Conditions: Allergic Rhinitis Conjunctivitis
Keywords: Birch Allergy Birch Pollen Season Monoclonal antibody(ies) Oak Pollen Season Subcutaneous immunotherapy Skin Prick Test
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 217
Healthy volunteers: yes

Brief summary:
Primary objective: To assess the efficacy of a single dose of the anti- Bet v 1 monoclonal antibodies (mAb(s ) in the reduction of allergic nasal symptoms during an out-of-season birch allergen environmental exposure unit (EEU) challenge in participants receiving REGN5713-5714-5715 versus placebo (Part A)

Detailed description:
The study consists of Part A and Part B. All participants will be asked to complete both Part A and Part B of the study. The study lasts for a total duration of up to approximately 46 weeks (including up to a 10-week screening period). Part A of the study lasts up to approximately 28 weeks (including the screening period). Part B of the study starts after completion of Part A and lasts up to approximately 18 weeks (including an approximately 4-week follow-up period after end of birch pollen season (BPS)), dependent on the start and end times of the natural BPS.

Arms:
arm 1: 3-mAb arm 2: 2-mAb arm 3: 1-mAb arm 4: None

Interventions: intervention 1: REGN5713 intervention 2: REGN5714 intervention 3: REGN5715 intervention 4: Placebo
Intervention descriptions: intervention 1: Administered subcutaneously (SC) intervention 2: Administered SC intervention 3: Administered SC intervention 4: Administered SC

Protocol document:
Prot_000.pdf: 
IND Number: 138377 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A TWO-PART RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY OF THE 
ANTI-BET V 1 MONOCLONAL ANTIBODIES TO REDUCE ALLERGIC 
RHINITIS AND CONJUNCTIVITIS SYMPTOMS AND SKIN TEST 
REACTIVITY UPON EXPOSURE TO BIRCH ALLERGEN 
Compounds: 
REGN5713; REGN5714; REGN5715 
Clinical Phase: 
2 
Protocol Number: 
R5713-5714-5715-ALG-21111 
Protocol Version: 
R5713-5714-5715-ALG-21111 Amendment 1 
Date of Issue:  
See appended electronic signature page 
Original Date of Issue: 
17 May 2022 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
Confidential: This submission contains confidential and proprietary commercial information 
and/or trade secrets which are subject to protection under laws and regulations worldwide 
including, but not limited to TRIPS Article 39 and regional, national or state laws whether by 
legislation or in equity. For the purposes of compliance with all applicable freedom of information 
laws, and regulations, and their equivalents anywhere in the world including but not limited to the 
US Freedom of Information Act 5 U.S.C. §552, Regeneron expects that, prior to disclosure to third 
parties of any information and/or data related to, or contained within, this submission, it will be 
given every opportunity under applicable laws to protect its commercial interests and/or its trade 
secrets including the opportunity to object to such disclosure and/or provide redaction proposals. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BOCF 
Baseline observation carried forward 
BPS 
Birch pollen season 
BUN 
Blood urea nitrogen 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CSMS 
Combined Symptom and Medication Score 
CSR 
Clinical study report 
DMS 
Daily Medication Score 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EC50 
Half maximal effective concentration 
EDC 
Electronic data capture 
EEU 
Environmental exposure unit 
EOS 
End-of-study 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FDA 
United States Food and Drug Administration 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
INCS 
Intranasal corticosteroids 
IRB 
Institutional Review Board 
IV 
Intravenous 
mAb(s) 
Monoclonal antibody(ies) 
MI 
Multiple imputation 
OPS 
Oak pollen season 
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Abbreviation 
Definition 
PFASQ 
Pollen Food Allergy Symptom Questionnaire 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
PI 
Principal investigator 
RBC 
Red blood cell 
RBQM 
Risk-Based Quality Monitoring 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RQLQ(S) 
Rhinoconjunctivitis Quality of Life Questionnaire 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
sIgE 
Allergen-specific immunoglobulin E 
SIT 
Specific immunotherapy 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
SPT 
Skin prick test [tSPT = SPT using serial allergen titrations] 
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 
WBC 
White blood cell 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
AMENDMENT HISTORY ...........................................................................................................10 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
1. 
INTRODUCTION ......................................................................................................20 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
2.1. 
Primary Objective and Endpoint ................................................................................23 
2.2. 
Secondary Objectives and Endpoints .........................................................................23 
2.3. 
Exploratory Objectives and Endpoints .......................................................................27 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................30 
3.1. 
Hypotheses ..................................................................................................................30 
3.2. 
Rationale .....................................................................................................................31 
3.2.1. 
Rationale for Study Design .........................................................................................31 
3.2.2. 
Rationale for Dose Selection ......................................................................................33 
3.3. 
Risk-Benefit ................................................................................................................34 
4. 
STUDY VARIABLES................................................................................................36 
4.1. 
Demographic and Baseline Characteristics ................................................................36 
4.2. 
Efficacy Variables ......................................................................................................36 
4.3. 
Safety Variables ..........................................................................................................36 
4.4. 
Pharmacokinetic Variables .........................................................................................36 
4.5. 
Immunogenicity Variables ..........................................................................................36 
4.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................36 
5. 
STUDY DESIGN .......................................................................................................37 
5.1. 
Study Description and Duration .................................................................................37 
5.1.1. 
Study Stopping Rules .................................................................................................42 
5.1.1.1. 
Study Stopping Criteria ..............................................................................................42 
5.1.2. 
End of Study Definition ..............................................................................................42 
5.2. 
Planned Analyses ........................................................................................................42 
5.3. 
Study Committees .......................................................................................................43 
5.3.1. 
Independent Data Monitoring Committee ..................................................................43 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS ........................................................................................................44 
6.1. 
Number of Participants Planned .................................................................................44 
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6.2. 
Study Population .........................................................................................................44 
6.2.1. 
Inclusion Criteria ........................................................................................................44 
6.2.2. 
Exclusion Criteria .......................................................................................................44 
6.3. 
Premature Withdrawal from the Study .......................................................................48 
6.4. 
Replacement of Participants .......................................................................................48 
7. 
STUDY TREATMENTS............................................................................................49 
7.1. 
Investigational and Reference Treatments ..................................................................49 
7.2. 
Rescue Treatments ......................................................................................................50 
7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................51 
7.3.1. 
Dose Modification ......................................................................................................51 
7.3.2. 
Study Drug Discontinuation .......................................................................................51 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................51 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................51 
7.4. 
Management of Acute Reactions ................................................................................52 
7.4.1. 
Acute Injection Reactions ...........................................................................................52 
7.4.1.1. 
Systemic Injection Reactions ......................................................................................52 
7.4.1.2. 
Local Injection Site Reactions ....................................................................................52 
7.5. 
Method of Treatment Assignment ..............................................................................52 
7.6. 
Blinding ......................................................................................................................52 
7.7. 
Emergency Unblinding ...............................................................................................53 
7.8. 
Treatment Logistics and Accountability .....................................................................53 
7.8.1. 
Packaging, Labeling, and Storage ..............................................................................53 
7.8.2. 
Supply and Disposition of Treatments .......................................................................54 
7.8.3. 
Treatment Accountability ...........................................................................................54 
7.8.4. 
Treatment Compliance ................................................................................................54 
7.9. 
Concomitant Medications and Procedures .................................................................54 
7.9.1. 
Prohibited Medications and Procedures .....................................................................54 
7.9.2. 
Permitted Medications and Procedures ......................................................................56 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................57 
8.1. 
Schedule of Events .....................................................................................................57 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................63 
8.1.2. 
Early Termination Visit ..............................................................................................67 
8.1.3. 
Unscheduled Visits .....................................................................................................67 
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8.2. 
Study Procedures ........................................................................................................67 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................67 
8.2.2. 
Efficacy Procedures ....................................................................................................67 
8.2.2.1. 
Total Nasal Symptom Score .......................................................................................67 
8.2.2.2. 
Total Ocular Symptom Score .....................................................................................68 
8.2.2.3. 
Total Symptom Score .................................................................................................68 
8.2.2.4. 
Daily Medication Score ..............................................................................................68 
8.2.2.5. 
Combined Symptom and Medication Score ...............................................................68 
8.2.2.6. 
Skin Prick Testing .......................................................................................................68 
8.2.2.7. 
Titrated Skin Prick Testing to Birch and Birch-Related Allergens ............................69 
8.2.2.8. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for Ages 
12+ ..............................................................................................................................69 
8.2.2.9. 
Pollen Food Allergy Syndrome Questionnaire ...........................................................69 
8.2.2.10. 
Outdoor Time Questionnaire ......................................................................................70 
8.2.3. 
Safety Procedures .......................................................................................................70 
8.2.3.1. 
Vital Signs ..................................................................................................................70 
8.2.3.2. 
Physical Examination .................................................................................................70 
8.2.3.3. 
Spirometry ..................................................................................................................70 
8.2.3.4. 
Laboratory Testing ......................................................................................................71 
8.2.4. 
Drug Concentration and Measurements .....................................................................72 
8.2.5. 
Immunogenicity Measurements and Samples ............................................................72 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................72 
8.2.6.1. 
Basophil Activation Test ............................................................................................72 
8.2.6.2. 
Nasal Fluid Collection ................................................................................................73 
8.2.7. 
Future Biomedical Research (Optional) .....................................................................73 
8.2.8. 
Pharmacogenomic Analysis (Optional) ......................................................................73 
9. 
SAFETY EVALUATION AND REPORTING .........................................................75 
9.1. 
Recording and Reporting Adverse Events ..................................................................75 
9.1.1. 
General Guidelines .....................................................................................................75 
9.1.2. 
Reporting Procedure ...................................................................................................76 
9.1.3. 
Events that Require Expedited Reporting to Sponsor ................................................77 
9.1.4. 
Other Adverse Events of Special Interest that do not Require Expedited 
Reporting to Sponsor ..................................................................................................77 
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9.2. 
Definitions ..................................................................................................................77 
9.2.1. 
Adverse Event .............................................................................................................77 
9.2.2. 
Serious Adverse Event ................................................................................................78 
9.2.3. 
Adverse Events of Special Interest .............................................................................78 
9.2.4. 
Severity .......................................................................................................................78 
9.2.5. 
Causality .....................................................................................................................79 
9.3. 
Safety Monitoring .......................................................................................................80 
9.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .........................................................................................................81 
10. 
STATISTICAL PLAN................................................................................................82 
10.1. 
Statistical Hypothesis ..................................................................................................82 
10.2. 
Justification of Sample Size........................................................................................82 
10.3. 
Analysis Sets ...............................................................................................................82 
10.3.1. 
Efficacy Analysis Sets ................................................................................................82 
10.3.2. 
Safety Analysis Set .....................................................................................................83 
10.3.3. 
Pharmacokinetic Analysis Set ....................................................................................83 
10.3.4. 
Immunogenicity Analysis Set .....................................................................................83 
10.4. 
Statistical Methods ......................................................................................................83 
10.4.1. 
Participant Disposition ................................................................................................83 
10.4.2. 
Demography and Baseline Characteristics .................................................................83 
10.4.3. 
Efficacy Analyses .......................................................................................................84 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................84 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................85 
10.4.3.3. 
Exploratory Efficacy Analysis ....................................................................................86 
10.4.4. 
Control of Multiplicity ................................................................................................86 
10.4.5. 
Safety Analysis ...........................................................................................................87 
10.4.5.1. 
Adverse Events ...........................................................................................................87 
10.4.5.2. 
Other Safety ................................................................................................................87 
10.4.5.3. 
Treatment Exposure ....................................................................................................88 
10.4.6. 
Pharmacokinetics ........................................................................................................88 
10.4.6.1. 
Analysis of Drug Concentration Data .........................................................................88 
10.4.7. 
Analysis of Immunogenicity Data ..............................................................................88 
10.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................89 
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10.5. 
Timing of Statistical Analysis ....................................................................................89 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........89 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................90 
11.1. 
Data Management and Electronic Systems ................................................................90 
11.1.1. 
Data Management .......................................................................................................90 
11.1.2. 
Electronic Systems ......................................................................................................90 
11.2. 
Study Monitoring ........................................................................................................90 
11.2.1. 
Monitoring of Study Sites ...........................................................................................90 
11.2.2. 
Source Document Requirements ................................................................................91 
11.2.3. 
Case Report Form Requirements ................................................................................91 
11.3. 
Audits and Inspections ................................................................................................91 
11.4. 
Study Documentation .................................................................................................92 
11.4.1. 
Certification of Accuracy of Data ...............................................................................92 
11.4.2. 
Retention of Records ..................................................................................................92 
12. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................93 
12.1. 
Good Clinical Practice Statement ...............................................................................93 
12.2. 
Informed Consent .......................................................................................................93 
12.3. 
Participants Confidentiality and Data Protection .......................................................93 
12.4. 
Institutional Review Board/Ethics Committee ...........................................................94 
12.5. 
Clinical Study Data Transparency ..............................................................................94 
13. 
PROTOCOL AMENDMENTS ..................................................................................95 
14. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................96 
14.1. 
Premature Termination of the Study ...........................................................................96 
14.2. 
Close-out of a Site ......................................................................................................96 
15. 
CONFIDENTIALITY ................................................................................................96 
16. 
FINANCING AND INSURANCE .............................................................................96 
17. 
PUBLICATION POLICY ..........................................................................................96 
18. 
REFERENCES ...........................................................................................................97 
19. 
INVESTIGATOR’S AGREEMENT ........................................................................101 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................102 
 
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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................58 
Table 2: 
Summary of Estimand for Primary Endpoint .............................................................85 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................38 
 
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AMENDMENT HISTORY 
Amendment 1 
The main purpose of this amendment is to decrease the minimum interval between study drug 
dose #1 and dose #2.  
The following table outlines the changes made to the protocol and the rationale.  
Description of Change 
Brief Rationale 
Sections Changed 
The minimum interval between study drug 
dose #1 and dose #2 was reduced from 18 
weeks to 12 weeks. 
- Time 
window 
for 
day 
85 
environmental exposure unit (EEU) 
challenges expanded from “±7d” to “-
28 to +14” days to allow participants 
with a shorter interval to complete 
Part A assessments prior to the birch 
season. Therefore, the day 85 visit can 
be completed from as early as day 57 
and up to day 99.   
- Minimum interval between EEU 
challenges clarified at approximately 
1 week or longer for all EEU 
challenges.  
- Participants who experience a high 
symptom burden that is assessed as 
due to tree pollens may not complete 
the day 57 and/or day 85 EEU 
challenge(s). Therefore, the primary 
analysis may be performed after all 
participants complete at least the day 
29, rather than the day 57, EEU 
challenges in Part A or discontinue.  
- Visit 10 may not be performed if 
participants are expected to be dosed 
within 3 weeks after the prior EEU 
visit. If visit 10 is not performed, then 
all visit 10 assessments (without any 
duplication) should be performed at 
the last prior EEU visit (including 
serum 
pregnancy 
test, 
e-diary, 
dispensing rescue medications, etc)  
A shorter interval between doses 
will allow participants to be enrolled 
over a longer duration within the 
seasonality constraints to complete 
both the out-of-season and in-season 
portions of the study and aid with 
enrollment timelines.  
Flexibility 
to 
decrease 
patient 
burden for visit assessments was 
added given the reduced timing 
between some visits that may apply. 
Protocol Synopsis: Study 
Duration; Statistical Plan 
Section 3.2.2 Rationale for Dose 
Selection 
Section 5.1 Study Description 
and Duration 
Section 5.2 Planned Analyses 
Figure 1: Study Flow Diagram 
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
footnotes #6, #14, #40 and #41  
Section 10.5 Timing of 
Statistical Analysis 
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Description of Change 
Brief Rationale 
Sections Changed 
The sponsor will define the last possible 
date for dosing in Part B in each 
geographical area based on the anticipated 
timing and duration of the local birch 
pollen season in consultation with the 
local pollen expert. Participants who are 
unable to receive dose #2 prior to the 
defined dosing end date will discontinue 
study drug (Section 7.3.2) but should be 
encouraged to remain in the study.   
This change prevents participants 
from receiving dose #2 when there 
may not be a reasonable opportunity 
for benefit during the season.  
Protocol Synopsis: Study 
Design 
Section 5.1 Study Description 
and Duration 
Text was added to clarify that screening 
and 
pre-season 
e-diary 
assessments 
should be obtained for a minimum of 
1 week.  
This clarifying text will ensure a 
minimum timeframe for baseline 
e-diary assessment collection.  
Section 5.1 Study Description 
and Duration 
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
footnotes #25 and #26   
Under the severity grading for injection 
site reactions (ISRs), the below text was 
removed: 
“Potentially Life Threatening: Pain that 
requires an emergency room visit or 
hospitalization; erythema characterized 
by necrosis or exfoliative dermatitis or 
induration characterized by necrosis” 
The description for potentially life 
threatening 
and 
severe 
ISR 
categories overlapped in the prior 
protocol version.  
The sponsor recommends that all 
adverse events (AEs), including 
ISRs, be graded as mild, moderate, 
or 
severe 
per 
the 
protocol 
descriptions. Life-threatening AEs 
should be reported as a serious 
adverse event (SAE), as applicable.  
Section 9.2.4 Severity 
A duplicate medication (systemic steroid 
treatment) was removed from the list of 
prohibited 
medications 
preceding 
environmental exposure unit visits and 
Part B assessments.  
This type of medication is already 
prohibited per the protocol with a 30 
day washout during the entire study.  
Section 7.9.1 Prohibited 
Medications and Procedures 
Minor changes to language were made for 
consistency and accuracy. Minor typos 
were corrected.  
Minor edits were made to improve 
clarity. 
Protocol Synopsis: Objectives; 
Statistical Plan 
Section 2.2 Secondary 
Objectives and Endpoints 
Section 5.1 Study Description 
and Duration 
Section 5.2 Planned Analyses 
Section 7.2 Rescue Treatments 
Section 7.9.2 Permitted 
Medications and Procedures 
Table 1: Schedule of Events 
Section 8.1.1 Footnotes for the 
Schedule of Events Table, 
footnotes #21 and #27  
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Description of Change 
Brief Rationale 
Sections Changed 
Section 8.2.2.6 Skin Prick 
Testing 
Section 8.2.2.7 Titrated Skin 
Prick Testing and Birch-Related 
Allergens 
Section 8.2.6.1 Basophil 
Activation Test 
Typos: Throughout the protocol.  
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Two-Part Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Efficacy of the Anti-Bet v 1 Monoclonal Antibodies to Reduce Allergic 
Rhinitis and Conjunctivitis Symptoms and Skin Test Reactivity upon 
Exposure to Birch Allergen 
Site Locations 
 
Principal Investigator 
North America 
 
Objectives 
Primary Objective: To assess the efficacy of a single dose of the anti-Bet v 
1 monoclonal antibodies in the reduction of allergic nasal symptoms during 
an out-of-season birch allergen environmental exposure unit (EEU) challenge 
in participants receiving REGN5713-5714-5715 versus placebo (Part A) 
Secondary Objectives:  
• To assess the magnitude and duration of efficacy of a single dose of the 
anti-Bet v 1 monoclonal antibodies (dose #1) in the reduction of allergic 
symptoms during the out-of-season birch allergen EEU challenges in 
participants 
receiving 
REGN5713-5714-5715 
versus 
placebo, 
REGN5713-5715 versus placebo, and REGN5715 versus placebo (Part 
A) 
• To assess the efficacy of the anti-Bet v 1 monoclonal antibodies (dose 
#1) in the reduction of skin test reactivity from pre-treatment baseline by 
inhibiting a wheal response to a titrated skin prick test with birch and 
related allergens (eg, alder, oak) during out-of-season assessments in 
participants who receive REGN5713-5714-5715 versus placebo, 
REGN5713-5715 versus placebo, and REGN5715 versus placebo (Part 
A) 
• To assess the efficacy of a single dose of the anti-Bet v 1 monoclonal 
antibodies (dose #1) in the reduction of allergic symptoms during the 
out-of-season oak allergen EEU challenge in the subpopulation of oak 
allergic participants in those receiving REGN5713-5714-5715 versus 
placebo, REGN5713-5715 versus placebo, and REGN5715 versus 
placebo (Part A) 
• To compare differences in the degree of reduction of allergic symptoms 
during the out-of-season EEU challenges in participants receiving the 
different combinations of the anti-Bet v 1 antibodies in those receiving 
REGN5713-5714-5715, REGN5713-5715, or REGN5715 (Part A) 
• To compare differences in the degree of reduction of skin test reactivity 
from pre-treatment baseline by inhibiting a wheal response to a titrated 
skin prick test with birch and related allergens (eg, alder, oak) during 
out-of-season assessments in participants receiving the different 
combinations of the anti-Bet v 1 antibodies in those receiving 
REGN5713-5714-5715, REGN5713-5715, or REGN5715 (Part A) 
• To assess the efficacy of the anti-Bet v 1 monoclonal antibodies (dose 
#2) in the reduction of allergic symptoms during the in-season birch 
allergen EEU challenge in participants receiving REGN5713-5714-5715 
versus placebo, REGN5713-5715 versus placebo, and REGN5715 
versus placebo (Part B) 
• To determine the efficacy of the anti-Bet v 1 monoclonal antibodies 
(dose #2) in the reduction of allergic symptoms during the birch pollen 
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season and peak birch pollen season in participants receiving 
REGN5713-5714-5715 versus placebo, REGN5713-5715 versus 
placebo, and REGN5715 versus placebo (Part B) 
• To determine the efficacy of the anti-Bet v 1 monoclonal antibodies 
(dose #2) in the reduction of skin test reactivity from pre-treatment 
baseline by inhibiting a wheal response to a titrated skin prick test with 
birch and related allergens (eg, alder, oak) after the natural birch pollen 
season in participants who receive REGN5713-5714-5715 versus 
placebo, REGN5713-5715 versus placebo, and REGN5715 versus 
placebo (Part B) 
• To assess health-related quality of life during the BPS and peak BPS in 
participants who receive REGN5713-5714-5715 versus placebo, 
REGN5713-5715 versus placebo, and REGN5715 versus placebo 
• To evaluate the safety and tolerability of the anti-Bet v 1 monoclonal 
antibodies as compared to placebo following single administration (dose 
#1) and after repeat dosing (dose #2) 
• To determine systemic concentrations over time of total antibody (free 
+ antigen-bound) for each of the individual monoclonal antibodies 
(mAbs): REGN5713, REGN5714, and REGN5715 at various time 
points following single administration (dose #1) and after repeat dosing 
(dose #2) 
• To assess the immunogenicity of REGN5713, REGN5714, and 
REGN5715 
in 
birch-allergic 
participants 
following 
single 
administration (dose #1) and after repeat dosing (dose #2) 
Study Design 
REGN5713-5714-5715-ALG-21111 is a 2-part randomized, double-blind, 
placebo-controlled study in birch-allergic participants to assess the efficacy 
of the anti-Bet v 1 monoclonal antibodies, in combination (the 3-mAb and the 
best 2-mAb) and as a single best antibody. Efficacy in the reduction of allergic 
rhinitis and conjunctivitis symptoms as well as birch skin test reactivity will 
be tested using assessments out-of-season (Part A: EEU challenges and 
titrated skin prick testing) and during the birch pollen season (Part B: EEU 
challenges, field assessments, and titrated skin prick testing). Participants will 
receive 2 doses of the study drug: a dose at randomization outside of the birch 
pollen season (dose #1; Part A) and a dose of the study drug in Part B ahead 
of the anticipated birch pollen season (dose #2; Part B). The sponsor will 
define the last possible date for dosing in Part B in each geographical area 
based on the anticipated timing and duration of the local birch pollen season; 
any participants who are unable to receive dose #2 prior to the defined dosing 
end date will discontinue study drug but should be encouraged to remain in 
the study. The efficacy will be tested out-of-season as well as in-season to 
fully evaluate treatment effects during experimental exposure to the allergen 
and during natural exposure to birch and other related/ unrelated pollens 
during the birch pollen season.  
Study Duration 
The study consists of 2 parts for a total study duration of up to approximately 
46 weeks (including up to a 10-week screening period). Part A of the study 
lasts up to approximately 28 weeks (including the screening period). Part B 
of the study starts after completion of Part A and lasts up to approximately 
18 weeks (including a 4-week follow-up period after end of birch pollen 
season), dependent on the start and end times of the natural birch pollen 
season.  
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End of Study Definition 
The end of study is defined as the date the last participant completes the last 
study visit, withdraws from the study, or is lost to follow-up (ie, the study 
participant can no longer be contacted by the investigator).  
Population 
 
 
Sample Size: 
The study will enroll approximately 300 participants.  
 
Target Population: 
Generally healthy male and female participants 18 years of age or older with 
birch pollen allergy will be enrolled in this study. 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Part A: 
Subcutaneous administration of a dose of study drug (dose #1): 
• 3-mAb cocktail REGN5713-5714-5715 900 mg (300 mg per mAb)  
• 2-mAb cocktail REGN5713-5715 600 mg (300 mg per mAb) plus 
placebo that replaces REGN5714 
• 1-mAb REGN5715 300 mg plus placebo that replaces REGN5713-5714 
Part B: 
Subcutaneous administration of dose of study drug (dose #2) 
• 3-mAb cocktail REGN5713-5714-5715 900 mg (300 mg per mAb)  
• 2-mAb cocktail REGN5713-5715 600 mg (300 mg per mAb) plus 
placebo that replaces REGN5714 
• 1-mAb REGN5715 300 mg plus placebo that replaces REGN5713-5714 
Participants will receive the same treatment in Part B that they were originally 
randomized to receive in Part A.  
 
Placebo 
 
Route/Schedule: 
Parts A and B:  
• Subcutaneous administration of matching placebo that replaces active 
drug 
Endpoints 
 
 
Primary: 
Primary endpoint: The mean of Total Nasal Symptom Score [TNSS (2 to 6 
hours)] during a birch allergen EEU challenge at day 29 
 
Secondary: 
Secondary Endpoints: 
• 
The mean of symptom scores during out-of-season birch allergen EEU 
challenges at days 29, 57, and 85 
o 
TNSS (2 to 6 hours) (except day 29 for 3-mAb) 
o 
Total Ocular Symptom Score (TOSS) (2 to 6 hours) 
o 
Total Symptom Score (TSS) (2 to 6 hours) 
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• 
The change and percent change from pre-treatment baseline in symptom 
scores during out-of-season birch allergen EEU challenges at days 29, 
57, and 85  
o 
TNSS (2 to 6 hours) 
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The change and percent change from pre-treatment baseline at days 29, 
57, 85, and 127 in the birch (and related allergens) titrated skin prick test 
(SPT) mean wheal diameter AUC 
• 
The mean of symptom scores during out-of-season oak allergen EEU 
challenge at day 36 
o 
TNSS (2 to 6 hours) 
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The change and percent change from pre-treatment baseline in symptom 
scores during an oak allergen EEU at day 36 in subpopulation of 
oak-allergic participants 
o 
TNSS (2 to 6 hours) 
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The mean of symptom scores during out-of-season birch allergen EEU 
challenges at days 29, 57, and 85 
o 
TNSS (2 to 6 hours)  
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The change and percent change from pre-treatment baseline in symptom 
scores during out-of-season birch allergen EEU challenges at days 29, 
57, and 85 
o 
TNSS (2 to 6 hours) 
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The proportions of participants achieving different degrees of clinical 
responses will be compared across different symptom response 
thresholds at days 29, 57, and 85 
o 
TNSS (2 to 6 hours) 
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The proportions of participants achieving different degrees of responses 
in the birch (and related allergens) titrated SPT mean wheal diameter 
AUC will be compared across different response thresholds at days 29, 
57, and 85 
• 
The mean of symptom scores during the peak-season birch allergen EEU 
challenge 
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o 
TNSS (2 to 6 hours) 
o 
TOSS (2 to 6 hours) 
o 
TSS (2 to 6 hours) 
• 
The daily symptom and medication scores, averaged during the BPS and 
peak BPS 
o 
Combined Symptom and Medication Score (CSMS), TSS, TNSS, 
TOSS, and Daily Medication Score (DMS), averaged during the BPS  
o 
CSMS, TSS, TNSS, TOSS, and DMS, averaged during the peak BPS 
• 
The change and percent change from baseline in the symptom and 
medication scores, averaged during the BPS and peak BPS 
o 
CSMS, TSS, TNSS, TOSS, and DMS, averaged during the BPS  
o 
CSMS, TSS, TNSS, TOSS, and DMS, averaged during the peak BPS 
• 
The change and percent change from pre-treatment baseline to end-of-
season and end-of-study (EOS) visits in the birch (and related allergens) 
titrated SPT mean wheal diameter AUC 
• 
The mean of the total Rhinoconjunctivitis Quality of Life Questionnaire 
(RQLQ[S]) score during BPS and peak BPS 
o 
RQLQ(S), averaged during the BPS and peak BPS 
o 
Change and percent change from baseline in the average RQLQ(S) 
during the BPS and peak BPS 
• 
Incidence rates of treatment-emergent adverse events (TEAEs) and 
serious TEAEs through end of study 
• 
Total REGN5713, REGN5714, REGN5715 concentration in serum over 
the duration of the study 
• 
Incidences and titers of anti-drug antibodies (ADA) to REGN5713, 
REGN5714, and REGN5715 over time 
Procedures and Assessments 
Procedures to determine study eligibility and/or baseline characteristics 
include SPT for birch, birch-related and unrelated common allergens, 
allergen-specific IgE, total IgE, electrocardiogram (ECG), laboratory testing, 
height measurement, weight measurement, pregnancy testing in women of 
childbearing potential, and follicle stimulating hormone determination (in 
postmenopausal women if postmenopausal status is in question).  
Procedures to assess measures of efficacy include the EEU chamber 
challenges (TNSS, TOSS), daily symptom and medication scores during the 
birch pollen season (TNSS, TOSS, TSS, DMS, CSMS), SPT to birch and 
related allergens, titrated SPT to birch and birch-related allergens, RQLQ(S), 
Pollen Food Allergy Symptom Questionnaire, and the Outdoor Time 
Questionnaire.  
Procedures to assess safety include measurement of vital signs, physical 
examination, spirometry, collection of adverse events, collection of 
concomitant medications, and laboratory testing.  
Blood draws will be performed to collect samples for analysis of drug 
concentration and immunogenicity measurements. Blood draws will also be 
performed to collect samples for pharmacodynamic and exploratory 
biomarker procedures, including for the basophil activation test.  
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Whole blood samples for DNA extraction will be collected for 
pharmacogenomic analysis from participants who opt to participate in the 
optional pharmacogenomic sub-study. Additional serum and plasma samples, 
as well as nasal fluid samples, will be collected from participants who opt to 
participant in the optional future biomedical research sub-study.  
Statistical Plan 
Justification of Sample Size 
This study is powered to detect differences between REGN5713-5714-5715 
900 mg and placebo on the primary endpoint of the mean TNSS during a birch 
pollen EEU challenge (2 to 6 hours) at day 29 in Part A. A sample size of 65 
participants per arm gives 90% power to detect a mean difference in average 
TNSS (2 to 6 hours) of 1.61 (30% reduction from placebo) between 
REGN5713-5714-5715 (mean TNSS = 3.74) and placebo (mean TNSS = 
5.35), assuming a common standard deviation of 2.8. Assuming 10% dropout, 
approximately 73 participants per arm will be required to detect a difference 
of 1.61 in mean TNSS between REGN5713-5714-5715 (3-mAb) and placebo. 
Across all 4 treatment arms, the proposed sample size is approximately 300 
participants. 
This sample size is calculated at a 2-sided significance level of 5% using a 2-
sample t-test. Estimates of mean in placebo and variability of the TNSS are 
based on birch tree SLIT‐tablet data, and a 30% treatment effect relative to 
placebo is in line with what was observed in the phase 1b proof-of-concept 
(POC) study for REGN5713-5714-5715. 
Efficacy Analysis Sets 
The efficacy endpoints in Part A will be analyzed using the full analysis set 
(FAS), which consists of all randomized participants. The efficacy analysis 
set is based on the treatment allocated (as randomized).  
The efficacy endpoints in Part B will be analyzed using the modified FAS 
(mFAS), which consists of participants who receive study drug in Part B. 
Primary Efficacy Analysis Methods 
The average of TNSS (2 to 6 hours) in a birch allergen EEU at day 29 in Part 
A will be analyzed by an analysis of covariance (ANCOVA) model, with the 
treatment group and randomization stratification factors (oak allergy, grass 
sensitization, EEU site) as fixed effects and the baseline TNSS as a covariate.  
If any rescue treatments are taken during the EEU challenge, the data from 
this EEU will be set as missing and day 29 will be imputed by baseline 
observation carried forward (BOCF). Otherwise, all observed data will be 
used.  
Missing data will be imputed by multiple imputation (MI). Additional details 
will be specified in the SAP. 
Secondary Efficacy Analysis Methods 
The secondary continuous efficacy endpoints will be analyzed in a manner 
similar to that described above for the primary efficacy endpoint analysis 
unless further specified below.  
The intercurrent events, strategies, and the corresponding missing data 
handling approaches for the estimand for the continuous secondary efficacy 
endpoint from EEU challenges may be the same as for the primary endpoint 
with details to be provided in the SAP. 
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For the secondary endpoints from titrated SPT, if the antihistamines are not 
withheld before the titrated SPT, the data from this titrated SPT will be 
assigned by worst observation from the participant, including baseline.  
The proportions of participants achieving different degrees of clinical 
responses and change/percent change from pre-treatment baseline in TNSS (2 
to 6 hours), TOSS (2 to 6 hours), and TSS (2 to 6 hours) will be compared 
graphically using the cumulative distribution function. The AUC of the 
responder curves may also be calculated as a descriptive summary to compare 
across different symptom thresholds at days 29, 57, and 85 after receiving a 
single dose of REGN5713-5714-5715, REGN5713-5715, or REGN5715. 
Titrated SPT endpoints will be analyzed in a similar manner.  
Safety Analysis Set 
The safety analysis will be based on the safety analysis set (SAF), defined as 
all randomized participants who receive any study drug, regardless of the 
amount of treatment administered. The SAF is based on the treatment 
received (as treated).  
Safety Analysis Methods 
The safety variables, including AEs, laboratory parameters, vital signs, and 
physical examinations, will be summarized using descriptive statistics. 
Timing of Statistical Analyses 
The primary analysis may be performed after all participants complete at least 
the day 29 EEU challenges (visit 6) in Part A or discontinue. A select team 
will be unblinded to review the results but to ensure study integrity, the team 
members directly involved in the continued conduct of the trial will remain 
blinded.  
Final unblinded analyses of the study results for efficacy endpoints may be 
performed when all randomized participants have completed visit 14 (after 
end of birch pollen season). These will be considered the final analyses for 
the efficacy endpoints. Additional data between this database lock and last 
participant completing the last visit will be summarized in the clinical study 
report (CSR). 
 
