Clinical trial NCT04203797
Conditions: Asthma
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-07-16; Completion date: 2023-07-15
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to demonstrate that dupilumab treatment improves exercise capacity in patients with moderate-to-severe asthma.

The secondary objectives of the study are:

* To demonstrate that dupilumab treatment increases physical activity of daily living in patients with moderate-to-severe asthma
* To demonstrate that dupilumab treatment improves pre- and post-exercise lung function in patients with moderate-to-severe asthma

Detailed description:

Arms: arm 1: A loading dose at the start of the treatment followed by once every two weeks (Q2W). arm 2: Matching dupilumab
Interventions: intervention 1: dupilumab intervention 2: Matching placebo
Intervention descriptions: intervention 1: Pre-filled syringe administered by subcutaneous (SC) injections intervention 2: Pre-filled syringe administered by subcutaneous (SC)

Protocol documents:
Prot_000.pdf: 
EudraCT: 2019-002742-20 
IND Number: 105379 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO EVALUATE THE EFFECT OF 
DUPILUMAB ON EXERCISE CAPACITY IN PATIENTS WITH 
MODERATE-TO-SEVERE ASTHMA 
Compound: 
Dupilumab 
Clinical Phase: 
4 
Protocol Number: 
R668-AS-1903 
Protocol Version: 
R668-AS-1903 Amendment 1 Global 
Amendment 1 Global Date of Issue: 
See appended electronic signature page 
Original Date of Issue:  
17 Sep 2019 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity.  For the purposes of compliance with all applicable freedom of 
information laws, and regulations, and their equivalents anywhere in the world including but not 
limited to the US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to 
disclosure to third parties of any information and/or data related to, or contained within, this 
submission, it will be given every opportunity under applicable laws to protect its commercial 
interests and/or its trade secrets including the opportunity to object to such disclosure and/or 
provide redaction proposals.  
VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00
NCT04203797


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 79 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Ab 
Antibody 
ACCP 
American College of Chest Physicians 
ACQ-5 
Asthma Control Questionnaire, 5-question version 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AQLQ(S) 
Asthma Quality of Life Questionnaire (Self-Administered) 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BID 
Twice a day 
BOCF 
Baseline observation carried forward 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease 2019 
CPET 
Cardiopulmonary exercise test 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRSwNP 
Chronic rhinosinusitis with nasal polyps 
CSR 
Clinical study report 
CTFG 
Clinical Trial Facilitation Group 
CWR 
Constant work rate 
CWRET 
Constant work rate exercise test 
Dynamic 
hyperinflation 
An increase in end expiratory lung volumes under conditions of increased minute 
ventilation (ie, during exercise) 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EGPA 
Eosinophilic granulomatous with polyangiitis 
ERS 
European Respiratory Society 
EU 
European Union 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 of 79 
CONFIDENTIAL 
FeNO 
Fractional Exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume in One Second 
FSH 
Follicle stimulating hormone 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBcAb 
Hepatitis B core antibody 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IC 
Inspiratory capacity, defined as the maximal amount of air a person can inhale at 
the end of a normal exhalation 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
ICS 
Inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IL-13 
Interleukin-13 
IL-4 
Interleukin-4 
IL-4Rα 
Interleukin-4 receptor alpha 
IL5 
Interleukin-5 
IL-5R 
Interleukin-5 receptor 
IRB 
Institutional Review Board 
Isotime 
Shortest equivalent exercise time achieved 
ISR 
Injection site reactions 
IVRS/IWRS 
Interactive voice response system/interactive web response system 
IWRET 
Incremental Work Rate Exercise Test 
LABA 
Long-acting beta agonist 
LAMA 
Long-acting muscarinic antagonists 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LTRA 
Leukotriene receptor antagonist 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 4 of 79 
CONFIDENTIAL 
mAb 
Monoclonal antibody 
MCID 
Minimum clinically important difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
Metabolic equivalent of task 
MI 
Multiple imputation 
OCS 
Oral corticosteroid 
PCSV 
Potentially clinically significant value 
PFT 
Pulmonary function test 
PGIC 
Patient Global Impression of Change 
PGII 
Patient Global Impression of Impact 
PT 
Preferred term 
Q1 
First quartile 
Q2W 
Once every 2 weeks 
Q3 
Third quartile 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SABA 
Short-acting beta agonist 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAMA 
Short acting muscarinic antagonist 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SOC 
System organ class 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
tLIM 
Time to limit of tolerance 
ULN 
Upper limit of normal 
VO2 
Oxygen consumption 
W/min 
Watts per minute 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 5 of 79 
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
AMENDMENT HISTORY ...........................................................................................................10 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
1. 
INTRODUCTION ......................................................................................................18 
2. 
STUDY OBJECTIVES ..............................................................................................19 
2.1. 
Primary Objective .......................................................................................................19 
2.2. 
Secondary Objectives .................................................................................................19 
2.3. 
Exploratory Objectives ...............................................................................................19 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................20 
3.1. 
Hypothesis ..................................................................................................................20 
3.2. 
Rationale .....................................................................................................................20 
3.2.1. 
Rationale for Study Design .........................................................................................20 
3.2.2. 
Rationale for Dose Selection ......................................................................................21 
3.3. 
Risk-Benefit ................................................................................................................22 
4. 
ENDPOINTS ..............................................................................................................23 
4.1. 
Primary and Secondary Endpoints..............................................................................23 
4.1.1. 
Primary Endpoint ........................................................................................................23 
4.1.2. 
Secondary Endpoints ..................................................................................................23 
4.1.3. 
Exploratory Endpoints ................................................................................................23 
5. 
STUDY VARIABLES................................................................................................24 
5.1. 
Demographic and Baseline Characteristics ................................................................24 
5.2. 
Efficacy Variables ......................................................................................................24 
5.3. 
Safety Variables ..........................................................................................................25 
6. 
STUDY DESIGN .......................................................................................................25 
6.1. 
Study Description and Duration .................................................................................25 
6.1.1. 
End of Study Definition ..............................................................................................28 
6.2. 
Planned Interim Analysis ............................................................................................28 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............28 
7.1. 
Number of Patients Planned .......................................................................................28 
7.2. 
Study Population .........................................................................................................28 
7.2.1. 
Inclusion Criteria ........................................................................................................28 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 6 of 79 
CONFIDENTIAL 
7.2.2. 
Exclusion Criteria .......................................................................................................29 
7.3. 
Premature Withdrawal from the Study .......................................................................34 
7.4. 
Replacement of Patients .............................................................................................34 
8. 
STUDY TREATMENTS............................................................................................34 
8.1. 
Investigational and Reference Treatments ..................................................................34 
8.2. 
Run-in Treatment ........................................................................................................35 
8.3. 
Background Treatments ..............................................................................................35 
8.4. 
Rescue Treatments ......................................................................................................35 
8.5. 
Dose Modification and Study Treatment Discontinuation Rules ...............................35 
8.5.1. 
Dose Modification ......................................................................................................35 
8.5.2. 
Study Drug Discontinuation .......................................................................................35 
8.5.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................36 
8.5.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................36 
8.6. 
Management of Acute Reactions ................................................................................37 
8.6.1. 
Acute Injection Reactions ...........................................................................................37 
8.6.1.1. 
Systemic Injection Reactions ......................................................................................37 
8.6.1.2. 
Local Injection Site Reactions ....................................................................................37 
8.7. 
Method of Treatment Assignment ..............................................................................37 
8.8. 
Blinding ......................................................................................................................38 
8.9. 
Emergency Unblinding ...............................................................................................38 
8.10. 
Treatment Logistics and Accountability .....................................................................38 
8.10.1. 
Packaging, Labeling, and Storage ..............................................................................38 
8.10.2. 
Supply and Disposition of Treatments .......................................................................39 
8.10.3. 
Treatment Accountability ...........................................................................................39 
8.10.4. 
Treatment Compliance ................................................................................................39 
8.11. 
Concomitant Medications and Procedures .................................................................39 
8.11.1. 
Prohibited Medications and Procedures .....................................................................39 
8.11.2. 
Permitted Medications and Procedures ......................................................................40 
8.12. 
Poststudy Treatments ..................................................................................................40 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................40 
9.1. 
Table 1 Schedule of Events ........................................................................................40 
9.1.1. 
Footnotes for the Schedule of Events Table (Table 1) ...............................................45 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 7 of 79 
CONFIDENTIAL 
9.1.2. 
Early Termination Visit ..............................................................................................49 
9.1.3. 
Unscheduled Visits .....................................................................................................49 
9.2. 
Study Procedures ........................................................................................................49 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visits ....................................49 
9.2.2. 
Efficacy Procedures ....................................................................................................50 
9.2.2.1. 
Accelerometers ...........................................................................................................50 
9.2.2.2. 
Patient-Reported Outcomes ........................................................................................51 
9.2.2.3. 
Fractional Exhaled Nitric Oxide (FeNO) Level .........................................................52 
9.2.2.4. 
Cardiopulmonary Exercise Testing (CPET) ...............................................................52 
9.2.2.5. 
Spirometry ..................................................................................................................55 
9.2.3. 
Safety Procedures .......................................................................................................56 
9.2.3.1. 
Vital Signs ..................................................................................................................56 
9.2.3.2. 
Physical Examination .................................................................................................56 
9.2.3.3. 
Electrocardiogram .......................................................................................................56 
9.2.3.4. 
Laboratory Testing ......................................................................................................57 
9.2.4. 
Future Biomedical Research (Optional) .....................................................................58 
9.2.5. 
Pharmacogenomic Analysis (Optional) ......................................................................58 
10. 
SAFETY EVALUATION AND REPORTING .........................................................59 
10.1. 
Recording and Reporting Adverse Events ..................................................................59 
10.1.1. 
General Guidelines .....................................................................................................59 
10.1.2. 
Reporting Procedure ...................................................................................................60 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................60 
10.2. 
Definitions ..................................................................................................................61 
10.2.1. 
Adverse Event .............................................................................................................61 
10.2.2. 
Serious Adverse Event ................................................................................................61 
10.2.3. 
Adverse Events of Special Interest .............................................................................61 
10.2.4. 
Severity .......................................................................................................................62 
10.2.5. 
Causality .....................................................................................................................62 
10.3. 
Safety Monitoring .......................................................................................................63 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics Committee, 
and Investigators .........................................................................................................64 
11. 
STATISTICAL PLAN................................................................................................64 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 8 of 79 
CONFIDENTIAL 
11.1. 
Statistical Hypothesis ..................................................................................................64 
11.2. 
Justification of Sample Size........................................................................................64 
11.3. 
Analysis Sets ...............................................................................................................65 
11.3.1. 
Efficacy Analysis Set ..................................................................................................65 
11.3.2. 
Safety Analysis Set .....................................................................................................65 
11.4. 
Statistical Methods ......................................................................................................65 
11.4.1. 
Patient Disposition ......................................................................................................65 
11.4.2. 
Demography and Baseline Characteristics .................................................................65 
11.4.3. 
Efficacy Analyses .......................................................................................................66 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................66 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................67 
11.4.4. 
Control of Multiplicity ................................................................................................68 
11.4.5. 
Safety Analysis ...........................................................................................................68 
11.4.5.1. 
Adverse Events ...........................................................................................................68 
11.4.5.2. 
Other Safety ................................................................................................................69 
11.4.5.3. 
Treatment Exposure ....................................................................................................69 
11.4.5.4. 
Treatment Compliance ................................................................................................69 
11.5. 
Interim Analysis ..........................................................................................................70 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........70 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................70 
12.1. 
Data Management and Electronic Systems ................................................................70 
12.1.1. 
Data Management .......................................................................................................70 
12.1.2. 
Electronic Systems ......................................................................................................70 
12.2. 
Study Monitoring ........................................................................................................71 
12.2.1. 
Monitoring of Study Sites ...........................................................................................71 
12.2.2. 
Source Document Requirements ................................................................................71 
12.2.3. 
Case Report Form Requirements ................................................................................71 
12.3. 
Audits and Inspections ................................................................................................71 
12.4. 
Study Documentation .................................................................................................72 
12.4.1. 
Certification of Accuracy of Data ...............................................................................72 
12.4.2. 
Retention of Records ..................................................................................................72 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................72 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 9 of 79 
CONFIDENTIAL 
13.1. 
Good Clinical Practice Statement ...............................................................................72 
13.2. 
Informed Consent .......................................................................................................73 
13.3. 
Patients Confidentiality and Data Protection ..............................................................73 
13.4. 
Institutional Review Board/Ethics Committee ...........................................................73 
13.5. 
Clinical Study Data Transparency ..............................................................................74 
14. 
PROTOCOL AMENDMENTS ..................................................................................74 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................74 
15.1. 
Premature Termination of the Study ...........................................................................74 
15.2. 
Close-out of a Site ......................................................................................................74 
16. 
CONFIDENTIALITY ................................................................................................75 
17. 
FINANCING AND INSURANCE .............................................................................75 
18. 
PUBLICATION POLICY ..........................................................................................75 
19. 
REFERENCES ...........................................................................................................76 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................78 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................79 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................42 
Table 2: 
Absolute and Relative Contraindications to CPET ....................................................53 
Table 3: 
Primary Estimands ......................................................................................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................25 
 
 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 10 of 79 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 1 
The purpose of this amendment is to provide eligibility criteria flexibility while ensuring 
appropriate patients qualify for the study and to reduce the number of site visits and ensure study 
objectives are met during the Coronavirus Disease 2019 (COVID-19) pandemic.  The following 
table outlines the changes made to the protocol and the rationales.  
Change 
Rationale 
Section Changed  
Inclusion criteria: 
 
• 
Modified FEV1 reversibility 
eligibility criterion to allow 
documented evidence of 
bronchodilator reversibility or 
positive methacholine challenge 
test within 12 months of the 
screening visit 
• 
Pre-bronchodilator FEV1 
percent predicted has been 
changed from between 30% and 
70% to between 30% and 75% 
at both the screening and 
baseline visits 
• 
Patients who do not meet the 
inclusion criteria due to a 
transient reason (eg, an 
abnormal laboratory value and 
judged to return to an 
acceptable range by the 
investigator within the 
screening period prior to day 1) 
may be allowed to repeat the 
test one additional time (up to a 
total of 2 attempts) on a 
different day during the 
screening period to meet the 
qualifying criteria. There is no 
need to screen fail such 
participants if the test finally 
meets the eligibility criteria. 
 
 
• 
To provide eligibility criteria 
flexibility in the context of the 
COVID-19 pandemic while 
ensuring appropriate patients 
are enrolled in the study 
without impacting study 
objectives and study 
assumptions  
Synopsis: Procedures and 
Assessments 
Section 6.1 Study Description and 
Duration 
Section 7.2.1 Inclusion Criteria, 
criteria #3 and 4 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnotes #5 and 6 
Section 9.2.1 Procedures Performed 
Only at the Screening/Baseline 
Visits 
Section 9.2.2.5 Spirometry 
Exclusion criteria: 
 
• 
Exclude treatment with a live 
(attenuated) vaccine within 
4 weeks prior to the baseline 
visit (previously excluded if 
within 12 weeks)  
• 
Exclude patients for any reason 
that the investigator believes 
would make cardiopulmonary 
exercise unsafe or inadvisable 
(new) 
 
 
• 
To align with current 
dupilumab protocols  
 
 
 
• 
To ensure patient safety  
 
 
 
Section 7.2.2 Exclusion Criteria, 
criteria #29, 38 (new), and 45 (new) 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 11 of 79 
CONFIDENTIAL 
Change 
Rationale 
Section Changed  
• 
Exclude patients for country-
specific exclusions (new) 
 
• 
To ensure compliance with 
local country-specific 
regulations 
The run-in period constant work rate 
exercise test (CWRET) can be 
repeated twice (up to a total of 3 
tests) to familiarize patients with the 
test and to determine the work rate 
that can achieve the qualifying 
exercise time criterion.  
 
 
 
Clarified that the same work rate 
must be used for the CWRET at the 
baseline and at the end of treatment 
visits.  
• 
To provide a detailed 
clarification for the 
objective/goals of the run-in 
CWRET and to clarify the 
guidance for repeating the 
CWRET (if necessary) to adjust 
the individualized work rate 
that can achieve the qualifying 
exercise time criterion.  
 
• 
Clarification added to avoid 
confusion and to ensure the 
same individualized work rate 
established during run-in 
CWERT is used at the baseline 
and end of treatment visit 
CWRET to evaluate change 
from baseline in exercise 
endurance time.  
Synopsis: Procedures and 
Assessments 
Section 6.1 Study Description and 
Duration 
Section 7.2.2 Exclusion Criteria, 
criterion #18 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnotes #15 and 16 
Section 9.2.2.4 Cardiopulmonary 
Exercise Testing (CPET) 
Removed requirement for baseline 
CWRET exercise duration between 
3 and 8 minutes. 
• 
The adjustment of 
individualized work rate to 
meet the qualifying requirement 
of exercise duration between 3 
and 8 minutes prior to 
randomization will be already 
established during the run-in 
CWRET and therefore, no 
longer necessary to repeat it at 
the baseline CWRET.   
Section 6.1 Study Description and 
Duration 
Section 7.2.2 Exclusion Criteria, 
criterion #18 
Section 9.2.2.4 Cardiopulmonary 
Exercise Testing (CPET) 
 
Combined visits 2 and 3 into 1 visit 
(visit 2) during the run-in period.  
• 
To decrease the number of in-
clinic site visits in the context 
of the COVID-19 pandemic 
while ensuring all required data 
are collected for the study. 
Synopsis: Study Duration 
Section 6.1 Study Description and 
Duration 
Figure 1 Study Flow Diagram 
Section 8.2 Run-in Treatment 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnote # 2 
Visits 6 and 7 (in the original 
protocol weeks 8 and 10 and now 
weeks 6 and 8) changed from in-
clinic to phone visits.  Changed 
accelerometry wear reminder to 
phone call.  Phone contacts (ie, 
phone visits) added at weeks 2 and 
6. 
• 
To decrease the number of in-
clinic site visits in the context 
of the COVID-19 pandemic 
while ensuring all required data 
are collected for the study.  
Table 1 Schedule of Events  
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnote #10 
Removed exploratory endpoint of 
‘Change from baseline to week 12 
in the weekly average of daily AM 
measures of FEV1 assessed by home 
spirometry’. 
• 
To ensure safety at home 
during the COVID-19 
pandemic for an exploratory 
endpoint whose measurement 
Synopsis: Procedures and 
Assessments, Statistical Plan 
Section 2.3 Exploratory Objectives 
Section 3.2.1 Rationale for Study 
Design 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 12 of 79 
CONFIDENTIAL 
Change 
Rationale 
Section Changed  
 
 
Changed the following exploratory 
endpoint from ‘Change from 
baseline to week 12 in number of 
nocturnal awakenings per night 
measured by accelerometry’ to 
‘Change from baseline to week 12 
in number of nocturnal awakenings 
per night from patient diary’. 
 
Removed exploratory endpoint of 
‘Change from baseline to week 12 
in sleep duration per night measured 
by accelerometry’. 
requires a daily aerosol 
generating procedure.  
 
• 
This exploratory endpoint is to 
evaluate asthma related 
nocturnal awakenings; these are 
to be recorded by patients daily 
only in the patient diary and not 
captured by accelerometry. 
Section 4.1.3 Exploratory Endpoints 
Section 5.2 Efficacy Variables 
Section 6.1 Study Description and 
Duration 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnotes #11 and 12 deleted in 
original protocol 
Section 9.2.2.1 Accelerometers 
Section 9.2.2.2 At Home Spirometer 
(prior section deleted) 
Section 11.4.2 Demography and 
Baseline Characteristics 
Modified criteria for discontinuing 
study drug due to elevated AST 
and/or ALT values. 
• 
To align with current 
dupilumab protocols  
 
Section 8.5.2.1 Reasons for 
Permanent Discontinuation of Study 
Drug 
Eliminated 2-minute time point for 
post-exercise spirometry. 
• 
To rectify a previous error for 
this time point of post-exercise 
spirometry assessment (was 
supposed to be at 5 minutes and 
not at 2 minutes post-exercise). 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnote #18 
Section 9.2.2.5 Spirometry 
Added a Cardiopulmonary Exercise 
Testing (CPET) contraindication 
table in protocol in addition to the 
contraindications listed in the CPET 
manual. 
• 
To further ensure patient safety 
for the cardiopulmonary 
exercise testing during the 
study by including the CPET 
contraindication table in the 
protocol. 
Section 3.3 Risk-Benefit 
Section 9.2.2.4 Cardiopulmonary 
Exercise Testing (CPET) 
Table 2 Absolute and Relative 
Contraindications to CPET 
Added text to clarify general 
changes to study conduct in the 
context of the COVID-19 pandemic 
(eg, to allow for study drug to be 
shipped to patient’s home). 
• 
To ensure study objectives 
continue to be met during the 
COVID-19 pandemic. 
Section 3.3 Risk-Benefit 
Section 6.1 Study Description and 
Duration 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the 
Schedule of Events (Table 1), 
footnotes #8 and 14 
Section 11 Statistical Plan 
Added an Estimand table; clarified 
primary and secondary efficacy 
analysis methods; streamlined the 
statistical plan section of the  
synopsis; updated summaries of 
patient disposition and AEs. 
• 
To implement a concept 
estimand and treatment policy 
in the analysis approaches for 
the primary efficacy endpoint 
based on ICH E9 (R1) 
guidance. 
• 
Streamlined text for clarity and 
consistency without changing 
analysis methods and 
assumptions 
Synopsis: Statistical Plan 
Section 8.4 Rescue Treatment 
Section 11.4.1 Patient Disposition 
Section 11.4.3.1 Primary Efficacy 
Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Confidentiality statement updated.  
• 
To comply with updated 
sponsor standard confidentiality 
language. 
Title page 
Minor editorial changes and text 
reorganization. 
• 
For clarification 
Throughout the protocol. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 13 of 79 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A randomized, double-blind, placebo-controlled, parallel-group study to 
evaluate the effect of dupilumab on exercise capacity in patients with 
moderate-to-severe asthma 
Site Location(s) 
 
Principal Investigator: 
Global 
To be determined 
Objective(s) 
Primary 
• 
To demonstrate that dupilumab treatment improves exercise 
capacity in patients with moderate-to-severe asthma 
Secondary 
• 
To demonstrate that dupilumab treatment increases physical 
activity of daily living in patients with moderate-to-severe asthma  
• 
To demonstrate that dupilumab treatment improves pre- and post-
exercise lung function in patients with moderate-to-severe asthma 
Study Design 
This is a phase 4, global, randomized, double-blind, placebo-controlled 
study to evaluate the effects of dupilumab on exercise capacity in patients 
with a ventilatory limitation to exercise and on activities of daily living in 
patients with moderate-to-severe asthma over a 12-week treatment period.  
Approximately 140 patients will be enrolled, with a 1:1 randomization 
ratio.  Up to 10% of patients on maintenance oral corticosteroids (OCS; 
≤10 mg/day OCS, prednisone/prednisolone or dose equivalent) will be 
allowed to participate in the study.  Randomization will be stratified by 
baseline Forced Expiratory Volume in One Second (FEV1, <50% vs. ≥50% 
predicted), use of maintenance OCS use (yes/no), and age (<35 vs. 
≥35 years) to balance effects these variables may have on exercise 
performance.   
Study Duration 
The duration of the study for a patient is approximately 14 weeks, 
excluding the screening and run-in periods.  The entire study consists of an 
up to 4-week screening period, up to 4-week run-in period, a 12-week 
treatment period, and a 2-week post-treatment follow-up period. 
End of Study Definition 
The end of study is defined as the last study visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately 140 patients will be enrolled (approximately 70 per arm) 
 
Target Population: 
Male and female adult patients ≥18 to ≤55 years of age at screening with 
moderate- to-severe asthma 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 14 of 79 
CONFIDENTIAL 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab, as 150 mg/mL solution in a pre-filled syringe for SC injection. 
A 600 mg loading dose SC on study day 1 and 300 mg once every 2 weeks 
(Q2W) SC from week 2 to week 10 
 
Placebo 
 
Route/Schedule: 
Placebo matching dupilumab dose in a pre-filled syringe for SC injection 
Administered SC, Q2W 
 
Background Treatment 
 
Dose/Route/Schedule: 
Patients should be on a stable dose of medium-to-high dose inhaled 
corticosteroid (ICS) – inhaled fluticasone propionate ≥250 μg to 1000 μg 
twice a day (BID) or equivalent and a second controller medication (eg, 
long-acting beta agonist [LABA]) throughout the study.  Patients who are 
also on a stable dose of a third, non-corticosteroid asthma controller 
medication eg, leukotriene receptor antagonist (LTRA) at screening are 
allowed to participate as long as they can be maintained on a stable dose 
throughout the study duration. 
Up to 10% of patients on maintenance OCS at screening and baseline 
(≤10 mg/day of oral corticosteroids, prednisone/prednisolone or dose 
equivalent) are allowed. 
Endpoint(s) 
 
