Clinical trial NCT04709575
Conditions: Allergic Rhinitis Conjunctivitis
Keywords: Birch Allergy
Sponsor: Regeneron Pharmaceuticals
Start date: 2021-01-14; Completion date: 2021-08-24
Enrollment: 353 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess the reduction of allergic symptoms as measured by combined symptom and medication score (CSMS) during birch pollen season after a single dose of REGN5713-5714-5715 versus placebo.

Detailed description:

Arms: arm 1: REGN5713-5714-5715 administered subcutaneously arm 2: Placebo matching REGN5713-5714-5715 administered subcutaneously
Interventions: intervention 1: REGN5713 intervention 2: REGN5714 intervention 3: REGN5715 intervention 4: Placebo
Intervention descriptions: intervention 1: Administered subcutaneously intervention 2: Administered subcutaneously intervention 3: Administered subcutaneously intervention 4: Placebo that replaces REGN5713-5714-5715

Protocol documents:
Prot_000.pdf: 
EudraCT: 2020-004094-52 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY ASSESSING THE EFFICACY OF  
ANTI-BET V 1 MONOCLONAL ANTIBODIES TO REDUCE 
SYMPTOMS OF SEASONAL ALLERGIC RHINITIS 
Compound: 
REGN5713-5714-5715 
Clinical Phase: 
3 
Protocol Number: 
R5713-5714-5715-ALG-2001 
Protocol Version: 
R5713-5714-5715-ALG-2001 Original 
Date of Issue:  
See appended electronic signature page 
Medical/Study Director: 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
VV-RIM-00121234-2.0 Approved - 28 Sep 2020 GMT-5:00
NCT04709575


Clinical Study Protocol 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACQ 
Asthma Control Questionnaire 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAT 
Basophil activation tests 
BUN 
Blood urea nitrogen 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CSMS 
Combined symptom and medication score 
CSR 
Clinical study report 
CTFG 
Clinical Trial Facilitation Group 
DMS 
Daily medication score 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
FIH 
First in human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
Ig 
Immunoglobulin  
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
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IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LAM 
Lactational amenorrhea method 
mAb 
Monoclonal antibody 
NAb 
Neutralizing antibody 
OAS 
Oral allergy syndrome 
PBMC 
Peripheral blood mononuclear cells 
PCA 
Percutaneous anaphylaxis 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic  
PFAS 
Pollen food allergy syndrome 
PFASQ 
Pollen food allergy symptom questionnaire 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
POC 
Proof of concept 
RBC 
Red blood cell 
RBQM 
Risk-Based Quality Monitoring 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RQLQ (S) 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire 
RSOC 
Regeneron Safety Oversight Committee 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
sIgE 
Allergen-specific IgE 
SIT 
Specific immunotherapy 
SLIT 
Sublingual immunotherapy 
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SMS 
Symptom and medical score 
SMT 
Safety Monitoring Team 
SOC 
System organ class 
SPT 
Skin prick test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
TSS 
Total symptom score 
WAO 
World Allergy Organization 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................11 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
Allergic Disease, Birch Allergy, and Allergen-Specific Immunotherapy ..................16 
1.2. 
Monoclonal Antibodies for the Treatment of Allergic Diseases ................................17 
1.3. 
REGN5713, REGN5714, and REGN5715: Fully Human Monoclonal 
Antibodies Against Bet v 1 .........................................................................................18 
2. 
STUDY OBJECTIVES ..............................................................................................19 
2.1. 
Primary Objective .......................................................................................................19 
2.2. 
Secondary Objectives .................................................................................................20 
2.3. 
Exploratory Objectives ...............................................................................................20 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................21 
3.1. 
Hypothesis ..................................................................................................................21 
3.2. 
Rationale .....................................................................................................................21 
3.2.1. 
Rationale for Study Design .........................................................................................21 
3.2.2. 
Rationale for Dose Selection ......................................................................................23 
3.2.3. 
Rationale for the Selected Anti-Bet v 1 Monoclonal Antibody Cocktail ...................24 
3.3. 
Risk-Benefit ................................................................................................................24 
4. 
ENDPOINTS ..............................................................................................................25 
4.1. 
Primary Endpoint ........................................................................................................25 
4.2. 
Secondary Endpoints ..................................................................................................25 
4.3. 
Exploratory Endpoints ................................................................................................26 
5. 
STUDY VARIABLES................................................................................................26 
5.1. 
Demographic and Baseline Characteristics ................................................................26 
5.2. 
Efficacy Variables ......................................................................................................26 
5.3. 
Safety Variables ..........................................................................................................27 
5.4. 
Pharmacokinetic Variables .........................................................................................27 
5.5. 
Immunogenicity Variables ..........................................................................................27 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................27 
5.7. 
Other Variables ...........................................................................................................27 
6. 
STUDY DESIGN .......................................................................................................27 
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6.1. 
Study Description and Duration .................................................................................27 
6.1.1. 
Study Stopping Rules .................................................................................................28 
6.1.2. 
End of Study Definition ..............................................................................................28 
6.2. 
Planned Interim Analysis ............................................................................................28 
6.3. 
Study Committees .......................................................................................................29 
6.3.1. 
Safety Monitoring Team .............................................................................................29 
6.3.2. 
Independent Data Monitoring Committee ..................................................................29 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS ..............29 
7.1. 
Number of Subjects Planned ......................................................................................29 
7.2. 
Study Population .........................................................................................................29 
7.2.1. 
Inclusion Criteria ........................................................................................................30 
7.2.2. 
Exclusion Criteria .......................................................................................................30 
7.3. 
Premature Withdrawal from the Study .......................................................................33 
7.4. 
Replacement of Subjects .............................................................................................33 
8. 
STUDY TREATMENTS............................................................................................33 
8.1. 
Investigational and Reference Treatments ..................................................................33 
8.2. 
Rescue Treatments ......................................................................................................33 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................34 
8.4. 
Management of Acute Reactions ................................................................................34 
8.4.1. 
Acute Injection Reactions ...........................................................................................34 
8.4.1.1. 
Systemic Injection Reactions ......................................................................................34 
8.4.1.2. 
Local Injection Site Reactions ....................................................................................34 
8.5. 
Method of Treatment Assignment ..............................................................................35 
8.6. 
Blinding ......................................................................................................................35 
8.7. 
Emergency Unblinding ...............................................................................................35 
8.8. 
Treatment Logistics and Accountability .....................................................................36 
8.8.1. 
Packaging, Labeling, and Storage ..............................................................................36 
8.8.2. 
Supply and Disposition of Treatments .......................................................................36 
8.8.3. 
Treatment Accountability ...........................................................................................36 
8.8.4. 
Treatment Compliance ................................................................................................37 
8.9. 
Concomitant Medications ...........................................................................................37 
8.9.1. 
Prohibited Medications ...............................................................................................37 
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8.9.2. 
Permitted Medications ................................................................................................38 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................38 
9.1. 
Schedule of Events .....................................................................................................38 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................41 
9.1.2. 
Early Termination Visit ..............................................................................................42 
9.1.3. 
Unscheduled Visits .....................................................................................................42 
9.2. 
Study Procedures ........................................................................................................42 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................42 
9.2.2. 
Pollen Counting ..........................................................................................................42 
9.2.3. 
Birch Allergen and Standard Regional Skin Prick Tests ............................................43 
9.2.4. 
Efficacy Procedures ....................................................................................................43 
9.2.4.1. 
Total Nasal Symptom Score .......................................................................................43 
9.2.4.2. 
Total Ocular Symptom Score .....................................................................................43 
9.2.4.3. 
Total Symptom Score .................................................................................................43 
9.2.4.4. 
Daily Medication Score ..............................................................................................43 
9.2.4.5. 
Combined Symptom and Medication Score ...............................................................43 
9.2.4.6. 
Asthma Control Questionnaire ...................................................................................44 
9.2.4.7. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire ..............................44 
9.2.4.8. 
Pollen Food Allergy Symptom Questionnaire ............................................................44 
9.2.4.9. 
Patient Global Impression of Severity ........................................................................44 
9.2.5. 
Safety Procedures .......................................................................................................44 
9.2.5.1. 
Vital Signs ..................................................................................................................44 
9.2.5.2. 
Physical Examination .................................................................................................44 
9.2.5.3. 
Body Weight ...............................................................................................................45 
9.2.5.4. 
Spirometry ..................................................................................................................45 
9.2.6. 
Electrocardiogram .......................................................................................................45 
9.2.7. 
Laboratory Testing ......................................................................................................45 
9.2.7.1. 
Hematology, Blood Chemistry, Pregnancy Test, and Urinalysis ...............................45 
9.2.7.2. 
Serum Antibodies .......................................................................................................46 
9.2.8. 
Drug Concentration and Measurements .....................................................................47 
9.2.9. 
Immunogenicity Measurements and Samples ............................................................47 
9.2.10. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................47 
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9.2.10.1. 
Exploratory Biomarker Research ...............................................................................47 
9.2.11. 
Future Biomedical Research (Optional) .....................................................................48 
9.2.12. 
Pharmacogenomic Analysis (Optional) ......................................................................48 
10. 
SAFETY EVALUATION AND REPORTING .........................................................49 
10.1. 
Recording and Reporting Adverse Events ..................................................................49 
10.1.1. 
General Guidelines .....................................................................................................49 
10.1.2. 
Reporting Procedure ...................................................................................................50 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................50 
10.2. 
Definitions ..................................................................................................................50 
10.2.1. 
Adverse Event .............................................................................................................50 
10.2.2. 
Serious Adverse Event ................................................................................................51 
10.2.3. 
Adverse Events of Special Interest .............................................................................51 
10.2.4. 
Severity .......................................................................................................................51 
10.2.5. 
Causality .....................................................................................................................52 
10.3. 
Safety Monitoring .......................................................................................................53 
10.4. 
Notifying Health Authorities, Institutional Review Board, Ethics Committee, 
and Investigators .........................................................................................................54 
11. 
STATISTICAL PLAN................................................................................................54 
11.1. 
Statistical Hypothesis ..................................................................................................54 
11.2. 
Justification of Sample Size........................................................................................55 
11.3. 
Analysis Sets ...............................................................................................................55 
11.3.1. 
Efficacy Analysis Sets ................................................................................................55 
11.3.2. 
Safety Analysis Set .....................................................................................................55 
11.3.3. 
Pharmacokinetic Analysis Set ....................................................................................55 
11.3.4. 
Immunogenicity Analysis Set .....................................................................................55 
11.4. 
Statistical Methods ......................................................................................................56 
11.4.1. 
Subject Disposition .....................................................................................................56 
11.4.2. 
Demography and Baseline Characteristics .................................................................56 
11.4.3. 
Efficacy Analyses .......................................................................................................56 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................56 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................57 
11.4.3.3. 
Exploratory Efficacy Analysis ....................................................................................57 
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11.4.4. 
Control of Multiplicity ................................................................................................57 
11.4.5. 
Safety Analysis ...........................................................................................................58 
11.4.5.1. 
Adverse Events ...........................................................................................................58 
11.4.5.2. 
Other Safety ................................................................................................................58 
11.4.5.3. 
Treatment Exposure ....................................................................................................59 
11.4.5.4. 
Treatment Compliance ................................................................................................59 
11.4.6. 
Pharmacokinetics ........................................................................................................59 
11.4.6.1. 
Analysis of Drug Concentration Data .........................................................................59 
11.4.7. 
Analysis of Immunogenicity Data ..............................................................................59 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................60 
11.5. 
Additional Statistical Data Handling Conventions .....................................................60 
11.6. 
Interim Analysis ..........................................................................................................61 
11.7. 
Statistical Considerations Surrounding the Premature Termination of a Study .........61 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................61 
12.1. 
Data Management and Electronic Systems ................................................................61 
12.1.1. 
Data Management .......................................................................................................61 
12.1.2. 
Electronic Systems ......................................................................................................61 
12.2. 
Study Monitoring ........................................................................................................62 
12.2.1. 
Monitoring of Study Sites ...........................................................................................62 
12.2.2. 
Source Document Requirements ................................................................................62 
12.2.3. 
Case Report Form Requirements ................................................................................62 
12.3. 
Audits and Inspections ................................................................................................63 
12.4. 
Study Documentation .................................................................................................63 
12.4.1. 
Certification of Accuracy of Data ...............................................................................63 
12.4.2. 
Retention of Records ..................................................................................................63 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................64 
13.1. 
Good Clinical Practice Statement ...............................................................................64 
13.2. 
Informed Consent .......................................................................................................64 
13.3. 
Subjects Confidentiality and Data Protection .............................................................64 
13.4. 
Institutional Review Board and Ethics Committee ....................................................65 
13.5. 
Clinical Study Data Transparency ..............................................................................65 
14. 
PROTOCOL AMENDMENTS ..................................................................................65 
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15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................65 
15.1. 
Premature Termination of the Study ...........................................................................65 
15.2. 
Close-out of a Site ......................................................................................................66 
16. 
CONFIDENTIALITY ................................................................................................66 
17. 
FINANCING AND INSURANCE .............................................................................66 
18. 
PUBLICATION POLICY ..........................................................................................66 
19. 
REFERENCES ...........................................................................................................67 
20. 
INVESTIGATOR’S AGREEMENT ..........................................................................73 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................74 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................39 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................28 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Assessing the Efficacy 
of Anti-Bet v 1 Monoclonal Antibodies to Reduce Symptoms of Seasonal Allergic Rhinitis 
Site Locations 
Principal 
Investigator 
Approximately 50 sites in North America and Europe 
To be determined 
Objectives 
Primary Objectives 
The primary objective is to assess the reduction of allergic symptoms as measured by 
combined symptom and medication score (CSMS) during birch pollen season after a single 
dose of REGN5713-5714-5715 versus placebo.  
Secondary Objectives 
The secondary objectives are: 
• 
To assess the reduction of allergic symptoms and use of allergy-relieving 
medications after a single dose of REGN5713-5714-5715 versus placebo, as 
measured by the total symptom score (TSS), total nasal symptom score (TNSS), 
total ocular symptom score (TOSS), and daily medication score (DMS) 
• 
To evaluate the safety and tolerability of REGN5713-5714-5715, including the 
incidence of hypersensitivity reactions and local injection site reactions 
• 
To evaluate the reduction in early allergic response to birch allergen after a 
single dose of REGN5713-5714-5715 versus placebo, as measured by skin 
prick test (SPT) mean wheal diameter 
• 
To determine systemic exposure of total antibody (ie, free and antigen-bound) 
in the form of concentration of REGN5713, REGN5714, and REGN5715 in 
serum 
• 
To assess the immunogenicity to REGN5713, REGN5714, and REGN5715 in 
subjects after a single dose of REGN5713-5714-5715  
• 
To evaluate “well days” 
Note: “Well days” are defined as days when the TSS is ≤2 without the use of 
anti-allergy rescue medications. 
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Exploratory Objectives 
The exploratory objectives are: 
• 
To assess asthma control as measured by the asthma control questionnaire 
(ACQ-5) 
• 
To assess quality of life as measured by the rhinoconjunctivitis quality of life 
questionnaire (RQLQ [S])  
• 
To evaluate the reduction in early allergic response to birch homologous 
allergens (alder and oak) as measured by SPT mean wheal diameter 
• 
To assess the relationship between allergy sensitization status to Bet v 1 or birch 
pollen at screening (as measured by serum allergen specific-IgE [sIgE]) and 
clinical response to REGN5713-5714-5715 treatment  
• 
To assess serum sIgE levels against Bet v 1 and birch pollen during birch pollen 
season to evaluate the relationship between the response to REGN5713-5714-
5715 and change in sIgE levels in-season  
• 
To assess the inhibitory effect of REGN5713-5714-5715 on the binding of 
endogenous serum IgE to birch allergen in an in vitro assay; to assess whether 
the degree of inhibition correlates with clinical improvement  
• 
To assess sIgE levels against other allergens (eg, Bet v 2, alder and oak) at 
screening and to evaluate the relationship between response to REGN5713-
5714-5715 and poly-allergic status 
• 
To assess additional subclasses of serum antibodies (eg, total IgG and IgG4 
against birch pollen and Bet v 1) to evaluate the relationship between 
endogenous anti-Bet v 1 antibodies and response to REGN5713-5714-5715  
• 
To assess the reduction in pollen food allergy syndrome (PFAS) and related 
symptoms as measured by pollen food allergy symptom questionnaire (PFASQ) 
• 
To assess patient rating of severity of seasonal allergy symptoms as measured 
by patient global impression of severity (PGI-S) 
Study Design 
This is a phase 3 multi-center, randomized, double-blind, placebo-controlled, parallel 
group study to assess the efficacy of anti-Bet v 1 monoclonal antibodies (mAbs; 
REGN5713-5714-5715) to reduce allergic rhinitis and conjunctivitis symptoms and the 
use of rescue medications during birch pollen season. Efficacy will be evaluated by 
assessing the reduction of allergic nose and eye symptoms and the reduction in the use of 
allergy rescue medications during birch pollen season, after a single SC dose of 
REGN5713-5714-5715 or placebo.  
The incidence and severity of treatment-emergent adverse events (TEAEs), including 
hypersensitivity reactions and local injection site reactions, will be assessed. Total 
concentration in serum and immunogenicity of REGN5713, REGN5714, and REGN5715 
will also be measured. 
Study Duration 
The total study duration is approximately 28 weeks including screening, dependent on the 
start and end times of the local birch pollen season. The length of birch pollen season will 
vary based on geography. 
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End of Study 
Definition 
The end of study is defined as the date the last subject completes the last study visit, 
withdraws from the study, or is lost to follow-up (ie, the study subject can no longer be 
contacted by the investigator). 
Population 
Approximately 300 generally healthy adult male and female subjects with birch allergy 
will be enrolled. Other inclusion and exclusion criteria apply. 
Study Drug and 
Placebo 
Dose/Route/Schedul
e: 
• 
REGN5713-5714-5715 900 mg (300 mg per mAb), single SC dose 
• 
Matching placebo that replaces REGN5713-5714-5715, single SC dose 
Endpoints 
Primary Endpoint 
The primary endpoint is the daily CSMS, averaged over the duration of the birch pollen 
season, in subjects who receive a single dose of REGN5713-5714-5715 versus placebo. 
Secondary Endpoints 
The secondary endpoints are: 
• 
TSS, TNSS, and TOSS, averaged over the duration of the birch pollen season, 
in subjects who receive a single dose of REGN5713-5714-5715 versus placebo  
• 
DMS, averaged over the duration of the birch pollen season, in subjects who 
receive a single dose of REGN5713-5714-5715 versus placebo 
• 
Incidence of TEAEs and serious TEAEs throughout the study  
• 
Change and percent change from baseline to the end of study in birch SPT mean 
wheal diameter in subjects who receive a single dose of REGN5713-5714-5715 
versus placebo 
• 
Total REGN5713, REGN5714, and REGN5715 concentration in serum over 
the study duration 
• 
Incidence of treatment emergent anti-drug antibodies (ADAs) to REGN5713, 
REGN5714, or REGN 5715 throughout the study 
• 
The number of “well days” in each of the treatment groups, where the “well 
days” are defined as days when rescue medication is not utilized and the TSS 
is ≤2/18 
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Exploratory Endpoints 
The exploratory endpoints are: 
• 
ACQ-5, averaged over the duration of the birch pollen season, for 
REGN5713-5714-5715 versus placebo  
• 
RQLQ (S), averaged over the duration of the birch pollen season, for 
REGN5713-5714-5715 versus placebo  
• 
Change and percent change from baseline to the end of study in SPT mean 
wheal 
diameter 
for 
birch 
homologous/cross-reactive 
allergens 
in 
REGN5713-5714-5715 versus placebo  
• 
Baseline allergen-specific IgE levels and correlation with average CSMS, TSS, 
TNSS, TOSS, DMS during birch pollen season 
• 
Change and percent change from baseline to the peak of birch pollen season in 
allergen-specific IgE  
• 
Change in inhibitory effect on serum IgE to birch allergen 
• 
Number of baseline sensitizations to other allergens (poly/mono-sensitization 
status, based on allergen-specific IgE levels) and correlation with CSMS, TSS, 
TNSS, TOSS, and DMS, averaged over the duration of the birch pollen season 
• 
Baseline serum antibody levels and correlation with CSMS, TSS, TNSS, TOSS, 
and DMS, averaged over the duration of the birch pollen season 
• 
To assess the reduction in PFAS and related symptoms, as measured by 
PFASQ, from baseline to end of study  
• 
To assess patient rating of severity of seasonal allergy symptoms, as measured 
by PGI-S, from baseline to end of study 
Procedures and 
Assessments 
The following procedures will be performed to determine study eligibility and characterize 
the baseline population: 
• 
Skin prick test (SPT) for birch and standard regional allergens 
• 
Serum allergen-specific IgE (sIgE) tests for birch tree pollen and Bet v 1  
• 
Serum sIgE tests for concomitant and homologous allergens 
• 
Medical history, demographics, weight, height, vital signs, physical 
examination, electrocardiogram (ECG), spirometry, hematology, and blood 
chemistry 
Efficacy assessments will include TNSS, TOSS, DMS, ACQ-5, RQLQ (S), PFASQ, and 
PGI-S. 
Safety assessments will include monitoring laboratory tests (hematology, blood chemistry, 
pregnancy tests), weight, vital signs, physical examination, adverse events (AEs), 
concomitant medications, and spirometry. 
Samples will also be collected for PK, ADA, and exploratory research. 
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Statistical Plan 
Justifications for Sample Size 
This study is powered to detect differences between REGN5713-5714-5715 and placebo 
on the primary endpoint of the average CSMS during birch pollen season. A sample size 
of 150 enrolled subjects per arm gives 90% power to detect a mean difference in average 
CSMS of 1.9 (30% reduction from placebo) in REGN5713-5714-5715 (mean 
CSMS = 4.4) and placebo (mean CSMS = 6.3), assuming a common standard deviation in 
CSMS of 4.5. The minimum significant difference in CSMS is 1.14, or approximately an 
18% reduction from placebo. This sample size calculation assumes a 20% drop out rate 
(30 subjects per arm) and a two-sample t-test with two-sided alpha of 0.05. Estimates of 
mean and variability of the CSMS are based on pooled estimates across several field 
studies for grass immunotherapy, and a 30% treatment effect relative to placebo is in line 
with what was observed in the phase 1b POC study for REGN5713-5714-5715. 
Primary Efficacy Analysis 
The primary analysis will focus on the comparison between the REGN5713-5714-5715 
arm and placebo arm. The average CSMS during birch pollen season will be compared in 
subjects receiving REGN5713-5714-5715 and subjects receiving placebo using a linear 
mixed-effect model, with the treatment group and randomization stratification factors as 
fixed effects and pollen region as a random effect, to account for potential differences in 
birch pollen seasons based on the geographical location of each pollen region. Clinical 
sites will be pooled into different pollen regions which will be specified in the SAP. 
Subjects with at least one day of post-baseline diary record with symptom and medical 
score (SMS) will be included. The CSMS will be calculated on all available data during 
the birch pollen season. The primary analysis will be based on the available values of daily 
symptom score and daily medication score to calculate the average CSMS and no 
imputation will be needed for the primary endpoint during the birch pollen season.  
The average CSMS will be calculated based on daily symptom score (TNSS and TOSS, 
max of 18/day) and daily medication score (max of 20/day) recorded over the duration of 
the birch pollen season. The start and end of the birch pollen season will be defined for 
each site based on the local birch pollen counts. Only days with observed data (including 
any available data of daily entries prior to subject discontinuation) will be included in the 
calculation of the average CSMS.  
 