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1. 
INTRODUCTION 
Birch-pollen-induced allergic rhinitis with or without conjunctivitis is common in Europe and 
North America, with clinically relevant sensitization to birch pollen affecting approximately 8% 
to 16% of the overall population (Chan-Yeung, 2010) (Salo, 2014) (Biedermann, 2019a) and 
approximately 20% to 30% of the population with allergic rhinitis (Burbach, 2009) (Galant, 1998) 
(Lin, 2002) (Pablos, 2016) (Sierra-Heredia, 2018). Regardless of the specific allergen, symptoms 
in allergic rhinoconjunctivitis include rhinorrhea, nasal congestion, nasal itching, sneezing, as well 
as ocular itching/redness/gritty feeling and eye tearing/watering. These symptoms can result in 
time away from work/school, medication usage, and overall reduced quality of life 
(Dykewicz, 2020) (Vandenplas, 2018) and similar is expected for patients with birch allergy. Birch 
pollen contains a mix of allergenic and non-allergenic proteins; Bet v 1 is the most abundant 
allergenic birch pollen protein (Erler, 2011) (Schenk, 2011). Sensitization rates to Bet v 1 among 
birch-allergic individuals reach >95% (Erler, 2011) (Jarolim, 1989) (Schenk, 2011).  
Antihistamines and intranasal corticosteroids (INCS) are standard of care for the treatment of 
allergic rhinoconjunctivitis regardless of the specific allergen inducing the symptoms, including 
for patients with birch pollen allergic disease. While the antihistamines are only modestly 
effective, INCS are more effective at treating nasal symptoms; however, they are less effective for 
allergic eye symptoms (Ciprandi, 2011) (Durham, 2016) (Dykewicz, 2020). Patients with 
uncontrolled symptoms on standard of care pharmacotherapy, including those with birch 
pollen-induced allergic rhinitis, are recommended allergen specific immunotherapy (SIT) 
(Dykewicz, 2020). Although disease-modifying, SIT can have several practical limitations 
including safety with a risk of local and systemic allergic reactions (including potentially 
life-threatening anaphylaxis), variable response and tolerability, challenges with time commitment 
and potential issues with poor patient adherence (Walker, 2011) (Zuberbier, 2010) (Cox, 2011) 
(Roberts, 2018). There is a need for new medications due to limitations of the current standards of 
care, such as antihistamines, INCS, and allergen immunotherapy.  
The Sponsor has demonstrated that high-affinity monoclonal “blocking antibodies” could be 
developed and administered as a form of “passive immunotherapy” for the treatment of allergy 
(Orengo, 2018) (Atanasio, 2022) (Gevaert, 2022). 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. Clinical symptom improvement 
has been shown to correlate with the ability of blocking IgG4s to compete with IgE for 
allergen-binding for some allergens during SIT (James, 2011) (Uermosi, 2010), and similarly 
expected for other allergens including birch.  
The REGN5713-5714-5715 treatment includes a combination of 3 human monoclonal antibodies 
(mAbs) that specifically target Bet v 1, the major birch tree allergen. Preclinical data indicate that 
all 3 mAbs are required to maximally inhibit binding of Bet v 1 to human polyclonal IgE, reduce 
in vitro effector cell degranulation, and subsequent Type 1 hypersensitivity reaction 
(Atanasio, 2022). REGN5713-5714-5715 was most effective in blocking Bet v 1 binding to 
polyclonal human IgE and inhibiting Bet v 1- or birch pollen extract-induced basophil activation. 
REGN5713-5715 was the best dual antibody cocktail when compared to REGN5713-5714 or 
REGN5714-5715, but less efficient than REGN5713-5714-5715 across all assays. REGN5715 
single mAb achieved the highest median percent blocking in-vitro as compared to REGN5713 or 
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REGN5714. In a humanized Passive Cutaneous Anaphylaxis mouse model, using human plasma 
containing polyclonal birch specific-IgE, REGN5713-5714-5715 achieves 90% blockade of mast 
cell degranulation in 4/5 donors evaluated while REGN5713-5715 achieves the same magnitude 
of blockade in only 1/5 donors evaluated. As compared with the single mAb or double mAb 
combination, these data suggest that greater blockade of Bet v 1-induced allergy may be achieved 
with REGN5713-5714-5715 triple antibody cocktail.  
Structural data show that simultaneous binding of REGN5713 and REGN5715 leaves more than 
half of the surface area of Bet v 1 exposed (Atanasio, 2022). REGN5714 binds in one exposed 
region, but cannot cover all of it, suggesting that it is not necessary to mask 100% of the allergen 
surface with an antibody cocktail in order to achieve robust blocking potency. Rather, 
identification and blockade of immunodominant IgE binding epitopes can achieve maximal 
blockade of the birch allergic response across a diverse and polyclonal birch allergic population. 
Taken together, the combinations of REGN5713, REGN5714, and REGN5715 that were selected 
for clinical studies represent the combinations most likely to succeed clinically based on preclinical 
data. 
The first-in-human study (R5713-5714-5715-HV-1857), a 2-part, phase 1, randomized, double-
blind, placebo-controlled study of the 3-mAb cocktail (REGN5713-5714-5715), was conducted in 
96 healthy subjects. Part A was an ascending dose-escalation study in 32 healthy subjects 
randomized to receive either a single dose of REGN5713-5714-5715 150 mg subcutaneous (SC), 
450 mg SC, 900 mg SC, or 900 mg intravenous (IV) or placebo. REGN5713-5714-5715 had a 
favorable safety profile and was well-tolerated for 3 months post-dose in Part A, which was the 
follow-up period for Part A of the study (Gevaert, 2022). Part B was a proof-of-concept (POC) 
study, conducted in generally healthy subjects with birch allergy (N=64), randomized 1:1 to 
REGN5713-5714-5715 or placebo. 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 
at all time points assessed, days 8, 29, and 57, resulting in a 32%, 27%, and 19% improvement 
relative to placebo in percent change from baseline in Total Nasal Symptom Score (TNSS) area 
under the curve (AUC) (hour 0 to 1), respectively (achieved nominal statistical significance 
compared with placebo at every time point except day 57). These data demonstrate 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) with serial dilutions of birch allergen was 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 systemic 
hypersensitivity observed.  
A 
phase 
3, 
randomized, 
double-blind, 
placebo-controlled 
clinical 
study 
(R5713-5714-5715-ALG-2001) in 353 birch-allergic participants has been completed. The 
primary endpoint, daily Combined Symptom and Medication Score (CSMS [TSS+DMS]), 
averaged over the duration of birch pollen season, met statistical significance. Numerical 
improvements were observed in TNSS, Total Ocular Symptom Score (TOSS), Daily Medication 
Score (DMS), and Total Symptom Score (TSS [TNSS+TOSS]); these improvements were more 
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pronounced during peak season and for participants dosed ahead of the birch season. Robust 
suppression of skin prick test to birch (and birch-related allergens) was observed in the overall 
population. REGN5713-5714-5715 900 mg was well tolerated in this subject population. The 
majority of TEAEs were mild or moderate in intensity and resolved without sequelae. The 
incidence of SAEs was low and none were deemed related to REGN5713-5714-5715; there were 
no deaths or adverse events of special interest (AESIs; no severe or systemic hypersensitivity 
reactions or severe injection site reactions). No new safety signal was observed and overall, 
REGN5713-5714-5715 900 mg SC had a favorable safety profile. 
Taken together, these clinical studies, during experimental and natural exposure to birch pollen, 
support the use of REGN5713-5714-5715 in the prevention of allergic symptoms in patients with 
birch pollen allergy upon exposure to birch pollen. The main purpose of this study is to confirm 
that a combination of all 3 antibodies is required for maximal treatment effect due to broader 
epitope coverage when 3 antibodies are utilized together.  
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure.  
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary Objective and Endpoint 
The primary objective and endpoint of the study are outlined below: 
Primary Objective 
Primary Endpoint 
To assess the efficacy of a single dose of the 
anti-Bet v 1 monoclonal antibodies in the reduction 
of allergic nasal symptoms during an out-of-season 
birch allergen environmental exposure unit (EEU) 
challenge in participants receiving REGN5713-
5714-5715 versus placebo (Part A) 
The mean of Total Nasal Symptom Score [TNSS 
(2 to 6 hours)] during a birch allergen EEU 
challenge at day 29 
2.2. 
Secondary Objectives and Endpoints 
The secondary objectives and endpoints of the study are outlined below: 
Secondary Objectives 
Secondary Endpoints 
• 
To assess the magnitude and duration of 
efficacy of a single dose of the anti-Bet v 1 
monoclonal antibodies (dose #1) in the 
reduction of allergic symptoms during the out-
of-season birch allergen EEU challenges in 
participants receiving REGN5713-5714-5715 
versus 
placebo, 
REGN5713-5715 
versus 
placebo, and REGN5715 versus placebo (Part 
A) 
• 
The 
mean 
of 
symptom 
scores 
during 
out-of-season birch allergen EEU challenges at 
days 29, 57, and 85 
o TNSS (2 to 6 hours) (except day 29 for 
3-mAb) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
The 
change 
and 
percent 
change 
from 
pre-treatment baseline in symptom scores 
during out-of-season birch allergen EEU 
challenges at days 29, 57, and 85 
o TNSS (2 to 6 hours) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
To assess the efficacy of the anti-Bet v 1 
monoclonal antibodies (dose #1) in the 
reduction 
of 
skin 
test 
reactivity 
from 
pre-treatment baseline by inhibiting a wheal 
response to a titrated skin prick test with birch 
and related allergens (eg, alder, oak) during out-
of-season assessments in participants who 
receive REGN5713-5714-5715 versus placebo, 
REGN5713-5715 
versus 
placebo, 
and 
REGN5715 versus placebo (Part A) 
• 
The 
change 
and 
percent 
change 
from 
pre-treatment baseline at days 29, 57, 85, and 
127 in the birch (and related allergens) titrated 
SPT mean wheal diameter AUC 
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Secondary Objectives 
Secondary Endpoints 
• 
To assess the efficacy of a single dose of the 
anti-Bet v 1 monoclonal antibodies (dose #1) in 
the reduction of allergic symptoms during the 
out-of-season oak allergen EEU challenge in the 
subpopulation of oak allergic participants in 
those receiving REGN5713-5714-5715 versus 
placebo, REGN5713-5715 versus placebo, and 
REGN5715 versus placebo (Part A) 
• 
The 
mean 
of 
symptom 
scores 
during 
out-of-season oak allergen EEU challenge at 
day 36 
o TNSS (2 to 6 hours) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
The 
change 
and 
percent 
change 
from 
pre-treatment baseline in symptom scores 
during an oak allergen EEU at day 36 in 
subpopulation of oak-allergic participants 
o TNSS (2 to 6 hours) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
To compare differences in the degree of 
reduction of allergic symptoms during the out-
of-season EEU challenges in participants 
receiving the different combinations of the 
anti-Bet v 1 antibodies in those receiving 
REGN5713-5714-5715, REGN5713-5715, or 
REGN5715 (Part A) 
• 
The 
mean 
of 
symptom 
scores 
during 
out-of-season birch allergen EEU challenges at 
days 29, 57, and 85 
o TNSS (2 to 6 hours)  
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
The 
change 
and 
percent 
change 
from 
pre-treatment baseline in symptom scores 
during out-of-season birch allergen EEU 
challenges at days 29, 57, and 85 
o TNSS (2 to 6 hours) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
The proportions of participants achieving 
different degrees of clinical responses will be 
compared across different symptom response 
thresholds at days 29, 57, and 85 
o TNSS (2 to 6 hours) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
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Secondary Objectives 
Secondary Endpoints 
• 
To compare differences in the degree of 
reduction 
of 
skin 
test 
reactivity 
from 
pre-treatment baseline by inhibiting a wheal 
response to a titrated skin prick test with birch 
and related allergens (eg, alder, oak) during out-
of-season assessments in participants receiving 
the different combinations of the anti-Bet v 1 
antibodies in those receiving REGN5713-
5714-5715, REGN5713-5715, or 
REGN5715 
(Part A) 
• 
The proportions of participants achieving 
different degrees of responses in the birch (and 
related allergens) titrated SPT mean wheal 
diameter AUC will be compared across 
different response thresholds at days 29, 57, and 
85  
• 
To assess the efficacy of the anti-Bet v 1 
monoclonal antibodies (dose #2) in the 
reduction of allergic symptoms during the in-
season birch allergen EEU challenge in 
participants receiving REGN5713-5714-5715 
versus 
placebo, 
REGN5713-5715 
versus 
placebo, and REGN5715 versus placebo (Part 
B) 
• 
The mean of symptom scores during the peak-
season birch allergen EEU challenge 
o TNSS (2 to 6 hours) 
o TOSS (2 to 6 hours) 
o TSS (2 to 6 hours) 
• 
To determine the efficacy of the anti-Bet v 1 
monoclonal antibodies (dose #2) in the 
reduction of allergic symptoms during the birch 
pollen season and peak birch pollen season in 
participants receiving REGN5713-5714-5715 
versus 
placebo, 
REGN5713-5715 
versus 
placebo, and REGN5715 versus placebo (Part 
B) 
• 
The daily symptom and medication scores, 
averaged during the BPS and peak BPS 
o CSMS, TSS, TNSS, TOSS, and DMS, 
averaged during the BPS  
o CSMS, TSS, TNSS, TOSS, and DMS, 
averaged during the peak BPS 
 
• 
The change and percent change from baseline in 
the symptom and medication scores, averaged 
during the BPS and peak BPS 
o CSMS, TSS, TNSS, TOSS, and DMS, 
averaged during the BPS  
o CSMS, TSS, TNSS, TOSS, and DMS, 
averaged during the peak BPS 
• 
To determine the efficacy of the anti-Bet v 1 
monoclonal antibodies (dose #2) in the 
reduction 
of 
skin 
test 
reactivity 
from 
pre-treatment baseline by inhibiting a wheal 
response to a titrated skin prick test with birch 
and related allergens (eg, alder, oak) after the 
natural birch pollen season in participants who 
receive REGN5713-5714-5715 versus placebo, 
REGN5713-5715 
versus 
placebo, 
and 
REGN5715 versus placebo (Part B) 
• 
The 
change 
and 
percent 
change 
from 
pre-treatment baseline to end-of-season and 
end-of-study (EOS) visits in the birch (and 
related allergens) titrated SPT mean wheal 
diameter AUC 
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Secondary Objectives 
Secondary Endpoints 
• 
To assess health-related quality of life during 
the BPS and peak BPS in participants who 
receive REGN5713-5714-5715 versus placebo, 
REGN5713-5715 
versus 
placebo, 
and 
REGN5715 versus placebo 
• 
The mean of the total Rhinoconjunctivitis 
Quality of Life Questionnaire (RQLQ[S]) score 
during BPS and peak BPS 
o RQLQ(S), averaged during the BPS and 
peak BPS 
o Change and percent change from baseline in 
the average RQLQ(S) during the BPS and 
peak BPS 
• 
To evaluate the safety and tolerability of the 
anti-Bet v 1 monoclonal antibodies as compared 
to placebo following single administration (dose 
#1) and after repeat dosing (dose #2) 
• 
Incidence rates of treatment-emergent adverse 
events (TEAEs) and serious TEAEs through 
end of study 
• 
To determine systemic concentrations over time 
of total antibody (free + antigen-bound) for each 
of 
the 
individual 
mAbs: 
REGN5713, 
REGN5714, and REGN5715 at various time 
points following single administration (dose #1) 
and after repeat dosing (dose #2) 
• 
Total REGN5713, REGN5714, REGN5715 
concentration in serum over the duration of the 
study 
• 
To assess the immunogenicity of REGN5713, 
REGN5714, and REGN5715 in birch-allergic 
participants following single administration 
(dose #1) and after repeat dosing (dose #2) 
• 
Incidences and titers of ADA to REGN5713, 
REGN5714, and REGN5715 over time 
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2.3. 
Exploratory Objectives and Endpoints 
The exploratory objectives and endpoints of the study are: 
Exploratory Objectives 
Exploratory Endpoints 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exploratory Objectives 
Exploratory Endpoints 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Exploratory Objectives 
Exploratory Endpoints 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
Part A Hypotheses:  
• A single dose of a cocktail of 3 anti-Bet v 1 monoclonal antibodies 
(REGN5713-5714-5715) is more effective than placebo in the reduction of allergic nasal 
symptoms in a birch allergen EEU and in the reduction of skin test reactivity. 
• A single dose of a cocktail of 2 anti-Bet v 1 monoclonal antibodies (REGN5713-5715) is 
more effective than placebo in the reduction of allergic nasal symptoms in a birch allergen 
EEU and in the reduction of skin test reactivity. 
• A single dose of a single monoclonal antibody (REGN5715) is more effective than placebo 
in the reduction of allergic nasal symptoms in a birch EEU and in the reduction of skin test 
reactivity. 
• A single dose of the 3 anti-Bet v 1 monoclonal antibodies (REGN5713-5714-5715) is more 
effective than the cocktail of 2 anti-Bet v 1 monoclonal antibodies (REGN5713-5715) and 
single REGN5715 mAb in a birch EEU as indicated by a numerically greater treatment 
effect across different endpoints (including allergic nasal and ocular symptoms as well as 
skin test reactivity), in addition to a higher proportion of participants achieving greater 
responses across different thresholds for these endpoints.  
• Similarly, a single dose of the cocktail of 2 anti-Bet v 1 monoclonal antibodies 
(REGN5713-5715) is more effective than the single monoclonal antibody (REGN5715) in 
a birch EEU as indicated by a numerically greater treatment effect across different 
endpoints, in addition to a higher proportion of participants achieving greater responses 
across different endpoint thresholds.  
Part B Hypotheses:  
• REGN5713-5714-5715 is more effective than placebo in the reduction of allergic 
symptoms during the natural birch pollen season and in the reduction of skin test reactivity 
to birch allergen. 
• REGN5713-5715 is more effective than placebo in the reduction of allergic symptoms 
during the natural birch pollen season and in the reduction of skin test reactivity to birch 
allergen. 
• REGN5715 is more effective than placebo in the reduction of allergic symptoms during 
the natural birch pollen season and in the reduction of skin test reactivity to birch allergen. 
• REGN5713-5714-5715 is more effective than REGN5713-5715 and REGN5715 during 
the natural birch pollen season as indicated by a numerically greater treatment effect across 
different endpoints in-season as well as higher proportion of participants achieving greater 
responses across these endpoint thresholds (including nasal and ocular symptoms, allergy 
medication use, and skin test reactivity).  
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• Similarly, REGN5713-5715 is more effective than REGN5715 during the natural birch 
pollen season as indicated by a numerically greater treatment effect across different 
endpoints in-season as well as higher proportion of participants achieving greater responses 
across these endpoint thresholds.  
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
R5713-5714-5715-ALG-21111 is a 2-part randomized, double-blind, placebo-controlled study in 
birch-allergic participants to assess the efficacy of the anti-Bet v 1 monoclonal antibodies. The 
study will assess the efficacy of the anti-Bet v 1 monoclonal antibodies, in combination (the 3-mAb 
and the best 2-mAb) and as a single best antibody (REGN5713-5714-5715, REGN5713-5715, and 
REGN5715). The efficacy will be tested out-of-season (Part A) as well as in-season (Part B) to 
fully evaluate treatment effects during experimental exposure to the allergen but also explore them 
during real-world exposure to birch and other related/ unrelated pollens during the birch pollen 
season.  
Day 29 was chosen as the primary endpoint as a period of expected maximum efficacy, also 
anticipated to coincide with approximate timing for the peak pollen season. Treatment effects will 
be evaluated at different out-of-season time points to ensure adequate coverage during an expected 
natural season accounting for the potential variability between timing of dosing relative to the start 
of the natural birch pollen seasons and also the year-to-year variability in the length and timing of 
the birch pollen seasons (Biedermann, 2019c) (Lo, 2019). 
Primary efficacy analyses may be performed after all participants complete at least the day 29 EEU 
challenges or discontinue (Section 10.4.3). Participants will receive the same treatment in Part B 
that they were originally randomized to receive in Part A (Section 7.5). Additionally, efficacy and 
safety of repeat dosing of the antibodies will be evaluated during the birch pollen season.  
A combination of pre-specified endpoints in Part A (Section 10.4.3) will be used to delineate the 
contribution of components.  
Rationale for the 2-Part “Hybrid” EEU and Field Study Design to Assess the Efficacy of the 
Anti-Bet v 1 Monoclonal Antibodies in the Reduction of Clinical Symptoms and Skin Test 
Reactivity 
Part A of this study employs the classic, phase 2, out-of-season EEU design to assess the primary 
and secondary endpoints to compare the efficacy of the anti-Bet v 1 mAb(s) in combination and 
as a single mAb (REGN5713-5714-5715 versus placebo, REGN5713-5715 versus placebo, and 
REGN5715 versus placebo), to reduce allergic rhinitis and conjunctivitis symptoms in 
birch-allergic participants. Skin test reactivity to birch and related allergens will be tested by the 
inhibition of the SPT mean wheal diameter to serial titrations of birch and related allergens.  
Part B of this study uses a hybrid design to incorporate both a “field study” and EEU challenges 
during the peak and end of natural birch season to examine the correlation between the treatment 
effect of the anti-Bet v 1 antibodies (REGN5713-5714-5715 and REGN5713-5715) on symptoms 
elicited in the EEU and the treatment effects on symptoms and medication use observed in the 
natural season. The in-season portion (Part B) allows for assessment of efficacy during continuous 
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and variable pollen exposures during the natural birch season (and overlapping other related and 
unrelated tree pollens) using a combination of chamber and field assessments. Similarly, the 
inhibition of skin test reactivity will be tested during the natural birch season and a 
within-participant comparison during out-of-season and in-season assessments.  
The same anti-allergic therapies will be investigated in the EEU outside of birch pollen season, 
during a natural birch pollen season, as well as in the EEU during the peak and end of the birch 
pollen season, for direct comparability of the treatment effect of REGN5713-5714-5715 in 
different birch pollen exposures in the same subject population.  
Traditionally, phase 2 EEU studies have been utilized to confirm dose selection and test efficacy 
of anti-allergic therapies (Biedermann, 2019b) (Couroux, 2009) (Didier, 2011) (Horak, 2009) 
(Nolte, 2016) (Nolte, 2015). Field studies can have large geographic variability in pollen exposures 
compounded by the limited ability to predict local seasonal and climate changes (Zhang, 2022) in 
addition to individual differences in exposures. Data indicate that the magnitude of treatment effect 
is impacted by degree of pollen exposures (Durham, 2014), which highlight the challenges in field 
studies. The current COVID-19 pandemic has also imposed several challenges and restrictions in 
activities, as well as mask mandates in recent times that have complicated field assessments of 
symptoms in the short term (Bergmann, 2021). Alternatively, field studies may be integrated into 
EEU studies as “hybrid” trials, to potentially demonstrate clinical efficacy for novel therapies with 
fewer participants with shorter timelines, but more importantly, allowing the interpretation of 
efficacy in both controlled allergen exposures, as well as real-world field-based assessments 
(Ellis, 2021a). To support a goal to use EEU studies as an adjunct to field studies, investigators 
have published data demonstrating that there is a high correlation between allergic symptoms 
elicited in the EEU and in the field (Jacobs, 2011) (Jacobs, 2014), that EEUs can be performed 
both in season and out-of-season (Badorrek, 2011) (Ellis, 2021b), and that 2 EEUs can be used 
together in dual-center clinical trials (Ellis, 2019), in addition to assessing different allergens 
sequentially in EEU trials (Couroux, 2019). 
Furthermore, testing of REGN5713-5714-5715, REGN5713-5715, and REGN5715 out-of-season 
and in-season, both in chamber and field settings, provides a comprehensive approach to the 
evaluation of these anti-Bet v 1 antibodies. 
Skin Prick Test Endpoints Support the Evaluation of the Anti-Bet v 1 Antibodies 
Development of allergen-specific polyclonal IgE antibodies is considered a hallmark of allergen 
“sensitization” (Flicker, 2003) (Murphy, 2017). A larger wheal size showing a greater degree of 
sensitization significantly increases the risk of having symptoms. This has also been demonstrated 
specifically for birch allergen (Haahtela, 2014) suggesting the relevance of the SPT wheal size in 
predicting clinical allergy with the likelihood of developing symptoms.  
The SPT assesses the immediate early phase IgE-mediated allergic response in the skin that is 
induced by mast cell degranulation after challenge with an allergen via skin prick in previously 
sensitized allergic subjects (Burks, 2019) (Friedman, 1988). As such, SPT is a highly sensitive, 
objective, easy-to-perform test to determine allergic sensitization, and in addition to its wide use 
diagnostically, it has been used to help understand the pathophysiology of the allergic response 
(Burks, 2019) and to evaluate the mechanisms of action of several anti-allergy therapeutics 
(Persi, 1999) (Frossard, 2008).  
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As expected, and in line with the mechanism of action of these anti-Bet v 1 antibodies, data from 
the first-in-human (FIH) study and phase 3 study show robust suppression of the SPT mean wheal 
diameter in participants treated with the anti- Bet v 1 antibodies (REGN5713-5714-5715). 
Corresponding to the reduction in TNSS seen in the FIH study at days 8, 29, and 57, 
REGN5713-5714-5715 inhibited a titrated SPT to birch allergen also as early as day 8 (earliest 
time point tested) and sustained on days 29, 57, and 113 (last time point tested). Similarly, there 
was robust SPT inhibition to alder, a birch related allergen. These data suggest that 
REGN5713-5714-5715 inhibits type I, immediate, IgE-mediated response compared to placebo. 
Similar to clinical endpoints, it is expected that the inhibition of SPT reactivity using a titrated 
SPT to serial dilutions of birch allergen will support the assessment the contribution of 
components. Therefore, the mechanism of action and clinical data support the use of the SPT test 
endpoints as an objective biomarker to test activity of the anti-allergen antibodies.  
3.2.2. 
Rationale for Dose Selection 
In Part A, a single SC dose of REGN5713-5714-5715 900 mg (300 mg per mAb), a single SC dose 
of REGN5713-5715 600 mg (300 mg per mAb), and a single SC dose of REGN5715 (300 mg), 
plus a matching placebo group are proposed. Participants will receive the same treatment in Part B 
that they were originally randomized to receive in Part A (Section 7.5).  
Clinical Experience and Rationale to Support Proposed Dose 
The proposed dose for this study is supported by the results of the phase 1b POC study, (Part B of 
the FIH study), which was conducted in healthy, birch-allergic participants, and the phase 3 field 
study conducted in birch allergic participants. In both studies, participants received 300 mg/mAb 
of REGN5713-5714-5715. In the FIH study, this dose was able to reduce allergic rhinitis 
symptoms for at least 2 months following periodic nasal allergen challenges with Bet v 1 pollen. 
In the phase 3 study, this dose was able to reduce (improve) CSMS during the birch pollen season.  
In addition to demonstrating effects on allergic rhinitis symptoms, 300 mg/mAb 
(REGN5713-5714-5715) was well-tolerated in both studies, with TEAEs generally of mild to 
moderate severity, and occurring in similar rates in the placebo and REGN5713-5714-5715 
treatment groups. Additionally, no participant developed treatment-emergent or treatment-boosted 
anti-drug antibodies (ADA) following administration of REGN5713-5714-5715 in either study.  
The pharmacokinetics (PK) of REGN5713-5714-5715 are consistent in both clinical studies, 
exhibiting linear, dose-proportional PK with a half-life of 26.9, 34.0, and 35.1 days for 
REGN5713, REGN5714, and REGN5715, respectively. Dose #2 in Part B of this study is expected 
to be administered at least 12 weeks from dose #1 in Part A. The dosing interval in this study is 
primarily driven by timing of participant enrollment and the pollen season while ensuring 
accumulation of study drug is within exposure (Cmax and AUC) observed in the FIH study 
following 300 mg/mAb IV dosing. With a minimum dosing interval of 12 weeks, accumulation of 
REGN5713-5714-5715 is expected to be approximately 15% between dose #1 and dose #2 and is 
predicted to be within the Cmax and AUC that were measured in the FIH trial following 
administration of 300 mg/mAb IV, which showed a favorable safety profile. Additionally, analysis 
of the concentration-response relationship between concentrations of REGN5713-5714-5715 and 
various clinical endpoints has shown consistent responses across a range of concentrations. 
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Additional information on clinical and preclinical PK, PD, and safety can be found in the 
Investigator’s Brochure. 
Based on the above summary of safety, PK, and PD data, a dose of 300 mg/mAb mg SC is expected 
to provide efficacy in an EEU setting, as well as in the field setting.  
3.3. 
Risk-Benefit 
REGN5713, REGN5714, and REGN5715 are 3 human mAbs of the IgG4 isotype that specifically 
bind to Bet v 1, the major birch tree allergen, with high affinity and at distinct epitopes 
(Atanasio, 2022). Preclinical data indicate that all 3 mAbs are required to maximally inhibit 
binding of Bet v 1 to human polyclonal IgE, reduce in vitro effector cell degranulation and 
subsequent Type 1 hypersensitivity reaction.  
The FIH study (R5713-5714-5715-HV-1857) was a 2-part phase 1, randomized, double-blind, 
placebo-controlled study of the 3-mAb cocktail (REGN5713-5714-5715) in 96 healthy 
participants (32 healthy subjects without birch allergy in part A and 64 subjects with birch pollen 
allergy in part B) (Gevaert, 2022). Part A demonstrated that doses up to 900 mg (300 mg/mAb) of 
REGN5713-5714-5715 administered via SC or IV were generally well tolerated. Part B was a 
nasal allergen challenge study in birch allergic healthy participants, which showed 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. These results 
suggest that a single 900 mg SC dose of REGN5713-5714-5715 reduced allergic rhinitis symptoms 
upon birch allergen exposure for as long as 2 months (last time point evaluated), the approximate 
duration of a typical birch pollen season.  
The phase 3 field study (R5713-5714-5715-ALG-2001) in adults with birch pollen-induced 
allergic rhinitis with or without conjunctivitis demonstrated a reduction in the combined symptom 
and medication composite score in birch allergic participants during birch pollen season in 
participants treated with REGN5713-5714-5715 versus placebo. While the numerical reductions 
seen in TNSS, TOSS, DMS, and TSS did not meet statistical significance in the overall population, 
in post-hoc analyses, the efficacy improved and most of these endpoints showed nominally 
significant results during peak season as well for participants dosed ahead of the season. Similar 
to the FIH study, a robust suppression of SPT reactivity to birch (and birch related allergens) was 
observed in the overall population. 
REGN5713-5714-5715 has been administered as a single dose to 229 healthy adult study 
participants in studies completed to date (24 healthy subjects without known birch allergy and 205 
subjects with known birch allergy) with no significant clinical safety findings observed including 
no deaths, cases of systemic hypersensitivity, or anaphylaxis. No severe injection site reactions 
were noted. No important identified risks have been established with REGN5713-5714-5715 
administration. The important potential risks with REGN5713-5714-5715 (based on preclinical 
evaluation, mechanism of action targeting an exogeneous antigen, and risks associated with mAbs 
in 
general) 
include 
systemic 
hypersensitivity 
reactions 
and 
immunogenicity. 
REGN5713-5714-5715 has been generally well tolerated and risks have been adequately managed. 
To date, no significant safety information with regard to the important potential risks of systemic 
hypersensitivity reactions or immunogenicity has been reported. Currently, the available safety 
data along with the risk minimization and monitoring activities support the continued development 
of REGN5713-5714-5715. 
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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.  
A safety monitoring team internal to the sponsor will monitor blinded safety data on an ongoing 
basis to assess the risk-benefit profile of REGN5713-5714-5715. Additionally, an Independent 
Data Monitoring Committee (IDMC) will be involved in the review of unblinded data in an 
ongoing manner (Section 5.3.1). 
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 participants 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 participants 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. 
For information regarding the permitted timing of COVID-19 vaccinations, see Section 7.9.2.  
Taken together, these clinical studies during experimental and natural exposure to birch pollen and 
a favorable safety profile support a positive benefit-risk assessment of REGN5713-5714-5715 in 
subjects with birch pollen allergy. The treatment with anti-Bet v 1 antibodies may offer a rapid 
and potentially effective approach for the treatment of birch pollen allergy. 
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4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc), 
medical history (including characterization of allergy and asthma history), medication history, SPT 
for birch, birch-related and other common allergens, titrated SPT for birch and related allergens, 
allergen-specific IgE levels, and total IgE, for each participant. Baseline screening EEU challenges 
to birch will provide baseline nasal and ocular symptoms for determining eligibility and the 
baseline screening EEU challenge to oak will characterize oak allergy status. Screening baseline 
assessment will evaluate daily nasal and ocular symptom and medication scores during screening.  
4.2. 
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). In addition, the mean wheal diameter 
of birch and related allergen titrated SPT, RQLQ(S) parameters, Pollen Food Allergy Symptom 
Questionnaire (PFASQ) parameters, and outdoor time questionnaire parameters will be evaluated.  
4.3. 
Safety Variables 
Safety variables include vital signs, physical examination findings, adverse events, spirometry, 
and laboratory safety tests.  
4.4. 
Pharmacokinetic Variables 
The PK variables are the concentrations of total REGN5713, REGN5714, and REGN5715 in 
serum at each time point as specified in Table 1. 
4.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, and time-point/visit. Samples in this study 
will be collected at the clinic visits specified in Table 1.  
4.6. 
Pharmacodynamic and Other Biomarker Variables 
Exploratory biomarker variables may include, but are not limited to, 
 