 
Primary: 
Change from baseline to week 12 in constant work rate exercise endurance 
time 
 
Secondary: 
• 
Change from baseline to week 12 in average number of steps 
walked per day (based on accelerometry data) 
• 
Change from baseline to week 12 in total energy expenditure 
(metabolic equivalents of tasks [METs]) (based on accelerometry 
data) 
• 
Change from baseline to week 12 in the mean duration of 
moderate-to-vigorous physical activity (defined as ≥3 METs) 
(based on accelerometry data) 
• 
Change from baseline to week 12 in pre- and post-exercise FEV1 
(based on spirometry data) 
Procedures and Assessments 
Efficacy procedures and assessments include the following: 
• 
Cardiopulmonary Exercise Testing (CPET):  A medically well-
accepted and standardized test that has been utilized to assess 
degree of exercise impairment in a variety of pulmonary diseases. 
o 
Qualifying Maximal Incremental Work Rate Exercise Test 
(IWRET):  Will be performed at screening to determine the 
peak work rate to use in calculating 80% of maximum work 
rate for the Constant Work Rate Exercise Testing (CWRET).  
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 15 of 79 
CONFIDENTIAL 
The IWRET can be performed up to a total of 3 times during 
the screening period to determine study eligibility. 
o 
CWRET:  Will be performed during run-in, at baseline, and  
at week 12.  The run-in CWRET will be performed to 
acquaint patients with the test and to determine the maximal 
individualized work rate that the patient can tolerate to 
achieve an exercise duration between 3 to 8 minutes (180 to 
480 seconds), (ie, time to limit of tolerance [tLIM]).  At the 
baseline visit, and at the end of treatment visit, CWRET must 
be performed utilizing the same constant work rate 
established for an individual patient at the qualifying run-in 
CWRET to evaluate change in exercise endurance time from 
baseline.  The following will be obtained during the baseline 
CWRET:  exercise endurance time, inspiratory capacity (IC), 
perception of dyspnea measured by the Borg Dyspnea Scale, 
perception of leg fatigue measured by the Borg Leg Fatigue 
Scale, and oxygen consumption (VO2). 
• 
Spirometry:  A spirometer that meets the American Thoracic 
Society (ATS) / European Respiratory Society (ERS) 
recommendations will be used.  Spirometry will be performed 
locally and read centrally in accordance with the ATS/ ERS 
guidelines.  Spirometry will be performed at the screening and 
baseline visits to determine study eligibility, and at other time 
points as specified in the schedule of events. 
• 
Accelerometers:  Wearable sensors which objectively record and 
measure physical activity, and energy expenditure in a “free 
living” environment, reflecting activities of daily living.  Patients 
will be instructed to wear an accelerometer day and night during 
the weeks per the schedule of events in the protocol.  The 
following data will be obtained from the accelerometer recording:  
number of steps walked per day, total energy expenditure 
(metabolic equivalents of task [METs]), and mean duration of 
moderate-to-vigorous physical activity (defined as ≥3 METs). 
• 
Fractional Exhaled Nitric Oxide (FeNO) Level:  A marker of 
airway inflammation.  FeNO levels will be assessed in accordance 
with ATS/ERS guidelines using the standardized nitric oxide 
measuring equipment (eg, Circassia NIOX VERO®). 
• 
Asthma Control Questionnaire, 5-question version (ACQ-5):  A 
patient-reported outcome measure used to assess asthma symptom 
control among patients with asthma. 
• 
Asthma Quality of Life Questionnaire with Standardized 
Activities (Self-Administered) [AQLQ(S)]:  A patient-reported 
disease-specific health-related quality of life instrument that 
measures both physical and emotional impact of asthma. 
• 
Patient Global Impression of Change (PGIC):  A patient-reported 
measure that assesses patients’ impression about the change in 
their ability to exercise since study treatment initiation.  Patients 
will be asked to recall the change in their ability to exercise since 
the baseline visit. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 16 of 79 
CONFIDENTIAL 
• 
Patient Global Impression of Impact (PGII):  A patient-reported 
measure that assesses patients’ impression about the impact of 
asthma on their ability to exercise during the past week. 
Safety procedures and assessments include the following:  monitoring and 
recording of adverse events (AEs); measurements of vital signs, including 
body temperature (°C), sitting systolic and diastolic blood pressure 
(mm Hg), pulse rate (beats per minute), and respiratory rate; physical 
examination; electrocardiogram (ECG); laboratory testing including 
hematology, blood chemistry, urinalysis, and pregnancy testing. 
Statistical Plan 
The null hypothesis and alternative to be tested: 
• 
Null hypothesis: The mean change from baseline in the constant 
work-rate exercise endurance time at week 12 is the same 
between dupilumab and placebo. 
• 
Alternative hypothesis: The mean change from baseline in the 
constant work rate exercise endurance time at week 12 differs 
between dupilumab and placebo. 
Justification for the sample size: The planned sample size of 
approximately 70 patients per treatment group will provide >85% power to 
detect a 105-second mean change in constant work rate exercise endurance 
time, with a standard deviation of 190 seconds, 2-sided α = 5%, and 10% 
drop out rate. 
Analysis Sets: 
• 
The full analysis set (FAS) includes all randomized patients. 
• 
The safety analysis set (SAF) includes all randomized patients 
who received any study drug; it is based on the treatment received 
(as treated). 
Baseline Definition 
Baseline for singular-value assessments, such as measurements from the 
CWRET, FEV1, and FVC from spirometry, will be the latest valid 
measurement taken prior to the first administration of study drug. 
Baseline for the 14-day average values of measurements from 
accelerometry is defined as the average of the non-missing values during 
the 14 days prior to the first administration of study drug. 
Primary Efficacy Analysis: 
The primary endpoint of change from baseline in constant work rate exercise 
endurance time at week 12 will be analyzed using an analysis of covariance 
(ANCOVA) model for the FAS population. The ANCOVA model will 
include terms for treatment group, randomization stratification factors and 
the baseline value for the constant work rate exercise endurance time. The 
intercurrent events handling strategy for systemic corticosteroid use or an 
increase in systemic corticosteroids for an asthma exacerbation during last 
4-weeks of the treatment period and for treatment discontinuation is 
specified in the Estimand table provided in the section for Primary Efficacy 
Analysis.  The imputation method for missing data based on the reasons for 
study discontinuation is defined below:  
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 17 of 79 
CONFIDENTIAL 
• 
Missing data due to: 
o 
AE or lack of efficacy will be imputed by baseline 
observation carried forward (BOCF).  
o 
Other reasons will be imputed using multiple imputation 
(MI) rules under a missing at random assumption.  A 
detailed imputation model will be specified in the SAP.   
 
Subgroup analysis may be performed for age, sex, weight, baseline FEV1, 
baseline constant work rate endurance time and baseline ACQ-5.  
Subgroup analyses may not be performed if the primary efficacy result is 
not statistically significant.   
Secondary Efficacy Analysis: 
The secondary efficacy endpoint of change from baseline to week 12 in 
pre-/post-exercise FEV1 will be analyzed using the same method as for the 
primary analysis. 
Other secondary endpoints measured by accelerometry (ie. change from 
baseline to week 12 in: average number of steps walked per day, total 
energy expenditure, and mean duration of moderate-to-vigorous physical 
activity) will be analyzed using a method similar to that for the primary 
endpoint, except that patients who initiate corticosteroids for the treatment 
of an asthma exacerbation within the last 4 weeks of the treatment period 
(or corticosteroid dose increase for those on maintenance OCS) will be 
included in the analysis. 
Multiplicity adjustment will be applied for testing of multiple endpoints.  
Type I error rate will be controlled using a hierarchical testing procedure 
for the primary and then key secondary endpoints at the 2-sided 0.05 level.  
The order of the endpoints for hierarchical testing will be specified in the 
SAP. 
Safety analysis will be based on the SAF.  This includes reported 
treatment-emergent AEs (TEAEs), adverse events of special interest 
(AESIs), and other safety data (eg, clinical laboratory evaluations, vital 
signs, and 12-lead ECG results).  A descriptive summary of safety results 
will be presented by treatment group. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 18 of 79 
CONFIDENTIAL 
1. 
INTRODUCTION 
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging.  
The inflammatory component of asthma involves many cell types, including mast cells, 
eosinophils, T-lymphocytes, neutrophils, and epithelial cells and their biological products.  The 
poor therapeutic response of some patients with asthma may reflect a number of cellular and 
molecular mechanisms operative in asthma.  Up-regulation of interleukin-4 (IL-4) and interleukin-
13 (IL-13) activity has been implicated as an important type 2 inflammatory component of asthma 
pathophysiology. 
It is well-established that exercise intolerance and difficulties engaging in physical activity are 
common complaints of patients with asthma, reported by at least 66% of patients 
(Fuhlbrigge, 2002).  In a survey in 1300 European patients, 70% of severe asthmatics receiving 
asthma medication reported limitation in physical activity (Dockrell, 2007).  Additionally, exercise 
capacity evaluated by cycle ergometry is known to be reduced in asthmatics when lung function 
is impaired.  Chronic expiratory flow limitation in patients with moderate-to-severe asthma may 
be a contributing factor to exercise intolerance.  Use of bronchodilators prior to exercise, though 
useful for blunting decrease in forced expiratory volume in one second (FEV1), does not reliably 
improve exercise capacity (Vermeulen, 2016).  A high unmet need exists to improve exercise 
capacity and activity levels in patients with asthma. 
Patients with obstructive lung disease, often develop dynamic hyperinflation (defined as an 
increase in end expiratory lung volume under conditions of increased minute ventilation [ie, during 
exercise]) due to expiratory air-flow limitation in the face of decreased time for exhalation with 
increasing respiratory rate.  This results in a decrease in inspiratory capacity (IC).  Dynamic 
hyperinflation increases inspiratory mechanical load and thereby results in sense of breathlessness 
and exercise intolerance in patients with obstructive lung disease.  Severity of dyspnea correlates 
with degree of expiratory flow limitation (measured by FEV1) and peripheral airway resistance 
(Mahler, 1991). 
There are no published, rigorously designed studies assessing the effects of pharmacotherapeutic 
intervention on assessing either maximal exercise capacity or activities of daily living in patients 
with asthma.  Dupilumab therapy has demonstrated improvement in lung function and asthma 
control.  Inhibition of IL-4/-13 is known to improve lung function and reduce airway inflammation 
(Gandhi, 2016) (Vatrella, 2014) (Castro, 2018) (Wenzel, 2016).  It is therefore hypothesized that 
dupilumab treatment may improve exercise capacity and increase physical activity in patients with 
moderate-to-severe asthma. 
Dupilumab is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that 
inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4Rα) 
subunit shared by the IL-4 and IL-13 receptor complexes.  Dupilumab inhibits IL-4 signaling via 
the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor 
(IL-4Rα/IL-13Rα).  Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced 
responses, 
including 
the 
release 
of 
proinflammatory 
cytokines, 
chemokines, 
and 
immunoglobulin E (IgE). 
Dupilumab (brand name DUPIXENT®) has been approved in the United States as an add-on 
maintenance treatment in patients with moderate-to-severe asthma aged 12 years and older with 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 19 of 79 
CONFIDENTIAL 
an eosinophilic phenotype or with oral corticosteroid (OCS) dependent asthma and in the European 
Union (EU) for patients aged 12 years and older with severe asthma with type 2 inflammation 
characterized by raised blood eosinophils and/or raised fractional exhaled nitric oxide (FeNO) who 
are inadequately controlled with high dose inhaled corticosteroid (ICS) plus another medicinal 
product for maintenance treatment.  Dupilumab has been approved in the United States for the 
treatment of patients aged 6 years and older with moderate-to-severe atopic dermatitis whose 
disease is not adequately controlled with topical prescription therapies or when those therapies are 
not advisable and in EU for the treatment of moderate-to-severe atopic dermatitis in adults and 
adolescents 6 years and older who are candidates for systemic therapy.  Dupilumab has also been 
approved in the United States as an add-on maintenance treatment in adult patients with 
inadequately controlled chronic rhinosinusitis with nasal polyps (CRSwNP) and in the EU for 
adults with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not 
provide adequate disease control.  Dupilumab has shown efficacy in a proof of concept study in 
patients with eosinophilic esophagitis.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective of the study is to demonstrate that dupilumab treatment improves exercise 
capacity in patients with moderate-to-severe asthma. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are:  
• To demonstrate that dupilumab treatment increases physical activity of daily living in 
patients with moderate-to-severe asthma  
• To demonstrate that dupilumab treatment improves pre- and post-exercise lung 
function in patients with moderate-to-severe asthma  
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are:  
• To demonstrate that dupilumab treatment decreases dynamic hyperinflation during 
constant work rate exercise in patients with moderate-to-severe asthma 
• To demonstrate that dupilumab treatment improves perception of dyspnea  
• To demonstrate that dupilumab treatment improves perception of leg fatigue 
• To demonstrate that dupilumab treatment increases oxygen consumption during the 
constant work rate exercise test (CWRET) 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 20 of 79 
CONFIDENTIAL 
• To demonstrate that dupilumab treatment improves asthma control in patients with 
moderate-to-severe asthma  
• To demonstrate that dupilumab treatment improves asthma-related quality of life in 
patients with moderate-to-severe asthma 
• To demonstrate that dupilumab treatment improves patients’ impression of ability to 
carry out exercise 
• To demonstrate that dupilumab treatment improves patients’ impression of the impact 
that asthma has on the ability to perform exercise 
• To demonstrate that dupilumab treatment decreases pre- and post-exercise FeNO 
• To measure nocturnal awakenings due to asthma measured by patient diary 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
Patients with moderate-to-severe asthma treated with dupilumab show improvement in exercise 
capacity and increase in physical activity of daily living. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
It has been shown that dupilumab treatment significantly improves FEV1, asthma control and 
reduces type 2 mediated inflammation in patients with moderate-to-severe asthma (Castro, 2018) 
(Rabe, 2018) (Wenzel, 2016).  This study will determine whether these improvements translate 
into (1) an increase in exercise capacity as measured by cycle ergometry and constant work rate 
exercise endurance time, and (2) an increase in physical activities of daily living assessed by 
accelerometry. 
Effects of pharmacotherapy on exercise capacity and physical activity in patients with asthma have 
not been rigorously examined in clinical studies.  Small studies in asthma with bronchodilators or 
bronchodilator + ICS intervention have shown inconsistent results regarding improvement in 
exercise capacity (Haverkamp, 2007) (Robertson, 1994).  A 6-week study of patients with mild-
to-moderate asthma treated with high dose fluticasone showed improvement in exercise endurance 
time and FEV1 (Haverkamp, 2007).  However, other studies in patients with asthma treated with 
bronchodilators demonstrated increases in FEV1 without consistent improvement in exercise 
capacity (Freeman, 1989).  An unblinded, small study of omalizumab in 20 consecutive patients 
with severe allergic asthma (10 receiving omalizumab and 10 placebo) demonstrated significant 
improvement in both FEV1 and exercise capacity after 16 weeks of omalizumab treatment 
(Schaper, 2011). 
Small, non-interventional, cross-sectional studies using various accelerometers worn at the wrist 
or hip have shown that patients with severe asthma walk approximately 27% to 30% fewer steps 
per day compared to age and gender matched healthy volunteers (mean steps/day severe asthma = 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 21 of 79 
CONFIDENTIAL 
5362; range 3999 to 7817 vs. healthy controls 7817; range 6072 to 10014) (Cordova-Rivera, 2018).  
Studies evaluating FEV1 as a marker of physical activity have shown conflicting results.  Bahmer 
et al reported that FEV1 and peak expiratory flow were poor markers of physical activity in asthma 
patients showing no significant correlation between FEV1 and steps walked per day 
(Bahmer, 2017), whereas Hennegrave, et al showed significant correlation between steps walked 
and FEV1 (Hennegrave, 2018).  
Dupilumab has been shown to increase lung function and improve asthma control.  It is 
hypothesized that this demonstrated efficacy may result in improvements in exercise capacity and 
physical activity of daily living.  Pulmonary limitation to exercise will be identified by 
demonstrating a decrease in IC from pre-exercise to the value during the maximal incremental 
exercise test performed at screening. 
This phase 4, randomized, placebo-controlled study is designed to evaluate whether treatment with 
dupilumab increases exercise endurance time evaluated using constant work rate exercise testing 
(CWRET).  Additionally, physical activities of daily living (steps walked per day, energy 
expenditure, and time spent in moderate-to-vigorous activity) will be assessed using 
accelerometry. 
A blinded, randomized design is chosen to minimize bias in data collection and result 
interpretation.  The presence of a placebo arm is appropriate for the objectives of this study since 
it will provide the most robust assessment of the efficacy of dupilumab.  A run-in period is planned 
to stabilize background asthma treatment, familiarize patients with the CWRET, determine an 
individualized work rate that a patient can tolerate for 3 to 8 minutes (180 to 480 seconds), and to 
collect pre-treatment accelerometry data.  A 12-week treatment period is selected based on the 
findings in dupilumab clinical studies in moderate-to-severe asthma patients where near-maximal 
improvements in lung function occurred by approximately 8 to 12 weeks after treatment initiation.  
A 2-week post-treatment follow-up period is chosen to ensure clinical stability of patients after the 
treatment period is complete. 
Cardiopulmonary exercise testing (CPET) has been utilized in several interventional studies to 
assess the degree of dynamic hyperinflation in patients with obstructive lung diseases, and its 
impact on exercise capacity (Benfante, 2018) (Casaburi, 2014) (Maltais, 2011) (O’Donnell, 2004).  
CPET can be performed on a stationary bicycle or a treadmill.  Cycle ergometry has been selected 
over a treadmill protocol because it requires relatively little patient practice (unlike treadmill 
exercise) and the external power output is accurately known.  A constant work-rate protocol is 
chosen to assess the primary endpoint versus a maximal incremental exercise test, as the former is 
more sensitive to discriminate change in exercise capacity.  To minimize variability in the 
measurements, the CPET will be done using a standardized CPET protocol, and only at sites 
proficient in CPET and pulmonary function testing. 
3.2.2. 
Rationale for Dose Selection 
The dose regimen selected for this study is dupilumab 300 mg administered subcutaneously (SC) 
every other week (Q2W) with a 600 mg loading dose for the first dose.  This dosing regimen is 
chosen as it has been shown to be efficacious, with an acceptable safety profile in asthma pivotal 
studies and is approved for the treatment of moderate-to-severe asthma, the patient population 
under study. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 22 of 79 
CONFIDENTIAL 
3.3. 
Risk-Benefit 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any new patients in this study 
unless the impact of the COVID-19 pandemic is deemed manageable and no longer interfering 
with the conduct of trials at individual sites, and patients can safely participate in this study.  Until 
then, the sponsor plans to obtain approvals from Health Authorities/Ethics Committees to enable 
continuation of study sites for this study, as allowed by local laws and regulations. 
Dupilumab has shown a favorable risk-benefit profile in patients with atopic dermatitis, asthma, 
and CRSwNP (see details in the DUPIXENT label and Dupilumab Investigator’s Brochure). 
The study population consists of a moderate-to-severe asthma patient population studied in the 
phase 3 studies of the dupilumab asthma clinical program, and for which dupilumab has been 
shown to have a positive risk-benefit profile.  The safety data available to date across multiple 
indications and risk-reducing measures planned in this study, in conjunction with the clinical 
benefit of dupilumab demonstrated in asthma patients, support a favorable risk-benefit profile for 
dupilumab for this study population. 
Multiple studies have shown that patients with obstructive lung disease and decreased lung 
function can perform a CPET safely.  A number of procedures are required to assure patient safety 
when performing a CPET.  At screening, patients will be carefully evaluated to determine 
appropriateness for a CPET; those not appropriate for the test will be excluded from the study.  
Both relative and absolute contraindications including, but not limited to, uncontrolled arrhythmia, 
uncontrolled elevated blood pressure (systolic blood pressure >180 mm Hg or diastolic blood 
pressure >95 mm Hg), clinically significant coronary artery disease,  unstable angina, etc, preclude 
participation in this study (a detailed list of absolute and relative contraindications for performing 
CPET is provided in Section 9.2.2.4, Table 2).  Any patient who the investigator judges to be 
unsuitable for exercise regardless of CPET contraindications cannot enroll or continue in the study.  
A CPET will be performed only at pulmonary function test (PFT) labs experienced in performing 
CPET and according to the American Thoracic Society (ATS)/ European Respiratory Society 
(ERS) recommendations.  Professionals experienced in performing CPET in patients with 
abnormal lung function, certified in advanced cardiac life support and experienced in interpreting 
physiologic responses to exercise will closely monitor each patient during the CPET.  A number 
of physiologic responses are assessed repeatedly during CPET, including electrocardiogram 
(ECG) parameters, oxygen saturation, blood pressure, pulmonary ventilation, oxygen uptake, and 
respiratory rate.  A medical doctor must be present in the room in which the initial incremental 
work rate exercise test (IWRET) is conducted and readily available for medical intervention, if 
needed, at all subsequent exercise tests.  Resuscitation equipment must be immediately available 
in the PFT lab where the exercise testing is performed.  A CPET laboratory manual, providing 
detailed instructions, including relative and absolute contraindications to testing and indications 
for exercise termination, will be distributed to each study site. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 23 of 79 
CONFIDENTIAL 
4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
The primary endpoint is change from baseline to week 12 in constant work rate exercise endurance 
time. 
4.1.2. 
Secondary Endpoints 
The secondary endpoints are: 
• Change from baseline to week 12 in average number of steps walked per day (based 
on accelerometry data) 
• Change from baseline to week 12 in total energy expenditure (metabolic equivalents 
of tasks [METs]) (based on accelerometry data) 
• Change from baseline to week 12 in the mean duration of moderate-to-vigorous 
physical activity (defined as ≥3 METs) (based on accelerometry data) 
• Change from baseline to week 12 in pre- and post-exercise FEV1 (based on 
spirometry data) 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Change from baseline to week 12 in isotime IC  
(Note: isotime is defined as the shortest equivalent exercise time achieved) 
• Change from baseline to week 12 in perception of dyspnea measured by the Borg 
Dyspnea Scale at isotime 
• Change from baseline to week 12 in perception of leg fatigue measured by the Borg 
Leg Fatigue Scale at isotime 
• Change from baseline to week 12 in end-exercise oxygen consumption (VO2) 
• Change from baseline in total ACQ-5 score (Asthma Control Questionnaire, 5-
question version) at week 12 
• Change from baseline to week 12 in total AQLQ(S) score (Asthma Quality of Life 
Questionnaire Standardized Version) 
• Proportion of patients responding with an improvement on the Patient Global 
Impression of Change (PGIC) at weeks 4 and 12 
• Proportion of patients responding with no or limited impact on the Patient Global 
Impression of Impact (PGII) at weeks 4 and 12 
• Change from baseline to week 12 in FeNO, pre- and post-exercise 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 24 of 79 
CONFIDENTIAL 
• Change from baseline to week 12 in forced vital capacity (FVC) pre- and post-
exercise  
• Change from baseline in FEV1 and FVC at week 4  
• Change from baseline to week 12 in the maximal percent fall in post-exercise FEV1 in 
patients with exercise-induced asthma (defined as patients who had a ≥20% fall in 
post-exercise FEV1 from pre-exercise value on the IWRET) 
• Change from baseline to week 12 in number of nocturnal awakenings per night due to 
asthma from patient diary 
5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, weight, height, sex, race, etc), 
disease characteristics, medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
The efficacy variables include measurements or scores for individual patients of the following:   
• Exercise endurance time measured from the CWRET 
• IC, perception of dyspnea, and leg fatigue during exercise measured by the Borg 
Dyspnea Scale and Borg Leg Fatigue Scale, and VO2 measured from the CWRET 
• Pre- and post-exercise FEV1 and FVC measured by in-clinic spirometry  
• FEV1 and FVC measured by in-clinic spirometry at the visit(s) when exercise testing 
is not performed 
• Number of steps walked per day, total energy expenditure per day (in METs), and mean 
duration of moderate-to-vigorous physical activity per day defined as ≥3 METs 
assessed by accelerometry  
• Nocturnal awakenings due to asthma  
• ACQ-5 
• AQLQ(S) 
• FeNO 
• PGIC 
• PGII 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 25 of 79 
CONFIDENTIAL 
5.3. 
Safety Variables 
Safety variables include recording, measurements or laboratory test results for individual patients 
of the following: adverse events (AEs), vital signs, physical examination findings, hematology, 
blood chemistry, urinary analysis, and ECG findings. 
6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This phase 4, global, randomized, double-blind study of dupilumab vs. placebo is designed to 
evaluate the effects of dupilumab on exercise capacity and daily activity in patients with moderate-
to-severe asthma over a 12-week treatment period.  Approximately 140 patients will be enrolled 
in the study, approximately 70 per treatment group with a 1:1 randomization ratio.  Up to 10% of 
patients 
on 
maintenance 
OCS 
at 
screening 
and 
baseline 
(≤10 
mg/day 
OCS, 
prednisone/prednisolone or dose equivalent) will be allowed to participate in the study. 
Randomization will be stratified by baseline FEV1 (<50% vs. ≥50% predicted) and age (<35 vs. 
≥35 years) to balance effects these variables may have on exercise performance.   
The study consists of an up to 4-week screening period, an up to 4-week run-in period, a 12-week 
treatment period, and a 2-week post-treatment follow-up period (see Figure 1). 
Figure 1: 
Study Flow Diagram 
 