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1. 
INTRODUCTION 
1.1. 
Allergic Disease, Birch Allergy, and Allergen-Specific Immunotherapy  
Allergic rhinitis with or without conjunctivitis is a common disease with a significant 
socioeconomic burden, due to direct costs (eg, medications and physician visits) and indirect costs 
(eg, loss of productivity/working day) (Vandenplas, 2018). The current prevalence of allergic 
rhinitis is 10% to 30% in adults worldwide, and up to 37% in children in some Western countries 
(Pawankar, 2011), affecting approximately 500 million people worldwide (Brozek, 2017). Allergic 
rhinitis is characterized by 1 or more symptoms including sneezing, itching, nasal congestion, and 
rhinorrhea on consecutive days. Allergic conjunctivitis is also commonly coexistent, occurring in 
approximately 65% of people with the nasal symptoms of allergic rhinitis (Navarro, 2009) 
(Rosario, 2011). Symptoms of fatigue, malaise, irritability, and neurocognitive deficits are 
prevalent (Wallace, 2008). Perennial allergic rhinitis is typically caused by sensitization to indoor 
allergens (eg, dust mites, mold, and animal dander), while seasonal allergic rhinitis is most often 
due to sensitization to pollen allergens (eg, trees, grass, and weeds). In addition, asthma prevalence 
is 10% to 40% in those with allergic rhinitis (Shaaban, 2008), and allergic rhinitis is a risk factor 
for the development of asthma (Guerra, 2002) (Leynaert, 2000).  
In Europe and North America, clinically relevant sensitization to birch tree pollen affects 
approximately 8% to 16% of the overall population (Biedermann, 2019a) (Chan-Yeung, 2010) 
(Salo, 2014) and approximately 20% to 30% of the population with allergic rhinitis 
(Burbach, 2009) (Galant, 1998) (Lin, 2002) (Pablos, 2016) (Sierra-Heredia, 2018). Birch pollen 
contains a mix of allergenic and non-allergenic proteins, and Bet v 1 is the most abundant 
allergenic pollen protein (Erler, 2011) (Schenk, 2011). Sensitization rates to Bet v 1 among birch-
allergic individuals reach >95% (Erler, 2011) (Jarolim, 1989) (Schenk, 2011). Birch pollen 
exposure is associated with an increase in asthma-related emergency department visits 
(Guilbert, 2018) (Ito, 2015). Up to 70% of people with pollen allergy also experience oral reactions 
to particular fresh fruits, vegetables, and nuts, a condition known as oral allergy syndrome (OAS), 
or pollen food allergy syndrome (PFAS). Pollen food allergy syndrome is not a separate food 
allergy but rather occurs because of cross-reactive epitopes present in pollen and associated foods 
(Ebner, 1995) (Vanek-Krebitz, 1995). Pollen food allergy syndrome symptoms typically manifest 
as itching of lips, mouth, and throat, but potentially involve lip and tongue swelling and 
angioedema (Bucher, 2004) (Eriksson, 1982), leading people to avoid these fresh fruits, 
vegetables, and nuts. Approximately 70% of people with birch allergy also have PFAS to foods 
with similar epitopes as Bet v 1, such as apple, carrot, stone fruits, and hazelnut 
(Biedermann, 2019b). 
Antihistamines and intra-nasal corticosteroids are first line therapy for allergic rhinitis, but only 
provide poor or partial symptom control and short-term relief to over half of allergic rhinitis 
sufferers (Halken, 2017) (Wallace, 2017a) (Wallace, 2008) (Wallace, 2017b) (Wei, 2016). Second 
line therapy for allergic rhinitis is allergen-specific immunotherapy (SIT), taken as either 
subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT) tablets or drops 
(Bousquet, 1998) (Calderon, 2007) (Durham, 1999) (Ewbank, 2003) (Nelson, 2004) 
(Walker, 2001). Birch pollen SIT is used to treat birch-sensitive allergic rhinitis, including 
allergies caused by pollen from the birch homologous group of trees (eg, alder and hazel) 
(Biedermann, 2019a) (Makela, 2018) (Mauro, 2007). Birch pollen SIT has been shown to reduce 
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asthma medication use and to reduce the risk of new-onset asthma (Wahn, 2019). Immunotherapy 
using natural or recombinant Bet v 1 is as effective as immunotherapy with birch pollen extract in 
reducing daily allergic rhinitis symptom scores compared to placebo groups, highlighting the 
immunodominance of Bet v 1 in birch pollen allergy (Pauli, 2008). Moreover, in vitro inhibition 
studies with birch pollen have shown a high degree of inhibition of human IgE binding to alder, 
hazel, and oak allergen extracts (Niederberger, 1998). Studies also demonstrate that birch pollen 
SIT may offer symptom amelioration of PFAS (Asero, 1998) (Asero, 2003) (Asero, 2004) 
(Bergmann, 2008) (Bolhaar, 2004) (Herrmann, 1995) (Kelso, 1995). 
However, SIT has many limitations. For the treatment of allergic rhinitis, SCIT or SLIT must be 
administered for at least 2 to 6 months prior to the onset of efficacy, and the efficacy of SIT requires 
high adherence to prevent rhinitis symptoms upon allergen exposure (Biedermann, 2019a) 
(Demoly, 2016) (Didier, 2011) (Durham, 2010) (Durham, 2012) (Durham, 2016) (Durham, 1999) 
(Lemberg, 2017) (Nolte, 2016). Subcutaneous immunotherapy is administered weekly during 
initiation of therapy and then monthly, under direct supervision in the clinic. Sublingual 
immunotherapy is administered daily at home. Both SCIT and SLIT have a high incidence of 
adverse events (AEs), including anaphylaxis. Anaphylaxis does not typically occur with routine, 
environmental pollen exposure. When allergens are administered through immunotherapy, there 
is higher allergen exposure, and therefore, there is risk of more significant allergic reactions 
including anaphylaxis. Anaphylaxis occurs more frequently with SCIT (up to 0.4%, affecting 7% 
of treated patients) compared to SLIT (Epstein, 2017). Since SLIT is administered at home, even 
though the risk of anaphylaxis with SLIT is lower compared to SCIT, any risk of severe allergic 
reactions causes a significant safety concern. Reactions to SCIT occur in 40% to 50% of patients, 
ranging from mild (eg, swelling, injection site reaction, de novo allergic response, and urticaria) 
to life-threatening (eg, asthma exacerbation and anaphylaxis) (Frew, 2006a) (Frew, 2010) 
(Frew, 2006b). Reactions to SLIT occur in the majority of patients, commonly involving irritation 
or swelling in the mouth or throat, predominantly over the first few weeks of therapy 
(Biedermann, 2019a). Subcutaneous immunotherapy and SLIT are generally contraindicated in 
patients with moderate to severe asthma (Cox, 2011). 
Adherence to SIT is poor, likely due to the slow time to onset of action, the significant risk of 
allergic reactions, and the requirement for strict adherence for efficacy, including frequent clinic 
visits and monitoring needs in the case of SCIT (Musa, 2017). Due to these limitations, there 
remains an unmet need for a more robust, safer, rapid, and more convenient therapeutic approach 
for the prevention and treatment of moderate to severe allergic rhinitis and comorbid asthma.  
1.2. 
Monoclonal Antibodies for the Treatment of Allergic Diseases 
It has been hypothesized that high-affinity monoclonal “blocking antibodies” could be developed 
and administered as a form of passive immunotherapy for the treatment of allergy. This concept 
grew out of the observation that allergen-specific polyclonal IgG4 titers increase during SIT and 
may inhibit effector cell activation by blocking allergen-binding to mast cell and basophil 
membrane-bound, high-affinity IgE receptors, effectively preventing early-phase allergic 
symptoms. During SIT, clinical symptom improvement correlates with the ability of blocking 
IgG4s to compete with IgE for allergen-binding (James, 2011) (Uermosi, 2010). To test the 
hypothesis that IgG4 blockade to an allergen can reduce allergic symptoms upon exposure to the 
allergen, a cocktail of 2 IgG4 monoclonal antibodies (mAbs; REGN1908-1909) that bind to 
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Fel d 1, the major allergen in cat dander, was developed. In allergic rhinitis patients with cat 
allergy, when symptom reduction was evaluated in a nasal allergen challenge model following 
administration of REGN1908-1909, total nasal symptom score (TNSS) area under the curve 
(AUC; hour 0 to 1) was reduced in REGN1908-1909-treated patients compared to placebo at days 
8, 29, and 85 (p = 0.0005, p = 0.0004, and p = 0.0187, respectively; by analysis of covariance 
[ANCOVA]) (Orengo, 2018). 
1.3. 
REGN5713, REGN5714, and REGN5715: Fully Human Monoclonal Antibodies 
Against Bet v 1 
Similar to REGN1908-1909 (Orengo, 2018), 3 IgG4 mAbs against Bet v 1 (REGN5713, 
REGN5714, and REGN5715) have been developed for the treatment of birch allergy. Preclinical 
studies demonstrate that the 3 mAbs bind independently and non-competitively to the Bet v 1 
allergen. Data also indicate that all 3 mAbs are required to optimally inhibit binding of Bet v 1 to 
human polyclonal IgE, and thus reduce in vitro effector cell degranulation and subsequent Type 1 
hypersensitivity reaction. A single ascending dose-escalation clinical trial of the 3 mAb cocktail 
(REGN5713-5714-5715; in 1:1:1 ratio) has been completed and demonstrated that a single 150 mg 
subcutaneous (SC), 450 mg SC, 900 mg SC, or 900 mg intravenous (IV) dose had a favorable 
safety profile and was well-tolerated for 3 months post-dose, which was the follow-up period for 
the study.  
In a phase 1b proof-of-concept (POC) study conducted in subjects with birch allergy (N=64), a 
single 900 mg SC dose of REGN5713-5714-5715 (300 mg per mAb) prophylactically blocked 
early allergic response to nasal challenge with birch allergen 8, 29, and 57 days post-dose, resulting 
in a 32%, 27%, and 19% improvement in TNSS AUC (hour 0 to 1), respectively, relative to 
placebo. Subjects showed improvement 8 weeks post-dose, demonstrating that a single 900 mg 
SC dose of REGN5713-5714-5715 could reduce allergic rhinitis symptoms upon birch allergen 
exposure for as long as 2 months. The effect of REGN5713-5714-5715 on early phase skin 
responses following titration skin prick test (SPT) was also observed up to 4 months post-dose, as 
measured by a significant reduction in the AUC of the SPT mean wheal diameters relative to 
placebo (placebo-adjusted percent changes relative to the baseline SPT of -72.39%,  
-65.61%, -77.90%, and -73.56% on study days 8, 29, 57, and 113, respectively). Overall, 
REGN5713-5714-5715 was well tolerated, with no anaphylaxis or evidence of hypersensitivity 
observed. Basophil activation tests (BAT) were also performed on a subset of subjects to 
characterize immune modulation during treatment. Significant suppression of basophil 
responsiveness to birch, alder, and hazel pollen extract was observed with treatment (n=13) versus 
placebo (n=13) as measured by percent change from baseline in EC50 (birch and alder on days 8, 
57, 113, all p <0.001; hazel on day 8, p <0.001, on day 57, p = 0.01). Thus, clinical efficacy of 
anti-Bet v 1 mAbs in birch-allergic subjects may be achieved partly through the suppression of 
basophils and mast cell-mediated allergic responses and may also be extended to those allergic to 
birch homologous trees such as alder and hazel. Pharmacokinetic (PK) and pharmacodynamic 
(PD) data also support the use of a single 900 mg SC dose of REGN5713-5714-5715 (300 mg per 
mAb) to prevent allergy symptoms and reduce the need for rescue medication for the duration of 
birch pollen season.  
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In summary, these data provide proof of principle evidence that direct administration of 
allergen-specific mAbs may offer a rapid and effective approach to reducing allergic symptoms. 
Utilizing human mAbs such as REGN5713-5714-5715 to treat birch allergy may overcome several 
limitations currently hampering SIT. As compared to SIT, blocking mAbs may:  
• Be safer: As the allergic subject is not exposed to native allergen, there is less risk of 
hypersensitivity events related to treatment. 
• Have a faster onset of action: For example, a single SC dose of 900 mg 
REGN5713-5714-5715 demonstrated clinical efficacy after 8 days (the earliest time 
point evaluated). 
• Offer more predictable efficacy: SIT efficacy is variable depending on how well the 
patient tolerates up dosing. 
• Offer more convenience: A single SC dose may treat allergic symptoms for the entire 
birch pollen season. The patient would not be constrained to a rigorous weekly or 
monthly schedule as is the case for SIT. 
• Potentially broaden benefit to include allergic reactions induced by birch-tree 
homologous pollens and/or birch related foods. 
• Offer an effective treatment option to patients with more persistent or uncontrolled 
asthma who may have previously been contraindicated to receive SIT.  
This phase 3 randomized, double-blind, placebo-controlled study will assess the efficacy of 
REGN5713-5714-5715 to reduce allergic rhinitis and conjunctivitis symptoms and the use of 
rescue medications in the field during birch pollen season. 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 is to assess the reduction of allergic symptoms as measured by combined 
symptom and medication score (CSMS) during birch pollen season after a single dose of 
REGN5713-5714-5715 versus placebo.  
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2.2. 
Secondary Objectives 
The secondary objectives are: 
• To assess the reduction of allergic symptoms and use of allergy-relieving medications 
after a single dose of REGN5713-5714-5715 versus placebo, as measured by the total 
symptom score (TSS), total nasal symptom score (TNSS), total ocular symptom score 
(TOSS), and daily medication score (DMS) 
• To evaluate the safety and tolerability of REGN5713-5714-5715, including the 
incidence of hypersensitivity reactions and local injection site reactions 
• To evaluate the reduction in early allergic response to birch allergen after a single dose 
of REGN5713-5714-5715 versus placebo, as measured by SPT mean wheal diameter 
• To determine systemic exposure of total antibody (ie, free and antigen-bound) in the 
form of concentration of REGN5713, REGN5714, and REGN5715 in serum 
• To assess the immunogenicity to REGN5713, REGN5714, and REGN5715 in subjects 
after a single dose of REGN5713-5714-5715  
• To evaluate “well days” 
Note: “Well days” are defined as days when the TSS is ≤2 without the use of anti-
allergy rescue medications. 
2.3. 
Exploratory Objectives 
The exploratory objectives are: 
• To assess asthma control as measured by the asthma control questionnaire (ACQ-5) 
• To assess quality of life as measured by the rhinoconjunctivitis quality of life 
questionnaire (RQLQ [S])  
• To evaluate the reduction in early allergic response to birch homologous allergens 
(alder and oak) as measured by SPT mean wheal diameter 
• To assess the relationship between allergy sensitization status to Bet v 1 or birch pollen 
at screening (as measured by serum allergen specific-IgE [sIgE]) and clinical response 
to REGN5713-5714-5715 treatment  
• To assess serum sIgE levels against Bet v 1 and birch pollen during birch pollen season 
to evaluate the relationship between the response to REGN5713-5714-5715 and change 
in sIgE levels in-season  
• To assess the inhibitory effect of REGN5713-5714-5715 on the binding of endogenous 
serum IgE to birch allergen in an in vitro assay; to assess whether the degree of 
inhibition correlates with clinical improvement  
• To assess sIgE levels against other allergens (eg, Bet v 2, alder and oak) at screening 
and to evaluate the relationship between response to REGN5713-5714-5715 and poly-
allergic status 
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• To assess additional subclasses of serum antibodies (eg, total IgG and IgG4 against 
birch pollen and Bet v 1) to evaluate the relationship between endogenous anti-Bet v 1 
antibodies and response to REGN5713-5714-5715  
• To assess the reduction in PFAS and related symptoms as measured by pollen food 
allergy symptom questionnaire (PFASQ) 
• To assess patient rating of severity of seasonal allergy symptoms as measured by 
patient global impression of severity (PGI-S) 
3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypothesis 
A single SC dose of REGN5713-5714-5715 is more effective than placebo in the reduction of 
CSMS during birch pollen season.  
Refer to Section 11.1 for the statistical hypothesis. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
Study design and duration 
This is a phase 3 multi-center, randomized, double-blind, placebo-controlled, parallel group study 
to assess the efficacy of anti-Bet v 1 mAbs (REGN5713-5714-5715) to reduce allergic rhinitis and 
conjunctivitis during birch pollen season. The study will last approximately 28 weeks, including 
screening (refer to Table 1 for a schedule of events). The actual duration of the study will vary 
depending on the start, peak, and end dates of the local birch pollen season for each study site, 
which will be variable across different geographies (refer to Section 9.2.2):  
• Screening: Generally healthy male and female subjects 18 years and older with a 
history of birch allergy for at least 2 years will undergo screening visits before the onset 
of the birch pollen season. Subjects will be asked to refrain from taking specific 
prohibited medications within the specified period preceding screening (refer to 
Section 8.9.1).  
• Randomization: Candidate subjects who meet all inclusion and no exclusion criteria 
will be randomized and receive the study drug. Randomization will be stratified based 
on geographical regions and sIgE levels at screening (refer to Section 8.5).  
• In-season visits: Approximately 1 month after randomization (timing will vary based 
on the local pollen season), a telephone contact will occur to collect any AEs and 
concomitant medication information. There will be an in-clinic visit at the anticipated 
local peak of birch pollen season. An additional telephone contact will occur at the end 
of the local birch pollen season. An in-clinic visit will occur at the end of the study. 
Subjects will be asked to stop using specific rescue medications within 5 days of the 
end of study visit (refer to Section 8.9.1).  
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Efficacy measurements  
Subjects will record symptom scores (TNSS, TOSS) daily. Subjects will be provided with rescue 
medications to treat allergic symptoms during the study (refer to Section 8.2) to treat their allergic 
rhinitis with or without conjunctivitis. Subjects will be asked to record their daily use of rescue 
medications using an e-diary throughout the birch pollen season to calculate the DMS. TNSS and 
TOSS are scored for a combined TSS. The TSS and DMS are combined for the CSMS. 
ACQ-5 will be completed weekly to assess asthma control in asthmatic subjects. To assess subject 
quality of life, RQLQ (S) will be assessed weekly in all subjects. In addition, PFASQ and PGI-S 
will be administered throughout the study to assess treatment effects on PFAS symptoms and 
overall patient impression of severity. Refer to Section 9.2.4 for more details on these efficacy 
measures.  
Primary objective 
The primary objective of the study is to assess the reduction of allergic symptoms as measured by 
CSMS during birch pollen season after a single dose of REGN5713-5714-5715 versus placebo. 
The primary endpoint is CSMS, averaged over the duration of the birch pollen season, in subjects 
who receive a single dose of REGN5713-5714-5715 versus placebo. Based on recent reviews of 
SLIT products, for registration, the Food and Drug Administration (FDA) expects a treatment to 
reduce average CSMS by at least 15% compared to placebo. The European Medicines Agency 
(EMA) has a set a similar standard (approximately 20% compared to placebo) based on guidance 
from the World Allergy Organization (WAO) task force (Canonica, 2014). As CSMS is the 
recommended endpoint for in-field studies for allergic rhinitis treatments, this study will provide 
data on the treatment effect of REGN5713-5714-5715 on the CSMS.  
Secondary objectives 
A secondary objective of the study is to evaluate the average TSS, TNSS, TOSS, and DMS during 
birch pollen season comparing subjects who receive a single dose of REGN5713-5714-5715 
versus placebo.  
Incidence rates of treatment-emergent AEs (TEAEs) and serious TEAEs, as well as 
hypersensitivity reactions and local injection site reactions, will be collected to determine safety 
and tolerability of REGN5713-5714-5715.  
Total concentration of REGN5713, REGN5714, and REGN5715 in serum will be assessed to 
determine systemic exposure of total antibody (ie, free and antigen-bound) throughout the study. 
In addition, immunogenicity to REGN5713, REGN5714, and REGN5715, as determined by the 
incidence, titer and clinical impact of treatment-emergent ADA responses will be assessed. 
“Well days” will also be assessed. Well days are defined as days when rescue medication is not 
utilized and the TSS is ≤2/18. This exploratory objective will provide information about the 
number of days a patient is not affected by their allergic rhinitis symptoms. 
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Exploratory objectives 
Sensitization to birch and birch homologous group (alder and oak) will be assessed by SPT at 
screening and after a single 900 mg SC dose of REGN5713-5714-5715 or placebo. 
Because these anti-Bet v 1 mAbs target Bet v 1 specifically, exploratory objectives will assess 
whether their efficacy is related to baseline levels of specific IgE to birch and Bet v 1. As it is 
known that allergen-specific IgE (sIgE) levels increase during the natural pollen season, other 
exploratory objectives are to determine whether efficacy is related to changes in birch and Bet v 1 
sIgE. In addition, allergen sensitization to a panel of allergens, including but not limited to alder 
and oak, will be determined by baseline serum sIgE (cutoff value 0.35 kUa). Also, of interest is 
whether the treatment response is associated with circulating levels of anti-birch or anti-Bet v 1 
IgG and IgG4. The regional SPT panel and sIgE panel that is performed before dosing will be 
analyzed to understand whether allergen sensitization to non-birch allergens is associated with 
treatment effect during birch pollen season.  
Local tree pollen counts will be obtained to assess whether the efficacy of the anti-Bet v 1 antibody 
cocktail is associated with non-birch trees or other plants that may be pollinating at similar times 
as birch.  
3.2.2. 
Rationale for Dose Selection 
The proposed doses for this study are based on the results of Part B of the phase 1b POC, first-in-
human (FIH) study, which was conducted in healthy, birch-allergic subjects. In that study, a single 
dose of 900 mg SC REGN5713-5714-5715 (300 mg per mAb) resulted in a significant reduction 
in allergic rhinitis symptoms following a nasal allergen challenge for at least 2 months post-dose. 
Additionally, reduction in SPT-induced skin reaction was maintained for approximately up to 
4 months post-dose in healthy subjects who were allergic to birch pollen. This dose was 
well-tolerated, with TEAEs generally of a mild to moderate severity, and occurred in similar rates 
in the placebo and REGN5713-5714-5715 treatment groups.  
REGN5713-5714-5715 exhibited linear PK. Throughout the duration of the study, the 
concentration of total REGN5713-5714-5715 in serum was maintained above 10 mg/L, which had 
been identified from preclinical testing in the mouse percutaneous anaphylaxis (PCA) model as 
the concentration above which response to Bet v 1 was fully blocked. 
Based on the above summary of safety, PK, and PD data, a single 900 mg SC dose of 
REGN 5713-5714-5715 (300 mg per mAb) is expected to prevent allergic symptoms and reduce 
the need for rescue medication for the duration of birch pollen season. Additional information on 
clinical and preclinical PK, PD, and safety can be found in the Investigator's Brochure. 
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3.2.3. 
Rationale for the Selected Anti-Bet v 1 Monoclonal Antibody Cocktail 
Preclinical studies were conducted to determine the optimal combination of anti-Bet v 1 mAbs 
REGN5713, REGN5714, and REGN5715. In addition to binding assays showing simultaneous, 
non-competitive binding to Bet v 1, a BAT using peripheral blood mononuclear cells (PBMCs) 
from birch-allergic donors showed near complete blocking efficacy using the 3-mAb cocktail. 
Specifically, when REGN5713-5714-5715 were added as a cocktail, there was 97% median 
blocking of Bet v 1-induced basophil activation with ≥90% blockade observed in 9 of 10 donors 
tested. The single antibodies (REGN5713, REGN5714, and REGN5715) achieved a median of 
50%, 55%, and 67% blocking, respectively, reaching ≥90% blockade in only ≤2 of 10 donors. 
Regeneron has developed other mAbs against exogenous targets, including REGN1908 and 
REGN1909 (for Fed d 1); REGN10933 and REGN10987 (for SARS-CoV-2); atoltivimab, 
odesivimab, and maftivimab (for Ebola); REGN3048 and REGN3051 (for MERS-CoV), and 
suptavumab (for respiratory syncytial virus [RSV]). These mAbs demonstrated specificity to their 
exogenous targets with no significant safety findings and low incidence of hypersensitivity, 
injection site reactions, or immunogenicity. Similarly, REGN5713-5714-5715 was generally well-
tolerated in the FIH study. In Part B of the FIH study, the overall frequency of treatment-related 
TEAEs was comparable between REGN5713-5714-5715 (21.9%) and placebo (25.0%), all of 
which were of mild or moderate intensity and resolved without sequalae. There were no SAEs or 
AEs leading to study discontinuation/death. 
3.3. 
Risk-Benefit 
REGN5713-5714-5715 has been administered as a single dose to 56 healthy adult subjects 
(24 without known birch allergy and 32 with known birch allergy) in a FIH study with no 
significant clinical safety findings observed. No important identified risks have been established 
with REGN5713-5714-5715. In birch-allergic subjects, a significant reduction in TNSS following 
a nasal allergen challenge was demonstrated through day 57, and a durable reduction in SPT 
response to birch was demonstrated through day 113. A potential benefit for subjects in this study 
and future patients may be to have an effective, rapid, and convenient therapeutic option with a 
favorable safety profile to prevent and treat birch-related allergic rhinitis. In a nonclinical 
toxicology study conducted in monkeys, REGN5713-5714-5715 was well tolerated at significantly 
higher doses than are planned for clinical evaluation.  
As with most other protein therapeutics that are administered SC, mild or moderate injection site 
reactions may occur and may be treated symptomatically. Allergy/hypersensitivity reactions may 
develop; the most concerning are those that may develop immediately or within a few hours of 
administration of REGN5713-5714-5715. Because REGN5713-5714-5715 is composed of 
antibodies whose sequence is fully human, the risk of these immediate reactions is considered to 
be extremely low. Emergency equipment and medication for the treatment of these potential 
adverse effects (including but not limited to antihistamines, corticosteroids, acetaminophen, and/or 
epinephrine) are available for immediate use in this study. Considering the safety data and the 
exogenous nature of the target antigen, the risk of other adverse reactions is considered to be 
extremely low. A risk-benefit statement with respect to the overall development program is 
provided in the Investigator’s Brochure.  
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A Safety Monitoring Team (SMT) will monitor blinded safety data on an ongoing basis to assess 
the risk-benefit profile of REGN5713-5714-5715 (refer to Section 6.3.1). Additionally, an 
Independent Data Monitoring Committee (IDMC) will be involved in the review of unblinded data 
in an ongoing manner (refer to Section 6.3.2). 
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 patients in this study until 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 initiation 
of study sites for this study, as allowed by local laws and regulations. 
4. 
ENDPOINTS 
4.1. 
Primary Endpoint 
The primary endpoint is the daily CSMS, averaged over the duration of the birch pollen season, in 
subjects who receive a single dose of REGN5713-5714-5715 versus placebo. 
4.2. 
Secondary Endpoints 
The secondary endpoints are: 
• TSS, TNSS, and TOSS, averaged over the duration of the birch pollen season, in 
subjects who receive a single dose of REGN5713-5714-5715 versus placebo  
• DMS, averaged over the duration of the birch pollen season, in subjects who receive a 
single dose of REGN5713-5714-5715 versus placebo 
• Incidence of TEAEs and serious TEAEs throughout the study  
• Change and percent change from baseline to the end of study in birch SPT mean wheal 
diameter in subjects who receive a single dose of REGN5713-5714-5715 versus 
placebo 
• Total REGN5713, REGN5714, and REGN5715 concentration in serum over the study 
duration 
• Incidence of treatment emergent anti-drug antibodies (ADAs) to REGN5713, 
REGN5714, or REGN 5715 throughout the study 
• The number of “well days” in each of the treatment groups, where the “well days” are 
defined as days when rescue medication is not utilized and the TSS is ≤2/18 
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4.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• ACQ-5, averaged over the duration of the birch pollen season, for REGN5713-5714-
5715 versus placebo  
• RQLQ (S), averaged over the duration of the birch pollen season, for REGN5713-5714-
5715 versus placebo  
• Change and percent change from baseline to the end of study in SPT mean wheal 
diameter for birch homologous/cross-reactive allergens in REGN5713-5714-5715 
versus placebo  
• Baseline allergen-specific IgE levels and correlation with average CSMS, TSS, TNSS, 
TOSS, DMS during birch pollen season 
• Change and percent change from baseline to the peak of birch pollen season in allergen-
specific IgE  
• Change in inhibitory effect on serum IgE to birch allergen 
• Number of baseline sensitizations to other allergens (poly/mono-sensitization status, 
based on allergen-specific IgE levels) and correlation with CSMS, TSS, TNSS, TOSS, 
and DMS, averaged over the duration of the birch pollen season 
• Baseline serum antibody levels and correlation with CSMS, TSS, TNSS, TOSS, and 
DMS, averaged over the duration of the birch pollen season 
• To assess the reduction in PFAS and related symptoms, as measured by PFASQ, from 
baseline to end of study  
• To assess patient rating of severity of seasonal allergy symptoms, as measured by 
PGI-S, from baseline to end of study  
5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
medical history, medication history, asthma history, SPT mean wheal diameter, and serum sIgE 
levels for each subject. 
5.2. 
Efficacy Variables 
Efficacy variables include TNSS, TOSS, TSS (which results from adding the TNSS and TOSS), 
DMS, CSMS (which results from adding the DMS and TSS), RQLQ (S), PFASQ, ACQ-5 (in 
subjects with a history of asthma), and PGI-S. 
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5.3. 
Safety Variables 
Safety variables include AEs, vital signs, physical examinations, electrocardiogram (ECG), and 
laboratory safety tests.  
5.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of total REGN5713, REGN5714, and REGN5715 in 
serum at the sampling time points specified in Table 1. 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time-point/visit. Samples for the 
assessment of immunogenicity in this study will be collected at the clinic visits specified in 
Table 1. 
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory biomarker variables include, but not be limited to: serum total IgE, serum sIgE for 
birch and Bet v 1, serum sIgE for concomitant allergens and homologous allergens, SPT results 
for birch, birch homologous, and other common allergens.  
These results may be reported outside of the clinical study report (CSR). 
5.7. 
Other Variables 
Outdoor pollen counts will be measured daily by the study site or by a vendor during the expected 
pollen season using a pollen sampler. 
6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a phase 3 multi-center, randomized, double-blind, placebo-controlled, parallel group study 
to assess the efficacy of REGN5713-5714-5715 to reduce allergic rhinitis and conjunctivitis 
symptoms and the use of rescue medications during birch pollen season.  
The total study duration is approximately 28 weeks including screening, dependent on the start 
and end times of the local birch pollen season (Figure 1). The length of birch pollen season will 
vary based on geography. Approximately 300 birch-allergic subjects will be randomized 1:1 to 
REGN5713-5714-5715 or placebo (refer to Section 8.1 for more details). 
Efficacy will be evaluated by assessing the reduction of allergic nose and eye symptoms and the 
reduction in the use of allergy rescue medications during birch pollen season, after a single SC 
dose of REGN5713-5714-5715 or placebo. The incidence and severity of TEAEs, including 
hypersensitivity reactions and local injection site reactions, will also be assessed. Total 
concentration in serum and immunogenicity of REGN5713, REGN5714, and REGN5715 will be 
measured at the sampling times specified in Table 1.  
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Figure 1: 
Study Flow Diagram 
 