 
. 
These results may be reported outside of the clinical study report (CSR) as a part of exploratory 
research analyses. 
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5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
REGN5713-5714-5715-ALG-21111 is a 2-part randomized, double-blind, placebo-controlled 
study in birch-allergic participants to assess the efficacy of the anti-Bet v 1 monoclonal antibodies. 
The study consists of 2 parts for a total study duration of up to approximately 46 weeks (including 
up to a 10-week screening period) (Figure 1). Part A of the study lasts up to approximately 28 
weeks (including the screening period). Part B of the study starts after completion of Part A and 
lasts up to approximately 18 weeks (including an approximately 4-week follow-up period after 
end of birch pollen season), dependent on the start and end times of the natural BPS.  
The study will assess the efficacy of the anti-Bet v 1 monoclonal antibodies, in combination and 
as a single antibody. Efficacy in the reduction of allergic rhinitis and conjunctivitis symptoms as 
well as birch skin test reactivity will be tested using assessments out-of-season (Part A: EEU 
challenges and titrated skin prick testing) and during the birch pollen season (Part B: EEU 
challenges, field assessments, and titrated skin prick testing). Participants will receive 2 doses of 
the study drug: a dose at randomization outside of the BPS (dose #1; Part A) and a dose of the 
study drug in Part B ahead of the anticipated BPS (dose #2; Part B). The efficacy will be tested 
out-of-season as well as in-season to fully evaluate treatment effects during experimental exposure 
to the allergen and during natural exposure to birch and other related/ unrelated pollens during the 
BPS.  
 
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Figure 1: 
Study Flow Diagram 
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Part A Overview: 
In Part A (out-of-season), participants will be randomized to 1 of 4 arms and receive a dose of 
either REGN5713-5714-5715 (3-mAb), REGN5713-5715 (2-mAb), REGN5715 (1-mAb), or 
matching placebo. Part A will assess whether a dose of either a monotherapy or a combination(s) 
of anti-Bet v 1 monoclonal antibodies (REGN5715, REGN5713-5715, REGN5713-5714-5715) 
demonstrates a greater reduction in TNSS than placebo in a birch EEU. Clinical efficacy in the 
EEU when exposed to oak allergen will also be tested for the anti-Bet v 1 monoclonal antibodies 
in the subpopulation of participants who are oak-allergic to determine if there is a treatment effect 
to another important North American pollen with similar epitopes as the birch pollen, given the 
shared homology. Additionally, the efficacy of the anti-Bet v 1 monoclonal antibodies in the 
reduction of skin test reactivity to birch and related allergens will be assessed using titrated skin 
prick testing and to determine the relationship of the symptom endpoints to the biomarker 
endpoints.  
Primary efficacy will be assessed during the out-of-season birch allergen EEU challenge on day 29 
after birch-allergic participants receive a dose of the study drug on day 1. Additionally, efficacy 
may be tested up to day 85 to ensure durability of the response through these time points. Primary 
analyses may be performed after all participants complete at least day 29 EEU challenges or 
discontinue.  
Part B Overview: 
In Part B (in-season), participants will receive a dose (dose #2) of the study drug (monoclonal 
antibody[ies] or placebo) administered ahead of the anticipated birch pollen season (determined 
using historical local pollen data), that is intended as a single dose for coverage of the entire birch 
season.  
Pollen counts will be monitored during the study period. 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. The OPS will be similarly defined.  
After completion of all Part A assessments outside of the BPS, participants start Part B of the study 
prior to the start of the BPS. Dosing in Part B of the study will begin at least 12 weeks from study 
drug dosing in Part A (Section 3.2.2). Participants will receive study drug (dose #2) ahead of the 
anticipated BPS (dosing window 0 to 3 weeks prior to the anticipated start of the BPS), which is 
intended as a single dose for coverage of the entire birch season. Dosing is expected to occur at 
least 12 weeks after initial dose in Part A, depending on the projected start of the local birch pollen 
season.  
To allow comparability of the within-subject treatment effect of the anti-Bet v 1 antibodies across 
different time points, the same anti-allergic therapies will be investigated in the same participant 
population during out-of-season and in-season exposures to birch allergen in the EEU as well as 
field settings. This will help reduce any potential impact of any potentially remaining active study 
drug from Part A on Part B on the placebo treatment effects in Part B. Participants will receive the 
same treatment in Part B that they were originally randomized to receive in Part A. 
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Part B will assess whether the anti-Bet v 1 antibodies, administered just prior to the start of the 
BPS, reduces allergic rhinitis and conjunctivitis symptoms during the birch pollen season as 
compared to placebo. Given the variable nature of exposure to birch and related pollens during the 
natural season, in-season birch allergen EEU challenges will be conducted at the peak and end of 
the birch season to evaluate and compare the treatment effects seen during the birch season. Field 
assessments with daily records of nasal and ocular symptom scores, allergy-relieving rescue 
medication scores as well as weekly rhinoconjunctivitis quality of life scores will be evaluated 
during the entire BPS. Similar to Part A, the efficacy of the anti-Bet v 1 mAbs in the reduction of 
skin test reactivity to birch and related allergens will be tested in-season using titrated skin prick 
testing. Part B allows for assessment of efficacy during continuous natural pollen exposures 
(exposure to birch allergen as well as other overlapping related and unrelated tree pollens) using a 
combination of chamber and field assessments. 
Within-participant differences will be evaluated at the different time points during the out-of-
season and in-season challenges and also correlated with the field assessments. A correlation of 
the peak in-season EEU efficacy with the daily symptoms recorded during the peak BPS and entire 
BPS will also be informative. 
Part A Study Periods: 
As outlined above in Figure 1, study Part A consists of a screening period, randomization, an 
on-treatment efficacy assessment period, and a primary data analysis. These study periods are 
described below.  
• Screening period: Up to 10 weeks with screening birch and oak challenges. Daily 
symptom and medication scores will be obtained during the screening baseline 
assessment for approximately 2 weeks or longer (at minimum 1 week) until 
randomization in eligible participants starting after the screening birch EEU challenge 
• Randomization: 1:1:1:1 to 1 of 4 arms 
Screening: Healthy male and female participants, age 18 years of age and older, with a history of 
birch pollen allergy for at least 2 years will undergo screening visits outside of BPS. There is an 
up to 14-week screening period, including an out-of-season screening EEU exposure to birch 
allergen, to determine eligibility. In eligible participants, oak allergen EEU challenge will be 
performed during screening to identify a subpopulation of oak-allergic participants.  
• During the first screening visit, participants will review and sign the informed consent, 
undergo a medical history, allergy history, medication history, physical examination, 
ECG, vital signs, birch allergen extract SPT, and blood will be drawn for serum for 
birch and Bet v 1-specific IgE, spirometry, standard SPT (such as dust mites, grass, 
other related and unrelated trees, cat, dog, etc), laboratory testing, complete baseline 
assessments, and be evaluated for the remainder of the study eligibility criteria.  
• Participants who meet all other inclusion and do not meet any exclusion criteria 
assessed at visit 1, will proceed to visit 2 for the screening birch EEU challenge. Using 
an e-diary, participants will record symptom scores (TNSS and TOSS) at baseline, and 
then at frequent time points while in the screening EEU. Participants must attain at least 
a TNSS ≥6 at 2 time points during the screening EEU exposure to be included in the 
study. Achieving the symptom threshold in the screening EEU challenge is required to 
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demonstrate that the participant has moderate to severe rhinitis symptoms during a 
birch pollen exposure. Participants will be asked to refrain from taking specific 
prohibited medications (Section 7.9.1) within the specified period preceding screening 
and EEU visits.  
• Screening baseline assessment: Eligible participants who meet eligibility criteria for 
the study (including screening birch EEU challenge requirement) will record daily 
symptom and medication scores for approximately 2 weeks or longer (at minimum 1 
week) until randomization 
• Screening EEU challenges and baseline symptom and medication assessment are 
recommended to be done outside of relevant pollen seasons for pollen-allergic 
participants.  
• Participants who are sensitized to oak and meet eligibility criteria for the study 
(including screening birch EEU challenge requirement) will also undergo an EEU 
challenge with oak allergen (visit 3) to determine clinical allergy to oak during 
screening. 
• Re-screening: Participants may be re-screened up to one time; however, rescreening is 
not permitted if a participant screen failed on birch sensitization criteria (birch SPT or 
sIgE to birch or sIgE to Bet v 1) or screening birch EEU challenge eligibility criteria.  
Randomization and study drug dosing (dose #1): Participants who meet all inclusion but no 
exclusion criteria will undergo randomization at visit 4. Stratification factors at randomization 
include oak allergy, grass sensitization status, and EEU site. Randomization and treatment 
assignment for Part A is discussed in Section 7.5. Participants will be observed for 2 hours after 
receiving the SC dose of study drug.  
A primary analysis will be performed after all participants complete at least day 29 EEU challenges 
or discontinue. 
Follow-up period after EEU exposures until visit 10.  
Part B Study Periods: 
As outlined above in Figure 1, study Part B consists of an on-treatment efficacy assessment period, 
an off-treatment safety follow-up period, and the end-of-study visit. These study periods are 
described below.  
• Study drug dosing (dose #2): Participants will be administered a SC dose of the study 
drug (dose #2 at visit 11) within approximately 3 weeks prior to the anticipated start of 
the natural BPS, intended as a single dose for coverage of the birch season. The goal 
dosing window is within 3 weeks prior to the anticipated start of the birch pollen season, 
at least 12 weeks after initial dose in Part A. The sponsor will define the last possible 
date for dosing in Part B in each geographical area based on the anticipated timing and 
duration of the local birch pollen season in consultation with the local pollen expert 
(eg, if season is expected to be ending soon based on consistently low birch pollen 
counts noted without any explanatory transient climactic condition such as rain/ cold 
weather, etc, then those participants may not receive dose #2). Participants who are 
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unable to receive dose #2 prior to the defined dosing end date will discontinue study 
drug (Section 7.3.2) but should be encouraged to remain in the study.  
• Randomization and treatment assignment for Part B is discussed in Section 7.5. 
− Participants will be observed for 2 hours after study drug dosing and will be called 
by telephone (visit 12) approximately 1 day after dosing to assess for any potential 
adverse events.  
• Follow-up period: after the end of the birch pollen season for approximately 4 weeks.  
Part B will be an approximately 18-week period based on timing and length of the natural BPS 
including an approximate 4-week safety follow up after the end of the season.  
5.1.1. 
Study Stopping Rules 
5.1.1.1. 
Study Stopping Criteria 
There are no pre-specified study stopping rules; however, appropriate action, if needed, will be 
taken based upon ongoing data reviews, in consultation with the Regeneron Safety Oversight 
Committee and the IDMC. 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.  
5.1.2. 
End of Study Definition 
The end of study is defined as the date the last participant completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the study participant can no longer be contacted by the 
investigator).  
5.2. 
Planned Analyses 
No formal interim analysis is planned. A primary analysis may be performed after all participants 
complete at least day 29 EEU challenges (visit 6) in Part A or discontinue. A select team will be 
unblinded to review the results but to ensure study integrity, the team members directly involved 
in the continued conduct of the trial will remain blinded. A description of the statistical methods 
to be employed is in Section 10.4.3, and blinding implications are discussed in Section 7.6.  
Final unblinded analyses of the study results for efficacy endpoints may be performed when all 
randomized participants have completed visit 14 (after end of BPS). These will be considered the 
final analyses for the efficacy endpoints. Additional data between this database lock and last 
participant completing the last visit will be summarized in the CSR or an addendum. 
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5.3. 
Study Committees 
5.3.1. 
Independent Data Monitoring Committee 
An IDMC will actively review data throughout the study to monitor participant 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 participant 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 participants enrolled 
in these studies. All activities and responsibilities of the IDMC will be described in the IDMC 
charter.  
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6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PARTICIPANTS 
6.1. 
Number of Participants Planned 
Approximately 300 healthy male and female participants 18 years of age or older with birch pollen 
allergy will be enrolled in this study. All participants will be asked to complete both Part A and 
Part B of the study.  
6.2. 
Study Population 
6.2.1. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. Generally healthy males and females, age 18 years or older at the time of screening.  
2. Documented or subject-reported history of birch tree pollen-triggered allergic rhinitis 
symptoms with or without conjunctivitis (for at least 2 seasons) 
3. Positive SPT with birch tree pollen extract (mean wheal diameter at least 5 mm greater 
than the negative control) in screening period 
4. Positive sIgE tests for birch tree pollen and Bet v 1 (≥0.7 kUa/L) in screening period 
5. Demonstrated TNSS ≥6 out of 12 on at least 2 time points during the birch EEU exposure 
challenge in screening period 
6. Willing and able to comply with clinic visits and study-related procedures 
7. Provide informed consent signed by study participant or legally acceptable representative 
8. Able to understand and complete study-related questionnaires 
6.2.2. 
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 
study and received 
REGN5713-5714-5715 antibodies (receipt of placebo in a previous study is allowed) 
2. Significant rhinitis, sinusitis, significant and/or severe allergies not associated with the 
birch pollen season, or due to daily contact with other non-birch related allergens causing 
symptoms that are expected to coincide or potentially interfere with the study EEU 
assessments or with the birch pollen season, as assessed by the investigator  
3. Subjects who anticipate major changes in allergen exposure during the birch pollen season 
that are expected to coincide with study assessments or planned travel that is expected to 
interfere with the study assessments, as assessed by the investigator (eg, anticipated travel 
during planned EEU sessions or birch pollen season) 
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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 visit 1. Subjects may be re-evaluated for eligibility after resolution of symptoms 
and specified duration.  
5. History of significant, recurrent sinusitis, defined as at least 3 episodes requiring antibiotic 
treatment per year for the last 2 years 
6. Abnormal lung function as judged by the investigator with FEV1<75% of predicted at 
screening or randomization 
7. A clinical history of moderate to severe asthma, uncontrolled asthma, global initiative for 
asthma [GINA] steps 3 to 5 (Bateman, 2008) (an isolated diagnosis of exercise-induced 
bronchospasm would be considered acceptable; eg, asthmatics requiring only intermittent 
use of a short-acting bronchodilator would be considered acceptable; per principal 
investigator [PI] judgement) 
8. Clinical history of asthma exacerbations or wheezing episodes during 2 prior tree pollen 
seasons or a prior history or asthma exacerbations due to tree pollen allergy, per PI 
judgement 
9. Asthma symptoms developed in the screening EEU challenge requiring intervention or 
inability to tolerate screening EEU session due to symptoms, per PI judgement 
10. A clinical history of asthma with treatment of asthma requiring systemic (oral or parenteral) 
corticosteroid treatment more than twice within prior 12 months or once within 3 months 
prior to screening or has been hospitalized or has attended the Emergency Room/Urgent 
Care facility for asthma in prior 12 months before screening. 
11. History of life-threatening asthma, defined as an asthma episode that required intubation 
and/or was associated with hypercapnia, respiratory arrest, and/or hypoxic seizures 
12. Active lung disease other than asthma  
13. History of nasal polyps  
14. History of birch or other tree allergen immunotherapy (eg, subcutaneous immunotherapy 
[SCIT], sublingual immunotherapy [SLIT], or oral immunotherapy) in the 3 years prior to 
screening.  
15. Use of anti-IgE or other biological therapy (including but not limited to anti IL-5, anti IL-4) 
that interferes with type 2 disease within 6 months prior to screening visit 1. 
16. Allergen-specific immunotherapy with any allergen other than birch or other trees at 
screening.  
17. History of clinically significant cardiovascular, respiratory, hepatic, renal, gastrointestinal, 
endocrine, hematological, psychiatric, or neurological disease, as assessed by the 
investigator, that may confound the results of the study or pose an additional risk to the 
subject by study participation 
18. Any physical examination findings and/or history of any illness/ disease and/or the use of 
any medication that, in the opinion of the investigator, might confound the results of the 
study or pose an additional risk to the subject by study participation. 
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19. 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(s), including but not limited to: 
Clinically significant/active underlying hepatobiliary disease. 
OR, 
Alanine aminotransferase (ALT) >3 upper limit of normal (ULN). 
Abnormal laboratory values at screening: 
- 
Platelets <100 ×103/μL 
- 
Neutrophils <1.5 × 103/μL 
- 
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 
NOTE: If an abnormal value is detected at screening, a repeat test can be performed to 
confirm the abnormality to categorize the subject as a screen failure. 
20. Hospitalization (>24 hours) for any reason within 30 days of the screening visit 1 
21. History of drug or alcohol abuse judged to be significant by the investigator within a year 
prior to screening visit 1 
22. 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  
23. Clinically significant abnormal electrocardiogram (ECG) in the screening period as 
assessed by the investigator 
24. History of acute hypersensitivity and/or anaphylaxis to protein therapeutics or components 
of formulation, or severe or significant allergies that in the opinion of the investigator could 
represent a substantial risk to the subject 
25. Treatment with an investigational drug or therapy within 2 months or at least 5 half-lives 
(if known), whichever is longer. 
26. Unwilling or unable to comply with the permitted and prohibited medication specifications 
for this study. 
27. Is committed to an institution by virtue of an order issued either by the judicial or the 
administrative authorities 
28. Members of the clinical site study team and/or his/her immediate family, unless prior 
approval granted by the sponsor. 
29. Pregnant or breastfeeding women. 
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30. Women of childbearing potential (WOCBP)* who are unwilling to practice highly 
effective contraception prior to the initial dose/start of the first treatment, during the study, 
and for at least 6 months after the last dose (whichever is longer). 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); and/or 
e. 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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6.3. 
Premature Withdrawal from the Study 
A participant 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 participant from the study if it is no 
longer in the interest of the participant to continue in the study, or if the participant’s continuation 
in the study places the scientific outcome of the study at risk (eg, if a participant does not or cannot 
follow study procedures). An excessive rate of withdrawals would render the study 
uninterpretable; therefore, unnecessary withdrawal of participants should be avoided. 
Participants who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 8.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.3.2. 
6.4. 
Replacement of Participants 
Participants prematurely discontinued from the study or from study drug will not be replaced. 
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7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
Part A:  
Subcutaneous administration of a dose of study drug (dose #1) 
• 3-mAb cocktail REGN5713-5714-5715 900 mg (300 mg per mAb)  
• 2-mAb cocktail REGN5713-5715 600 mg (300 mg per mAb) plus placebo that replaces 
REGN5714 
• 1-mAb REGN5715 300 mg plus placebo that replaces REGN5713-5714 
• Matching placebo that replaces active drug 
Part B:  
Subcutaneous administration of a dose of study drug (dose #2) 
• 3-mAb cocktail REGN5713-5714-5715 900 mg (300 mg per mAb)  
• 2-mAb cocktail REGN5713-5715 600 mg (300 mg per mAb) plus placebo that replaces 
REGN5714 
• 1-mAb REGN5715 300 mg plus placebo that replaces REGN5713-5714 
• Matching placebo that replaces active drug 
Participants will receive the same treatment in Part B that they were originally randomized to 
receive in Part A. 
Parts A and B: 
Study drug will be provided as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
. It is recommended that for each dose, the 3 SC 
injections be given in separate locations, either the abdomen, thighs, or upper arms. During the 
treatment period, there will be 2 visits during which study drug will be administered for a total of 
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6 injections. Participants will be randomized to receive placebo or 1 of 3 active treatment arms. In 
order to maintain blinding, all participants will receive three 2-mL SC injections.  
• For REGN5713-5714-5715 (300 mg/mAb); 
 
 injections will be 
administered for 900 mg total.  
• For REGN5713-5715 (300 mg/mAb), 
 
 injections will be administered for 600 mg 
total. 
 placebo injection will be used to match volume. 
• For REGN5715 (300 mg/mAb); at 150 mg/mL REGN5715; One 2.0 mL SC injection 
will be administered for 300 mg total. Two 2.0 mL placebo injections will be used to 
match volume. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.2. 
Rescue Treatments 
For all EEU challenges and in study Part B, participants will be provided with the following 
allergy-relieving rescue medications (or appropriate in-class equivalent, after agreement with 
sponsor) to treat allergic symptoms as needed during the study:  
1. oral desloratadine 5 mg (second generation antihistamine) 
2. topical olopatadine 1 mg/mL (antihistamine eye drops) 
3. topical mometasone furoate 50 μg/dose (INCS) 
During specified periods, including Part B of the study, participants will be asked to record their 
daily medication use using an e-diary, including the name and amount of these pre-specified 
medications.  
For EEU Exposure(s) and Skin Prick Testing  
Allergen exposure can induce immediate or late allergic reactions, such as allergic conjunctivitis, 
allergic rhinitis, asthma symptoms, or rarely anaphylaxis, in sensitized participants, which will 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, as needed, can be 
dispensed after study endpoint data collection is obtained (eg, after EEU challenge data are 
collected, after the skin wheals are measured after application of allergen during skin prick testing). 
During the study, participants will be asked to refrain from taking specific prohibited medications, 
including as specified within the time period preceding screening and EEU visits (Section 7.9.1).  
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7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification for an individual participant is not allowed. 
7.3.2. 
Study Drug Discontinuation 
Participants who permanently discontinue from study drug should be encouraged to remain in the 
study. Those who agree and do not withdraw from the study will be asked to return to the clinic 
for all remaining study visits per the visit schedule. 
Participants who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 8.1.2. 
7.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction (eg, Hy’s law is met; (FDA, 2009)) 
• Participant withdraws consent 
• If, in the investigator’s opinion or at the specific request of the sponsor, continuation 
of study drug would be detrimental to the participant’s well-being, or there is no longer 
any potential for benefit, or if continuation would undermine the scientific integrity of 
the study 
• In the event of an important protocol deviation, at the discretion of the investigator or 
the sponsor 
7.3.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• Sustained ALT/AST values greater than 3x the ULN plus total bilirubin >2x ULN or 
isolated AST/ALT >5x ULN (except if criteria for permanent study drug 
discontinuation are met as noted in Section 7.3.2.1) 
• Hospitalization  
• Other intercurrent illness or adverse event or use of prohibited medication or major 
surgery that could, in the opinion of the investigator, present an unreasonable risk to 
the participant as a result of his/her continued use of the study drug  
After the condition leading to temporary discontinuation of study drug resolves, study drug dosing 
may resume if participant is within the appropriate dosing window. A decision to temporarily 
discontinue study drug and/or resume study drug dosing should be discussed with the Regeneron 
medical monitor. 
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The investigator may temporarily discontinue study drug dosing at any time, even without 
consultation with the medical monitor if the urgency of the situation requires immediate action 
and if this is determined to be in the participant’s best interest. However, the Regeneron medical 
monitor should be contacted as soon as possible. Resumption of study drug dosing requires 
consultation and agreement between the investigator and the Regeneron medical monitor. 
If a participant requires a prohibited medication at any time during the study, the PI should contact 
the Regeneron medical monitor (except for illness requiring prompt treatment). Based on the 
discussions, study drug may be continued or temporarily or permanently discontinued. 
7.4. 
Management of Acute Reactions  
7.4.1. 
Acute Injection Reactions 
7.4.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as AEs (as defined in Section 9.2.1) 
and graded using the grading scales as instructed in Section 9.2.4. 
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.  
7.4.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 9.2.4. 
7.5. 
Method of Treatment Assignment 
In Part A, at visit 4 (Table 1), approximately 300 participants will be randomized to 1 of 4 
treatment arms (1:1:1:1) (described in Section 7.1) according to a central randomization scheme 
provided by an in interactive voice response system (IVRS)/interactive web response system 
(IWRS) to the designated study pharmacist (or qualified designee). Randomization will be 
stratified according to oak allergy status (yes or no) determined based on oak EEU challenge and 
grass sensitization status (grass sensitized: grass SPT ≥3 mm or sIgE ≥0.35; not grass sensitized: 
grass SPT <3 mm and sIgE <0.35) and EEU site.  
All participants will be asked to complete both Part A and Part B of the study. Participants will 
receive the same treatment in Part B that they were originally randomized to receive in Part A. 
7.6. 
Blinding 
Study participants, the PIs, and study site personnel will remain blinded to all randomization 
assignments and blinded procedures 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 participant randomization 
assignments. 
 
