal will only occur when the code break call is made at the site level, not the 
study level. This means that if the Emergency Unblinding transaction is performed by the 
Investigator (ie, at the site level), then the subject will be withdrawn from treatment. However, if 
the Emergency Unblinding transaction is performed by the Global Safety Officer (GSO) (ie, at the 
study level, as the GSO is not site based), then the subject will not be withdrawn from treatment. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
Randomized treatment kit number lists will be generated centrally by Sanofi. The investigational 
product (SAR440340 or matching placebo and dupilumab or matching placebo) will be packaged 
in accordance with these lists. The Sanofi clinical supplies team will provide the randomized 
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treatment kit number lists and the randomization scheme to the centralized treatment allocation 
system (IVRS/IWRS). This centralized treatment allocation system will generate the patient 
randomization list according to which it will allocate the treatment to the patients. Patients who 
meet the entry criteria will be randomized to receive either SAR440340 or matching placebo in 
combination with either dupilumab or matching placebo. The Investigator obtains treatment kit 
numbers at randomization and subsequent scheduled visits via an IVRS/IWRS that will be 
available 24 hours a day. Patients will be randomized in a 1:1:1:1 ratio to receive SC 
administrations of either: 
• SAR440340 300 mg q2w, and coadministration of dupilumab placebo or 
• Dupilumab 300 mg q2w and coadministration of SAR440340 placebo or 
• SAR440340 300 mg and dupilumab 300 mg q2w coadministration or 
• Placebo to both SAR440340 and dupilumab q2w coadministration. 
If certain dynamic laboratory tests do not meet the eligibility criteria, these laboratory assessments 
may be repeated, at the discretion of the Investigator, if it is judged to be likely to return to 
acceptable range for study inclusion within the screening visit window (28 days) prior to Day 1. 
These patients do not need to sign a new informed consent form (ICF) and be allocated a new 
patient number within this same screening window.  
Patients who meet exclusion criteria may be rescreened once during the open screening period of 
the study; a different patient identification number will be issued. Re-screening is not permitted if 
the patient fails to meet inclusion criteria. There is no requirement for a waiting period between 
the screen-failure date and the rescreening date. The IVRS/IWRS report will flag rescreened 
patients. Patients that are rescreened must sign a new ICF and all Visit 1 procedures must be 
repeated. 
Randomization will be stratified by Screening Visit 1 eosinophil count and by country.  
To ensure enrollment according to intended distribution of baseline eosinophil count, alerts will 
be built into the IVRS/IWRS system to limit enrolling patients in the following 2 stratification 
groups: 
• Eosinophil <150 /mm3 not more than approximately 25% (60) patients  
• Eosinophil ≥300 /mm3 at least approximately 45% (108) patients 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING 
SAR440340 and placebo will be supplied as 1 glass vial packed in a patient kit box. Both glass 
vial and box will be labeled. 
Dupilumab and placebo will be supplied as 1 glass prefilled syringe packed in a patient kit box. 
Both glass prefilled syringe and box will be labeled. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
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8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/NIMP in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound must be 
managed according to the rules provided by the Sponsor in the pharmacy manual. 
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/NIMP 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/NIMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP/NIMP (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP/NIMP may be subject to initiation of a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party, allow the 
IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
8.7.1 Treatment accountability and compliance 
The Investigator or pharmacist will also keep accurate records of the quantities of the IMP/NIMP 
dispensed, used, and unused. The IMP/NIMP tracking log and inventory form is to be updated 
each time IMP/NIMP is dispensed. The study monitor will periodically check the supplies of the 
IMP/NIMP held by the Investigator or pharmacist to verify accountability. Treatment kit number 
has to be recorded on the appropriate page of the electronic Case Report Form (eCRF) and also on 
the IMP/NIMP tracking log and inventory log form. 
The monitoring team in charge of the study will have to check case report form data comparing 
them with the centralized treatment allocation system information, the IMP kit and IMP tracking 
log and inventory form. 
For NIMP not provided by the Sponsor, tracking and reconciliation has to be achieved by the 
Investigator and must be captured in standard site documents and records (eg, medical notes). 
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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 study 
site. 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.  
For NIMP not provided by the Sponsor, tracking and reconciliation has to be achieved by the 
Investigator and need to be captured in standard site documents and records (eg, medical notes). 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The following concomitant treatments are not permitted during the screening or treatment phases: 
• Any inhaled steroid other than the standardized fluticasone/salmeterol or fluticasone  
background therapy administered as per protocol 
• Systemic steroids (except systemic steroids to treat asthma exacerbations)  
• LABA other than the salmeterol component of the fixed dose combination administered 
per protocol 
• Ipratropium bromide or other inhaled anti-cholinergic agents (tiotropium)* 
• Methylxanthines (theophylline, aminophyllines)* 
• Leukotriene receptor antagonists or leukotriene synthesis inhibitors* 
• Lipoxygenase inhibitors 
• Cromones 
• Anti-IL5 mAb 
• Anti-IgE therapy (eg, omalizumab [Xolair®])  
• Systemic immunosuppressant (eg, methotrexate, any anti-TNF mAbs, B and/or T cell 
targeted immunosuppressive therapies) 
• Bronchial thermoplasty  
• Intravenous Ig (IVIG) therapy 
• Live Attenuated Vaccines:  refer to Appendix B  
• Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor 
blocker used with dose stabled 1 month prior to Visit 1) 
• Asthma relievers other than salbutamol/albuterol or levosalbutamol/levalbuterol: their use 
is not recommended during the study period. In case of use in exceptional circumstances 
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(eg, prescribed by a physician not participating in the study), their use will be documented 
in the patient's file and reported in the eCRF. 
• Other investigational drugs 
Note: The following is a list of permitted concomitant medications during the study 
• Antihistamines are permitted as concomitant medication. 
• Ocular, intranasal, and topical corticosteroids are permitted during the study. 
* The third controller is not allowed to be used for an additional 4 weeks prior to screening visit 
(V1).  
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
9.1 
PRIMARY ENDPOINT 
The primary endpoint is the proportion of patients with LOAC (for definition, see Section 5).  
9.2 
SECONDARY AND OTHER EFFICACY ENDPOINTS 
The secondary endpoint for this study is: 
• FEV1 change from baseline at Week 12 (pre- and post-bronchodilator). 
9.2.1 Other efficacy endpoints 
• Change from baseline in other lung function measurement (peak expiratory flow [PEF], 
forced vital capacity [FVC], forced expiratory flow [FEF] 25-75%) at Week 12 and at each 
assessment time point. 
• Asthma Control Questionnaire-5 (ACQ-5) score change from baseline at Week 12 and at 
each assessment time point. 
• Asthma Quality of Life Questionnaire with Standardized Activities (AQLQ[S]) 
Self-Administered change from baseline at Week 12 and at each assessment time point. 
• Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score change from baseline at 
Week 12 in patients with a secondary diagnosis of allergic rhinitis. 
• Change from baseline at Week 12 and change from baseline at each week for asthma 
symptom scores in the morning and evening, and nocturnal awakenings. 
• Change from baseline at Week 12 and change from baseline at each week in number of 
inhalations/day of albuterol or levalbuterol for symptom relief. 
9.2.2 Disease-specific efficacy measures 
9.2.2.1 Spirometry 
Spirometry should be performed in accordance with the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) guidelines (21) and prior to administration of 
investigational product.  
For prebronchodilator measured parameters, including FEV1, PEF, FVC and FEF 25%-75%, 
spirometry will be performed after a wash out period of bronchodilators according to their action 
duration, for example, withholding the last dose of salbutamol/albuterol or 
levosalbutamol/levalbuterol for at least 6 hours and withholding the last dose of LABA for at least 
12 hours. 
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At all visits, spirometry will be performed preferably in the AM; PM is allowable in the 
exceptional circumstance when AM spirometry cannot be performed; spirometry should be done 
at approximately the same time at each visit throughout the study. The same spirometer and 
standard spirometric techniques, including calibration, will be used to perform spirometry at all 
visits and, whenever possible, the same person should perform the measurements.  
Three measurements fulfilling the ATS acceptability and repeatability criteria should be obtained 
at every visit, if possible.  
Reversibility is defined as an increase of the absolute FEV1 after administration of 
bronchodilator, and is measured by spirometry as postbronchodilator increase of FEV1 in percent 
of the prebronchodilator FEV1. After spirometry for measuring prebronchodilator FEV1, patients 
will receive 2-4 puffs of albuterol/salbutamol or levalbuterol/levosalbutamol from a primed MDI. 
Alternatively, and only if it is consistent with usual office practice (to be documented), 
reversibility may be performed using inhalation of nebulized albuterol/salbutamol or 
levalbuterol/levosalbutamol. The postbronchodilator spirometry may be repeated several times 
within 30 minutes after administration of bronchodilator. If the subject does not meet reversibility 
at Visit 1/Screening, up to 2 additional attempts during the screening period, each on a different 
day prior to Visit 2/Baseline, may be performed. When reversibility assessment is repeated during 
the screening period, the prebronchodilator FEV1 should again meet the inclusion criterion (I 03) 
of >40% of predicted normal. 
Further details on spirometry will be available in a separate operational manual provided to the 
sites. 
9.2.2.2 Disease-specific, daily efficacy assessments 
9.2.2.2.1 Electronic diary/PEF meter 
The electronic diary/PEF meter is dispensed at Visit 1 and recorded information is downloaded 
from this device on the other indicated days (Section 1.2). The electronic diary/PEF meter is used 
for daily recording of salbutamol/albuterol or levosalbutamol/levalbuterol use, asthma controller 
drug use, asthma symptoms, nocturnal awakenings due to asthma symptoms and AM and PM 
PEF.  
On a daily basis throughout the study (except the Post IMP Treatment Period), the patient uses an 
electronic diary/PEF meter to: 
• Measure morning and evening PEF. 
• Respond to the morning and evening asthma symptom score Numerical Rating Scale 
(NRS) questions. 
• Indicate the number of inhalations/day of salbutamol/albuterol or 
levosalbutamol/levalbuterol for symptom relief. 
• Record the number of inhalations/day of ICS/LABA or ICS background therapy. 
• Record the number of nocturnal awakenings due to asthma symptoms. 
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At screening (Visit 1), patients will be issued an electronic diary and PEF meter. Patients will be 
instructed on the use of the devices, and written instructions on the use of the electronic PEF 
meter will be provided to the patients. In addition, the Investigator will instruct the patients on 
how to record the following variables in the electronic PEF meter: 
• AM PEF performed within 15 minutes after arising (between 5:30 AM and 12 PM)  
• PM PEF performed in the evening (between 5:30 PM and 12 AM)  
• 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 will be recorded by the 
electronic PEF meter, and the highest value will be used for evaluation 
Baseline AM PEF will be the mean AM measurement recorded for the 7 days prior to the first 
dose of IMP, and baseline PM PEF will be the mean PM measurement recorded for the 7 days 
prior to the first dose of investigational product. Period stability limit is defined as the respective 
mean AM or PM PEF obtained over the last 7 days prior to Day 1. There should be at least 4 days 
of measurements for setting up the stability limit, and the first dosing visit may be rescheduled 
until data for 4 days are available. 
Information derived from the electronic PEF meter will be evaluated by the Investigator at study 
visits. 
In the Post IMP Treatment Period, the patient's response in the electronic diary/PEF meter will not 
be recorded daily; questionnaires will only be administered at on-site visits. 
9.2.2.3 ACQ (Asthma Control Questionnaire) 
The ACQ was designed to measure both the adequacy of asthma control and change in asthma 
control which occurs either spontaneously or as a result of treatment (see Appendix D).  
Measurement properties such as reliability and ability to detect change have been documented in 
the literature (22). 
The ACQ-5 is short version of ACQ-7, and ACQ-5 score is the mean of the first 5 questions and, 
therefore, between 0 (totally controlled) and 6 (severely uncontrolled). Higher score indicates 
lower asthma control. Patients with a score below 1.0 reflect adequately controlled asthma and 
patients with scores above 1.0 reflect inadequately controlled asthma. On the 7-point scale of the 
ACQ-5, a change or difference in score of 0.5 is the smallest change that can be considered 
clinically important, corresponding to the Minimal Clinically Important Difference (MCID) 
defined by the developer. 
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9.2.2.4 Asthma Quality Of Life Questionnaire with Standardized Activities 
Self-Administered   
The Asthma Quality Of Life Questionnaire with Standardized Activities (AQLQ[S]) was designed 
as a self-administered patient reported outcome to measure the functional impairments that are 
most troublesome as a result of their asthma (23). 
The instrument is comprised of 32 items (see Appendix E), 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) 
Patients are asked to recall how their asthma has been during the previous 2 weeks. 
A global score is calculated ranging from 1 to 7 and a score by domain. Higher scores indicate 
better quality of life.  
The magnitude of effect of asthma treatments is measured by the mean change from baseline 
between treatment and control groups. The instrument has been used in many clinical trials, and it 
has been shown to be reliable, valid (patient interviews), and sensitive to change. A change or 
difference in AQLQ(S) score of 0.5 is the smallest change that can be considered clinically 