6.1.1. 
Study Stopping Rules 
If there are significant safety concerns based on an ongoing assessment by the IDMC or a 
Regeneron SMT, a recommendation may be made to temporarily pause, alter, or terminate the 
study. Once SMT or IDMC recommendations have been received, further discussions and 
consultation with Regeneron Safety Oversight Committee (RSOC) may be conducted to determine 
if these or other actions should be taken. Refer to Section 6.3.1 and Section 6.3.2 for more 
information on the SMT and IDMC, respectively. 
6.1.2. 
End of Study Definition 
The end of study is defined as the date the last subject completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the study subject can no longer be contacted by the 
investigator).  
6.2. 
Planned Interim Analysis 
No formal interim analysis will be conducted. 
A description of the statistical methods to be employed is in Section 11.5, and blinding 
implications are discussed in Section 8.6. 
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6.3. 
Study Committees 
6.3.1. 
Safety Monitoring Team 
A Regeneron SMT will meet periodically to review blinded safety data as needed. The team may 
be comprised of the Medical/Study Director, a Global Patient Safety representative, 
representatives from Biostatistics and Data Management, as well as representatives from Clinical 
Operations and Regulatory Affairs. The data to be reviewed will include, but are not limited to:  
• Treatment-emergent adverse events that result in an early study withdrawal 
• Serious adverse events 
• Severe AEs 
• Selected laboratory tests, as deemed appropriate by the SMT 
• Additional adverse events of special interest (AESIs), as defined in Section 10.1.3  
Appropriate action, if needed, will be taken based upon this review and in consultation with the 
Medical Monitor. The SMT may make a recommendation to the RSOC to halt the study or make 
other changes in study conduct. Applicable regulatory procedures will be adhered to as required 
by local laws in relation to any decisions related to a change in study conduct, temporary halt, 
study termination, or study restart. 
6.3.2. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor subject safety and efficacy 
data. The IDMC is composed of members who are independent from the Sponsor and the study 
investigators. The IDMC will provide oversight of subject safety by conducting formal reviews of 
accumulated safety data that will be blinded by treatment group; if requested, the IDMC may have 
access to the treatment allocation code or any other requested data for the purposes of a risk-benefit 
assessment. The IDMC will provide the Sponsor with appropriate recommendations on the 
conduct of the clinical study to ensure the protection and safety of the subjects enrolled in these 
studies. All activities and responsibilities of the IDMC are described in the IDMC charter.  
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
SUBJECTS 
7.1. 
Number of Subjects Planned 
Approximately 300 adult subjects will be enrolled at multiple sites in Canada, United States, and 
Europe. 
7.2. 
Study Population 
Generally healthy adult male and female subjects with birch allergy will be enrolled. 
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7.2.1. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. Generally healthy men and women 18 years of age and older at the time of screening  
2. Documented or subject-reported history of birch pollen-triggered allergic rhinitis 
symptoms, with or without conjunctivitis, for at least 2 years 
3. Positive SPT with birch pollen extract (ie, mean wheal diameter at least 5 mm greater than 
a negative control) in the screening period 
4. Positive sIgE tests for birch pollen and Bet v 1 (ie, ≥0.7 kUa/L) in the screening period 
5. Willing and able to comply with clinic visits and study-related procedures   
6. Provide informed consent signed by study subject or legally acceptable representative 
7. Able to understand and complete study-related questionnaires 
7.2.2. 
Exclusion Criteria  
A subject who meets any of the following criteria will be excluded from the study: 
1. Participation in a prior REGN5713-5714-5715 clinical trial  
2. Recurrent or chronic rhinitis or sinusitis not associated with birch pollen season, or due to 
daily contact with other allergens causing symptoms that are expected to coincide with 
birch pollen season, as assessed by the investigator 
3. Subjects who anticipate major changes in allergen exposure in their home or work 
environments that are expected to coincide with study assessments, per investigator 
discretion 
4. Persistent chronic or recurring acute infection requiring treatment with antibiotics, 
antivirals, or antifungals, or any untreated respiratory infections within 4 weeks prior to 
screening. Participants may be re-evaluated for eligibility after symptoms resolve  
5. Documentation of active SARS-CoV-2 infection 
Note: A subject with a documented, positive PCR or serology test for SARS-CoV-2 may 
be enrolled, provided that the subject has:  
• Recovered from COVID-19 (all COVID-19-related symptoms and major clinical 
findings which can potentially affect the safety of the patient should be resolved to 
baseline), and  
• Had 2 negative results from a health authority-authorized nucleic acid amplification 
(PCR) test for COVID-19 taken at least 48 hours apart 
6. Abnormal lung function as judged by the investigator with FEV1 <70% of predicted at 
screening or randomization 
7. A clinical history of moderate to severe asthma with 2 or more asthma exacerbations 
requiring hospitalizations or systemic corticosteroids in the previous year  
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8. History of significant, recurrent sinusitis, defined as at least 3 episodes requiring antibiotic 
treatment per year for the last 2 years prior to screening 
9. History of nasal polyps 
10. Active lung disease other than asthma  
11. History of birch or related tree allergy immunotherapy (SCIT, SLIT, or oral 
immunotherapy) within 5 years prior to screening 
12. Use of anti-IgE or other biological therapy that modifies Type 2 inflammation within 
6 months prior to screening  
13. Allergen-specific immunotherapy with any allergen other than birch within 6 months prior 
to screening  
14. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, psychiatric, or neurological disease that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
subject by study participation   
15. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
subject by study participation   
16. Subjects with any laboratory findings showing evidence of organ dysfunction or any 
clinically significant deviation from the normal range, as decided by the investigator at the 
screening visit, including but not limited to: 
a. Clinically significant/active underlying hepatobiliary disease 
b. Abnormal laboratory values at screening, such as: 
• Neutrophils <1.5 × 103/μL 
• Platelets <100,000 cells/mm3 
17. History of drug or alcohol abuse within a year prior to screening  
18. Any malignancy within the past 5 years, except for basal cell or squamous epithelial cell 
carcinomas of the skin or carcinoma in situ of the cervix or anus that have been resected, 
with no evidence of local recurrence or metastatic disease for 3 years  
19. Clinically significant abnormal ECG in the screening period as assessed by the investigator 
20. History of acute hypersensitivity and/or anaphylaxis to excipients in the study medication 
or allergies that could represent a substantial risk to the subject in the opinion of the 
investigator 
21. Treatment with an investigational drug or therapy within 2 months or at least 5 half-lives 
(if known), whichever is longer  
22. Unwilling or unable to comply with the permitted and prohibited medication specifications 
for this study 
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23. Member of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the Sponsor   
24. Pregnant or breastfeeding women  
25. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to study drug administration, during the study, and for at least 
6 months after the dose of study medication. 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†,‡. 
* WOCBP 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 the 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 
subject. 
‡ 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. 
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26. Sexually active men who are unwilling to use the following forms of medically acceptable 
birth control during the study drug follow-up period and for 6 months after the study drug 
administration: vasectomy with medical assessment of surgical success or consistent use 
of a condom. Sperm donation is prohibited during the study and for up to 9 months after 
the study drug administration.  
7.3. 
Premature Withdrawal from the Study  
A subject 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 subject from the study if it is no 
longer in the interest of the subject to continue in the study, or if the subject’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a subject does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of subjects should be avoided.  
Subjects who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
7.4. 
Replacement of Subjects 
Subjects who are randomized, receive study drug, and/or are prematurely discontinued from study 
will not be replaced. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
REGN5713, REGN5714, and REGN5715 are provided individually in open-label vials in carton. 
Each 20 mL vial contains 265 mg of lyophilized protein. Matching placebo is provided as a 
lyophilized powder in 20 mL open-label vials in carton. 
Instructions are provided in the pharmacy manual to create the following treatments: 
• Single SC dose of REGN5713-5714-5715 900 mg (300 mg per mAb) 
• Single SC dose of matching placebo that replaces REGN5713-5714-5715 
Randomization will be stratified as described in Section 8.5. 
8.2. 
Rescue Treatments 
Subjects will be provided with the following medications to treat allergic symptoms during the 
study:  
• Desloratadine 5 mg (second generation antihistamine) 
• Olopatadine 1 mg/mL (antihistamine eye drop) 
• Mometasone furoate 50 ug/dose (intranasal steroid) 
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From the time of study drug dosing throughout the birch pollen season, subjects will be asked to 
record their daily medication use using an e-diary, including information regarding which 
medications was used and the amount of the pre-specified medications that was used. Utilization 
of rescue medications should be initiated when subjects reach a symptoms threshold of 
approximately TSS ≥4/18. Subjects will be provided with training to understand the severity of 
symptoms associated with a TSS ≥4/18.  
Subjects should be instructed not to utilize rescue medications in the anticipation of the birch 
pollen season. Subjects should also be instructed not to utilize antihistamines (ie, desloratadine or 
olopatadine) for 5 days before the end of study visit. 
For skin prick tests 
Local allergen exposure through SPT typically only results in local allergic reactions that dissipate 
within a short time. Uncommonly, systemic immediate or late allergic reactions can occur. Such 
reactions should be treated appropriately, at the discretion of the investigator. With the exception 
of severe or clinically concerning reactions (as judged by the investigator), rescue treatments 
should be given after study endpoint data collection is obtained (eg, after the skin wheals are 
measured after application of allergen). 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
This is a single dose study. Dose modification for an individual subject is not allowed. Study 
treatment discontinuation is not applicable to this study. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Injection Reactions 
8.4.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use if required for treatment. 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.  
8.4.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
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8.5. 
Method of Treatment Assignment  
Subjects will be randomized according to a central randomization scheme provided by interactive 
response technology (IRT) to the designated study pharmacist (or qualified designee) as per 
Table 1.  
Subjects will be randomized 1:1 as below (refer to Section 8.1 for more details): 
• REGN5713-5714-5715  
• Matching placebo  
Randomization will be stratified based on the following:  
• Serum specific birch pollen IgE levels at screening (<17.5 kUa/L versus ≥17.5 kUa/L)  
• In North America only: Serum specific oak pollen IgE levels at screening 
(<0.7 kUa/L versus ≥0.7 kUa/L) 
• Geographical region (North America versus Europe) 
8.6. 
Blinding 
Study subjects, the principal investigators, and study site personnel (excluding the unblinded 
pharmacy staff) 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 subject randomization assignments. 
Selected individuals not involved in the conduct of the study may have access to unblinded data 
as needed for safety review or other data review.  
8.7. 
Emergency Unblinding 
Unblinding of treatment assignment for a subject 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 subject's treatment assignment.  
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment 
− Only the affected subjects 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/unmask the subject. Unblinding is performed 
using the interactive voice/web response system (IVRS/IWRS) which will notify 
Regeneron 
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the subject 
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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 subject'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. 
8.8. 
Treatment Logistics and Accountability 
8.8.1. 
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. 
The unblinded pharmacist will prepare the unblinded investigational product and dispense it in a 
blinded manner to the blinded study staff for administration to the subject.  
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.8.2. 
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 at site with approval by 
Regeneron or returned for destruction. 
Rescue medications may be procured and distributed by the study site.  
8.8.3. 
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 subject 
• Returned from each subject (if applicable) 
• 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. 
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8.8.4. 
Treatment Compliance 
As the investigational study drug will be administered in the clinic, treatment compliance is not 
applicable. 
All drug compliance records must be kept current and made available for inspection by the Sponsor 
and regulatory agency inspectors. 
8.9. 
Concomitant Medications  
Any treatment administered from the time of informed consent to the final study visit will be 
considered concomitant medication. This includes medications that were started before the study 
and are ongoing during the study. 
8.9.1. 
Prohibited Medications  
Preceding screening  
Use of the below concomitant medications is prohibited within the following time period preceding 
the screening and randomization visits: 
• Topical or systemic first generation H1 antihistamines (eg, diphenhydramine and 
chlorpheniramine) (3 days) 
• Second generation and long-acting H1 antihistamines (eg, cetirizine) (5 days) 
• Cromoglycates (14 days) 
• Leukotriene modifiers (30 days) 
• Intranasal corticosteroids (14 days) 
• Systemic steroid treatment (30 days) 
• Topical steroids, with the exception of hydrocortisone (≤1%) (48 hours) 
• Anticholinergics (eg, Ipratropium [Atrovent 40 μg]) (12 hours) 
• Intramuscular corticosteroids (3 months prior to screening and during the study) 
• Systemic or topical calcineurin inhibitors (14 days prior to screening and during the 
study) 
• Topical or oral decongestants (72 hours) 
• Tricyclic antidepressants/typical antipsychotics (14 days)  
• Birch-specific allergen immunotherapy (5 years) 
• Immune-directed biologic therapies that would interfere with Type 2 allergic disease 
or suppress the immune system (6 months) 
• Long-acting anti-muscarinic agents (7 days) 
• Ultra-long-acting β-agonists (eg, indacaterol, vilanterol, olodaterol) (14 days) 
• Methylxanthines (eg, oral theophylline) (24 hours) 
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Preceding the end of study visit 
Use of the below medications is prohibited within the following time period preceding the end of 
study visit. Refer to Section 8.2 for more information on rescue medications: 
• Desloratadine (5 days) 
• Olopatadine (5 days) 
• Topical steroids, with the exception of hydrocortisone (≤1%) (48 hours) 
Any time throughout the study 
• Anticholinergics 
• Leukotriene modifiers 
• Cromoglycates 
• Topical or oral decongestants 
• Systemic steroid treatment 
• Tricyclic antidepressants/typical antipsychotics  
• Any allergen immunotherapy 
• Immune-directed biologics therapies that would interfere with Type 2 allergic disease 
or suppress the immune system 
• Methylxanthines (eg, oral theophylline) 
• Anti-allergic medications (antihistamines, anti-allergic eye drops, anti-allergic nasal 
sprays) outside of study-related anti-allergic medications as they will be supplied as 
part of the study (refer to Section 8.2) 
8.9.2. 
Permitted Medications  
Use of standard-of-care medications not prohibited per Section 8.9.1 will be allowed. Treatment 
for acute reactions is allowed during the study (see Section 8.2). 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events 
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, are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
Study assessments and procedures are presented by study period and visit in Table 1.  
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Table 1: 
Schedule of Events 
 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Study Procedure 
Screening  
Visit 11 
Randomization 
Visit 22-4 
Visit 3 
Tel. 
Visit 4  
Tel. 
Visit 53 Visit 6 
Tel. 
EOS/ET  
Visit 73 
Unscheduled 
Visit 
Day 
-84 to -7 
13 
2 
283 
573 
85 
1133 
 
Window (Days) 
+7 
±3 
 
±7 
±14 
±14 
±14 
 
Inclusion/exclusion2 
X 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X4 
  
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
SPT for birch and birch homologous allergens and 
select regional or relevant allergens1 
X 
 
 
 
 
 
X 
 
Standard regional SPT for birch and other common 
allergens1 
X 
 
 
 
 
 
 
 
FSH (in postmenopausal women) 
X 
 
 
 
 
 
 
 
Treatment 
Randomization2 
 
X 
 
 
 
 
 
 
Study drug administration2 
 
X 
 
 
 
 
 
 
Efficacy 
E-diary and rescue medications dispensation/return5 
 
X 
 
 
 
 
X 
 
TNSS6 
 
Daily via e-diary  
 
TOSS6 
 
Daily via e-diary  
 
DMS6 
 
Daily via e-diary 
 
ACQ-5 (in subjects with asthma)7 
 
Weekly via e-diary 
X 
RQLQ (S)8 
 
Weekly via e-diary 
X 
PFASQ9 
 
X 
 
 
 
 
X 
 
PGI-S10 
 
X 
 
 
X 
 
X 
 
Safety 
Vital signs11 
X 
X11 
 
 
X 
 
 
X 
Physical examination12 
X 
X 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry 
X4 
X 
 
 
 
 
 
X 
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SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Study Procedure 
Screening  
Visit 11 
Randomization 
Visit 22-4 
Visit 3 
Tel. 
Visit 4  
Tel. 
Visit 53 Visit 6 
Tel. 
EOS/ET  
Visit 73 
Unscheduled 
Visit 
Day 
-84 to -7 
13 
2 
283 
573 
85 
1133 
 
Window (Days) 
+7 
±3 
 
±7 
±14 
±14 
±14 
 
Laboratory Testing 
Hematology 
X4 
 
 
 
X 
 
X 
X 
Blood chemistry 
X4 
 
 
 
X 
 
X 
X 
Pregnancy test, urine (in WOCBP)13 
 
X13 
 
X13 
X 
X13 
X 
X 
Pregnancy test, serum (in WOCBP)13 
X 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
X 
Serum total IgE 
 
X 
 
 
X 
 
X 
 
Serum sIgE for birch pollen and Bet v 1 and other 
regional or relevant allergens 
X 
X 
 
 
X 
 
X 
X 
Serum sIgE for concomitant and homologous 
allergens 
 
X 
 
 
X 
 
X 
 
Interference assay, serum 
 
X 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity 
PK14 
 
X14 
 
 
X 
 
X 
X 
ADA14 
 
X14 
 
 
 
 
X 
X 
Biomarkers and Pharmacogenomics 
FBR samples, serum and plasma (optional)15 
 
X 
 
 
X 
 
X 
 
Genomic DNA sample (optional)16 
 
X16 
 
 
 