 
. 
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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.  
One primary analysis may be performed. The team performing the primary analysis will be 
separate from the ongoing study team. Each study site will be required to have blinded and 
unblinded study teams. No study personnel involved in the day-to-day conduct of the study will 
have access to any unblinded data before the final database is locked for this study.  
7.7. 
Emergency Unblinding 
Unblinding of treatment assignment for a participant 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 participant’s treatment assignment. Study drug will be discontinued for 
participants whose treatment has been unblinded (Section 7.3.2).  
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected participants will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the participant. Unblinding is performed using 
the IVRS/IWRS which will notify Regeneron.  
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the participant 
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 participant’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. 
7.8. 
Treatment Logistics and Accountability 
7.8.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label open-label 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 participant. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
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7.8.2. 
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/returned to the sponsor 
or designee. 
7.8.3. 
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 participant 
• returned from each participant (if applicable), and 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.8.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.9. 
Concomitant Medications and Procedures 
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. 
7.9.1. 
Prohibited Medications and Procedures  
Prohibited at Screening (Washout) and Any Time Throughout the Study  
• Birch-specific or any tree allergen specific immunotherapy (3 years prior to screening 
and during the study) 
• Allergen specific immunotherapy (SIT) to any allergen excluding birch or trees (during 
the study) 
• Systemic steroid treatment (30 days prior to screening and during the study) 
• Intramuscular corticosteroids or extended duration corticosteroids (eg, intra-articular, 
intra-vitreal) (3 months prior to screening and during the study) 
• Systemic calcineurin inhibitors (14 days prior to screening and during the study) 
• Biologic therapies or immune therapeutics impacting type 2 allergic disease (6 months 
prior to screening and during the study) 
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• Methylxanthines (eg, oral theophylline) (24 hours prior to screening and during the 
study) 
• Tricyclic antidepressants/typical antipsychotics (14 days prior to screening and during 
the study) 
• Ultra-long-acting β-agonists (eg, indacaterol, vilanterol, olodaterol) (during the study) 
• Long-acting anti-muscarinic agents (eg, tiotropium) (during the study) 
• Beta blockers (during the study) 
Prohibited Preceding Environmental Exposure Unit Visits and Part B Assessments 
Use of these concomitant medications are prohibited preceding and during an EEU visit. These 
medications are also prohibited in Part B from visit 10 to visit 15 (end of study) for field efficacy 
assessments.  
• Topical (intranasal or ocular) or systemic first generation H1 antihistamines (eg, 
diphenhydramine and chlorpheniramine) (3 days) [except study provided rescue 
medication as specified for part B] 
• Second generation and long-acting H1 antihistamines (eg, cetirizine) (5 days) [except 
study provided rescue medication as specified for part B] 
• Intranasal or ocular corticosteroids (14 days) [except study provided rescue medication 
as specified for part B] 
• Topical or oral decongestants (72 hours) 
• Leukotriene modifiers (30 days) 
• Cromoglycates (14 days) 
• Anticholinergics (eg, Ipratropium [Atrovent 40 μg]) (12 hours) 
• Inhaled corticosteroids (14 days) 
• Long-acting β-agonists (eg, salmeterol) (7 days) 
• Inhaled corticosteroids/long-acting β-agonists (14 days) 
• Beta blockers (14 days) 
Anti-allergic medications (eg, antihistamines, anti-allergic eye drops, anti-allergic nasal sprays, 
intranasal or ocular steroids, herbal anti-allergic preparations) outside of study-related anti-allergic 
medications as they will be supplied as part of the study (eg, desloratadine, olopatadine, 
mometasone furoate).  
For EEU visits, rescue medications, as needed, will be dispensed at the end of symptom score 
collection when subjects leave the site for participants to use as needed after symptom data are 
collected. For Part B field assessments, all participants are provided allergy-relieving study rescue 
medications (including desloratadine, olopatadine eye drops, and mometasone intranasal spray or 
appropriate class equivalent) to use as needed during the birch season. This washout for study 
provided allergy rescue medications is not required for the peak in-season EEU challenge but 
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participants are recommended to use these allergy rescue medications after completion of the peak 
season EEU challenge and not in anticipation prior to the challenge.  
Any additional medication(s) that, in the opinion of the investigator, may confound the results of 
the study or pose an additional risk to the participant may be prohibited during the study or specific 
periods in the study. 
Skin prick testing: Antihistamines should be withheld for prior to all SPT assessments including 
titrated SPT: First generation antihistamines for 3 days (eg, diphenhydramine); second generation 
antihistamines for 5 days (eg, cetirizine, desloratadine) (longer acting antihistamines such as 
hydroxyzine, cyproheptadine are recommended to be withheld for longer [eg, 10 days]). 
7.9.2. 
Permitted Medications and Procedures  
Study-provided rescue medications (desloratadine, olopatadine, and mometasone furoate [or 
in-class equivalent in consultation with the Sponsor]) can be used, as needed, during the study 
(except during pre-specified washouts as required for EEU challenges and/or SPT testing). With 
the exception of severe or clinically concerning reactions (as judged by the investigator), rescue 
treatments should be dispensed to participants for use, if needed, after study endpoint data 
collection is obtained for EEU challenges. Treatment for acute reactions is allowed during the 
study.  
COVID-19 Vaccination 
A participant may receive a COVID-19 vaccine (initial series or booster) during the study as long 
as it is not administered within 72 hours (but ideally not within at least 1 week) of study drug 
dosing or the EEU chamber session(s). Administration of a COVID-19 vaccination should be 
separated from the time of administration of the investigational product or EEU session in order 
to avoid confounding the effects (eg, adverse effects) of the vaccine/booster with the effects of 
study drug or the allergen exposure via the chamber session.  
Consistent with the receipt of any vaccination during the study, the COVID-19 vaccine will be 
recorded a concomitant medication.  
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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
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 
 
PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Screening: 
Inclusion/exclusion 
X 
X 
X 
X 
 
X19 
X19 
X19 
X19 
X19 
X19 
 
X19 
X19 
 
 
Informed consents 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and allergy 
history34 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
women only)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Sensitization/ Specialty Labs: 
SPT birch, birch-
related and 
unrelated common 
allergens2 
X2*,35 
 
 
 
 
X4 
 
X4 
X4 
X4 
 
 
 
X4 
X4 
X4 
Titrated SPT to 
birch and birch-
related allergens3 
 
X 
 
 
 
X4 
 
X4 
X4 
X4 
 
 
 
X4 
X4 
 
Serum allergen-
specific IgE (eg, 
birch and Bet v 1 
sIgE, other related/ 
unrelated allergens) 
X 
 
 
X39 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
Serum total IgE 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for 
basophil activation 
test 31 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Nasal fluid 
collection33 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
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PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Exploratory 
research serum and 
plasma32 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Treatment: 
Randomization 
 
 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study 
drug16 
 
 
 
X 
 
 
 
 
 
 
X11,14 
 
 
 
 
 
Dispense rescue 
medications27 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Efficacy: 
EEU visits: TNSS, 
TOSS7,8,9  
 
X5 
X 
 
 
X7 
X7 
X7 
X7 
 
 
 
X8 
X8 
 
 
e-Diary: TNSS, 
TOSS, and DMS24 
 
X25 
 
 
 
 
 
X26 
 
RQLQ(S)28 
 
X 
 
 
 
 
 
X 
 
PFASQ29 
 
X 
 
 
 
 
 
X 
 
Outdoor time 
questionnaire30 
 
X 
 
 
 
 
 
X 
 
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PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Safety: 
Vital signs18 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Physical 
examination17 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry/PEF23 
X23* 
X 
X 
X23* 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Laboratory Testing20: 
Hematology32 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
Blood chemistry32 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
Pregnancy test 
(urine) (WOCBP)21 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test 
(serum) 
(WOCBP)21 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pharmacokinetics and Immunogenicity Sampling: 
Drug concentration 
sample36 
 
 
 
X36 
 
X 
 
X 
X 
X 
X36 
 
X 
X 
X 
X 
ADA sample36 
 
 
 
X36 
 
 
 
 
X  
 
X36 
 
 
 
X 
X 
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PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Future Biomedical Research (optional sub-study): 
 
 
 
 
 
 
 
 
 
 
 
Serum sample 
collection for future 
biomedical research 
(optional)32 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Plasma sample 
collection for future 
biomedical research 
(optional)32 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Pharmacogenomics (optional sub-study): 
Blood for DNA 
(optional)37 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. Screening visit 1 can be split into additional visits, if required, to ensure medication 
washouts prior to any assessments being performed (per PI discretion). 
2. Screening skin prick test (SPT) for birch and for other birch-related (eg, alder, oak) and 
unrelated common allergens (eg, grass, dust mites, etc) is performed as described in the 
study reference manual. SPT source documentation is required (eg, tape transfer method). 
*If screening SPT for birch does not meet eligibility at screening visit 1 (mean wheal 
diameter less than at least 5 mm greater than the negative control), then other screening 
visit 1 procedures may not be performed, as the subject will have failed screening based 
upon birch skin prick testing (eg, recommend performing birch skin prick testing prior to 
blood draw, spirometry, etc).  
3. Titrated SPT with serial allergen titration for birch and related allergens is performed as 
described in the study reference manual. The titrated SPT should be performed prior to the 
EEU challenge during visits when both are scheduled.   
4. Post-randomization SPT and titrated SPT will be performed in a blinded fashion (as 
described in the study reference manual). 
5. All other eligibility criteria need to be met prior to the screening birch allergen EEU 
challenge (visit 2). It is recommended that the screening birch challenge is scheduled 
outside of relevant pollen seasons when pollen-allergic subjects are not significantly 
symptomatic due to other pollens.  
6. It is recommended that EEU challenges (including birch and oak EEU sessions) be 
separated by approximately 1 week or longer between the challenges for a subject to avoid 
potential impact of any residual symptoms on the assessments, per PI judgement. Similarly, 
approximately 1 week or longer is recommended between EEU challenges and dosing to 
avoid any overlap of symptoms, per PI judgement. Eligible subjects who are oak-sensitized 
will also complete the oak EEU challenge at screening. Oak allergy status for stratification 
and day 36 challenges will be determined similar to birch EEU criteria during the screening 
oak challenges.   
7. Part A EEU challenges: TNSS and TOSS are recorded using an e-diary at baseline and then 
every ~20 minutes while in the EEU, then continued ~ every 2 hours until ~24 hours after 
the start of the EEU exposure (except during sleep). After completion of the EEU 
challenges, use of allergy medicines will be recorded in the e-diary until ~24 hours after 
the start of the EEU challenges.  An assessment of TNSS is performed once prior to the 
start of the EEU exposure at visits 2, 3, 6, 7, 8, 9. If TNSS ≤2, then the visit activities can 
proceed. If TNSS is >2, then the visit can be rescheduled within the window. Washouts for 
medications prior to EEU visits are specified in prohibited medications (Section 7.9.1).  
8. Part B EEU challenges: There are no TNSS thresholds for the peak birch pollen season 
EEU visit (visit 13). The birch EEU challenge at the end of the season (visit 14) may not 
be performed in grass-allergic participants who are highly symptomatic or unable to wash 
out allergy relieving rescue medications due to grass pollen allergy symptoms, per PI 
discretion.  
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9. On a case-by-case basis, an EEU challenge visit window post-randomization may be 
extended up to +14 days for any illnesses (eg, respiratory illness, common cold, etc) that 
may potentially confound the assessments and/or potentially impact participant safety, per 
PI discretion in consultation with the sponsor.  
10. Randomization may occur within 1 day prior to study drug administration.  
11. In Part B, participants who received either 3-mAb, 2-mAb, 1-mAb, or placebo in Part A 
will continue the same treatment in Part B. 
12. Dosing window for visit 11 is within approximately 0 to 3 weeks prior to start of the 
anticipated BPS. 
13. Visit timeframes in Part B (visits 10 to 15) may vary based on the timing and duration of 
the anticipated BPS. End-of-season EEU challenge (visit 14) should occur after the end of 
the protocol-defined end of the BPS. 
14. Dose #2 should be administered at minimum 12 weeks after dose #1. 
15. Participants will be contacted within 1 day (visit 12) after dose 2 (visit 11) via telephone 
to monitor safety trends. 
16. All safety assessments performed at screening must be normal and checked against the 
inclusion/exclusion criteria prior to study drug administration at visit 4. Similarly, it is 
recommended to review relevant safety assessments prior to dosing at visit 11. Participants 
will be observed for 2 hours after receiving the SC dose of study drug. Safety labs may be 
repeated if any concerns, per PI discretion.  
17. A full physical exam must be done at screening, visits 4, 11, and 15. A limited relevant 
physical exam will be done at the remaining visits, per PI judgement, depending on 
presentation of the participant. Additional relevant physical exams may be conducted 
during and after completion of the EEU challenges, per PI discretion. 
18. Vital signs include systolic and diastolic blood pressure, respiratory rate, heart rate, and 
temperature. Vital signs will be collected in a seated position.  
*On visit 4 (day 1) and visit 11, vital signs are taken prior to study drug administration and 
at 2 hours (approximately ±15 min) after completion of study drug administration. 
Additional vital signs may be recorded during and after completion of the EEU challenges, 
per PI discretion. 
19. Inclusion/ exclusion criteria will be verified only to document any changes, not to 
determine study eligibility. 
20. Testing for COVID-19 or other respiratory infections may be performed at visits, per site 
local protocols. 
21. If the urine pregnancy test is positive, the site must perform a serum pregnancy test for 
confirmation. For visit 4 (randomization) if a serum pregnancy test must be performed, 
study drug cannot be administered unless the serum pregnancy test is negative. For all EEU 
visits (visits 2, 3, 6, 7, 8, 9, 13, and 14) and early termination, if a pregnancy test must be 
performed, EEU and associated procedures cannot be performed unless the pregnancy test 
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is negative. Urine pregnancy test can be performed on day -1 of EEU visits and early 
termination, at the investigator’s discretion. 
22. Electrocardiogram will be performed locally by the site. 
23. Spirometry will be performed locally by the site. *Spirometry at screening and 
randomization is required for all participants for eligibility. At other visits, spirometry 
and/or peak expiratory flow (PEF) may be performed for participants, per PI judgement. 
24. Daily TNSS, TOSS, and DMS assessments will being collected by e-diary during screening 
and in Part B from visit 10 to visit 15. The e-diary is returned at visit 15. 
25. Screening baseline assessment: e-diary assessments for symptoms and allergy rescue 
medication use should be obtained for an approximate 2-week period or longer (at 
minimum 1 week) starting after the screening birch EEU challenge until randomization 
(visit 4) in eligible subjects. It is recommended that it is performed outside of relevant 
pollen seasons when pollen-allergic subjects are not significantly symptomatic due to other 
pollens. 
26. Pre-season baseline assessment: e-diary assessments for symptoms and allergy rescue 
medication use should be obtained approximately 2 weeks or longer up (at minimum 1 
week) to receipt of dose 2 given ahead of the anticipated BPS (starting at visit 10 [Part B]) 
and prior to receiving dose 2 at visit 11 ahead of the BPS). 
27. Allergy relieving rescue medications, as needed, should be dispensed at the end of 
symptom score collection on visits 2, 3, 6, 7, 8, and 9. Rescue medications are dispensed 
starting at visit 10 for management of symptoms during the pollen season up to visit 15.  
28. RQLQ(S) is administered weekly starting at visit 2 (during screening baseline assessment 
period) and then weekly using an e-diary in Part B starting at visit 10 until visit 15. 
29. Pollen food allergy questionnaire (PFASQ) is administered every 2 weeks at baseline 
starting at visit 2 (during screening baseline assessment period) and then every 2 weeks in 
Part B starting at visit 10 until visit 15.   
30. Outdoor time questionnaire is administered daily at baseline starting at visit 2 (during 
screening baseline assessment period) and then daily using an e-diary in Part B starting at 
visit 10 until visit 15. 
31. Basophil activation test (BAT) samples may be collected from approximately 100 
randomized participants (subset of the total enrolled population at one or both EEU sites; 
additional samples may be collected at the screening EEU visit to account for potential 
screen failures). The initial samples for a BAT assay are to be collected prior to the 
administration of study drug and subsequent BAT assay samples are to be collected prior 
to the respective EEU challenges. 
32. Samples are to be collected prior to the administration of study drug and prior to EEU 
challenges, when applicable.  
33. Nasal fluid samples may be collected from a subset of participants. It is recommended to 
collect these samples in the same participants from whom BAT assay samples were 
collected. It will be collected in approximately 100 randomized participants at visits 2, 6, 
8, 13, and 14 (subset of the total enrolled population at one or both EEU sites; additional 
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samples may be collected at the screening EEU visit to account for potential screen 
failures). At each visit, the nasal fluid samples will be collected at 2 time points, prior to 
the start of the EEU challenge and then at 6 hours after completion of the challenge. 
34. Medical, surgical, allergy and medication history, demographic and social history may be 
obtained from historical data for participants who have available source documentation of 
these within 6 months prior to screening. At screening, all historical data should be 
reviewed/ confirmed for accuracy and completeness with addition of any other relevant 
missing and/or interval changes since that last historical assessment. Eligibility criteria 
must be reviewed during screening to ensure that all inclusion criteria are met, and no 
exclusion criteria are met. 
35. Skin prick testing data for allergens using standard diagnostic concentrations of allergen 
extracts [except birch, other trees (birch-related or unrelated), or grasses] may be obtained 
from historical data for participants who have source documentation of prior SPT 
performed within 6 months prior to screening.  
Note: Appropriate source documentation (eg, tape transfer method) must be available to 
calculate and verify the mean wheal diameter as per study requirements. Participants who 
do not have historical data for any of the other SPTs as specified in the study reference 
manual within 6 months prior to screening will need to perform them during the screening 
period. All participants are required to have an SPT for birch, other trees (birch-related 
or unrelated), and grasses during the study screening period regardless of the availability 
of historical data.  
36. Pharmacokinetic (drug concentration) and immunogenicity (ADA) samples are to be 
collected prior to the administration of study drug. In the event of suspected serious adverse 
events (SAEs), such as anaphylaxis or systemic hypersensitivity, additional samples for the 
analysis of ADA as well as REGN5713, REGN5714, and REGN5715 drug concentration 
may be collected as close to the event as practically possible. 
37. Pharmacogenomics sub-study is optional for all participants enrolling in the main study. 
One DNA sample is to be collected on day 1/randomization prior to receiving the study 
drug, but if this sample collection was omitted at baseline, it can be collected at any 
subsequent visit.  
38. Unscheduled visit procedures may be performed per PI discretion based on the reason for 
the visit. 
39. Allergen-specific IgE should be drawn prior to administration of study drug at the 
randomization visit (visit 4). 
40. Day 57 and/or day 85 EEU challenges may not be performed in participants who have a 
high symptom burden assessed due to tree pollens.  
41. Visit 10 may not be performed in participants if they are expected to be dosed within 
3 weeks after the prior EEU visit. If visit 10 is not performed, then all visit 10 assessments 
(without any duplication) should be performed at the last prior EEU visit (including serum 
pregnancy test, e-diary, dispensing rescue medications, etc)  
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8.1.2. 
Early Termination Visit 
Participants who are withdrawn from the study before the primary endpoint visit (day 29, week 4, 
visit 6) will be asked to return to the clinic: once for an early termination visit consisting of the 
end of study assessments described in Table 1 and again at select visits (eg, the primary endpoint 
visit and key secondary endpoint visit(s), as applicable). 
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep participants 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. 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed only at screening/baseline to determine study 
eligibility or to characterize the baseline population: demographics, medical and allergy history, 
serum total IgE sample collection, ECG*, height measurement**, weight measurement***, 
urinalysis, and FSH determination (in postmenopausal women if postmenopausal status is in 
question). 
*  A standard 12-lead ECG will be performed. Heart rate will be recorded from the 
ventricular rate and the PR, QRS, and QT (identify QTcB or QTcF) intervals will be 
recorded. The ECG strips or reports will be retained with the source. 
**  Height will be recorded to the nearest 1 cm. 
***  Body weight will be assessed using calibrated scales and will be recorded to the nearest 
0.1 kg. 
8.2.2. 
Efficacy Procedures  
8.2.2.1. 
Total Nasal Symptom Score 
TNSS will be recorded at the time points according to Table 1. Instantaneous TNSS measures (ie, 
an evaluation of symptom severity at the time point of assessment) are used in the EEU. Reflective 
TNSS measures (ie, an evaluation of symptom severity over the past 24 hours, before going to bed 
for the night) are implemented in the field study portion. A TNSS assessment is performed prior 
to the start of EEU exposure at visits 2, 3, 6, 7, 8, and 9. If TNSS ≤2 then the EEU visit activities 
can proceed. If TNSS is >2, then the visit can be rescheduled within the window. TNSS is recorded 
using an e-diary at baseline and then every ~20 minutes while in the EEU, then continued ~ every 
2 hours until ~24 hours after the start of the EEU exposure (except during sleep). There is no TNSS 
threshold for the peak season EEU challenge. TNSS is recorded daily during the field portion of 
the study using an e-diary from visit 10 to visit 15, in addition to an approximately 2-week period 
during screening.  
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 nasal congestion, itching, and runny nose, and 
sneezing.  
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8.2.2.2. 
Total Ocular Symptom Score 
TOSS will be recorded at the time points according to Table 1. Instantaneous TOSS measures (ie, 
an evaluation of symptom severity at the time point of assessment) are used in the EEU. Reflective 
TOSS measures (ie, an evaluation of symptom severity over the past 24 hours, before going to bed 
for the night) are implemented in the field study portion. TOSS is recorded using an e-diary at 
baseline and then every ~20 minutes while in the EEU, then continued ~ every 2 hours until 
~24 hours after the start of the EEU exposure (except during sleep). TOSS is recorded once daily 
during the field portion of the study using an e-diary from visit 10 to visit 15, in addition to a 
~2-week period during screening. 
The TOSS ranges from 0 to 6 and is based on 2 eye symptoms: itching/redness/gritty feeling and 
tearing/watering. Each of the 2 symptoms is graded on a Likert scale ranging from 0 (none) to 3 
(severe).  
8.2.2.3. 
Total Symptom Score 
The TSS is calculated by adding the TNSS (see Section 8.2.2.1) and TOSS (see Section 8.2.2.2) 
together, for a combined TSS of 0 to 18. 
8.2.2.4. 
Daily Medication Score 
DMS will be recorded at the time points according to Table 1. For the DMS, before going to bed 
for the night, participants 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 for the following medications or the approved in-
class equivalents, 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 µg/dose 2.0 points/spray; maximum daily score 8 points). The maximum DMS score is 
20 (Calderon, 2014). DMS is recorded using an e-diary from visit 10 to visit 15, in addition to a 
~2-week period during screening. After completion of the EEU challenges, use of allergy 
medicines will be recorded in the e-diary until ~24 hours after the start of the EEU challenges. 
8.2.2.5. 
Combined Symptom and Medication Score 
The CSMS is defined as TSS (see Section 8.2.2.3) plus DMS (see Section 8.2.2.4). 
8.2.2.6. 
Skin Prick Testing  
SPT to birch, related and unrelated allergens will be performed according to the time points at 
Table 1 to determine sensitization status. A negative control (such as saline/ diluent), and a 
histamine positive control will also be performed. Eligibility criteria for birch allergen SPT is 
defined by a mean wheal diameter at least 5 mm greater than the negative control, in which SPT 
mean wheal diameter is defined as ([longest diameter + longest perpendicular]/2). For other 
allergens, a positive sensitization is defined as a mean wheal diameter of at least 3 mm greater than 
a negative control. 
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Allergen exposure can induce immediate or late allergic reactions, such as allergic conjunctivitis, 
allergic rhinitis, asthma symptoms, or rarely anaphylaxis, in sensitized participants, which will 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, as needed, should be 
dispensed after study endpoint data collection is obtained (eg, after the skin wheals are measured 
after application of allergen). 
Specific medications to be withheld prior to SPT are described in Prohibited Medications 
(Section 7.9.1). Details will be provided in a study reference manual for the sites. 
8.2.2.7. 
Titrated Skin Prick Testing to Birch and Birch-Related Allergens 
Titrated SPT to birch and birch-related or cross-reactive allergens (eg, alder, oak) will be 
performed according to the time points at Table 1. The titrated SPT will be performed with serial 
dilutions of the allergen extracts, a negative control (sch as saline/ diluent), and a histamine 
positive control. SPT mean wheal diameter is defined as ([longest diameter + longest 
perpendicular]/2).  
Allergen exposure can induce immediate or late allergic reactions, such as allergic conjunctivitis, 
allergic rhinitis, asthma symptoms, or rarely anaphylaxis, in sensitized participants, which will 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, as needed, should be 
dispensed after study endpoint data collection is obtained (eg, after the skin wheals are measured 
after application of allergen). 
Specific medications to be withheld prior to SPT are described in Prohibited Medications 
(Section 7.9.1). Details will be provided in a study reference manual for the sites.  
8.2.2.8. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for Ages 12+ 
RQLQ(S) will be recorded at the time points according to Table 1. The RQLQ(S) is a 
self-administered questionnaire to measure health-related quality of life in those 12 years of age 
and above, as a result of perennial or seasonal allergic rhinitis. There are 28 items with 1-week 
recall on the RQLQ(S) in 7 domains: activity limitation, sleep problems, nasal symptoms, eye 
symptoms, non-nasal/eye symptoms, practical problems, and emotional function. The RQLQ(S) 
responses are based on a 7-point Likert scale with responses ranging from 0 (not troubled) to 
6 (extremely troubled). 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. Higher scores indicated 
more health-related quality of life impairment (lower scores were better).  
8.2.2.9. 
Pollen Food Allergy Syndrome Questionnaire 
The PFASQ will be administered at the time points according to Table 1 to assess patient-reported 
symptom burden associated with pollen-food allergy (before going to bed for the night).  
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8.2.2.10. Outdoor Time Questionnaire 
The Outdoor Time Questionnaire will be administered via e-diary at the time points according to 
Table 1 to assess patient-reported average daily time spent outdoors (before going to bed for the 
night).  
8.2.3. 
Safety Procedures 
8.2.3.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration, will be collected 
pre-dose at time points according to Table 1. 
8.2.3.2. 
Physical Examination 
A full physical examination or a limited relevant physical examination will be performed, as 
indicated, at time points according to Table 1. Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the participant’s medical history.   
8.2.3.3. 
Spirometry 
Spirometry measurements include FVC (L), FEV1 (L), FEV1/FVC (%), PEF (L/s), 
FEF 25-75 (L/s). Spirometry, as adjudicated by the site investigator, will be performed locally 
during the study at specified time points (Table 1) (American Thoracic Society [ATS]/European 
Respiratory Society [ERS]-compliant) (Graham, 2019).  
Spirometry will be performed in-clinic at screening and randomization for all participants to 
exclude any participants with abnormal lung function and/or poorly controlled asthma. FEV1 
eligibility criteria are specified in exclusion criteria (Section 6.2.2).  
Spirometry will be performed after a washout period of bronchodilators according to their action 
duration to avoid interference with spirometry assessments and the investigator will discuss this 
with the participants. Examples of washout periods that investigators can discuss with the 
participant include withholding the last dose of short acting bronchodilator (SABA, such as 
salbutamol/albuterol or levosalbutamol/levalbuterol) for at least 6 hours, long acting 
bronchodilator (LABA, such as formoterol or salmeterol) for at least 12 hours, ultra-long-acting 
LABA (such as vilanterol, indacaterol) for at least 24 hours, short acting muscarinic antagonist 
(SAMA, such as ipratropium) for at least 8 hours, and long acting muscarinic antagonist (LAMA, 
such as tiotropium, umeclidinium) for at least 24 hours. Withholding times will be verified before 
performing the measurements.  
Details will be provided in a study reference manual for the sites. 
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8.2.3.4. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed. 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 
Aspartate aminotransferase (AST) 
Potassium 
Creatinine 
Alanine aminotransferase (ALT) 
Chloride 
Blood urea nitrogen (BUN) 
Alkaline phosphatase 
Carbon dioxide 
Total bilirubin  
Albumin 
Calcium 
Glucose  
 
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 
WBC 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Yeast 
Protein 
 