important, corresponding to the MCID defined by the developer. Measurement properties such as 
reliability and ability to detect change have been documented in the literature. The proportion of 
patients achieving clinically relevant responder thresholds is defined as the percentage of patients 
with a change or difference in individual score of at least 0.5. In addition, the total score on each 
domain could be useful for the interpretation of the magnitude of effect. 
9.2.2.5 Standardized Rhinoconjunctivitis Quality of Life Questionnaire in those patients 
with comorbid allergic rhinitis 
Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ[S]) is a self-administered questionnaire 
(Appendix F) with standardized activities developed to measure health-related quality of life signs 
and symptoms that are most problematic in adults, as a result of perennial or seasonal allergic 
rhinitis (24). 
There are 28 items on the RQLQ(S) in 7 domains: 
• Activities (3 items),  
• Sleep (3 items),  
• Non-Hay Fever Symptoms (7 items),  
• Practical Problems (3 items),  
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• Nasal Symptoms (4 items),  
• Eye Symptoms (4 items),  
• Emotional (4 items). 
The RQLQ(S) responses are based on 7-point Likert scale with responses ranging from 0 (not 
troubled) to 6 (extremely troubled). Higher scores indicated more health-related quality of life 
impairment (lower scores better). 
The magnitude of effect of asthma treatment is measured by the mean change from baseline 
between treatment and control groups. An MCID of 0.5 has been established as the minimal 
important difference indicative of a clinically meaningful change defining responders. The 
proportion of patients achieving clinically relevant responder thresholds is defined as the 
percentage of patients with a change or difference in individual score of at least 0.5. In addition, 
the total score on each domain could be useful for the interpretation of the magnitude of effect. 
9.2.2.6 Asthma Symptom Score Numerical Rating Scale (NRS) 
Patients will record overall symptom scores in an electronic diary/PEF meter twice a day prior to 
measuring PEF. The patient’s overall asthma symptoms experienced during the waking hours will 
be recorded in the evening (PM symptom score) and asthma symptoms experienced during the 
night will be recorded in the morning (AM symptom score). Baseline symptom scores will be the 
mean AM and mean PM scores recorded for the 7 days prior to randomization. The baseline 
AM/PM symptom score will be computed following the same algorithm used for baseline 
AM/PM PEF. Scores range between 0-4 with 0 indicating more mild symptoms and 4 indicating 
more severe symptoms. There is no global score, just an AM score and a PM score. An MCID of 
0.35 is being used (25) (see Appendix G). 
9.2.3 Safety and tolerability endpoints 
The same safety assessments will be applied across all arms. Adverse events, including SAEs and 
AEs of special interest (AESI), will be collected at every visit. The Investigator will ask the 
patient how he/she has felt since the last study visit. The study-specific and general safety criteria 
are detailed in Section 10.6.  
9.2.3.1 Adverse events 
Adverse events for each patient will be monitored and documented from the time the patient gives 
informed consent at Visit 1 until the End-of-Study visit (Visit 17) except for: 
• Serious AEs 
• Adverse events that are ongoing at database lock 
Adverse events, AESI, and SAEs will be reported as described in Section 10.4.3. 
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9.2.3.1.1 Physical examination 
Complete physical examinations will include an assessment of skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal 
systems. All deviations from normal will be recorded, including those attributable to the patient’s 
disease. 
Refer to Section 1.2 for the schedule of physical examinations performed throughout this study. 
9.2.3.2 Vital signs 
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats per minute), 
and respiratory rate (breaths per minute) and body temperature will be measured at all visits. Vital 
signs will be measured in the sitting position using the same arm (preferably). Height (cm) will be 
measured at screening (Visit 1) only.  
Body weight (kg) will be measured at screening (Visit 1), baseline (Visit 2), and EOT (Visit 14). 
Refer to Section 1.2 for the schedule of vital signs performed throughout this study. 
9.2.3.3 Electrocardiogram  
Recording of a standard 12-lead ECG will be performed at the clinical site. Refer to Section 1.2 
for the schedule of ECG performed throughout this study. At the postrandomization visits, ECGs 
will be performed prior to investigational product administration. A minimum of 3 complexes in 
an appropriate lead (lead II) will be averaged to determine the PR-interval, QT/QTc-interval, 
QRS-complex and heart rate will be measured for each ECG. Refer to ECG reading manual for 
more details. All ECG recordings will be centrally read by independent experts. 
9.2.3.4 Clinical laboratory tests  
The clinical laboratory tests will be conducted by an accredited (College of American Pathologists 
or equivalent) central laboratory with national and regional clinical licenses as required for 
diagnostic testing and must provide evidence of participation in proficiency testing, as 
appropriate. After reviewing the laboratory report and evaluating any results that are outside the 
normal range, the Investigator must sign and date the laboratory report.   
Abnormal laboratory values that are considered to be clinically significant by the Investigator 
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. 
Refer to Section 1.2 for the description of the clinical laboratory evaluations and the schedule of 
laboratory evaluations performed throughout this study. 
The clinical laboratory parameters that will be measured are: 
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• Hematology: To include hemoglobin, hematocrit, platelet count, total white blood cell 
(WBC) count with 5-part differential count, and total red blood cell (RBC) count. 
Neutrophil and eosinophil counts (study biomarkers) will also be evaluated as a part of 
hematology testing. 
• Serum chemistry: To include creatinine, blood urea nitrogen, glucose, uric acid, total 
cholesterol, total protein, albumin, total bilirubin (in case of values above the normal 
range, differentiation in conjugated and nonconjugated bilirubin), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), alkaline phosphatase, electrolytes (sodium, 
potassium, chloride), bicarbonate, and creatine phosphokinase (CPK).  
• Urinalysis will include specific gravity, pH, glucose, ketones, blood, protein, nitrate, 
leukocyte esterase, urobilinogen, and bilirubin. If any parameter on the dipstick is 
abnormal, a urine sample should be sent to the central laboratory for quantitative 
measurement. If positive for protein and/or red blood cells, microscopic analysis will be 
performed by the central laboratory. 
• Clinical laboratory testing at Screening Visit 1 will include hepatitis screen covering HBs 
Ag, hepatitis B surface antibody (HBs Ab), HBc Ab, hepatitis C virus antibodies (HCV 
Ab), HIV screen (Anti-HIV-1 and HIV-2 antibodies) and anti-nuclear antibody (ANA). In 
case of results showing HBs Ag (negative), and HBc Ab (positive), an HBV DNA testing 
may be performed prior to randomization to rule out a false positivity if the Investigator 
believes the patient is a false positive, or to clarify the serological status if the Investigator 
finds it unclear to interpret in absence of known HBV infection. In case of results showing 
HCV Ab (positive), an HCV RNA testing may be performed to rule out a false positivity, 
if the Investigator believes the patient is a false positive.  
Note: Anti-ds DNA antibody will be tested if ANA is positive (≥1:160 titer).  
• Clinical laboratory testing at Screening Visit 1 will also include Quantiferon gold testing 
for all patients. If the result is confirmed positive, the patient should be referred to an 
Infectious Disease specialist.  Please refer to the central laboratory manual for additional 
details. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix H. 
9.2.3.5 Pregnancy test 
For women of childbearing potential only: serum pregnancy test at Screening/Visit 1 and urine 
pregnancy tests at Visits 2, 6, 10, 14/EOT and Visit 17/EOS. A negative result must be obtained at 
Visit 1 and at Visit 2 prior to randomization. In case of positive urinary test, the study treatment 
will be withheld and a serum pregnancy test should be performed as soon as possible to confirm 
the pregnancy. Pregnancy will lead to definitive treatment discontinuation in all cases. Refer to 
Section 1.2 for the schedule of pregnancy test performed throughout this study. 
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9.3 
OTHER ENDPOINTS 
9.3.1 Systemic drug concentration and anti-drug antibodies 
• Serum functional SAR440340 or dupilumab concentrations 
• Anti-drug antibodies (ADA) against SAR440340  
• Anti-drug antibodies (ADA) against dupilumab 
9.3.1.1 Sampling time 
Predose blood samples will be collected for determination of functional SAR440340 and 
dupilumab concentrations in serum (PK profile) and ADA against SAR440340 and dupilumab in 
serum (immunogenicity and safety) as summarized in the study flow chart (Section 1.2). The date 
of collection should be recorded in the patient eCRF. In a patient with treatment-emergent ADA 
response, if the sample at week 12 or the first post-treatment time point analyzed is positive in the 
ADA assay, then ADA assessments may be performed on PK samples collected at Week 4. 
If an SAE or listed AESI (anaphylaxis, systemic hypersensitivity reaction, and severe injection 
site reaction [ISR] lasting 24 hours), occurs in a patient, blood samples should be collected for 
determination of functional IMP concentration, and ADA assessment at or near the onset and 
completion of the occurrence of the event, if possible. The exact date and time of sample 
collection must be recorded and entered into the database by the central laboratory. An 
unscheduled systemic drug concentration page in the eCRF must be completed as well. If 
necessary for safety monitoring, additional additional blood for an ADA sample may be drawn 
after the EOS Visit until resolution of AE. 
Further follow-up of individual patients will be considered based on the overall assessment of 
antibody titers and clinical presentation. 
9.3.1.2 Handling procedures 
Special procedures for collection, storage, and shipping of serum are described in separate 
operational manuals. An overview of handling procedure for samples used in the determination of 
systemic drug concentration and ADA is provided in Table 2. 
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Table 2 - Summary of handling procedures for samples 
Sample type 
PK (SAR440340 or dupilumab) 
ADA (SAR440340 or Dupilumab) 
Matrix 
Serum 
Serum 
Blood sample volume 
5 mL 
5 mL 
Anticoagulant 
None 
None 
Blood handling procedures 
See Operational Manual 
See Operational Manual 
Serum aliquot split 
Two aliquots 
Two aliquots  
Serum shipment condition 
In dry ice 
In dry ice 
Additional samples can be collected for safety. 
9.3.1.3 Bioanalytical method 
Serum samples will be assayed using validated methods as described in Table 3. 
Table 3 - Summary of bioanalytical methods for pharmacokinetics and antidrug antibody 
Analyte 
PK (SAR440340 or dupilumab) 
ADA (SAR440340 or dupilumab) 
Matrix 
Serum 
Serum 
Analytical technique 
ELISA 
Electrochemiluminescence 
Site of bioanalysis 
Regeneron 
Regeneron 
ADA = anti-drug antibody; ELISA: enzyme-linked immunosorbent assay; PK: pharmacokinetics. 
9.3.2 Pharmacodynamics and phenotyping  
9.3.2.1 Pharmacodynamic variables 
• Blood eosinophil and neutrophil counts (Section 9.3.2.2) 
• Fraction of exhaled nitric oxide (FeNO) level compared with baseline (Section 9.3.2.3) 
• Total IL33 and soluble IL33 receptor (sST2; serum sample) 
• Calcitonin (serum sample) 
• Pulmonary and activation-regulated chemokine (PARC) (serum samples) 
• Eotaxin-3 (sodium heparinized samples) 
• Total IgE (serum samples) 
• Periostin (serum samples) 
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• Optional: Messenger ribonucleic acid (mRNA) sequencing or whole transcriptome 
analysis (PaxGene samples) 
• Optional: Blood sample archival for exploratory research (serum and plasma) 
• Optional: Deoxyribonucleic acid (DNA) sample will be collected for assessment of  
pharmacogenomic effects (blood sample) 
For timing of pharmacodynamic sample collection refer to study flow chart Section 1.2. 
Assay methodologies are briefly summarized below. More detailed information on the collection, 
handling, transport, and preservation of samples (eg, minimum volumes required for blood 
collection and for aliquots for each biomarker assay) will be provided in a separate laboratory 
manual. 
9.3.2.2 Whole blood biomarkers 
Blood eosinophil and neutrophil count will be measured as part of the standard 5-part WBC 
differential cell count on a hematology autoanalyzer. 
9.3.2.3 Exhaled nitric oxide 
Fractional exhaled nitric oxide (FeNO) will be analyzed using a NIOX instrument (Aerocrine AB, 
Solna, Sweden), or similar analyzer using a flow rate of 50 mL/s, and reported in parts per billion 
(ppb). This assessment should be conducted prior to spirometry and following a fast of at least 1 
hour. Further details on the procedure for measuring exhaled nitric oxide with NIOX will be 
provided in a separate instruction manual. 
9.3.2.4 Plasma/serum biomarkers  
Total IL33 and sST2 will be measured in serum samples. Pulmonary and activation-regulated 
chemokine (PARC) will be assayed using a validated enzyme immunoassay. Periostin will be 
assessed using the SHINO test.  
For calcitonin, developement of the method is currently ongoing.  
Eotaxin-3 will be measured in heparinized plasma with a validated enzyme immunoassay (Human 
Eotaxin-3 Quantikine ELISA kit). 
Total IgE will be measured with a fluorenzyme immunoassay (Phadia 1000) approved for 
diagnostic testing. 
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9.3.3 Pharmacogenetics 
9.3.3.1 Stored DNA (optional) and RNA (optional) samples  
Pharmacogenetic testing is optional and voluntary. Written informed consent must be obtained 
before sampling.  
For those patients who provided written consent to the collection of the optional pharmacogenetic 
samples, blood samples for exploratory genetic analysis of DNA will be collected at the study 
visit as specified in the study flow chart, and these samples will be stored for future analysis. 
Specific procedures for collection, storage, and shipping of pharmacogenetic samples will be 
provided in a lab manual.  
Deoxyribonucleic acid (DNA) samples for the genomics sub study will be used to identify 
genomic associations with clinical or biomarker response, other clinical outcome measures and 
possible AEs. In addition, association between genomic variants and prognosis or progression of 
diseases may also be studied. These data may be used or combined with data collected from other 
studies to identify and validate genomic markers related to the study drug or diseases. The DNA 
may be subjected to a genome-wide association study by whole exome sequencing, single 
nucleotide polymorphism studies of candidate genes, DNA copy number variations or whole 
genome analysis in order to thoroughly explore genetic associations with disease progression or 