 
 
 
ACQ-5=asthma control questionnaire-5; ADA=anti-drug antibody; AE=adverse event; DMS=daily medication score; ECG=electrocardiogram; EOS=end of 
study; ET=early termination; FBR=future biomedical research; FSH=follicle stimulating hormone; PFASQ=pollen food allergy symptom questionnaire; PGI-
S=patient global impression of severity; PK=pharmacokinetics; RQLQ (S)=standardized rhinoconjunctivitis quality of life questionnaire; sIgE=allergen-specific 
immunoglobulin E; SPT=skin prick test; Tel=telephone; TNSS=total nasal symptom score; TOSS=total ocular symptom score; WOCBP=women of childbearing 
potential. 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Screening SPT for birch, birch homologous trees, and other common allergens will be 
performed as described in the study manual. Skin prick test for birch should be performed 
prior to other screening assessments. If screening SPT for birch is negative (ie, mean wheal 
diameter <5 mm greater than a negative control), then other screening visit procedures do 
not need to be performed as the subject will have failed screening (refer to Section 7.2.1 
Inclusion Criteria, #3).  
2. Randomization may occur within 1 day prior to study drug administration. All safety 
assessments performed at screening must be normal and checked against the 
inclusion/exclusion criteria prior to study drug administration.  
3. The timing of in-clinic visits may vary for each study site, depending on the start, peak, 
and end dates of the local birch pollen season (as determined by local pollen counts; refer 
to Section 9.2.2). The randomization visit will be scheduled approximately 2 weeks before 
the start of birch pollen season, and the end of study (EOS) visit approximately 16 weeks 
after the randomization visit (depending on the duration of the local birch pollen season). 
In addition, visit 5 will be scheduled to occur within 2 weeks of the anticipated local peak 
of the birch pollen season.  
4. If randomization occurs >60 days after the screening visit, medical history, blood 
chemistry, hematology, and spirometry must be repeated prior to randomization. 
5. E-diary and rescue medications will be dispensed at the randomization visit. E-diary and 
any unused rescue medications will be returned at the EOS visit. Refer to Section 8.2 for 
more information on rescue treatments. 
6. TNSS, TOSS, and DMS will be recorded daily via e-diary, starting at the randomization 
visit until EOS. Refer to Section 9.2.4.1, Section 9.2.4.2, and Section 9.2.4.4 for procedural 
details. 
7. In asthmatic subjects, ACQ-5 scores will be recorded weekly via e-diary, starting from the 
randomization visit until EOS. Refer to Section 9.2.4.6 for procedural details.  
8. In all subjects, RQLQ (S) scores will be recorded weekly via e-diary starting from the 
randomization visit until EOS. Refer to Section 9.2.4.7 for procedural details. In asthmatic 
subjects, the weekly RQLQ (S) and ACQ-5 assessments may be performed on the same 
day.  
9. Refer to for Section 9.2.4.8 procedural details. 
10. Refer to for Section 9.2.4.9 procedural details. 
11. Vital signs include systolic and diastolic blood pressure, respiratory rate and heart rate. 
Vital signs will be collected in a seated position. At the randomization visit, vital signs are 
taken prior to PK blood draw, prior to study drug administration, and at 2 hours (±10 min) 
after completion of the injection.  
12. A full physical exam must be performed at screening, at baseline, and at EOS. A limited 
physical exam will be done at remaining visits depending on presentation of the subject. 
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13. If the urine pregnancy test is positive, the site must perform a serum pregnancy test for 
confirmation. At the randomization visit, if a serum pregnancy test must be performed, 
study drug cannot be administered unless the serum pregnancy test is negative. Urine 
pregnancy test can be performed on day -1 of the visit at the investigator’s discretion.  
At-home pregnancy testing: WOCBP will be provided with urine pregnancy tests for 
at-home testing prior to visits 4 and 6. Study sites will collect the results by telephone at 
these visits. If the urine pregnancy test is positive, the site must perform a serum pregnancy 
test for confirmation.  
14. PK and ADA samples are to be collected prior to study drug administration. In the event 
of suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for PK and 
ADA analyses may be collected as close to the event as practically possible. 
15. Refer to Section 9.2.11. 
16. Genomic analysis is optional for all subjects enrolling in the study. One DNA sample is to 
be collected at the randomization visit, but if this sample collection was omitted at baseline, 
it can be collected at any subsequent visit. Refer to Section 9.2.12. 
9.1.2. 
Early Termination Visit 
Subjects who are withdrawn from the study after randomization or at any time before the end of 
study visit will be asked to return to the study site for an early termination (ET) visit. Refer to 
Table 1 for assessments to be performed at an ET visit. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep subjects 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. Refer to Table 1 for assessments to be performed at unscheduled visits. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed primarily for determining study eligibility or 
characterizing the baseline population: medical history, demographics, and standard regional SPT. 
However, these assessments may also be performed at any unscheduled visit at the investigator’s 
discretion.  
9.2.2. 
Pollen Counting 
Local pollen levels will be monitored throughout the study by the study sites or by a vendor. The 
start and the end of birch pollen season will be determined for each site using current standards for 
defining pollen seasons, factoring in local pollen counts from each site due to regional variability 
in pollen seasons (Pfaar, 2017). The start of the birch pollen season is defined as the first of 
3 consecutive days with a pollen count of 10 grains/m3 or greater. The end of the birch pollen 
season is defined as the last day of the last occurrence of 3 consecutive days with a pollen count 
of 10 grains/m3 or greater. 
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9.2.3. 
Birch Allergen and Standard Regional Skin Prick Tests 
An SPT with birch allergen extract and a regional SPT (such as with dust mites, grasses, other 
trees, including other birch homologous trees [such as alder and oak], cat, and dog) will be 
performed to assess sensitization status. Skin prick test data may be used to determine the 
relationship between birch and regional allergen sensitization at baseline and pharmacodynamic 
effects of REGN5713-5714-5715 to reduce allergic symptoms upon birch pollen allergen 
challenges. Mean wheal diameter is measured approximately 15 minutes after placement. Aside 
from the birch skin test requirement for enrollment, a positive response is defined by a mean wheal 
diameter at least 3 mm greater than a negative control. 
For patients who enroll in the study, SPT will be performed as noted in Table 1 and the mean 
wheal diameters will be used to assess clinical responses to treatment. The allergens used for SPT 
will include birch pollen and 1 or 2 additional related homologous tree allergens. 
9.2.4. 
Efficacy Procedures  
Efficacy measures will be assessed at time points indicated on Table 1. 
9.2.4.1. 
Total Nasal Symptom Score 
The TNSS ranges from 0 to 12 and is based on assessment of 4 nasal symptoms graded on a Likert 
scale ranging from 0 (none) to 3 (severe) for congestion, itching, and rhinorrhea, and for sneezing. 
The TNSS will be recorded using an e-diary. 
9.2.4.2. 
Total Ocular Symptom Score 
The TOSS ranges from 0 to 6 and is based on 2 symptoms: itching/redness/gritty feeling and 
tearing/watering. Each of the 2 symptoms is graded 0 (absent), 1 (mild), 2 (moderate), or 
3 (severe). The TOSS will be recorded using an e-diary.  
9.2.4.3. 
Total Symptom Score 
The TSS is calculated by adding the TNSS and TOSS together, for a combined TSS of 0 to 18. 
9.2.4.4. 
Daily Medication Score 
Subjects will be asked to record their daily rescue medication use using an e-diary, including which 
medications and the amount of these pre-specified medications. This information will be used to 
calculate the DMS as follows: desloratadine 5 mg 6 points/dose; maximum daily score 6 points, 
olopatadine 1 mg/mL each drop 1.5 points/drop; maximum daily score 6 points, mometasone 
furoate 50 ug/dose 2.0 points/spray; maximum daily score 8 points). The maximum DMS score is 
20 (Calderon, 2014).  
9.2.4.5. 
Combined Symptom and Medication Score 
The CSMS is calculated by adding the DMS and TSS together, with scores ranging between 0 and 
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9.2.4.6. 
Asthma Control Questionnaire 
The ACQ measures the adequacy of asthma control and change in asthma control that occurs 
spontaneously or as a result of treatment. The ACQ-5 is comprised of 5, patient-reported items 
that were rated by clinicians as the most important to evaluate control: (1) awakening at night due 
to symptoms, (2) morning symptoms, (3) limitation of daily activities, (4) shortness of breath, and 
(5) wheezing. The total score ranges from 0 to 6 with higher scores denoting less asthma control. 
A score of ≥1.5 is considered as uncontrolled asthma. The ACQ-5 will be recorded using an 
e-diary.  
9.2.4.7. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire 
The RQLQ (S) has 28 questions in 7 domains: activity limitation, sleep problems, nose symptoms, 
eye symptoms, non-nose/eye symptoms, practical problems, and emotional function. There are 
3 subject-specific questions in the activity domain that allow subjects to select 3 activities in which 
they are most limited by their rhinoconjunctivitis. Subjects recall how bothered they have been by 
their rhinoconjunctivitis during the previous week and respond to each question on a 7-point scale 
(0 [not impaired at all] to 6 [severely impaired]). The overall RQLQ (S) score is the mean of all 
28 responses, and the individual domain scores are the means of the items in those domains 
(Juniper, 1991). The RQLQ (S) will be recorded using an e-diary.  
9.2.4.8. 
Pollen Food Allergy Symptom Questionnaire 
The PFASQ will be performed at time points according to Table 1 to determine the types of food 
that produce an allergic reaction, the type of reaction, and how soon the reactions occur [adapted 
from (Geroldinger-Simic, 2011)]. 
9.2.4.9. 
Patient Global Impression of Severity 
The PGI-S assesses the severity of seasonal allergy symptoms over the past 1 week. Symptom 
severity ranges from 0 (no symptoms), 1 (mild), 2 (moderate), and 3 (severe) symptoms. 
9.2.5. 
Safety Procedures  
Safety measures will be assessed at time points indicated on Table 1.  
9.2.5.1. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure, respiratory rate and heart rate. Vital signs 
will be collected in a seated position. On the day of study drug administration, vital signs are taken 
prior to PK blood draw, prior to study drug administration, and at 2 hours (±10 min) after 
completion of the injection.  
9.2.5.2. 
Physical Examination 
A complete physical examination will be performed according to Table 1. 
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9.2.5.3. 
Body Weight 
Body weight will be assessed using calibrated scales. Subjects should remove shoes during weight 
assessments. Body weight will be recorded to the nearest 0.1 kg. 
9.2.5.4. 
Spirometry 
Spirometry (American Thoracic Society [ATS]/European Respiratory Society [ERS]-compliant) 
as adjudicated by the site investigator, including measurements of forced vital capacity (FVC [L]), 
forced expiratory volume (FEV1 [L]), FEV1/FVC (%), peak expiratory flow (L/s), forced 
expiratory flow 25 to 75 (L/s), will be performed during screening and randomization to exclude 
any subjects with abnormal lung function and/or poorly controlled asthma. 
9.2.6. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to according to Table 1. Heart 
rate will be recorded from the ventricular rate and the PR, QRS, and QT intervals will be recorded. 
The ECG strips or reports will be retained with the source documentation. 
To minimize variability, it is important that the patient be in a resting position for ≥10 minutes 
prior to the ECG evaluation. Body position should be consistently maintained for each ECG to 
prevent changes in heart rate.  
9.2.7. 
Laboratory Testing 
9.2.7.1. 
Hematology, Blood Chemistry, Pregnancy Test, and Urinalysis 
Hematology, chemistry, pregnancy test, and urinalysis will be analyzed by a central laboratory. 
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. 
Samples for laboratory testing will be collected at visits according to Table 1. Tests will include: 
Blood chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Triglycerides 
Chloride 
Blood urea nitrogen (BUN) 
Uric acid 
Carbon dioxide 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
 
 
Hematology 
Hemoglobin 
Differential:  
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
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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 
Subjects will be tested for FSH levels (postmenopausal women only) and will undergo serum and 
urine pregnancy testing (WOCBP only); pregnancy testing is not required of women confirmed 
postmenopausal. If any urine pregnancy test is positive, the site must perform a serum pregnancy 
test for confirmation. If a serum pregnancy test must be performed, study drug cannot be 
administered unless the serum pregnancy test is negative.  
Samples will be collected for quantitative assessment of total and allergen-specific IgE and will 
be analyzed by a central laboratory. 
Abnormal laboratory values and laboratory adverse events 
All laboratory values must be reviewed by the investigator or authorized designee. 
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. 
9.2.7.2. 
Serum Antibodies 
Levels of anti-birch pollen sIgE and anti-Bet v 1 sIgE will be measured according to Table 1 to 
evaluate the relationship between clinical response to REGN5713-5714-5715 and sensitization to 
birch pollen and Bet v 1. After the randomization visit, the detection of anti-Bet v 1 sIgE will be 
inhibited by study drug REGN5713-5714-5715, therefore the data will be used to assess effective 
competition between endogenous sIgE and study drug.  
Serum total IgE will be measured according to Table 1 to assess the overall allergic disease burden 
in study subjects. The results will be used to evaluate the relationship between response to 
REGN5713-5714-5715 and overall allergic status.  
Allergen-specific IgE levels against regional allergens and common perennial allergens will be 
measured according to Table 1 to assess sensitization status to other common allergens and to 
evaluate the relationship between response to REGN5713-5714-5715 and poly/mono-sensitization 
(Van Ree, 1999). 
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Additional subclasses of serum antibodies (eg, IgG and IgG4 against birch pollen and Bet v 1) will 
be measured at screening. These results will be part of exploratory research analysis and will be 
included in an exploratory biomarker report. 
9.2.8. 
Drug Concentration and Measurements 
Samples for drug concentration measurement will be collected at visits listed in Table 1.  
Any unused samples may be used for exploratory research. 
9.2.9. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment for REGN5713, REGN5714 and REGN5715 will be collected at 
time points listed in Table 1. Anti-REGN5713, REGN5714, and REGN5715 neutralizing 
antibodies (NAb) analysis may be performed on ADA-positive serum samples. The overall 
immunogenicity risk will be taken into consideration to assess the need for NAb analysis. Serum 
samples will be banked, if NAb analysis is to be conducted at a later time. 
Any unused samples may be used for exploratory research. 
9.2.10. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Blood samples will be obtained for additional exploratory research to better understand the effects 
of various anti-Bet v 1 antibodies on birch allergy. This will include the assessment of effective 
competition between REGN5713, REGN5714, and REGN5715 (either alone or in combination) 
and endogenous sIgE in serum for allergen binding in an in vitro interference/ inhibition assay.  
These results will be part of exploratory research analysis and will be included in an exploratory 
biomarker report, which will not be described in the clinical study report.  
9.2.10.1. Exploratory Biomarker Research 
Blood samples will be obtained for additional exploratory research to better understand the effects 
of various anti-Bet v 1 antibodies on birch allergy. This will include the assessment of effective 
competition between REGN5713, REGN5714, REGN5715 (either alone or in combination), and 
endogenous serum IgE for allergen binding in an in-vitro interference/ inhibition assay.  
Additional blood samples will be collected for measuring subclasses of serum antibodies (eg, IgG 
and IgG4 against birch pollen and Bet v 1) at screening.  
Exploratory biomarker results not required for protocol-defined endpoint analyses will not be 
reported in the CSR. These results will be included in an exploratory biomarker report. 
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9.2.11. 
Future Biomedical Research (Optional) 
Subjects 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. Additional 
samples will be collected for FBR. 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 CSR. 
9.2.12. 
Pharmacogenomic Analysis (Optional) 
Subjects 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 (predose) but can be collected at a later study visit. DNA 
sample 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 birch 
allergy and related 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 REGN5713-5714-5715, other birch allergy clinical outcome measures and 
possible AEs. In addition, associations between genomic variants and prognosis or progression of 
birch allergy as well as related allergic 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 birch allergy 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, and DNA copy number variation may also be performed. 
The list of methods may be expanded to include novel methodology that may be developed during 
the course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
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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, from the time of signing the ICF to the end of on-treatment period (see 
Section 11.4.5.1). 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 
subject. Adverse events may be directly observed, reported spontaneously by the subject, or by 
questioning the subject at each study visit. Subjects 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 SAEs (and 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 on-treatment period) that 
the investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.2 and Section 10.1.3. 
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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 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 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 
• Selected Adverse Events of Special Interest (AESI; serious and nonserious): Adverse 
events of special interest for this study include systemic or severe hypersensitivity 
reactions and severe injection site reactions.  
• 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 or female partner of a male, during the study or 
within 6 months of the last dose of study drug. Any complication of pregnancy affecting 
a female study subject or female partner of a male study subject, 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. 
10.2. 
Definitions 
10.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject 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 E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994). 
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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 subject is a passenger). 
• Is life-threatening – in the view of the investigator, the subject 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 a 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 subject 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.  
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 subject 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 subject 
• 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 subject’s health. Treatment for symptom may be given and/or 
subject hospitalized 
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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 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 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 versus 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  
• Subject’s medical and social history  
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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, subject’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, subject’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, 
subject’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, subject’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 subject 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, Global Patient Safety; Biostatistics and Data Management). Safety monitoring will be 
performed on an ongoing basis (eg, individual review of SAEs) and on a periodic cumulative 
aggregate basis. 
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10.4. 
Notifying Health Authorities, Institutional Review Board, Ethics 
Committee, and Investigators 
During the study, the Sponsor and/or the contract research organization (CRO) will inform health 
authorities, IECs/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 (REGN5713-5714-5715), 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 (REGN5713-5714-5715) 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 first database lock. 
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
11.1. 
Statistical Hypothesis 
For comparison of a single dose of REGN5713-5714-5715 to placebo, the following hypothesis 
of the primary endpoint (average CSMS over birch pollen season) will be tested: 
• H0: There is no difference in CSMS, averaged over the duration of the birch pollen 
season, in subjects receiving REGN5713-5714-5715 and placebo. 
• H1: The CSMS, averaged over the duration of the birch pollen season, is statistically 
significant different in subjects receiving REGN5713-5714-5715 and placebo. 
The statistical hypothesis above is to test in a hierarchical procedure for primary efficacy and 
secondary endpoints at 2-sided 5% significance level. 
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11.2. 
Justification of Sample Size 
This study is powered to detect differences between REGN5713-5714-5715 and placebo on the 
primary endpoint of the average CSMS during birch pollen season. A sample size of 150 enrolled 
subjects per arm gives 90% power to detect a mean difference in average CSMS of 1.9 (30% 
reduction from placebo) in REGN5713-5714-5715 (mean CSMS = 4.4) and placebo (mean CSMS 
= 6.3), assuming a common standard deviation in CSMS of 4.5. The minimum significant 
difference in CSMS is 1.14, or approximately an 18% reduction from placebo. This sample size 
calculation assumes a 20% drop out rate (30 subjects per arm) and a two-sample t-test with two-
sided alpha of 0.05. Estimates of mean and variability of the CSMS are based on pooled estimates 
across several field studies for grass immunotherapy, and a 30% treatment effect relative to 
placebo is in line with what was observed in the phase 1b POC study for REGN5713-5714-5715. 
11.3. 
Analysis Sets  
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized subjects who had at least 1 e-diary entry with 
symptoms or medication score recorded during the birch pollen season; it is based on the treatment 
allocated (as randomized). Efficacy endpoints will be analyzed using the FAS. 
The per protocol set (PPS) includes all subjects in the FAS except for those who are excluded due 
to specified important protocol violations. Final determination of the PPS will be made prior to the 
database lock and will be outlined in the SAP. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized subjects 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. 
11.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all treated subjects who received any study drug (safety 
population) and had at least 1 non-missing serum drug concentration following at least a single 
dose of REGN5713-5714-5715. Subjects will be analyzed according to the treatment actually 
received. 
11.3.4. 
Immunogenicity Analysis Set 
The ADA analysis set will consist of all subjects who received any study drug and who had at least 
1 non-missing ADA result after the first dose of the study drug. Subjects will be analyzed 
according to the treatment actually received. 
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11.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information: the number 
of subjects reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
11.4.1. 
Subject Disposition 
The following will be provided: 
• The total number of screened subjects: met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized subjects: received a randomization number 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
• The total number of subjects who discontinued from study treatment, and the reasons 
for discontinuation 
• A listing of subjects treated but not randomized, subjects randomized but not treated, 
and subjects randomized but not treated as randomized 
• A listing of subjects prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all subjects combined.  
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The efficacy endpoints will be analyzed using the FAS defined in Section 11.3.1.  
The primary analysis will focus on the comparison between the REGN5713-5714-5715 arm and 
placebo arm. The average CSMS during birch pollen season will be compared in subjects receiving 
REGN5713-5714-5715 and subjects receiving placebo using a linear mixed-effect model, with the 
treatment group and randomization stratification factors (as described in Section 8.5) as fixed 
effects and pollen region as a random effect, to account for potential differences in birch pollen 
seasons based on the geographical location of each pollen region. Clinical sites will be pooled into 
different pollen regions which will be specified in the SAP. Subjects with at least 1 day of post-
baseline diary record with symptom and medical score (SMS) will be included. The CSMS will 
be calculated on all available data during the birch pollen season. The primary analysis will be 
based on the available values of daily symptom score and daily medication score to calculate the 
average CSMS and no imputation will be needed for the primary endpoint during the birch pollen 
season.  
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The average CSMS will be calculated based on daily symptom score (TNSS and TOSS, max of 
18/day) and daily medication score (max of 20/day) recorded over the duration of the birch pollen 
season. The start and end of the birch pollen season will be defined for each site based on the local 
birch pollen counts. Only days with observed data (including any available data of daily entries 
prior to subject discontinuation) will be included in the calculation of the average CSMS.  
Any rescue medication use will not be set to missing for the CSMS, but relevant prohibited 
medications (as listed in Section 8.9.1) that may have a long-term impact on symptom 
measurements will result in subsequent symptoms and medication scores to not be utilized in the 
CSMS for that subject for a specified period of time (determined by medication type). Relevant 
prohibited medications and corresponding time frames for censoring will be specified in the SAP. 
In addition, as a supportive analysis, a non-parametric analysis using the Wilcoxon rank-sum test 
will be compared 2 group median in term of risk reduction from placebo for the primary endpoint 
of the average CSMS during the birch pollen season between REGN5713-5714-5715 and placebo. 
The Hodges-Lehmann estimator of median treatment difference for 95% confidence interval will 
be provided. With respect to the missing data handling of daily entries, sensitivity analyses may 
be performed to evaluate the robustness of the conclusion drawn based on the main model for 
primary analysis considering a minimum number of daily entries during the birch pollen season. 
Details of the sensitivity analyses will be provided in the SAP. 
Subgroup analysis (eg, by baseline anti-birch pollen IgE level <17.5 kUa/L versus ≥17.5 kUa/L) 
may also be performed.  
11.4.3.2. Secondary Efficacy Analysis 
The average daily TNSS, TSS, TOSS, and DMS during the birch pollen season will be analyzed 
in the same fashion as the primary analysis for the subjects receiving REGN5713-5714-5715 
versus placebo. Subjects with at least 1 day of post-baseline diary record will be included in the 
analysis, and only days with observed data (including any available data of daily entries prior to 
subject discontinuation) will be included in the calculation of average score. 
11.4.3.3. Exploratory Efficacy Analysis 
Exploratory efficacy endpoints, including the average ACQ-5, RQLQ (S), and PGI-S scores during 
the birch pollen season will be analyzed in the same fashion as the primary analysis for the subjects 
receiving REGN5713-5714-5715 versus placebo. Subjects with at least 1 day of data will be 
included in the analysis. 
11.4.4. 
Control of Multiplicity 
Type I error rate will be controlled using a hierarchical testing strategy for the primary and key 
secondary endpoints at the 2-sided significant level of 0.05. The hierarchical order of the primary 
and key secondary endpoints will be specified in the SAP. 
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11.4.5. 
Safety Analysis 
11.4.5.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
• The pre-treatment 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 day from first dose of study drug to the end 
of study visit. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the on-treatment 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 will include: 
• The number (n) and percentage (%) of subjects 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 
• 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 (eg, pulse, blood pressure, and respiration rate) will be summarized by baseline and 
change from baseline to each scheduled assessment time with descriptive statistics. 
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 subjects with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test for all subjects 
and separately for subjects in whom the PCSV criterion was normal or missing at baseline.  
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. 
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Listings will be provided with flags indicating the out of laboratory range values. 
11.4.5.3. Treatment Exposure 
This is a single dose study. 
11.4.5.4. Treatment Compliance 
Treatment compliance will be assessed via the summary of treatment exposure as described in 
Section 11.4.5.3. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of total REGN5713, REGN5714, and REGN5715 over time will be 
summarized by descriptive statistics for each of the treatment groups.  
No formal statistical hypothesis testing will be performed. 
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response  and titer observed:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 9-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative 
• Treatment boosted ADA response, defined as any post-dose positive ADA assay 
response that is 9-fold over baseline titer levels when baseline is positive in the ADA 
assay  
• Maximum ADA Titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, and ADA 
titers presented by subject, time point, and treatment group will be provided separately for 
REGN5713, REGN5714, and REGN5715. Incidence of treatment-emergent ADA will be assessed 
as absolute occurrence (N) and percent of subjects (%), grouped by treatment group and ADA titer 
level. 
Plots of drug concentrations will be examined and the influence of ADA responses on individual 
PK profiles evaluated separately for REGN5713, REGN5714, and REGN5715. Assessment of 
impact of ADA responses on safety and efficacy may be provided. 
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11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The change and percent change from baseline in the birch skin prick test mean wheal diameters 
will be analyzed using an analysis of covariance (ANCOVA) model, with treatment, 
randomization stratification factors, visit and the treatment by visit interaction as factors in the 
model and the baseline mean wheal diameter as a covariate. Between group estimates comparing 
REGN5713-5714-5715 versus placebo will be presented for the end of study. 
The prevalence of poly-allergy for tree homologue allergens and others being tested in this study 
will be assessed based on SPT and sIgE test results. The relationship between baseline SPT and 
sIgE of birch and homologue tree allergens will also be evaluated, as well as the correlation 
between SPT and sIgE and symptom scores. The within-subject variability in sIgE in and out of 
birch pollen season will also be evaluated. 
11.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline 
The last assessment before the administration of study drug on day 1 will be considered as the 
baseline evaluation. 
Handling data in case of grass pollen season overlap with birch pollen season 
Grass pollen season may start as birch pollen season is ending, thus potentially confounding 
allergic symptoms evaluated during the overlap of birch and grass pollen seasons. If birch pollen 
season overlaps with grass pollen season during this study, symptom and medication data collected 
from days after the start of the grass pollen season will be excluded from analyses.  
General rules for handling missing data 
If the start date of an AE or concomitant medication is incomplete or missing, it will be assumed 
to have occurred on or after the intake of study medication, except if an incomplete date (eg, month 
and year) clearly indicates that the event started prior to treatment. If the partial date indicates the 
same month or year of the intake of study medication date, then the start date by the study 
medication intake date will be imputed; otherwise, the missing day or month by the first day or the 
first month will be imputed.  
No imputations for missing laboratory data, ECG data, vital sign data, or physical examination 
data will be made. 
Visit windows 
Assessments taken outside of protocol-allowable windows will be displayed according to the case 
report form (CRF) assessment recorded by the investigator. 
Unscheduled assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing AEs) will be included in listings, but not 
summaries. If more than 1 laboratory value is available for a given visit, the first observation will 
be used in summaries and all observations will be presented in listings. 
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11.6. 
Interim Analysis  
No formal interim analysis will be conducted. 
11.7. 
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) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) system, 
Medidata Rave. 
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 
• Electronic diary and tablet for collection of patient-reported outcomes data 
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12.2. 
Study Monitoring  
12.2.1. 
Monitoring of Study Sites 
Regeneron uses a study-specific risk-based approach to study monitoring and oversight, aligned 
with risk-based quality principles, outlined in ICH E6 (R2) Guideline for Good Clinical Practice. 
Risk-Based Quality Monitoring (RBQM) methodology focuses on employing a fit-for-purpose 
monitoring strategy, supported either directly by Regeneron as Sponsor, or via our CRO partners. 
RBQM strategies include: reduced source data verification (SDV), targeted source data review 
(SDR), the use of off-site/remote and triggered on-site monitoring visits, and Centralized 
Monitoring to identify site level risks and study level trends. The investigator must allow study-
related monitoring activities to occur. 
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 subjects 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 subject records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
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 subject 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 subject, the investigator must provide an electronic signature. 
A copy of each subject 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. 
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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 
• 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 eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of subject final 
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.  
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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. 
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 subject 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 subject in 
language that he/she can understand. The ICF should be signed and dated by the subject and by 
the investigator or authorized designee who reviewed the ICF with the subject.  
• Subjects who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
• Subjects 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 subject's study record, and a 
copy of the signed ICF must be given to the subject. 
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 subjects 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 subject’s study record and a copy must be given to the subject. 
13.3. 
Subjects Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained. Subjects should be identified by a subject 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 subject '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. 
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13.4. 
Institutional Review Board and 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 subjects 
(eg, advertising) before any subject 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 subject, in which 
case the IRB/EC should be informed as soon as possible  
• 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 subjects 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. 
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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. 
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 subject 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 subjects 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 subjects’ 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. 
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Wallace DV, Dykewicz MS. Seasonal Allergic Rhinitis: A focused systematic review and practice 
parameter update. Curr Opin Allergy Clin Immunol 2017a; 17(4):286-94. 
Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, et al. The 
diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol 
2008; 122(2 Suppl):S1-84. 
Wallace DV, Dykewicz MS, Oppenheimer J, Portnoy JM, Lang DM. Pharmacologic Treatment of 
Seasonal Allergic Rhinitis: Synopsis of Guidance From the 2017 Joint Task Force on Practice 
Parameters. Ann Intern Med 2017b; 167(12):876-81. 
Wei C. The efficacy and safety of H1-antihistamine versus Montelukast for allergic rhinitis: A 
systematic review and meta-analysis. Biomed Pharmacother 2016; 83(989-97). 
 