 
Other Laboratory Tests 
Participants will be tested for FSH levels (if postmenopausal status is in question) and will undergo 
serum and urine pregnancy testing (women of childbearing potential only); pregnancy testing is 
not required of women confirmed to be menopausal. Samples will be collected for quantitative 
assessment of allergen specific IgE. 
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 9.1.1. 
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8.2.4. 
Drug Concentration and Measurements 
Samples for drug concentration measurement will be collected at visits listed in Table 1. The 
samples are to be collected prior to the administration of study drug. In the event of suspected 
SAEs, such as anaphylaxis or systemic hypersensitivity, additional samples for the analysis of 
REGN5713, REGN5714, and REGN5715 drug concentration may be collected as close to the 
event as practically possible. 
8.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA measurement will be collected at visits listed in Table 1. The samples are to be 
collected prior to the administration of study drug. In the event of suspected SAEs, such as 
anaphylaxis or systemic hypersensitivity, additional samples for the analysis of ADA may be 
collected as close to the event as practically possible. 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
This section describes planned exploratory PD/biomarker analyses, some of which may be 
reported in the CSR. Samples will be collected at time points according to Table 1. The biomarkers 
studied will be those known or hypothesized to be relevant to the pathophysiology of birch allergy, 
mechanism of action and/or safety of REGN5713-5714-5715, REGN5713-5715, and REGN5715. 
Detailed instructions for blood sample collection are included in the laboratory manual.  
Any biological samples (eg, blood, serum, plasma) collected during the study, which are not used 
for their planned purpose, or for which material remains after their planned analysis, may be kept 
for up to 15 years after study completion (or for a shorter time period if required per regional laws 
and regulations) for use in exploratory research related to REGN5713-5714-5715, 
REGN5713-5715, and REGN5715 safety and/or efficacy, birch allergy and related allergies, the 
biology of Bet v 1 and/or for related assay development and/or validation. 
8.2.6.1. 
Basophil Activation Test 
In this study, exploratory biomarker assessments will be performed to better understand the effects 
of REGN5713-5714-5715, REGN5713-5715, and REGN5715 administration on biomarkers of 
birch allergy or relevant physiological and pathogenic processes. This will include the assessment 
of allergen-specific IgE levels in serum samples during the study. Additionally, whole blood may 
be collected and processed as per the laboratory manual for basophil responsiveness testing in the 
basophil activation test (BAT). If an indirect basophil activation assay is available, frozen serum 
samples may be tested. 
Basophils are an effector cell type involved in acute allergic reactions. A BAT assay is an in vitro 
cellular functional test that measures basophil activation by the flow cytometric assessment of the 
degree of degranulation following stimulation of the sample with allergens or controls, providing 
an objective method to quantify the allergen-specific reactivity and sensitivity of basophils. 
In a previous randomized, double-blind, placebo-controlled, 2-part phase 1 study, where in Part B, 
patients were administered a single dose of REGN5713-5714-5715 at 900 mg SC, it was 
demonstrated that treatment with REGN5713-5714-5715 significantly lowered basophil 
responsiveness to birch pollen extract as compared to placebo (Gevaert, 2022). A correlation 
between the basophil response as measured by BAT assay and the clinical symptom improvements 
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in TNSS and SPT was observed, indicating that the less sensitive the basophils are to birch pollen 
in a BAT assay, the greater the clinical benefit the patients may achieve. As such, it is possible 
that the inhibition of basophil/mast cell degranulation may be a key mechanism by which 
REGN5713-5714-5715 ameliorates the allergic symptoms downstream of birch pollen exposure. 
Therefore, in this study a BAT assay may be used to assess the inhibitory effect of anti-Bet v 1 
antibodies (which may include but not be limited to assessments such as EC50 and/or % change in 
EC50 from baseline/pre-dose/EEU exposure) on basophil activation after ex-vivo stimulation with 
birch pollen and/or Bet v 1 in REGN5713-5714-5715, REGN5713-5715, and REGN5715 treated 
participants vs placebo. Correlations to clinical symptom measurements may also be made. A BAT 
assay may be performed for approximately 100 of the randomized participants (subset of the total 
enrolled population at one or both EEU sites; additional samples may be required at the screening 
visit since participants may screen fail after the EEU challenge). Assessments will be done in each 
of the active treatment arms versus placebo.  
8.2.6.2. 
Nasal Fluid Collection 
Nasal fluid may be collected from a subset of participants. It is recommended to collect these 
samples in the same participants from whom BAT samples were collected. Samples will be 
collected in approximately 100 randomized participants at specified visits in Table 1. At each visit, 
the nasal fluid samples will be collected at 2 time points, prior to the start of the EEU challenge 
and then at 6 hours after completion of the challenge. 
Exploratory biomarker results not required for protocol-defined endpoint analyses will not be 
reported in the CSR. These results may be in a separate exploratory biomarker report. 
8.2.7. 
Future Biomedical Research (Optional) 
Participants 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 (plasma and serum) will be collected for FBR. Residual biomarker/biological 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. 
8.2.8. 
Pharmacogenomic Analysis (Optional) 
Participants 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 (pre-dose) but can be collected at a later study visit (Table 1). 
DNA samples will be collected for pharmacogenomics analyses to understand the genetic 
determinants of efficacy and safety associated with the treatments in this study and the molecular 
basis of 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 
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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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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Recording and Reporting Adverse Events 
9.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data 
collection, from the time of signing the informed consent form (ICF) to the end of on-treatment 
period (see Section 10.4.5.1). 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 
participant. Adverse events may be directly observed, reported spontaneously by the participant, 
or by questioning the participant at each study visit. Participants 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 9.2. 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. 
Although not considered an adverse event, if a pregnancy occurs during the study, information 
about the progress and outcome of the pregnancy will be collected. This should include the date 
that the participant became pregnant, information about the health of the participant, any 
medication treatments received during the pregnancy, any medical problems affecting or related 
to the pregnancy and/or the baby, whether the pregnancy came to term, the date of the child’s birth, 
and the health of the child after birth. To collect this information, the study staff should contact 
the participant every trimester for updates on the pregnancy. The participant should also be asked 
to contact the site as soon as possible in the event of any medical problem affecting or related to 
the pregnancy and/or baby. Once the baby is born, the study staff will ask for a final update after 
one well-baby visit with the pediatrician.  
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. 
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For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (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 ICF) 
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 9.2 
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 9.1.3.  
9.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with investigator’s assessment of the event’s 
seriousness, severity, and causality to the (when applicable: blinded) study drug. For SAEs and 
AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE case report form (CRF). Specific or 
estimated dates of event onset, treatment, and resolution should be included, when available. 
Medical history, concomitant medications, and laboratory data that are relevant to the event should 
also be summarized in the narrative. For fatal events, the narrative should state whether an autopsy 
was or will be performed, and include the results if available. Information not available at the time 
of the initial report must be documented in a follow-up report. Source documents (including 
hospital or medical records, diagnostic reports, etc) will be summarized in the narrative on the AE 
CRF, and retained at the study center and available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up. 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study with the exception of allergic symptoms that occur in response to 
the EEU challenge within 24 hours following the EEU. Allergic symptoms that occur in response 
to the EEU are not to be reported as AEs, as they will be recorded as outcome measures. However, 
AEs that occur in response to allergen exposure in the EEU that are outside of expected symptoms, 
including events which qualify as SAEs, up to 24 hours after EEU session, should be reported as 
AEs and SAEs, as applicable. 
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9.1.3. 
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 the following:  
− Systemic or severe hypersensitivity reactions 
• NOTE: Anaphylaxis will be prospectively analyzed using the criteria discussed in 
the statement paper from the Second Symposium on the definition and Management 
of Anaphylaxis (Sampson, 2006) 
• 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 participant during the study or within 6 months of 
the last dose of study drug, whichever is longer. Any complication of pregnancy 
affecting a female study participant 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.  
9.1.4. 
Other Adverse Events of Special Interest that do not Require Expedited 
Reporting to Sponsor 
Although these AESIs do not require expedited reporting to Sponsor, the following events are of 
interest and will involve specific data collection to characterize better:  
• Systemic or severe hypersensitivity reactions 
9.2. 
Definitions 
9.2.1. 
Adverse Event 
An AE is any untoward medical occurrence in a participant 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 that 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). 
For studies with patient reported outcomes (PRO), the PRO data are generally not reportable as 
individual AEs and thus will not be reported or reconciled as such. 
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9.2.2. 
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 participant is a passenger). 
• Is life-threatening – in the view of the investigator, the participant 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 participant 
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.  
9.2.3. 
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.  
9.2.4. 
Severity 
The severity of AEs will be graded according to the following scale: 
Mild: Does not interfere in a significant manner with the participant’s 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 participant. 
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 participant’s health. Treatment for symptom may be given and/or participant 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 
emergency room visit or hospitalization; necrosis or exfoliative dermatitis 
9.2.5. 
Causality 
The investigator must provide causality assessment as to whether or not there is a reasonable 
possibility that the drug caused the AE, 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. 
For double blinded studies using an active comparator, the investigator should consider all study 
drugs in determining event causality.  
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable  
• Participant’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, participant’s 
clinical state (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, participant’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, 
participant’s clinical state (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, participant’s clinical 
state (eg, disease under study, concurrent diseases, and concomitant medications) 
or other external factors. 
9.3. 
Safety Monitoring 
The investigator will monitor the safety of study participant 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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9.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, Institutional Review 
Boards (IRBs)/Ethics Committees (ECs), and the participating investigators of any Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring in other study centers or other studies 
of the active study drug (REGN5713-5714-5715, REGN5713-5715, or REGN5715), 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 IRB/EC unless delegated to the sponsor. 
Event expectedness for study drug (REGN5713-5714-5715, REGN5713-5715, or REGN5715) 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 CSR to health authorities and IRB/EC as appropriate. 
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10. 
STATISTICAL PLAN 
10.1. 
Statistical Hypothesis 
The following hypotheses of the primary endpoint will be tested for each active treatment group 
versus placebo: 
H0: The mean of TNSS in a birch allergen EEU at day 29 in Part A is equal between active 
treatment group and placebo. 
H1: The mean of TNSS in a birch allergen EEU at day 29 in Part A is different between 
active treatment group and placebo. 
The statistical hypothesis specified above can be tested on the selected secondary endpoints at a 
2-sided 5% significance level. The study will be declared positive if at least the null hypothesis for 
the primary efficacy endpoint for REGN5713-5714-5715 versus placebo is rejected. 
10.2. 
Justification of Sample Size 
This study is powered to detect differences between REGN5713-5714-5715 900 mg and placebo 
on the primary endpoint of the mean of TNSS during a birch pollen EEU challenge (2 to 6 hours) 
at day 29 in Part A. A sample size of 65 participants per arm gives 90% power to detect a mean 
difference in average TNSS (2 to 6 hours) of 1.61 (30% reduction from placebo) between 
REGN5713-5714-5715 (mean TNSS = 3.74) and placebo (mean TNSS = 5.35), assuming a 
common standard deviation of 2.8. Assuming 10% dropout, approximately 73 participants per arm 
will be required to detect a difference of 1.61 in mean TNSS between REGN5713-5714-5715 
(3-mAb) and placebo with a minimum detectable difference of 1.0 (~19% reduction from placebo 
in mean TNSS). Across all 4 treatment arms, the proposed sample size is approximately 300 
participants. 
This sample size is calculated at a 2-sided significance level of 5% using a 2-sample t-test. 
Estimates of mean in placebo and variability of the TNSS are based on birch tree SLIT‐tablet data 
(Couroux, 2019), 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. 
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
The efficacy endpoints in Part A will be analyzed using the full analysis set (FAS), which consists 
of all randomized participants. The efficacy analysis set is based on the treatment allocated (as 
randomized).  
The efficacy endpoints in Part B will be analyzed using the modified FAS (mFAS), which consists 
of participants who receive study drug in Part B.  
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10.3.2. 
Safety Analysis Set 
The safety analysis will be based on the safety analysis set (SAF), defined as all randomized 
participants who receive any study drug, regardless of the amount of treatment administered. The 
SAF is based on the treatment received (as treated).  
10.3.3. 
Pharmacokinetic Analysis Set 
The PK analysis population includes all participants who received any study drug (safety 
population) and who had a at least 1 non-missing serum drug concentration following a single dose 
of REGN5713-5714-5715, REGN5713-5715, and/or REGN5715. Participants will be analyzed 
according to the treatment actually received. 
10.3.4. 
Immunogenicity Analysis Set 
The ADA analysis set will consist of all participants who received any study drug and had at least 
1 non-missing ADA result after a single dose of study drug. Participants will be analyzed according 
to the treatment actually received. 
10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of participants 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. 
10.4.1. 
Participant Disposition 
The following will be provided: 
• The total number of screened participants who have signed the ICF 
• The total number of randomized participants: received a randomization number 
• The total number of participants in each analysis set (eg, FAS, provided in 
Section 10.3.1) 
• The total number of participants who discontinued the study, and the reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic variables (eg, age, race, and gender), baseline characteristics, medical history, and 
prior and concomitant mediations and therapies will be summarized by treatment group. See 
Section 4.1 for a full list of demographic and baseline variables. No statistical hypothesis tests will 
be performed on these characteristics.  
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10.4.3. 
Efficacy Analyses 
Part A data (as described below) will be used to evaluate the efficacy of the anti-Bet v 1 
antibody(ies) and delineate the contribution of components using comparisons with placebo and 
between active treatment arms: 
a. Assess the efficacy in the reduction of allergic symptoms during birch EEU challenges 
and birch skin test reactivity (TNSS [2 to 6 hours], TOSS [2 to 6 hours], TSS [2 to 6 
hours]) and titrated SPT AUC] to determine treatment effects and durability of 
response.  
b. Compare the proportions of birch-allergic participants achieving different degrees of 
clinical responses (TNSS [2 to 6 hours], TOSS [2 to 6 hours], TSS [2 to 6 hours] and 
titrated birch SPT AUC) across different response thresholds to evaluate the benefit of 
added epitope coverage.  
c. In the subpopulation of oak-allergic participants, assess the treatment effect in the 
reduction of allergic symptoms during the oak EEU challenge and oak skin test 
reactivity (TNSS [2 to 6 hours], TOSS [2 to 6 hours], TSS [2 to 6 hours] and titrated 
oak SPT AUC) at day 36 to evaluate clinical efficacy against oak  
Other relevant differences identified between the antibody combinations may also be considered 
in the decision-making process. 
Six comparisons between treatment groups can be made: 
1. REGN5713-5714-5715 versus placebo 
2. REGN5713-5715 versus placebo 
3. REGN5715 vs placebo 
4. REGN5713-5714-5715 versus REGN5715 
5. REGN5713-5714-5715 versus REGN5713-5715 
6. REGN5713-5715 versus REGN5715 
These 6 comparisons may be applied for efficacy endpoints. Additional details will be provided in 
the statistical analysis plan (SAP). 
10.4.3.1. Primary Efficacy Analysis 
The average of TNSS (2 to 6 hours) in a birch allergen EEU at day 29 in Part A will be analyzed 
by an analysis of covariance (ANCOVA) model, with the treatment group and randomization 
stratification factors (oak allergy, grass sensitization, EEU site) as fixed effects and the baseline 
TNSS (average TNSS [2 to 6 hours] during birch allergen EEU at screening) as a covariate.  
If any rescue treatments are taken during the EEU challenge, the data from this EEU will be set as 
missing and day 29 will be imputed by baseline observation carried forward (BOCF). Otherwise, 
all observed data will be used.  
Missing data will be imputed by multiple imputation (MI). Additional details will be specified in 
the SAP.  
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The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the estimand for the primary endpoint are summarized in Table 2.  
Table 2: 
Summary of Estimand for Primary Endpoint 
Endpoint 
Category 
Estimand 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy and missing data handling 
Population-level 
summary 
Primary endpoint 
– Continuous 
Mean of Total 
Nasal 
Symptom 
Score (TNSS) 
(2 to 6 hours) 
in a birch 
allergen EEU 
at day 29 in 
Part A 
FAS 
The intercurrent events will be handled 
as follows: 
• Relevant prohibited medication1 
taken prior to the EEU challenge:  
all available data will be utilized 
(treatment policy) 
• Rescue treatment taken during the 
EEU challenge2 : the data from 
this EEU after the use of the 
rescue medication will be set to 
missing and assigned by baseline 
observation carried forward 
(composite strategy) 
In addition, missing data due to any 
reason will be imputed using multiple 
imputation (MI).  
ANCOVA model 
with treatment 
group and 
stratification factors 
as fixed effect and 
baseline as a 
covariate. 
[1] Relevant prohibited medication will be defined in the SAP 
[2] Per Section 7.2, rescue medication may be given during the EEU challenge if any severe or clinically concerning 
reactions (as judged by the investigator) 
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be performed for the primary efficacy endpoint with respect to age group, gender, and other 
factors that will be specified in the SAP. 
10.4.3.2. Secondary Efficacy Analysis 
The secondary continuous efficacy endpoints will be analyzed in a manner similar to that described 
above (Section 10.4.3.1) for the primary efficacy endpoint analysis unless further specified below. 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the estimand for the continuous secondary efficacy endpoint from out-of-season EEU challenges 
may be the same as in Table 2, with details to be specified in the SAP. Descriptive analyses may 
be applied for efficacy endpoints unless specified in the SAP.  
Additional details will be specified in the SAP. 
The proportions of participants achieving different degrees of clinical responses and 
change/percent change from pre-treatment baseline in TNSS (2 to 6 hours), TOSS (2 to 6 hours), 
and TSS (2 to 6 hours) will be compared graphically using the cumulative distribution function.  
The AUC of the responder curves may also be calculated as a descriptive summary to compare 
across different symptom thresholds at days 29, 57, and 85 after receiving a single dose of 
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For the secondary endpoints from titrated SPT, if the antihistamines are not withheld before the 
titrated SPT, the data from this titrated SPT will be assigned by worst observation from the 
participant, including baseline.  
The proportions of participants achieving different degrees of change and percent change from 
pre-treatment baseline in the birch (and related allergens) titrated SPT mean wheal diameter AUC 
will be compared graphically using the cumulative distribution function. The AUC of the 
responder curves may also be calculated as a descriptive summary to compare across different 
thresholds at days 29, 57, 85 in participants receiving REGN5713-5714-5715, REGN5713-5715, 
or REGN5715. Additional details will be specified in the SAP. 
10.4.3.3. Exploratory Efficacy Analysis 
The exploratory efficacy endpoints, including mean of symptom scores (ie, TNSS [2 to 6 hours], 
TOSS [2 to 6 hours], and TSS [2 to 6 hours]) during end-of-season birch allergen EEU challenges, 
daily CSMS, TSS, TNSS, TOSS, and DMS averaged during the OPS, change and percent change 
from baseline in CSMS, TSS, TNSS, TOSS, and DMS averaged during the OPS, will be analyzed 
in the same fashion as the primary analysis. 
Within-participant comparisons of the treatment effect of anti-Bet v 1 antibodies or placebo to 
reduce allergic symptoms between the EEU challenges and the field may be explored via the 
correlation coefficient, mean difference, and heteroscedasticity calculated on the following 
metrics: 
• Average symptom score (2 to 6 hours) for TNSS, TOSS, TSS in a birch pollen EEU as 
compared to average symptom score for TNSS, TOSS, TSS during the birch pollen 
season and peak birch pollen season 
Similar analysis will be performed for the within-participant comparisons of the treatment effect 
of the anti-Bet v 1 antibodies or placebo to reduce allergic symptoms between out-of-season and 
in-season during the EEU challenges based on the following metrics: 
• Change and percent change from pre-treatment baseline for TNSS, TOSS, TSS in birch 
pollen EEU challenges 
Within-participant comparisons of the treatment effect of the anti-Bet v 1 antibodies or placebo to 
inhibit the skin test reactivity (using birch and related allergen titrated skin prick tests) will be 
explored similarly based on the following metrics: 
• Change and percent change from pre-treatment baseline for titrated SPT mean wheal 
diameter AUC 
10.4.4. 
Control of Multiplicity 
The study is powered on the comparison of the primary endpoint between REGN5713-5714-5715 
and placebo for Part A of the study with 2-sided alpha level of 0.05. 
Multiplicity controlled testing procedures will be used to control the overall type I error rate in 
Part A, for testing multiple comparison groups. Additional details will be specified in the SAP. 
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10.4.5. 
Safety Analysis 
The safety analysis will be based on the SAF.  
The safety variables, including AEs, laboratory parameters, vital signs, and physical examinations, 
will be summarized using descriptive statistics. 
10.4.5.1. Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
• The pretreatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The on-treatment period is defined as the day from first dose of study drug to the end 
of the study.  
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 and follow-up period. 
Analysis 
All adverse events reported in this study will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA®).  
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of participants with at least 1 TEAE by system 
organic class (SOC) and preferred term (PT) 
• TEAEs by severity (according to the grading scale outlined in Section 9.2.4), presented 
by SOC and PT 
• Treatment-related TEAEs, presented by SOC and PT 
• Treatment-emergent AESIs (which are defined in Section 9.1.4) 
• Deaths, SAEs, and TEAE leading to permanent treatment discontinuation will be 
summarized by SOC and PT. 
10.4.5.2. Other Safety 
Vital Signs 
Vital signs (pulse, blood pressure, respiration rate, and temperature) will be summarized by 
baseline and change from baseline to each scheduled assessment time point with descriptive 
statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time point with descriptive statistics. 
Number and percentage participants with a potentially clinically significant value (PCSV) at any 
post-randomization time point will be summarized for each clinical laboratory test.  
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10.4.5.3. Treatment Exposure 
Treatment exposure is defined as the number of study treatment administrations for each 
participant in each study part. Since each part only has a single-dose, participants will have 1 study 
treatment administration, given as 3 injections sequentially on one day. Summary of the number 
of 
injections 
will 
be 
provided. 
Treatment 
compliance 
is 
not 
applicable.  
For each study part, the duration of observation period is calculated as: 
(Date of the last visit in the corresponding part – date of the investigational product administration) 
+1. 
Duration of observation period will be summarized for each treatment group using the number of 
participants, means, SD, minimums, medians, and maximums. 
10.4.6. 
Pharmacokinetics 
10.4.6.1. Analysis of Drug Concentration Data 
The concentrations of total REGN5713, total REGN5714, and total REGN5715 over time will be 
summarized by descriptive statistics for each of the treatment groups.  
No formal statistical hypothesis testing will be performed.  
10.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA response 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, ADA titers 
positivity presented by participant, time point, and treatment arm will be provided separately for 
REGN5713, REGN5714, and REGN5715. Incidence of treatment-emergent ADA will be assessed 
as absolute occurrence (N) and percent of participants (%), grouped by study cohorts and ADA 
titer level. 
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
evaluated separately for REGN5713, REGN5714, and REGN5715. Assessment of impact of ADA 
on safety and efficacy may be provided. 
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10.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Biomarker results will be summarized by baseline, measured values, change from baseline, and 
percent change from baseline to each scheduled assessment time point with descriptive statistics. 
The correlation between clinical response to anti-Bet v 1 antibodies and poly/mono-sensitization 
during EEU challenges and field data assessments will be explored. Subgroup analyses in 
participants polysensitized (to unrelated allergens) and those with comorbid pollen food allergy 
syndrome will be conducted. 
10.5. 
Timing of Statistical Analysis 
The primary analysis may be performed after all participants complete at least the day 29 EEU 
challenges (visit 6) in Part A or discontinue. A select team will be unblinded to review the results 
but to ensure study integrity, the team members directly involved in the continued conduct of the 
trial will remain blinded. Further study blinding implications are discussed in Section 7.6.  
Final unblinded analyses of the study results for efficacy endpoints may be performed when all 
randomized participants have completed visit 14 (after end of BPS). These will be considered the 
final analyses for the efficacy endpoints. Additional data between this database lock and last 
participant completing the last visit will be summarized in the CSR. 
10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 14.1. 
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11. 
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.  
11.1. 
Data Management and Electronic Systems 
11.1.1. 
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. 
11.1.2. 
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 – Argus 
• e-diary 
11.2. 
Study Monitoring 
11.2.1. 
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 participants are being protected, and that the study is being conducted 
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in accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements. 
11.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate participants 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. 
11.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel. All required CRFs must be completed for each and 
every participants 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 participant, the investigator must provide an electronic signature. A copy of each participant 
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. 
11.3. 
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. 
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In all instances, the confidentiality of the data must be respected. 
11.4. 
Study Documentation 
11.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of 
participant final CRF/eCRF that will be provided to the sponsor. 
11.4.2. 
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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12. 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1. 
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. 
12.2. 
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 participant 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 
participant in language that he/she can understand. The ICF should be signed and dated by the 
participant and by the investigator or authorized designee who reviewed the ICF with the 
participant.  
• Participants who can write but cannot read will have the ICF read to them before 
signing and dating the ICF. 
• Participants 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 participant’s study record, and 
a copy of the signed ICF must be given to the participant. 
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 participants 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 participant’s study record and a copy must be given to the participant. 
12.3. 
Participants Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
participant will be maintained. Participants should be identified by a participant 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 participant’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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12.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, and any other materials to be provided to the participants 
(eg, advertising) before any participant 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 participant, 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 participants 
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. 
12.5. 
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. 
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13. 
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.  
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14. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
14.1. 
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. 
14.2. 
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 participant 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 participants 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 participants’ interests. 
15. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
16. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
17. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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Communications 2018; 9(1). 
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Pablos I, Wildner S, Asam C, Wallner M,Gadermaier G. Pollen Allergens for Molecular 
Diagnosis. Curr Allergy Asthma Rep 2016; 16(4):31. 
Persi L, Demoly P, Harris AG, Tisserand B, Michel FB,Bousquet J. Comparison between nasal 
provocation tests and skin tests in patients treated with loratadine and cetirizine. J Allergy Clin 
Immunol 1999; 103(4):591-594. 
Roberts G, Pfaar O, Akdis CA, Ansotegui IJ, Durham SR, Gerth van Wijk R, et al. EAACI 
Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis. Allergy 2018; 73(4):765-
798. 
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):350-359. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol 2006; 117(2):391-397. 
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):1290-1300. 
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). 
Uermosi C, Beerli RR, Bauer M, Manolova V, Dietmeier K, Buser RB, et al. Mechanisms of 
allergen-specific desensitization. J Allergy Clin Immunol 2010; 126(2):375-383. 
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-
1286.e1279. 
Walker SM, Durham SR, Till SJ, Roberts G, Corrigan CJ, Leech SC, et al. Immunotherapy for 
allergic rhinitis. Clinical & Experimental Allergy 2011; 41(9):1177-1200. 
Zhang Y,Steiner AL. Projected climate-driven changes in pollen emission season length and 
magnitude over the continental United States. Nature Communications 2022; 13(1):1234. 
Zuberbier T, Bachert C, Bousquet PJ, Passalacqua G, Walter Canonica G, Merk H, et al. 
GA2LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and 
asthma. Allergy 2010; 65(12):1525-1530. 
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19. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Two-Part Randomized, Double-Blind, Placebo-Controlled 
Study to Assess the Efficacy of the Anti-Bet v 1 Monoclonal Antibodies to Reduce Allergic 
Rhinitis and Conjunctivitis Symptoms and Skin Test Reactivity upon Exposure to Birch Allergen 
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 Two-Part Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy of the Anti-Bet v 1 Monoclonal Antibodies to Reduce Allergic Rhinitis and Conjunctivitis 
Symptoms and Skin Test Reactivity upon Exposure to Birch Allergen  
Protocol Number: 
R5713-5714-5715-ALG-21111 
Protocol Version:  
Amendment 1 
 
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-00184270 v2.0
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Approval/eSignature
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Approval/eSignature
11-Nov-2022 17:01:50 GMT+0000
Approval/eSignature
11-Nov-2022 17:31:44 GMT+0000
Approval/eSignature
11-Nov-2022 17:31:56 GMT+0000
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SAP_001.pdf: 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 68 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-3.0 
July 1, 2022 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: 
A Two-Part Randomized, Double-Blind, Placebo-
Controlled Study to Assess the Efficacy of the Anti-
Bet v 1 Monoclonal Antibodies to Reduce Allergic 
Rhinitis and Conjunctivitis Symptoms and Skin 
Test Reactivity upon Exposure to Birch Allergen  
Compound: 
REGN5713, REGN5714, REGN5715 
Protocol Number: 
R5713-5714-5715-ALG-21111 Amendment 1 
Clinical Phase: 
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Versions/Dates: 
Original Statistical Analysis Plan / 31 May, 2023 
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Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 2 of 68 
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 Clinical Pharmacologist 
 
See appended electronic signature page 
Study Bioanalytical Scientist 
 
See appended electronic signature page 
Study Medical Director 
 
See appended electronic signature page 
Project Biostatistician
 
See appended electronic signature page 
Head of BDM or designee 
 
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Statistical Analysis Plan 
Date: May 31, 2023 
 
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Page 3 of 68 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Study Description and Objectives ................................................................................8 
1.1.1. 
Primary Objective(s) .....................................................................................................8 
1.1.2. 
Secondary Objective(s) .................................................................................................8 
1.1.3. 
Exploratory Objectives ...............................................................................................10 
1.2. 
Statistical Hypothesis ..................................................................................................11 
1.3. 
Interim Analysis/Planned Analyses ............................................................................11 
1.4. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design ...............................................................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................15 
3. 
ANALYSIS SETS ......................................................................................................16 
3.1. 
The Full Analysis Set (FAS) .......................................................................................16 
3.2. 
Modified Intent-to-Treat Set (mITT) ..........................................................................16 
3.3. 
Part A Completers Set (CS-A) ....................................................................................16 
3.4. 
The Safety Analysis Set (SAF) ...................................................................................16 
3.5. 
Immunogenicity Analysis Sets ...................................................................................17 
3.5.1. 
ADA Analysis Set (AAS) ...........................................................................................17 
3.6. 
Pharmacokinetic Analysis Set (PKAS) ......................................................................17 
4. 
GENERAL STATISTICAL ANALYSIS CONSIDERATIONS ...............................18 
5. 
PATIENT DISPOSITION ..........................................................................................19 
5.1. 
Screening Dispositions ...............................................................................................19 
5.2. 
Treatment Period Dispositions ...................................................................................19 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................20 
6.1. 
Demographics .............................................................................................................20 
6.2. 
Baseline Disease Characteristics ................................................................................20 
6.3. 
Medical History ..........................................................................................................21 
7. 
EFFICACY/PHARMACODYNAMIC DATA ..........................................................22 
7.1. 
Description of Efficacy/Pharmacodynamic Data .......................................................22 
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7.1.1. 
Primary Efficacy Data ................................................................................................25 
7.1.2. 
Secondary Efficacy Data ............................................................................................25 
7.1.3. 
Exploratory Efficacy Data ..........................................................................................27 
7.2. 
Analysis of Efficacy/Pharmacodynamic Data ............................................................28 
7.2.1. 
Analysis of the Primary Endpoint...............................................................................28 
7.2.1.1. 
Estimand Framework for the Primary Endpoint .........................................................28 
7.2.1.2. 
Sensitivity Analyses/Supplemental Analyses .............................................................30 
7.2.1.3. 
Subgroup Analyses .....................................................................................................31 
7.2.2. 
Analyses of Secondary Endpoints ..............................................................................31 
7.2.2.1. 
Estimand Framework for Secondary Endpoints .........................................................32 
7.2.3. 
Analysis of Exploratory Endpoints .............................................................................34 
8. 
HYPOTHESIS TESTING METHODS AND MULTIPLICITY CONTROL ...........35 
8.1. 
Hypotheses Testing Methods ......................................................................................35 
8.2. 
Multiplicity Control ....................................................................................................35 
9. 
SUMMARY OF EXPOSURE DATA ........................................................................36 
9.1. 
Investigation Study Drug Exposure and Compliance .................................................36 
9.2. 
Duration of Follow-up ................................................................................................36 
9.3. 
Prior and Concomitant Medications ...........................................................................36 
9.4. 
Prior and Concurrent Procedures ................................................................................37 
10. 
ANALYSIS OF SAFETY DATA ..............................................................................38 
10.1. 
Adverse Events ...........................................................................................................38 
10.1.1. 
Adverse Events of Special Interest .............................................................................39 
10.2. 
Laboratory Parameters ................................................................................................40 
10.3. 
Vital Signs ..................................................................................................................41 
10.4. 
Other Safety Data .......................................................................................................41 
10.5. 
Immunogenicity Data .................................................................................................41 
10.5.1. 
Immunogenicity Variables ..........................................................................................41 
10.5.2. 
Analysis of Immunogenicity Data ..............................................................................42 
10.5.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................43 
10.5.3.1. 
Immunogenicity and Exposure ...................................................................................43 
10.5.3.2. 
Immunogenicity and Safety and Efficacy ...................................................................43 
10.6. 
Pharmacokinetic Data .................................................................................................44 
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Statistical Analysis Plan 
Date: May 31, 2023 
 
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10.6.1. 
Pharmacokinetic Variables .........................................................................................44 
10.6.2. 
Analysis of Pharmacokinetic Data ..............................................................................44 
10.7. 
Biomarker Data ...........................................................................................................44 
11. 
DATA CONVENTIONS ............................................................................................45 
11.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................45 
11.2. 
Data Convention .........................................................................................................45 
11.3. 
Data for Non-Efficacy Endpoints ...............................................................................46 
11.4. 
Assignment of Data to Visit Windows and Unscheduled Assessments .....................48 
11.5. 
Pooling of Categorical Variables for Statistical Analyses ..........................................50 
12. 
TECHNICAL DETAILS PERTAINING TO INTERIM ANALYSIS/(ES) ..............51 
13. 
REFERENCES ...........................................................................................................52 
14. 
APPENDIX.................................................................................................................53 
14.1. 
Summary of Statistical Analyses ................................................................................53 
14.2. 
Schedule of Events .....................................................................................................55 
14.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................64 
14.4. 
Search Criteria for TEAE of Special Interest .............................................................66 
14.5. 
Sensitization Status by SPT or sIgE ...........................................................................67 
 
LIST OF TABLES 
Table 1: 
Modifications from the Statistical Section in the Protocol Amendment 1 .................11 
Table 2: 
Summary of Estimand for Primary Endpoint .............................................................29 
Table 3: 
Summary of Estimands for Secondary Endpoints ......................................................33 
Table 4: 
Analysis Visit Window for Safety and Laboratory Testings ......................................49 
Table 5: 
Summary of EEU Nominal and Derived Times .........................................................50 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................13 
 
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Statistical Analysis Plan 
Date: May 31, 2023 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADA     
Anti-drug antibody 
AE      
Adverse event 
AESI    
Adverse event of special interest 
ALT     
Alanine aminotransferase 
AST     
Aspartate aminotransferase 
AUC     
Area under the curve 
BOCF    
Baseline observation carried forward 
BPS     
Birch pollen season 
BUN     
Blood urea nitrogen 
CRF     
Case report form (electronic or paper) 
CSAC 
Clinique Spécialisée en Allergie de la Capitale 
CSMS    
Combined Symptom and Medication Score 
DMS     
Daily Medication Score 
ECG     
Electrocardiogram 
EEU     
Environmental exposure unit 
EOS     
End-of-study 
FAS     
Full analysis set 
FDA     
United States Food and Drug Administration 
ICF     
Informed consent form 
ISR 
Injection Site Reaction 
mAb(s)  
Monoclonal antibody(ies) 
MWD 
Mean wheal diameter 
MI      
Multiple imputation 
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Statistical Analysis Plan 
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OPS     
Oak pollen season 
PFASQ   
Pollen Food Allergy Symptom Questionnaire 
PK      
Pharmacokinetic 
PI      
Principal investigator 
RBC     
Red blood cell 
Regeneron  
Regeneron Pharmaceuticals, Inc. 
RQLQ(S)    
Rhinoconjunctivitis Quality of Life Questionnaire 
SAE        
Serious adverse event 
SAF        
Safety analysis set 
SAP        
Statistical analysis plan 
SC         
Subcutaneous 
sIgE       
Allergen-specific immunoglobulin E 
SCIT        
Subcutaneous immunotherapy 
SLIT       
Sublingual immunotherapy 
SOC        
System organ class 
SPT        
Skin prick test [tSPT = SPT using serial allergen titrations] 
TEAE       
Treatment-emergent adverse event 
TNSS       
Total Nasal Symptom Score 
TOSS       
Total Ocular Symptom Score 
TSS        
Total Symptom Score 
WBC   
White blood cell 
 