 
D = study day; R = randomization; EOS = end of study; EOT = end of treatment; W = study week 
Note: The study drug dosing regimen is dupilumab 600 mg loading dose on study day 1 and 300 mg Q2W from 
week 2 to week 10 or matching placebo. 
Screening Period (Up to 4 Weeks/Visit 1): 
After providing informed consent, the patients will be assessed for study eligibility at the screening 
visit.  During the screening period, patients will perform qualifying ACQ-5, spirometry, 
bronchodilator reversibility testing (if applicable) , and laboratory assessments.  
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 26 of 79 
CONFIDENTIAL 
Patients must meet all screening eligibility requirements prior to conducting incremental work rate 
exercise testing (IWRET).  Patients who meet these eligibility requirements will undergo a 
symptom-limited, incremental, maximal effort, cycle cardiopulmonary exercise test (IWRET) to 
determine the maximum work rate he/she can achieve.  During the IWRET, work rate will be set 
to increase at either 10, 15, 20, or 25 W/min depending on the investigator’s assessment of the 
patient’s ability to exercise.  The primary goals of the IWRET are to determine peak work rate 
patients can endure, to assess development of dynamic hyperinflation and determine the patient’s 
exercise endurance time.  Patients must exercise until exhaustion, for between 4 and 16 minutes 
inclusive, and must have documented dynamic hyperinflation defined as decrease in IC during the 
IWRET of more than 100 mL from the pre-exercise value .  If the exercise time is outside of the 4 
to 16 minute required window or IC does not decrease by >100 mL, the test may be repeated with 
a change in the work rate from that previously used by ±10% or 5 W/min, whichever is greater.  
The IWRET can be repeated twice (up to a total of 3 times) to determine study eligibility.  A 
patient who exercises <4 or >16 minutes or who does not drop IC by >100 mL after 3 IWRET 
attempts will be considered a screen failure.  
The IWRET (to be performed at screening) and the CWRET (to be performed during the run-in 
period, at baseline and at the end of the treatment period) will be administered according to 
guidelines for CPET published in the Joint Statement of the ATS and the American College of 
Chest Physicians (ACCP) (American Thoracic Society, 2003).  CPET is a non-invasive, well-
accepted, standard protocol-driven method to assess the performance of the heart and lungs during 
exercise (Puente-Maestu, 2016).  The test will be performed on an electromagnetically-braked 
cycle ergometer in an exercise physiology laboratory overseen by a trained pulmonologist or 
medical doctor designee.  A medical doctor must be present in the room in which the initial IWRET 
is conducted and readily available for medical intervention, at all subsequent exercise tests.  
Resuscitation equipment must be immediately available in the PFT lab (ie, in the room) in which 
the exercise testing is performed.  Patients will exercise until exhaustion (time to limit of tolerance 
[tLIM]) breathing through a mouthpiece with noseclip in place or while wearing a mask. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 27 of 79 
CONFIDENTIAL 
Run-in Period ( Up to 4 Weeks/Visit 2): 
During the run-in period patients must maintain a stable dose of background asthma controller 
medication including OCS, if applicable, for at least 4 weeks prior to the baseline visit.  Patients 
will perform a run-in CWRET using a standardized CWRET protocol on an electromagnetically-
braked cycle ergometer.  The CWRET will be performed at 80% of the maximal work rate 
previously determined from the IWRET.  The goal of the run-in CWRET is to determine the 
individualized work rate the patient can tolerate to achieve an exercise duration time between 3 to 
8 minutes, and to familiarize the patient with the test.  For those achieving exercise times outside 
of these limits (ie, <3 to >8 minutes) a second CWRET may be performed after a work rate 
adjustment by  ±10% or 5 W/min, whichever is greater.  In rare cases, a third test may need to be 
performed after a further work rate adjustment to achieve a 3 to 8 minute exercise endurance time.  
Patients who are unable to achieve an exercise endurance duration between 3 to 8 minutes (180 to 
480 seconds) after 3 attempts will be considered screen failures.  
At visit 2, patients will be given the accelerometer and instructed on its proper use.  Patients will 
be instructed to wear the accelerometer on their wrist, 24 hours/day, 7 days/week (except during 
charging time, bathing, and any other water activities) for a total of 3 weeks during the run-in 
period and record daily how much time spent bathing or swimming, total time charging the device, 
physical activity (eg, walking, moderate physical activities, and vigorous physical activities), and 
nocturnal awakenings due to asthma in the patient diary.  The first week is a training period for 
the patient to become familiar with the accelerometer.  The subsequent 2 weeks of daily 
accelerometry are to obtain the pre-treatment baseline data.    
Baseline and Treatment Period (12 Weeks/Visits 3 to 9): 
Eligible patients will be randomized 1:1 on day 1 to receive dupilumab or placebo.  Background 
asthma controller medication must remain constant throughout the treatment period.  Patients will 
be asked to wear an accelerometer on their wrist 24 hours/day, 7 days/week for 14 consecutive 
days prior to visit 3/randomization, and for 14 consecutive days prior to visit 9/end of treatment 
Visit (except during charging time, bathing, and any other water activities).  The CWRET will be 
performed at baseline and week 12 to assess the change in constant work rate exercise endurance 
time from baseline, the primary endpoint for the study.  In-clinic spirometry will be assessed pre- 
and post-exercise as part of the CWRET per the schedule of events.  Note: The same exercise work 
rate established at the qualifying run-in CWRET which achieves an exercise time between 3 and 
8 minutes must also be applied for the baseline and end of treatment CWRET.  Pulmonary 
ventilation, breathing pattern, gas exchange (all assessed from the respired gases by a metabolic 
cart), arterial oxygen saturation (assessed by pulse oximetry), ECG parameters, IC, perceived 
dyspnea and perceived leg fatigue (by Borg Dyspnea and Leg Fatigue Scales, respectively) will be 
assessed during the CWRET.  Details of cardiopulmonary exercise testing procedures including 
absolute and relative contraindications for performing exercise testing are provided in Table 2 and 
will also be provided to each site in the CPET laboratory manual.  Asthma control, asthma quality 
of life, nocturnal awakenings due to asthma, and airway inflammation will be assessed at baseline 
and during the treatment period using the ACQ-5, AQLQ, PGII, and PGIC questionnaires, patient 
diary and FeNO measurements, respectively.  Additional in-clinic spirometry will be performed at 
week 4 using the same equipment utilized to perform spirometry pre- and post-exercise testing. 
Safety, including adverse events, will be assessed throughout the study. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 28 of 79 
CONFIDENTIAL 
Post-treatment Follow-up Period: (2 Weeks/Visit 10) 
All patients will have a follow up visit 2 weeks after completing the treatment period. 
NOTE: If there are restrictions to the clinical study as a result of the COVID-19 pandemic, it may 
be necessary to adjust the visit schedule, convert in-person visits to telephone contacts, and 
postpone study procedures until the next available study visit.  All visits when CPET is performed 
must occur in the clinic including the randomization visit.  All temporary mechanisms utilized, 
and deviations from planned study procedures in response to COVID-19 are to be documented as 
being related to COVID-19 and will remain in effect only for the duration of the public health 
emergency.  Once local COVID-19 conditions resolve, all study visits and procedures should 
follow the schedule of events as specified in Table 1. 
6.1.1. 
End of Study Definition 
The end of study is defined as the last study visit of the last patient. 
6.2. 
Planned Interim Analysis 
No interim analysis is planned for this study. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 140 patients (approximately 70 per arm) are planned to be enrolled in the study. 
7.2. 
Study Population 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male and female ≥18 to ≤55 years of age at screening 
2. A physician diagnosis of asthma according to Global Initiative for Asthma (GINA) 2018 
step 4 or 5 asthma for at least 12 months prior to the screening visit 
3. Pre-bronchodilator FEV1 between 30% and 75% predicted (the Third National Health 
and Nutrition Examination Survey [NHANES III] reference values) at both the screening 
and baseline visits 
4. Bronchodilator reversibility defined as >200 mL and 12% increase in FEV1 post-
administration of a short-acting beta agonist (SABA)*.  A patient may also qualify if 
there is a documented history of bronchodilator reversibility or positive methacholine 
challenge test within 12 months prior to the screening visit. 
 
*Dose of SABA:  200 to 400 μg albuterol/salbutamol or levalbuterol/levosalbutamol (2 to 
4 inhalations of albuterol/salbutamol or levalbuterol/levosalbutamol, or of a nebulized 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 29 of 79 
CONFIDENTIAL 
solution of albuterol/salbutamol or levalbuterol/levosalbutamol, if considered as a 
standard office practice) 
5. Demonstrate dynamic hyperinflation as defined by a decrease in IC of >100 mL during 
the IWRET at screening 
6. Stable background therapy for at least 3 months with a stable dose ≥4 weeks prior to the 
baseline visit of a medium-to-high dose ICS (fluticasone propionate ≥250 to 1000 μg 
twice daily [BID] or equivalent) in combination with at least a second controller 
medication (eg, long-acting beta agonist [LABA], long-acting muscarinic antagonist 
[LAMA], leukotriene receptor antagonist [LTRA], theophylline, etc); a third controller is 
allowed and with the same stabilization requirements.  
 
Note: Up to 10% of patients on maintenance OCS at screening and baseline (≤10 mg/day 
OCS, prednisone/prednisolone or dose equivalent) will be allowed to participate in the 
study.  Patients must be on a stable dose of OCS for at least 4 weeks prior to the 
screening visit and between the screening and baseline/randomization visits and 
throughout the study. 
7. Blood eosinophil count ≥300 cells/μL for patients not on maintenance OCS at the 
screening visit 
8. ACQ-5 score ≥1.5 at the screening and baseline visits 
9. Able to provide signed informed consent  
10. Willing and able to comply with clinic visits and study-related procedures 
NOTE: Patients who do not meet the inclusion criteria for a reason that could be transient 
(eg, an abnormal laboratory value and judged to return to an acceptable range by the 
investigator within the screening period prior to day 1) may be allowed to repeat the test one 
additional time (up to a total of 2 attempts) on a different day to meet the qualifying criteria.  
There is no need to screen fail such participants if the test finally meets the eligibility criteria. 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Body mass index >35 kg/m2 at screening 
2. Current smoking, vaping or tobacco chewing or cessation of any of these within 6 months 
prior to randomization, or >10 pack-years smoking history 
3. Asthma exacerbation requiring systemic corticosteroids within 8 weeks prior to screening 
or between screening and baseline visits  
4. Upper or lower respiratory tract infection within 4 weeks prior to screening (visit 1) or 
between screening and baseline visit 
5. History of life-threatening asthma (eg, severe exacerbation that required intubation within 
the last 5 years) 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 30 of 79 
CONFIDENTIAL 
6. On or initiation of bronchial thermoplasty within 3 years prior to visit 1 or plan to begin 
therapy during the screening period or during the study after screening 
7. Significant chronic pulmonary disease other than asthma (eg, cystic fibrosis, idiopathic 
pulmonary fibrosis, sarcoidosis, interstitial lung disease, chronic obstructive pulmonary 
disease (COPD), eosinophilic granulomatous with polyangiitis (EGPA), also called 
Churg-Strauss Syndrome) or another diagnosed pulmonary or systemic disease associated 
with elevated peripheral eosinophil counts at screening 
8. Pulmonary embolus or pulmonary infarction within 1 year of screening or thrombosis of 
lower extremities unless previously treated with at least 3 months of anti-coagulant 
therapy or patient has an inferior vena cava filter  
9. Diagnosis/history of pulmonary hypertension 
10. Patients who require supplemental oxygen at screening  
11. Clinically significant cardiac disease (eg, history or presence of left or right sided heart 
failure, active endocarditis, current myocarditis or pericarditis, moderate or severe 
valvular heart disease, history of hypertrophic cardiomyopathy, or suspected dissecting 
aneurysm) 
a. Myocardial infarction within 6 months prior to screening 
b. Clinically significant coronary artery disease or a history of angina within the last 
3 years, unless the patients has a negative cardiac stress test within 1 year prior to 
randomization 
12. History of uncontrolled arrhythmias causing symptoms or hemodynamic compromise 
within 6 months of screening or history of clinically significant tachyarrhythmias or 
bradyarrhythmias  
13. Any clinically significant abnormality on screening ECG  
14. Syncope within 6 months of screening 
15. Uncontrolled hypertension (>180 mm Hg systolic, >95 mm Hg diastolic) at screening or 
baseline.   
16. Participation in exercise or physical rehabilitation program within last 6 months prior to 
screening or planned during the study 
17. Patients who exercised <4 minutes or >16 minutes during the screening IWRET  
18. Patients unable to achieve a constant work rate exercise time between 3 and 8 minutes 
during run-in CWRET, despite work rate adjustments 
19. History of clinically significant renal, hepatic, 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 
20. Known or suspected history of immunosuppression or immunodeficiency disorder 
including history of invasive opportunistic infections (eg, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystis), despite infection resolution; or unusually frequent, 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 31 of 79 
CONFIDENTIAL 
recurrent, or prolonged infections, suggesting an immune-compromised status, as judged 
by the investigator 
21. Patients with active autoimmune disease or patients using immunosuppressive therapy for 
autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary 
biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc)  
22. History of malignancy within 5 years before the screening visit, except completely 
treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic 
squamous or basal cell carcinoma of the skin 
23. Initiation, discontinuation, or change in the dosage regimen of allergen immunotherapy 
(ie, subcutaneous or sublingual) within 3 months prior to screening (visit 1) 
• Patients on a stable dose of these medications for at least 3 months prior to visit 1 
may be included in the study, but must not change the dose during the study. 
24. Previous use of dupilumab. 
25. Use of any investigational drugs (other than the study drug) within 3 months or at least 
5 half-lives prior to visit 1, whichever is longer 
26. Anti-IgE therapy (eg, omalizumab [Xolair®]) within 130 days prior to visit 1 or any 
other biologic therapy (including anti-IL5, anti-IL-5R, anti-IL4Rα, anti-IL-13 mAb) or 
systemic immunosuppressant (eg, methotrexate, any anti-tumor necrosis factor mAbs, 
Janus kinase inhibitors, 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 3 months or 5 half-lives prior to screening, 
whichever is longer 
27. Exposure to another investigative drug (monoclonal antibodies as well as small 
molecules) within a period prior to screening, of <3 months or <5 half-lives (whichever is 
longer)  
28. History of systemic hypersensitivity or anaphylaxis to any biologic therapy, including 
any excipients 
29. Treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit or 
planned live attenuated vaccinations during the study 
30. Patients with active tuberculosis or non-tuberculous mycobacterial infection, latent 
untreated tuberculosis, or a history of incompletely treated tuberculosis will be excluded 
from the study unless it is well documented by a specialist that the patient has been 
adequately treated and can now start treatment with a biologic agent, in the medical 
judgment of the investigator and/or infectious disease specialist.  (Tuberculosis testing 
will be performed on a country-by-country basis according to local guidelines if required 
by regulatory authorities or ethic committees.) 
31. Diagnosed active parasitic infection (helminths), suspected or high risk of parasitic 
infection, unless clinical and (if necessary) laboratory assessments have ruled out active 
infection before randomization 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 32 of 79 
CONFIDENTIAL 
32. Human immunodeficiency virus (HIV) by clinical or serological history 
33. Established diagnosis of hepatitis B viral (HBV) infection at the time of screening or 
positive for hepatitis B surface antigen (HBsAg) at the time of screening 
• Patients who have gained immunity for hepatitis B virus infection after vaccination 
(patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] positive, 
and hepatitis B core antibody [HBcAb] negative) are eligible for the study. 
• Patients with positive HBcAb are eligible for the study only if hepatitis B viral DNA 
level is undetectable.  
34. Established diagnosis of hepatitis C viral (HCV) infection at the time of screening.  
Patients positive for hepatitis C Ab are eligible for the study only if HCV RNA test is 
negative prior to randomization. 
35. Liver injury-related criteria: 
• Clinically significant/active hepatobiliary disease or evidence of liver disease as 
indicated by persistent (confirmed by repeated tests ≥2 weeks apart) elevated 
transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase 
[AST]) more than 3 times the upper limit of normal [ULN] during the screening). 
36. Any of the following abnormal lab values at screening: 
• Creatine phosphokinase (CPK) >10×ULN or 
• Platelets <100,000 cells/mm3  
• Clinically significant electrolyte abnormalities in the opinion of the principal 
investigator 
NOTE: If an abnormal value is detected at screening, a repeat test should be performed to 
confirm the abnormality.  Only if the repeat test confirms the abnormality would the 
patient be categorized as a screen failure. 
37. Known or suspected alcohol and/or drug abuse OR positive pre-study drug/alcohol screen 
38. Any relative or absolute contraindication to CPET listed in Table 2 or any other reason 
not provided in the list of relative or absolute contraindications to CPET (Table 2) that 
the investigator believes would make CPET unsafe or inadvisable. 
39. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study patient as a result of 
his/her participation in this study, may make patient’s participation unreliable, or may 
interfere with study assessments.  The specific justification for patients excluded under 
this criterion will be noted in study documents. 
40. Inability to follow instructions or complete study-related procedures (eg, due to language 
problems or psychological disorders) 
41. Individuals accommodated in an institution because of regulatory or legal order; 
prisoners or patients who are legally institutionalized 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 33 of 79 
CONFIDENTIAL 
42. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the Sponsor 
43. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study 
44. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the 
study, and for at least 12 weeks after the last dose.  Highly effective contraceptive 
measures include:  
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening 
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS)  
c. bilateral tubal ligation  
d. vasectomized partner (provided that the male vasectomized partner is the sole sexual 
partner of the WOCBP study participant and that the vasectomized partner has 
obtained medical assessment of surgical success for the procedure) 
e. and/or sexual abstinence†, ‡. 
*Women of child bearing potential are defined as women who are fertile following 
menarche until becoming postmenopausal, unless permanently sterile.  Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  However, in the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a 
postmenopausal state.  The above definitions are according to Clinical Trial Facilitation 
Group (CTFG) guidance.  Pregnancy testing and contraception are not required for 
women with documented hysterectomy or tubal ligation. 
†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 
drugs.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception.  Female condom and male condom should not be 
used together. 
45. Any country-specific regulation that would prevent the participant from entering the 
study 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 34 of 79 
CONFIDENTIAL 
7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures).  An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.5.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study or study drug will not be replaced. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
The study drug dosing regimen is dupilumab 600 mg loading dose on study day 1 and 300 mg 
Q2W from week 2 to week 10 or matching placebo. 
Dupilumab drug product is supplied for this study in the following concentration:   
• Dupilumab 150 mg/mL:  Each 2.0 mL single-use prefilled glass syringe with snap-off 
cap delivers 300 mg of study drug (2.0 mL of a 150 mg/mL solution) 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα mAb). 
Study drug will be administered by SC injections.  Subcutaneous injection sites of study drug 
should be alternated among the different quadrants of the abdomen (avoiding navel and waist 
areas), upper thighs, and upper arms so that the same site is not injected for 2 consecutive 
administrations.  To allow for adequate assessment of possible injection site reactions (ISRs), study 
drug should be administered only into areas of normal looking skin.  Instructions for recording and 
reporting ISRs will be provided in the study binder. 
Patients and/or caregivers who are willing and able to self-administer some dupilumab doses 
outside of the clinic will be trained on injecting the study drug. 
The procedure for preparing and administering dupilumab will be provided in the pharmacy 
manual. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 35 of 79 
CONFIDENTIAL 
8.2. 
Run-in Treatment 
Patients' background asthma controller medication will be stabilized during the up to 4-week run-
in period. 
8.3. 
Background Treatments 
Patients must be on a stable dose of medium-to-high dose ICS – inhaled fluticasone propionate 
≥250 μg to 1000 μg BID or equivalent and a second controller medication (eg, LABA) throughout 
the study.   Patients who are also on a stable dose of a third, non-corticosteroid asthma controller 
medication, eg, LTRA, at screening are allowed to participate as long as they can be maintained 
on a stable dose throughout the study duration.  For the up to 10% of patients who are on 
maintenance OCS (≤10 mg/day OCS, prednisone/prednisolone or dose equivalent) at screening 
and baseline; their OCS dose must remain constant during the study  
8.4. 
Rescue Treatments 
Short-acting bronchodilators (either SABA or short acting muscarinic antagonists [SAMAs]) are 
permitted as rescue therapy throughout the study, except within 6 hours of exercise testing or 
spirometry.  In the event that a SABA is required within 6 hours (or 8 hours for SAMA) prior to 
exercise on the day of exercise testing or spirometry, the exercise test and/or spirometry must be 
rescheduled within the time window per the schedule of events (Table 1). 
Systemic corticosteroids are allowed as rescue treatment for asthma exacerbations.  Need for 
rescue therapy, dosage, and corticosteroid taper regimen will be determined by the site principal 
investigator and/or the patient's personal physician. 
Patients who experience an asthma exacerbation in the last 4 weeks of the double blind treatment 
period and require treatment with systemic corticosteroids or an increase in systemic 
corticosteroids (for those patients on OCS) will not undergo CWRET at week 12, but the patient 
will be followed to perform other efficacy assessments including accelerometry, spirometry and 
safety assessments.  
8.5. 
Dose Modification and Study Treatment Discontinuation Rules 
8.5.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.5.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study.  Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.2. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 36 of 79 
CONFIDENTIAL 
8.5.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction (eg, Hy’s law is met (Guidance for Industry Drug 
Induced Liver Injury: Premarketing Clinical Evaluation FDA, 2009)) 
• Patient withdraws consent 
• If, in the investigator’s opinion, continuation in the study would be detrimental to the 
patient’s well-being 
• In the event of a protocol deviation, at the discretion of the investigator or the 
Sponsor 
• Any patient unblinding requested by the investigator will lead to permanent treatment 
discontinuation 
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin 
• Other intercurrent illnesses or major surgery which could, in the opinion of the 
investigator, present an unreasonable risk to the patient as a result of his/her 
continued participation in the study 
• Development of a condition that precludes exercise 
• Infections or infestations that do not respond to medical treatment 
• Any opportunistic infection, or other infections whose nature or course may suggest 
an immunocompromised status  
• Serum ALT and/or AST >3×ULN with total bilirubin >2×ULN , excluding confirmed 
Gilbert’s syndrome  
• Confirmed AST and/or ALT >5×ULN (for more than 2 weeks) 
• Neutrophils <1500/mm3  
• Platelets <100000/mm3  
• Suspicion of rhabdomyolysis or CPK >10×ULN 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for confirmation 
before making a decision of permanent discontinuation of the study drug for the concerned patient. 
8.5.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• Surgical procedure 
• Hospitalization 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 37 of 79 
CONFIDENTIAL 
• Severe laboratory abnormalities (as noted in Section 8.5.2.1) where a causal 
relationship to study drug can be reasonably excluded, (ie, an alternative cause is 
evident):  study drug will be discontinued but may be resumed when the laboratory 
abnormality is sufficiently normalized.  At minimum, the laboratory value(s) must 
return to a level that no longer meets the specified criteria for discontinuation, as 
defined in Section 8.5.2.1.  A decision to resume study treatment will be made jointly 
by the investigator and medical monitor (medical monitor’s written approval is 
required). 
• An infection that requires parenteral treatment with antibiotic, antifungal, antiviral, 
antiparasitic, or antiprotozoal agents, or requires oral treatment with such agents for 
longer than 2 weeks 
After the condition leading to temporary discontinuation of study drug resolves, study drug dosing 
may resume.  A decision to temporarily discontinue study drug and/or resume study drug dosing 
should be discussed with the Regeneron medical monitor. 
The investigator may temporarily discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the patient’s best interest.  However, the Regeneron medical 
monitor should be contacted as soon as possible.  Resumption of study drug dosing requires 
consultation and agreement between the investigator and the Regeneron medical monitor. 
If a patient requires a prohibited medication at any time during the study, the principal investigator 
should contact the Regeneron medical monitor (except for illness or medical circumstance 
requiring prompt treatment).  Based on the discussions, study drug may be continued or 
temporarily or permanently discontinued. 
8.6. 
Management of Acute Reactions  
8.6.1. 
Acute Injection Reactions 
8.6.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use.  All injection reactions must be reported as AEs (as defined in Section 10.2.1) 
and graded using the grading scales as instructed in Section 10.2.4. 
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice. 
8.6.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.7. 
Method of Treatment Assignment 
Approximately 140 patients will be randomized in a 1:1 ratio to receive either dupilumab or 
placebo according to a central randomization scheme provided by an interactive voice response 
system (IVRS)/interactive web response system (IWRS) to the designated study pharmacist (or 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 38 of 79 
CONFIDENTIAL 
qualified designee).  Up to 10% of patients on maintenance OCS at screening and baseline 
(≤10 mg/day OCS, prednisone/prednisolone or dose equivalent) will be allowed to participate in 
the study.  Randomization will be stratified by baseline FEV1 (<50% vs. ≥50% predicted), use of 
maintenance OCS use (yes/no), and age (<35 vs. ≥35 years). 
8.8. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study.  The Regeneron Medical/Study Director, Study 
Monitor, and any other Regeneron and contract research organization (CRO) personnel who are 
in regular contact with the study site will remain blinded to all patient randomization assignments. 
8.9. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient's treatment assignment.  Study drug will be discontinued for patients whose 
treatment has been unblinded (Section 8.5.2). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator.  If there is no study pharmacist, the 
investigator for the site will unblind the patient.  Unblinding is performed using 
the IVRS/IWRS which will notify Regeneron. 
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency and when a treatment decision is contingent on knowing the patient's treatment 
assignment.  In the event that there is no study pharmacist, the individual at the site fulfilling that 
role will be the only unblinded member of the site personnel. 
8.10. 
Treatment Logistics and Accountability 
8.10.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug.  Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging.  In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 39 of 79 
CONFIDENTIAL 
8.10.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study.  At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed or returned to the 
sponsor or designee. 
8.10.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug.  These records 
should contain the dates, quantity, and study medication 
• dispensed to each patient 
• returned from each patient (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.10.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
Patient will complete a paper diary to record dosing information. 
8.11. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent to final study visit will be recorded.  
This includes medications that were started before the study and are ongoing during the study.  
Any treatment administered from the time of first dose of study drug to the final study visit will 
be considered concomitant treatment. 
8.11.1. 
Prohibited Medications and Procedures 
The following concomitant treatments are not permitted during the study (from screening to end 
of study visit): 
• Biologic therapy (biologic therapy is not allowed to be used from 3 months or at least 
5 half-lives prior to visit 1, whichever is longer, and during the study). 
• Chronic immunosuppressants (immunosuppressants are not allowed to be used from 
3 months or at least 5 half-lives prior to visit 1, whichever is longer, and during the 
study) except maintenance OCS (≤10 mg/day of oral corticosteroids 
prednisone/prednisolone or dose equivalent) in up to 10% of patients. 
• Allergen immunotherapy (except if initiated more than 3 months prior to visit 1 and 
dose stabilized 1 month prior to visit 1). 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 40 of 79 
CONFIDENTIAL 
• Bronchial thermoplasty 
• Exercise or physical rehabilitation program 
• Intravenous immunoglobulin (IVIG) therapy 
• Live Attenuated Vaccines  
Chickenpox (varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (vaccinia) 
Yellow fever 
Bacille Calmette-Guerin 
Rotavirus 
Varicella zoster (shingles) 
• Beta-adrenergic receptor blockers (except for a selective beta-1 adrenergic receptor 
blocker used with dose stabilized at least 4 weeks prior to visit 1) 
• Any investigational drugs (other than the study drug) 
8.11.2. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 8.11.1, treatment with concomitant 
medications are permitted during the study: 
If there is any question regarding whether a concomitant medication may be used during the study, 
the study site should contact the medical monitor. 
8.12. 
Poststudy Treatments 
No poststudy treatments are required or planned.  Patients may continue dupilumab treatment with 
commercial supplies per product label.  Patients should continue their background asthma 
medication as prescribed by their personal physician. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Table 1 Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms.  
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff.  Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted.  All 
temporary mechanisms utilized, and deviations from planned study procedures in response to 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 41 of 79 
CONFIDENTIAL 
COVID-19 are to be documented as being related to COVID-19 and will remain in effect only for 
the duration of the public health emergency. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 42 of 79 
CONFIDENTIAL 
Table 1: 
Schedule of Events 
 