treatment response. The list of methods may be expanded to include novel methodology that may 
be developed during the course of this study or sample storage period. 
The blood DNA sample, and the DNA that is extracted, will be assigned a second number, a 
Genetic ID (de-identification code) that is different from the patient ID. This “double coding” is 
performed to separate a patient’s medical information and DNA data. 
The clinical study data (coded by patient ID) will be stored in the clinical data management 
system (CDMS), which is a distinct database in a separate environment from the database 
containing the pharmacogenetic data (coded by Genetic ID). The key linking patient ID and 
Genetic ID will be maintained by a third party, under appropriate access control. The matching of 
clinical data and pharmacogenetic data, for the purpose of data analysis, will be possible only by 
using this key, which will be under strict access control. All data will be reported only in coded 
form in order to maintain confidentiality. 
The aliquots of DNA sent to the bioanalytical laboratories for specific genetic testing will be 
destroyed after completion of that specific analysis and issuance of the related analytical data.  
9.4 
FUTURE USE OF SAMPLES 
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For patient(s) who have consented to it, the samples that are archived, unused or left 
over after planned testing may be used for additional research purposes (any genetic analysis 
subject to additional consent per Section 9.3.3). For patients who have consented to it, archival 
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blood samples will be collected at the visits specified in the study flow chart. Additional details 
will be provided in the laboratory manual. 
These archived serum and plasma samples, and any residual or leftover serum, plasma or blood 
remaining from planned laboratory work, may be used for research purposes related to 
inflammatory diseases (eg, exploratory biomarkers of disease or drug effect), pathway biology, 
additional drug safety assessments or development and validation of bioassay methods beyond 
those defined in the present protocol. These samples will remain labelled with the same identifiers 
as the ones used during the study (ie, patient ID, sample ID). They will be transferred to a Sanofi 
site (or a subcontractor site) which can be located outside of the country where the study is 
conducted. The Sponsor has included safeguards for protecting patient confidentiality and 
personal data (see Section 14.3 and Section 14.5).  
9.5 
APPROPRIATENESS OF MEASUREMENTS  
The efficacy and safety assessments used in this study are standard for the evaluation of therapy in 
patients with asthma. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The clinical trial consist of 3 periods, including an add-on ICS/LABA (fluticasone/salmeterol, 
standardized at screening) background therapy that is withdrawn during the 12-week randomized 
IMP (SAR440340 and/or dupilumab and/or placebo) treatment period and resumed at the end of 
the IMP treatment period for the 20-week safety follow-up period (Section 1.1 and Section 1.2), 
as outlined below: 
• Screening period (4 weeks [±3 days]) 
• Randomized IMP treatment (12 weeks [±3 days]) 
- 
Background therapy stable phase (4 weeks)  
- 
Background therapy withdrawal phase (4-5 weeks, see Section 6.1.1 and for more 
details see Section 8.2.1)  
- 
No background therapy phase (3-4 weeks, see Section 1.2) 
• Post IMP treatment safety follow-up period (20 weeks [±5 days]) 
The study visits occur on the planned dates (relative to the first injection), as scheduled. The visit 
schedule should be adhered to within ±3 days for the screening period and randomized IMP 
treatment period and ±5 days for the 3 visits during the post IMP treatment safety follow-up 
period. 
Spirometry should be performed at approximately the same time of the day (either in the AM or 
PM, but preferably in the AM, as detailed in Section 9.2.2.1) at each visit throughout the study. 
Patients who discontinue IMP prior to 12 weeks of treatment will be asked and encouraged to 
return to the clinic, as soon as possible, for EOT assessments and participate in follow-up 
assessments according to the visit schedule. 
Reminder: sexually active patients (both male and female) of reproductive potential are required 
to practice an effective contraception throughout the participation in the study including follow-up 
period. Sites should counsel all study patients, regarding the importance of practicing responsible 
and effective contraception throughout the participation in the study including follow-up period. 
Prior to all screening assessments, after discussion of participation in the study, the written 
consent form (including voluntary participation in pharmacogenetic testing/future use of blood 
samples) must be signed and dated. 
Although the screening assessments for this study are grouped under the heading of a single visit 
in this protocol, it is possible for them to be performed over more than 1 site visit if necessary, as 
long as the screening visit window prior to randomization (Day 1) is respected. If certain dynamic 
laboratory tests do not meet the eligibility criteria, these laboratory assessments may be repeated, 
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at the discretion of the Investigator, if it is judged to be likely to return to acceptable range for 
study inclusion within the screening visit window (4 weeks ± 3 days) prior to Day 1. These 
patients do not need to sign a new ICF or be allocated a new patient number within this same 
screening window.  
If the subject does not meet the qualifying criteria for reversibility at Visit 1/Screening, up to 
2 additional attempts during the screening period, each on a different day prior to Visit 2/Baseline, 
may be performed. When reversibility assessment is repeated during the screening period, the 
prebronchodilator FEV1 should again meet the inclusion criterion (I 03) of >40% of predicted 
normal. 
Patients that fail the initial screening for exclusion criteria (eg, concomitant medications) may be 
rescreened for study eligibility 1 additional time. Patients that are rescreened must sign a new 
consent form and will be allocated a new patient number; all of the Visit 1 procedures must be 
repeated (refer to Section 8.4 for further instructions related to rescreening) unless a prior 
assessment is performed within the time frame permitted prior to study entry. 
It is recommended that assessments/procedures at a site visit are performed in the following order 
if applicable and possible: 
1. Patient-reported outcomes and other questionnaires 
2. ECG 
3. Procedures: 
a) FeNO 
b) Spirometry (FEV1) and Reversibility 
c) Electronic Diary download 
4. Safety and laboratory assessments 
5. Administration of IMP  
10.1.1 Visit 1/Screening (Week -4 to Week 0 [zero], Day -28 to Day 0) – Screening Visit  
Following a discussion of participation in the clinical trial, informed consent must be obtained and 
documented. These steps precede any study procedures. The visit schedule should be adhered to 
within the ±3 day visit window allowed during the treatment phase of the study. 
The following procedures will then be performed: 
• Call IVRS/IWRS to assign patient number and register screening visit. 
• Interview to collect patient demographic information, asthma history (including smoking 
habits), previous medical history and surgical history, and prior and concomitant 
medications. Inquire about AEs/SAEs. 
• Administer ACQ-5 via handheld device 
• Perform 12-lead ECG 
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• Review entry criteria to assess eligibility (Section 7.1 for details) , with special attention to 
verify the following: 
- 
Existing treatment with medium to high dose ICS (≥250 mcg of fluticasone propionate 
BID or equipotent ICS daily dosage to a maximum of 2000 mcg/day of fluticasone 
propionate or clinically comparable) in combination with a LABA as second controller 
for at least 3 months with a stable dose ≥1 month prior to Visit 1.  
• Perform Spirometry (review eligibility criteria) and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
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. This will be verified before performing the measurements. 
- 
Patients with reversibility of at least 12% and 200 mL in FEV1 after administration of 
2 to 4 puffs (200-400 mcg) of albuterol/salbutamol or levalbuterol/levosalbutamol 
during screening or documented history of a reversibility test that meets this criteria 
within 12 months prior to Visit 1 or documented positive response to methacholine 
challenge (a decrease in FEV by 20% [PC20] of <8mg/mL) within 12 months prior to 
Visit 1/Screening is considered acceptable to meet this inclusion criterion. 
Note: If the subject does not meet the qualifying criteria for reversibility at 
Visit 1/Screening, up to 2 additional attempts during the screening period, each on a 
different day prior to Visit 2/Baseline, may be performed. When reversibility 
assessment is repeated during the screening period, the prebronchodilator FEV1 should 
again meet the inclusion criterion (I 03) of >40% of predicted normal. 
• Perform physical examination (refer to Section 9.2.3.1.1). Complete physical examination 
will include skin, nasal cavities, eyes, ears, respiratory, cardiovascular, gastrointestinal, 
neurological, lymphatic, and musculoskeletal systems. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], heart rate 
[beats per minute], respiration rate [breaths per minute], body temperature [°C], body 
weight [kg], and height [cm]).  
After determination of preliminary eligibility: 
• Obtain blood samples for screening clinical laboratory (see Section 9.2.3.4 for details) 
determinations: hematology and serum chemistry. 
• Obtain blood samples for screening serology: HBs Ag, HBs Ab, HBc Ab, hepatitis C virus 
antibodies (HCV Ab), anti-HIV-1 and HIV-2 antibodies, and ANA. 
• Obtain urine sample for urinalysis.  
• Quantiferon gold testing. 
Note: If the result is confirmed positive, the patient should be referred to an Infectious 
Disease specialist. 
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• Obtain serum β-hCG pregnancy test if female of childbearing potential 
• Perform blood sampling for the following tests: 
- 
Biomarker set: blood eosinophils and neutrophils, total IL33, sST2, calcitonin, PARC, 
eotaxin-3, total IgE and periostin (refer to Section 9.3.2.4), 
- 
Optional: Sample for RNA panel testing for those patients who have consented to it 
- 
Optional: Archival of serum and plasma for those patients who have consented to 
Future Use of Specimens (refer to Section 9.4) 
• Dispense electronic diary/PEF meter handheld device, provide instructions for daily use, 
and remind patient to bring the device to the next visit.  
The electronic diary/PEF meter is a handheld device used for daily recording of 
salbutamol/albuterol or levosalbutamol/levalbuterol use, asthma controller drug use, 
nocturnal awakenings due to asthma symptoms and AM and PM PEF, and recordings of 
patient’s answers to the ACQ-5, AQLQ(S), and RQLQ questionnaires during the 
scheduled visits. These handheld devices are dispensed at Visit 1 (including instructions 
for use) and recorded information is downloaded from the devices on the other indicated 
days (Section 1.2). At Visit 14/EOT, recorded information is downloaded from the 
handheld devices and the devices are returned at EOS as the lastest. 
• All eligible patients will be switched to the study-specific ICS/LABA background therapy, 
which consists of BID fluticasone/salmeterol inhalations, at clinically comparable doses 
(to each individual patient’s prescribed ICS/LABA dose level prior to screening, ie, 
meeting the preprotocol definition of medium or high dose ICS/LABA; Section 7.1), as 
approved for region (Section 8.2): 
- 
Fluticasone/salmeterol – dry powder inhaler (DPI):  
1 puff of 250/50 mcg twice daily (BID) or  
1 puff of 500/50 mcg BID 
OR  
- 
Fluticasone/salmeterol – metered dose inhaler (MDI):  
2 puffs of 115/21 mcg (230/42 mcg) BID or  
2 puffs of 230/21 mcg (460/42 mcg) BID 
OR  
- 
Fluticasone/salmeterol – metered dose inhaler (MDI):  
2 puffs of 125/25 mcg (250/50 mcg) BID or  
2 puffs of 250/25 mcg (500/50 mcg) BID 
• Dispense study-specific ICS/LABA medication (DPI or MDI). 
• Remind patients to use fluticasone/salmeterol combination as background therapy 
medication. Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
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• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours and 
LABA for at least 12 hours prior to next visit. 
• Schedule a site visit for Visit 2, Day 1 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2 Randomized IMP Treatment Phase – Week 0 to Week 12 
10.1.2.1 Background therapy stabilization phase – Week 0 to Week 3 (Visits 2 to 5) 
The visit schedule should be adhered to within the ±3 day visit window allowed during the 
treatment phase of the study. 
10.1.2.1.1 Visit 2/Randomization/Baseline (Week 0/Day 1) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and background asthma therapy tolerability and compliance. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S) via handheld device. 
• Perform spirometry and measure exhaled nitric oxide:   
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements.  
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device, and remind patient to 
bring the device to the next visit. 
• Perform physical examination. 
• Perform urine pregnancy test (for women of childbearing potential) 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], body weight [kg], respiratory rate [breaths per minute] and body 
temperature [°C]). 
If the patient meets all inclusion and does not meet any exclusion criteria: 
• Call IVRS/IWRS to register visit, randomize the patient if entry criteria are met, and 
receive the first assignment for treatment kit numbers. 
- 
Note: Please screen-fail the patient if entry criteria are not met. 
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• Perform baseline blood sampling (prior to administration of IMP) for the following tests: 
- 
PK analysis 
- 
Hematology and serum chemistry 
- 
Anti-SAR440340 antibody and anti-dupilumab antibody 
- 
Biomarker set: blood eosinophils and neutrophils, total IL33, sST2, calcitonin, PARC, 
eotaxin-3, total IgE, and periostin (refer to Section 9.3.2.4) 
- 
Optional: Sample for RNA panel testing  
- 
Optional: Archival of serum and plasma for those patients who have consented to 
Future Use of Specimens (refer to Section 9.4) 
- 
Optional: Sample for DNA for those patients who have consented to pharmacogentics,  
please refer to Section 9.3.3) 
• Obtain urine sample for urinalysis. 
• Administration of IMP.  
- 
Patients should be monitored by site personnel for at least 30 minutes after 
administration of all IMP injections. Monitoring period may be extended up to 2 hours 
as per country specific requirements. 
• Remind patients to use fluticasone/salmeterol combination as background therapy 
medication. Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours and 
LABA for at least 12 hours prior to next visit. 
• Schedule a site visit for Visit 3 (Day 8, Week 1) and request patient to come at 
approximately the same time of day as this visit. 
10.1.2.1.2 Visit 3, Day 8 (Week 1)  
• Record all concomitant medication use; inquire about AEs/SAEs and asthma therapy 
tolerability. 
• Evaluate patient for a LOAC event. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements.  
- 