 
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Clinical Study Protocol 
 
R5713-5714-5715-ALG-2001 Original  
 
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Page 73 
CONFIDENTIAL 
20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A PHASE 3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY ASSESSING THE EFFICACY OF ANTI-BET V 1 MONOCLONAL 
ANTIBODIES TO REDUCE SYMPTOMS OF SEASONAL ALLERGIC RHINITIS 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) 
 
 
 
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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 Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Assessing the 
Efficacy of Anti-Bet v 1 Monoclonal Antibodies to Reduce Symptoms of Seasonal Allergic 
Rhinitis  
Protocol Number: 
R5713-5714-5715-ALG-2001 
Protocol Version:  
R5713-5714-5715-ALG-2001 Original 
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 
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Signature Page for VV-RIM-00121234 v2.0
Signature Page for VV-RIM-00121234 v2.0 Approved
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ESig Approval
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ESig Approval
-2020 15:17:57 GMT+0000
ESig Approval
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 56 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: AMENDMENT 1 
Clinical Study Protocol Title: 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study Assessing the Efficacy of 
Anti-Bet v 1 Monoclonal Antibodies to Reduce Symptoms of Seasonal Allergic Rhinitis 
Compound: 
REGN5713-5714-5715 
Protocol Number: 
R5713-5714-5715-ALG-2001 Original 
Clinical Phase:  
Phase 3 
Sponsor:  
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
Clinical Trial Manager: 
Study Medical Director: 
Version/Date:  
Amendment 1 / 28Jul2021 
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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 
Study Biostatistician   
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................11 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.4. 
Revision History for SAP Amendments .....................................................................11 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Statistical Hypothesis ..................................................................................................13 
2.3. 
Sample Size and Power Considerations .....................................................................13 
2.4. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
The Full Analysis Set (FAS) .......................................................................................15 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................15 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................15 
3.4. 
The Immunogenicity Analysis Set..............................................................................15 
3.5. 
Subgroups ...................................................................................................................15 
4. 
ANALYSIS VARIABLES .........................................................................................17 
4.1. 
Demographic and Baseline Characteristics ................................................................17 
4.2. 
Medical History ..........................................................................................................17 
4.3. 
Pre-treatment / Concomitant Medication and Procedures ..........................................17 
4.4. 
Prohibited or Rescue Medication/Procedure ..............................................................18 
4.4.1. 
Prohibited Medications ...............................................................................................18 
4.4.2. 
Rescue medication ......................................................................................................19 
4.5. 
Efficacy Variable ........................................................................................................20 
4.5.1. 
Primary Efficacy Variable ..........................................................................................20 
4.5.2. 
Secondary Efficacy Variables .....................................................................................21 
4.5.3. 
Exploratory Efficacy Variables ..................................................................................21 
4.6. 
Safety Variables ..........................................................................................................22 
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4.6.1. 
Adverse Events and Serious Adverse Events .............................................................22 
4.6.2. 
Adverse Events of Special Interest .............................................................................23 
4.6.3. 
Laboratory Safety Variables .......................................................................................23 
4.6.4. 
Vital Signs and Weight/Height ...................................................................................23 
4.6.5. 
12-Lead Electrocardiography (ECG) ..........................................................................24 
4.6.6. 
Physical Examination Variables .................................................................................24 
4.6.7. 
Spirometry ..................................................................................................................24 
4.7. 
Pharmacokinetic Variables .........................................................................................24 
4.8. 
Immunogenicity Variables ..........................................................................................24 
4.9. 
Biomarker Variables ...................................................................................................25 
4.10. 
Other Variables ...........................................................................................................25 
5. 
STATISTICAL METHODS .......................................................................................27 
5.1. 
Demographics and Baseline Characteristics ...............................................................27 
5.2. 
Medical History ..........................................................................................................27 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................27 
5.4. 
Subject Disposition .....................................................................................................27 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................28 
5.6. 
Analyses of Efficacy Variables ..................................................................................28 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................30 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................31 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................31 
5.6.4. 
Subgroup Analysis ......................................................................................................32 
5.6.5. 
Analysis of Exploratory Efficacy Variables ...............................................................32 
5.7. 
Analysis of Safety Data ..............................................................................................32 
5.7.1. 
Adverse Events ...........................................................................................................32 
5.7.2. 
Clinical Laboratory Measurements.............................................................................33 
5.7.3. 
Analysis of Vital Signs ...............................................................................................34 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................34 
5.9. 
Analysis of Immunogenicity Data ..............................................................................34 
5.9.1. 
Analysis of ADA Data ................................................................................................34 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................34 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................35 
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5.10.1. 
Immunogenicity and Exposure ...................................................................................35 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................35 
5.11. 
Analysis of Biomarker Data .......................................................................................36 
6. 
DATA CONVENTIONS ............................................................................................37 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................37 
6.2. 
Data Handling Conventions ........................................................................................37 
6.3. 
Data Handling Convention for Missing Data .............................................................37 
6.4. 
Analysis Visit Windows .............................................................................................39 
6.5. 
Statistical Technical Issues .........................................................................................40 
7. 
INTERIM ANALYSIS ...............................................................................................41 
8. 
SOFTWARE ...............................................................................................................42 
9. 
REFERENCES ...........................................................................................................43 
10. 
APPENDIX.................................................................................................................48 
10.1. 
Summary of Statistical Analyses ................................................................................48 
10.1.1. 
Summary of Efficacy Analyses ..................................................................................48 
10.1.2. 
Summary of Safety Analyses ......................................................................................49 
10.2. 
Schedule of Time and Events .....................................................................................50 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................54 
10.4. 
Search Criteria for TEAE of Special Interest .............................................................56 
 
LIST OF TABLES 
Table 1: 
Primary Estimand for the Primary Endpoint ..............................................................29 
Table 2: 
Data Utilization for Relevant Prohibited Medications ...............................................30 
Table 3: Schedule of Events ..........................................................................................................50 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................14 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACQ 
Asthma Control Questionnaire 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
BAT 
Basophil activation test 
BUN 
Blood urea nitrogen 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CSMS 
Combined symptom and medication score 
CSR 
Clinical study report 
CTFG 
Clinical Trial Facilitation Group 
DMS 
Daily medication score 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EMA 
European Medicines Agency 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
Food and Drug Administration 
FIH 
First in human 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HRQoL 
Health-related quality of life 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
Ig 
Immunoglobulin  
INCS 
Intranasal Corticosteroids 
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IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IV 
Intravenous 
IVRS 
Interactive voice response system 
IWRS 
Interactive web response system 
LAM 
Lactational amenorrhea method 
mAb 
Monoclonal antibody 
NAb 
Neutralizing antibody 
OAS 
Oral allergy syndrome 
PBMC 
Peripheral blood mononuclear cells 
PCA 
Percutaneous anaphylaxis 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamic  
PFAS 
Pollen food allergy syndrome 
PFASQ 
Pollen food allergy symptom questionnaire 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
POC 
Proof of concept 
RBC 
Red blood cell 
RBQM 
Risk-Based Quality Monitoring 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RQLQ (S) 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire 
RSOC 
Regeneron Safety Oversight Committee 
RSV 
Respiratory syncytial virus 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
sIgE 
Allergen-specific IgE 
SIT 
Specific immunotherapy 
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SLIT 
Sublingual immunotherapy 
SMT 
Safety Monitoring Team 
SOC 
System organ class 
SPT 
Skin prick test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
TSS 
Total symptom score 
WAO 
World Allergy Organization 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
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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 analysis of data for R5713-5714-5715-ALG-2001 study. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned analyses. 
A final plan will be issued prior to data lock and before treatment code breaking. 
1.1. 
Background/Rationale 
Allergic rhinitis with or without conjunctivitis is a common disease with a significant 
socioeconomic burden, due to direct costs (eg, medications and physician visits) and indirect costs 
(eg, loss of productivity/working day) (Vandenplas, 2018). The current prevalence of allergic 
rhinitis is 10% to 30% in adults worldwide, and up to 37% in children in some Western countries 
(Pawankar, 2011), affecting approximately 500 million people worldwide (Brozek, 2017). Allergic 
rhinitis is characterized by 1 or more symptoms including sneezing, itching, nasal congestion, and 
rhinorrhea on consecutive days. Allergic conjunctivitis is also commonly coexistent, occurring in 
approximately 65% of people with the nasal symptoms of allergic rhinitis (Navarro, 2009) 
(Rosario, 2011). Symptoms of fatigue, malaise, irritability, and neurocognitive deficits are 
prevalent (Wallace, 2008). Perennial allergic rhinitis is typically caused by sensitization to indoor 
allergens (eg, dust mites, mold, and animal dander), while seasonal allergic rhinitis is most often 
due to sensitization to pollen allergens (eg, trees, grass, and weeds). In addition, asthma prevalence 
is 10% to 40% in those with allergic rhinitis (Shaaban, 2008), and allergic rhinitis is a risk factor 
for the development of asthma (Guerra, 2002) (Leynaert, 2000). 
In Europe and North America, clinically relevant sensitization to birch tree pollen affects 
approximately 8% to 16% of the overall population (Biedermann, 2019a) (Chan-Yeung, 2010) 
(Salo, 2014) and approximately 20% to 30% of the population with allergic rhinitis (Burbach, 
2009) (Galant, 1998) (Lin, 2002) (Pablos, 2016) (Sierra-Heredia, 2018). Birch pollen contains a 
mix of allergenic and non-allergenic proteins, and Bet v 1 is the most abundant allergenic pollen 
protein (Erler, 2011) (Schenk, 2011). Sensitization rates to Bet v 1 among birch-allergic 
individuals reach >95% (Erler, 2011) (Jarolim, 1989) (Schenk, 2011). Birch pollen exposure is 
associated with an increase in asthma-related emergency department visits (Guilbert, 2018) 
(Ito, 2015). Up to 70% of people with pollen allergy also experience oral reactions to particular 
fresh fruits, vegetables, and nuts, a condition known as oral allergy syndrome (OAS), or pollen 
food allergy syndrome (PFAS). Pollen food allergy syndrome is not a separate food allergy but 
rather occurs because of cross-reactive epitopes present in pollen and associated foods 
(Ebner, 1995) (Vanek-Krebitz, 1995). Pollen food allergy syndrome symptoms typically manifest 
as itching of lips, mouth, and throat, but potentially involve lip and tongue swelling and 
angioedema (Bucher, 2004) (Eriksson, 1982), leading people to avoid these fresh fruits, 
vegetables, and nuts. Approximately 70% of people with birch allergy also have PFAS to foods 
with similar epitopes as Bet v 1, such as apple, carrot, stone fruits, and hazelnut 
(Biedermann, 2019b). 
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Antihistamines and intra-nasal corticosteroids (INCS) are first line therapy for allergic rhinitis, but 
only provide poor or partial symptom control and short-term relief to over half of allergic rhinitis 
sufferers (Halken, 2017) (Wallace, 2017a) (Wallace, 2008) (Wallace, 2017b) (Wei, 2016). The 
best reported treatment effects for antihistamines and INCs are 5% to 22% relative reduction of 
total nasal symptoms compared to placebo (Durham, 2016b), and INCS are considered to have 
limited efficacy for allergic eye symptoms (Bielory, 2011). Second line therapy for allergic rhinitis 
is allergen-specific immunotherapy (SIT), taken as either subcutaneous immunotherapy (SCIT) or 
sublingual immunotherapy (SLIT) tablets or drops (Bousquet, 1998) (Calderon, 2007) (Durham, 
1999) (Ewbank, 2003) (Nelson, 2004) (Walker, 2001). Birch pollen SIT is used to treat birch-
sensitive allergic rhinitis, including allergies caused by pollen from the birch homologous group 
of trees (eg, alder and hazel) (Biedermann, 2019a) (Makela, 2018) (Mauro, 2007). Birch pollen 
SIT has been shown to reduce asthma medication use and to reduce the risk of new-onset asthma 
(Wahn, 2019).  
However, SIT has many limitations. For the treatment of allergic rhinitis, SCIT or SLIT must be 
administered for at least 2 to 6 months prior to the onset of efficacy, and the efficacy of SIT requires 
high adherence to prevent rhinitis symptoms upon allergen exposure (Biedermann, 2019a) 
(Demoly, 2016) (Didier, 2011) (Durham, 2010) (Durham, 2012) (Durham, 2016a) (Durham, 1999) 
(Lemberg, 2017) (Nolte, 2016). Subcutaneous immunotherapy is administered weekly during 
initiation of therapy and then monthly, under direct supervision in the clinic. Sublingual 
immunotherapy is administered daily at home. Both SCIT and SLIT have a high incidence of 
adverse events (AEs), including anaphylaxis. Anaphylaxis occurs more frequently with SCIT 
compared to SLIT (Epstein, 2017). Reactions to SCIT occur in 40% to 50% of patients, ranging 
from mild (eg, swelling, injection site reaction, de novo allergic response, and urticaria) to life-
threatening (eg, asthma exacerbation and anaphylaxis) (Frew, 2006a) (Frew, 2010) (Frew, 2006b). 
Reactions to SLIT occur in the majority of patients, commonly involving irritation or swelling in 
the mouth or throat, predominantly over the first few weeks of therapy (Biedermann, 2019a). 
Subcutaneous immunotherapy and SLIT are generally contraindicated in patients with moderate 
to severe or uncontrolled asthma (Cox, 2011). 
Adherence to SIT is poor, likely due to the slow time to onset of action, the significant risk of 
allergic reactions, and the requirement for strict adherence for efficacy, including frequent clinic 
visits and monitoring needs in the case of SCIT (Musa, 2017). Due to these limitations, there 
remains an unmet need for a more robust, safer, rapid, and more convenient therapeutic approach 
for the prevention and treatment of moderate to severe allergic rhinitis and comorbid asthma. 
Three IgG4 mAbs against Bet v 1 (REGN5713, REGN5714, and REGN5715) have been 
developed for the treatment of birch allergy. Preclinical studies demonstrate that the 3 mAbs bind 
independently and non-competitively to the Bet v 1 allergen. Data also indicate that all 3 mAbs 
are required to optimally inhibit binding of Bet v 1 to human polyclonal IgE, and thus reduce in 
vitro effector cell degranulation and subsequent Type 1 hypersensitivity reaction. A single 
ascending dose-escalation clinical trial of the 3-mAb cocktail (REGN5713-5714-5715; in 1:1:1 
ratio) has been completed in healthy adults (FIH: Part A) and demonstrated that a single 150 mg 
subcutaneous (SC), 450 mg SC, 900 mg SC, or 900 mg intravenous (IV) dose had a favorable 
safety profile and was well-tolerated for 3 months post-dose, which was the follow-up period for 
the study. Part B of this FIH study demonstrated efficacy in healthy individuals with birch pollen 
allergy in reducing nasal symptoms assessed by TNSS AUC during nasal allergen challenges at 
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days 8, 29 and 57 after a single dose of 900 mg of REGN5713-5714-5715. There were no serious 
adverse events, no deaths and no TEAEs resulting in discontinuation for both parts A and B. 
This phase 3 randomized, double-blind, placebo-controlled study will assess the efficacy of 
REGN5713-5714-5715 to reduce allergic rhinitis and conjunctivitis symptoms and the use of 
rescue medications in the field during birch pollen season. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective is to assess the reduction of allergic symptoms as measured by combined 
symptom and medication score (CSMS) during birch pollen season after a single dose of 
REGN5713-5714-5715 versus placebo. 
1.2.2. 
Secondary Objectives 
The secondary objectives are: 
• To assess the reduction of allergic symptoms and use of allergy-relieving medications 
after a single dose of REGN5713-5714-5715 versus placebo, as measured by the total 
symptom score (TSS), total nasal symptom score (TNSS), total ocular symptom score 
(TOSS), and daily medication score (DMS) 
• To evaluate the safety and tolerability of REGN5713-5714-5715, including the 
incidence of hypersensitivity reactions and local injection site reactions 
• To evaluate the reduction in early allergic response to birch allergen after a single dose 
of REGN5713-5714-5715 versus placebo, as measured by SPT mean wheal diameter 
• To determine systemic exposure of total antibody (ie, free and antigen-bound) in the 
form of concentration of REGN5713, REGN5714, and REGN5715 in serum 
• To assess the immunogenicity to REGN5713, REGN5714, and REGN5715 in subjects 
after a single dose of REGN5713-5714-5715 
• To evaluate “well days” 
Note: “Well days” are defined as days when the TSS is ≤2 without the use of antiallergy rescue 
medications. 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
• The per protocol analysis set (PPS) was removed since estimands are constructed with 
aligned method of analysis that better address the objective, and analysis of PPS might 
not provide additional insights.  
1.2.4. 
Revision History for SAP Amendments 
The purpose of this amendment is to update the intercurrent events strategy for use of prohibited 
medications per FDA’s suggestion. A composite strategy will be applied only for the use of 
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systemic steroids and Type 2 biologics. For the other prohibited medications, a treatment policy 
will be applied.  
Section 
Description of Additions/Updates 
Section 5.6 Table 1 
• Update the intercurrent events strategy for use of relevant 
prohibited medications 
Section 5.6.1 Table 2  
• Update the list of relavant prohibited medications that will affect 
efficacy 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 3 multi-center, randomized, double-blind, placebo-controlled, parallel group study 
to assess the efficacy of REGN5713-5714-5715 to reduce allergic rhinitis (nose) and conjunctivitis 
(eye) symptoms and the use of rescue medications during birch pollen season. 
Efficacy will be evaluated by assessing the reduction of allergic nose and eye symptoms and the 
reduction in the use of allergy rescue medications during birch pollen season, after a single SC 
dose of REGN5713-5714-5715 or placebo. The incidence and severity of TEAEs, including 
hypersensitivity reactions and local injection site reactions, will also be assessed. Total 
concentration in serum and immunogenicity of REGN5713, REGN5714, and REGN5715 will be 
measured throughout the study. 
Subjects will be randomized according to a central randomization scheme provided by interactive 
response Technology (IRT) to the designated study pharmacist (or qualified designee). Subjects 
will be randomized 1:1 as below: 
• REGN5713-5714-5715 
• Matching placebo 
Randomization will be stratified based on the following: 
• Serum specific birch pollen IgE levels at screening (<17.5 kUa/L versus 
≥17.5 kUa/L) 
• In North America only: Serum specific oak pollen IgE levels at screening (<0.7 kUa/L 
versus ≥0.7 kUa/L) 
• Geographical region (North America (NA) versus Europe (EU)) 
2.2. 
Statistical Hypothesis 
For comparison of a single dose of REGN5713-5714-5715 to placebo, the following hypothesis 
of the primary endpoint (average CSMS over birch pollen season) will be tested: 
• H0: There is no difference in CSMS, averaged over the duration of the birch pollen 
season, in subjects receiving REGN5713-5714-5715 and placebo. 
• H1: The CSMS, averaged over the duration of the birch pollen season, is statistically 
significant different in subjects receiving REGN5713-5714-5715 and placebo. 
The statistical hypothesis above is to test in a hierarchical procedure for primary efficacy and 
secondary endpoints at 2-sided 5% significance level. 
2.3. 
Sample Size and Power Considerations 
This study is powered to detect differences between REGN5713-5714-5715 and placebo on the 
primary endpoint of the average CSMS during birch pollen season. A sample size of 120  subjects 
per arm gives 90% power to detect a mean difference in average CSMS of 1.9 (30% reduction 
from placebo) in REGN5713-5714-5715 (mean CSMS = 4.4) and placebo (mean CSMS = 6.3), 
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assuming a common standard deviation in CSMS of 4.5 with a two-sample t-test at 2-sided 
significance level of 0.05. Assuming 20% drop out rate during the birch pollen season, the target 
is to randomize 150 subjects per arm.  
Estimates of mean and variability of the CSMS are based on pooled estimates across several field 
studies for grass sublingual immunotherapy, and a 30% treatment effect relative to placebo is in 
line with what was observed in the phase 1b POC study for REGN5713-5714-5715.  
This planned sample size (150 subjects per arm) also gives 93% power to detect a mean difference 
in TNSS of 0.6 (26% reduction from placebo) in REGN5713-5714-5715 (mean TNSS=1.7) and 
placebo (mean TNSS=2.3), assuming a common standard deviation in TNSS of 1.5 at 2-sided 
alpha of 0.05 using a two-sample t-test. The assumptions of TNSS endpoint are based on effects 
observed in the GT-08 trial of timothy grass sublingual tablet (Dahl, 2006). With the same mean 
for placebo and common standard deviation from GT-08 but a 30% reduction from placebo for 
REGN5713-5714-5715 as observed in the phase 1b POC study, the study will have a greater 
power.  
The sample size and power calculations were performed using nQuery Advisor 7.0 
2.4. 
Study Plan 
The total study duration is approximately 28 weeks including screening, dependent on the start 
and end times of the local birch pollen season (Figure 1). The length of birch pollen season will 
vary based on geography. Approximately 300 birch-allergic subjects will be randomized 1:1 to 
REGN5713-5714-5715 or placebo. 
The Schedule of Event table is presented in Section 10.2. 
Figure 1: 
Study Flow Diagram 
 