Screening and Run-
in Period 
Treatment Period 
Follow-
up 
Early 
Termination 
Visit 
Unscheduled 
Visit(s)28 
 
Screening1 
Run-in 
period1,2 
 
 
 
 
 
 
 
 
 
 
Study Procedure 
Visit 1 
Visit 2 
 
 
Baseline1,2 
Visit 3 
Ph 
Visit 
4 
Visit 
5 
Ph 
Visit 
6 
Ph 
Visit 
7 
Ph 
Visit 
8 
End of 
Treatment  
Visit 9 
End of 
Study 
Visit 10 
 
 
Week 
-8 to -4 
-4 to 0 
 
 
1 
2 
4 
6 
8 
10 
12 
14 
 
 
Day 
-56 to -28 
-27 to -1 
1 
15 
29 
43 
57 
71 
85 
99 
 
 
Window (day) 
±7 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±5 
 
 
Screening/Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Qualifying ACQ-53 
X 
 
X 
 
 
 
 
 
 
 
 
 
Qualifying ECG (central 
reading)4 
X 
 
 
 
 
 
 
 
 
 
 
 
Qualifying bronchodilator 
reversibility testing5 
X 
 
 
 
 
 
 
 
 
 
 
 
Qualifying spirometry for 
FEV1% predicted6 
X 
 
X 
 
 
 
 
 
 
 
 
 
Qualifying IWRET4,7 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
Training on self-
administration of study 
drug 
 
 
X 
 
 
 
 
 
 
 
 
 
Administer study drug8 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Patient diary recording 
dosing information9 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 43 of 79 
CONFIDENTIAL 
 
Screening and Run-
in Period 
Treatment Period 
Follow-
up 
Early 
Termination 
Visit 
Unscheduled 
Visit(s)28 
 
Screening1 
Run-in 
period1,2 
 
 
 
 
 
 
 
 
 
 
Study Procedure 
Visit 1 
Visit 2 
 
 
Baseline1,2 
Visit 3 
Ph 
Visit 
4 
Visit 
5 
Ph 
Visit 
6 
Ph 
Visit 
7 
Ph 
Visit 
8 
End of 
Treatment  
Visit 9 
End of 
Study 
Visit 10 
 
 
Week 
-8 to -4 
-4 to 0 
 
 
1 
2 
4 
6 
8 
10 
12 
14 
 
 
Day 
-56 to -28 
-27 to -1 
1 
15 
29 
43 
57 
71 
85 
99 
 
 
Window (day) 
±7 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±5 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
Accelerometry10 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
ACQ-5 
 
 
X 
 
 
 
 
 
X 
 
 
 
Patient diary to record 
removal of the 
accelerometer, nocturnal 
awakening due to asthma, 
physical activity11 
 
X 
 
 
 
 
 
X 
X 
 
 
 
AQLQ(S)12 
 
 
X 
 
 
 
 
 
X 
 
 
 
Patient Global Impression 
of Change (PGIC)13 
 
 
 
 
X 
 
 
 
X 
 
 
 
Patient Global Impression 
of Impact (PGII)14 
 
 
X 
 
X 
 
 
 
X 
 
 
 
CWRET4 
 
X15 
X16 
 
 
 
 
 
X17 
 
 
 
Spirometry (pre- and 
post-exercise)18  
 
 
X 
 
 
 
 
 
X 
 
 
 
Exercise serial IC 
 
 
X 
 
 
 
 
 
X 
 
 
 
Borg dyspnea scale19 
 
 
X 
 
 
 
 
 
X 
 
 
 
Borg leg fatigue scale19 
 
 
X 
 
 
 
 
 
X 
 
 
 
VO2 
 
 
X 
 
 
 
 
 
X 
 
 
 
Spirometry not associated 
with CPET20 
 
 
 
 
X 
 
 
 
X 
 
 
 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs21 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
 
Physical Examination22 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 44 of 79 
CONFIDENTIAL 
 
Screening and Run-
in Period 
Treatment Period 
Follow-
up 
Early 
Termination 
Visit 
Unscheduled 
Visit(s)28 
 
Screening1 
Run-in 
period1,2 
 
 
 
 
 
 
 
 
 
 
Study Procedure 
Visit 1 
Visit 2 
 
 
Baseline1,2 
Visit 3 
Ph 
Visit 
4 
Visit 
5 
Ph 
Visit 
6 
Ph 
Visit 
7 
Ph 
Visit 
8 
End of 
Treatment  
Visit 9 
End of 
Study 
Visit 10 
 
 
Week 
-8 to -4 
-4 to 0 
 
 
1 
2 
4 
6 
8 
10 
12 
14 
 
 
Day 
-56 to -28 
-27 to -1 
1 
15 
29 
43 
57 
71 
85 
99 
 
 
Window (day) 
±7 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±5 
 
 
Laboratory Testing 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
X 
 
 
 
 
 
 
X 
X 
 
Blood Chemistry 
X 
 
 
 
 
 
 
 
 
X 
X29 
 
Pregnancy Test (beta 
HCG)23 
Xser 
 
XUr 
 
XUr 
 
 
 
XUr 
XUr 
XUr 
 
Urinalysis  
X 
 
 
 
 
 
 
 
X 
 
X29 
 
Hepatitis and HIV 
Serology24 
X 
 
 
 
 
 
 
 
 
 
 
 
Tuberculosis testing: 
QuantiFERON gold 
testing, or PPD per local 
regulations25 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers and 
pharmacogenomics 
 
 
 
 
 
 
 
 
 
 
 
 
FeNO Measurement26 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Future biomarker research 
serum and plasma 
(optional) 
 
 
X 
 
 
 
 
 
X 
 
 
 
DNA27 (optional) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 45 of 79 
CONFIDENTIAL 
9.1.1. 
Footnotes for the Schedule of Events Table (Table 1) 
1. Prior to baseline, patients must be on a medium-to-high dose ICS and at least a second 
asthma controller agent (eg, LABA, LAMA, or LTRA) or maintenance OCS if applicable 
for at least 3 months with a stable dose for at least 4 weeks prior to the baseline visit.  A 
third controller is allowed and with the same stabilization requirements.   The screening 
period can be completed once a patient passes ALL screening assessments/procedures.  
The patient can then proceed to the run-in period ensuring that the asthma background 
medication stabilization of at least 4 weeks has been met prior to the baseline visit 
(visit 3).  
2. The run-in period (visit 2) may be completed and a patient can proceed to baseline once 
the following occurs: 
• Run-in CWRET achieved an exercise time between 3 to 8 minutes 
• Patient performs 1 week of accelerometry training followed by 2 consecutive weeks 
of accelerometry wear time.  During the entire 3 week period, the accelerometer must 
be worn continuously (24 hours/day, 7 days/week) on the patient’s wrist except 
during charging time, bathing, and any other water activities. 
• All other run-in assessments/procedures have been performed 
• Background asthma medication remains stable for at least 4 weeks (which can include 
the screening period) prior to the baseline visit (visit 3) 
3. The Asthma Control Questionnaire-5 (ACQ-5) will be performed prior to spirometry.  
* ACQ is a patient-reported outcome measure used to assess asthma symptom control 
among patients with asthma.  The 5-item version of the ACQ (ACQ-5) is composed of 
the 5 patient-reported items on awakening at night due to symptoms, awakening in the 
morning with symptoms, limitation of daily activities, shortness of breath, and wheezing. 
4. In addition to the centrally read screening ECG performed at visit 1 for qualification, a 
locally performed ECG must be done prior to every CPET and demonstrate no clinically 
significant abnormalities, as evaluated by the investigator, to be eligible to continue in the 
study. 
5. Patients are required to demonstrate FEV1 reversibility of at least 12% and 200 mL after 
the administration of 200 to 400 µg albuterol/salbutamol or levalbuterol/levosalbutamol 
(2 to 4 inhalations of albuterol/salbutamol or levalbuterol/levosalbutamol, or of a 
nebulized solution of albuterol/salbutamol or levalbuterol/levosalbutamol, if considered 
as a standard office practice) during the screening period to qualify.  Assessment may be 
performed up to a total of 2 times to qualify.  Patients may also qualify if there is 
documented evidence of bronchodilator reversibility or positive methacholine challenge 
test within 12 months prior to the screening visit. 
6. In-clinic spirometry - Patients must demonstrate a pre-bronchodilator FEV1 between 30% 
and 75% predicted at both the screening and baseline visits to qualify.  This assessment 
may be repeated once during the screening period and once at the baseline visit to qualify 
NOTE: Spirometry and all CPETs should ideally be conducted in the morning and at 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 46 of 79 
CONFIDENTIAL 
approximately the same time of day at each visit.  Spirometry will be done locally, and 
read centrally, according to European Respiratory Society (ERS)/American Thoracic 
Society (ATS) guidance.  Spirometry and all CPETs will be performed during a trough 
period of bronchodilators according to their duration of action, for example, withholding 
the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, 
withholding the last dose of ipratropium for at least 8 hours, withholding the last dose of 
LABA for at least 12 hours (ultra-long acting LABA like vilanterol should be withheld 
for at least 24 hours) and withholding the last dose of LAMA for 48 hours.  This will be 
verified before performing the measurements. 
 
If bronchodilators have not been withheld, the CPET or spirometry, as applicable, must 
be rescheduled to occur within the time window of the assessment per the schedule of 
events. 
7. The IWRET will be performed during the screening period to determine study eligibility.  
Exercise testing with continuous ECG, pulse oximetry and blood pressure monitoring 
will be performed during a trough period of bronchodilators according to their duration of 
action (see footnote #6).  This will be verified before performing the exercise test.  If the 
above has not occurred, the exercise test must be rescheduled to occur within the time 
window of the assessment per the schedule of events.  IWRET can be performed up to a 
total of 3 times during the screening period to determine patient eligibility.  
 
NOTE: Prior to performing the IWRET, the patient must meet all other eligibility criteria. 
8. Every 2 weeks (Q2W) study drug administrations must be separated by at least 11 days.  
Treatment can be administered Q2W in office at scheduled visits or at home (by patient, 
caregiver, or health care professional).  Patients/caregivers, if preferred, may choose to 
have injections administered in the clinic.  Due to the COVID-19 pandemic, study drug 
may be shipped from the clinical site to the patient's home if necessary. 
9. When study drug is administered outside of the clinic, the patient (or caregiver) will 
record administration in the paper patient diary.  He/she will return the study box kit at 
each subsequent in-clinic visit where drug accountability will be performed. 
10. At visit 2, patients will be trained on the proper use of and wear an accelerometer on 
his/her wrist for a 1-week period, in order to get acclimated to the device.  Patients will 
be instructed to wear the accelerometer continuously for 3 consecutive weeks (up until 
the baseline visit [visit 3]).  The first week will be the training period on accelerometer 
use.  The subsequent next 2 weeks will be to determine baseline pre-treatment daily 
physical activity.  The study site will utilize the phone call at visit 7 to remind patients to 
also wear the accelerometer continuously starting 2 weeks prior to the end of treatment 
visit (visit 9) (ie, from week 10 to week 12).  The accelerometer must be worn 
24 hours/day, 7 days/week on the patient’s wrist during both pre-treatment and end-of-
treatment wear periods except during charging time, bathing, and any other water 
activities. 
11. During the 2 consecutive weeks prior to baseline visit and the 2 consecutive weeks prior 
to week 12 visit, patients will record daily how much time spent bathing or swimming, 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 47 of 79 
CONFIDENTIAL 
total time charging the device, physical activity (eg, walking, moderate physical 
activities, and vigorous physical activities), and nocturnal awakenings due to asthma in 
the patient diary.  
12. The Asthma Quality of Life Questionnaire (AQLQ) will be performed prior to 
spirometry.*  The AQLQ comprises 32 items across 4 domains: symptoms (12 items), 
activity limitations (11 items), environmental stimuli (4 items), and emotional function 
(5 items).  
13. The Patient Global Impression of Change (PGIC) will be performed prior to spirometry.*  
PGIC is a single item patient-reported measure, which will assess patient’s impression 
about the change in their ability to carry out exercise since study treatment initiation. 
14. The Patient Global Impression of Impact (PGII) will be performed prior to spirometry.*  
The PGII is a single item patient-reported measure, to assess the patient’s impression of 
the impact of asthma on their ability to carry out exercise during the past week. 
 
*Patient questionnaires: If COVID-19 restrictions limit the availability of staff or the 
patient to have in-clinic visits, site staff should make every effort to conduct telephone 
interviews to complete these questionnaires.  Site staff should conduct the telephone 
interviews on the date of the scheduled site visit by following an interview guide 
provided by the sponsor.  Patient responses from the interviewer administered 
questionnaires will be captured by the site staff. 
15. Run-in CWRET at 80% of the previously determined individualized maximal work rate 
from the IWRET will be performed during run-in (visit 2) to familiarize patients with the 
test procedure and to determine work rate to meet the 3 to 8 minute exercise endurance 
time requirement.  Run-in CWRET may be repeated twice (up to total of 3 tests) during 
the run-in period to determine work rate that achieves the qualifying criteria for exercise 
duration.  ECG, pulse oximetry, and blood pressure monitoring are performed throughout 
the exercise test.  Exercise tests will be performed during a trough period of 
bronchodilators according to their duration of action (see footnote #6).  
16. The baseline CWRET will be performed utilizing the work rate established at the 
qualifying run-in CWRET.  The same constant work rate established for an individual 
patient at the qualifying run-in CWRET must also be applied at the baseline and end of 
treatment visit. 
17. Patients who require systemic corticosteroids or an increase in systemic corticosteroid 
dose for those receiving maintenance OCS for the treatment of an asthma exacerbation 
within the last 4 weeks of the double-blind treatment period will not perform a CWRET 
at week 12 (visit 9) but will have all other efficacy procedures performed (ie, 
accelerometry and spirometry without CWRET). 
18. Spirometry will be performed within 15 minutes prior to exercise and at minutes 5±1, 
10±1, and 20±1 post-exercise (CWRET) at baseline (visit 3) and end of study treatment 
(visit 9).  Pre-exercise spirometry will be conducted prior to the patient sitting on the 
cycle ergometer and post-exercise spirometry once the patient has dismounted from the 
cycle ergometer.  Details of the pre- and post-exercise spirometry procedures will be 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 48 of 79 
CONFIDENTIAL 
detailed in the eRT user manual.  The same in-clinic spirometry equipment will be used 
throughout the study.  
19. Borg dyspnea and Borg leg fatigue will be assessed by the patient pre-exercise, every 
2 minutes during exercise, and at peak exercise. 
20. At visit 5 (week 4) when exercise testing is not performed, spirometry will be performed 
to assess FEV1 and FVC.  At visit 9, in the event that CWRET is not performed due to an 
exacerbation, spirometry will still be performed at the investigator’s discretion. 
21. Vital signs, including sitting systolic and diastolic blood pressure (mm Hg), pulse rate 
(beats per minute), body temperature (°C), and respiratory rate will be measured at 
screening, and predose at baseline and at every subsequent scheduled on-site visit.  
Height (cm) will be measured at screening (visit 1) only.  Body weight (kg) will be 
measured at screening (visit 1) and at end of treatment and end of study visits. 
22. Complete physical examinations will include skin, nasal cavities, eyes, ears, respiratory, 
cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal systems. 
23. Beta human chorionic gonadotropin (HCG) serum (Ser) pregnancy test at visit 1 and 
urine dipstick (Ur) pregnancy tests at other visits.  A negative result must be obtained at 
visits 1 and 3 prior to randomization. 
24. Clinical laboratory testing at screening visit 1 will include hepatitis screen covering 
hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B 
core antibody (HBcAb), hepatitis C virus antibodies (HCV Ab), and human 
immunodeficiency virus (HIV) screen (anti-HIV-1 and HIV-2 antibodies).  In case of 
results showing HBsAg (negative), and HBcAb (positive), an HBV DNA testing will be 
performed prior to randomization to rule out a false positivity if the investigator believes 
the patient’s test 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 has a false positive result. 
25. Tuberculosis testing (QuantiFERON gold testing or purified protein derivative [PPD]) 
will be performed on a country-by-country basis according to local guidelines if required 
by regulatory authorities or ethic committees. 
26. Fractional exhaled nitric oxide (FeNO) assessment should be conducted prior to exercise 
testing, prior to spirometry, and after administering ACQ-5, AQLQ, and PGII 
questionnaires following a fast of ≥1 hour.  Ensure the FeNO device is ready to use.  
After completing the exercise test the patient should sit comfortably in a chair to prepare 
for the post-exercise FeNO and serial spirometry measurements. 
 