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Statistical Analysis Plan 
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1. 
OVERVIEW 
The Statistical Analysis Plan (SAP) is intended to be a comprehensive and detailed description of 
the statistical methods, timing and presentation of analyses to be used for the study, as specified 
in protocol R5713-5714-5715-ALG-21111, amendment 1 dated Nov 11, 2022. 
1.1. 
Study Description and Objectives 
This two-part randomized, double-blind, placebo-controlled study is designed to assess the 
efficacy of the anti-Bet v 1 monoclonal antibodies to reduce allergic rhinitis and conjunctivitis 
symptoms and skin test reactivity upon exposure to birch allergen. The study will assess the 
efficacy of the anti-Bet v 1 monoclonal antibodies, in combination and as a single antibody. 
1.1.1. 
Primary Objective(s) 
The primary objective of this study is to assess the efficacy of a single dose of the anti-Bet v 1 
monoclonal antibodies in the reduction of allergic nasal symptoms during an out-of-season birch 
allergen environmental exposure unit (EEU) challenge in participants receiving REGN5713-5714-
5715 versus placebo (Part A).  
1.1.2. 
Secondary Objective(s) 
The secondary objectives are: 
Out-of-season Birch EEU challenges (Part A):  
• To assess the magnitude and duration of efficacy of a single dose of the anti-Bet v 1 
monoclonal antibodies (dose #1) in the reduction of allergic symptoms during the out-
of-season birch allergen EEU challenges in participants receiving REGN5713-5714-
5715 versus placebo, REGN5713-5715 versus placebo, and REGN5715 versus placebo  
• To compare differences in the degree of reduction of allergic symptoms during the out-
of-season EEU challenges in participants receiving the different combinations of the 
anti-Bet v 1 antibodies in those receiving REGN5713-5714-5715, REGN5713-5715, or 
REGN5715  
Out-of-season Oak EEU challenge (Part A): 
• To assess the efficacy of a single dose of the anti-Bet v 1 monoclonal antibodies (dose 
#1) in the reduction of allergic symptoms during the out-of-season oak allergen EEU 
challenge in the subpopulation of oak allergic participants in those receiving 
REGN5713-5714-5715 versus placebo, REGN5713-5715 versus placebo, and 
REGN5715 versus placebo  
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Statistical Analysis Plan 
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Titrated skin prick test endpoints (parts A and B): 
• To assess the efficacy of the anti-Bet v 1 monoclonal antibodies (dose #1) in the 
reduction of skin test reactivity from pre-treatment baseline by inhibiting a wheal 
response to a titrated skin prick test (SPT) with birch and related allergens (eg, alder, 
oak) during out-of-season assessments in participants who receive REGN5713-5714-
5715 versus placebo, REGN5713-5715 versus placebo, and REGN5715 versus placebo  
• To compare differences in the degree of reduction of skin test reactivity from pre-
treatment baseline by inhibiting a wheal response to a titrated SPT with birch and 
related allergens (eg, alder, oak) during out-of-season assessments in participants 
receiving the different combinations of the anti-Bet v 1 antibodies in those receiving 
REGN5713-5714-5715, REGN5713-5715, or REGN5715  
• To determine the efficacy of the anti-Bet v 1 monoclonal antibodies (dose #2) in the 
reduction of skin test reactivity from pre-treatment baseline by inhibiting a wheal 
response to a titrated SPT with birch and related allergens (eg, alder, oak) after the 
natural BPS in participants who receive REGN5713-5714-5715 versus placebo, 
REGN5713-5715 versus placebo, and REGN5715 versus placebo  
Peak season EEU challenge (Part B): 
• To assess the efficacy of the anti-Bet v 1 monoclonal antibodies (dose #2) in the 
reduction of allergic symptoms during the in-season birch allergen EEU challenge in 
participants receiving REGN5713-5714-5715 versus placebo, REGN5713-5715 versus 
placebo, and REGN5715 versus placebo  
In-season field data during birch pollen season (BPS) and peak BPS (Part B): 
• To determine the efficacy of the anti-Bet v 1 monoclonal antibodies (dose #2) in the 
reduction of allergic symptoms during the birch pollen season (BPS) and peak BPS in 
participants receiving REGN5713-5714-5715 versus placebo, REGN5713-5715 versus 
placebo, and REGN5715 versus placebo  
• To assess health-related quality of life during the BPS and peak BPS in participants 
who receive REGN5713-5714-5715 versus placebo, REGN5713-5715 versus placebo, 
and REGN5715 versus placebo 
Drug Concentration, Safety and Immunogenicity (Part A and Part B) 
• To evaluate the safety and tolerability of the anti-Bet v 1 monoclonal antibodies as 
compared to placebo following single administration (dose #1) and after repeat dosing 
(dose #2) 
• To determine systemic concentrations over time of total antibody (free + antigen-
bound) for each of the individual monoclonal antibody (mAb): REGN5713, 
REGN5714, and REGN5715 at various time points following single administration 
(dose #1) and after repeat dosing (dose #2) 
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• To assess the immunogenicity of REGN5713, REGN5714, and REGN5715 in birch-
allergic participants following single administration (dose #1) and after repeat dosing 
(dose #2). The study objectives must be copied verbatim from the corresponding 
protocol amendment. 
1.1.3. 
Exploratory Objectives 
The exploratory objectives are: 
• To assess the efficacy of a dose of the anti-Bet v 1 monoclonal antibodies (dose #2), 
given ahead of the anticipated BPS, in the reduction of allergic symptoms during the 
birch allergen EEU challenge at the end of the BPS in participants receiving the 
REGN5713-5714-5715 versus placebo, REGN5713-5715 versus placebo, and 
REGN5715 versus placebo (Part B) 
• To compare the within-participant magnitude of treatment effects as degree of 
responses in the reduction of allergic symptoms during the EEU challenges (out-of-
season and in-season) with the field data during BPS and peak BPS in participants 
receiving the anti-Bet v 1 antibodies or placebo 
• To compare the within-participant degree of responses in the reduction of allergic 
symptoms during the EEU challenges at different time points (out-of-season and in-
season) in participants receiving the anti-Bet v 1 antibodies or placebo 
• To compare the within-participant degree of responses in the reduction of skin test 
reactivity using titrated SPTs at different timepoints in participants receiving the anti-
Bet v 1 antibodies versus placebo 
• To determine the efficacy of the anti-Bet v 1 antibodies in the reduction of allergic 
symptoms during the natural oak pollen season (OPS) in the subpopulation of oak-
allergic participants in those receiving REGN5713-5714-5715 versus placebo, 
REGN5713-5715 versus placebo, and REGN5715 versus placebo (Part B) 
• To assess reduction in allergic reactions to foods associated with pollen food allergy 
syndrome in participants treated with anti-Bet v 1 antibodies versus placebo 
• To assess allergen-specific IgE levels (Bet v 1 and birch pollen) at screening/baseline to 
assess sensitization status and to evaluate the relationship between clinical response to 
anti-Bet v 1 antibodies and poly/mono-sensitization during EEU challenges and field 
data assessments 
• To assess allergen-specific IgE levels to other allergens (eg, Bet v 2, alder, grass) using 
blood samples collected at baseline to assess relationship between polysensitized status 
and response to anti-Bet v 1 antibodies during EEU challenges and field data 
assessments 
• To assess the inhibitory effect of anti-Bet v 1 antibodies on basophil activation after ex-
vivo stimulation with birch pollen extract 
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1.2. 
Statistical Hypothesis 
The following hypotheses of the primary endpoint will be tested: 
H0: The mean of TNSS in a birch allergen EEU at day 29 in Part A is equal between 
REGN5713-5714-5715 versus placebo. 
H1: The mean of TNSS in a birch allergen EEU at day 29 in Part A is different between 
REGN5713-5714-5715 versus placebo. 
1.3. 
Interim Analysis/Planned Analyses 
No formal interim analysis is planned.  
A primary analysis may be performed after all participants complete at least day 29 EEU 
challenges (visit 6) in Part A or discontinue from study. (Note: day 29 EEU challenge will be 
considered complete if visit 6 is not performed for any reason and participant is continuing into 
the subsequent part of the study). A select team will be unblinded at the database lock of Part A to 
review the results but to ensure study integrity, the team members directly involved in the 
continued conduct of the trial will remain blinded.  
Final database lock and unblinded analyses of the study results for efficacy endpoints will be 
performed when all randomized participants have completed visit 15 (EOS). These will be 
considered the final analyses for the efficacy endpoints. Additional data between this database lock 
and last participant completing the last visit will be summarized in the CSR or an addendum. 
1.4. 
Modifications from the Statistical Section in the Final Protocol 
No significant changes have been made to the key endpoints or statistical methods outlined in the 
protocol. However, there are some minor modifications, which are listed below: 
Table 1: 
Modifications from the Statistical Section in the Protocol Amendment 1 
Section 
Modification 
Section 3.1 
The abbreviation of “FAS – B” in Section 3.1 is  different from “mFAS” in 
protocol section 10.3.1 in format but the definition is still the same. 
Section 3.2 and 
Section 3.3 
Modified Intent-to-Treat Set (mITT) and Part A Completers Set (CS-A) are 
added in the analysis sets for supplemental analyses and within-participant 
comparisons. 
Section 7.1.2 
The following endpoints listed in protocol will be analyzed based on both 
pre-treatment and pre-season baseline: 
• The change and percent change from baseline in the symptom and 
medication scores (CSMS, TSS, TNSS, TOSS, and DMS), averaged 
during the BPS and peak BPS 
• The change and percent change from baseline in the symptom and 
medication scores, averaged during the OPS 
• Change and percent change from baseline in the Rhinoconjunctivitis 
Quality of Life Questionnaire (RQLQ(S]) score during BPS and peak 
BPS  
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Section 
Modification 
Section 7.2.1.1  
The pollen season occurring before Day 29 is identified as an intercurrent 
event of study primary objective and added in Section 7.2.1.1. As a result, 
associated estimands for efficacy endpoints at Day 29 are established. 
Section 7.2.3  
There are some additional exploratory analyses added. 
The combined active group is defined as participants who received any active 
treatment (REGN5713-5714-5715, REGN5713-5715, or REGN5715). For the 
oak allergen EEU challenge, the following endpoints will be analyzed by 
comparing the combined active group versus the placebo group.  
• The mean of symptom scores (TNSS [2-6 hours], TOSS [2-6 hours] 
and TSS [2-6 hours]) during out-of-season oak allergen EEU 
challenge at day 36  
• The change and percent change from pre-treatment baseline in 
symptom scores (TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 
hours]) during an oak allergen EEU at day 36  
• The change and percent change from pre-treatment baseline in the red 
oak titrated SPT mean wheal diameter (MWD) AUC  
The rationale is specified in Section 7.2.3.  
1.5. 
Revision History for SAP Amendments 
This is the original version of the SAP. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design  
The study consists of 2 parts for a total study duration of up to approximately 46 weeks (including 
up to a 10-week screening period) (Figure 1). Part A of the study lasts up to approximately 28 
weeks (including the screening period). Part B of the study starts after completion of Part A and 
lasts up to approximately 18 weeks (including an approximately 4-week follow-up period after 
end of BPS), dependent on the start and end times of the natural BPS. During the treatment period, 
there will be 2 visits during which study drug will be administered for a total of 6 injections. 
Participants will be randomized to receive placebo or 1 of 3 active treatment arms according to a 
central randomization scheme provided by an interactive voice response system (IVRS)/interactive 
web response system (IWRS). Stratification factors at randomization include oak allergy, grass 
sensitization status, and EEU site. 
Figure 1: 
Study Flow Diagram 
 