 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis. 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized subjects who had at least 1 e-diary entry with 
symptoms or medication score recorded during the birch pollen season; it is based on the treatment 
allocated (as randomized). Since the TNSS, TOSS and DMS will be completed sequentially, all 
randomized subjects with at lease 1 TNSS e-diary entry will be included in FAS. Efficacy 
endpoints will be analyzed using the FAS.  
3.2. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized subjects who received any study drug; it is 
based on the treatment received (as treated). Treatment administration and all clinical safety 
variables will be analyzed using the SAF. 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set includes all treated subjects who received any study drug (safety population) 
and had at least 1 non-missing serum drug concentration following at least a single dose of 
REGN5713-5714-5715. Subjects will be analyzed according to the treatment actually received.  
3.4. 
The Immunogenicity Analysis Set 
The anti-drug antibody (ADA) analysis set will consist of all subjects who received any study drug 
and who had at least 1 non-missing ADA result after the first dose of the study drug. Subjects will 
be analyzed according to the treatment actually received. 
The neutralizing antibody (NAb) analysis set (NAS) includes all subjects who received any study 
drug and who tested negative at all ADA sampling times or tested positive with at least 1 non-
missing result in the NAb assay after the first dose of the study drug. Subjects who are ADA-
negative are set to negative in the NAb analysis set. Subjects will be analyzed according to the 
treatment actually received. 
3.5. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as follows. 
Subgroups to be considered for both efficacy and safety analyses: 
• Age group (years; 18 to <50; ≥50) 
• Sex (Male, Female) 
• Ethnicity: Hispanic or Latino (Yes, No) 
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• Race (White, Other) 
Subgroups to be considered for efficacy analysis only: 
• Serum specific birch pollen IgE level at screening(<17.5 kUa/L; ≥17.5 kUa/L) 
• Serum specific oak pollen IgE level at screening (<0.7 kUa/L; ≥0.7 kUa/L) (North 
America) 
• History of asthma (Yes, No) 
• Region (North America (NA),  Europe (EU)) 
• Baseline sensitization status based on sIgE or SPT (only sensitized to birch and birch 
related allergens, sensitized to birch, birch related allergens and any of other 
allergens) 
Note: birch and birch related allergens are listed as below based on sIgE and SPT: 
  
Birch 
Birch-related 
SPT 
Birch 
Alder 
sIgE 
Birch Silver 
Alder Grey 
rBet v1 
Hazelnut 
rBet v2 
Hornbeam  
 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized:  
• Demographic variables:  
− Age at screening as a continuous variable  
− Age group (years; 18 to <50, ≥50) 
− Sex (Male, Female) 
− Race (White, Black or African American, Asian, American indian or Alaska 
native, Native Hawaiian or other pacific islander) 
− Ethnicity (Hispanic/Latino: Yes or No) 
− Baseline Weight (kg) 
− Baseline Height (cm) 
− Region (NA, EU) 
• Baseline characteristics: 
− Standard regional skin prick test (SPT) for birch (mm) 
− Serum birch pollen sIgE at screening 
− Serum oak pollen sIgE at screening (North America) 
− Serum Bet v1 sIgE at screening 
− Baseline FEV1  
− Baseline sensitization status based on sIgE or SPT (e.g. sensitization to birch and 
birch related allergens only, sensitization to birch, birch related allergens and any 
of other allergens) 
4.2. 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA®). 
4.3. 
Pre-treatment / Concomitant Medication and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded using WHO Drug Dictionary (WHODD). Subjects will be 
counted once in each medication class linked to the medication. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the study drug. 
Concomitant medications/procedures (CMs/CPs): medications taken or procedures performed 
following the dose of study drug through the EOS visit. 
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4.4. 
Prohibited or Rescue Medication/Procedure 
4.4.1. 
Prohibited Medications  
Preceding screening 
Use of the below concomitant medications is prohibited within the following time period preceding 
the screening and randomization visits: 
• Topical or systemic first generation H1 antihistamines (eg, diphenhydramine and 
chlorpheniramine) (3 days) 
• Second generation and long-acting H1 antihistamines (eg, cetirizine) (5 days) 
• Cromoglycates (14 days) 
• Leukotriene modifiers (30 days) 
• Intranasal corticosteroids (14 days) 
• Systemic steroid treatment (30 days) 
• Topical steroids, with the exception of hydrocortisone (≤1%) (48 hours) 
• Anticholinergics (eg, Ipratropium [Atrovent 40 µg]) (12 hours) 
• Intramuscular corticosteroids (3 months prior to screening and during the study) 
• Systemic or topical calcineurin inhibitors (14 days prior to screening and during the 
study) 
• Topical or oral decongestants (72 hours) 
• Tricyclic antidepressants/typical antipsychotics (14 days) 
• Birch-specific allergen immunotherapy (5 years) 
• Immune-directed biologic therapies that would interfere with Type 2 allergic disease 
or suppress the immune system (6 months) 
• Long-acting anti-muscarinic agents (7 days) 
• Ultra-long-acting β-agonists (eg, indacaterol, vilanterol, olodaterol) (14 days) 
• Methylxanthines (eg, oral theophylline) (24 hours) 
Preceding the end of study visit 
Use of the below medications is prohibited within the following time period preceding the end of 
study visit. 
• Desloratadine (5 days) 
• Olopatadine (5 days) 
• Topical steroids, with the exception of hydrocortisone (≤1%) (48 hours) 
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Any time throughout the study 
• Anticholinergics 
• Leukotriene modifiers 
• Cromoglycates 
• Topical or oral decongestants 
• Systemic steroid treatment 
• Tricyclic antidepressants/typical antipsychotics 
• Any allergen immunotherapy 
• Immune-directed biologics therapies that would interfere with Type 2 allergic disease 
or suppress the immune system 
• Methylxanthines (eg, oral theophylline) 
• Anti-allergic medications (antihistamines, anti-allergic eye drops, anti-allergic nasal 
sprays) outside of study-related anti-allergic medications as they will be supplied as 
part of the study 
Blinded adjudication of prohibited medications will be implemented before the database lock by 
the study medical director, considering the type of medication, indication, timing, frequency and 
the potential impact of the use of the prohibited medication. The adjudication procedure will be 
documented. 
4.4.2. 
Rescue medication 
Subjects will be provided with the following medications to treat allergic symptoms during the 
study: 
• Desloratadine 5 mg (second generation antihistamine) 
• Olopatadine 1 mg/mL (antihistamine eye drop) 
• Mometasone furoate 50 ug/dose (intranasal steroid) 
From the time of study drug dosing throughout the birch pollen season, subjects will be asked to 
record their daily medication use using an e-diary, including information regarding which 
medications was used and the amount of the pre-specified medications that was used. Utilization 
of rescue medications should be initiated when subjects reach a symptoms threshold of 
approximately TSS ≥4/18. Subjects will be provided with training to understand the severity of 
symptoms associated with a TSS ≥4/18. 
Subjects should be instructed not to utilize rescue medications in the anticipation of the birch 
pollen season. Subjects should also be instructed not to utilize antihistamines (ie, desloratadine or 
olopatadine) for 5 days before the end of study visit. 
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4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable 
The primary efficacy endpoint in the study is the daily CSMS, averaged over the duration of the 
birch pollen season, in subjects who receive a single dose of REGN5713-5714-5715 versus 
placebo. Details of duration of birch pollen season are described in section 4.10. 
Total Nasal Symptom Score (TNSS) 
The TNSS ranges from 0 to 12 and is based on assessment of 4 nasal symptoms graded on a Likert 
scale ranging from 0 (none) to 3 (severe) for congestion, nasal itching, and rhinorrhea, and for 
sneezing. The TNSS will be recorded daily using an e-diary. 
The average TNSS will be calculated using all observed daily scores during birch pollen season. 
Total Ocular Symptom Score (TOSS) 
The TOSS ranges from 0 to 6 and is based on 2 symptoms: itching/redness/gritty feeling and 
tearing/watering. Each of the 2 symptoms is graded 0 (absent), 1 (mild), 2 (moderate), or 3 
(severe). The TOSS will be recorded daily using an e-diary.  
If a patient has at least 1 TOSS during the birch pollen season, average TOSS will be calculated 
using all observed daily scores during birch pollen season. 
If a patient has no TOSS during the birch pollen season, the mean of average TOSS during birch 
pollen season in the treatment group that the patient is randomized to will be used for the missing. 
Total Symptom Score (TSS) 
The daily TSS is calculated by adding the TNSS and TOSS together, for a combined TSS of 0 to 
18 if both of them are not missing. 
The average TSS will be calculated by adding average TNSS and average TOSS during birch 
pollen season. Imputed TOSS will be used if all TOSS data were missing (described above). 
Daily Medication Score (DMS) 
Subjects will be asked to record their daily rescue medication use using an e-diary, including which 
medications and the amount of these pre-specified medications. This information will be used to 
calculate the DMS as follows: desloratadine 5 mg 6 points/dose; maximum daily score 6 points, 
olopatadine 1 mg/mL each drop 1.5 points/drop; maximum daily score 6 points, mometasone 
furoate 50 ug/dose 2.0 points/spray; maximum daily score 8 points). The maximum DMS score is 
20.  
The average DMS will be calculated using the same method as described for TOSS. 
Combined Symptom and Medication Score (CSMS) 
The daily CSMS is calculated by adding the DMS and TSS together, with scores ranging 
between 0 and 38 if both of them are not missing. 
The average CSMS will be calculated by adding average TNSS, average TOSS and average DMS 
during birch pollen season. Imputed TOSS and/or DMS will be used if missing is occurred. 
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4.5.2. 
Secondary Efficacy Variables 
The secondary efficacy endpoints are: 
• TSS, TNSS, and TOSS, averaged over the duration of the birch pollen season, in 
subjects who receive a single dose of REGN5713-5714-5715 versus placebo 
• DMS, averaged over the duration of the birch pollen season, in subjects who receive a 
single dose of REGN5713-5714-5715 versus placebo 
• Change and percent change from baseline to the end of study in birch SPT mean 
wheal diameter in subjects who receive a single dose of REGN5713-5714-5715 
versus placebo 
• The number of “well days” in each of the treatment groups, where the “well days” are 
defined as days when rescue medication is not utilized and the TSS is ≤ 2/18 
Birch Allergen and Standard Regional Skin Prick Tests 
An SPT with birch allergen extract and a regional SPT (such as with dust mites, grasses, ragweed, 
other trees, including other birch homologous trees [such as alder and oak], mold, cat, and dog) 
will be performed to assess sensitization status. Skin prick test data may be used to determine the 
relationship between birch and regional allergen sensitization at baseline and pharmacodynamic 
effects of REGN5713-5714-5715 to reduce allergic symptoms upon birch pollen allergen 
challenges. Mean wheal diameter is measured approximately 15 minutes after placement. Aside 
from the birch skin test requirement for enrollment (which is >=5mm compared to the negative 
control), a positive response is defined by a mean wheal diameter at least 3 mm greater than a 
negative control. 
4.5.3. 
Exploratory Efficacy Variables 
Exploratory efficacy endpoints include: 
• RQLQ (S), averaged over the duration of the birch pollen season, for REGN5713-
5714- 5715 versus placebo 
• ACQ-5, averaged over the duration of the birch pollen season, for REGN5713-5714-
5715 versus placebo (only for patients with asthma) 
• Change and percent change from baseline to the end of study in SPT mean wheal 
diameter for birch homologous/cross-reactive allergens in REGN5713-5714-5715 
versus placebo 
• Baseline allergen-specific IgE levels and correlation with average CSMS, TSS, 
TNSS, TOSS, DMS during birch pollen season 
• Number of baseline sensitizations to other allergens (poly/mono-sensitization status, 
based on allergen-specific IgE levels) and correlation with CSMS, TSS, TNSS, 
TOSS, and DMS, averaged over the duration of the birch pollen season 
• Baseline serum antibody levels and correlation with CSMS, TSS, TNSS, TOSS, and 
DMS, averaged over the duration of the birch pollen season 
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• To assess the reduction in PFAS and related symptoms, as measured by PFASQ, from 
baseline to end of study  
• To assess patient rating of severity of seasonal allergy symptoms, as measured by 
PGI-S, from baseline to end of study 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ (S)] 
The RQLQ (S) has 28 questions in 7 domains: activity limitation, sleep problems, nose symptoms, 
eye symptoms, non-nose/eye symptoms, practical problems, and emotional function. There are 3 
subject-specific questions in the activity domain that allow subjects to select 3 activities in which 
they are most limited by their rhinoconjunctivitis. Subjects recall how bothered they have been by 
their rhinoconjunctivitis during the previous week and respond to each question on a 7-point scale 
(0 [not impaired at all] to 6 [severely impaired]). The overall RQLQ (S) score is the mean of all 
28 responses, and the individual domain scores are the means of the items in those domains 
(Juniper, 1991). The RQLQ (S) will be recorded using an e-diary. 
Asthma Control Questionnaire 
The ACQ measures the adequacy of asthma control and change in asthma control that occurs 
spontaneously or as a result of treatment. The ACQ-5 is comprised of 5, patient-reported items 
that were rated by clinicians as the most important to evaluate control: (1) awakening at night due 
to symptoms, (2) morning symptoms, (3) limitation of daily activities, (4) shortness of breath, and 
(5) wheezing. The total score ranges from 0 to 6 with higher scores denoting less asthma control. 
A score of ≥1.5 is considered as uncontrolled asthma. The ACQ-5 will be recorded using an e-
diary for patients with asthma. 
Pollen Food Allergy Symptom Questionnaire (PFASQ) 
The PFASQ will be performed to determine the types of food that produce an allergic reaction, the 
type of reaction, and how soon the reactions occur. 
Patient Global Impression of Severity (PGI-S) 
The PGI-S assesses the severity of seasonal allergy symptoms over the past 1 week. Symptom 
severity ranges from 0 (no symptoms), 1 (mild), 2 (moderate), and 3 (severe) symptoms. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events (AEs) and serious adverse events (SAEs) defined in study protocol 10.2.1 and 
10.2.2 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 using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
Treatment-emergent adverse events (TEAEs) are defined as those that are not present at baseline 
or represent the exacerbation of a pre-existing condition during the on-treatment period. 
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4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) for this study include systemic or severe hypersensitivity 
reactions and severe injection site reactions. 
4.6.3. 
Laboratory Safety Variables 
Hematology, chemistry, pregnancy test, and urinalysis will be analyzed by a central laboratory. 
Samples for laboratory testing will be collected at visits according to Table 3. Tests will include: 
Blood chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Triglycerides 
Chloride 
Blood urea nitrogen (BUN) 
Uric acid 
Carbon dioxide 
Aspartate aminotransferase (AST) 
 
Calcium 
Alanine aminotransferase (ALT) 
 
Glucose 
Alkaline phosphatase 
 
Albumin 
 
 
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 
Subjects will be tested for FSH levels (postmenopausal women only) and will undergo serum and 
urine pregnancy testing (WOCBP only); pregnancy testing is not required of women confirmed 
postmenopausal. If any urine pregnancy test is positive, the site must perform a serum pregnancy 
test for confirmation. If a serum pregnancy test must be performed, study drug cannot be 
administered unless the serum pregnancy test is negative.  
Samples will be collected for quantitative assessment of total and allergen-specific IgE and will 
be analyzed by a central laboratory. 
4.6.4. 
Vital Signs and Weight/Height 
Vital signs include systolic and diastolic blood pressure, respiratory rate and heart rate. Vital signs 
will be collected in a seated position. On the day of study drug administration, vital signs are taken 
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prior to PK blood draw, prior to study drug administration, and at 2 hours (±10 min) after 
completion of the injection. 
Weight and height are measured at screening visit 1 only. 
4.6.5. 
12-Lead Electrocardiography (ECG) 
A standard 12-lead ECG will be performed at the screening visit 1 only. Heart rate will be recorded 
from the ventricular rate and the PR, QRS, and QT intervals will be recorded. The ECG strips or 
reports will be retained with the source documentation. 
To minimize variability, it is important that the patient be in a resting position for ≥10 minutes 
prior to the ECG evaluation. Body position should be consistently maintained for each ECG to 
prevent changes in heart rate. 
4.6.6. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal.  
4.6.7. 
Spirometry 
Spirometry (American Thoracic Society [ATS]/European Respiratory Society [ERS]-compliant) 
as adjudicated by the site investigator, including measurements of forced vital capacity (FVC [L]), 
forced expiratory volume (FEV1 [L]), FEV1/FVC (%), peak expiratory flow (L/s), forced 
expiratory flow 25 to 75 (L/s), will be performed during screening and randomization to exclude 
any subjects with abnormal lung function and/or poorly controlled asthma. 
4.7. 
Pharmacokinetic Variables  
Concentrations in serum of total (free+bound to target) REGN5713, REGN5714, and REGN5715 
will be determined at time points specified in the study schedule of events in Section 10.2. 
Pharmacokinetic variables consist of invididual antibody, as well as total drug, concentration in 
serum and time (both nominal and actual). 
4.8. 
Immunogenicity Variables  
The immunogenicity variables are ADA status, ADA titer, NAb status and time point/visit. 
Samples in this study will be collected at the clinic visits specified in Section 10.2. Samples 
positive in the ADA assay will be further characterized for ADA titers. Anti-REGN5713, 
REGN5714, and REGN5715 neutralizing antibodies (NAb) analysis may be performed on ADA-
positive serum samples. The overall immunogenicity risk will be taken into consideration to assess 
the need for NAb analysis. Serum samples will be banked, if NAb analysis is to be conducted at a 
later time. 
Immunogenicity will be characterized by the ADA response and titer categories observed: 
ADA response category: 
• ADA Negative, defined as ADA negative response in the ADA assay at all time points, 
regardless of any missing samples. 
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• Pre-existing immunoreactivity: defined as either an ADA positive response in the ADA 
assay at baseline with all post first dose ADA results negative, OR a positive response 
at baseline with all post first dose ADA responses less than 9-fold over baseline titer 
levels. 
• Treatment-emergent ADA response: defined as a positive response in the ADA assay 
post first dose when baseline results are negative or missing. 
• Treatment-boosted ADA response: defined as a positive response in the ADA assay 
post first dose that is greater than or equal to 9-fold over baseline titer levels, when 
baseline results are positive 
Titer category (Maximum titer values) 
• Low (titer <1,000) 
• Moderate (1,000≤ titer ≤10,000) 
• High (titer >10,000) 
The NAb status is categorized as follows: 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay 
• Positive: Samples positive in the NAb assay  
4.9. 
Biomarker Variables  
Exploratory biomarker variables include: 
• Total serum IgE at baseline, day 57 (V5) and day 113 (V7)  
• Allergen-specific IgE levels (birch pollen, Bet v 1) at screening visit 1 (V1) and 
baseline (V2) 
• Allergen-specific IgE levels (Bet v 1 and other common allergens) at screening and 
baseline to assess sensitization status and to evaluate the relationship between response 
to REGN5713-5714-5715 treatment and poly/mono-sensitization  
• Allergen-specific IgE levels (Bet v 1 and other common allergens) on day 57 and day 
113 
4.10. 
Other Variables  
Outdoor pollen counts will be measured daily by the study site or by a vendor during the expected 
pollen season using a pollen sampler. 
Birch Pollen Regions: 
Clinical sites will be pooled into different pollen regions geographically. The pollen regions for 
this study include Belgium, Denmark, Germany, Canada, west-US and east-US.  
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Birch Pollen Season: 
Local site-specific pollen count data will be used for each patient to determine the start and end of 
the birch pollen season. The start of the birch pollen season is defined as the first of 3 consecutive 
days with a pollen count of 10 grains/m3 or greater. The end of the birch pollen season is defined 
as the last day of the last occurrence of 3 consecutive days with a pollen count of 10 grains/m3 or 
greater. The peak birch pollen season is defined as the 15 consecutive days within the birch pollen 
season with the highest 15-day moving average pollen count.  
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, Q1, Q3, standard deviation, minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Missing values at baseline will not be imputed unless otherwise specified. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and Baseline Characteristics will be summarized by treatment groups and overall 
based on the FAS.  
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT for each treatment group and for 
study total based on the SAF. The table will be sorted by decreasing frequency of SOC followed 
by PT based on the overall incidence across treatment groups.  
5.3. 
Prior/Concomitant Medications/Procedures  
Number and proportion of subjects taking prior/concomitant medications, prohibited medications 
and will be summarized for study total based on the SAF by Anatomical Therapeutic Chemical 
(ATC) level 2 and ATC level 4, sorted by decreasing frequency of ATC level 2 and ATC level 4 
based on the overall incidence. Subjects will be counted only once for each medication class (ATC 
levels 2 and 4) linked to the medication. 
Number of patients taking rescue medications will be summarized by medication name based on 
rescue medication e-diary. 
Number and proportion of patients taking prior/concomitant procedures will be summarized for 
study total based on the SAF, sorted by decreasing frequency of SOC and PT based on the overall 
incidence. Patients will be counted only once for each SOC and PT linked to the procedure.  
5.4. 
Subject Disposition 
The following summaries will be provided for each treatment group and study total (unless 
otherwise specified): 
• The total number of screened subjects 
• The total number of randomized patients: received a randomization number from 
IWRS 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study and the reasons for 
discontinuation (including COVID-19 related reasons) 
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5.5. 
Extent of Study Treatment Exposure and Compliance 
Treatment exposure is defined as the number of study treatment administrations for each subject. 
Since this is a single dose study, subjects will have 1 study treatment administration, given as 3 
injections sequentially on one day. Summary of number of injections will be provided. Treatment 
compliance is not applicable. 
The duration of observation period during the study is calculated as: 
(Date of the last study visit – date of the investigational product administration) +1. 
Duration of observation period will be summarized for each treatment group using number of 
subjects, means, SD, minimums, medians and maximums. 
The number (%) of subjects with observation periods will be presented by specific time periods. 
The time periods of interest are specified as: ≥1 day, ≥28 days, ≥57 days, ≥85 days, and ≥113 days. 
5.6. 
Analyses of Efficacy Variables 
The analyses of efficacy variables are described in the subsections below and summarized in 
Appendix 10.1. The intercurrent events, strategies, and the corresponding missing data handling 
approaches for the primary estimands of interest for the primary endpoint are provided in Table 1  
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Table 1: 
Primary Estimand for the Primary Endpoint 
Endpoint 
Category 
Estimands 
Endpoint(s)1 
Population 
Intercurrent event(s) strategy and missing data handling 
Population-level 
summary/Analysis 
Primary 
Endpoint 
Daily CSMS, 
averaged over the 
duration of the 
birch pollen season 
 
FAS 
The intercurrent events will be handled as follows: 
• 
Taking rescue medications to treat allergic symptoms 
during the study: data after rescue medication will be 
utilized (Treatment policy strategy) 
• 
Taking relavant prohibited medications2 during the 
study: the worst calculated CSMS score (worst observed 
TOSS+TNSS+DMS) during the birch pollen season 
from the same patient will be use to impute the daily 
CSMS after the medication usage (details are provided 
in section 5.6.1 Table 2). If the patient dose not have 
any data to be utilized during birch pollen season, the 
mean of average CSMS during the birch pollen season in 
the treatment that the patient is randomized to will be 
used for imputation. The average CSMS during the birch 
pollen season will be calculated based on observed and 
imputed daily CSMS. 
Missing data handling: If all TOSS and/or DMS during the 
birch pollen season are missing, the missing will be imputed 
using the mean of the average of TOSS and/or DMS during 
birch pollen season in the treatment group that the patient is 
randomized to. The average CSMS during the birch pollen 
season will be calculated by adding average of observed 
TNSS, average of observed/imputed TOSS and average of 
observed/imputed DMS. 
Linear mixed-effect model, 
with the treatment group and 
randomization stratification 
factors as fixed effects and 
pollen region as a random 
effect will be used.  
The least squares means (LS-
means) estimate for each 
treatment, and LS-means for 
between-treatment difference 
with its 95% confidence 
interval and p-value will be 
provided based on the model. 
[1] Secondary endpoints are not included in this table but would be handled with a similar strategy as the primary endpoint.  
[2] Prohibited medications will be adjudicated by study medical monitor before the database lock and corresponding data utilization rules for selected prohibited medications 
are listed in Table 2 . 
 