NOTE: When the patient is ready to perform the post-exercise FeNO assessment, the 
study staff will start a stopwatch and record the starting time.  This will start the timer for 
the post-exercise serial spirometry measurements.  The post-exercise FeNO 
measurements should be started as soon as the time has been entered. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 49 of 79 
CONFIDENTIAL 
27. Optional DNA sample is to be collected prior to study drug administration at baseline, 
but can be collected at a later study visit. 
28. For unscheduled visit, besides the required recording of AEs and concomitant 
medications/procedures, other assessments may be performed at the discretion of the 
investigator and based on patients’ condition (eg, laboratory test monitoring an AE). 
29. Optional assessment at the early termination visit. 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (week 12) will be 
asked to return to the clinic once for an early termination visit consisting of the end of study 
assessments described in Table 1. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
Patient-reported outcome scales should be completed by the patient, independently from their 
physician, the study nurse or any other medical personnel and without any help from friends or 
relatives.  The scales should be completed by the patients before the consultation and/or clinical 
tests, in a quiet place. 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visits  
The following assessments are performed only at the screening, run-in, or baseline visits. 
Procedures Performed Only at the Screening Visit 
After signing informed consent, the following procedures will be performed for the sole purpose 
of determining study eligibility or characterizing the baseline population:   
• Medical/surgical history 
• Demographics 
• Bronchodilator reversibility testing (see description in Section 9.2.2.5) or documented 
evidence of bronchodilator reversibility or positive methacholine challenge test 
within 12 months of the screening visit  
• Qualifying IWRET (may be performed up to total of 3 times) 
• Qualifying ECG with central reading 
• Height 
• Beta HCG serum pregnancy test 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 50 of 79 
CONFIDENTIAL 
• TB testing: QuantiFERON gold testing, or purified protein derivative (PPD) as 
required.  Tuberculosis testing will be performed on a country-by-country basis 
according to local guidelines if required by regulatory authorities or ethic committees. 
• Hepatitis serology:  HBsAg, HBsAb, HBcAb, and HCV Ab.  In case of results 
showing HBsAg (negative), and HBcAb (positive), an HBV DNA testing will be 
performed prior to randomization to rule out a false positivity if the investigator 
believes the patient’s test 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. 
• Human Immunodeficiency Virus (HIV) screen (including anti-HIV-1 and HIV-2 
antibodies) 
• Blood eosinophil count for patients not on maintenance OCS at the screening visit 
Procedures Performed Only at the Baseline Visit 
• Randomization 
• Training on self-administration of study drug 
• DNA sample (optional) (see Section 9.2.5) 
Procedures Performed Only at the Screening and Baseline Visits 
• Qualifying % predicted FEV1 
• Qualifying ACQ-5 
Procedures Performed Only at the Screening, Run-In, and Baseline Visits 
• Review of inclusion/exclusion criteria 
9.2.2. 
Efficacy Procedures 
All procedures, eg, ACQ-5, AQLQ, PGII, PGIC, and FeNO, must be performed prior to the CPET 
and all patient-reported outcome assessments (eg, ACQ-5, AQLQ, etc) must be performed prior 
to spirometry in the order listed and specified in the schedule of events.  FeNO measurement will 
also be done pre- and post-exercise as detailed in the eRT user manual.  Every effort should be 
made to have patients perform study procedures in the morning.  In the event this is not possible, 
procedures can be performed in the afternoon.  Regardless, procedures must be performed at 
approximately the same time of day at each study visit, ie, if the baseline testing is performed in 
the morning, all subsequent study procedures must be performed in the morning. 
9.2.2.1. 
Accelerometers 
Accelerometers are wearable sensors which objectively record and measure physical activity and 
energy expenditure in a “free living” environment, reflecting activities of daily living 
(Attal, 2015) (Kim, 2012).  Accelerometers can record steps walked, energy expenditure, and time 
spent performing physical activities of various intensity based on energy expenditure.   
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 51 of 79 
CONFIDENTIAL 
Patients will be instructed to wear an accelerometer on their wrist day and night during the 3 weeks 
prior to the baseline visit and for the 2 weeks prior to the end of treatment visit (24 hours per day, 
7 days/week [except during charging time, bathing, and any other water activities]) per the 
schedule in Table 1.  The following data will be obtained from the accelerometer recording: 
• Number of steps walked per day 
• Total Energy Expenditure (metabolic equivalents [METs]) 
• Mean duration of moderate-to-vigorous physical activity (defined as ≥3 METs) 
Accelerometers will be provided to sites and appropriate training will be provided to the 
investigator regarding patient use. 
Patients will complete a diary to record removal of the accelerometer, nocturnal awakenings due 
to asthma and physical activities. 
9.2.2.2. 
Patient-Reported Outcomes 
Patient-reported outcome assessments must occur prior to other visit procedures. 
Asthma Control Questionnaire, 5-question version (ACQ-5) 
The ACQ-5 is a patient-reported outcome measure used to assess asthma symptom control among 
patients with asthma.  The instrument has 5 questions that assess the most common asthma 
symptoms:  1. frequency awoken by asthma during the night, 2. severity of asthma symptoms in 
the morning, 3. limitation of daily activities due to asthma, 4. shortness of breath due to asthma, 
and 5. wheeze.  Patients are asked to recall how their asthma has been during the previous week 
and to respond to the symptom questions on a 7-point scale (0=no impairment, 6=maximum 
impairment).  The ACQ-5 score is the mean score of the 5 questions and, therefore, between 
0 (totally controlled) and 6 (severely uncontrolled).  A higher score indicates lower asthma control.  
A score below 1.5 reflects adequately controlled asthma and a score above 1.5 reflects inadequately 
controlled asthma.  On the 7-point scale of the ACQ-5, a change or difference in score of 0.5 is the 
smallest change that can be considered clinically important, corresponding to the Minimal 
Clinically Important Difference (MCID) defined by the developer. 
Measurement properties such as reliability and ability to detect change have been documented in 
the literature (Juniper, 2005). 
ACQ-5 will be completed prior to spirometry during clinic visits per the schedule in Table 1. 
Asthma Quality of Life Questionnaire with Standardized Activities (Self-Administered) 
[AQLQ(S)] 
The AQLQ(S) is designed as a self-administered patient-reported disease-specific health-related 
quality of life instrument that measures both physical and emotional impact of asthma in adults 
and adolescents ≥12 years of age.  The instrument is comprised of 32 items, each rated on a 7-
point Likert scales from 1 to 7.  The AQLQ(S) has 4 domains.  The domains and the number of 
items in each domain are as follows: 
• Symptoms (12 items) 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 52 of 79 
CONFIDENTIAL 
• Activity limitation (11 items) 
• Emotional function (5 items) 
• Environmental stimuli (4 items) 
A global score is calculated ranging from 1 to 7 and a score by domain.  Higher scores indicate 
better quality of life. 
The instrument has been used in many clinical trials, and it has been shown to be reliable, valid 
(patient interviews), and sensitive to change.  The MCID for AQLQ(S) is 0.5 (Juniper, 1994). 
Patient Global Impression of Change (PGIC) 
The Patient Global Impression of Change (PGIC) is a patient-reported measure that assesses 
patients’ impression about the change in their ability to exercise since study treatment initiation.  
Patients will be asked to recall the change in their ability to exercise since the baseline visit.  The 
PGIC will be administered at site visits per the schedule in Table 1. 
Patient Global Impression of Impact (PGII) 
The Patient Global Impression of Impact (PGII) is a patient-reported measure that assesses 
patients’ impression about the impact of asthma on their ability to exercise during the past week.  
The PGII will be administered at baseline and at site visits per the schedule in Table 1. 
9.2.2.3. 
Fractional Exhaled Nitric Oxide (FeNO) Level 
Measurement of FeNO level in asthmatic patients is used as a marker of airway inflammation.  
FeNO levels will be assessed in accordance with ATS/ERS guidelines using the standardized nitric 
oxide measuring equipment (eg, Circassia NIOX VERO®).  Patients will be instructed to refrain 
from eating and drinking for at least 1 hour prior to FeNO measurements.  FeNO measurements 
should be made prior to any spirometry.  During the study, patients will be required to undergo 
FeNO measurement at study visits per the schedule in Table 1.  Sites will be provided with 
equipment and instructions regarding FeNO measurement. 
9.2.2.4. 
Cardiopulmonary Exercise Testing (CPET) 
Tests will be performed on an electromagnetically-braked cycle ergometer in an exercise 
physiology laboratory overseen by a trained pulmonologist or medical doctor designee.  A medical 
doctor must be present in the room in which the initial IWRET is conducted and readily available 
for medical intervention, at all subsequent exercise tests.  Resuscitation equipment must be 
immediately available in the PFT lab where the exercise testing is performed.  Patients will 
exercise until exhaustion breathing through a mouthpiece with noseclip in place or while wearing 
a mask.  
A CPET is a medically well-accepted and standardized test that has been utilized to assess degree 
of exercise impairment in a variety of pulmonary diseases, including pulmonary arterial 
hypertension, COPD, and interstitial lung diseases, as well as in asthma (Puente-Maestu, 2016).  
It is frequently performed clinically in specialized centers with proper exercise equipment and 
training.  For safety purposes, physiologic responses are assessed repeatedly during CPET, 
including ECG parameters, oxygen saturation, blood pressure, pulmonary ventilation, oxygen 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 53 of 79 
CONFIDENTIAL 
uptake, and respiratory rate.  Heart rate and blood pressure must be measured just prior to all 
CPETs with the patient seated on the cycle ergometer (eg, at rest).  Patients must have a heart rate 
<100 bpm and a systolic blood pressure ≤180 mm Hg and diastolic blood pressure ≤95 mm Hg 
measured just prior to performing exercise. 
CPET testing performed according to standardized procedures can employ either an incremental 
or constant work rate protocol.  A maximal incremental test involves exercise to exhaustion under 
conditions of increasing work rate.  A constant work rate protocol in this study is performed at 
80% of the maximal work rate attained from the incremental maximal test and involves exercising 
until exhaustion.  A constant work rate protocol is chosen for this study as opposed to a maximal 
incremental exercise test, as the former has been shown to be more sensitive to discriminate change 
in exercise capacity.  Also, use of a constant work rate test allows measurement of a well-
understood variable: cycling endurance time.  To minimize variability in measurements, CPET 
will be done using a standardized CPET protocol, with site quality control and only at sites 
proficient in CPET testing (American Thoracic Society, 2003).  
Relative and absolute contraindications to CPET are listed in Table 2 and the CPET laboratory 
manual distributed to each study site. 
Table 2: 
Absolute and Relative Contraindications to CPET 
Absolute 
Relative 
• 
Acute myocardial infarction (3 to 5 days) 
• 
Unstable angina 
• 
Uncontrolled arrhythmias causing symptoms 
or hemodynamic compromise 
• 
Syncope 
• 
Active endocarditis 
• 
Acute myocarditis or pericarditis 
• 
Symptomatic severe aortic stenosis 
• 
Uncontrolled heart failure 
• 
Acute pulmonary embolus or pulmonary 
infarction 
• 
Thrombosis of lower extremities 
• 
Suspected dissecting aneurysm 
• 
Acute asthma exacerbation 
• 
Pulmonary edema 
• 
Room air oxygen desaturation at rest <85%* 
• 
Respiratory failure 
• 
Acute noncardiopulmonary disorder that may 
affect exercise performance or be aggravated 
by exercise (ie, infection, renal failure, 
thyrotoxicosis) 
• 
Mental impairment leading to inability to 
cooperate 
• 
Left main coronary stenosis or its equivalent 
• 
Moderate stenotic valvular heart disease 
• 
Severe untreated arterial hypertension at rest 
(>200 mm Hg systolic, >120 mm Hg 
diastolic) 
• 
Tachyarrhythmias or bradyarrhythmias 
• 
High-degree atrioventricular block 
• 
Hypertrophic cardiomyopathy 
• 
Significant pulmonary hypertension 
• 
Advanced or complicated pregnancy 
• 
Electrolyte abnormalities 
• 
Orthopedic impairment that compromises 
exercise performance 
*Exercise patient with supplemental O2. 
Source:  Adapted from Amj J Respir Crit Care Med 2003;167:211-277 (American Thoracic Society, 2003). 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 54 of 79 
CONFIDENTIAL 
Qualifying Maximal Incremental Work Rate Exercise Test (IWRET) 
Qualifying IWRET (American Thoracic Society, 2003) will be performed only at screening 
(see Table 1) to determine the peak work rate to use in calculating 80% of maximal work rate for 
the CWRET.  The procedure is as follows: 
Medical history and screening ECG are performed directly prior to testing to ensure patients do 
not have a contraindication to exercise testing.  Patients deemed eligible, are familiarized with the 
bicycle (stationary electromagnetically-braked cycle ergometer).  Subsequently, patients will have 
3 minutes of rest on the cycle, 3 minutes of unloaded pedaling, and then the work rate will be 
increased continuously under computer control in ramp-like fashion (ramp protocol) until the 
patient reaches volitional exhaustion or the supervising clinician terminates the test for safety 
reasons.  It is important that prior to exercise the patient is informed that the test requires exercise 
until exhaustion.  The individual supervising the exercise test should provide verbal 
encouragement to the patient during the test to help ensure maximal patient effort.   
The peak work rate is that at which the patient reaches volitional exhaustion, usually marked by 
inability to maintain pedaling cadence >50 rpm.  The work rate should be set to increase at either 
10, 15, 20, or 25 W/min depending on the investigator’s assessment of the patient’s ability to 
exercise, with the goal of having the patient exercise between 4 and 16 minutes.  Patients must 
develop dynamic hyperinflation defined as more than 100 mL decrease in IC from the pre-exercise 
value.  If the exercise time is outside of the 4 to 16 minute window, the test may be repeated with 
a change in the work rate from that previously used by ±10% or 5 W/min, whichever is greater to 
achieve an exercise duration between 4 and 16 minutes.  The IWRET can be performed up to a 
total of 3 times during the screening period to determine study eligibility.  A repeated test must be 
performed at least 2 hours after the previous one.  A patient who exercises <4 or >16 minutes or 
does not have a decrease in IC >100 ml during the third qualifying IWRET will be considered a 
screen failure.   
Constant Work Rate Exercise Testing (CWRET) 
CWRET will be performed on an electromagnetically-braked cycle ergometer in an exercise 
physiology laboratory overseen by a trained pulmonologist or medical doctor designee.  While 
sitting on the cycle ergometer, patients will have 3 minutes of rest, 3 minutes of unloaded pedaling, 
and then an immediate increase in work rate to approximately 80% of the previously determined 
individualized peak work rate value from the incremental test.  Exercise will continue until 
volitional exhaustion.  It is important that prior to exercise the patient is informed that the test 
requires exercise until exhaustion.  The individual supervising the exercise test should provide 
strong verbal encouragement to the patient during the test to obtain maximal patient effort.   
If at the run-in CWRET, the patient’s exercise duration is not within the range of 3 to 8 minutes, 
the test can be repeated 2 more times with the wattage changed by ±10% or 5 W/min, whichever 
is greater.  If CWRET needs to be repeated, the repeat test must be performed at least 2 hours after 
the previous one.  The exercise endurance time will be collected at time points per the schedule of 
events in Table 1.  
During the CWRET, other measurements including serial IC, perception of dyspnea measured by 
the Borg Dyspnea Scale, perception of leg fatigue measured by the Borg Leg Fatigue Scale, and 
VO2 will be obtained. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 55 of 79 
CONFIDENTIAL 
Note: The same exercise work rate applied at the qualifying run-in CWRET test that achieves an 
exercise time between 3 and 8 minutes must also be applied at the baseline and end of treatment 
CWRET. 
Borg Dyspnea and Leg Fatigue Scales  
Borg Dyspnea and Leg Fatigue Scales are validated scales to assess perceived symptoms of 
dyspnea and leg fatigue respectively when undergoing strenuous exercise (Borg, 2010) 
(Borg, 1982).  The scales are from 0 (nothing at all) to 10 (very, very strong).  Patients will report 
their Borg dyspnea and Borg leg fatigue scores at rest, every 2 minutes during exercise and at peak 
exercise.   
The Borg Dyspnea and Leg Fatigue Scales will be performed at time points per the schedule in 
Table 1. 
Details of all exercise-related testing procedures will be provided in the exercise testing procedure 
manual. 
9.2.2.5. 
Spirometry 
A spirometer that meets the ATS/ERS recommendations will be used.  Spirometry will be 
performed locally, and read centrally, in accordance with the ATS/ERS guidelines (Miller, 2005).  
Screening Spirometry to Determine FEV1% Predicted and Bronchodilator Reversibility 
Up to 2 spirometry attempts may be made during the screening period until the baseline visit to 
meet the qualifying criteria for FEV1 % predicted and establish bronchodilator reversibility.  Note: 
patients may qualify if they have documented evidence of bronchodilator reversibility or a positive 
methacholine challenge test within 12 months of the screening visit.  Spirometry will be done 
locally at the site, and read centrally, according to ATS/ERS guidelines.  Spirometry at all visits 
will be performed during a trough period of bronchodilators according to their duration of action, 
for example, withholding the last dose of salbutamol/albuterol or levosalbutamol/levalbuterol for 
at least 6 hours, withholding the last dose of ipratropium for at least 8 hours, withholding the last 
dose of LABA for at least 12 hours (ultra-long acting LABA like vilanterol should be withheld for 
at least 24 hours) and withholding the last dose of LAMA for 48 hours.  This will be verified by 
the principal investigator or designee before performing the measurements.   
Pre- and Post-Exercise (CWRET) FEV1 
For pre-exercise FEV1, spirometry will be performed during a trough period of bronchodilators 
according to their duration of action, for example, withholding the last dose of salbutamol/albuterol 
or levosalbutamol/levalbuterol for at least 6 hours, withholding the last dose of ipratropium for at 
least 8 hours, withholding the last dose of LABA for at least 12 hours (ultra-long acting LABA 
like vilanterol should be withheld for at least 24 hours) and withholding the last dose of LAMA 
for 48 hours.  This will be verified by the principal investigator or designee before performing the 
measurements.   
Pre-exercise FEV1 will be assessed within 15 minutes prior to the start of the exercise testing and 
post-exercise FEV1 will be performed at minutes 5±1, 10±1, and 20±1 post-exercise at visits per 
the schedule in Table 1. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 56 of 79 
CONFIDENTIAL 
Pre- and post-exercise FVC will also be assessed.  
Details of the spirometry procedures will be provided in the eRT user manual. 
Patients who require systemic corticosteroids or an increase in systemic corticosteroid dose for 
those receiving maintenance OCS for the treatment of an asthma exacerbation within the last 
4 weeks of the double-blind treatment period will not undergo a CWRET at week 12 (visit 9) but 
will have FEV1 and FVC assessed by spirometry at rest. 
The same spirometer and standard spirometric techniques, including calibration, will be used to 
perform spirometry at all visits, at approximately the same time of day and, whenever possible, 
the same person should perform the measurements. 
The spirometer must be calibrated following the principles of the ATS/ERS guidelines every day 
that a study patient is seen and spirometry is carried out.  The calibration records should be kept 
in a reviewable log.  It is preferred that the calibration equipment (ie, 3-liter syringe) that is used 
to calibrate the spirometer be subjected to a validated calibration according to the manufacturer’s 
specifications. 
Spirometry Not Associated with Exercise (at Visit 5)  
At week 4 (visit 5) when exercise testing is not performed, spirometry will be performed to assess 
FEV1 and FVC.  At visit 9, in the event that CWRET is not performed due to an exacerbation, 
spirometry will still be performed at the investigator’s discretion. 
9.2.3. 
 Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including body temperature (°C), sitting systolic and diastolic blood pressure 
(mm Hg), pulse rate (beats per minute), and respiratory rate, will be collected predose at time 
points according to Table 1.   
Body weight and height will be measured at time points according to Table 1. 
9.2.3.2. 
Physical Examination 
A thorough and complete physical examination, including skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal 
systems, will be performed at time points according to Table 1.  Care should be taken to examine 
and assess any abnormalities that may be present, as indicated by the patient’s medical history. 
9.2.3.3. 
Electrocardiogram 
An ECG will be performed just prior to CPET to ensure that the patient does not have a 
contraindication to CPET (see Section 9.2.2.4).  An ECG will be performed throughout the 
exercise tests as indicated in the schedule of events (Table 1).  Heart rate will be recorded from 
the ventricular rate and the PR, QRS, and QT (identify QTcB or QTcF) intervals will be recorded.  
The ECG strips or reports will be retained with the source documentation, and the results will be 
documented in the electronic case report form (eCRF). 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 57 of 79 
CONFIDENTIAL 
The results of the qualifying ECG will be interpreted by a central reading center.  All other ECGs 
will be read locally.  Instructions for performing the qualifying ECG and transmitting ECG data 
are provided in the eRT user manual.  
9.2.3.4. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  Samples will be collected predose at time points listed in Table 1.  Detailed instructions 
for blood sample collection are in the laboratory manual provided to study sites.  Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen 
Low-density lipoprotein (LDL) 
Carbon dioxide 
Aspartate aminotransferase (AST) 
High-density lipoprotein (HDL) 
Calcium 
Alanine aminotransferase (ALT) 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
Creatine phosphokinase (CPK); 
CPK isoenzymes will be measured 
when CPK >5 × ULN 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices  
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
 
Other Laboratory Tests 
Pregnancy testing will be performed for all women of childbearing potential.  Serum or urine 
pregnancy testing will be performed at time points listed in Table 1. 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 58 of 79 
CONFIDENTIAL 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality.  When necessary, appropriate ancillary investigations 
should be initiated.  If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.1.1. 
9.2.4. 
Future Biomedical Research (Optional) 
Patients who agree to participate in the future biomedical research (FBR) sub-study will be 
required to consent to this optional sub-study before samples are banked for FBR.  In these patients, 
samples for FBR will be collected per Table 1.  Residual biomarker samples for study-related 
research, as well as unused PK and ADA samples, will be stored for up to 15 years after the final 
date of the database lock (or for a shorter time period if required per regional laws and regulations).  
The samples may be utilized for FBR that may or may not be directly related to the study, including 
being used as reference samples and assay development or validation.  The results of these future 
biomedical research analyses will not be presented in the clinical study report (CSR). 
9.2.5. 
Pharmacogenomic Analysis (Optional) 
Patients who agree to participate in the genomics sub-study will be required to consent to this 
optional sub-study before collection of the samples.  Whole blood samples for DNA extraction 
should be collected on day 1/baseline, but can be collected at a later study visit.  DNA samples 
will be collected for pharmacogenomics analyses to understand the genetic determinants of 
efficacy and safety associated with the treatments in this study and the molecular basis of asthma 
and other related inflammatory diseases.  These samples will be single-coded as defined by the 
International Council for Harmonisation (ICH) guideline E15.  Samples will be stored for up to 
15 years after the final date of the database lock (or for a shorter time period if required per regional 
laws and regulations).  If there are specific site or country requirements involving the 
pharmacogenomic analyses which the sponsor is unable to comply with, samples will not be 
collected at those sites.   
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to dupilumab, other asthma clinical outcome measures and possible AEs.  In 
addition, associations between genomic variants and prognosis or progression of asthma as well 
as related allergic/atopic/type 2 inflammation 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, target pathway, or asthma and related diseases. 
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions.  Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed.  The list 
of methods may be expanded to include novel methodology that may be developed during the 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 59 of 79 
CONFIDENTIAL 
course of this study or sample storage period.  Results from the genomic analyses will not be 
reported in the CSR. 
10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period, from the time of signing the informed consent form (ICF) to the end of study.  Medical 
conditions that existed or were diagnosed prior to the signing of the Informed Consent will be 
recorded as part of medical history.  Abnormal laboratory values and vital signs observed at the 
time of Informed Consent should also be recorded as medical history.  Any subsequent worsening 
(ie, any clinically significant change in frequency and/or intensity) of a pre-existing condition that 
is temporally associated with the use of the study drug should also be recorded as an AE. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient.  Adverse events may be directly observed, reported spontaneously by the patient, or by 
questioning the patient at each study visit.  Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms.  The Investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2.  
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature.  The investigator should follow up on serious adverse events (SAEs) 
and adverse events of special interest [AESIs]) until they have resolved or are considered clinically 
stable; AEs should be followed until they are resolved or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported 
as AEs if they are symptomatic, lead to study drug discontinuation, dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the serious adverse event (diagnosis or symptom requiring hospitalization).  A procedure is not 
an AE or SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the Informed Consent Form) procedures, treatments requiring hospitalization for pre-
existing conditions that do not worsen in severity, and admission for palliative or social care should 
not be reported as SAEs (see Section 10.2 for Definitions).   
For deaths, the underlying or immediate cause of death should always be reported as an SAE.   
Any SAE that may occur subsequent to the reporting period (end of the follow-up period) that the 
investigator assesses as related to study drug should also be reported. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 60 of 79 
CONFIDENTIAL 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.   
10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable: blinded) study drug.  For SAEs and 
AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE case report form (CRF).  Specific or 
estimated dates of event onset, treatment, and resolution should be included, when available.  
Medical history, concomitant medications, and laboratory data that are relevant to the event should 
also be summarized in the narrative.  For fatal events, the narrative should state whether an autopsy 
was or will be performed and include the results if available.  Information not available at the time 
of the initial report must be documented in a follow-up report.  Source documents (including 
hospital or medical records, diagnostic reports, etc) will be summarized in the narrative on the AE 
CRF and retained at the study center and available upon request.   
Urgent safety queries must be followed up and addressed promptly.  Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Adverse Events of Special Interest (AESI; serious and nonserious):  Adverse events 
of special interest for this study include the following:   
o Anaphylactic reactions 
o Systemic or severe hypersensitivity reactions  
o Severe injection site reactions lasting for >24 hours 
o Helminthic infections  
o Any severe type of conjunctivitis or blepharitis  
o Keratitis 
o Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
• Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility 
of the investigator to report to the sponsor (or designee), within 24 hours of 
identification, any pregnancy occurring in a female , during the study or within 
12 weeks of the last dose of study drug.  Any complication of pregnancy affecting a 
female study patient and/or fetus and/or newborn that meets the SAE criteria must be 
reported as an SAE.  Outcome for all pregnancies should be reported to the sponsor. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 61 of 79 
CONFIDENTIAL 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug 
(ICH Harmonized Tripartite Guideline: Clinical Safety Data Management: Definitions and 
Standards For Expedited Reporting (E2A), 1994). 
10.2.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger) 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  In-
patient hospitalization is defined as hospital admission (any duration) or an 
emergency room visit for longer than 24 hours.  Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event, or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events.  
10.2.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
interest specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate.  Such an event might warrant 
further investigation in order to characterize and understand it.   
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 62 of 79 
CONFIDENTIAL 
10.2.4. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient normal functioning level.  It may 
be an annoyance.  Prescription drugs are not ordinarily needed for relief of symptoms, but may be 
given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health.  It is 
uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient's health.  Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of injection site reactions (ISRs) will be graded according to the following scale 
(semi-colon indicates “or” within description of grade): 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires an 
emergency room (ER) visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.5. 
Causality 
The investigator must provide causality assessment as whether or not there is a reasonable 
possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical 
judgment, and the following definitions.  The causality assessment must be made based on the 
available information and can be updated as new information becomes available. 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset vs time drug was administered 
• Nature of the reactions: immediate vs. long term 
• Clinical and pathological features of the events  
• Existing information about the drug & same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 63 of 79 
CONFIDENTIAL 
• Response to rechallenge (re-introduction of the drug) or dose increase, when 
applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
(eg, disease under study, concurrent diseases, concomitant medications), or other 
external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study or its class of drugs or is 
predicted by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol specified 
procedure and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol specified 
procedure or can be reasonably explained by the nature of the reaction, patient’s 
clinical state (eg, disease under study, concurrent diseases, and concomitant 
medications) or other external factors. 
10.3. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance; Risk Management; Biostatistics and Data Management).  
Safety monitoring will be performed on an ongoing basis and periodic cumulative aggregate basis. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 64 of 79 
CONFIDENTIAL 
10.4. 
Notifying Health Authorities, Institutional Review Board /Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, Independent Ethics 
Committees (IECs) / Institutional Review Boards (IRBs), and the participating investigators of any 
SUSARs (Suspected Unexpected Serious Adverse Reactions) occurring in other study centers or 
other studies of the active study drug (dupilumab), as appropriate per local reporting requirements.  
In addition, the sponsor and/or CRO will comply with any additional local safety reporting 
requirements.  All notifications to investigators will contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the Institutional Review Board (IRB)/Ethics Committee (EC) unless 
delegated to the sponsor. 
Event expectedness for study drug (dupilumab) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure that is effective for expedited safety reporting. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the Clinical Study Report  to health authorities and IECs/IRB as appropriate. 
11. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP will 
be revised prior to the end of the study to accommodate amendments to the clinical study protocol 
and to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses.  The final SAP will be issued before the database lock. 
Endpoints are listed in Section 4.  Analysis variables are listed in Section 5.  
Data collected through the implementation of CRFs regarding the impact of the COVID-19 
pandemic on patients will be summarized (eg, discontinuation due to COVID-19).  Any additional 
analyses and methods required to investigate the impact of COVID-19 on the efficacy (eg, missing 
data due to COVID-19) and safety evaluation will be specified in the SAP. 
11.1. 
Statistical Hypothesis 
The following null hypothesis and alternative will be tested: 
• Null hypothesis: The mean change from baseline in the constant work-rate exercise 
endurance time at week 12 is the same between dupilumab and placebo. 
• Alternative hypothesis: The mean change from baseline in the constant work rate 
exercise endurance time at week 12 differs between dupilumab and placebo. 
11.2. 
Justification of Sample Size 
The planned sample size of approximately 70 patients per treatment group will provide >85% 
power to detect a 105-second mean change in constant work rate exercise endurance time, with a 
standard deviation of 190 seconds, 2-sided α = 5%, and 10% drop out rate. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 65 of 79 
CONFIDENTIAL 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Set 
The full analysis set (FAS) includes all randomized patients.  It will be based on the treatment 
allocated by the IVRS/IWRS at randomization (as randomized).  All efficacy endpoints will be 
analyzed using the FAS. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized patients who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, first quartile (Q1), median, 
third quartile (Q3), minimum, and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.   
Baseline Definitions: 
Baseline for singular-value assessments, such as measurements from the CWRET, FEV1 and FVC 
from spirometry, will be the latest valid measurement taken prior to the first administration of 
study drug. 
Baseline for the 14-day average values of measurements from accelerometry is defined as the 
average of the non-missing values during the 14 days prior to the first administration of study drug. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 66 of 79 
CONFIDENTIAL 
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The primary endpoint of change from baseline in constant work rate exercise endurance time at 
week 12 will be analyzed using an analysis of covariance (ANCOVA) model for the FAS 
population.  The ANCOVA model will include terms for treatment group, randomization 
stratification factors and the baseline value for the constant work rate exercise endurance time. 
The intercurrent events handling strategy for systemic corticosteroid use for an asthma 
exacerbation or an increase in systemic corticosteroids during last 4-week of the treatment period 
and for treatment discontinuation is specified in Table 3 (Primary Estimands).  The imputation 
method for missing data based on the reasons for study discontinuation is defined below:  
• Missing data due to: 
− AE or lack of efficacy will be imputed by baseline observation carried forward 
(BOCF).  
− Other reasons will be imputed using multiple imputation (MI) rules under a 
missing at random assumption.  A detailed imputation model will be specified in 
the SAP.  
The primary estimands of interest for the primary endpoint, definitions of intercurrent events and 
corresponding strategies, and missing data handling approaches are provided in Table 3: 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 67 of 79 
CONFIDENTIAL 
Table 3: 
Primary Estimands 
 