Prebronchodilator FEV1 should be determined. 
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• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
• Remind patients to use fluticasone/salmeterol combination as background therapy 
medication. Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours and 
LABA for at least 12 hours prior to next visit. 
• Schedule a site visit for Visit 4, Day 15 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.1.3 Visit 4, Day 15 (Week 2) 
• Record all concomitant medication use; inquire about AEs/SAEs and asthma therapy 
tolerability. 
• Evaluate patient for a LOAC event. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S) via handheld device. 
• Perform spirometry and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
 Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements. 
- 
Prebronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit  
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
• Perform blood sampling (prior to administration of IMP) for the following tests: 
- 
PK analysis 
- 
Biomarkers: blood eosinophils and neutrophils  
• Call IVRS/IWRS to register visit and obtain next treatment kit numbers  
• Administration of IMP. 
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- 
Patients should be monitored by site personnel for at least 30 minutes after 
administration of all IMP injections.  Monitoring period may be extended up to 2 hours 
as per country specific requirements. 
• Remind patients to use fluticasone/salmeterol combination as background therapy 
medication. Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 5, Day 22 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.1.4 Visit 5, Day 22 (Week 3) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements. 
- 
Prebronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
• Remind patients to use fluticasone/salmeterol combination as background therapy 
medication. Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 6, Day 29 and request patient to come at approximately the 
same time of day as this visit (fasting if morning visit). 
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10.1.2.2 Background therapy withdrawal phase – Week 4 to Week 9 (Visits 6 to 11): 
LABA withdrawal at Week 4, ICS step-wise withdrawal starting at Week 6  
PLEASE NOTE: depending on high or medium dose fluticasone backgound therapy at 
Visit 2/baseline, patients will have a 5- or 4-week ICS/LABA withdrawal phase, respectively, and 
thus will be on IMP treatment without background therapy for 3 or 4 weeks, respectively, before 
resuming original (prescreening) ICS/LABA therapy at Visit 14/EOT (for overview, please see 
Section 1.1, Section 1.2, Section 8.2.1 and Table 1). 
10.1.2.2.1 Visit 6, Day 29 (Week 4) – Withdrawal of LABA  
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S) via handheld device. 
• Perform 12-lead ECG. 
• Perform spirometry and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements.  
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Perform physical examination. 
• Perform urine pregnancy test (for women of childbearing potential). 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate [breaths per minute] and body temperature [°C]).  
• Perform blood sampling (prior to administration of IMP) for the following tests: 
- 
PK analysis 
- 
Hematology and serum chemistry  
- 
Biomarker set: blood eosinophils and neutrophils, total IL33, sST2, calcitonin, PARC, 
eotaxin-3, total IgE, periostin (refer to Section 9.3.2.4) 
- 
RNA panel testing (optional) 
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- 
Archival serum for those patients who have consented to collection for Future Use of 
Specimens (refer to Section 9.4) 
• Obtain urine sample for urinalysis 
• Call IVRS/IWRS to register visit and obtain next treatment kit numbers  
• Administration of IMP 
- 
Patients should be monitored by site personnel for at least 30 minutes after 
administration of all IMP injections.  Monitoring period may be extended up to 2 hours 
as per country specific requirements.   
• At Week 4 (Visit 6), the LABA component (salmeterol) will be withdrawn, and all 
patients will be switched from their BID fluticasone/salmeterol combination therapy (from 
Screening Visit 1 up to Visit 6) to a clinically comparable ICS dose of fluticasone BID 
monotherapy (Section 8.2.1), as approved for region: 
- 
Fluticasone (DPI formulation):  
1 puff of 250 mcg BID or 
2 puffs of 250 mcg (500 mcg) BID,  
OR  
- 
Fluticasone (MDI formulation):  
2 puffs of 110 mcg (220 mcg) BID or  
2 puffs of 220 mcg (440 mcg) BID 
OR  
- 
Fluticasone (MDI formulation):  
2 puffs of 125 mcg (250 mcg) BID or  
2 puffs of 250 mcg (500 mcg) BID 
• Dispense ICS monotherapy MDI or DPI (see above) for use in the evening of this visit day 
and until morning of the next visit day. Please update controller profile in the electronic 
diary web portal accordingly. 
• Remind patients to use fluticasone monotherapy as background therapy medication. 
Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 7, Day 36 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.2.2 Visit 7, Day 36 (Week 5) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
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• Evaluate patient for a LOAC event. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements. 
- 
Prebronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
• Remind patients to use fluticasone monotherapy as background therapy medication. 
Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 8, Day 43 and request patient to come at approximately the 
same time of day as this visit.  
10.1.2.2.3 Visit 8, Day 43 (Week 6) – Begin ICS withdrawal steps 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S) via handheld device. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements.   
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate [breaths per minute], and body temperature [°C]).  
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• Collection of blood samples for: 
- 
Biomarkers: blood eosinophils and neutrophils  
• Call IVRS/IWRS to register visit and obtain next treatment kit numbers  
• Administration of IMP 
- 
Patients should be monitored by site personnel for at least 30 minutes after 
administration of all IMP injections.  Monitoring period may be extended up to 2 hours 
as per country specific requirements.   
Step-wise ICS fluticasone withdrawal commences at this Visit 8 (Week 6): 
• If no new LOAC event, proceed with next lower ICS dose level of fluticasone for each 
individual patient (Week 6, Visit 8). Please update controller profile in the electronic diary 
web portal accordingly. 
• Dispense ICS monotherapy at the next lower ICS dose level of fluticasone for each 
individual patient, as approved for region (please refer to Table 1), for use in the evening 
of this visit day and until morning of the next visit day. 
• Remind patients to use fluticasone monotherapy as background therapy medication. 
Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 9, Day 50 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.2.4 Visit 9, Day 50 (Week 7) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements.  
- 
Prebronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
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• If no new LOAC event, proceed with next lower ICS dose level of fluticasone for each 
individual patient (Week 7, Visit 9). 
• Dispense ICS monotherapy at the next lower ICS dose level of fluticasone for each 
individual patient, as approved for region (please refer to Table 1), for use in the evening 
of this visit day and until morning of the next visit day. Please update controller profile in 
the electronic diary web portal accordingly. 
• Remind patients to use fluticasone monotherapy as background therapy medication. 
Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 10, Day 57 and request patient to come at approximately the 
same time of day as this visit (fasting if morning visit). 
10.1.2.2.5 Visit 10, Day 57 (Week 8) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S) via handheld device. 
• Perform spirometry and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements.   
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Perform physical examination. 
• Perform urine pregnancy test (for women of childbearing potential) 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate [breaths per minute] and body temperature [°C]).  
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• Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests: 
- 
PK analysis 
- 
Biomarker set: blood eosinophils and neutrophils, total IL33, sST2, calcitonin, PARC, 
eotaxin-3 (refer to Section 9.3.2.4) 
- 
Hematology and serum chemistry 
• Obtain urine sample for urinalysis.  
• Call IVRS/IWRS to register visit and obtain next treatment kit number  
• Administration of IMP 
- 
Patients should be monitored by site personnel for at least 30 minutes after 
administration of all IMP injections. Monitoring period may be extended up to 2 hours 
as per country specific requirements.   
• If no new LOAC event, proceed with next lower ICS dose level of fluticasone for each 
individual patient (Week 8, Visit 10), or proceed with no background therapy (please refer 
to Table 1) until LOAC or Visit 14 (Week 12), whichever comes first. 
• Dispense ICS monotherapy at the next lower ICS dose level of fluticasone for each 
individual patient on high dose ICS, as approved for region (please refer to Table 1), for 
use in the evening of this visit day and until morning of the next visit day. Please update 
controller profile in the electronic diary web portal accordingly. 
• Remind patients on lowest ICS dose to use fluticasone monotherapy as background 
therapy medication. Instruct patient to record daily usage in the electronic diary. 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 11, Day 64 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.3 No ICS/LABA background therapy phase – Week 9 to Week 12 (Visits 11 to 14) 
PLEASE NOTE: depending on high or medium dose fluticasone backgound therapy at 
Visit 2/baseline, patients will have a 5- or 4-week ICS/LABA withdrawal phase, respectively, and 
thus will be on IMP treatment without background therapy for 3 or 4 weeks, respectively, before 
resuming original (prescreening) ICS/LABA therapy at Visit 14/EOT (for more details, see 
Section 1.2 and Table 1). 
10.1.2.3.1 Visit 11, Day 64 (Week 9) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
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• Evaluate patient for a LOAC event. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements. 
- 
Prebronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
• If no new LOAC event, proceed without background therapy (see Table 1) until LOAC or 
Visit 14 (Week 12), whichever comes first. Please update controller profile in the 
electronic diary web portal accordingly if appropriate.  
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit.  
• Schedule a site visit for Visit 12, Day 71 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.3.2 Visit 12, Day 71 (Week 10) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S) via handheld device. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements. 
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
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• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate [breaths per minute] and body temperature [°C]).  
• Call IVRS/IWRS to register visit and obtain next treatment kit numbers  
• Administration of IMP 
- 
Patients should be monitored by site personnel for at least 30 minutes after 
administration of all IMP injections. Monitoring period may be extended up to 2 hours 
as per country specific requirements.   
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 13, Day 78 and request patient to come at approximately the 
same time of day as this visit. 
10.1.2.3.3 Visit 13, Day 78 (Week 11) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Perform spirometry:  
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements.   
- 
Prebronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device and remind patient to 
bring the device to the next visit. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate and body temperature [°C]). 
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study. Instruct patient to record usage in the electronic diary. 
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours prior to 
next visit. 
• Schedule a site visit for Visit 14, Day 85 and request patient to come at approximately the 
same time of day as this visit (fasting if morning visit). 
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10.1.2.4 Week 12 (Visit 14) – End of Treatment – End of Randomized IMP Treatment Period 
10.1.2.4.1 Visit 14, Day 85 (Week 12)/EOT Visit/for Patients that Discontinue Study Treatment 
Prematurely: Individual EOT Visit – Begin of Post-IMP-treatment Safety Follow-up 
Period with Resumed Prescreening ICS/LABA Background Therapy  
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Evaluate patient for a LOAC event. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S).  
• Perform 12-lead ECG 
• Perform spirometry and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours. This will be 
verified before performing the measurements.   
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Download electronic diary information from the handheld device, and collect the PEF and 
e-diary devices from the patient, or ensure collection at EOS.  
• Perform physical examination. 
• Perform urine pregnancy test (for women of childbearing potential, including women that 
discontinue IMP treatment early due to any reason) 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], body weight [kg], respiratory rate [breaths per minute] and body 
temperature [°C]).  
• Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests: 
- 
PK analysis 
- 
Hematology and serum chemistry 
- 
Anti-SAR440340 antibody and anti-dupilumab antibody 
- 
Biomarker set: Blood eosinophils and neutrophils, total IL33, sST2, calcitonin, PARC, 
eotaxin-3, total IgE, and periostin (refer to Section 9.3.2.4) 
- 
RNA panel testing (optional) 
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- 
Archival serum for those patients who have consented to collection for Future Use of 
Specimens (refer to Section 9.4) 
• Obtain urine sample for urinalysis 
Upon completing 12 weeks of treatment with IMP (or following early discontinuation of IMP), 
patients enter the 20-week Post IMP Treatment Period. During the Post IMP Treatment Period 
patients should resume original dose of ICS/LABA combination therapy. If asthma is unable to be 
consistently controlled on original therapy and there is a safety concern, additional controller 
therapies may be prescribed based upon Investigator clinical judgement. 
• Patients resume their original ICS/LABA treatment, with the same prescriptions as prior to 
the Screening Visit 1. 
• Remind patients to use their original ICS/LABA background therapy medication.  
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study.  
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours and 
LABA for at least 12 hours prior to next visit. 
• Call IVRS/IWRS to register EOT or Premature Treatment Withdrawal. 
• Schedule a site visit for Visit 15, Day 141 and request patient to come at approximately 
the same time of day as this visit (fasting if morning visit). 
Note: Patients who discontinue IMP treatment early (prior to completing the 12-week IMP 