Randomization and Study Treatment 
Part A:  
Subcutaneous (SC) administration with a randomization ratio of 1:1:1:1 to 1 of 4 arms in a dose 
of study drug (dose #1) 
• REGN5713-5714-5715 900 mg (300 mg per mAb) [3-mAb cocktail] 
• REGN5713-5715 600 mg (300 mg per mAb) plus placebo that replaces REGN5714 
[2-mAb cocktail] 
• REGN5715 300 mg plus placebo that replaces REGN5713-5714 
• Matching placebo that replaces active drug 
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Part B:  
SC administration of a dose of study drug (dose #2) 
• REGN5713-5714-5715 900 mg (300 mg per mAb) [3-mAb cocktail] 
• REGN5713-5715 600 mg (300 mg per mAb) plus placebo that replaces REGN5714 
[2-mAb cocktail] 
• REGN5715 300 mg plus placebo that replaces REGN5713-5714 
• Matching placebo that replaces active drug 
Participants will receive the same treatment in Part B that they were originally randomized to 
receive in Part A. 
Randomization will be stratified based on following factors: 
• Oak allergy (yes or no) (oak allergy: TNSS ≥ 6 out of 12 on at least 2 timepoints 
during the oak EEU exposure challenge in screening period) 
• Grass sensitization status (grass sensitized: grass SPT ≥3 mm or allergen-specific 
immunoglobulin E (sIgE) ≥0.35; not grass sensitized: grass SPT <3 mm and sIgE 
<0.35) 
• EEU site 
Part A (out-of-season) and Part B (in-season)  
The efficacy will be tested out-of-season (Part A) as well as in-season (Part B) to fully evaluate 
treatment effects during experimental exposure to the allergen and also explore them during real-
world exposure to birch and other related/ unrelated pollens during the BPS. 
Out-of-season EEU challenges at visit 6, visit 8 and visit 9 with birch pollen and visit 7 with oak 
pollen (Part A) are expected to be completed outside of the local BPS.  
• Some participants that are symptomatic due to tree pollens may not complete day 57 
(visit 8) and/or day 85 (visit 9) birch EEU challenges.  
• For some participants that were enrolled later, out-of-season EEU challenges may not 
be performed if there is not sufficient time to complete the visit (within the protocol 
specified visit window) before the start of the local birch season. 
Timeframes for visits 10 to 15 (part B) are based upon the timing and duration of the anticipated 
local BPS. Therefore, the timing of these visits can vary and are dependent on the local pollen 
season and on timing of participant enrollment.  
(Note: Anticipated birch season timeframes are based on pollen projections, local climate 
predictions and historical pollen data (based on recommendations and data from local pollen 
expert in Canada [Aerobiology]. Current BPS and peak BPS are defined after local current pollen 
counts become available for the study year.) 
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• The daily symptom and medication scores are collected starting at visit 10 (visit 10 is 
intended to occur prior to the start of the local birch season to obtain a pre-season 
baseline) to the end of the study (visit 15).  
− For some participants, visit 10 may occur prior to completion of Part A visits as 
visit 10 is expected to be conducted prior to anticipated birch season start to allow 
for the collection of nasal and ocular allergy symptoms and allergy medication 
use before the start of the BPS.  
• At minimum, a 12-week interval between doses #1 and #2 is required. Dose #2 is 
intended to be given within 3 weeks prior to an anticipated birch season and a dosing 
stop date is defined within approximately 1 week after the concurrent birch pollen 
season start. Some participants may receive dose #2 after start of the birch pollen 
season. Some participants that are enrolled later in the study may not receive dose #2 
if they do not meet the minimum 12-week interval prior to the defined dosing stop 
date.   
• In-season peak EEU challenge at visit 13 is intended to be conducted in the birch 
season during the approximate anticipated peak season (after dose #2 for those 
expected to receive it) 
• End-of-season EEU challenge (visit 14) is expected to be performed after the end of 
the local birch season. (Note: Participants that are highly symptomatic to grass 
pollens or unable to wash out allergy rescue medications may not perform this EEU 
challenge.) 
2.2. 
Sample Size and Power Considerations 
During the study design stage, a sample size of 65 participants per arm was calculated to obtain 
90% power to detect a mean difference in average TNSS (2 to 6 hours) of 1.61 (30% reduction 
from placebo) between REGN5713-5714-5715 (mean TNSS = 3.74) and placebo (mean 
TNSS = 5.35), assuming a common standard deviation of 2.8. Assuming 10% dropout, 
approximately 73 participants per arm will be required to detect a difference of 1.61 in mean TNSS 
between REGN5713-5714-5715 (3-mAb) and placebo with a minimum detectable difference of 
1.0 (~19% reduction from placebo in mean TNSS). Across all 4 treatment arms, the proposed 
sample size is approximately 300 participants.  
This sample size is calculated at a 2-sided significance level of 5% using a 2-sample t-test. 
Estimates of mean in placebo and variability of the TNSS are based on birch tree SLIT‐tablet data 
(Couroux P, 2019), 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. 
Pollen related allergy trials are dependent on timing of the specific pollen seasons. As such, 
enrollment is affected by pollen season start dates. A sample size of 50 participants per arm gives 
approximately 80% power to detect a mean difference in average TNSS (2 to 6 hours) using the 
same assumptions. This study is powered to detect differences between REGN5713-5714-5715 
900 mg and placebo on the primary endpoint of the mean of TNSS during a birch pollen EEU 
challenge (2 to 6 hours) at day 29 in Part A. 
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3. 
ANALYSIS SETS 
The following defines the set(s) of subjects whose data will be used for statistical analyses. 
3.1. 
The Full Analysis Set (FAS) 
The efficacy endpoints in Part A will be analyzed using the Full Analysis Set (FAS), which consists 
of all randomized participants. The efficacy analysis set is based on the treatment allocated (as 
randomized).  
The efficacy endpoints in Part B will be analyzed using the FAS - B, which consists of 
participants who receive study drug in Part B.  
3.2. 
Modified Intent-to-Treat Set (mITT) 
The mITT includes all randomized participants that were eligible to complete their day 29 EEU 
challenge (visit 6) prior to the start of local birch pollen season. This mITT analysis set excludes 
any participants that were unable to complete their day 29 EEU challenge prior to their local birch 
season start (due to earlier than expected birch season start). 
3.3. 
Part A Completers Set (CS-A) 
The CS-A includes all randomized participants who complete all out-of-season birch EEU 
challenges in Part A (visit 6, visit 8, and visit 9). CS-A will be used to assess the durability of 
response in part A and evaluate within-participant changes over time in Part A. 
3.4. 
The Safety Analysis Set (SAF) 
The safety analysis will be based on the safety analysis set (SAF), defined as all randomized 
participants who receive any study drug, regardless of the amount of treatment administered. The 
SAF is based on the treatment received (as treated). As-treated is defined as when a patient receives 
at least one dose of any amount of study drug, in case of interrupted dosing. The patient will be 
regarded as treated with 3-mAb cocktail study drug REGN5713-5714-5715 if the patient receives 
at least 1 dose of the 3-mAb cocktail. Similarly, if a patient receives at least one dose of the 2-
mAb cocktail, but no doses of REGN5714, the patient will be considered treated with REGN5713-
5715.  If a patient receives at least one dose of the single mAb REGN5715 but no doses of 
REGN5713 or REGN5714, then the patient will be considered treated with REGN5715. If the 
patient receives no REGN5713, REGN5714, or REGN5715, the patient is considered as treated 
with placebo. 
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3.5. 
Immunogenicity Analysis Sets 
3.5.1. 
ADA Analysis Set (AAS) 
The ADA analysis sets (AAS) are defined for each study drug separately and include all treated 
participants who received any amount of study drug (active or placebo [SAF]) and had at least one 
non-missing ADA result following the first dose of the respective study drug or placebo. The ADA 
analysis set is based on the actual treatment received (as treated) rather than as randomized. 
3.6. 
Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set (PKAS) includes all participants who received any active drug and who had a 
at least 1 non-missing serum drug concentration following a single dose of study drug. Participants 
will be analyzed according to the treatment actually received rather than as randomized. 
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4. 
GENERAL STATISTICAL ANALYSIS CONSIDERATIONS 
Unless otherwise stated, the following conventions will be applied when presenting summary level 
statistics for data. 
Continuous variables will be summarized within each treatment group, presenting the following 
summary statistics.  The sample size (i.e. number of observations with an available value of the 
variable), average, sample standard deviation, median, minimum, maximum, 1st quartile and 3rd 
quartile. 
Categorical data will be summarized within each treatment group by frequency (i.e., total number 
of observations within each level of the categorical variable in a given treatment group).  All levels 
of the categorical variable will be included.  If there are observations where the level of the 
categorical variable is missing, a separate category titled “Missing” will be created.  For categorical 
variables that are ordinal in nature, the order in which the levels of the categories are displayed 
will be consistent with the natural ordering of the category levels.  Percentages will also be 
calculated for each level of the categorical variables with respect to the total sample size for the 
respective treatment arm.   
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5. 
PATIENT DISPOSITION 
5.1. 
Screening Dispositions 
The number of enrolled participants (i.e. participants who signed the informed consent form (ICF)) 
who are randomized (i.e. assigned a randomization number in the IWRS system) and screen-fail 
will be presented.  Participants who screen-fail will be broken out by screen-fail reason.  If 
applicable, the number of participants who are improperly randomized (i.e. did not meet study 
eligibility criteria yet were assigned a randomization number in the IWRS system) will also be 
displayed.  The corresponding percentages with respect to the total number of enrolled participants 
will also be presented. 
5.2. 
Treatment Period Dispositions  
A patient is considered to have completed the study treatment period if they make it to the End-
of-Study Visit (visit 15/day 253).  The disposition of all randomized participants during the study 
treatment period will be displayed by treatment group.   
The following summaries will be provided for each treatment group and total (unless otherwise 
specified): 
• Study drug administration 
• The total number of participants in each analysis set 
• The number of participants who complete the study treatment period 
• Duration of study treatment period  
• The number of participants completing each visit 
• The number of participants who withdraw from the study treatment period. This 
number will be further broken out by reason for early withdrawal and whether the 
early termination/ withdrawal was prior to or after the start of the local BPS. 
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6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1. 
Demographics 
The following demographic variables will be summarized by treatment group and overall:  
• Age at screening (years) as a continuous variable 
• Age categories (years, 18 to <50, >= 50) 
• Sex (Male, Female) 
• Race (American Indian or Alaskan Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not Reported) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported) 
• Weight (kg) 
• Height (cm) 
• Body mass index (BMI) (kg/m2) 
• EEU location (Cliantha, Kingston) 
• Site location (Cliantha, Kingston, CSAC) 
6.2. 
Baseline Disease Characteristics 
The following disease characteristics will be summarized by treatment group and overall:  
• Birch EEU Mean TNSS (2 to 6 hours), Mean TOSS (2 to 6 hours), Mean TSS (2 to 6 
hours) at Visit 2 
• Oak EEU Mean TNSS (2 to 6 hours), Mean TOSS (2 to 6 hours), Mean TSS (2 to 6 
hours) at Visit 3 [only for oak-allergic participants, i.e., those who developed a TNSS 
of at least 6 out of 12 at 2 or more timepoints during the screening oak EEU at visit 3] 
• Screening and randomization FEV1 (L and percent predicted) 
• Baseline history for allergic disease, including duration of disease [e.g., allergic 
rhinitis, allergic conjunctivitis, asthma and pollen food allergy, and prior SIT] (as 
recorded in CRF)  
• SPT mean wheal diameter for birch allergens, birch-related allergens, and unrelated 
allergens  (mm)  
• Serum total IgE (kU/L) 
• Serum allergen-specific IgE for birch allergens, birch-related allergens, and unrelated 
allergens (kU/L)  
• Serum allergen-specific birch IgE (<17.5 kUa/L; ≥17.5 kUa/L) 
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• Sensitization to allergens by either sIgE or by SPT 
• Sensitization status by sIgE or by SPT (sensitized to birch and related allergens only; 
sensitized to unrelated trees; sensitized to non-tree pollens; sensitized to indoor 
perennial allergens) 
• Serum Bet v 1 sIgG, birch sIgG, and oak sIgG (if data are available)  
Note: Refer to Section 14.5 for allergen definitions. 
6.3. 
Medical History 
Patient medical histories will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®).  The frequency and percentage of each medical history will be summarized by SOC 
and PT for each treatment arm, and overall using the FAS. 
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7. 
EFFICACY/PHARMACODYNAMIC DATA 
7.1. 
Description of Efficacy/Pharmacodynamic Data 
EEU Data (symptom scores recorded during the 6 hour EEU challenges): 
Nasal and ocular symptom data will be collected during EEU visits that occur during the screening 
period, out-of-season efficacy period, in-season efficacy period, and at end-of-season. The 
methodology for collecting and scoring the nasal and ocular symptom data in the EEU is consistent 
across all periods stated previously. 
• TNSS (2 to 6 hours):  
Instantaneous TNSS measures nasal symptom severity at the time point of 
assessment. In the EEU, instantaneous TNSS is recorded using an e-diary prior to 
start of pollen exposure and then approximately every 20 min during the 6-hour EEU 
pollen exposure.  
The instantaneous TNSS score 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 nasal 
congestion, itching, and runny nose, and sneezing. Higher score indicates worse 
symptoms. 
The mean TNSS (2-6 hours) is calculated as an average of the observed instantaneous 
TNSS scores during the 12 timepoints from hour 2 to 6 during the EEU session 
(details in Section 11.4). 
• TOSS (2 to 6 hours): 
Instantaneous TOSS measures ocular symptom severity at the time point of 
assessment. In the EEU, instantaneous TOSS is recorded using an e-diary prior to 
start of pollen exposure and then approximately every 20 min during the 6-hour EEU 
pollen exposure.  
The intantaenous TOSS score ranges from 0 to 6 and is based on 2 groups of eye 
symptoms: itching/redness/gritty feeling and tearing/watering. Each of the 2 symptom 
groups is graded on a Likert scale ranging from 0 (none) to 3 (severe). Higher score 
indicates worse symptoms. 
The mean TOSS (2-6 hours) is calculated as an average of the observed instantaneous 
TOSS scores during the 12 timepoints from hour 2 to 6 during the EEU session 
(details in Section 11.4). 
• TSS (2 to 6 hours) (calculated): 
The mean TSS (2 to 6 hours) is calculated as an average of the sum of observed 
instantaneous TNSS and instantaneous TOSS scores during the 12 timepoints from 
hour 2 to 6 during the EEU session (details in Section 11.4). The mean TSS (2 to 6 
hours) score ranges from 0 to 18 with higher scores indicating worse symptoms. 
Note: Baseline data are obtained from the screening baseline EEU challenge for birch (visit 2) 
and oak (visit 3).  
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Daily scores:  
Daily nasal, ocular, and medication data will be collected during pre-treatment baseline, pre-season 
baseline, and then starting at visit 10 until end of the study. The methodology for collecting and 
scoring the daily nasal, ocular, and medication data is consistent across all periods stated 
previously.  
• TNSS (daily) 
Reflective TNSS measures nasal symptom severity over the past 24 hours and is 
recorded before the participant goes to bed for the night. It is recorded daily using an 
e-diary in the Part B. All daily TNSS scores during the season after the dose #2 will 
be used to calculate the average TNSS, except for the day of and one day following 
EEU challenge in Part B. 
• TOSS (daily) 
Reflective TOSS is similar to the reflective TNSS defined above. 
• TSS (calculated) 
The TSS is calculated by adding the TNSS and TOSS together, with scores ranging 
between 0 and 18. Higher score indicates worse symptoms. 
• DMS (daily)  
To calculate the DMS, participants will be asked to record their daily rescue 
medication use using an e-diary before going to bed for the night, including which 
medications and the amount of these pre-specified medications. This information will 
be used to calculate the DMS for the following medications or the approved in-class 
equivalents, 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). DMS is recorded using an e-diary from 
visit 10 to visit 15, in addition to an approximately 2-week period during screening. After 
completion of the EEU challenges, use of allergy medicines will be recorded in the e-diary 
until approximately  24 hours after the start of the EEU challenges. All daily e-diary scores 
during the season after dose #2 will be used to calculate the average, except for the day of 
and one day following EEU challenge in Part B. 
• Daily CSMS (calculated) 
The CSMS is calculated by adding the DMS and TSS together, with scores ranging 
between 0 and 38. For each participant, an average of the daily symptom and 
medication scores is calculated during their local BPS. 
Note: Daily TNSS, TOSS, DMS, CSMS scores on the day of and the day after an EEU challenge 
will not be used as part of the field data calculations (to avoid any potential overlap of symptoms 
related to the EEU).  
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• Standardized RQLQ(S) for Ages 12+ 
The RQLQ(S) is a self-administered questionnaire to measure health-related quality 
of life in those 12 years of age and above, as a result of perennial or seasonal allergic 
rhinitis.  
There are 28 items on the RQLQ(S) in 7 domains: activity limitation, sleep problems, 
nasal symptoms, eye symptoms, non-nasal/eye symptoms, practical problems, and 
emotional function. The RQLQ(S) responses are based on a 7-point Likert scale with 
responses ranging from 0 (not troubled) to 6 (extremely troubled). 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. Higher scores indicated more health-related 
quality of life impairment (lower scores are better).  
Questionnaire is administered weekly (starting at visit 10 to the end of the study) and 
an average of the questionnaires during the BPS will be calculated.  
Titrated Skin Prick Testing for European White Birch, White Alder, and Red Oak 
Allergens 
The titrated SPT will be performed with 6 serial dilutions for three allergen extracts (European 
White Birch, White Alder, and Red Oak), a negative control, and a histamine positive control. 
Serial dilutions for each of the allergens will be created using diagnostic allergen extract (1:20 
weight/volume concentration). The 6 dilutions for the titrated SPT will be created as sequential 
50% dilutions to yield 1:40 w/v, 1:80 w/v, 1:160 w/v, 1:320 w/v, 1:640 w/v and 1:1280 w/v 
concentrations for each allergen. The mean wheal diameters for the 6 serial dilutions for each 
allergen will be used in the calculation of the area under the curve of the titrated SPT. 
The AUC of the titrated SPT mean wheal diameters will be derived using the trapezoidal rule.  For 
each patient, the AUC will be calculated for the mean wheal diametercalculated over the titrated 
concentrations of birch allergen on a log scale. For example, the AUC will be calculated using the 
formula (Orengo J, 2018): 
𝐴𝑈𝐶[Titrated SPT MWD] = [∑(𝑙𝑖+1
5
𝑖=1
−𝑙𝑖) ∗(𝐷𝑖+1 + 𝐷𝑖)/2] /(𝑙6 −𝑙1) 
Where  
• Di is the mean wheal diameter(in mm) obtained at concentration ci 
• 𝑙𝑖= log(𝑐𝑖), where ci is the concentration (in w/v units) for which Di is measured, 
such as c1 =1:40, c2 =1:80, c3 =1:160, c4 =1:320, c5 =1:640, c6 =1:1280. 
Note: c0  (1:20 w/v concentration of the diagnostic allergen extract) will not be used to 
calculated the AUC of the titrated SPT mean wheal diameters. Histamine phosphate 1 mg/ml for 
SPT will be used as the positive control. All normalized SPT values will be considered positive if 
>=3mm greater than the negative control 
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Definition Pollen Sites and Pollen Seasons  
Pollen Sites 
Pollen sites, based on local pollen counter locations, will be used to define the start and end of 
the local pollen season at the patient level.  
Birch pollen season 
Local pollen count data will be used to determine the start and end of the BPS for participants at 
each pollen site. The start of the BPS is defined as the first of 3 consecutive days with a pollen 
count of 10 grains/m3 or greater. The end of the BPS is defined as the last day of the last occurrence 
of 3 consecutive days with a pollen count of 10 grains/m3 or greater. Additionally, a threshold 
using 30 grains/m3 for defining the birch season may be used (higher threshold may be more 
consistent in predicting the onset of symptoms in birch allergic participants) (Caillaud, 2023; 
Taudorf, 1988; Biedermann, 2019). 
Peak birch pollen season 
Peak BPS is defined as the 15 consecutive days within the BPS with the highest 15-day moving 
average pollen count. 
Oak Pollen season 
The start of the OPS is defined as the first of 3 consecutive days with a pollen count of 10 grains/m3 
or greater. The end of the OPS 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 OPS is defined similarly to peak 
BPS, which is the 15 consecutive days within the OPS with the highest 15-day moving average 
pollen count. 
7.1.1. 
Primary Efficacy Data 
The primary efficacy endpoint in the study is the mean of Total Nasal Symptom Score [TNSS (2 
to 6 hours)] during a birch allergen EEU challenge at day 29. The primary comparison will be in 
participants receiving REGN5713-5714-5715 versus placebo. 
7.1.2. 
Secondary Efficacy Data  
Secondary endpoints, specified without order, are: 
Out-of-season Birch EEU challenges: Symptom endpoints (Part A) 
• The mean of symptom scores during out-of-season birch allergen EEU challenges at 
days 29, 57, and 85  
− TNSS (2 to 6 hours)  
− TOSS (2 to 6 hours) 
− TSS (2 to 6 hours) 
• The change and percent change from pre-treatment baseline in symptom scores 
(TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 hours]) during out-of-season 
birch allergen EEU challenges at days 29, 57, and 85  
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• The proportions of participants achieving different degrees of clinical responses will 
be compared across different symptom response thresholds (TNSS [2-6 hours], TOSS 
[2-6 hours] and TSS [2-6 hours]) at days 29, 57, and 85  
Out-of-season Oak EEU challenge: Symptom endpoints (Part A) 
(Note: Day 36 oak EEU challenges are performed only in the subgroup of oak allergic 
participants, [developed a TNSS of at least 6 out of 12 at 2 or more timepoints during the 
screening oak EEU at visit 3]) 
• The mean of symptom scores (TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 
hours]) during out-of-season oak allergen EEU challenge at day 36  
• The change and percent change from pre-treatment baseline in symptom scores 
(TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 hours]) during an oak allergen 
EEU at day 36  
Titrated skin prick test endpoints (parts A and B) 
• The change and percent change from pre-treatment baseline at days 29, 57, 85 and 
127 in the birch, alder and red oak titrated SPT mean wheal diameter AUC  
• The proportions of participants achieving different degrees of responses in the birch, 
alder and red oak titrated SPT mean wheal diameter AUC will be compared across 
different response thresholds at days 29, 57, and 85  
• The change and percent change from pre-treatment baseline to end-of-season and 
end-of-study (EOS) visits in the birch (and related allergens) titrated SPT mean wheal 
diameter AUC  
Peak season EEU challenge: Symptom endpoints (Part B)  
(Note: Peak season EEU is an in-season challenge corresponding to approximate timing of the 
peak BPS)  
• The mean of symptom scores (TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 
hours]) during the peak-season birch allergen EEU challenge  
In-season field data during birch pollen season (BPS) and peak BPS (Part B) 
• The daily symptom and medication scores (CSMS, TSS, TNSS, TOSS, and DMS), 
averaged during the BPS and peak BPS 
• The change and percent change from pre-treatment and pre-season baseline in the 
symptom and medication scores (CSMS, TSS, TNSS, TOSS, and DMS), averaged 
during the BPS and peak BPS 
• The mean of the total RQLQ(S) score during BPS and peak BPS  
• Change and percent change from pre-treatment and pre-season baseline in the 
RQLQ(S) score during BPS and peak BPS  
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Drug Concentration, Safety and Immunogenicity (Part A and Part B) 
• Incidence rates of treatment-emergent adverse events (TEAEs) and serious TEAEs 
through EOS 
• Total REGN5713, REGN5714, and REGN5715 concentration in serum over the 
duration of the study 
• Incidences and titers of ADA to REGN5713, REGN5714, and REGN5715 over time 
7.1.3. 
Exploratory Efficacy Data 
Exploratory endpoints, specified without order, are: 
• The mean of symptom scores (TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 
hours]) during end-of-season birch allergen EEU challenge (visit 14)  
• Within participant comparisons of the treatment effect of anti-Bet v 1 antibodies or 
placebo to reduce allergic symptoms between the EEU challenges (out-of-season and 
in-season) and the field, as estimated by the correlation coefficient, mean difference, 
and heteroscedasticity calculated on the following metrics: 
− Average symptom scores for TNSS (2-6 hours), TOSS (2-6 hours), TSS (2-6 
hours) in a birch pollen EEU as compared to average symptom score for TNSS, 
TOSS, TSS during the BPS and peak BPS 
− Change and percent change from pre-treatment baseline for TNSS (2-6 hours), 
TOSS (2-6 hours), TSS (2-6 hours) in birch pollen EEU challenges 
• Within participant comparisons of the treatment effect of the anti-Bet v 1 antibodies 
or placebo to inhibit the skin test reactivity (using birch and related allergen titrated 
SPTs), as estimated by the correlation coefficient, mean difference, and 
heteroscedasticity calculated on the following metrics: 
− Change and percent change from pre-treatment baseline for titrated SPT mean 
wheal diameterAUC 
• The pooled estimate for symptom scores (TNSS, TOSS and TSS) during peak-season 
birch allergen EEU challenge and daily scores during the BPS  
• The daily symptom and medication scores (CSMS, TSS, TNSS, TOSS, and DMS), 
averaged during the OPS  
− CSMS, TSS, TNSS, TOSS, and DMS, averaged during the OPS  
− The change and percent change from pre-treatment and pre-season baseline in the 
symptom and medication scores, averaged during the OPS 
• The incidence and severity of allergic reactions upon consumption of a food 
associated with birch pollen food allergy syndrome in participants receiving anti-Bet 
v 1 antibodies 
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7.2. 
Analysis of Efficacy/Pharmacodynamic Data  
Six comparisons between treatment groups will be made: 
1. REGN5713-5714-5715 versus placebo 
2. REGN5713-5715 versus placebo 
3. REGN5715 vs placebo 
4. REGN5713-5714-5715 versus REGN5715 (numerical comparison) 
5. REGN5713-5714-5715 versus REGN5713-5715 (numerical comparison) 
6. REGN5713-5715 versus REGN5715 (numerical comparison) 
7.2.1. 
Analysis of the Primary Endpoint 
The analysis of the primary efficacy variable will be performed using an analysis of covariance 
(ANCOVA) model, with the treatment group, randomization stratification factors (as stratified) as 
fixed-effects and TNSS baseline as a covariate.  
7.2.1.1. 
Estimand Framework for the Primary Endpoint 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the primary estimands of interest for the primary endpoint are provided in detail in Table 2. Day 29 
EEU data during out-of-birch pollen season are planned to assess in the protocol amendment #1 
dated November 2022. However, some randomized participants are not eligible to complete EEU 
Day 29 challenges due to early start of the pollen season. The pollen season occurring before 
Day 29 is identified as an intercurrent event for the study primary objective. The corresponding 
estimand framework is used by hypothetical setting not to collect EEU data at Day 29 (all values 
during EEU Visit 6 are missing). In cases where EEU assessments at Day 29 are collected after 
the pollen season, these collected EEU data will be set to missing (hypothetical strategy). 
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Table 2: 
Summary of Estimand for Primary Endpoint 
Endpoint 
Category 
Estimand 
Endpoint 
Population 
Intercurrent event(s) handling strategy and 
missing data handling 
Population-
level 
summary 
Primary 
endpoint – 
Continuous 
Mean Total 
Nasal 
Symptom 
Score 
(TNSS) (2 to 
6 hours) in a 
birch 
allergen 
EEU at day 
29 in Part A 
FAS 
The intercurrent events will be handled as follows: 
• 
Relevant prohibited medication1 taken prior to 
the EEU challenge: all available data will be 
utilized (treatment policy).  
• 
Any severe or clinically concerning adverse 
event necessitating removal from the chamber 
and/or use of rescue treatment2 taken during the 
EEU challenge:  data after exiting the EEU or 
the use of the rescue medication will be set to 
mean TNSS from 2 to 6 hours in the baseline 
EEU (BOCF, composite strategy) 
In addition, if all values during the EEU visit are 
missing due to any other reason, e.g., early start of 
BPS, then the averaged value will be imputed using 
multiple imputation (MI).  
ANCOVA 
model with 
treatment 
group and 
stratification 
factors as fixed 
effect and the  
baseline mean 
TNSS (2 to 
6 hours) at 
visit 2 as a 
covariate. 
[1] Relevant prohibited medications include allergy relieving medications (treatment policy); no participants used 
systemic steroids, biologics or immune therapeutics or allergen specific immunotherapy that are expected to 
impact type 2 allergic disease prior to completion of expected out-of-season EEU visits.   
[2] Per Section 7.2 in Protocol, rescue medication may be given during the EEU challenge if any severe or clinically 
concerning reactions (as judged by the principle investigator (PI)). These rescue medications used during the 
EEU may include but not limited to antihistamines, topical steroids, systemic steroids, bronchodilators, 
epinephrine (considered treatment failure and handled using composite strategy).  
For the MI procedure, the average EEU TNSS (2 to 6 hours) will be imputed 50 times to generate 
50 complete data sets utilizing the SAS procedure PROC MI. Note that any imputation by baseline 
EEU TNSS (2 to 6 hours) score as specified in Table 2 will occur prior to MI.  
Missing values of average EEU TNSS (2 to 6 hours) at day 29 will be imputed using a monotone 
regression method.  The imputation model will include the covariates in the ANCOVA model. 
Any score imputed outside the range of EEU TNSS (2 to 6 hours) (0 to 12) will be truncated to the 
nearest value of TNSS (2 to 6 hours) according to the following algorithm: 
− If the imputed score > 12, then the final imputed score will be 12. 
− If the imputed score < 0, then the final imputed score will be 0. 
Sample SAS syntax code for MI: 
proc mi data=mi3 out=mi4 nimpute=50 seed=571345; 
class TRTP STRAT1 STRAT2 STRAT3; 
monotone reg; 
var TRTP STRAT1 STRAT2 STRAT3 BASELINE TNSS29; 
run; 
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Each imputed data set will then be analyzed by ANCOVA as previously described. The SAS 
procedure PROC MIANALYZE will be used to generate valid statistical inferences by combining 
results from these 50 ANCOVA analyses using Rubin’s formula. The least squares means (LS-
means) estimates for the average EEU TNSS (2 to 6 hours) at day 29 of the treatment period for 
each treatment group, as well as the difference between the REGN5713-5714-5715 and placebo 
will be provided along with the corresponding 2-sided p-value and associated 95% confidence 
interval. 
7.2.1.2. 
Sensitivity Analyses/Supplemental Analyses 
Sensitivity analyses are planned to assess alternative missing data mechanisms. With respect to 
the missing data handling of EEU symptom score entries, sensitivity analyses will be performed 
to confirm robustness of the conclusion drawn based on the main model for primary analysis.  
Two supplemental analyses will be performed. One with all intercurrent events handled via a 
treatment policy for primary endpoint and only using all observed data. The other one with the 
primary endpoint analyzed using the mITT population. 
7.2.1.2.1. Tipping Point Analysis 
Sensitivity analysis using a tipping point approach with MI will be performed to assess the 
robustness of the results due to data that may be missing not-at-random (MNAR).  This approach 
will introduce a sensitivity parameter, delta.  Estimations will be performed using MI 
methodology.  The delta is 0%, 10%, 20%, 30%,…, 100% of the observed mean treatment 
difference between REGN5713-5714-5715 and placebo until conclusion from the primary analysis 
is overturned. When delta = 0, the missing data pattern is MAR; when delta>0, the missing data 
pattern is MNAR. The steps of performing tipping analysis are as below: 
1. Using a standard MAR-based MI approach from PROC MI to impute the data. Missing 
data will be imputed 50 times to generate multiple data sets with complete data. 
2. For participants in any of REGN5713-5714-5715 with a dropout from the corresponding 
scenario, a delta will be added after the dropout time.  
3. Using ANCOVA model in the primary analysis to analyze the completed data using 
PROC MIXED on the multiple imputed data  
4. Obtaining the overall results using PROC MIANALYZE 
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7.2.1.3. 
Subgroup Analyses  
Subgroups are defined by key baseline factors recorded on the CRF (unless otherwise specified) 
and listed as follows. The analysis for the subgroups (except for Race and Ethnicity) may not be 
performed if the number of participants within the subgroup is small, e.g., 20% or 11 participants 
for participants receiving REGN5713-5714-5715 and participants receiving placebo. 
Subgroups to be considered for primary efficacy endpoint: 
• Age group (Years: 18 to <50, ≥50) 
• Sex (Male, Female) 
• Ethnicity: Hispanic or Latino (Yes, No) 
• Race (White, Other) 
• Serum specific birch pollen IgE level at screening (<17.5 kUa/L, ≥17.5 kUa/L) 
• Oak allergy status (Based on the symptom scores collected at visit 3: Yes, No) 
• Pollen food allergy syndrome (Yes, No) 
• EEU site location (Cliantha, Kingston)   
• Baseline sensitization status based on sIgE or SPT (Sensitized to indoor perennial 
allergens, Not sensitized to indoor perennial allergens)  
Note: The stratification factor of grass sensitization status, is rather more related to field study 
in Part B, not to EEU. Thus, the stratification factor will not be used as the subgroup variable. 
Subgroups defined above for the primary endpoint for the participants receiving REGN5713-5714-
5715 versus placebo will be analyzed based on the FAS. If 2-mAb or 1-mAb arm demonstrates 
reasonable efficacy over placebo, then similarly, subgroup analyses may be performed on these 
arms. 
To assess the consistency in treatment effects across different subgroup levels, subgroup analyses 
will be performed for the primary efficacy endpoint using analysis method described in 
Section 7.2.1.1. If the model-based inferential statistics cannot be computed, or are deemed 
inappropriate, e.g. small number of participants in a subgroup, only descriptive statistics will be 
provided. 
Treatment difference and its 95% confidence interval in subgroups of subjects will be presented 
in forest plots. 
7.2.2. 
Analyses of Secondary Endpoints 
The secondary continuous efficacy endpoints will be analyzed in a manner similar to that described 
above (Section 7.2.1.1 Table 2) for the primary efficacy endpoint analysis unless further specified 
in Table 3. In addition, MI will only be applied for endpoints measured at Day 29.  
The proportions of participants achieving different degrees of clinical responses and percent 
change from pre-treatment baseline in TNSS (2 to 6 hours), TOSS (2 to 6 hours), and TSS (2 to 6 
hours) will be compared numerically and graphically using the cumulative distribution function. 
Participants receiving different combinations of the anti-Bet v 1 antibodies in those receiving 
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REGN5713-5714-5715, REGN5713-5715, or REGN5715 will be compared with placebo, as well 
as the comparison between any two active groups. The minimum percent improvement in relevant 
score will be plotted on the horizontal axis and proportion of participants will be plotted on the 
vertical axis for each treatment group separately.   The AUC of the responder curves derived using 
the trapezoidal rule will also be calculated as a descriptive summary to compare across different 
symptom thresholds [as well as including response thresholds such as 30%, 50%, 60%, 75% and 
90%], at days 29, 57, and 85 after receiving a single dose of REGN5713-5714-5715, REGN5713-
5715, or REGN5715.  
The proportions of participants achieving different degrees of change and percent change from 
pre-treatment baseline in the birch (and related allergens) titrated SPT mean wheal diameterAUC 
will be compared graphically using the cumulative distribution function. The AUC of the 
responder curves may also be calculated as a descriptive summary to compare across different 
thresholds [as well as including response threshold such as 30%, 50%, 60%, 75% and 90%] at 
days 29, 57, 85 in participants receiving REGN5713-5714-5715, REGN5713-5715, or 
REGN5715. 
Subgroups listed in Section 7.2.1.3 might also be applied for secondary endpoints for exploratory 
analysis. Additional potential sub-group analyses for in-season data: 
• Grass sensitization status  
• Timing of receipt of dose #2 relative to the local BPS (prior to the season start or after 
season start), as applicable 
• The interval between dose #1 and dose #2 ( the cutoff will be decided by the distribution 
of data, e.g., the median may be used), as applicable 
In addition, some in-season efficacy analyses in Part B may be performed including participants 
with available in-season data irrespective of whether they received dose 2. 
More details concerning other secondary endpoints, see Section 14.1. 
7.2.2.1. 
Estimand Framework for Secondary Endpoints 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the secondary estimands of interest for the secondary endpoints are provided in detail in Table 3:  
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Table 3: 
Summary of Estimands for Secondary Endpoints 
Endpoint 
Category 
Estimand 
Endpoint 
Population 
Intercurrent event(s) handling strategy and 
missing data handling 
Population-level 
summary 
Secondary 
endpoint - 
Continuous 
Titrated 
SPT 
MWD 
FAS1 
If the antihistamines are not withheld before the 
titrated SPT, the post-randomized data will be 
assigned by worst observation (including baseline) 
before the collection of the assessment from the 
same participant (composite strategy).  
If all dilutions are missing due to any reason, e.g., 
early start of BPS, then the averaged value will be 
imputed using multiple imputation (MI). 
ANCOVA model 
with treatment 
group and 
stratification 
factors as fixed 
effect and the  
baseline tSPT as a 
covariate. 
EEU 
symptom 
scores3 in 
Part B 
FAS-B 
Same manner as the primary endpoint with the 
following exception:  
If systemic steroids, biologics or immune 
therapeutics impacting type 2 allergic disease are 
used due to birch pollen related symptoms6 prior to 
the EEU challenge, data will be set to mean score 
from 2 to 6 hours in the baseline EEU (BOCF, 
composite strategy). 
Same manner as 
the primary 
endpoint 
Field 
symptom 
scores4 in 
BPS5 and 
peak BPS 
FAS-B 
The intercurrent events will be handled as follows: 
• 
If Systemic steroids, Biologics or immune 
therapeutics impacting type 2 allergic disease 
are used due to birch pollen related symptoms6, 
data will be set to mean score from the other 
participants in the same treatment group 
(composite strategy). If due to any other reason, 
data after the use of medication will be set to 
missing (hypothetical strategy).  
• 
Study provided anti-allergy rescue treatment 
taken during the study: all available data will be 
utilized (treatment policy) 
• 
Data during travel periods with no exposure to 
birch pollen will be set to missing and other 
observed data during exposure to birch pollen 
will be used to calculate the mean scores (while 
on treatment policy) 
ANCOVA model 
with treatment 
group, 
stratification 
factors as fixed 
effect, average 
pollen count 
during local BPS 
and the 
corresponding 
pre-treatment 
baseline symptom 
scores as 
covariate. 
[1] Endpoints related to tSPT at day 127 will be analyzed in subgroup that had a visit 10 performed at least 12 
weeks after Part A dose (not included if visit 10 combined with other visits or if visit 10 done prior to other out-
of-season visits). 
[2] Rescue medication may be given during the EEU challenge if any severe or clinically concerning reactions (as 
judged by the PI). 
[3] EEU symptom scores include TNSS (2 to 6 hours), TOSS (2 to 6 hours), TSS (2 to 6 hours). 
[4] Field symptom scores from e-diary include CSMS [TSS+DMS], TSS [TNSS+TOSS], daily TNSS, daily TOSS, 
and DMS.  
[5] If there is no protocol defined BPS due to local climactic conditions at any pollen site, then those data will not 
be included in the calculation for field data. 
[6] Whether the medication is used due to birch pollen related symptoms (considered treatment failure) or not will 
be adjudicated in a blinded manner. 
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7.2.3. 
Analysis of Exploratory Endpoints 
Continuous exploratory efficacy variables, e.g., change and percent change from pre-treatment 
baseline for TNSS, TOSS, TSS in birch pollen EEU challenges, will be analyzed by using an 
ANCOVA model similar to the analyses of primary endpoint. For categorical exploratory 
variables, only descriptive summary will be provided. In addition, the duration of the BPS and the 
average pollen counts will be provided by pollen site for Part B analysis.  
Within-participants comparisons will be conducted using FAS and CS-A.  
The combined active group is defined as participants who received any active treatment 
(REGN5713-5714-5715, REGN5713-5715, or REGN5715). For the oak allergen EEU challenge, 
the following endpoints will be analyzed by comparing the combined active group versus the 
placebo group:  
• The mean of symptom scores (TNSS [2-6 hours], TOSS [2-6 hours] and TSS [2-6 hours]) 
during out-of-season oak allergen EEU challenge at day 36  
• The change and percent change from pre-treatment baseline in symptom scores (TNSS [2-6 
hours], TOSS [2-6 hours] and TSS [2-6 hours]) during an oak allergen EEU at day 36  
• The change and percent change from pre-treatment baseline in the red oak titrated SPT 
mean wheal diameter (MWD) AUC  
Rationale: REGN5715 is the only monoclonal antibody that has been demonstrated to exhibit 
binding to oak in pre-clinical ELISA experiments (REGN5713 and REGN5714 have not 
demonstrated binding). Therefore, symptom endpoints during day 36 oak EEU challenge and oak 
titrated SPT endpoints will be assessed in participants receiving active treatment (REGN5713-
5714-5715, REGN5713-5715 or REGN5715) versus placebo (3:1) in subpopulation of oak allergic 
participants if the individual active arms versus placebo are reasonably comparable. 
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8. 
HYPOTHESIS TESTING METHODS AND MULTIPLICITY 
CONTROL 
8.1. 
Hypotheses Testing Methods 
The statistical hypothesis specified in Section 1.2 will be tested on the selected secondary 
endpoints at a 2-sided 5% significance level. The study will be declared positive if at least the null 
hypothesis for the primary efficacy endpoint for REGN5713-5714-5715 versus placebo is rejected. 
The hypothesis for other endpoints will be performed using the same procedure and testing method 
as above. 
8.2. 
Multiplicity Control 
The study is powered on the comparison of the primary endpoint between REGN5713-5714-5715 
and placebo for Part A of the study with 2-sided alpha level of 0.05. 
A hierarchical procedure will be used to control overall Type-1 error rate at 0.05 for the primary 
endpoint, TNSS (2-6 hours) in birch challenge EEU at day 29 and change from pre-treatment 
baseline in titrated SPT mean wheal diameter at day 29 in Part A, for testing multiple comparison 
groups. 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 below: 
1. The mean of Total Nasal Symptom Score [TNSS (2 to 6 hours)] during a birch allergen 
EEU challenge at day 29, in subjects who receive  REGN5713-5714-5715 versus placebo  
2. The percent change from pre-treatment baseline in birch allergen titrated SPT mean 
wheal diameter AUC at day 29 in subjects who receive  REGN5713-5714-5715 versus 
placebo  
3. The percent change from pre-treatment baseline in birch allergen titrated SPT mean 
wheal diameter AUC at day 29 in subjects who receive  REGN5713-5715 versus placebo 
4. The mean of Total Nasal Symptom Score [TNSS (2 to 6 hours)] during a birch allergen 
EEU challenge at day 29, in subjects who receive  REGN5713-5715 versus placebo 
5. The percent change from pre-treatment baseline in birch allergen titrated SPT mean 
wheal diameter AUC at day 29 in subjects who receive  REGN5715 versus placebo 
6. The mean of Total Nasal Symptom Score [TNSS (2 to 6 hours)] during a birch allergen 
EEU challenge at day 29, in subjects who receive  REGN5715 versus placebo 
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9. 
SUMMARY OF EXPOSURE DATA 
9.1. 
Investigation Study Drug Exposure and Compliance  
Part A observation duration: 
The number (%) of subjects with observation periods will be presented by specific time periods. 
The time periods of interest are specified as: ≥1 day,  ≥29 days,  ≥36 days,  ≥57 days, ≥85 days in 
Part A and before the 2nd dose. 
Part B observation duration: 
The time periods of interest are specified as: days during BPS in Part B and after the 2nd dose. 
The summary of exposure to study drug will include the duration of exposure in Part A and Part 
B and the number of study drug administered in each of the two doses, given as 3 injections 
sequentially on one day for each dose. Duration of exposure will be summarized for each treatment 
group using the number of participants, mean, SD, minimum, median, Q1, Q3, and maximum. 
Treatment compliance is not applicable since the subject will only have two treatment 
administrations in the study. 
9.2. 
Duration of Follow-up 
There are two study follow-up periods. The first follow up period is after the last out-of-season 
EEU exposures until visit 10, where applicable, and the second one is after the end of the BPS 
until EOS.  
9.3. 
Prior and Concomitant Medications 
Medications will be recorded from the day of informed consent until the end-of-study (EOS) visit 
and will be coded using WHO Drug Dictionary (WHODD). The prior and concomitant 
medications are defined as below: 
Prior medications: medications taken, prior to administration of the first dose of study drug. 
Concomitant medications (CMs) for the whole study: medications taken following the first dose 
of study drug through the EOS visit. The number and proportion of subjects taking prior 
medications will be summarized by treatment group, as well as the number and proportion taking 
concomitant medications during the pretreatment period, on-treatment as defined in Section 10.1 
based on the FAS.  
Prohibited Medications  
The prohibited medications will not be analyzed in an independent section but will be included in 
the prior and concomitant medications. 
The number and proportion of subjects performing prior medication will be summarized by 
treatment group, as well as the number and proportion performing concomitant procedures during 
the pre-treatment period, on-treatment as defined in Section 10.1 based on the FAS. Similar tables 
will be provided for the number and proportion of subjects taking prohibited procedures.  Each 
table will be sorted by decreasing frequency of Anatomical Therapeutic Chemical (ATC) level 2 
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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. 
Rescue Medications  
Participants will be provided with the following allergy-relieving rescue medications (or 
appropriate in-class equivalent, after agreement with sponsor) to treat allergic symptoms as needed 
during the study:  
1. oral desloratadine 5 mg (second generation antihistamine) 
2. topical olopatadine 1 mg/mL (antihistamine eye drops) 
3. topical mometasone furoate 50 μg/dose (INCS) 
During the screening baseline period and post visit 10 through the end of the study, participants 
will be asked to record their daily rescue medication use using an e-diary, including the name and 
amount of these pre-specified medications.  
9.4. 
Prior and Concurrent Procedures 
Procedures will be recorded from the day of informed consent until the end-of-study (EOS) visit 
and all procedures will be coded to a “Preferred Term (PT)” and associated primary “System Organ 
Class (SOC)” according to the Medical Dictionary for Regulatory Activities (MedDRA). The prior 
and concomitant procedures are defined as below: 
Prior procedures: procedures performed, prior to administration of the first dose of study drug. 
Concomitant procedures (CPs) for the whole study: procedures performed following the dose of 
study drug through the EOS visit. 
Number and proportion of participants 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. Participants will be counted only once for each SOC and PT linked to the 
procedure. Number of participants receiving prior immunotherapy (Subcutaneous Immunotherapy 
(SCIT), Sublingual Immunotherapy (SLIT)) will be summarized separately.  
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10. 
ANALYSIS OF SAFETY DATA 
The analysis of safety will be performed on the SAF, as defined in Section Section 3.4 . The safety 
analysis will be based on the reported AEs and other safety information (vital signs, physical 
examination and clinical laboratory parameters). 
Thresholds for treatment-emergent Potential Clinically Significant Values (PCSV) in laboratory 
variables are defined in Section 14.3. Treatment-emergent PCSV is any PCSV that developed or 
worsened in severity compared to the baseline during the on-treatment period which also includes 
the follow-up period. The baseline when determining treatment-emergent PCSV refers to the 
baseline value of the study. 
The summary of safety results will be presented for each treatment group. The time interval to 
detect any event or abnormality is during on-treatment period as defined in Section 10.1. 
In addition, the summary of safety results (including TEAEs, clinical laboratory, vital signs, and 
physical examination) will be performed for subjects who were impacted by COVID-19 pandemic 
and not impacted by COVID-19 pandemic in each study part, respectively if deemed appropriate. 
The summary will be performed for pre-, during, and post-COVID-19 periods for participants 
impacted by COVID-19, if deemed appropriate.  
10.1. 
Adverse Events 
Adverse events (AEs) and serious adverse events (SAEs) as defined in ther study protocol 
(Section 9.2.1 and Section 9.2.2) will be collected from the time of informed consent signature and 
then at each visit until the end of the study.  
For safety variables, following observation periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF but before 
receiving the first administration of study drug. 
• The on-treatment period in study is defined as the first dose date to the end of study 
(visit 15).  
Treatment-emergent adverse events are defined as those that are not present prior to randomization 
or represent the exacerbation of a pre-existing condition during the on-treatment period (which 
includes the follow-up period after the end of the local BPS). 
All new or worsening AEs occurring between signing of the ICF and the end of the study will be 
recorded and coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be summarized with incidence tables for Part A and Part B separately.  AE incidence 
tables will present the number (n) and percentage (%) of participants experiencing an AE within 
each treatment arm, sorted by decreasing frequency of SOC and PT in the 3-mAb (REGN-5713-
5714-5715) treatment arm. Multiple occurrences of the same event in a patient will only be counted 
once in the summary.  For tables showing AE severity, for instances where a patient has multiple 
occurrences of the same PT or SOC, only the worst severity will be counted in the summary. 
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The following AE summaries will be presented for TEAEs: 
• Overview of TEAEs  
• TEAEs by Primary SOC and PT  
• TEAEs by PT 
• TEAEs by Primary SOC, HLT and PT  
• TEAEs by Primary SOC, PT, and Severity 
• TEAEs Related to Study Drug by Primary SOC and PT 
• Treatment-emergent AESIs by Primary SOC and PT  
• Serious TEAEs by Primary SOC and PT 
• Serious TEAEs Related to Study Drug by Primary SOC and PT 
• Serious TEAEs Related to Study Drug by PT 
• TEAEs by severity  
• Injection Site Reactions (ISRs) 
• ISRs by severity 
• TEAEs leading to permanent treatment withdrawal by Primary SOC and PT  
• TEAEs leading to study discontinuation by Primary SOC and PT  
• Death due to TEAEs by Primary SOC and PT 
10.1.1. 
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 PI to the sponsor can be appropriate. Such an event might warrant further 
investigation in order to characterize and understand it. AESI will be identified using both CRF 
flag and SMQ search criteria, and needs clinical adjudication. 
List of below is AESI for this study: 
• Systemic or severe hypersensitivity reactions 
Detailed filter of AESI criteria is specified in Section 14.4. 
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10.2. 
Laboratory Parameters 
The following laboratory tests will be collected and summarized according to the Schedule Events 
in Section 14.2: 
Blood Chemistry 
Sodium 
Total protein, serum 
Aspartate aminotransferase (AST) 
Potassium 
Creatinine 
Alanine aminotransferase (ALT) 
Chloride 
Blood urea nitrogen (BUN) 
Alkaline phosphatase 
Carbon dioxide 
Total bilirubin 
Albumin 
Calcium 
Glucose 
 
Albumin 
 
 
 
 
 
Blood chemistry samples should be collected prior to the administration of study drug and prior to EEU 
challenges, when applicable.  
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 
WBC 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocytes esterase 
Epithelial cells 
Ketones 
Nitrite 
Yeast 
Protein 
 