Estimands 
Endpoint 
category 
Endpoints 
Population Intercurrent event(s) handling strategy and missing data 
handling 
Population-level 
summary/Analysis 
method 
Primary 
(Continuous) 
Change from 
baseline to 
week 12 in 
constant work 
rate exercise 
endurance 
time 
 
FAS  
The intercurrent events will be handled as follows: 
 
• Initiation of systemic corticosteroids for the treatment 
of an asthma exacerbation or increase in systemic 
corticosteroid dose for those receiving maintenance 
OCS, within the last 4 weeks of the double-blind 
treatment period:  Constant work rate exercise 
endurance time for each patient at week 12 will be 
assigned by his/her baseline values of constant work 
rate exercise endurance time (Hypothetical strategy) 
 
• Asthma exacerbation prior to week 8 of the double-blind 
treatment period requiring systemic corticosteroids or an 
increase in systemic corticosteroid dose for those 
receiving maintenance OCS: Data collected after the 
intercurrent event will be included in the analyses 
(Treatment policy strategy). 
 
• Initiation of prohibited medications: Data collected after 
the intercurrent event will be included in the analyses 
(Treatment policy strategy). 
 
 
• Treatment discontinuation: Data collected after the 
intercurrent event will be included in the analyses 
(Treatment policy strategy). 
 
Missing data imputation rules: 
• BOCF will be used to impute the missing values for 
discontinuation of the study either due to AE or lack of 
efficacy. 
 
• Missing data due to any other reason including COVID-
19 will be imputed using multiple imputation (MI) 
Mean change from 
baseline/The ANCOVA 
model with treatment 
group, randomization 
stratification factors and 
the baseline value for the 
constant work rate 
exercise endurance time 
as covariates. 
Subgroup analysis may be performed for age, sex, weight, baseline FEV1, baseline constant work 
rate endurance time and baseline ACQ-5.  Subgroup analyses may not be performed if the primary 
efficacy result is not statistically significant.  
11.4.3.2. Secondary Efficacy Analysis 
The secondary efficacy endpoint of change from baseline to week 12 in pre-/post-exercise FEV1 
will be analyzed using the same method as for the primary analysis. 
Other secondary endpoints measured by accelerometry (ie, change from baseline to week 12 in: 
average number of steps walked per day, total energy expenditure, and mean duration of moderate-
to-vigorous physical activity) will be analyzed using a method similar to that for the primary 
endpoint, except that patients who initiate corticosteroids for the treatment of an asthma 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 68 of 79 
CONFIDENTIAL 
exacerbation within the last 4 weeks of the treatment period (or corticosteroid dose increase for 
those on maintenance OCS) will be included in the analysis. 
11.4.4. 
Control of Multiplicity 
Multiplicity adjustment will be applied for testing of multiple endpoints.  Type I error rate will be 
controlled using a hierarchical testing procedure for the primary and then key secondary endpoints 
at the 2-sided 0.05 level.  The order of the endpoints for hierarchical testing will be specified in 
the SAP. 
11.4.5. 
Safety Analysis 
Safety analysis will be based on the SAF.  This includes reported treatment-emergent AEs 
(TEAEs), AESIs, and other safety information (eg, clinical laboratory evaluations, vital signs, and 
12-lead ECG results).  A summary of safety results for each treatment group will be presented. 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 3 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the days from the date of the first dose of study 
drug to the week 12 visit date (study day 85 starting from the first dose of study drug 
if week 12 visit date is unavailable) or early termination date, whichever comes first. 
• The post-treatment period or follow-up period is defined as the days from the date 
after week 12 visit date (study day 85 starting from first dose of study drug if week 12 
visit date is unavailable) to end of study. 
The treatment-emergent period is defined as the day from first dose of study drug to end of study.  
Treatment-emergent AEs are defined as those that are not present at baseline or represent the 
exacerbation of a pre-existing condition during the treatment-emergent period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group during the overall study period, during the treatment-
emergent period, during the 12-week treatment period, and during the follow-up period will 
include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.2.4), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 69 of 79 
CONFIDENTIAL 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics.  
The number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable.  The criteria for treatment emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a PCSV at any post-randomization time point will be 
summarized for each clinical laboratory test for all patients and separately for patients in whom 
the PCSV criterion was normal or missing at baseline.  
The number and percentage of patients with a treatment-emergent PCSV will be summarized for 
each clinical laboratory test.  The criteria for treatment-emergent PCSVs will be defined in the 
SAP. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.5.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment group and calculated as:  
Date of last study drug injection – date of first study drug injection + 14 days 
The number (%) of patients randomized and exposed to double-blind study drug will be presented 
by specific time periods for each treatment group.  The time periods of interest will be specified 
in the SAP. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of patients, means, standard deviation, minimums, Q1, medians, Q3, and 
maximums. 
A summary of the number of doses by treatment group will be provided. 
11.4.5.4. Treatment Compliance 
The compliance with protocol-defined investigational product will be calculated as follows: 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 70 of 79 
CONFIDENTIAL 
Treatment Compliance = (Number of study drug injections during exposure 
period)/ (Number of planned study drug injections during exposure period) x 100% 
The treatment compliance will be presented by specific ranges for each treatment group.  The 
ranges of interest will be specified in the SAP. 
11.5. 
Interim Analysis 
No interim analysis is planned. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized.  Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 15.1. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s).  The planned quality assurance and quality 
control procedures for the study are described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan, specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing), will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC). 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 71 of 79 
CONFIDENTIAL 
12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.  This study will 
use the principles of risk-based monitoring (ICH).  This means that the number of visits for any 
given site may vary based on site risk indicators.  The investigator must allow study-related 
monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents).  The site is responsible to ensure quality within their records and systems and is 
accountable for ensuring that all source data and CRF data are timely, accurate and complete. 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel.  All required CRFs must be 
completed for each and every patient enrolled in the study.  The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs.  After 
review of the clinical data for each patient, the investigator must provide an electronic signature.  
A copy of each patient CRF casebook is to be retained by the investigator as part of the study 
record and must be available at all times for inspection by authorized representatives of the sponsor 
and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system.  For corrections made via data queries, a reason for any alteration 
must be provided. 
12.3. 
Audits and Inspections 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as 
notification is received, and authorizing the sponsor’s participation in the inspection 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 72 of 79 
CONFIDENTIAL 
• Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities.  Conditions of study material storage are also subject to inspection.  In 
addition, representatives of the sponsor may observe the conduct of any aspect of the clinical study 
or its supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF/eCRF must be 
signed electronically by the investigator.  This signed declaration accompanies each set of patient 
final CRF/eCRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities.  The investigator must obtain written approval from the sponsor before 
discarding or destroying any essential study documents during the retention period following study 
completion or discontinuation.  Records must be destroyed in a manner that ensures 
confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 73 of 79 
CONFIDENTIAL 
13.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient prior to his/her participation in the study and after the 
aims, methods, objectives, and potential hazards of the study have been explained to the patient in 
language that he/she can understand.  The ICF should be signed and dated by the patient and by 
the investigator or authorized designee who reviewed the ICF with the patient.   
• Patients who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient. 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately.  All study patients must be informed of the new information and provide their 
written consent if they wish to continue in the study.  The original signed revised ICF must be 
maintained in the patient’s study record and a copy must be given to the patient. 
13.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained.  Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor.  Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in 
which case the IRB/EC should be informed as soon as possible  
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 74 of 79 
CONFIDENTIAL 
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator.  The 
approval letter should include the study number and title, the documents reviewed, and the date of 
the review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment.  Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-
OUT OF A SITE 
15.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
15.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice.  The final decision should be made through mutual agreement with the sponsor.  
Both parties will arrange the close-out procedures after review and consultation. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 75 of 79 
CONFIDENTIAL 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
• The investigator has received all items and information necessary to perform the 
study, but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 76 of 79 
CONFIDENTIAL 
19. 
REFERENCES 
American Thoracic Society, American College of Chest Physicians. ATS/ACCP Statement on 
cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003; 167(2):211-77. 
Attal F, Mohammed S, Dedabrishvili M, Chamroukhi F, Oukhellou L, Amirat Y. Physical 
Human Activity Recognition Using Wearable Sensors. Sensors (Basel) 2015; 15(12):31314-38. 
Bahmer T, Waschki B, Schatz F, Herzmann C, Zabel P, Kirsten AM, et al. Physical activity, 
airway resistance and small airway dysfunction in severe asthma. Eur Respir J 2017; 49(1). 
Benfante A, Di Marco F, Terraneo S, Centanni S, Scichilone N. Dynamic hyperinflation during 
the 6-min walk test in severely asthmatic subjects. ERJ Open Res 2018; 4(2). 
Borg E, Borg G, Larsson K, Letzter M, Sundblad BM. An index for breathlessness and leg 
fatigue. Scand J Med Sci Sports 2010; 20(4):644-50. 
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14(5):377-
81. 
Casaburi R, Maltais F, Porszasz J, Albers F, Deng Q, Iqbal A, et al. Effects of tiotropium on 
hyperinflation and treadmill exercise tolerance in mild to moderate chronic obstructive 
pulmonary disease. Ann Am Thorac Soc 2014; 11(9):1351-61. 
Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and 
Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018; 378(26):2486-96. 
Cordova-Rivera L, Gibson PG, Gardiner PA, Powell H, McDonald VM. Physical Activity and 
Exercise Capacity in Severe Asthma: Key Clinical Associations. J Allergy Clin Immunol Pract 
2018; 6(3):814-22. 
Dockrell M, Partridge MR, Valovirta E. The limitations of severe asthma: the results of a 
European survey. Allergy 2007; 62(2):134-41. 
Freeman W, Packe GE, Cayton RM. Effect of nebulised salbutamol on maximal exercise 
performance in men with mild asthma. Thorax 1989; 44(11):942-7. 
Fuhlbrigge AL, Adams RJ, Guilbert TW, Grant E, Lozano P, Janson SL, et al. The burden of 
asthma in the United States: level and distribution are dependent on interpretation of the national 
asthma education and prevention program guidelines. Am J Respir Crit Care Med 2002; 
166(8):1044-9. 
Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key 
proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 2016; 15(1):35-50. 
Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation FDA. 2009. 
US Department of Health and Human Services Food and Drug Administration. 
Haverkamp HC, Dempsey JA, Pegelow DF, Miller JD, Romer LM, Santana M, et al. Treatment 
of airway inflammation improves exercise pulmonary gas exchange and performance in 
asthmatic subjects. J Allergy Clin Immunol 2007; 120(1):39-47. 
Hennegrave F, Le Rouzic O, Fry S, Behal H, Chenivesse C, Wallaert B. Factors associated with 
daily life physical activity in patients with asthma. Health Sci Rep 2018; 1(10):e84. 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 77 of 79 
CONFIDENTIAL 
ICH Harmonized Tripartite Guideline: Clinical Safety Data Management: Definitions and 
Standards For Expedited Reporting (E2A).  1994.  International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use  
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. 
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. Respir Med 2005; 99(5):553-8. 
Kim Y, Beets MW, Welk GJ. Everything you wanted to know about selecting the "right" 
Actigraph accelerometer cut-points for youth, but...: a systematic review. J Sci Med Sport 2012; 
15(4):311-21. 
Mahler DA, Faryniarz K, Lentine T, Ward J, Olmstead EM, O'Connor GT. Measurement of 
breathlessness during exercise in asthmatics. Predictor variables, reliability, and responsiveness. 
Am Rev Respir Dis 1991; 144(1):39-44. 
Maltais F, Celli B, Casaburi R, Porszasz J, Jarreta D, Seoane B, et al. Aclidinium bromide 
improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. 
Respir Med 2011; 105(4):580-7. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of 
spirometry. Eur Respir J 2005; 26(2):319-38. 
O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, et al. Effects of 
tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 
23(6):832-40. 
Puente-Maestu L, Palange P, Casaburi R, Laveneziana P, Maltais F, Neder JA, et al. Use of 
exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur 
Respir J 2016; 47(2):429-60. 
Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of 
Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med 2018; 378(26):2475-85. 
Robertson W, Simkins J, O'Hickey SP, Freeman S, Cayton RM. Does single dose salmeterol 
affect exercise capacity in asthmatic men? Eur Respir J 1994; 7(11):1978-84. 
Schaper C, Glaser S, Felix SB, Gogolka A, Koch B, Krull M, et al. Omalizumab treatment and 
exercise capacity in severe asthmatics - results from a pilot study. Respir Med 2011; 105(1):3-7. 
Vatrella A, Fabozzi I, Calabrese C, Maselli R, Pelaia G. Dupilumab: a novel treatment for 
asthma. J Asthma Allergy 2014; 7(123-30. 
Vermeulen F, Garcia G, Ninane V, Laveneziana P. Activity limitation and exertional dyspnea in 
adult asthmatic patients: What do we know? Respir Med 2016; 117(122-30. 
Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled 
corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled 
pivotal phase 2b dose-ranging trial. Lancet 2016; 388(10039):31-44. 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 78 of 79 
CONFIDENTIAL 
20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: R668-AS-1903, a randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the effect of dupilumab on exercise capacity in patients with 
moderate-to-severe asthma with type 2 inflammation and agree to abide by all provisions set forth 
therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved.  I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the IRB/EC.  I agree to ensure that this 
information will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Clinical Study Protocol 
 
R668-AS-1903 Amendment 1 Global 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 79 of 79 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
A randomized, double-blind, placebo-controlled, parallel-group study to evaluate 
the effect of dupilumab on exercise capacity in patients with moderate-to-severe asthma with type 
2 inflammation 
Protocol Number: 
R668-AS-1903 
Protocol Version:   
Amendment 1 Global 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00


Signature Page for VV-RIM-00147293 v1.0
Signature Page for VV-RIM-00147293 v1.0 Approved
ESig Approval
16-Jun-2021 15:36:16 GMT+0000
ESig Approval
16-Jun-2021 15:57:40 GMT+0000
ESig Approval
17-Jun-2021 12:23:16 GMT+0000
ESig Approval
17-Jun-2021 13:27:45 GMT+0000
                                        VV-RIM-00147293-1.0 Approved - 17 Jun 2021 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affair  
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 1 of 46 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL
Clinical Study Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study to Evaluate the Effect of 
Dupilumab on Exercise Capacity in Patients with 
Moderate-to-Severe Asthma 
Compound: 
Dupilumab 
Protocol Number: 
R668-AS-1903 
Clinical Phase: 
Phase 4 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Versions/Dates: 
Original Statistical Analysis Plan / April 30, 2023 
VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00
NCT04203797


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 2 of 46 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
See appended electronic signature page 
  
 
 