treatment) due to a LOAC event or due to other reasons, will be evaluated as soon as possible at 
the individual patients’ EOT Visit, using procedures as planned for the EOT Visit at Week 12 
(Visit 14). At their EOT visit, patients will resume their prescreening ICS/LABA background 
therapy and enter the 20-week Post IMP Treatment Period (Visit 15 to Visit 17). 
10.1.2.5 Post IMP treatment observation period (Visits 15 and 17) 
10.1.2.5.1 Visit 15, Day 141 (Week 20) 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S).  
• Perform spirometry and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted prior to spirometry and following a fast 
of ≥1 hour. 
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements.   
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- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Perform physical examination. 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate [breaths per minute] and body temperature [°C]) 
• Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests: 
- 
PK analysis 
- 
Hematology and serum chemistry 
- 
Biomarker set: Blood eosinophils and neutrophils, total IL33, and sST2, Calcitonin 
(refer to Section 9.3.2.4) 
• Obtain urine sample for urinalysis 
• Remind patients to use their original ICS/LABA background therapy medication.  
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study.  
• Schedule a site visit or phone call (Visit 16, Day 183) within a maximum of 47 days. 
10.1.2.5.2 Visit 16, Day 183 (Week 26) 
This visit can be either on site visit or phone call. 
• Inquire about AEs/SAEs, new concomitant medications and asthma therapy tolerability 
and compliance. 
• Remind patients to use their original ICS/LABA background therapy medication.  
• Remind patients to use salbutamol/albuterol or levosalbutamol/levalbuterol as reliever 
medication throughout the study.  
• Remind patient to withhold albuterol or levalbuterol (if any) for at least 6 hours and 
LABA for at least 12 hours prior to next visit. 
• Schedule a site visit (Visit 17, Day 225) within a maximum of 47 days and request patient 
to come at approximately the same time of day as prior visits (fasting if morning visit). 
10.1.2.6 Visit 17, Day 225 (Week 32) – End of Study Visit 
• Record all concomitant medication use with start date and dose in eCRF; inquire about 
AEs/SAEs and asthma therapy tolerability and compliance. 
• Administer ACQ-5, AQLQ(S), and, only to patients with history of allergic rhinitis, 
RQLQ(S).  
• Perform 12-lead ECG 
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• Perform spirometry and measure exhaled nitric oxide:  
- 
Exhaled nitric oxide assessment is conducted following a fast of ≥1 hour. 
- 
Spirometry will be performed at approximately the same time of day as the last visit, 
prior to administration of IMP and 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. This will be verified before 
performing the measurements.   
- 
Prebronchodilator FEV1 should be determined. 
- 
Postbronchodilator FEV1 should be determined. 
• Perform physical examination. 
• Perform urine pregnancy test (for women of childbearing potential) 
• Measure vital signs (including systolic and diastolic blood pressure [mmHg], pulse rate 
[beats per minute], respiratory rate [breaths per minute] and body temperature [°C]).  
• Perform blood sampling (fasting if morning visit, prior to administration of IMP) for the 
following tests: 
- 
PK analysis 
- 
Hematology and serum chemistry 
- 
Anti-SAR440340 antibody and anti-dupilumab antibody 
- 
Biomarker set: Blood eosinophils and neutrophils, total IL33, and sST2, Calcitonin 
(refer to Section 9.3.2.4) 
• Obtain urine sample for urinalysis 
• If not already done so at Visit 14/EOT, patient will return electronic devices to the site at 
this EOS visit. Electronic devices will be returned to the sponsor after EOS. 
• 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 are but not limited to hospital records, clinic and office 
charts, laboratory notes, memorandum, pharmacy dispensing records, recorded data from 
automated instruments, etc. 
All the data collected in the eCRF should be transcribed directly from source documents. Data 
downloaded from the study-associated central laboratories, electronic data/information sources 
including IVRS/IWRS notifications, and computer generated print-outs, spirometry, nitric oxide 
measurement, ECG, patient questionnaire forms, and patient electronic diary/PEF meter, will be 
considered as source data. 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiation of treatment with the IMP will be done under close and appropriate clinical/and 
or laboratory monitoring once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely and if the selection criteria for the study are still met (refer to Section 7.1 and 
Section 7.2). For all temporary treatment discontinuations, duration must be recorded by the 
Investigator in the appropriate pages of the eCRF.  
Following a temporary interruption the drug should be reinitiated at the next scheduled visit, 
maintaining the original dosing schedule. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to reexpose the patient to the IMP at any time during 
the study, or from the patient not to be reexposed to the IMP whatever the reason. 
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 reason(s) for treatment discontinuation and this should be documented in the eCRF. 
Patients must be withdrawn from the study treatment for the following reasons:  
• At their own request or at the request of their legally authorized representative (legally 
authorized representative means an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective patient to the patient’s participation in 
the procedure(s) involved in the research). 
• If, in the Investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being. 
• At the specific request of the Sponsor. 
• In the event of a protocol deviation, at the discretion of the Investigator or the Sponsor. 
• Pregnancy. 
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• Loss of asthma control: Patients will be instructed to contact the Investigator if a patient 
feels that his or her asthma is not adequately controlled (clinical exacerbation, intolerable 
or incapacitating symptoms, frequent nocturnal awakenings, frequent albuterol or 
levalbuterol use).  
If a patient meets the criteria for a LOAC at any time during the 12-week IMP treatment 
period, he/she will be permanently withdrawn from IMP treatment and treated by the 
Investigator with standard of care according to standard medical practice.  
• Anaphylactic reactions or systemic allergic reactions that are related to IMP and require 
treatment (see Appendix J).  
• Diagnosis of a malignancy during study, excluding squamous or basal cell carcinoma of 
the skin. 
• Any situation that meets permanent discontinuation rule as outlined in Appendix H. 
‘General Guidance for the follow-up of laboratory abnormalities by Sanofi’. 
• Any opportunistic infection, such as TB or other infections whose nature or course may 
suggest an immunocompromised status (see Appendix I). 
• Serum ALT >3 ULN and total bilirubin >2 ULN (see Appendix H). 
• Serum ALT >5 ULN if baseline ALT ≤2 ULN or ALT >8 ULN if baseline ALT >2 ULN 
(see Appendix H). 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the IMP for the concerned 
patient. 
10.3.4 Handling of patients after permanent treatment discontinuation  
Patients will be followed-up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
At the time of permanent treatment discontinuation before the EOT visit, patients will perform 
early treatment discontinuation visit with all the assessment designed for the EOT visit. At the 
time of study discontinuation after EOT visit, patients will perform early study discontinuation 
visit with all the assessment designed for the EOS visit.  
Patients who discontinue early from treatment may be asked to return to the clinic to have 
additional PK/ADA samples collected for up to 20 weeks after treatment discontinuation. Samples 
for biomarker analysis should be collected following EOT visit. Biomarker samples for future 
research could be suspended. 
Patients who permanently discontinue the study medication will be asked and encouraged to 
return to the clinic and participate in follow-up assessments according to the visit schedule 
described in the Post IMP Treatment Period. The Post IMP Treatment Period will start at Week 12 
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for patients who complete the IMP treatment period, and may start earlier than Week 12 for 
patients who meet the criteria for a LOAC and discontinue IMP prior to 12 weeks of treatment. 
For patients who permanently discontinue the study, under exceptional circumstances where there 
is no possibility for a patient to come to the site for the scheduled follow-up visit, a phone contact 
may be made after Sponsor’s approval is given (with exception of Visit 16 that is allowed to be a 
phone visit as per protocol). During that phone contact, at least information about AEs, 
concomitant medication, and asthma exacerbation events must be collected and the schedule for 
these calls should still reflect the visit schedule described in the Post IMP Treatment Period.  
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for discontinuation of study treatment 
should be distinguished from withdrawal of consent for follow-up visits and from withdrawal of 
consent for non patient contact follow-up, eg, medical records check. Patients will be told that 
they are free to withdraw from the study at any time without any adverse effect on their care. 
However, if they no longer wish to take the IMP, they will be encouraged to remain in the study 
and attend the follow-up visits. The value of all their critical study data collected during their 
continued involvement will be emphasized as important to the public health value of the study.  
The patient will resume his/her original ICS/LABA (ie, prior to screening) background therapy 
and will be followed for safety, if possible, for the 20-week Post IMP Treatment Period, as 
planned per protocol. If a patient’s asthma cannot be consistently controlled on his/her original 
ICS/LABA therapy, and there is a safety concern, additional controller therapies may be 
prescribed based on the Investigator’s clinical judgement. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site after withdrawing from the study, unless the patient 
withdraws consent for follow-up, the Investigator should make the best effort to recontact the 
patient (eg, contact patient’s family or private physician, review available registries or health care 
databases), and to determine his/her health status, including at least his/her vital status. Attempts 
to contact such patients must be documented in the patient’s records (eg, times and dates of 
attempted telephone contact, receipt for sending a registered letter). 
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Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
Asthma exacerbations should only be reported as AEs if they fulfill a seriousness criterion.   
For this study, asthma exacerbations should be managed by the Investigators based on their 
medical judgment and applicable national/international asthma management guidelines. 
10.4.1.2 Serious adverse event 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• Intensive treatment in an emergency medical care visit or at home for: 
- 
Allergic bronchospasm  
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- 
Anaphylaxis (refer to Appendix J 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 the upper limit of normal (ULN) + total bilirubin >2 x ULN or asymptomatic 
ALT increase >10 x ULN  
• Suicide attempt or any event suggestive of suicidality 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• Bullous cutaneous eruptions 
• Cancers diagnosed during the study  
• Chronic neurodegenerative diseases (newly diagnosed)  
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. 
For these AESIs, the Sponsor will be informed immediately (ie, within 24 hours), per SAE 
notification described Section 10.4.4, even if not fulfilling a seriousness criterion, using the 
corresponding pages in the CRF (to be sent) or screens in the eCRF. 
• Anaphylactic reactions, systemic allergic reactions that require treatment (refer to 
Appendix J for Definition of Anaphylaxis) 
• Severe ISRs that last longer than 24 hours 
Note: A severe ISR (for AE reporting) is any event that meets one of the following 
criteria: 
- 
With a diameter of at least 10 cm. 
- 
Impacting daily activities. 
- 
With ulceration or necrosis.  
- 
For which operative intervention is required. 
• Any infection meeting at least one of the following criteria: 
- 
Any serious infection (SAE). 
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- 
Requires parenteral (IV, intramuscular, SC) antimicrobial therapy 
Note: Antimicrobial therapy refers to antibiotic, antiviral, and antifungal agents. 
- 
Requires oral antimicrobial therapy for longer than 14 days. 
- 
Is a parasitic infection.  
- 
Is an opportunistic infection (see Appendix I). 
• Significant ALT elevation (see Appendix H) 
- 
ALT >3 x the ULN associated with total bilirubin >2 x ULN; or 
- 
ALT >5 x ULN if baseline ALT ≤2 x ULN; or 
- 
ALT >8 x ULN and baseline >2 x ULN. 
• Malignancy 
• Pregnancy occurring in a female patient enrolled in a study or in a female partner of a male 
patient enrolled in the study with IMP/NIMP. 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. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
intended dose during an interval of <8 days. The circumstances (ie, accidental or 
intentional) should be clearly specified in the verbatim and symptoms, if any, entered 
on separate AE forms. 
- 
An overdose (accidental or intentional) with any NIMP is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as at least twice the 
maximum daily dose as specified in a drug label, within the intended therapeutic 
interval. The circumstances (ie, accidental or intentional) should be clearly specified in 
the in the overdose form and symptoms, if any, entered on separate AE forms. 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities 
Not applicable. 
10.4.3 General guidelines for reporting adverse events  
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) of the eCRF. 
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• When a safety event is categorized as a primary outcome, the event will be reported as an 
AE but will be waived from reporting to regulatory authorities provided an agreement has 
been reached with them. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s). In studies that require the use of 
combined/multiple IMPs/NIMPs, the GSO with input from other appropriate study team 
members must determine if the causal relationship will either be assessed for the combined 
product as a regimen or as distinct entities. The GSO must communicate this decision to 
the study team for inclusion in the protocol and AE CRF. 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
Patients who experience an ongoing SAE or an AESI, at the prespecified study end-date, 
should be followed until resolution, stabilization, or death and related data will be 
collected. The duration of poststudy follow-up and reporting of AEs will be specified 
(eg, until AE CRF). 
• 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 4 summarizes the reporting timelines: 
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Table 4 - Adverse event reporting 
Adverse event/laboratory abnormality 
Reporting timeframe 
Serious adverse event 
 