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5.6.1. 
Analysis of Primary Efficacy Variable 
The primary analysis will focus on the comparison between the REGN5713-5714-5715 arm and 
placebo arm. The average CSMS during birch pollen season will be compared in subjects receiving 
REGN5713-5714-5715 and subjects receiving placebo using a linear mixed-effect model, with the 
treatment group and randomization stratification factors (serum specific birch pollen IgE levels at 
screening (<17.5 kUa/L,  ≥17.5 kUa/L), serum specific oak pollen IgE levels at screening 
(<0.7 kUa/L, ≥0.7 kUa/L for NA) and geographical region (NA, EU)) as fixed effects and pollen 
region as a random effect, to account for potential differences in birch pollen seasons based on the 
geographical location of each pollen region. Subjects with at least 1 day of post-baseline diary 
record with CSMS during the birch pollen season will be included. The CSMS will be calculated 
on all available data during the birch pollen season. The least squares means (LS-means) estimate 
for each treatment, and LS-means for between-treatment difference with its 95% confidence 
interval and p-value will be provided. 
The average CSMS will be calculated based on total symptom score (TNSS and TOSS, max of 
18/day) and daily medication score (max of 20/day) recorded over the duration of the birch pollen 
season. The start and end of the birch pollen season is defined in section 4.10 for each site based 
on the local pollen counts. 
Data after any rescue medication use will be used for the calculation of the average CSMS, but 
relevant prohibited medications that may have an impact on symptom measurements will result in 
subsequent symptoms and medication scores not be utilized in the CSMS for that subject for a 
specified period of time (determined by medication type). The prohibited medications will be 
adjudicated by study medical monitor before the database lock. A list of those relevant prohibited 
medication and the rules of data utilization are detailed in Table 2 . 
Table 2: 
Data Utilization for Relevant Prohibited Medications 
Name of Medication 
Rule of Data Utilization 
Systemic steroids (oral/ IV/ IM/ intra-articular/ other) 
Data will not be used after the 
medication usage. 
Type 2 Biologics 
In additional, if a patient has major change in birch pollen exposure (e.g. travel out of country), 
the data will be set to missing during this major change and no imputation will be applied. 
For patients with data not utilized due to prohibited medication, the following data imputation rule 
will be apply: 
• For a patient with at least one day data to use during the birch pollen season, the worst 
observed score from the same patient during the birch pollen season will be used to 
impute the daily TNSS, TOSS and DMS in this affected period. Daily CSMS will be 
calculated by adding the worst daily TOSS, TNSS and DMS. Average CSMS will be 
calculated based on the observed scores and imputed scores.  
• For a patient without any data to use during the birch pollen season, average CSMS 
will be imputed using the mean of average CSMS during the birch pollen season in the 
treatment that the patient is randomized to. 
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Sensitivity analysis 
A sensitivity analysis is planned to assess an alternative method to impute missing data. The 
alternative method of calculation of average CSMS is detailed as below: 
• If TOSS and/or DMS are missing on any single day with TNSS completed, it will be 
assumed to be 'No ocular symptom' and/or ‘No rescue use’ and a score of 0 will be 
assigned. Daily CSMS will be calculated for days with at least TNSS completed. 
• The daily CSMS will be set to missing for the days that are affected by prohibited 
medication and/or major change in birch pollen exposure. 
• The average CSMS will be calculated only based on non-missing daily CSMS during 
birch pollen season.  
The same linear mixed-effect model will be used for the sensitivity analysis. Patients without any 
data during birch pollen season will not be part of the sensitivity analysis. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
Secondary efficacy variables will be analyzed using linear mixed-effect model in the same fashion 
as the primary analysis for primary endpoint, average CSMS during birch pollen season. Subjects 
with at least 1 day of post-baseline diary record will be included in the analysis, and only days 
with observed data (including any available data of daily entries prior to subject discontinuation) 
will be included in the calculation of average score. Data after rescue will be utilized and data after 
relevant prohibited medications will be set to missing according to Table 2 . 
5.6.3. 
Adjustment for Multiple Comparison 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
overall Type-1 error rate at 0.05 for the primary endpoint and the secondary endpoints. Each 
hypothesis will be formally tested only if the preceding one is significant at the 2-sided 0.05 
significance level. The hierarchical testing order is shown as follows. 
1. Primary endpoint: Daily CSMS, averaged over the duration of the birch pollen season, in 
subjects who receive a single dose of REGN5713-5714-5715 versus placebo 
2. TNSS, averaged over the duration of the birch pollen season, in subjects who receive a 
single dose of REGN5713-5714-5715 versus placebo 
3. TSS, averaged over the duration of the birch pollen season, in subjects who receive a single 
dose of REGN5713-5714-5715 versus placebo 
4. Change from baseline to the end of study in birch SPT mean wheal diameter in subjects 
who receive a single dose of REGN5713-5714-5715 versus placebo 
5. Percent change from baseline to the end of study in birch SPT mean wheal diameter in 
subjects who receive a single dose of REGN5713-5714-5715 versus placebo 
6. TOSS, averaged over the duration of the birch pollen season, in subjects who receive a 
single dose of REGN5713-5714-5715 versus placebo 
7. DMS, averaged over the duration of the birch pollen season, in subjects who receive a 
single dose of REGN5713-5714-5715 versus placebo 
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5.6.4. 
Subgroup Analysis 
Subgroups described in Section 3.5 for the primary endpoint will be summarized. Treatment 
difference and its 95% confidence interval in subgroups of subjects will be presented in forest 
plots.  
5.6.5. 
Analysis of Exploratory Efficacy Variables 
For continuous exploratory efficacy variables, e.g. average ACQ-5 and change and percent change 
in SPT mean wheal diameter for birch homologous/cross-reactive allergens, they will be analyzed 
by using a linear mixed effects model similar to the analyses of primary endpoint. 
For categorical exploratory variables, e.g. PFASQ and PGI-S, only descriptive summary will be 
provided. 
For endpoints related to biomarker, e.g. serum total IgE, serum sIgE for birch and Bet v 1, 
analysis method will be detailed in section 5.11. 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations and vital 
signs. 
Thresholds for treatment-emergent Potential Clinically Significant Values (PCSV) in laboratory 
variables and vital signs are defined in Appendix 10.3. Treatment-emergent PCSV is any PCSV 
developed or worsened in severity compared to the baseline during the treatment and follow-up 
period. The baseline when determining treatment-emergent PCSV refers to the baseline value of 
the study. 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
5.7.1. 
Adverse Events  
The number and proportion of subjects reporting TEAEs will be summarized on SAF as described 
in Section 3.2. 
AE incidence tables will be presented by treatment group for the SAF as well as subgroups for 
safety. TEAE summaries will present the number (n) and percentage (%) of subjects experiencing 
an TEAE by SOC and PT, sorted by decreasing frequency of SOC and PT for the REGN 5713-
5714-5715 treatment group. Multiple occurrences of AEs of the same PT (or SOC) in the same 
subject will be counted only once for that PT (or SOC). For tables presenting severity of events, 
the worst severity will be chosen for subjects with multiple instances of the same event. The 
denominator for computation of percentage is the number of subjects in each treatment group for 
safety analysis. 
An overall summary of TEAEs will be provided with number and proportion of subjects with any: 
• TEAE 
• Serious TEAE 
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• Serious TEAE leading to death 
• Study drug related TEAE/serious TEAE 
• TEAE leading to study discontinuation 
• Maximum intensity for TEAE 
Note: TEAE leading to treatment discontinuation will be not provided since the study only has a 
single dose. 
Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by primary SOC/PT 
− TEAEs by PT 
− TEAEs by primary SOC/PT with incidence of PT ≥ 5% 
− TEAEs by severity and by primary SOC/PT 
− TEAEs related to study drug as assessed by the investigator by primary SOC/PT 
• Serious TEAE 
− Serious TEAEs by primary SOC/PT 
• Fatal AEs by primary SOC/PT 
• TEAE leading to study discontinuation by primary SOC/PT 
• AESI by AESI category (see section 10.4), primary SOC/HLT/PT 
Number and proportion of subjects reporting pre-treatment adverse events will be tabulated by 
primary SOC and PT. 
The number and proportion of subjects with injection site reaction by PT will be summarized. 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units. Summaries of laboratory variables will include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSVs. This 
summary will be provided based on the subgroup of SAF subjects who did not meet 
the PCSV criterion at baseline 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
The graph of mean change and/or percent change from baseline value for lab parameters by visit 
will be provided. 
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5.7.3. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
5.8. 
Analysis of Pharmacokinetic Data 
Descriptive statistics of total REGN51713, total REGN5714, total REGN5715, and total drug 
(REGN5713+REGN5714+REGN5715) concentrations in serum at each sampling timepoint will 
be provided. Plots of mean concentration versus nominal time will be presented. Select PK 
parameters may be calculated. 
Exposure-response analysis for biomarkers, efficacy, and safety endpoints may be conducted as 
appropriate, and presented in separate reports. 
5.9. 
 Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Analysis described in this section will be performed separately for ADA to REGN5713, 
ADA to REGN5714 and ADA to REGN5715 in all treatment groups unless otherwise specified. 
The following analysis will be provided by treatment groups and ADA titer categories: 
• Number (n) and percent (%) of ADA-negative subjects  
• Number (n) and percent (%) of pre-existing immunoreactivity subjects 
• Number (n) and percent (%) of treatment-emergent ADA positive subjects  
• Number (n) and percent (%) of treatment-boosted ADA positive subjects  
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data 
Anti-REGN5713, REGN5714, and REGN5715 neutralizing antibodies (NAb) analysis may be 
performed on ADA-positive serum samples. The overall immunogenicity risk will be taken into 
consideration to assess the need for NAb analysis. Serum samples will be banked, if NAb analysis 
is to be conducted at a later time.  
The absolute occurrence (n) and percent of subjects (%) with NAb status in the NAb analysis set 
will be provided by treatment groups. Analysis described in this section will be performed 
separately for NAb to REGN5713, NAb to REGN5714 and NAb to REGN5715 in all treatment 
groups unless otherwise specified. 
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5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity variables and systemic exposure to REGN5713, 
REGN5714 or REGN5715 will be explored. Plots of drug concentration may be provided for 
analyzing the potential impact of ADA response status, titer and NAb status on PK. 
5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• TEAEs  
• SAEs  
• Injection site reaction (HLT: Injection site reaction) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow] followed by manual adjudication 
(same as AESI ‘Hypersensitivity’)) 
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
Note: TEAE leading to treatment discontinuation will be not provided since the study only has a 
single dose. 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
in the study (e.g. scatter plot or spaghetti plot).   
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA positive subjects, that is subjects/patients with treatment-emergent or treatment-
boosted response. 
• ADA negative subjects, that is subjects/patients with pre-existing immunoreactivity 
or negative in the ADA assay at all time points. 
• NAb positive subjects, that is ADA positive subjects who were positive in the NAb 
assay at any time point analyzed. 
• Maximum post-baseline titer in treatment-emergent or treatment-boosted ADA 
positive subjects: 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
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5.11. 
Analysis of Biomarker Data 
All biomarker analyses will be performed on the FAS using all observed data.   
Descriptive statistics for the observed values and change and percent change from baseline in 
detectable allergen specific IgE by treatment and visit will be provided for the biomarker variables.   
Baseline serum total IgE, serum birch pollen sIgE, and serum bet v 1 sIgE and the ratio of serum 
Bet v 1 sIgE/ serum birch pollen sIgE will be correlated to the primary and secondary clinical 
efficacy endpoints using spearman’s rho test.   
The percent of detectable IgE at each visit (V5 and V7) compared to baseline will also be correlated 
to the primary and secondary clinical efficacy endpoints using spearman’s rho test. Both the 
spearman correlation coefficients and p-values will be reported. Multiple linear regression models 
will also be used to explore these relationships, with the efficacy endpoints as dependent variables 
and the IgE values at baseline (log transformed if appropriate) as dependent variables.    
The poly-allergen sensitization status for each study subject will be determined by the number of 
allergen-specific IgE values that are equal to or above 0.35kUa/L. A descriptive report will be 
provided based on the allergen-specific IgE results at screening/ baseline for all concomitant or 
homologous allergen to birch pollen.  The number of allergen that each subject were sensitized to 
will be correlated with the primary and secondary clinical outcomes.  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. The 
following rules specify the determination of baseline by both date/time information: 
• The date and time of first injection will be used to determine the baseline for the AE, 
lab, PK and ADA data. 
• Only the date of first injection will be used to determine the baseline for other data 
except the AE, lab, PK and ADA data. 
6.2. 
Data Handling Conventions 
For the laboratory safety variables and biomarker data, if the data are below the lower limit of 
quantification (LLOQ)/limit of linearity, half the lower limit value (i.e., LLOQ/2) will be used for 
quantitative analyses. For data above the upper limit of quantification (ULOQ)/ limit of linearity, 
the upper limit value (i.e., ULOQ) will be used for quantitative analyses 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.5.1  and Section 4.5.2. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
Adverse event start date 
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will be used to indicate which date component is 
missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and AE start month is the same as first dose month, then AE start day will 
be imputed using the day of first dose. If this leads to a date after the AE end date, AE end date 
will be used instead. If AE start year is the same as first dose year and AE start month different 
from first dose month, AE start day will be imputed using the first day of the month. If this leads 
to a date before informed consent date, the informed consent date will be used. Imputation flag is 
‘D’. 
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If AE start month is missing, and AE start year is not missing: If AE start year is before the first 
dose year, the informed consent day and month will be used. If AE start year is the same as first 
dose year, the first dose day and month will be used. If this leads to a date after AE end date, AE 
end date will be used instead. If AE start year is after the first dose year, January 1st will be used. 
Imputation flag is ‘M’. 
If AE start year is missing: The date of first dose will be used. If this leads to a date after the AE 
end date, AE end date will be used instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE start date imputation, to carry through the logic for programming, the following 
intermediate step will be used. Afterwards, only the original character/numeric date recorded in 
CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: AE end date will be imputed 
using the last day of the month. If this leads to a date after end of study follow up date, the end of 
follow up date will be used instead. 
If AE end month is missing, and AE end year is not missing: AE end date will be imputed using 
December 31st as the day and month. If this leads to a date after end of study follow up date, the 
end of follow up date will be used instead.  
If AE end year is missing: AE end date will be imputed using end of follow up date. 
Prior or concomitant medication 
Medication start and end date missing 
To determine whether a medication is prior 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 listing.  
Prior medication start date 
If start day is missing, and start month and year are not missing: the start day will be imputed using 
the first day of the month. Imputation flag is ‘D’. 
If start month is missing, and start year is not missing: the day and month will be imputed using 
January 1st. Imputation flag is ‘M’. 
If start year is missing: the start date will be imputed using 2 years before informed consent date. 
Imputation flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, to 
simplify the programming flow, the imputation is proposed to align with protocol which specifices 
to collect up to 2 years prior medication. Since the start date of prior medication will not be used 
in any analysis, the rule will not impact the analysis result.  
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Prior medication end date 
If end day is missing, and end month and year are not missing: the end date will be imputed using 
the last day of the month. If this leads to a date on or after first dose intake date, the first dose 
intake date – 1  will be used. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: the end date will be imputed using December 
31st as the day and month. If this leads to a date on or after first dose intake date, the first dose 
intake date – 1 will be used instead. Imputation flag is ‘M’. 
If end year is missing: the end date will be imputed using the first dose intake date – 1. Imputation 
flag is ‘Y’. 
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: the end date will be imputed using 
the last day of the month. If this leads to a date after end of study follow up date, the end of follow 
up date will be used. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: the end date will be imputed using December 
31st as the day and month. If this leads to a date after end of study follow up date, the end of follow 
up date will be used instead. Imputation flag is ‘M’. 
If end year is missing: the end date will be imputed using the end of follow up date. Imputation 
flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study data manager and study medical director. 
PCSV 
Subjects who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment-emergent PCSV  
6.4. 
Analysis Visit Windows 
Data analyzed by-visit-analysis (efficacy [excluding daily diary data], laboratory data, vital sign) 
will be summarized by the study scheduled visits described in the study protocol and SAP 
“Schedule of Event”.  
The analysis visit windows are created per study Schedule of Events (SOE) table for each 
parameter and will be applied if the data from study scheduled visits are unavailable. The following 
general rules will be applied to unscheduled visit and/or early termination (ET) visit mapping for 
each parameter. 
1. If ET visit falls in an analysis window which already has non-missing observed value of 
this parameter from the scheduled visit, ET will be mapped to the next scheduled visit. 
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2. If both ET visit and unscheduled visit of the same parameter are available in the same 
analysis visit window, only ET visit will be mapped. 
3. If multiple unscheduled visits of the same parameter are available in the same analysis 
visit window, the unscheduled visis will be mapped using the following rules: 
a. The closest unscheduled visit from the target day will be selected 
b. If multiple unscheduled visits exist on the same day, the first unscheduled visit will 
be used. 
4. If mapping distance is greater than 4 weeks, the unscheduled visit will not be mapped. 
Unscheduled visits and early termination (ET) visit will be mapped per the following analysis 
visit windows based on the study day/visit of each parameter. 
Analysis Visit Window for Efficacy Endpoints 
Visit from SOE 
Target Study Day* 
PFASQ, SPT 
PGI-S 
Baseline 
1 
≤ 1 
≤ 1 
Visit 5 
57 
 
[2, 85] 
Visit 7 (EOS) 
113 
≥ 2 
≥ 86 
*Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date + 1) when 
date of assessment ≥1st injection date; otherwise study day = (date of assessment – 1st injection date). If subject never 
received any dose of study drug, randomization date will be used in the place of 1st injection date. 
Analysis Visit Window for Safety and Biomarkers 
Visit from 
SOE 
Target 
Study 
Day* 
Vital Sign 
Physical 
Exam 
Laboratory#, 
PK 
ADA 
Serum total IgE, 
Serum sIgE for birch 
pollen and Bet v 1 and 
other regional or 
relevant allergens, 
Serum sIgE for 
concomitant and 
homologous allergens 
Baseline 
1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
≤ 1 
Visit 5 
57 
≥2 
 
[2, 85] 
 