See appended electronic signature page 
 
 
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 3 of 46 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background .................................................................................................................10 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objective .......................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Exploratory Objectives ...............................................................................................11 
1.3. 
Hypothesis and Rationale ...........................................................................................12 
1.3.1. 
Hypothesis ..................................................................................................................12 
1.3.2. 
Rationale .....................................................................................................................12 
1.3.2.1. 
Rationale for Study Design .........................................................................................12 
1.3.2.2. 
Rationale for Dose Selection ......................................................................................14 
2. 
INVESTIGATION PLAN ..........................................................................................15 
2.1. 
Study Design and Duration .........................................................................................15 
2.1.1. 
End of Study Definition ..............................................................................................17 
2.2. 
Statistical Hypothesis ..................................................................................................18 
2.3. 
Sample Size and Power Considerations .....................................................................18 
2.4. 
Study Plan ...................................................................................................................18 
2.4.1. 
Schedule of Events .....................................................................................................18 
2.4.2. 
Early Termination Visit ..............................................................................................21 
2.4.3. 
Unscheduled Visits .....................................................................................................21 
3. 
ANALYSIS POPULATIONS ....................................................................................22 
3.1. 
Full Analysis Set (FAS) ..............................................................................................22 
3.2. 
Safety Analysis Set (SAF) ..........................................................................................22 
4. 
ANALYSIS VARIABLES .........................................................................................23 
4.1. 
Demographic and Baseline Characteristics ................................................................23 
4.2. 
Medical History ..........................................................................................................23 
4.3. 
Pre-treatment/ Concomitant Medications and Procedures .........................................23 
4.4. 
Efficacy Variables ......................................................................................................24 
4.4.1. 
Primary Efficacy Variable ..........................................................................................24 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 4 of 46 
4.4.2. 
Secondary Efficacy Variables .....................................................................................24 
4.4.3. 
Exploratory Variables .................................................................................................25 
4.5. 
Safety Variables ..........................................................................................................25 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................25 
4.5.2. 
Adverse Events of Special Interest .............................................................................27 
4.5.3. 
Laboratory Safety Variables .......................................................................................27 
4.5.4. 
Vital Signs ..................................................................................................................27 
4.5.5. 
Electrocardiography (ECG) ........................................................................................28 
4.5.6. 
Physical Examination Variables .................................................................................28 
5. 
STATISTICAL METHODS .......................................................................................29 
5.1. 
Patient Disposition ......................................................................................................29 
5.2. 
Demographics and Baseline Characteristics ...............................................................29 
5.3. 
Medical History ..........................................................................................................29 
5.4. 
Prior/Conconcomitant Medications and Procedures ..................................................30 
5.5. 
Measurement of Compliance ......................................................................................30 
5.6. 
Extent of Study Treatment Exposure ..........................................................................30 
5.7. 
Analysis of Efficacy Data ...........................................................................................30 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................30 
5.7.2. 
Analysis of Key Secondary Efficacy Variable ...........................................................31 
5.7.3. 
Analysis of Exploratory Variables ..............................................................................31 
5.7.3.1. 
Measurements associated with CPET .........................................................................31 
5.7.3.2. 
Patient Diary ...............................................................................................................31 
5.7.3.3. 
Spirometry not associated with CPET ........................................................................31 
5.7.3.4. 
Patient-Reported Outcomes ........................................................................................31 
5.8. 
Analysis of Safety Data ..............................................................................................31 
5.8.1. 
Adverse Events ...........................................................................................................32 
5.8.2. 
Clinical Laboratory Measurements.............................................................................33 
5.8.3. 
Vital Signs ..................................................................................................................33 
5.8.4. 
Electrocardiography (ECG) ........................................................................................33 
5.8.5. 
Physical Exams ...........................................................................................................33 
6. 
DATA HANDLING CONVENTIONS ......................................................................34 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 5 of 46 
6.1. 
Data Handling Convention for Missing Data .............................................................34 
6.1.1. 
Medication ..................................................................................................................34 
6.1.2. 
PCSV ..........................................................................................................................34 
6.2. 
Unscheduled visits ......................................................................................................34 
7. 
INTERIM ANALYSIS ...............................................................................................35 
8. 
SOFTWARE ...............................................................................................................36 
9. 
REFERENCES ...........................................................................................................37 
10. 
APPENDIX.................................................................................................................40 
10.1. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................40 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................19 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................15 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 6 of 46 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ab 
          Antibody 
ACCP           American College of Chest Physicians 
ACQ-5          Asthma Control Questionnaire, 5-question version 
AE 
          Adverse event 
AESI             Adverse event of special interest 
ALT 
          Alanine aminotransferase 
ANCOVA     Analysis of covariance 
AQLQ (S)     Asthma Quality of Life Questionnaire (Self-Administered) 
AST              Aspartate aminotransferase 
ATS              American Thoracic Society 
BID               Twice a day 
BOCF            Baseline observation carried forward 
COPD           Chronic obstructive pulmonary disease 
COVID-19    Coronavirus Disease 2019 
CPET            Cardiopulmonary exercise test 
CPK               Creatine phosphokinase 
CRF 
          Case report form (electronic and/or paper) 
CRO              Contract research organization 
CRSwNP       Chronic rhinosinusitis with nasal polyps 
CSR 
           Clinical study report 
CTFG             Clinical Trial Facilitation Group 
CWR               Constant work rate 
CWRET          Constant work rate exercise test 
Dynamic hyperinflation          An increase in end expiratory lung volumes under conditions of 
increased minute ventilation (ie, during exercise)                
EC 
              Ethics Committee 
ECG                  Electrocardiogram 
eCRF                 Electronic case report form 
EDC                Electronic data capture 
EGPA                Eosinophilic granulomatous with polyangiitis 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 7 of 46 
ERS                   European Respiratory Society 
EU                     European Union 
FAS                   Full analysis set 
FDA                Food and Drug Administration 
FeNO                 Fractional Exhaled Nitric Oxide 
FEV1                 Forced Expiratory Volume in One Second 
FSH                   Follicle stimulating hormone 
FVC                   Forced vital capacity 
GCP                Good Clinical Practice 
GINA                 Global Initiative for Asthma 
HBsAb               Hepatitis B surface antibody 
HBsAg               Hepatitis B surface antigen 
HBcAb               Hepatitis B core antibody 
HBV                   Hepatitis B virus 
HCG                   Human chorionic gonadotropin 
HCV                   Hepatitis C virus 
HDL                   High-density lipoprotein 
HIV                    Human immunodeficiency virus 
IC                        Inspiratory capacity, defined as the maximal amount of air a person can inhale at 
                            the end of a normal exhalation 
ICF 
                Informed consent form 
ICH 
                International Council for Harmonisation 
ICS                      Inhaled corticosteroid 
IEC                      Independent Ethics Committee 
IgE 
                Immunoglobulin E 
IgG4                    Immunoglobulin G4 
IL-13                   Interleukin-13 
IL-4                     Interleukin-4 
IL-4Rα                Interleukin-4 receptor alpha 
IL5                      Interleukin-5 
IL-5R                  Interleukin-5 receptor 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 8 of 46 
IRB 
                Institutional Review Board 
Isotime                Shortest equivalent exercise time achieved 
ISR                      Injection site reactions 
IVRS/IWRS        Interactive voice response system/interactive web response system 
IWRET                Incremental Work Rate Exercise Test 
LABA                  Long-acting beta agonist 
LAMA                 Long-acting muscarinic antagonists 
LDH                     Lactate dehydrogenase 
LDL                      Low-density lipoprotein 
LTRA                   Leukotriene receptor antagonist 
mAb                     Monoclonal antibody 
MCID                   Minimum clinically important difference 
MedDRA              Medical Dictionary for Regulatory Activities 
MET                     Metabolic equivalent of task 
MI                         Multiple imputation 
OCS                     Oral corticosteroid  
PCSV                   Potentially clinically significant value 
PFT                      Pulmonary function test 
PGIC                    Patient Global Impression of Change 
PGII                     Patient Global Impression of Impact 
PT                        Preferred term 
Q1                        First quartile 
Q2W                    Once every 2 weeks 
Q3                        Third quartile 
RBC                     Red blood cell 
Regeneron 
     Regeneron Pharmaceuticals, Inc. 
SABA                  Short-acting beta agonist 
SAE 
                 Serious adverse event 
SAF 
                 Safety analysis set 
SAMA                 Short acting muscarinic antagonist 
SAP 
                 Statistical analysis plan 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 9 of 46 
SAS                      Statistical Analysis System 
SC                        Subcutaneous 
SCIT                    Subcutaneous immunotherapy 
SOC                     System organ class 
SUSAR                Suspected unexpected serious adverse reaction 
TEAE                   Treatment-emergent adverse event 
tLIM                     Time to limit of tolerance 
ULN                     Upper limit of normal 
VO2                     Oxygen consumption 
W/min                  Watts per minute 
WBC                    White blood cell 
WOCBP               Women of childbearing potential 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 10 of 46 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the data analysis of R668-AS-1903 
1.1. 
Background 
Asthma is a chronic inflammatory disease of the airways characterized by airway 
hyperresponsiveness, acute and chronic bronchoconstriction, airway edema, and mucus plugging. 
The inflammatory component of asthma involves many cell types, including mast cells, 
eosinophils, T-lymphocytes, neutrophils, and epithelial cells and their biological products. The 
poor therapeutic response of some patients with asthma may reflect a number of cellular and 
molecular mechanisms operative in asthma. Up-regulation of interleukin-4 (IL-4) and interleukin-
13 (IL-13) activity has been implicated as an important type 2 inflammatory component of asthma 
pathophysiology. 
It is well-established that exercise intolerance and difficulties engaging in physical activity are 
common complaints of patients with asthma, reported by at least 66% of patients 
(Fuhlbrigge, 2002). In a survey in 1300 European patients, 70% of severe asthmatics receiving 
asthma medication reported limitation in physical activity (Dockrell, 2007). Additionally, exercise 
capacity evaluated by cycle ergometry is known to be reduced in asthmatics when lung function 
is impaired. Chronic expiratory flow limitation in patients with moderate-to-severe asthma may be 
a contributing factor to exercise intolerance. Use of bronchodilators prior to exercise, though useful 
for blunting decrease in forced expiratory volume in one second (FEV1), does not reliably improve 
exercise capacity (Vermeulen, 2016). A high unmet need exists to improve exercise capacity and 
activity levels in patients with asthma. 
Patients with obstructive lung disease, often develop dynamic hyperinflation (defined as an 
increase in end expiratory lung volume under conditions of increased minute ventilation [ie, during 
exercise]) due to expiratory air-flow limitation in the face of decreased time for exhalation with 
increasing respiratory rate. This results in a decrease in inspiratory capacity (IC). Dynamic 
hyperinflation increases inspiratory mechanical load and thereby results in sense of breathlessness 
and exercise intolerance in patients with obstructive lung disease. Severity of dyspnea correlates 
with degree of expiratory flow limitation (measured by FEV1) and peripheral airway resistance 
(Mahler, 1991). 
There are no published, rigorously designed studies assessing the effects of pharmacotherapeutic 
intervention on assessing either maximal exercise capacity or activities of daily living in patients 
with asthma. Dupilumab therapy has demonstrated improvement in lung function and asthma 
control. Inhibition of IL-4/-13 is known to improve lung function and reduce airway inflammation 
(Gandhi, 2016) (Vatrella, 2014) (Castro, 2018) (Wenzel, 2016). It is therefore hypothesized that 
dupilumab treatment may improve exercise capacity and increase physical activity in patients with 
moderate-to-severe asthma. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 11 of 46 
Dupilumab is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that 
inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4Rα) 
subunit shared by the IL-4 and IL-13 receptor complexes. Dupilumab inhibits IL-4 signaling via 
the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor 
(IL-4Rα/IL-13Rα). Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 cytokine-induced 
responses, including the release of proinflammatory cytokines, chemokines, and immunoglobulin 
E (IgE). 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
1.2. 
Study Objectives  
In this section, primary, secondary and exploratory objectives are specified. However, all the 
objectives are for exploratory and hypothesis-generating purposes only. There will be no formal 
hypothesis testing of any of the listed objectives.  
1.2.1. 
Primary Objective 
The primary objective of the study is to demonstrate that dupilumab treatment improves exercise 
capacity in patients with moderate-to-severe asthma.  
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To demonstrate that dupilumab treatment increases physical activity of daily living in 
patients with moderate-to-severe asthma 
• To demonstrate that dupilumab treatment improves pre- and post-exercise lung 
function in patients with moderate-to-severe asthma 
1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are to: 
• To demonstrate that dupilumab treatment decreases dynamic hyperinflation during 
constant work rate exercise in patients with moderate-to-severe asthma 
• To demonstrate that dupilumab treatment improves perception of dyspnea 
• To demonstrate that dupilumab treatment improves perception of leg fatigue 
• To demonstrate that dupilumab treatment increases oxygen consumption during the 
constant work rate exercise test (CWRET) 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 12 of 46 
• To demonstrate that dupilumab treatment improves asthma control in patients with 
moderate-to-severe asthma 
• To demonstrate that dupilumab treatment improves asthma-related quality of life in 
patients with moderate-to-severe asthma 
• To demonstrate that dupilumab treatment improves patients’ impression of ability to 
carry out exercise 
• To demonstrate that dupilumab treatment improves patients’ impression of the impact 
that asthma has on the ability to perform exercise 
• To demonstrate that dupilumab treatment decreases pre- and post-exercise FeNO 
• To measure nocturnal awakenings due to asthma measured by patient diary 
1.3. 
Hypothesis and Rationale 
The study is exploratory and hypothesis-generating only. There will be no formal statistical 
testing of any of the hypotheses listed. 
1.3.1. 
Hypothesis  
The pre-defined hypothesis was that patients with moderate-to-severe asthma treated with 
dupilumab would show improvement in exercise capacity and increase in physical activity of daily 
living. However, due to under enrollment, study is not sufficiently powered for the primary 
endpoint. Therefore, there will be no formal hypothesis testing for any of the specified endpoints 
in the study. 
1.3.2. 
Rationale 
1.3.2.1. 
Rationale for Study Design 
It has been shown that dupilumab treatment significantly improves FEV1, asthma control and 
reduces type 2 mediated inflammation in patients with moderate-to-severe asthma (Castro, 2018) 
(Rabe, 2018) (Wenzel, 2016). This study will determine whether these improvements translate into 
(1) an increase in exercise capacity as measured by cycle ergometry and constant work rate 
exercise endurance time, and (2) an increase in physical activities of daily living assessed by 
accelerometry. 
Effects of pharmacotherapy on exercise capacity and physical activity in patients with asthma have 
not been rigorously examined in clinical studies. Small studies in asthma with bronchodilators or 
bronchodilator + ICS intervention have shown inconsistent results regarding improvement in 
exercise capacity (Haverkamp, 2007) (Robertson, 1994). A 6-week study of patients with mild to-
moderate asthma treated with high dose fluticasone showed improvement in exercise endurance 
time and FEV1 (Haverkamp, 2007). However, other studies in patients with asthma treated with 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 13 of 46 
bronchodilators demonstrated increases in FEV1 without consistent improvement in exercise 
capacity (Freeman, 1989). An unblinded, small study of omalizumab in 20 consecutive patients 
with severe allergic asthma (10 receiving omalizumab and 10 placebo) demonstrated significant 
improvement in both FEV1 and exercise capacity after 16 weeks of omalizumab treatment 
(Schaper, 2011). 
Small, non-interventional, cross-sectional studies using various accelerometers worn at the wrist 
or hip have shown that patients with severe asthma walk approximately 27% to 30% fewer steps 
per day compared to age and gender matched healthy volunteers (mean steps/day severe asthma = 
5362; range 3999 to 7817 vs. healthy controls 7817; range 6072 to 10014) (Cordova-Rivera, 2018). 
Studies evaluating FEV1 as a marker of physical activity have shown conflicting results. Bahmer 
et. al. reported that FEV1 and peak expiratory flow were poor markers of physical activity in 
asthma patients showing no significant correlation between FEV1 and steps walked per day 
(Bahmer, 2017), whereas Hennegrave et. al. showed significant correlation between steps walked 
and FEV1 (Hennegrave, 2018). 
Dupilumab has been shown to increase lung function and improve asthma control. It is 
hypothesized that this demonstrated efficacy may result in improvements in exercise capacity and 
physical activity of daily living. Pulmonary limitation to exercise will be identified by 
demonstrating a decrease in IC from pre-exercise to the value during the maximal incremental 
exercise test performed at screening. 
This phase 4, randomized, placebo-controlled study was designed to evaluate whether treatment 
with dupilumab increases exercise endurance time evaluated using constant work rate exercise 
testing (CWRET). Additionally, assessment of physical activities of daily living (steps walked per 
day, energy expenditure, and time spent in moderate-to-vigorous activity) was planned using 
accelerometry. 
A blinded, randomized design was chosen to minimize bias in data collection and result 
interpretation. The presence of a placebo arm was considered appropriate for the objectives of this 
study to explore the efficacy of dupilumab. A run-in period was planned to stabilize background 
asthma treatment, to familiarize patients with the CWRET, determine an individualized work rate 
that a patient can tolerate for 3 to 8 minutes (180 to 480 seconds), and to collect pre-treatment 
accelerometry data. A 12-week treatment period was selected based on the findings in dupilumab 
clinical studies in moderate-to-severe asthma patients where near-maximal improvements in lung 
function occurred by approximately 8 to 12 weeks after treatment initiation. A 2-week post-
treatment follow-up period was chosen to ensure clinical stability of patients after the treatment 
period is complete. 
Cardiopulmonary exercise testing (CPET) has been utilized in several interventional studies to 
assess the degree of dynamic hyperinflation in patients with obstructive lung diseases, and its 
impact on exercise capacity (Benfante, 2018) (Casaburi, 2014) (Maltais, 2011) (O’Donnell, 2004). 
CPET can be performed on a stationary bicycle or a treadmill. Cycle ergometry has been selected 
over a treadmill protocol because it requires relatively little patient practice (unlike treadmill 
exercise) and the external power output is accurately known. A constant work-rate protocol was 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 14 of 46 
chosen to assess the primary endpoint versus a maximal incremental exercise test, as the former is 
more sensitive to discriminate change in exercise capacity. To minimize variability in the 
measurements, the CPET was to be done using a standardized CPET protocol, and only at sites 
proficient in CPET and pulmonary function testing. 
1.3.2.2. 
Rationale for Dose Selection 
The dose regimen selected for this study is dupilumab 300 mg administered subcutaneously (SC) 
every other week (Q2W) with a 600 mg loading dose for the first dose. This dosing regimen is 
chosen as it has been shown to be efficacious, with an acceptable safety profile in asthma pivotal 
studies and is approved for the treatment of moderate-to-severe asthma, the patient population 
under study. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 15 of 46 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Duration 
This phase 4, global, randomized, double-blind study of dupilumab vs. placebo was originally 
designed to evaluate the effects of dupilumab on exercise capacity and daily activity in patients 
with moderate-to-severe asthma over a 12-week treatment period. Approximately 140 patients 
were planned to be enrolled in the study, approximately 70 per treatment group with a 1:1 
randomization ratio. Due to enrollment challenges,  the study is going to be terminated early with 
approximately 40 patients enrolled. Up to 10% of patients on maintenance OCS at screening and 
baseline (≤10 mg/day OCS, prednisone/prednisolone or dose equivalent) will be allowed to 
participate in the study. Randomization will be stratified by baseline FEV1 (<50% vs. ≥50% 
predicted) and age (<35 vs. ≥35 years) to balance effects these variables may have on exercise 
performance. 
The study consists of an up to 4-week screening period, an up to 4-week run-in period, a 12-
week treatment period, and a 2-week post-treatment follow-up period (see Figure 1). 
Figure 1: 
Study Flow Diagram 
 