Within 24 hours 
Pregnancy 
 
Within 24 hours 
Overdose 
Symptomatic 
Within 24 hours 
 
Asymptomatic 
Routine 
ALT elevation 
 
 
 
ALT >3 x ULN and associated with  
total bilirubin >2 x ULN 
ALT >5 ULN if baseline ALT is ≤2 ULN 
Within 24 hours 
 
Within 24 hours 
 
ALT >8 ULN  if baseline ALT is >2 ULN 
Within 24 hours 
Anaphylactic or systemic allergic reactions that require treatment. 
Within 24 hours 
Severe injection site reactions that last longer than 24 hours. 
Within 24 hours 
Infections as defined in Section 10.4.1.3 
Malignancy                                                                                                                                 
Within 24 hours 
Within 24 hours 
ALT: alanine aminotransaminase; ULN: upper limit of normal. 
10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
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• Any SAE brought to the attention of the Investigator at any time after the end of the study 
for the patient and considered by him/her to be caused by the IMP with a reasonable 
possibility, should be reported to the monitoring team. 
10.4.5 
Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the AE reporting instructions summarized in Section 10.4.3. 
10.4.6 
Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix H.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia 
• Thrombocytopenia 
• Increase in ALT 
• Increase in serum creatinine 
• Increase in CPK 
Note: In some clinical trials these laboratory abnormalities can be considered as AESIs. For this 
study, only significant ALT increase will be considered as AESIs (see Section 10.4.1.3)  
In addition, on treatment eosinophil counts >3000/mm3 (3.0 giga/L) (confirmed by retest) are to 
be reported as AEs. 
10.4.7 
Guidelines for reporting product complaints (IMP/NIMP) 
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected adverse drug reaction [SUSAR]), to the regulatory authorities, Independent 
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Ethics Committee (IECs)/Institutional Review Boards (IRBs) as appropriate and to the 
Investigators.   
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected (eg, wheezing related to asthma). 
Any other AE not listed as an expected event in the IB or in this protocol or AE by itself is listed 
as expected in the IB but upon case assessment will be noted to be more severe or has an outcome 
of death (unless specified in the protocol), will be considered unexpected. 
For safety, the treatment code will be unblinded by the Sponsor for reporting to the Health 
Authority of any SUSAR and reasonably associated with the use of the IMP according to either 
the judgment of the Investigator and/or the Sponsor. 
In case of a SUSAR, Sanofi Global Pharmacovigilance and Epidemiology will utilize XGRID to 
reveal medication assignment for regulatory reporting requirements for the particular case. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypersensitivity 
Allergic reaction is a potential risk associated with the administration of most therapeutic mAb. 
Acute allergic reactions may be defined as allergic reaction-mediated signs and symptoms 
experienced by patients during or shortly after the pharmacologic or biologic agent given. These 
reactions may present in a variety of ways, including dizziness, headache, anxiety, dyspnea, 
hypotension, tachycardia, pruritus, rash, urticaria/angioedema, flushing, nausea, or vomiting. 
Anaphylaxis may represent the most severe form of allergic reaction, but these events may also 
occur via non-IgE mediated mechanisms (eg, anaphylactoid reactions), or may occur via other 
immune-mediated mechanisms (eg, cytokine-mediated). Allergic reactions may begin within a 
few hours and persist up to 24 hours post dosing. Refer to Appendix J. “Definition of 
Anaphylaxis”, which describes the clinical criteria for the diagnosis of anaphylaxis. Delayed onset 
or late phase hypersensitivity reactions (ie, Type 1 hypersensitivity reaction) may manifest 
between 10 and 12 hours post dosing. 
Patients should be monitored for at least 30 minutes after IMP dose administration for any signs 
or symptoms of a hypersensitivity reaction throughout the study. Trained personnel and 
medications should be available to treat anaphylaxis or any severe allergic reaction if it occurs. 
Anaphylactic reactions, systemic allergic reactions that require treatment must be reported as an 
AESI with immediate notification (for further details see Section 10.4.1.3 and Appendix J). If an 
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anaphylactic reaction, systemic allergic reaction requiring treatment occurs and is considered 
related to IMP by the investigator the study treatment should be permanently discontinued. 
Anti-drug antibodies and PK samples will be collected near the onset and resolution of the AESI 
for any additional analysis. 
10.6.2 Severe injection site reactions 
Based on the SC mode of administration of high doses of protein ISRs are considered as a 
potential risk for SAR440340.  
In dupilumab clinical studies, the incidence of ISRs was higher in the dupilumab treated patients 
compare to placebo treated patients. The ISRs were generally non serious, mild to moderate 
intensity. 
Patients who experience an ISR must be closely monitored for the possibility of a more intense 
ISR with a future injection. Any severe ISR that lasts over 24 hours will be reported as an AESI 
with immediate notification (for further details please see Section 10.4.1.2). Anti-drug antibodies 
and PK samples will be collected near the onset and resolution of the AESI for any additional 
analysis 
If there is any consideration being given to premedicating before the next dose (for preceding an 
ISR), please contact Sponsor prior to dosing patients. 
10.6.3 Infections, including parasitic infections 
Some biologic therapies have been associated with an increased risk of infection, including 
opportunistic infection.  
IL33 is a proinflammatory cytokine released by damaged epithelial cells in response to insults 
such as allergens, viruses, or bacteria. IL33 signaling initiates and amplifies multiple downstream 
inflammatory pathways resulting in effects characteristic of both Type 1 and Type 2 immune 
inflammations. Although blockade or knockout of IL33 signaling in mice did not reveal any 
unique role for IL33 in mounting an acute immune response to viral challenge and did not lead to 
worsening of symptoms or outcome, subjects will be monitored for signs or symptoms of 
infection. 
Dupilumab and SAR440340 inhibit the T-helper 2 (Th2) cytokines production. Infections with a 
diversity of helminthic parasites elicit eosinophilia via stimulation of Th2-like lymphocyte 
responses. The Th2 response is characterized by production of IL4, IL13, and IL5, subsequently 
generating IgG1 and IgE-secreting cells, and eliciting eosinophilia. Eosinophilia is prominent in a 
number of helminthic parasitic diseases. The eosinophilic response to helminths is determined 
both by the host's immune response and by the parasite, including its distribution, migration, and 
development within the infected host. Therefore, patients treated with dupilumab and/or 
SAR440340 may potentially have an increased risk of parasitic infection.  
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To minimize the risk, patients with certain type of infections are not allowed to participate in the 
study (eg, patients with active opportunistic or parasitic infections or at high risk of developing 
the infections, patients with medical history of invasive opportunistic infections, patients with 
HIV infection or HIV seropositivity, patients with positive screening for hepatitis B and C). 
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. 
During the study, appearance of signs or symptoms (such as abdominal pain, cough, diarrhea, 
fever, fatigue hepatosplenomegaly) that could be associated with a parasitic infection should be 
carefully evaluated, especially if there is a history of parasitic exposure through recent travel to/or 
residence in endemic areas, especially when conditions are conducive to infection (eg, extended 
stay, rural or slum areas, lack of running water, consumption of uncooked, undercooked, or 
otherwise potentially contaminated food, close contact with carriers and vectors, etc). Subsequent 
medical assessments (eg, stool exam, blood tests, etc) must be performed in order to rule out 
parasitic infection/infestation.  
Infections defined in Section 10.4.1.3 should be reported as AESIs with immediate notification. 
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 drug 
discontinued until the infection is resolved. 
For any opportunistic infection, such as TB, or other infections whose nature or course may 
suggest an immunocompromised status (see Appendix I), patients must be permanently 
discontinued from study medication. 
10.6.4 Elevated liver function tests 
No preclinical and clinical data has suggested any hepatic toxicity of SAR440340 or dupilumab; 
however, as a 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 (in case of values above the normal range, differentiation in conjugated and 
nonconjugated bilirubin), alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase are measured as part of the clinical laboratory testing.  
Guidance for the investigation of elevated LFTs as well as concurrent management of IMP is 
provided in Appendix H. 
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Alanine transaminase elevations defined in Section 10.4.1.3 should be reported as AESIs with 
immediate notification. 
10.6.5 Malignancy 
Available literature data related to the IL-4Rα inhibition, and data from animal toxicology studies 
in which monkeys received chronic treatment with an IL-4Rα blocker, do not support an increased 
risk of cancer for dupilumab. There is no evidence from the clinical studies to date that the 
treatment with dupilumab increases the risk of malignancy. In toxicology studies on 
REGN3500-mediated IL33 blockade, the effect of REGN3500 administration has not 
demonstrated the development of malignancy. Long-term use has not been studied. 
The investigator should carefully monitor for any signs or symptoms of malignancy. Malignancy 
should be reported as AESI with immediate notification. 
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 
Data from a previous study with dupilumab with similar design (ACT11457) showed a 44% rate 
of LOAC in the placebo group in a 12-week study with a similar population and background 
treatment compared to a 6% rate of LOAC in the dupilumab group, for an 87% relative reduction 
with dupilumab.  
The sample size calculations are based on the primary endpoint, incidence of LOAC with the 
following assumptions:  
- 
Incidence rate of 40% in the placebo group, based on a previous study with dupilumab 
with similar design (ACT11457) (19) 
- 
A 26% reduction in the rate of LOAC (to 14%) in the SAR440340 group 
- 
A 2-sided χ2 test at 5% significance level with 80% power 
Based on the above assumptions, and allowing for approximately 15% dropout rate, 60 patients 
per treatment group are needed. 
Calculations were made using nQuery Advisor 7.0. 
Patients will be randomized using a 1:1:1:1 ratio to one of the 4 treatment groups. Randomization 
will be stratified by Screening Visit 1 eosinophil count (using the following 3 strata: <150 /mm3 
[not more than approximately 25% or 60 patients], 150-299 /mm3, ≥300 /mm3 [at least 
approximately 45% or 108 patients]) and by country. For eosinophil count, alerts will be built into 
the IVRS/IWRS system to limit enrolling patients in 2 of the 3 eosinophil count strata. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who signed the informed consent.  
Randomized patients consist of all patients with a treatment kit number allocated and recorded in 
the IVRS database, regardless of whether the treatment kit was used or not. These patients form 
the randomized population.  
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. Data from these patients will be summarized separately.  
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
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11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Modified intent-to-treat population 
The analysis population for the efficacy endpoints will be the modified intent-to-treat (mITT) 
population: all randomized patients who have received at least one dose of investigational product 
analyzed according to the treatment group allocated by randomization.  
Randomized patients for whom it is unclear whether they took the study medication will be 
included in the mITT population. 
11.3.2 Safety population 
The safety population is defined as all patients who have received at least one dose of the IMP, 
analyzed according to the treatment actually received. 
11.3.3 Pharmacokinetic analysis population  
The PK population will consist of all patients in the safety population with at least one postdose, 
nonmissing serum SAR440340 or serum dupilumab concentration. 
11.3.3.1 Antidrug antibody population 
The ADA population will consist of all patients who received any study drug and who had at least 
one nonmissing ADA result in the anti-SAR440340 or anti-dupilumab assay, after first dose of the 
study drug. Patients will be analyzed according to the treatment actually received. 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
Duration of IMP exposure is defined as: last dose date – first dose date +14 day, regardless of 
unplanned intermittent discontinuations. 
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11.4.1.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance will be summarized descriptively (N, mean, standard deviation [SD], 
median, first quartile [Q1], third quartile [Q3], min, and max). The percentage of patients with 
compliance <80% will be summarized.  
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint 
The primary endpoint of incidence of LOAC will be analyzed using a logistic regression model. 
The model will include terms for treatment, baseline eosinophil strata, region (pooled country), 
baseline background ICS dose level and number of exacerbation events within 1 year prior to 
screening.  
Each of the comparisons will be tested at a two-sided 5% significance level: 
• SAR440340 versus placebo  
• Coadministration of SAR440340 and dupilumab versus placebo  
The odds ratio and 95% confidence interval (CI) for each comparison will be estimated from this 
model.  
Comparisons between other treatment groups on incidence of LOAC will be analyzed in a similar 
fashion in an exploratory manner. 
As a supportive analysis, time to LOAC postrandomization will be analyzed using a Cox 
regression model with treatment, baseline eosinophil strata, and region (pooled country) as 
covariates. The Kaplan-Meier (KM) method will be used to estimate the probabilities of the event 
at specific time points for each treatment group. P-value from log-rank test stratified by baseline 
eosinophil strata and region will also be provided. 