[2, 85] 
Visit 7 
(EOS) 
113 
 
≥2 
≥86 
≥2 
≥86 
* Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date + 1) 
when date of assessment ≥1st injection date; otherwise study day = (date of assessment – 1st injection date). If subject 
never received any dose of study drug, randomization date will be used in the place of 1st injection date. 
# Post-baseline urinalysis will not be mapping since no scheduled measurements will be collected per protocol.  
6.5. 
Statistical Technical Issues 
None. 
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7. 
INTERIM ANALYSIS 
No formal interim analysis will be conducted. 
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Statistical Analysis Plan 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
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9. 
REFERENCES 
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13. Didier A, Worm M, Horak F, Sussman G, de Beaumont O, Le Gall M, et al. Sustained 3-
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128(3):559-66. 
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75. 
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clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-
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125(1):131-8.e1-7. 
16. Durham SR, Emminger W, Kapp A, de Monchy JG, Rak S, Scadding GK, et al. SQ-
standardized sublingual grass immunotherapy: confirmation of disease modification 2 
years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol 2012; 
129(3):717-25.e5. 
17. Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic 
rhinitis? J Allergy Clin Immunol 2016a; 137(2):339-49.e10.  
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perennial allergic rhinitis: pooled analyses. Journal of Allergy and Clinical Immunology. 
2016b;138(4):1081-8. 
19. Ebner C, Hirschwehr R, Bauer L, Breiteneder H, Valenta R, Ebner H, et al. Identification 
of allergens in fruits and vegetables: IgE cross-reactivities with the important birch pollen 
allergens Bet v 1 and Bet v 2 (birch profilin). J Allergy Clin Immunol 1995; 95(5 Pt 
1):962-9. 
20. Epstein TG, Calabria C, Cox LS, Dreborg S. Current Evidence on Safety and Practical 
Considerations for Administration of Sublingual Allergen Immunotherapy (SLIT) in the 
United States. J Allergy Clin Immunol Pract 2017; 5(1):34-40.e2. 
21. Eriksson NE, Formgren H, Svenonius E. Food hypersensitivity in patients with pollen 
allergy. Allergy 1982; 37(6):437-43. 
22. Erler A, Hawranek T, Kruckemeier L, Asam C, Egger M, Ferreira F, et al. Proteomic 
profiling of birch (Betula verrucosa) pollen extracts from different origins. Proteomics 
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23. Ewbank PA, Murray J, Sanders K, Curran-Everett D, Dreskin S, Nelson HS. A double-
blind, placebo-controlled immunotherapy dose-response study with standardized cat 
extract. J Allergy Clin Immunol 2003; 111(1):155-61. 
24. Frew AJ. Immunotherapy: how safe is safe? Clin Exp Allergy 2006a; 36(3):251-3. 
25. Frew AJ, Powell RJ, Corrigan CJ, Durham SR, Group UKIS. Efficacy and safety of 
specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic 
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Protocol: R5713-5714-5715-ALG-2001 
Statistical Analysis Plan 
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26. Frew AJ. Allergen immunotherapy. J Allergy Clin Immunol 2010; 125(2 Suppl 2):S306-
13. 
27. Galant S, Berger W, Gillman S, Goldsobel A, Incaudo G, Kanter L, et al. Prevalence of 
sensitization to aeroallergens in California patients with respiratory allergy. Allergy Skin 
Test Project Team. Ann Allergy Asthma Immunol 1998; 81(3):203-10. 
28. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor 
for adultonset asthma. J Allergy Clin Immunol 2002; 109(3):419-25. 
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Relationships between aeroallergen levels and hospital admissions for asthma in the 
Brussels-Capital Region: a daily time series analysis. Environ Health 2018; 17(1):35. 
30. Halken S, Larenas-Linnemann D, Roberts G, Calderon MA, Angier E, Pfaar O, et al. 
EAACI guidelines on allergen immunotherapy: Prevention of allergy. Pediatr Allergy 
Immunol 2017; 28(8):728-45. 
31. Ito K, Weinberger KR, Robinson GS, Sheffield PE, Lall R, Mathes R, et al. The 
associations between daily spring pollen counts, over-the-counter allergy medication 
sales, and asthma syndrome emergency department visits in New York City, 2002-2012. 
Environ Health 2015; 14(71).  
32. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical 
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33. Jarolim E, Rumpold H, Endler AT, Ebner H, Breitenbach M, Scheiner O, et al. IgE and 
IgG antibodies of patients with allergy to birch pollen as tools to define the allergen 
profile of Betula verrucosa. Allergy 1989; 44(6):385-95. 
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clinical trials in rhinoconjunctivitis. Clin Exp Allergy 1991; 21(1):77-83. 
35. Lemberg ML, Berk T, Shah-Hosseini K, Kasche EM, Mosges R. Sublingual versus 
subcutaneous immunotherapy: patient adherence at a large German allergy center. Patient 
Prefer Adherence 2017; 11(63-70). 
36. Leynaert B, Neukirch F, Demoly P, Bousquet J. Epidemiologic evidence for asthma and 
rhinitis comorbidity. J Allergy Clin Immunol 2000; 106(5 Suppl):S201-5. 
37. Lin RY, Clauss AE, Bennett ES. Hypersensitivity to common tree pollens in New York 
City patients. Allergy Asthma Proc 2002; 23(4):253-8. 
38. Makela MJ, Gyllfors P, Valovirta E, Steffensen MA, Gronager PM, Savolainen J, et al. 
Immunotherapy With the SQ Tree SLIT-tablet in Adults and Adolescents With Allergic 
Rhinoconjunctivitis. Clin Ther 2018; 40(4):574-86.e4. 
39. Mauro M, Russello M, Incorvaia C, Gazzola GB, Di Cara G, Frati F. Comparison of 
efficacy, safety and immunologic effects of subcutaneous and sublingual immunotherapy 
in birch pollinosis: a randomized study. Eur Ann Allergy Clin Immunol 2007; 39(4):119-
22. 
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Statistical Analysis Plan 
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40. Musa F, Al-Ahmad M, Arifhodzic N, Al-Herz W. Compliance with allergen 
immunotherapy and factors affecting compliance among patients with respiratory 
allergies. Hum Vaccin Immunother 2017; 13(3):514-7. 
41. Navarro A, Colas C, Anton E, Conde J, Davila I, Dordal MT, et al. Epidemiology of 
allergic rhinitis in allergy consultations in Spain: Alergologica-2005. J Investig Allergol 
Clin Immunol 2009; 19 Suppl 2(7-13).  
42. Nelson HS. Advances in upper airway diseases and allergen immunotherapy. J Allergy 
Clin Immunol 2004; 113(4):635-42. 
43. Nolte H, Bernstein DI, Nelson HS, Kleine-Tebbe J, Sussman GL, Seitzberg D, et al. 
Efficacy of house dust mite sublingual immunotherapy tablet in North American 
adolescents and adults in a randomized, placebo-controlled trial. J Allergy Clin Immunol 
2016; 138(6):1631-8. 
44. Pablos I, Wildner S, Asam C, Wallner M, Gadermaier G. Pollen Allergens for Molecular 
Diagnosis. Curr Allergy Asthma Rep 2016; 16(4):31. 
45. Pawankar R, Canonica GW, Casale T, RF L. The World Allergy Organization white 
book on allergy. In. Milwaukee: World Allergy Organization; 2011. 
46. Rosario N, Bielory L. Epidemiology of allergic conjunctivitis. Curr Opin Allergy Clin 
Immunol 2011; 11(5):471-6.  
47. Salo PM, Arbes SJ, Jr., Jaramillo R, Calatroni A, Weir CH, Sever ML, et al. Prevalence 
of allergic sensitization in the United States: results from the National Health and 
Nutrition Examination Survey (NHANES) 2005-2006. J Allergy Clin Immunol 2014; 
134(2):350-9. 
48. Schenk MF, Cordewener JH, America AH, Peters J, Smulders MJ, Gilissen LJ. 
Proteomic analysis of the major birch allergen Bet v 1 predicts allergenicity for 15 birch 
species. J Proteomics 2011; 74(8):1290-300. 
49. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and 
onset of asthma: a longitudinal population-based study. Lancet 2008; 372(9643):1049-57. 
50. Sierra-Heredia C, North M, Brook J, Daly C, Ellis AK, Henderson D, et al. Aeroallergens 
in Canada: Distribution, Public Health Impacts, and Opportunities for Prevention. Int J 
Environ Res Public Health 2018; 15(8). 
51. Vandenplas O, Vinnikov D, Blanc PD, Agache I, Bachert C, Bewick M, et al. Impact of 
Rhinitis on Work Productivity: A Systematic Review. J Allergy Clin Immunol Pract 
2018; 6(4):1274-86.e9. 
52. Vanek-Krebitz M, Hoffmann-Sommergruber K, Laimer da Camara Machado M, Susani 
M, Ebner C, Kraft D, et al. Cloning and sequencing of Mal d 1, the major allergen from 
apple (Malus domestica), and its immunological relationship to Bet v 1, the major birch 
pollen allergen. Biochem Biophys Res Commun 1995; 214(2):538-51. 
53. Wahn U, Bachert C, Heinrich J, Richter H, Zielen S. Real-world benefits of allergen 
immunotherapy for birch pollen-associated allergic rhinitis and asthma. Allergy 2019; 
74(3):594-604. 
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54. Walker SM, Pajno GB, Lima MT, Wilson DR, Durham SR. Grass pollen immunotherapy 
for seasonal rhinitis and asthma: a randomized, controlled trial. J Allergy Clin Immunol 
2001; 107(1):87-93. 
55. Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, et al. 
The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin 
Immunol 2008; 122(2 Suppl):S1-84.  
56. Wallace DV, Dykewicz MS. Seasonal Allergic Rhinitis: A focused systematic review and 
practice parameter update. Curr Opin Allergy Clin Immunol 2017a; 17(4):286-94. 
57. Wallace DV, Dykewicz MS, Oppenheimer J, Portnoy JM, Lang DM. Pharmacologic 
Treatment of Seasonal Allergic Rhinitis: Synopsis of Guidance From the 2017 Joint Task 
Force on Practice Parameters. Ann Intern Med 2017b; 167(12):876-81. 
58. Wei C. The efficacy and safety of H1-antihistamine versus Montelukast for allergic 
rhinitis: A systematic review and meta-analysis. Biomed Pharmacother 2016; 83(989-97). 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
10.1.1. 
Summary of Efficacy Analyses 
Endpoint 
Analysis 
Populations 
Primary Statistical 
Method 
Supportive/Sensitive 
Statistical Method 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoints 
Daily CSMS, averaged 
over the duration of the 
birch pollen season 
FAS 
Linear-mixed effect model N/A 
Yes 
Plot 
Secondary Endpoints 
TSS, TNSS and TOSS 
averaged over the duration 
of the birch pollen season 
FAS 
Linear-mixed effect model N/A 
No 
Plot 
DMS, averaged over the 
duration of the birch 
pollen season 
FAS 
Linear mixed effect model 
N/A 
No 
Plot 
Change and percent 
change from baseline to 
the end of study in birch 
SPT mean wheal diameter  
FAS 
Linear mixed effect model 
N/A 
No 
Plot 
The number of “well 
days” in each of the 
treatment groups, 
FAS 
Linear mixed effect model 
N/A 
No 
Plot 
 
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10.1.2. 
Summary of Safety Analyses 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics and 
model-based analyses 
No 
Yes, for 
selected AE 
summary 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
 
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10.2. 
Schedule of Time and Events 
Table 3: Schedule of Events 
 
SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Study Procedure 
Screening Visit 
11 
Randomization 
Visit 22-4 
Visit 3 
Tel. 
Visit 4  
Tel. 
Visit 53 Visit 6 
Tel. 
EOS/ET  
Visit 73 
Unscheduled 
visit 
Day 
-84 to -7 
13 
2 
283 
573 
85 
1133 
 
Window (Days) 
+7 
±3 
 
±7 
±14 
±14 
±14 
 
Inclusion/exclusion2 
X 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X4 
  
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
SPT for birch and birch homologous allergens and 
select regional or relevant allergens1 
X 
 
 
 
 
 
X 
 
Standard regional SPT for birch and other common 
allergens1 
X 
 
 
 
 
 
 
 
FSH (in postmenopausal women) 
X 
 
 
 
 
 
 
 
Treatment 
Randomization2 
 
X 
 
 
 
 
 
 
Study drug administration2 
 
X 
 
 
 
 
 
 
Efficacy 
E-diary and rescue medications dispensation/return5 
 
X 
 
 
 
 
X 
 
TNSS6 
 
Daily via e-diary  
 
TOSS6 
 
Daily via e-diary  
 
DMS6 
 
Daily via e-diary 
 
ACQ-5 (in subjects with asthma)7 
 
Weekly via e-diary 
X 
RQLQ (S)8 
 
Weekly via e-diary 
X 
PFASQ9 
 
X 
 
 
 
 
X 
 
PGI-S10 
 
X 
 
 
X 
 
X 
 
Safety 
Vital signs11 
X 
X11 
 
 
X 
 
 
X 
Physical examination12 
X 
X 
 
 
 
 
X 
X 
ECG 
X 
 
 
 
 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
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SCREENING 
PERIOD 
TREATMENT PERIOD 
FOLLOW-UP PERIOD 
 
Study Procedure 
Screening Visit 
11 
Randomization 
Visit 22-4 
Visit 3 
Tel. 
Visit 4  
Tel. 
Visit 53 Visit 6 
Tel. 
EOS/ET  
Visit 73 
Unscheduled 
visit 
Day 
-84 to -7 
13 
2 
283 
573 
85 
1133 
 
Window (Days) 
+7 
±3 
 
±7 
±14 
±14 
±14 
 
Spirometry 
X4 
X 
 
 
 
 
 
X 
Laboratory Testing 
Hematology 
X4 
 
 
 
X 
 
X 
X 
Blood chemistry 
X4 
 
 
 
X 
 
X 
X 
Pregnancy test, urine (in WOCBP)13 
 
X13 
 
X13 
X 
X13 
X 
X 
Pregnancy test, serum (in WOCBP)13 
X 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
X 
Serum total IgE 
 
X 
 
 
X 
 
X 
 
Serum sIgE for birch pollen and Bet v 1 and other 
regional or relevant allergens 
X 
X 
 
 
X 
 
X 
X 
Serum sIgE for concomitant and homologous 
allergens 
 
X 
 
 
X 
 
X 
 
Interference assay, serum 
 
X 
 
 
 
 
 
 
Pharmacokinetics and Immunogenicity 
PK14 
 
X14 
 
 
X 
 
X 
X 
ADA14 
 
X14 
 
 
 
 
X 
X 
Biomarkers and Pharmacogenomics 
FBR samples, serum and plasma (optional)15 
 
X 
 
 
X 
 
X 
 
Genomic DNA sample (optional)16 
 
X16 
 
 
 
 
 
 
ACQ-5=asthma control questionnaire-5; ADA=anti-drug antibody; AE=adverse event; DMS=daily medication score; ECG=electrocardiogram; EOS=end of 
study; ET=early termination; FBR=future biomedical research; FSH=follicle stimulating hormone; PFASQ=pollen food allergy symptom questionnaire; PGI-
S=patient global impression of severity; PK=pharmacokinetics; RQLQ (S)=standardized rhinoconjunctivitis quality of life questionnaire; sIgE=allergen-specific 
immunoglobulin E; SPT=skin prick test; Tel=telephone; TNSS=total nasal symptom score; TOSS=total ocular symptom score; WOCBP=women of childbearing 
potential. 
 
 
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Footnotes for the Schedule of Events Table 
1. Screening SPT for birch, birch homologous trees, and other common allergens will be 
performed as described in the study manual. Skin prick test for birch should be performed 
prior to other screening assessments. If screening SPT for birch is negative (ie, mean wheal 
diameter <5 mm greater than a negative control), then other screening visit procedures do 
not need to be performed as the subject will have failed screening (refer to Protocol 
Section 7.2.1  Inclusion Criteria, #3).  
2. Randomization may occur within 1 day prior to study drug administration. All safety 
assessments performed at screening must be normal and checked against the 
inclusion/exclusion criteria prior to study drug administration.  
3. The timing of in-clinic visits may vary for each study site, depending on the start, peak, 
and end dates of the local birch pollen season (as determined by local pollen counts; refer 
to Protocol Section 9.2.2). The randomization visit will be scheduled approximately 2 
weeks before the start of birch pollen season, and the end of study (EOS) visit 
approximately 16 weeks after the randomization visit (depending on the duration of the 
local birch pollen season). In addition, visit 5 will be scheduled to occur within 2 weeks of 
the anticipated local peak of the birch pollen season.  
4. If randomization occurs >60 days after the screening visit, medical history, blood 
chemistry, hematology, and spirometry must be repeated prior to randomization. 
5. E-diary and rescue medications will be dispensed at the randomization visit. E-diary and 
any unused rescue medications will be returned at the EOS visit. Refer to Protocol Section 
8.2 for more information on rescue treatments. 
6. TNSS, TOSS, and DMS will be recorded daily via e-diary, starting at the randomization 
visit until EOS. Refer to Protocol Section 9.2.4.1, 9.4.2.2 and 9.4.2.4 for procedural details. 
7. In asthmatic subjects, ACQ-5 scores will be recorded weekly via e-diary, starting from the 
randomization visit until EOS. Refer to Protocol Section 9.2.4.6 for procedural details.  
8. In all subjects, RQLQ (S) scores will be recorded weekly via e-diary starting from the 
randomization visit until EOS. Refer to Protocol Section 9.2.4.7 for procedural details. In 
asthmatic subjects, the weekly RQLQ (S) and ACQ-5 assessments may be performed on 
the same day.  
9. Refer to for Protocol Section 9.2.4.8 procedural details. 
10. Refer to for Protocol Section 9.2.4.9 procedural details. 
11. Vital signs include systolic and diastolic blood pressure, respiratory rate and heart rate. 
Vital signs will be collected in a seated position. At the randomization visit, vital signs are 
taken prior to PK blood draw, prior to study drug administration, and at 2 hours (±10 min) 
after completion of the injection.  
12. A full physical exam must be performed at screening, at baseline, and at EOS. A limited 
physical exam will be done at remaining visits depending on presentation of the subject. 
13. If the urine pregnancy test is positive, the site must perform a serum pregnancy test for 
confirmation. At the randomization visit, if a serum pregnancy test must be performed, 
                                        VV-RIM-00163457-1.0 Approved - 04 Aug 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-2001 
Statistical Analysis Plan 
Date: 28Jul2021 
 
CONFIDENTIAL 
Page 53 of 56 
study drug cannot be administered unless the serum pregnancy test is negative. Urine 
pregnancy test can be performed on day -1 of the visit at the investigator’s discretion.  
At-home pregnancy testing: WOCBP will be provided with urine pregnancy tests for 
at-home testing prior to visits 4 and 6. Study sites will collect the results by telephone at 
these visits. If the urine pregnancy test is positive, the site must perform a serum pregnancy 
test for confirmation.  
14. PK and ADA samples are to be collected prior to study drug administration. In the event 
of suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for PK and 
ADA analyses may be collected as close to the event as practically possible. 
15. Refer to Protocol Section 9.2.11. 
16. Genomic analysis is optional for all subjects enrolling in the study. One DNA sample is to 
be collected at the randomization visit, but if this sample collection was omitted at baseline, 
it can be collected at any subsequent visit. Refer to Protocol Section 9.2.12. 
 
 
                                        VV-RIM-00163457-1.0 Approved - 04 Aug 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-2001 
Statistical Analysis Plan 
Date: 28Jul2021 
 
CONFIDENTIAL 
Page 54 of 56 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
PCSV 
Comments 
Clinical Chemistry 
ALT* 
>3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 
5 ULN 
>10 and ≤ 20 ULN and baseline 
≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required; multiple levels are optional for 
phase 2/3 studies. If it is desirable to get the distribution across 
the different PCSV levels, additional shift table on ≤3, >3 to ≤5, 
> 5 to ≤10, >10 to ≤20, and > 20 category for baseline vs. post 
baseline may be provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 
5 ULN 
>10 and ≤ 20 ULN and baseline 
≤ 10 ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzymes activities must be expressed in ULN, not in IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple levels are optional for 
phase 2/3 studies. If it is desirable to get the distribution across 
the different PCSV levels, additional shift table on ≤3, >3 to ≤5, 
> 5 to ≤10, >10 to ≤20, and > 20 category for baseline vs. post 
baseline may be provided 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 
ULN 
Enzyme activity must be expressed in ULN, not in IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Total Bilirubin* >1.5 and ≤ 2 ULN and baseline ≤ 
1.5 ULN* 
>2 ULN and baseline ≤ 2.0 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. 
* At least one level is required, multiple levels are optional for 
phase 2/3 studies. If it is desirable to get the distribution of 
significant level, additional shift table on ≤1.5, >1.5 to ≤2.0 and 
> 2.0 category for baseline vs. post baseline may be provided 
(ALT or AST) 
and Total 
Bilirubin 
((ALT >3 ULN or AST>3 ULN) 
and TBILI>2 ULN) and baseline 
((ALT ≤3 ULN and AST ≤3 
ULN) or TBILI ≤2 ULN)) 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Creatinine 
≥150 μmol/L (Adults) and 
baseline < 150 μmol/L 
≥30%  change from baseline and 
<100% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
3 independent criteria  
Uric Acid  
<120 μmol/L and ≥ 120 μmol/L 
at baseline 
>408 μmol/Land ≤ 408 μmol/L at 
baseline 
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen (BUN) 
≥17 mmol/L and <17 mmol/L at 
baseline 
Two independent criteria 
Chloride 
<80 mmol/L and baseline ≥ 80 
mmol/L  
>115 mmol/L and baseline  ≤115 
mmol/L  
Two independent criteria  
Sodium 
≤129 mmol/L  and baseline > 
129 mmol/L  
≥160 mmol/L  and baseline < 
160 mmol/L  
Two independent criteria 
                                        VV-RIM-00163457-1.0 Approved - 04 Aug 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-2001 
Statistical Analysis Plan 
Date: 28Jul2021 
 
CONFIDENTIAL 
Page 55 of 56 
Parameter 
PCSV 
Comments 
Potassium 
<3 mmol/L and baseline ≥ 3 
mmol/L  
≥5.5 mmol/L and baseline < 5.5 
mmol/L  
FDA Feb 2005. 
Two independent criteria 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L 
at baseline 
Threshold for therapeutic intervention. 
Glucose 
                
Hypoglycaemia 
 
               
Hyperglycaemia 
≤3.9 mmol/L and <LLN and 
baseline >3.9 mmol/L or ≥ LLN  
≥11.1 mmol/L (unfasted); ≥7 
mmol/L (fasted) and baseline < 
11.1 mmol/L (unfasted); <7 
mmol/L (fasted)  
 
 
ADA Jan 2008. 
Albumin 
≤25 g/L and >25 g/L at baseline  
Hematology 
WBC 
<3.0 Giga/L and ≥3.0 Giga/L at 
baseline (Non-Black);  
<2.0 Giga/L and ≥2.0 Giga/L at 
baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L at 
baseline 
Increase in WBC: not relevant. 
*The default criteria. Summary by race (black and Non-black) 
are optional. 
 
To be interpreted only if no differential count available. 
Lymphocytes 
(ALC) 
>4.0 Giga/L and ≤4.0 Giga/L at 
baseline  
 
Neutrophils 
<1.5 Giga/L and ≥1.5 Giga/L at 
baseline (Non-Black);  
<1.0 Giga/L and ≥1.0 Giga/L at 
baseline (Black) 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
*The default criteria. By race (black and Non-black) are 
optional. 
Monocytes  
>0.7 Giga/L and ≤ 0.7 Giga/L at 
baseline 
 
Basophils 
>0.1 Giga/L and ≤ 0.1 Giga/L at 
baseline 
 
Eosinophils 
(>0.5 Giga/L and >ULN) and 
(≤0.5 Giga/L or ≤ ULN at 
baseline) 
Harrison- Principles of Internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L and > 115 g/L at 
baseline for male; ≤95 g/L and> 
95 g/L at baseline for Female. 
≥185 g/L and <185 g/L at 
baseline for Male; ≥165 g/L and 
< 165 g/L at baseline for Female 
Decrease from Baseline ≥20 g/L 
Three criteria are independent. 
 
*The default criteria. By gender (male and female) are optional. 
 
Criteria based upon decrease from baseline are more relevant 
than 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 and > 0.37 v/v at 
baseline for Male ; ≤0.32 v/v and 
> 0.32 v/v at baseline for Female 
≥0.55 v/v and < 0.55 v/v at 
baseline for Male ; ≥0.5 v/v and 
< 0.5 v/v at baseline for Female 
Two Criteria are independent 
 
*The default criteria. By gender (male and female) are optional. 
                                        VV-RIM-00163457-1.0 Approved - 04 Aug 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-2001 
Statistical Analysis Plan 
Date: 28Jul2021 
 
CONFIDENTIAL 
Page 56 of 56 
Parameter 
PCSV 
Comments 
RBC 
<4 Tera/L and  ≥ 4 Tera/L at 
baseline for Male ; <3 Tera/L and 
≥ 3 Tera/L at baseline for Female 
≥7 Tera/L and   <7 Tera/L at 
baseline for Male ; ≥6 Tera/L and 
<6 Tera/L at baseline for Female 
Unless specifically required for particular drug development, the 
analysis is redundant with that of Hb. 
Platelets 
<100 Giga/L and ≥100 Giga/L at 
baseline 
≥700 Giga/L and < 700 Giga/L at 
baseline 
International Consensus meeting on drug-induced blood 
cytopenias, 1991. 
Two independent criteria 
Vital signs 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
 
SBP  
≤95 mmHg and decrease from 
baseline ≥20mmHg 
≥160 mmHg and increase from 
baseline ≥20 mmHg 
 
DBP 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
≥110 mmHg and increase from 
baseline ≥10 mmHg 
 
Respiratory rate < 12 per minutes and ≥12 per 
minute at baseline 
>20 per minute and ≤20 per 
minute at baseline 
 
 
10.4. 
Search Criteria for TEAE of Special Interest 
AESI 
Search Criteria 
Systemic or severe 
hypersensitivity reactions  
Narrow SMQ for hypersensitivity  
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Severe injection site 
reactions 
HLT=Injection Site Reactions 
AND 
Serious AE= “Yes” OR Severity= “severe” 
 
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                                        VV-RIM-00163457-1.0 Approved - 04 Aug 2021 GMT-5:00