D = study day; R = randomization; EOS = end of study; EOT = end of treatment; W = study week 
Note: The study drug dosing regimen is dupilumab 600 mg loading dose on study day 1 and 300 mg Q2W from 
week 2 to week 10 or matching placebo. 
Screening Period (Up to 4 Weeks/Visit 1): 
After providing informed consent, the patients will be assessed for study eligibility at the 
screening visit. During the screening period, patients will perform qualifying ACQ-5, 
spirometry, bronchodilator reversibility testing (if applicable), and laboratory assessments. 
Patients must meet all screening eligibility requirements prior to conducting incremental work 
rate exercise testing (IWRET). Patients who meet these eligibility requirements will undergo a 
symptom-limited, incremental, maximal effort, cycle cardiopulmonary exercise test (IWRET) to 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 16 of 46 
determine the maximum work rate he/she can achieve. During the IWRET, work rate will be set 
to increase at either 10, 15, 20, or 25 W/min depending on the investigator’s assessment of the 
patient’s ability to exercise. The primary goals of the IWRET are to determine peak work rate 
patients can endure, to assess development of dynamic hyperinflation and determine the patient’s 
exercise endurance time. Patients must exercise until exhaustion, for between 4 and 16 minutes 
inclusive, and must have documented dynamic hyperinflation defined as decrease in IC during 
the IWRET of more than 100 mL from the pre-exercise value. If the exercise time is outside of 
the 4 to 16 minute required window or IC does not decrease by >100 mL, the test may be 
repeated with a change in the work rate from that previously used by ±10% or 5 W/min, 
whichever is greater. The IWRET can be repeated twice (up to a total of 3 times) to determine 
study eligibility. A patient who exercises <4 or >16 minutes or who does not drop IC by 
>100 mL after 3 IWRET attempts will be considered a screen failure. 
The IWRET (to be performed at screening) and the CWRET (to be performed during the run-in 
period, at baseline and at the end of the treatment period) will be administered according to 
guidelines for CPET published in the Joint Statement of the ATS and the American College of 
Chest Physicians (ACCP) (American Thoracic Society, 2003). CPET is a non-invasive, well 
accepted, standard protocol-driven method to assess the performance of the heart and lungs during 
exercise (Puente-Maestu, 2016). The test will be performed on an electromagnetically-braked 
cycle ergometer in an exercise physiology laboratory overseen by a trained pulmonologist or 
medical doctor designee. A medical doctor must be present in the room in which the initial IWRET 
is conducted and readily available for medical intervention, at all subsequent exercise tests. 
Resuscitation equipment must be immediately available in the PFT lab (ie, in the room) in which 
the exercise testing is performed. Patients will exercise until exhaustion (time to limit of tolerance 
[tLIM]) breathing through a mouthpiece with noseclip in place or while wearing a mask. 
Run-in Period (Up to 4 Weeks/Visit 2): 
During the run-in period patients must maintain a stable dose of background asthma controller 
medication including OCS, if applicable, for at least 4 weeks prior to the baseline visit. Patients 
will perform a run-in CWRET using a standardized CWRET protocol on an electromagnetically 
braked cycle ergometer. The CWRET will be performed at 80% of the maximal work rate 
previously determined from the IWRET. The goal of the run-in CWRET is to determine the 
individualized work rate the patient can tolerate to achieve an exercise duration time between 3 to 
8 minutes, and to familiarize the patient with the test. For those achieving exercise times outside 
of these limits (ie, <3 to >8 minutes) a second CWRET may be performed after a work rate 
adjustment by ±10% or 5 W/min, whichever is greater. In rare cases, a third test may need to be 
performed after a further work rate adjustment to achieve a 3 to 8 minute exercise endurance time. 
Patients who are unable to achieve an exercise endurance duration between 3 to 8 minutes (180 to 
480 seconds) after 3 attempts will be considered screen failures. 
At visit 2, patients will be given the accelerometer and instructed on its proper use. Patients will 
be instructed to wear the accelerometer on their wrist, 24 hours/day, 7 days/week (except during 
charging time, bathing, and any other water activities) for a total of 3 weeks during the run-in 
period and record daily how much time spent bathing or swimming, total time charging the device, 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 17 of 46 
physical activity (eg, walking, moderate physical activities, and vigorous physical activities), and 
nocturnal awakenings due to asthma in the patient diary. The first week is a training period for the 
patient to become familiar with the accelerometer. The subsequent 2 weeks of daily accelerometry 
are to obtain the pre-treatment baseline data. 
Baseline and Treatment Period (12 Weeks/Visits 3 to 9): 
Eligible patients will be randomized 1:1 on day 1 to receive dupilumab or placebo. Background 
asthma controller medication must remain constant throughout the treatment period. Patients will 
be asked to wear an accelerometer on their wrist 24 hours/day, 7 days/week for 14 consecutive 
days prior to visit 3/randomization, and for 14 consecutive days prior to visit 9/end of treatment 
Visit (except during charging time, bathing, and any other water activities). The CWRET will be 
performed at baseline and week 12 to assess the change in constant work rate exercise endurance 
time from baseline, the primary endpoint for the study. In-clinic spirometry will be assessed pre- 
and post-exercise as part of the CWRET per the schedule of events. Note: The same exercise work 
rate established at the qualifying run-in CWRET which achieves an exercise time between 3 and 
8 minutes must also be applied for the baseline and end of treatment CWRET. Pulmonary 
ventilation, breathing pattern, gas exchange (all assessed from the respired gases by a metabolic 
cart), arterial oxygen saturation (assessed by pulse oximetry), ECG parameters, IC, perceived 
dyspnea and perceived leg fatigue (by Borg Dyspnea and Leg Fatigue Scales, respectively) will be 
assessed during the CWRET. Asthma control, asthma quality of life, nocturnal awakenings due to 
asthma, and airway inflammation will be assessed at baseline and during the treatment period using 
the ACQ-5, AQLQ, PGII, and PGIC questionnaires, patient diary and FeNO measurements, 
respectively. Additional in-clinic spirometry will be performed at week 4 using the same 
equipment utilized to perform spirometry pre- and post-exercise testing. 
Safety, including adverse events, will be assessed throughout the study. 
Post-treatment Follow-up Period: (2 Weeks/Visit 10) 
All patients will have a follow up visit 2 weeks after completing the treatment period. 
NOTE: If there are restrictions to the clinical study as a result of the COVID-19 pandemic, it may 
be necessary to adjust the visit schedule, convert in-person visits to telephone contacts, and 
postpone study procedures until the next available study visit. All visits when CPET is performed 
must occur in the clinic including the randomization visit. All temporary mechanisms utilized, and 
deviations from planned study procedures in response to COVID-19 are to be documented as being 
related to COVID-19 and will remain in effect only for the duration of the public health emergency. 
Once local COVID-19 conditions resolve, all study visits and procedures should follow the 
schedule of events as specified in Table 1. 
2.1.1. 
End of Study Definition 
The end of study is defined as the last study visit of the last patient. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 18 of 46 
2.2. 
Statistical Hypothesis 
The following null and alternative hypotheses are specified for reference. There is no formal 
hypothesis testing. All p-values will be nominal and for exploratory and hypothesis-generating 
purposes only.  
• Null hypothesis: The mean change from baseline in the constant work-rate exercise 
endurance time at week 12 is the same between dupilumab and placebo. 
• Alternative hypothesis: The mean change from baseline in the constant work rate 
exercise endurance time at week 12 differs between dupilumab and placebo. 
2.3. 
Sample Size and Power Considerations   
The originally planned sample size of approximately 70 patients per treatment group (N=140 
total) was to provide >85% power to detect a 105-second mean change in exercise endurance 
time, with a standard deviation of 190 seconds, 2-sided α = 5%, and 10% drop out rate. 
However, due to enrollment challenges, the study will be terminated early at a smaller-than-
planned sample size, and all the analyses will be exploratory (with no alpha control).  
2.4. 
Study Plan  
2.4.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 19 of 46 
Table 1: 
Schedule of Events 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 20 of 46 
 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 21 of 46 
2.4.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (week 12) will be 
asked to return to the clinic once for an early termination visit consisting of the end of study 
assessments described in Table 1 . 
2.4.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 22 of 46 
3. 
ANALYSIS POPULATIONS  
3.1. 
Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients. The FAS is based on the treatment 
allocated (as randomized). All efficacy endpoints will be analyzed using the FAS. 
3.2. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who received any study drug. 
This set is based on the treatment received (as treated). Treatment compliance/administration and 
all clinical safety variables will be analyzed using the SAF by treatment group. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 23 of 46 
4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Age at screening in years 
• Sex (Male, Female) 
• Ethnicity (Hispanic/Latino or not) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
• ACQ-5 
• Qualifying IWRET information including exercise duration, end exercise VO2, 
inspiratory capacity at rest, inspiratory capacity at peak exercise, and rest-peak 
exercise inspiratory capacity 
• Qualifying ECG 
• Pre-exercise ECG during IWRET 
• Exercise ECG during IWRET 
• Bronchodilator reversibility  
• Pre-bronchodilator FEV1 (L) 
• Post-bronchodilator FEV1 (L) 
• FEV1 Percent Predicated (%) 
• Blood eosinophil count (cells/uL) 
• Pre-bronchodilator Forced Vital Capacity (FVC) 
• Post-bronchodilator Forced Vital Capacity (FVC) 
4.2. 
Medical History 
General medical history and surgical medical history are collected. 
General medical history will be coded to a Preferred Term (PT) and associated primary System 
Organ Class (SOC) according to the latest available version of MedDRA. 
4.3. 
Pre-treatment/ Concomitant Medications and Procedures 
Medications/Procedures were recorded from the day of informed consent to final study visit. 
Medications will be coded to the anatomical therapeutic chemical (ATC) level 2 (therapeutic 
main group) and ATC level 4 (chemical/therapeutic subgroup), according to the latest available 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 24 of 46 
version of WHO Drug Dictionary (WHODD). Patients will be counted once in all ATC 
categories linked to the medication. 
Pre-treatment medications/procedures: medications taken, or procedures performed prior to 
administration of the study drug will be summarized. 
Concomitant medications/procedures: any treatment administered from the time of first dose of 
study drug until last study visit will be considered concomitant treatment. This includes 
medications and other therapies for which administration started before the study drug and will 
continue during the study, as well as any therapies started in the follow-up period to treat a study 
drug related AE. All concomitant treatments must be recorded in the study case report form 
(CRF) with the generic name, dose, dose unit, frequency, indication, and start/stop date, as 
appropriate. 
4.4. 
Efficacy Variables 
This section provides more details on the primary, secondary and exploratory endpoints. 
However, no endpoints listed will be formally tested and all p-values are nominal. 
Additional endpoints and analytical methods may be used for exploratory and hypothesis-
generating purposes.  
4.4.1. 
Primary Efficacy Variable 
The primary endpoint is change from baseline to week 12 in constant work rate exercise 
endurance time measured from the CWRET (refer to Protocol Section 9.2.2.4 for definition). 
4.4.2. 
 Secondary Efficacy Variables 
The secondary endpoints are: 
• Change from baseline to week 12 in pre- and post-exercise (5 seconds, 10 seconds 
and 20 seconds, respectively) FEV1 (based on spirometry data; refer to Protocol 
Section 9.2.2.5 for detailed definition) 
• Change from baseline to week 12 in average number of steps walked per day (based 
on accelerometry data; refer to Protocol Section 9.2.2.1 for detailed definition.) 
• Change from baseline to week 12 in total energy expenditure (metabolic equivalents 
of tasks [METs]) (based on accelerometry data) 
• Change from baseline to week 12 in the mean duration of moderate-to-vigorous 
physical activity (defined as ≥3 METs) (based on accelerometry data) 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 25 of 46 
4.4.3. 
Exploratory Variables 
• Change from baseline to week 12 in isotime IC (Note: isotime is defined as the 
shortest equivalent exercise time achieved) 
• Change from baseline to week 12 in perception of dyspnea measured by the Borg 
Dyspnea Scale at isotime. Refer to Protocol Section 9.2.2.2 for detailed definition. 
• Change from baseline to week 12 in perception of leg fatigue measured by the Borg 
Leg Fatigue Scale at isotime. Refer to Protocol Section 9.2.2.2 for detailed definition. 
• Change from baseline to week 12 in end-exercise oxygen consumption (VO2) 
• Change from baseline to week 12 in FeNO, pre- and post-exercise 
• Change from baseline to week 12 in forced vital capacity (FVC) pre- and post-
exercise 
• Change from baseline in FEV1 and FVC at week 4 
• Change from baseline to week 12 in the maximal percent fall in post-exercise FEV1 in 
patients with exercise-induced asthma (defined as patients who had a ≥20% fall in 
post-exercise FEV1 from pre-exercise value on the IWRET) 
• Change from baseline to week 12 in number of nocturnal awakenings per night due to 
asthma from patient diary 
• Change from baseline in total ACQ-5 score (Asthma Control Questionnaire, 5- 
question version) at week 12 
• Change from baseline to week 12 in total AQLQ(S) score (Asthma Quality of Life 
Questionnaire Standardized Version). Refer to Protocol Section 9.2.2.2 for detailed 
definition. 
• Proportion of patients responding with an improvement on the Patient Global 
Impression of Change (PGIC) at weeks 4 and 12. Refer to Protocol Section 9.2.2.4 for 
detailed definition. 
• Proportion of patients responding with no or limited impact on the Patient Global 
Impression of Impact (PGII) at weeks 4 and 12. Refer to Protocol Section 9.2.2.4 for 
detailed definition. 
4.5. 
Safety Variables 
Patient safety will be assessed through the collection of reported adverse events (AEs), clinical 
laboratory data, vital signs, ECG and physical exam. Unless otherwise noted, the baseline value 
is defined as the last available value before the first dose of study treatment. 
4.5.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded to a 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 26 of 46 
Preferred Term (PT) and associated primary System Organ Class (SOC) according to the latest 
available version of Medical Dictionary for Regulatory Activities (MedDRA). 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered a study 
drug which may or may not have a causal relationship with the study drug.  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a patient is a passenger) 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. In-
patient hospitalization is defined as hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
The severity of AEs will be graded according to the following scale: 
• Mild: Does not interfere in a significant manner with the patient normal functioning 
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief 
of symptoms, but may be given because of personality of the patient. 
• Moderate: Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
• Severe: Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the patient's health. Treatment for symptom may be given and/or 
patient hospitalized. 
The severity of injection site reactions (ISRs) will be graded according to the following scale 
(semi-colon indicates “or” within description of grade): 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 27 of 46 
• Mild: Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity 
• Moderate: Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity 
• Severe: Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires an emergency room (ER) visit or hospitalization; necrosis or 
exfoliative dermatitis 
4.5.2. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical interest specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. 
• Anaphylactic reactions 
• Systemic or severe hypersensitivity reactions  
• Helminthic infections 
• Any severe type of Conjunctivitis, Blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
• Severe injection site reactions lasting for >24 hours 
4.5.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of serum chemistry, hematology, and urinalysis. Clinical 
laboratory values will be converted to standard international (SI) units and grouped by function 
in summary tables using SI units. The same set of analysis will also be prepared in US units.  
Functions are defined as follows: 
• Chemistry 
• Hematology 
• Urinalysis 
• Serology 
4.5.4. 
Vital Signs 
Vital signs will be collected at time points specified in the study protocol: 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 28 of 46 
• Diastolic Blood Pressure 
• Systolic Blood Pressure 
• Heart Rate 
• Respiratory Rate 
• Height 
• Weight 
• Body Mass Index 
• Temperature 
4.5.5. 
Electrocardiography (ECG) 
An ECG will be be performed just prior to CPET to ensure that the patient does not have a 
contraindication to CPET. An ECG will be performed throughout the exercise tests as indicated 
in the schedule of events (Table 1). The results of the qualifying ECG will be interpreted by a 
central reading center. All other ECGs will be read locally. 
• ECG Mean Heart Rate 
• PR Interval, Aggregate 
• QRS Duration, Aggregate 
• QT Interval, Aggregate 
• QTcB Interval, Aggregate 
• QTcF Interval, Aggregate 
• RR Interval, Aggregate 
4.5.6. 
Physical Examination Variables 
A thorough and complete physical examination, including skin, nasal cavities, eyes, ears, 
respiratory, cardiovascular, gastrointestinal, neurological, lymphatic, and musculoskeletal 
systems, will be performed at time points according to Table 1. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 29 of 46 
5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, standard deviation, first quartile (Q1), median, third 
quartile (Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
5.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who signed the ICF 
• The total number of randomized patients: received a randomization number (as 
randomized) 
• The total number of patients in the SAF 
• The total number of patients in the FAS 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for treatment discontinuation 
• Summary table will be provided if applicable 
5.2. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined based on the FAS population. 
Baseline for singular-value assessments, such as measurements from the CWRET, FEV1 and 
FVC from spirometry, will be the latest valid measurement taken prior to the first administration 
of study drug. 
Baseline for the 7-day average values of measurements from accelerometry is defined as the 
average of the valid values during the 7 days prior to the first administration of study drug. 
5.3. 
Medical History 
Medical history will be summarized based on the SAF population. 
Summary tables will be sorted by decreasing frequency of SOC followed by PT.  
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 30 of 46 
5.4. 
Prior/Conconcomitant Medications and Procedures 
The prior and concomitant medications will be presented for FAS. Number and proportion of 
subjects taking concomitant medications, prohibited medications/procedures and rescue 
medications/procedures will be summarized based on FAS, sorted by decreasing frequency of 
ATC Level 2 and ATC level 4 according to the World Health Organization Drug Dictionary. 
5.5. 
Measurement of Compliance 
Compliance will be assessed and summarized by actual treatment within SAF. The compliance 
with protocol-defined investigational product will be calculated as follows: 
              Treatment Compliance = (Number of study drug injections during exposure period)/ 
(Number of planned study drug injections during exposure period) x 100% 
The percentage of subjects who have <70%, and >=70% compliance will be summarized for 
each group. 
5.6. 
Extent of Study Treatment Exposure 
The extent of treatment exposure will be assessed and summarized by actual treatment within 
SAF. Exposure to study treatment will be examined for each subject and the following variables 
will be summarized: 
• The total number of study doses administered  
• Duration of treatment exposure (in weeks) calculated as: 
• (Date of last study drug injection – date of first study drug injection + 14 days)/7 
The number of subjects exposed to study drug will be presented by specific time point periods 
for each group. The time periods of interest are weeks 2, 4, 6, 8, 12. 
5.7. 
Analysis of Efficacy Data 
The efficacy analyses will be performed based on the FAS according to assigned treatment 
group. 
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary endpoint of change from baseline in constant work rate exercise endurance time at 
week 12 will be descriptively summarized.  
Please note that the primary endpoint of change from baseline in constant work rate exercise 
endurance time at week 12 was originally planned to be analyzed using ANCOVA model for the 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 31 of 46 
FAS with treatment group, randomization stratification factor, and relevant baseline 
measurement as covariates included in the model.  
5.7.2. 
Analysis of Key Secondary Efficacy Variable  
Pre-exercise FEV1 will be assessed within 15 minutes prior to the start of the exercise testing 
and post-exercise FEV1 will be performed at minutes 5±1, 10±1, and 20±1 post-exercise. Pre-
exercise FEV1 and Post-exercise FEV1 will be analyzed descriptively.  
Continuous secondary efficacy endpoints that are to be measured by accelerometry will be 
summarized. 7-day average values of measurements from accelerometry are calculated for 
baseline and week 12 if days with a wear time of at least 22 hours (accounting for non-wear 
periods as permissible in protocol) and at least 5 valid days per week are available. 
5.7.3. 
Analysis of Exploratory Variables 
5.7.3.1. 
Measurements associated with CPET 
Continuous secondary efficacy endpoints that are to be measured associated with CPET will be 
analyzed in the same fashion as the primary endpoint. 
5.7.3.2. 
Patient Diary 
7-day average values of measurements from patient diary are calculated for baseline and week 12 
and will be summarized descriptively if at least 5 valid days per week are available. 
Additionally, the same analysis is repeated for patients with at least 4 valid days per week.  
• Change from baseline to week 12 in number of nocturnal awakenings per night due to 
asthma from patient diary 
5.7.3.3. 
Spirometry not associated with CPET 
Pre-exercise FEV1 and FVC at baseline will be used as baseline value. Change from baseline in 
FEV1 and FVC at week 4 will be summarized. 
5.7.3.4. 
Patient-Reported Outcomes 
PRO data (ACQ-5, AQLQ(S), PGIC, PGII) will be summarized descriptively, as described in 
Section 4  
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF. The summary of safety 
results will be presented by treatment group and in overall total. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 32 of 46 
5.8.1. 
Adverse Events  
The verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be 
displayed in subject listings. Summaries that include number and proportions of patients 
reporting AEs will include the PTs and the SOCs. 
 Period of observation: The observation period will be divided into three periods:  pre-
treatment, on-treatment and post-treatment. 
• The pre-treatment period is defined as the time between signing the ICF to before the 
first dose of study drug.  
• The on-treatment period is defined as the time from the date of the first dose of study 
drug to the week 12 visit date (study day 85 starting from the first dose of study drug 
if week 12 visit date is unavailable) or early termination date, whichever comes first.  
• The post-treatment period is defined as days from the date after week 12 visit date 
(study day 85 starting from first dose of study drug if week 12 visit date is 
unavailable) to end of study.  
Treatment-emergent AEs are defined as AEs that developed or worsened during the on-treatment 
period and post-treatment period. 
Summaries of all TEAEs by treatment group during the 12-week treatment period, and during 
the follow-up period will include: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
•  TEAEs by severity, presented by SOC and PT 
• Treatment related TEAEs, presented by SOC and PT 
• Serious and treatment related serious TEAEs, presented by SOC and PT 
• TEAEs leading to permanent treatment discontinuation, presented by SOC and PT 
• TEAEs leading to death, presented by SOC and PT 
For each TEAE summary presented by SOC and PT, the summary table will be sorted by 
decreasing frequency of SOC and PT. For TEAE summary presented by PT, the summary table 
will be sorted by decreasing frequency of PT of the dupilumab arm. 
Counts will be provided for each patient within each SOC and PT. Percentages will be calculated 
using the number of patients from the SAF in each group. 
For details on handling missing data and partial dates, see Section 6. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 33 of 46 
5.8.2. 
Clinical Laboratory Measurements 
Laboratory measurements include clinical chemistry, hematology, and urinalysis results, and will 
be converted to values in standard international units. Summaries of laboratory variables will 
include: 
• Descriptive statistics of laboratory result and change from baseline by visit, if 
applicable.  
• The number (n) and percentage (%) of subjects with treatment-emergent PCSVs. This 
summary will be provided based on all patients in the SAF as well as in the subgroup 
of SAF patients who did not meet the PCSV criterion at baseline (normal or missing). 
• Shift tables based on baseline normal/abnormal will be presented  
5.8.3. 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be listed and 
summarized by baseline and change from Baseline to each scheduled assessment time with 
descriptive statistics. 
The number and percentage of patients with a treatment-emergent potentially clinically 
significant value (PCSV) will be summarized for each vital sign variable. 
5.8.4. 
Electrocardiography (ECG) 
ECG status (i.e., normal, abnormal but not clinically significant, abnormal and clinically 
significant) will be reported.  
5.8.5. 
Physical Exams 
Physical examination findings at baseline as well as post-treatment abnormal findings by body 
system and status (normal, abnormal and not done) will be provided with Listing and Tables if 
applicable.  
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 34 of 46 
6. 
DATA HANDLING CONVENTIONS 
6.1. 
Data Handling Convention for Missing Data 
No missing data imputation is planned in this study unless specified otherwise. 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
6.1.1. 
Medication 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing 
medication end date is estimated as late as possible. If the medication start date is missing, the 
onset day will not be calculated in medication listings. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit 
date instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
6.1.2. 
PCSV 
Patients who had post-baseline PCSV, but missing baseline value will be regarded as having 
treatment emergent PCSV. Refer to Appendix for PCSV table.  
6.2. 
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be included in the 
computation of baseline, worst values, and PCSVs, if applicable.  
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 35 of 46 
7. 
INTERIM ANALYSIS 
No interim analysis was planned for this study. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 36 of 46 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above.  
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 37 of 46 
9. 
REFERENCES 
American Thoracic Society, American College of Chest Physicians. ATS/ACCP Statement on 
cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003; 167(2):211-77. 
Attal F, Mohammed S, Dedabrishvili M, Chamroukhi F, Oukhellou L, Amirat Y. Physical 
Human Activity Recognition Using Wearable Sensors. Sensors (Basel) 2015; 15(12):31314-38. 
Bahmer T, Waschki B, Schatz F, Herzmann C, Zabel P, Kirsten AM, et al. Physical activity, 
airway resistance and small airway dysfunction in severe asthma. Eur Respir J 2017; 49(1). 
Benfante A, Di Marco F, Terraneo S, Centanni S, Scichilone N. Dynamic hyperinflation during 
the 6-min walk test in severely asthmatic subjects. ERJ Open Res 2018; 4(2). 
Borg E, Borg G, Larsson K, Letzter M, Sundblad BM. An index for breathlessness and leg 
fatigue. Scand J Med Sci Sports 2010; 20(4):644-50. 
Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14(5):377-
81. 
Casaburi R, Maltais F, Porszasz J, Albers F, Deng Q, Iqbal A, et al. Effects of tiotropium on 
hyperinflation and treadmill exercise tolerance in mild to moderate chronic obstructive 
pulmonary disease. Ann Am Thorac Soc 2014; 11(9):1351-61. 
Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab Efficacy and 
Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med 2018; 378(26):2486-96. 
Cordova-Rivera L, Gibson PG, Gardiner PA, Powell H, McDonald VM. Physical Activity and 
Exercise Capacity in Severe Asthma: Key Clinical Associations. J Allergy Clin Immunol Pract 
2018; 6(3):814-22. 
Dockrell M, Partridge MR, Valovirta E. The limitations of severe asthma: the results of a 
European survey. Allergy 2007; 62(2):134-41. 
Freeman W, Packe GE, Cayton RM. Effect of nebulised salbutamol on maximal exercise 
performance in men with mild asthma. Thorax 1989; 44(11):942-7. 
Fuhlbrigge AL, Adams RJ, Guilbert TW, Grant E, Lozano P, Janson SL, et al. The burden of 
asthma in the United States: level and distribution are dependent on interpretation of the national 
asthma education and prevention program guidelines. Am J Respir Crit Care Med 2002; 
166(8):1044-9. 
Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key 
proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 2016; 15(1):35-50. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 38 of 46 
Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation FDA. 2009. 
US Department of Health and Human Services Food and Drug Administration. 
Haverkamp HC, Dempsey JA, Pegelow DF, Miller JD, Romer LM, Santana M, et al. Treatment 
of airway inflammation improves exercise pulmonary gas exchange and performance in 
asthmatic subjects. J Allergy Clin Immunol 2007; 120(1):39-47. 
Hennegrave F, Le Rouzic O, Fry S, Behal H, Chenivesse C, Wallaert B. Factors associated with 
daily life physical activity in patients with asthma. Health Sci Rep 2018; 1(10):e84. 
ICH Harmonized Tripartite Guideline: Clinical Safety Data Management: Definitions and 
Standards For Expedited Reporting (E2A). 1994. International Conference on Harmonization of 
Technical Requirements for Registration of Pharmaceuticals for Human Use 
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. 
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. Respir Med 2005; 99(5):553-8. 
Kim Y, Beets MW, Welk GJ. Everything you wanted to know about selecting the "right" 
Actigraph accelerometer cut-points for youth, but...: a systematic review. J Sci Med Sport 2012; 
15(4):311-21. 
Mahler DA, Faryniarz K, Lentine T, Ward J, Olmstead EM, O'Connor GT. Measurement of 
breathlessness during exercise in asthmatics. Predictor variables, reliability, and responsiveness. 
Am Rev Respir Dis 1991; 144(1):39-44. 
Maltais F, Celli B, Casaburi R, Porszasz J, Jarreta D, Seoane B, et al. Aclidinium bromide 
improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. 
Respir Med 2011; 105(4):580-7. 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of 
spirometry. Eur Respir J 2005; 26(2):319-38. 
O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, et al. Effects of 
tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 
23(6):832-40. 
Puente-Maestu L, Palange P, Casaburi R, Laveneziana P, Maltais F, Neder JA, et al. Use of 
exercise testing in the evaluation of interventional efficacy: an official ERS statement. Eur 
Respir J 2016; 47(2):429-60. 
Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and Safety of 
Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med 2018; 378(26):2475-85. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 39 of 46 
Robertson W, Simkins J, O'Hickey SP, Freeman S, Cayton RM. Does single dose salmeterol 
affect exercise capacity in asthmatic men? Eur Respir J 1994; 7(11):1978-84. 
Schaper C, Glaser S, Felix SB, Gogolka A, Koch B, Krull M, et al. Omalizumab treatment and 
exercise capacity in severe asthmatics - results from a pilot study. Respir Med 2011; 105(1):3-7. 
Vatrella A, Fabozzi I, Calabrese C, Maselli R, Pelaia G. Dupilumab: a novel treatment for 
asthma. J Asthma Allergy 2014; 7(123-30. 
Vermeulen F, Garcia G, Ninane V, Laveneziana P. Activity limitation and exertional dyspnea in 
adult asthmatic patients: What do we know? Respir Med 2016; 117(122-30. 
Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and 
safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled 
corticosteroids plus a long-acting beta2 agonist: a randomised double-blind placebo-controlled 
pivotal phase 2b dose-ranging trial. Lancet 2016; 388(10039):31-44 
 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 40 of 46 
10. 
APPENDIX  
10.1. 
Criteria for Potentially Clinically Significant Values (PCSV) 
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT 
By distribution 
analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero 
can be deleted. 
AST 
By distribution 
analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero 
can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. Categories 
are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin 
and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
(ALT or AST) and 
Total Bilirubin 
((ALT ≤3 × ULN and 
AST ≤3 × ULN) or 
TBILI ≤2 × ULN) at 
baseline and ((ALT 
>3 × ULN or AST >3 
× ULN) and TBILI 
>2 × ULN) post-
baseline 
  
  
  
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 41 of 46 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero 
can be deleted. 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on 
the Cokcroft-Gault 
equation) 
<15 (end stage renal 
disease) 
≥15 - <30 (severe 
decrease in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild 
decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study 
design, data analysis, and impact on dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation) 
 
<15 (end stage renal 
disease) 
≥15 - <30 (severe 
decrease in GFR) 
≥30 - < 60 (moderate 
decrease in GFR) 
≥60 - <90 (mild 
decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal function-study 
design, data analysis, and impact on dosing and labeling 
Creatinine 
≥150 μmol/L 
(Adults) 
≥30% change from 
baseline 
≥100% change from 
baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia 
Hypouricemia 
 
>408 μmol/L 
<120 μmol/L 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 42 of 46 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and 
<LLN 
≥11.1 mmol/L 
(unfasted); ≥7 
mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L 
(if ULN not 
provided) 
FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-
Black); <2.0 Giga/L 
(Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-
Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or 
>ULN (if ULN≥0.5 
Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 43 of 46 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
Hemoglobin 
 >115 g/L at baseline 
and ≤115 g/L post-
baseline for Male; 
>95 g/L at baseline 
and ≤95 g/L post-
baseline for Female 
<185 g/L at baseline 
and ≥185 g/L post-
baseline for Male; 
<165 g/L at baseline 
and ≥165 g/L post-
baseline for Female 
Decrease from 
baseline by ≥20 g/L 
  
Three criteria are independent. 
Criteria based upon decrease from baseline are more relevant 
than those based on absolute value. Other categories for 
decrease from baseline can be used (≥30 g/L, ≥40 g/L, ≥50 g/L). 
 
 
Hematocrit 
 >0.37 v/v at baseline 
and ≤0.37 v/v post-
baseline for Male; 
>0.32 v/v at baseline 
and ≤0.32 v/v post-
baseline for Female 
<0.55 v/v at baseline 
and ≥0.55 v/v post-
baseline for Male; 
<0.5 v/v at baseline 
and ≥0.5 v/v post-
baseline for Female 
 
RBC 
≥4 Tera/L at baseline 
and <4 Tera/L post-
baseline for Male; ≥3 
Tera/L at baseline 
and <3 Tera/L post-
baseline for Female 
<7 Tera/L at baseline 
and ≥7 Tera/L post-
baseline for Male; <6 
Tera/L at baseline 
and ≥6 Tera/L post-
baseline for Female 
 
Unless specifically required for particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 44 of 46 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
Vital signs 
HR 
≤50 bpm and 
decrease from 
baseline ≥20 bpm 
≥120 bpm and 
increase from 
baseline≥20 bpm 
 
 
 
 
 
 
To be applied for all positions (including missing) except 
STANDING. 
 
 
 
Respiratory rate 
 
 
 
 
 
 
SBP 
≥12 breaths per 
minute at baseline 
and <12 breaths per 
minute post-baseline 
≤20 breaths per 
minute at baseline 
and >20 breaths per 
minute post-baseline 
 
 
≤95 mmHg and 
decrease from 
baseline ≥20mmHg 
≥160 mmHg and 
increase from 
baseline ≥20 mmHg 
 
To be applied for all positions (including missing) except 
STANDING. 
DBP 
≤45 mmHg and 
decrease from 
baseline ≥10 mmHg 
≥110 mmHg and 
increase from 
baseline ≥10 mmHg 
 
To be applied for all positions (including missing) except 
STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 45 of 46 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
Weight 
≥5% increase from 
baseline 
≥5% decrease from 
baseline 
 
FDA Feb 2007 
ECG 
Ref.: ICH E14 
guidance (2005) and 
E14 Q&A (2012), 
and Cardiac Safety 
Research Consortium 
White Paper on PR 
and QRS (Nada et al. 
Am Heart J. 2013; 
165(4) : 489-500) 
 
HR 
 ≤50 bpm post-
baseline and decrease 
from baseline by ≥20 
bpm 
≥120 bpm post-
baseline and increase 
from baseline by ≥20 
bpm 
 
Categories are cumulative 
Ref.: CPMP 1997 guideline 
PR 
≥220 ms post-
baseline and increase 
from baseline by ≥20 
ms 
 
Ref.: CPMP 1997 guideline. 
 
QRS 
<120 ms at baseline 
and ≥120 ms post-
baseline 
 
Ref.: CPMP 1997 guideline. 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc.  
Protocol Number R668-AS-1903 
Statistical Analysis Plan v1.0 
 
REGENERON CONFIDENTIAL 
Page 46 of 46 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT VALUES (PCSV) 
Parameter 
PCSV 
Comments 
 
QTcB/QTcF 
 
 Borderline: 
<431 ms at baseline 
and 431-450 ms post-
baseline for Male;  
<451 ms at baseline 
and 451-470 ms post-
baseline for Female 
Prolonged: 
≤450 ms at baseline 
and >450 to <500 ms 
post-baseline for 
Male;  
≤470 ms at baseline 
and >470 to <500 ms 
post-baseline for 
Female 
<500 ms at baseline 
and ≥500 ms post-
baseline 
Increase from 
baseline 
Borderline: Increase 
from baseline by 30-
60 ms 
Prolonged: Increase 
from baseline by >60 
ms 
  
  
 
 
Ref.: CPMP 1997 guideline. 
 
5 independent criteria 
 
 
  
 
 
 
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00


Signature Page for VV-RIM-00299848 v1.0
Signature Page for VV-RIM-00299848 v1.0 Approved
Approval/eSignature
15-May-2023 16:10:16 GMT+0000
Approval/eSignature
15-May-2023 16:14:38 GMT+0000
Approval/eSignature
15-May-2023 21:05:32 GMT+0000
                                        VV-RIM-00299848-1.0 Approved - 15 May 2023 GMT-5:00