11.4.2.2 Analyses of secondary and other efficacy endpoints 
The change from baseline for continuous endpoints (eg. FEV1, PEF, ACQ-5 score, asthma 
symptom scores, nocturnal awakenings, number of inhalations/day of albuterol or levalbuterol) 
will be analyzed using a mixed effect model with repeated measures (MMRM) approach. Details 
regarding the inclusion of values for analysis depending on concurrent events/treatments that 
could be confounded with efficacy will be detailed in the SAP. No imputation will be performed 
on missing values. The covariates to be included are treatment, baseline eosinophil strata, region 
(pooled country), baseline background ICS dose level, visit, treatment-by-visit interaction, the 
corresponding baseline value and baseline-by-visit interaction. Additionally, gender and height 
will be included in the models for spirometry variables. The repeated measures analysis will be 
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based on the restricted maximum likelihood method assuming an unstructured covariance 
structure to model the within-subject errors. A Kenward-Roger approximation will be used for the 
denominator degree of freedom. Descriptive statistics including number of patients, mean, 
standard error, and least squares (LS) means will be provided. In addition, differences in LS 
means, the corresponding 95% CI and p-value will be derived from the MMRM model. 
11.4.2.3 Multiplicity considerations 
No adjustments for multiplicity are planned for this Phase 2a study. More specifically, no 
adjustments will be made in comparing the multiple treatment groups based on the primary and 
secondary efficacy endpoint(s) and no adjustments will be made for the subgroup analyses. 
Reported p-values will be nominal p-values. 
11.4.2.4 Handling of missing data 
Missing data handling and sensitivity analyses for the primary and secondary endpoints will be 
detailed in the SAP.  
11.4.3 Analyses of safety data 
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the safety population using the following common rules: 
The baseline value is defined generally as the last available value before the first dose of IMP.   
The following definitions will be applied to laboratory parameters, vital signs, and ECG. 
• 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.  
• Potentially clinically significant abnormality (PCSA) criteria will determine which 
patients had at least 1 PCSA during the TEAE period, taking into account all evaluations 
performed during the TEAE period, including unscheduled or repeated evaluations. The 
number of all such patients will be the numerator for the on-treatment PCSA percentage.  
11.4.3.1 Adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, and the number (n) and 
percentage (%) of patients experiencing an AE. Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
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The proportion of patients with at least 1 TEAE, serious TEAE, and TEAE leading to 
discontinuation of the study will be tabulated by treatment group. In addition, TEAEs will be 
described according to maximum intensity and relation to the study drug. Serious AEs and AEs 
leading to study discontinuation that occur outside the treatment-emergent period will be 
summarized separately. 
11.4.3.1.1 Adverse events of special interests 
The following summaries will be generated: 
• Incidence of each AESI will be tabulated by treatment group 
• The time-to-first event analyzed using K-M methods and displayed as K-M plots 
(cumulative incidence (%) versus time based on K-M estimates) will be provided to depict 
the course of onset over time. When TEAE start date or worsening date is partially 
available, the maximum of the earliest possible TEAE start date and the treatment start 
date will be used. When TEAE start date or worsening date is completely missing, the 
treatment start date will be used.  
• An overview summary of the number (%) of patients with 
- 
any TEAE 
- 
any SAE (regardless of treatment-emergent status) 
- 
any treatment-emergent SAE 
- 
any AE leading to death 
- 
any TEAE leading to permanent study drug discontinuation 
- 
any TEAE by maximum intensity, corrective treatment, and final outcome 
Definitions of AESIs and the method to identify AESIs will be specified in the SAP. 
11.4.3.1.2 Death 
The following summaries will be generated depending on the overall incidence: 
• Number (%) of patients who died by study period (TEAE, on-study) and reasons for death 
summarized on the safety population 
• Death in nonrandomized patients or randomized and not treated patients  
• Treatment-emergent adverse events (TEAE) leading to death (death as an outcome on the 
AE CRF/eCRF page as reported by the Investigator) by primary SOC, HLGT, HLT, and 
PT showing number (%) of patients sorted by internationally agreed order of SOC and 
alphabetic order of HLGT, HLT, and PT.  
Patient data listings will be provided for all TEAEs, treatment-emergent SAEs, AEs leading to 
treatment discontinuation, AESIs, and deaths. 
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11.4.3.1.3 Clinical laboratory evaluation, vital signs, and electrocardiogram data  
Results and change from baseline for the parameters will be summarized by treatment group for 
baseline and each post baseline time point, endpoint, minimum, and maximum value. Summary 
statistics will include number of patients, mean, SD, median, Q1, Q3, minimum, and maximum. 
The proportion of patients who had at least 1 incidence of PCSA at any time during the treatment 
emergent period will be summarized by treatment group. Shift tables showing changes with 
respect to the baseline status will be provided. 
Listings will be provided with flags indicating clinically out-of range values, as well as PCSA 
values. 
11.4.4 Pharmacokinetics, pharmacodynamics, and analyses of antidrug antibodies 
11.4.4.1 Pharmacokinetic analysis 
Serum concentrations of functional SAR440340 and 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 treatment per visit. 
11.4.4.2 Anti-drug antibodies analysis 
The ADA analysis will be detailed in the SAP. 
11.4.4.3 Pharmacodynamics 
The values to be used as baseline will be those collected on Day 1 (predose assessments). If any 
of the scheduled assessments on Day 1 are technically disqualified (eg, insufficient sample) and 
the parameters are measured at any of the screening visits, then values determined at screening 
can be used as the baseline. 
For all parameters, raw data, absolute changes from baseline and percent changes from baseline 
will be summarized by treatment group and time point using descriptive statistics. 
Summary plots (mean±standard error of the mean) on raw data, absolute changes from baseline, 
and percent changes from baseline will be provided by treatment group. 
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 and the 4 domains of AQLQ and 
RQLQ will be analyzed using an MMRM approach, described previously for the continuous 
efficacy variables. Descriptive statistics including number of patients, mean, standard error, and 
LS means will be provided. In addition, the difference in LS means, the corresponding 95% CIs, 
and the p-values will be provided. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis is planned. Analyses will be performed for safety monitoring and 
internal decision making. No formal stopping rules or adjustment for multiplicity will be applied. 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Conference on Harmonisation (ICH) guidelines for good clinical practice (GCP), all applicable 
laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written ICF should be signed, name filled 
in and personally dated by the patient or by the patient’s legally acceptable representative, and by 
the person who conducted the informed consent discussion. A copy of the signed and dated 
written ICF will be provided to the patient.  
If informed consent is obtained under special circumstances (emergency, etc), the method should 
be specified following the ICH requirements.  
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic section of ICF 
(written) should be completed by the patient or by the subject’s legally acceptable representative, 
and by the person who conducted the informed consent discussion.  
The ICF, including the optional pharmacogenetic sample and optional future use of samples, used 
by the Investigator for obtaining the patient's informed consent must be reviewed and approved by 
the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) for 
approval/favorable opinion. 
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12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical trial (study number, clinical trial protocol title, and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents [summary of 
product characteristics, package insert], Investigator’s curriculum vitae [CV], etc) and the date of 
the review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the IB or labeling information will 
be sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use, and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the preidentified source data directly recorded in the eCRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the eCRFs (eg, patient's medical file, appointment 
books, original laboratory records, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor trial master file. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the IB, and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations 
Analyses of patient genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetics analyses required for the purposes of the study or by regulatory authorities. 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
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obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, good clinical practice, and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 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. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be recollected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and 
Prevention, updated 2017. 
2. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS 
guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-
73 
3. To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, et al. Global asthma 
prevalence in adults: findings from the cross-sectional world health survey. BMC Public 
Health 2012;12:204 
4. Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J, et al. Economic 
burden of asthma: a systematic review. BMC Pulm Med 2009;9:24 
5. McCracken JL, Tripple JW, Calhoun WJ. Biologic therapy in the management of asthma. Curr 
Opin Allergy Clin Immunol 2016;16:375-82 
6. Bousquet J, Cabrera P, Berkman N, Buhl R, Holgate S, Wenzel S, et al. The effect of 
treatment with omalizumab, an anti-IgE antibody, on asthma exacerbations and emergency 
medical visits in patients with severe persistent asthma. Allergy 2005;60:302-8 
7. Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab 
treatment in patients with severe eosinophilic asthma. New Engl J Med 2014;371:1198-207 
8. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab 
for inadequately controlled asthma with elevated blood eosinophil counts: results from two 
multicenter, parallel, double-blind, randomized, placebo-controlled, phase 3 trials. Lancet 
Respir Med 2015;3:355-66 
9. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and 
safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled 
corticosteroids and long-acting b2-agonsits (SIROCCO): a randomized, multicenter, placebo-
controlled phase 3 trial. Lancet 2016;388:2115-27 
10. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma desite use of medium-to-high-dose inhaled 
corticosteroids plus a long-acting beta2 agonist: a randomized double-blind placebo-controlled 
pivotal phase 2b dose-ranging trial. Lancet 2016;388:31-44 
11. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral 
Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma. New Engl J Med 
2014;371:1189-97 
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12. Custovic A, Johnston SL, Pavord I, Gaga M, Fabbri L, Bel EH, et al. EAACI position 
statement on asthma exacerbations and severe asthma. Allergy. 2013 Dec;68(12):1520-31 
13. Cayrol C and Girard P. IL-33: an alarmin cytokine with crucial roles in innate immunity, 
inflammation and allergy. Curr Opin Immunol 2014;31:31-7 
14. Grotenboer NS, Ketelaar ME, Koppelman GH and Nawijn MC. Decoding asthma: Translating 
genetic variation in IL33 and IL1RL1 into disease pathophysiology. J Allergy Clin Immunol 
2013;131:856-65 
15. Christenson, S.A.; Steiling, K.; van den Berge, M.; Hijazi K.; Hiemstra PS.; Postma DS., et al. 
Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in 
chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191(7):758-66 
16. Oboki, K.; Ohno, T.; Kajiwara, N.; Arae K.; Morita H.; Ishii A., et al. IL-33 is a crucial 
amplifier of innate rather than acquired immunity. Proc Natl Acad Sci. 2010;107(43):18581-6 
17. Kurowska-Stolarska, M.; Kewin, P.; Murphy, G.; Russo RC.; Stollarski B.; Garcia CC, et al. 
IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway 
inflammation independent of IL-4. J Immunol. 2008;181(7):4780-90 
18. Lynch JP, Werder RB,  Simpson J, Loh Z, Zhang V, Haque A, et al. Aeroallergen-induced IL-
33 predisposes to respiratory virus–induced asthma by dampening antiviral immunity. J 
Allergy Clin Immunol. 2016 Nov;138(5):1326-37 
19. 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: 2455-66 
20. Ramirez-Carrozzi V, Sambandam A, Zhou M, Yan D, Kang J, Wu X, et al. Combined 
blockade of the IL-13 and IL-33 pathways leads to a greater inhibition of type 2 inflammation 
over inhibition of either pathway alone. J Allergy Clin Immunol. 2017;139(2):705-8. 
21. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardization 
of spirometry. Series ‘‘ATS/ERS TASK FORCE: Standardization of Lung Function Testing"  
Edited by Brusasco V, Crapo R, and Viegi G. Eur Resir J. 2005;26:319-38. 
22. Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553-8. 
23. 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 
24. Juniper EF, Guyatt GH, O'Byrne PM, Viveiros M. Aqueous beclomethasone dipropionate 
nasal spray "regular" versus "as required" use in the treatment of seasonal allergic rhinitis. J 
Allergy Clin Imunol 1990; 863 (3Pr1) :380-6. 
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25. Norman GR, Sloan JA, Wyrwich KW. Point/Counterpoint, Interpretation of Changes in 
Health-related Quality of Life, The Remarkable Universality of Half a Standard Deviation 
Medical Care, (41):5,582–592 
26. Summary of regulatory action for Fluticasone furoate and vilanterol. May 9, 2013. Available 
from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204275Orig1s000SumR.pdf. 
Accessed 30 August 2018. 
27. Assessment report for Revinty Ellipta and Relvar Ellipta - Committee for Medicinal Products 
for Human Use (CHMP). 25 January 2018.  Available from 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-
_Variation/human/002673/WC500247954.pd. Accessed 04 September 2018 
  
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17 
APPENDICES 
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Appendix A 
Highly Effective Contraceptive Methods 
 
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition 
of ovulationb 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormone contraception associated with inhibition of ovulation 
− oral 
− injectable 
Highly Effective Methods That Are User Independenta 
• Implantable progestogen-only hormonal contraception associated with inhibition of ovulation 
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner 
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies. 
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Appendix B 
List of Prohibited Live Attenuated Vaccines 
Bacillus Calmette-Guérin (BCG) antituberculosis vaccine 
Chickenpox (Varicella) 
Intranasal influenza (FluMist-Influenza); inactive influenza vaccine delivered by injection is 
permitted 
Measles (Rubeola) 
Measles-mumps-rubella (MMR) combination 
Measles-mumps-rubella-varicella (MMRV) combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rotavirus 
Rubella 
Smallpox (Vaccinia) 
Varicella Zoster (shingles) 
Yellow fever 
This list is indicative and not exhaustive. 
 
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Appendix C 
Low, medium, and high dose inhaled corticosteroids 
 
Total Daily Dose (mcg) 
Inhaled Corticosteroid 
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 furoate (DPI) 
100* 
n.a. 
200 
Fluticasone propionate (DPI) 
100–250 
>250–500 
>500 
Fluticasone propionate (HFA) 
100–250 
>250–500 
>500 
Mometasone furoate  
110–220 
>220–440 
>440 
Triamcinolone acetonide 
400–1000 
>1000–2000 
>2000 
CFC = chlorofluorocarbon propellant; DPI = dry powder inhaler; HFA = hydrofluoroalkane 
propellant; n.a. = not applicable; nebules = nebulized solution 
Source: Adapted from Global Initiative for Asthma (GINA) 2017 guidelines 
*It has been shown that fluticasone furoate 100 mcg daily is clinically comparable to fluticasone 
proprionate 500 mcg daily and thus fluticasone furoate 100 mcg daily is considered medium inhaled 
corticosteroid dose in the ACT15102 study (26, 27). 
 
 
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Appendix D 
Asthma Control Questionnaire (ACQ)  
Asthma Control Questionnaire, 5-question version (ACQ-5) 
 
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Appendix E 
Asthma Quality of Life Questionnaire 
 
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Appendix F 
Standardized Rhinoconjunctivitis Quality Of Life Questionnaire 
  
RQLQ(S) 
 
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Appendix G 
Asthma Symptom Score Numerical Rating Scale (NRS) 
 
Morning Diary: 
Please rate your asthma symptoms since last night 
• No asthma symptoms, slept through the night 
• Slept well, but some complaints in the morning. No nighttime awakenings 
• Woke up once because of asthma (including early awakening) 
• Woke up several times because of asthma (including early awakening) 
• Bad night, awake most of the night because of asthma 
 
Evening Diary: 
Please rate your asthma symptoms since this morning 
• Very well, no asthma symptoms 
• One episode of wheezing, cough, or breathlessness 
• More than one episode of wheezing, cough, or breathlessness without interference with 
normal activities 
• Wheezing, cough, or breathlessness most of the day, which interfered to some extent with 
normal activities 
• Asthma very bad. Unable to carry out daily activities as usual 
 
 
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Appendix H 
General guidance for the follow-up of laboratory abnormalities by 
 
Sanofi 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met. 
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met. 
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INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
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)
 
*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 10.4.6 for guidance on safety reporting. 
• 
Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
INCREASE IN SERUM CREATININE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
investigational medicinal product by 
renal route
1.
Investigational medicinal 
product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
investigational medicinal product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
 
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Section 10.4.3 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
INCREASE IN CPK SUSPECTED TO BE OF NON-CARDIAC ORIGIN 
AND NOT RELATED TO INTENSIVE PHYSICAL ACTIVITY
 
Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting AEs in Section 10.4.3 is met. 
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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 (severe/disseminated) 
• Herpes Zoster 
• Histoplasmosis (pulmonary or disseminated; most common tropical areas Tennessee-
Ohio-Mississippi river basins) 
• Listeriosis 
• Mycobacterium avium 
• Nontuberculosis mycobacteria 
• Pneumocystis pneumonia (PCP) 
• Tuberculosis (TB) 
This list is indicative and not exhaustive. 
 
 
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Appendix J 
Definition of Anaphylaxis  
“Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death." 
(Adapted from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA , Branum A, et al.  Second 
symposium on the definition and management of anaphylaxis: Summary report—Second National Institute of Allergy 
and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol  2006;117:391-7) 
Clinical criteria for diagnosing anaphylaxis 
 
 
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Appendix K 
Country-specific Requirements 
Not applicable 
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Appendix L 
Protocol Amendment History 
The changes for this amended protocol are described in the Protocol Amendment Summary of 
Changes section. 
 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACT15102 Amended Protocol 01
Clinical Approval
Clinical Approval