 
Other Laboratory Tests 
Participants will be tested for FSH levels (if postmenopausal status is in question) and will undergo 
serum and urine pregnancy testing (women of childbearing potential only); pregnancy testing is 
not required of women confirmed to be menopausal. Samples will be collected for quantitative 
assessment of allergen specific IgE. 
Clinical laboratory analytes will be converted to standard international (SI) units and grouped by 
function in summary tables.  Below statistic summaries will be provided: 
• Descriptive statistics of clinical laboratory values and change from baseline in clinical 
laboratory values to all scheduled assessment times by visit and by treatment group 
• Number (n) and percentage (%) of participants with a treatment-emergent potentially 
clinically significant value (PCSV) at any post-randomization time point  
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Patient laboratory parameter measurements will be evaluated by PCSV criteria, specifically 
identifying participants with at least one post-baseline measurement that meets the PCSV criteria 
(Section 14.3). Participants meeting the PCSV criteria will be summarized by patient count (and 
percent) for a post-baseline PCSV measurement by treatment group, regardless of baseline PCSV 
status. When the PCSV definition involves a change from baseline value, participants must have 
a baseline value to be included in the summaries. All measurements collected during the study 
including, values from unscheduled visits, will be used in the PCSV analyses. 
10.3. 
Vital Signs 
The following vital signs parameters will be recorded pre-dose and 2 hours post dose, and 
summarized according to the Schedule Events in Section Section 14.2: 
• Temperature 
• Systolic/diastolic blood pressure 
• Heart rate 
• Respiration rate  
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit by 
treatment group 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV 
10.4. 
Other Safety Data 
A standard 12-lead ECG will be performed at the screening visit/baseline only. Heart rate will be 
recorded from the ventricular rate and the PR, QRS, and QT (identify QTcB or QTcF) will be 
recorded. The ECG strips or reports will be retained with the source documentation. 
10.5. 
Immunogenicity Data 
Samples for ADA measurement will be collected at visits listed according to Schedule Events in 
Section 14.2. The samples are to be collected prior to the administration of study drug. In the event 
of suspected SAEs, such as anaphylaxis or systemic hypersensitivity, additional samples for the 
analysis of ADA may be collected as close to the event as practically possible. 
10.5.1. 
Immunogenicity Variables 
The immunogenicity variables include ADA status, titer at nominal sampling time/visit. Serum 
samples for ADA will be collected at the clinic visits specified in Section 14.2. For each study 
drug, samples positive in the ADA assay will be further characterized for ADA titers.  
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10.5.2. 
Analysis of Immunogenicity Data 
The immunogenicity variables described in Section 10.5.1 will be summarized using descriptive 
statistics. Immunogenicity will be characterized per drug molecule by ADA status, ADA category 
and maximum titer observed in participants in the ADA analysis sets. For samples confirmed as 
drug specific ADA positive, but found negative at the lowest titer dilution, the lowest dilution in 
the titer assay is imputed. 
The ADA status of each participant may be classified as one of the following:  
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 9-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay. 
The ADA category of each positive participants is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥ 9-fold the baseline titer value  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Participants that are treatment-
emergent will be further categorized as follows: 
Treatment-emergent is further sub-categorized as: 
• Persistent - A positive result in the ADA assay detected in at least 2 consecutive post 
baseline samples separated by at least a 16-week post baseline period [based on 
nominal sampling time], with no ADA-negative results in-between, regardless of any 
missing samples 
• Transient - Not persistent or indeterminate, regardless of any missing samples 
• Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
The maximum titer category of each  participant is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative participants 
• Number (n) and percent (%) of pre-existing  participants 
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• Number (n) and percent (%) of treatment-emergent ADA positive participants 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
participants 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
participants 
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
participants 
• Number (n) and percent (%) of treatment-boosted ADA positive participants 
Listing of all ADA titer levels will be provided for participants with pre-existing, treatment-
emergent and treatment-boosted ADA response. 
10.5.3. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
10.5.3.1. Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to REGN5713, REGN5714, 
and REGN5715 will be explored by treatment groups. Plots of individual REGN5713 , 
REGN5714, and REGN5715 concentration time profiles by ADA status or titer may be provided 
to examine the potential impact of ADA on systemic exposure.  
10.5.3.2. 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:  
• 
Injection site reaction (serious or severe) 
• 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• 
Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoints may be explored 
(e.g., scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 
categories: 
• ADA Positive 
− Treatment-emergent 
− Treatment-boosted 
• Maximum post-baseline titer category in ADA positive participants 
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10.6. 
Pharmacokinetic Data 
10.6.1. 
Pharmacokinetic Variables 
Concentrations in serum of total (free + antigen bound) REGN5713, REGN5714, and/or 
REGN5715 will be measured at time points specified in the study schedule of events in 
Section 14.2 
. 
Pharmacokinetic 
variables 
consist 
of 
concentrations 
of 
individual 
antibodies (REGN5713, 
REGN5714, 
and/or 
REGN5715) 
as 
well 
as 
total 
drug 
(REGN5713+REGN5714+REGN5715 or REGN5713+REGN5715) in serum, and time (both 
nominal and actual time). 
10.6.2. 
Analysis of Pharmacokinetic Data 
Descriptive statistics of total REGN5713, total REGN5714, total REGN5715, and/or total drug 
(REGN5713+REGN5714+REGN5715 or REGN5713+REGN5715) concentrations in serum at 
each sampling timepoint will be provided. Plots of mean concentration versus nominal time may 
be presented. Select PK parameters may be calculated.  
Exposure Response analysis of biomarkers, efficacy, and safety endpoints may be conducted as 
necessary and presented in separate reports.  
10.7. 
Biomarker Data 
Exploratory biomarker data may be described in a separate exploratory analysis plan. Analyses 
may include (but are not limited to) evaluating relationships between biomarkers and clinical 
responses. Exploratory biomarker variables may include (but are not limited to) serum allergen-
specific IgE levels (birch, Bet v 1, Bet v 2, and other common allergens) and basophil activation. 
Relevant biomarker data analyses may be included in the CSR and/or a separate biomarker report. 
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11. 
DATA CONVENTIONS 
11.1. 
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. 
For the efficacy endpoints, the baseline is defined as following: 
• For all symptom scores (TNSS or TOSS) collected in EEU chambers, the baseline is 
defined as the mean of the corresponding measurements (2 to 6 hours) during the 
allergen EEU challenge in screening period. The baseline visit for Birch is Visit 2, 
and the baseline visit for Oak is Visit 3. 
• For daily e-diary scores (daily TNSS, daily TOSS, DMS, daily TSS, daily CSMS, 
RQLQ(S), PFASQ, and outdoor questionnaire), there are two baselines defined, pre-
treatment baseline and pre-season baseline. 
− The pre-treatment baseline is defined as the average of the daily score during the 
screening period before the first dose. All days with scores during the screening 
period will be used to calculate the average, except for the day of and one day 
following EEU challenge.  
− The pre-season baseline is defined as the average of the daily score start from the 
Visit 10 to the day before the local BPS, except for the day of and one day 
following EEU challenge.  
The number of non-missing daily records must be at least 3 after excluding the records 
happening on the same day and the next day of the EEU visit for pre-treatment and pre-
season baseline (both pre-treatment baseline) calculation. If the baseline value is smaller 
than 1, the baseline will be set to 1. 
For the rescreened participants, only data from the enrolled subject ID will be used. 
11.2. 
Data Convention  
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. 
Note that for total IgE, Birch sIgE, and Bet v 1 sIgE, samples whose data are above the ULOQ 
will be re-analyzed at 1:10 dilution and IgE/sIgE levels will be derived from the results of the 
dilution assay (i.e, calculated using a factor of 10).For mis-stratification, data from oak allergy 
status (yes or no) determined based on oak EEU challenge, grass sensitization status (grass 
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sensitized: grass SPT ≥3 mm or sIgE ≥0.35; not grass sensitized: grass SPT <3 mm and sIgE <0.35) 
and EEU site as collected from CRF will be used for analysis rather than as randomized. 
11.3. 
Data for Non-Efficacy Endpoints 
Missing data will not be imputed in listings. 
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 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’. 
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 EOS 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 EOS 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. 
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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 specifies 
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.  
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 prior medication 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 EOS 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 EOS 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’. 
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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. 
11.4. 
Assignment of Data to Visit Windows and Unscheduled Assessments 
Unscheduled Assessments 
Data analyzed by-visit-analysis (including efficacy, laboratory data, vital sign, ADA) will be 
summarized by the study scheduled visits described in the “Schedule of Events” of study protocol 
and SAP. 
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 in 
the same part. 
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 visits will be mapped using the following rules: 
a. The closest unscheduled visit from the target day will be selected. 
b. If the distance is a tie, the unscheduled visit after the target day of the scheduled visit 
will be used. 
c. If multiple unscheduled visits exist on the same day, the first unscheduled visit will 
be used. 
4. If mapping distance is greater than 6 weeks, the unscheduled visit will not be mapped. 
Unscheduled visits and ET visit will be mapped per the following analysis visit windows for Part 
A and Part B based on the study day/visit of each parameter, respectively.  
1. Part A visit window: All data collected after the last out-of-season EEU visit and/or the 
Visit 10 (whichever is later) will not be used for Part A analysis.  
2. Part B visit window: All data not in Part A visit window will be included in Part B visit 
window. 
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Table 4: 
Analysis Visit Window for Safety and Laboratory Testings  
Part 
Visit 
from 
SOE 
Target 
Study Day1 
Vital Sign, Physical 
examination 
Hematology, 
Blood 
chemistry 
Drug 
Concentration 
sample 
ADA sample 
Allergic 
to Oak2 
Not 
Allergic 
to Oak2 
 
Baseline 
<=1 
<=1 
<=1 
Part 
A 
Visit 6 
29 
[2, 33] 
[2, 43] 
[2, 43] 
[2, 43] 
- 
Visit 7 
36 
[34, 47] 
- 
- 
- 
- 
Visit 8 
57 
[48, 61] 
[44, 61] 
[44, 61] 
[44, 61] 
- 
Visit 9 
85 
>=62  
>=62   
>=62   
>=2  
Part 
B 
Visit 103 
Before the 
dose in Part 
B 
All data after the last out-of-season EEU visit and before the dose in Part B. 
Visit 11 
~0 to 3 
weeks prior 
to start of 
BPS 
- 
Visit 13 
During peak 
BPS 
Assessment during the actual local BPS 
- 
Visit 14 
At the end of 
BPS 
Assessment at the end of the actual local BPS 
- 
Visit 15 
(EOS) 
After BPS 
Assessment after the 
actual local BPS 
- 
Assessment 
after the 
actual local 
BPS 
Assessment 
after the 
actual local 
BPS 
[1] Study days in Part A 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. Visit timeframes in Part B (visits 10 to 15) may vary based on the timing and 
duration of the anticipated BPS. 
[2] The visit mapping rule for participants who are allergic to oak is slightly different with participants who are 
not allergic to oak for vital sign and physical examination. 
[3] If visit 10 is combined with visit 6, visit 8, or visit 9, there will be no assessment for visit 10 and no titrated 
SPT in unscheduled visit will be mapped to visit 10. If visit 10 is combined with visit 7, the unscheduled 
titrated SPT collected after the last out-of-season EEU visit and before the dose in Part B will be mapped to 
visit 10. 
Mapping rule for EEU symptom scores 
All symptom scores collected in EEU will be mapped to nominal time due to an allowed window 
to answer the questionnaire.    
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Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 50 of 68 
Table 5: 
Summary of EEU Nominal and Derived Times 
EEU Time 
Analysis Timepoint 
Nominal Time 
Window for Derived Time1,2 
EEU Qualification 
-1 
-0:15 
< -0:10 
Pre-EEU 
0  
0:00 
[-0:10, 0:10) 
In EEU 
0 to <2 hours 
1 
0:20 
[0:10, 0:30) 
2 
0:40 
[0:30, 0:50) 
3 
1:00 
[0:50, 1:10) 
4 
1:20 
[1:10, 1:30) 
5 
1:40 
[1:30, 1:50) 
6 
2:00 
[1:50, 2:10) 
In EEU 
2-6 hours3 
7 
2:20 
[2:10, 2:30) 
8 
2:40 
[2:30, 2:50) 
9 
3:00 
[2:50, 3:10) 
10 
3:20 
[3:10, 3:30) 
11 
3:40 
[3:30, 3:50) 
12 
4:00 
[3:50, 4:10) 
13 
4:20 
[4:10, 4:30) 
14 
4:40 
[4:30, 4:50) 
15 
5:00 
[4:50, 5:10) 
16 
5:20 
[5:10, 5:30) 
17 
5:40 
[5:30, 5:50) 
18 
6:00 
[5:50, 6:10) 
[1] Derived time = actual assessment calendar time (hh:mm) – EEU entry calendar time (hh:mm) for Cliantha site, 
as well as the EEU qualification and pre-EEU measurement in Kingston site. Derived time = actual assessment 
calendar time (hh:mm) – EEU entry calendar time (hh:mm)-15 min for Kingston Site (15 mins for Kingston site 
to prepare the pollen exposure after participants enter the EEU).  
[2] If a patient has 2 or more timepoints within the same window, the first non-missing value will be used for 
analysis. 
[3] Records during this period will be used to calculate the average symptom scores in EEU from 2 to 6 hours. 
 
11.5. 
Pooling of Categorical Variables for Statistical Analyses 
No categorical variables will be pooled in the analyses. 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 51 of 68 
12. 
TECHNICAL DETAILS PERTAINING TO INTERIM 
ANALYSIS/(ES) 
Not applicable as no formal interim analysis is planned. 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 52 of 68 
13. 
REFERENCES 
1. https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf 
2. Couroux P, Ipsen H, Stage BS, Damkjaer JT, Steffensen MA, Salapatek AM, et al. A 
birch sublingual allergy immunotherapy tablet reduces rhinoconjunctivitis symptoms 
when exposed to birch and oak and induces IgG4 to allergens from all trees in the birch 
homologous group. Allergy 2019; 74(2):361-369. 
3. Calderon MA, Bernstein DI, Blaiss M, Andersen JS,Nolte H. A comparative analysis of 
symptom and medication scoring methods used in clinical trials of sublingual 
immunotherapy for seasonal allergic rhinitis. Clin Exp Allergy 2014; 44(10):1228-1239. 
4. Orengo J, Radin A, Kamat V, Badithe A, Ben L, Bennett B, Sharon Zhong S, Birchard D, 
Limnander A, Rafique A,Bautista J, Kostic A, Newell D, Duan X, Franklin M, Olson W, 
Huang T, Gandhi N, Lipsich L, Stahl N, Papadopoulos N, Murphy A, and Yancopoulos 
G. Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent 
IgE engagement. Nature Communications Nat Commun. 2018 Apr 12;9(1):1421. 
5. Caillaud D, Martin S, Segala C, Besancenot JP, Clot B, Thibaudon M; French 
Aerobiology Network. Effects of airborne birch pollen levels on clinical symptoms of 
seasonal allergic rhinoconjunctivitis. Int Arch Allergy Immunol. 2014;163(1):43-50. doi: 
10.1159/000355630. Epub 2013 Nov 16. PMID: 24247974. 
6. Taudorf E, Moseholm L. Pollen count, symptom and medicine score in birch pollinosis. 
A mathematical approach. Int Arch Allergy Appl Immunol. 1988;86(2):225-33. doi: 
10.1159/000234576. PMID: 3391687. 
7. Biedermann T, Kuna P, Panzner P, Valovirta E, Andersson M, de Blay F, Thrane D, 
Jacobsen SH, Stage BS, Winther L. The SQ tree SLIT-tablet is highly effective and well 
tolerated: Results from a randomized, double-blind, placebo-controlled phase III trial. J 
Allergy Clin Immunol. 2019 Mar;143(3):1058-1066.e6. doi: 10.1016/j.jaci.2018.12.1001. 
Epub 2019 Jan 15. PMID: 30654054. 
 
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Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 53 of 68 
14. 
APPENDIX 
14.1. 
Summary of Statistical Analyses 
Efficacy/PD Analysis: 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
EEU 
TNSS (2-
6 hours) 
FAS 
Mean at day 29 for 
3-mAb versus 
placebo 
ANCOVA 
model with 
treatment 
group and 
stratification 
factors as fixed 
effect and the  
baseline mean 
TNSS (2 to 6 
hours) at visit 2 
as a covariate. 
Yes, 
sensitivity 
and 
supplemental  
analysis 
described in 
Section 
7.2.1.2  
Yes, 
subgroups 
are listed 
in 
Section 7.2
.1.3  
Plots 
Secondary Endpoints 
EEU (2-6 
hours): 
TNSS, 
TOSS, 
TSS  
FAS 
Mean, change and 
percent change from 
pre-treatment 
baseline, at days 29*, 
57, 85 for each of 
anti-bet v 1 
monoclonal 
antibodies versus 
placebo 
Same as above 
No 
No 
Numerical 
comparison 
between three 
anti-bet v 1 
monoclonal 
antibodies. 
EEU (2-6 
hours): 
TNSS, 
TOSS,  
TSS 
FAS with 
subjects 
allergic to 
oak  
Mean, change and 
percent change from 
pre-treatment 
baseline, at days 36 
for each of anti-bet v 
1 monoclonal 
antibodies versus 
placebo 
Same as above 
No 
No 
Comparison 
between 
combined 
active group 
versus 
placebo 
EEU (2-6 
hours): 
TNSS, 
TOSS ,  
TSS 
FAS - B 
Mean for each of 
anti-bet v 1 
monoclonal 
antibodies versus 
placebo 
Same as above 
No 
No 
No 
CSMS, 
TSS, 
TNSS, 
TOSS, 
DMS 
FAS - B 
Mean, change and 
percent change from 
pre-treatment and 
pre-season baseline, 
in BPS, peak BPS 
for each of anti-bet v 
1 monoclonal 
antibodies versus 
placebo 
Same as above 
except for  the 
average pollen 
count during 
local BPS will 
also be used as 
a covariate in 
the model. 
No 
No 
Analyses 
using 30 
grains/ m3 as 
the cutoff for 
defining BPS 
start and end 
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REGENERON CONFIDENTIAL 
Page 54 of 68 
Endpoint 
Analysis 
Populations 
Primary Analysis 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
RQLQ(S) 
FAS - B 
Mean , change and 
percent change from 
pre-treatment and 
pre-season baseline, 
in BPS, peak BPS 
for each of anti-bet v 
1 monoclonal 
antibodies versus 
placebo 
Same as above 
No 
No 
No 
Titrated 
SPT 
MWD 
AUC 
FAS for Day 
29, 57, and 
85 
FAS with 
visit 10 
performed at 
least 12 
weeks after 
dose #1 for 
Day 127 
Change and percent 
change from pre-
treatment baseline, at 
days 29, 57, 85 and 
127 for each of anti-
bet v 1 monoclonal 
antibodies versus 
placebo 
Same as above 
No 
No 
Plots; 
Numerical 
comparison 
between three 
anti-Bet v 1 
monoclonal 
antibodies. 
Titrated 
SPT 
MWD 
AUC 
FAS - B 
Change and percent 
change from pre-
treatment baseline, 
end-of-season to 
EOS for each of 
anti-bet v 1 
monoclonal 
antibodies versus 
placebo 
Same as above 
No 
No 
Plots; 
Analyses 
using FAS 
with available 
in-season 
data 
irrespective 
of whether 
they received 
dose 2 
Note: *except day 29. 
Safety Analysis: 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other Analyses 
AEs 
SAF 
Descriptive 
statistics 
No 
No 
No 
Laboratory 
Measures 
SAF 
Descriptive 
statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive 
statistics 
No 
No 
No 
Physical 
examination 
SAF 
Descriptive 
statistics 
No 
No 
No 
 
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Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 55 of 68 
14.2. 
Schedule of Events 
 
PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Screening: 
Inclusion/exclusion 
X 
X 
X 
X 
 
X19 
X19 
X19 
X19 
X19 
X19 
 
X19 
X19 
 
 
Informed consents 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and allergy 
history34 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH 
(postmenopausal 
women only)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 56 of 68 
 
PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Sensitization/ Specialty Labs: 
SPT birch, birch-
related and 
unrelated common 
allergens2 
X2*,35 
 
 
 
 
X4 
 
X4 
X4 
X4 
 
 
 
X4 
X4 
X4 
Titrated SPT to 
birch and birch-
related allergens3 
 
X 
 
 
 
X4 
 
X4 
X4 
X4 
 
 
 
X4 
X4 
 
Serum allergen-
specific IgE (eg, 
birch and Bet v 1 
sIgE, other related/ 
unrelated allergens) 
X 
 
 
X39 
 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
Serum total IgE 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Whole blood for 
basophil activation 
test 31 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Nasal fluid 
collection33 
 
X 
 
 
 
X 
 
X 
 
 
 
 
X 
X 
 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 57 of 68 
 
PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Exploratory 
research serum and 
plasma32 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Treatment: 
Randomization 
 
 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study 
drug16 
 
 
 
X 
 
 
 
 
 
 
X11,14 
 
 
 
 
 
Dispense rescue 
medications27 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
Efficacy: 
EEU visits: TNSS, 
TOSS7,8,9  
 
X5 
X 
 
 
X7 
X7 
X7 
X7 
 
 
 
X8 
X8 
 
 
e-Diary: TNSS, 
TOSS, and DMS24 
 
X25 
 
 
 
 
 
X26 
 
RQLQ(S)28 
 
X 
 
 
 
 
 
X 
 
PFASQ29 
 
X 
 
 
 
 
 
X 
 
Outdoor time 
questionnaire30 
 
X 
 
 
 
 
 
X 
 
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Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 58 of 68 
 
PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Safety: 
Vital signs18 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Physical 
examination17 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spirometry/PEF23 
X23* 
X 
X 
X23* 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
Laboratory Testing20: 
Hematology32 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
Blood chemistry32 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
Pregnancy test 
(urine) (WOCBP)21 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Pregnancy test 
(serum) 
(WOCBP)21 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Pharmacokinetics and Immunogenicity Sampling: 
Drug concentration 
sample36 
 
 
 
X36 
 
X 
 
X 
X 
X 
X36 
 
X 
X 
X 
X 
ADA sample36 
 
 
 
X36 
 
 
 
 
X  
 
X36 
 
 
 
X 
X 
                                        VV-RIM-00303525-2.0 Approved - 11 Jun 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 59 of 68 
 
PART A 
PART B 
 
 
SCREENING 
RAND 
Out-of-Season 
 
FOLLOW-
UP 
 
Study Procedure 
Screening 
Birch 
EEU  
Oak 
EEU  
Rand/ 
Dosing 
Tel 
Birch 
EEU 
Oak 
EEU 
Birch 
EEU 
Birch 
EEU 
In-
Clinic 
Dosing 
Tel15 
Birch 
EEU 
Birch 
EEU 
EOS/ ET  
Unsc. 
Visit38 
Visit (V) Number 
V11 
V25 
V36 
V4 
V5 
V6 
V76 
V840 
V941 
V1013,41 
V1112,13 
V1213 
V1313 
V1413 
V1513 
 
Appx. Week (wk) 
 
 
wk1 
wk4 
wk5 
wk8 
wk12 
~wk18 
~wk22 
 
~wk27 
~wk32 
~wk36 
 
Visit Day (d) 
-d70 to -d1 
d1 
d8 
d29 
d36 
d57 
d85 
d127 
d155 
d156 
d190 
d225 
d253 
 
Visit Window 
(days) 
 
 
±3d 
±7d 
-7d 
to 
+14d 
±7d 
-28d 
to 
+14d 
±7d 
±7d 
+1d 
±7d 
±7d 
±7d 
 
Future Biomedical Research (optional sub-study): 
 
 
 
 
 
 
 
 
 
 
 
Serum sample 
collection for future 
biomedical research 
(optional)32 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Plasma sample 
collection for future 
biomedical research 
(optional)32 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
Pharmacogenomics (optional sub-study): 
Blood for DNA 
(optional)37 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00303525-2.0 Approved - 11 Jun 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
Page 60 of 68 
Footnotes for the Schedule of Events Table 
1. Screening visit 1 can be split into additional visits, if required, to ensure medication 
washouts prior to any assessments being performed (per PI discretion). 
2. Screening skin prick test (SPT) for birch and for other birch-related (eg, alder, oak) and 
unrelated common allergens (eg, grass, dust mites, etc) is performed as described in the study 
reference manual. SPT source documentation is required (eg, tape transfer method). 
* If screening SPT for birch does not meet eligibility at screening visit 1 (mean wheal diameter less 
than at least 5 mm greater than the negative control), then other screening visit 1 procedures may 
not be performed, as the subject will have failed screening based upon birch skin prick testing (eg, 
recommend performing birch skin prick testing prior to blood draw, spirometry, etc).  
3. Titrated SPT with serial allergen titration for birch and related allergens is performed as 
described in the study reference manual. The titrated SPT should be performed prior to the 
EEU challenge during visits when both are scheduled.   
4. Post-randomization SPT and titrated SPT will be performed in a blinded fashion (as described 
in the study reference manual). 
5. All other eligibility criteria need to be met prior to the screening birch allergen EEU challenge 
(visit 2). It is recommended that the screening birch challenge is scheduled outside of relevant 
pollen seasons when pollen-allergic subjects are not significantly symptomatic due to other 
pollens.  
6. It is recommended that EEU challenges (including birch and oak EEU sessions) be separated 
by approximately 1 week or longer between the challenges for a subject to avoid potential 
impact of any residual symptoms on the assessments, per PI judgement. Similarly, 
approximately 1 week or longer is recommended between EEU challenges and dosing to 
avoid any overlap of symptoms, per PI judgement. Eligible subjects who are oak-sensitized 
will also complete the oak EEU challenge at screening. Oak allergy status for stratification 
and day 36 challenges will be determined similar to birch EEU criteria during the screening 
oak challenges.   
7. Part A EEU challenges: TNSS and TOSS are recorded using an e-diary at baseline and then 
every ~20 minutes while in the EEU, then continued ~ every 2 hours until ~24 hours after the 
start of the EEU exposure (except during sleep). After completion of the EEU challenges, use 
of allergy medicines will be recorded in the e-diary until ~24 hours after the start of the EEU 
challenges.  An assessment of TNSS is performed once prior to the start of the EEU exposure 
at visits 2, 3, 6, 7, 8, 9. If TNSS ≤2, then the visit activities can proceed. If TNSS is >2, then 
the visit can be rescheduled within the window. Washouts for medications prior to EEU visits 
are specified in prohibited medications (Protocol Section 7.9.1).  
8. Part B EEU challenges: There are no TNSS thresholds for the peak birch pollen season EEU 
visit (visit 13). The birch EEU challenge at the end of the season (visit 14) may not be 
performed in grass-allergic participants who are highly symptomatic or unable to wash out 
allergy relieving rescue medications due to grass pollen allergy symptoms, per PI discretion.  
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REGENERON CONFIDENTIAL 
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9. On a case-by-case basis, an EEU challenge visit window post-randomization may be extended 
up to +14 days for any illnesses (eg, respiratory illness, common cold, etc) that may potentially 
confound the assessments and/or potentially impact participant safety, per PI discretion in 
consultation with the sponsor.  
10. Randomization may occur within 1 day prior to study drug administration.  
11. In Part B, participants who received either 3-mAb, 2-mAb, 1-mAb, or placebo in Part A will 
continue the same treatment in Part B. 
12. Dosing window for visit 11 is within approximately 0 to 3 weeks prior to start of the 
anticipated BPS. 
13. Visit timeframes in Part B (visits 10 to 15) may vary based on the timing and duration of the 
anticipated BPS. End-of-season EEU challenge (visit 14) should occur after the end of the 
protocol-defined end of the BPS. 
14. Dose #2 should be administered at minimum 12 weeks after dose #1. 
15. Participants will be contacted within 1 day (visit 12) after dose 2 (visit 11) via telephone to 
monitor safety trends. 
16. All safety assessments performed at screening must be normal and checked against the 
inclusion/exclusion criteria prior to study drug administration at visit 4. Similarly, it is 
recommended to review relevant safety assessments prior to dosing at visit 11. Participants 
will be observed for 2 hours after receiving the SC dose of study drug. Safety labs may be 
repeated if any concerns, per PI discretion.  
17. A full physical exam must be done at screening, visits 4, 11, and 15. A limited relevant 
physical exam will be done at the remaining visits, per PI judgement, depending on 
presentation of the participant. Additional relevant physical exams may be conducted during 
and after completion of the EEU challenges, per PI discretion. 
18. Vital signs include systolic and diastolic blood pressure, respiratory rate, heart rate, and 
temperature. Vital signs will be collected in a seated position.  
*On visit 4 (day 1) and visit 11, vital signs are taken prior to study drug administration and at 2 hours 
(approximately ±15 min) after completion of study drug administration. 
Additional vital signs may be recorded during and after completion of the EEU challenges, 
per PI discretion. 
19. Inclusion/ exclusion criteria will be verified only to document any changes, not to determine 
study eligibility. 
20. Testing for COVID-19 or other respiratory infections may be performed at visits, per site local 
protocols. 
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Statistical Analysis Plan 
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REGENERON CONFIDENTIAL 
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21. If the urine pregnancy test is positive, the site must perform a serum pregnancy test for 
confirmation. For visit 4 (randomization) if a serum pregnancy test must be performed, study 
drug cannot be administered unless the serum pregnancy test is negative. For all EEU visits 
(visits 2, 3, 6, 7, 8, 9, 13, and 14) and early termination, if a pregnancy test must be performed, 
EEU and associated procedures cannot be performed unless the pregnancy test is negative. 
Urine pregnancy test can be performed on day -1 of EEU visits and early termination, at the 
investigator’s discretion. 
22. Electrocardiogram will be performed locally by the site. 
23. Spirometry will be performed locally by the site. *Spirometry at screening and randomization 
is required for all participants for eligibility. At other visits, spirometry and/or peak expiratory 
flow (PEF) may be performed for participants, per PI judgement. 
24. Daily TNSS, TOSS, and DMS assessments will being collected by e-diary during screening 
and in Part B from visit 10 to visit 15. The e-diary is returned at visit 15. 
25. Screening baseline assessment: e-diary assessments for symptoms and allergy rescue 
medication use should be obtained for an approximate 2-week period or longer (at minimum 
1 week) starting after the screening birch EEU challenge until randomization (visit 4) in 
eligible subjects. It is recommended that it is performed outside of relevant pollen seasons 
when pollen-allergic subjects are not significantly symptomatic due to other pollens. 
26. Pre-season baseline assessment: e-diary assessments for symptoms and allergy rescue 
medication use should be obtained approximately 2 weeks or longer up (at minimum 1 week) 
to receipt of dose 2 given ahead of the anticipated BPS (starting at visit 10 [Part B]) and prior 
to receiving dose 2 at visit 11 ahead of the BPS). 
27. Allergy relieving rescue medications, as needed, should be dispensed at the end of symptom 
score collection on visits 2, 3, 6, 7, 8, and 9. Rescue medications are dispensed starting at visit 
10 for management of symptoms during the pollen season up to visit 15.  
28. RQLQ(S) is administered weekly starting at visit 2 (during screening baseline assessment 
period) and then weekly using an e-diary in Part B starting at visit 10 until visit 15. 
29. Pollen food allergy questionnaire (PFASQ) is administered every 2 weeks at baseline starting 
at visit 2 (during screening baseline assessment period) and then every 2 weeks in Part B 
starting at visit 10 until visit 15.   
30. Outdoor time questionnaire is administered daily at baseline starting at visit 2 (during 
screening baseline assessment period) and then daily using an e-diary in Part B starting at visit 
10 until visit 15. 
31. Basophil activation test (BAT) samples may be collected from approximately 100 randomized 
participants (subset of the total enrolled population at one or both EEU sites; additional 
samples may be collected at the screening EEU visit to account for potential screen failures). 
The initial samples for a BAT assay are to be collected prior to the administration of study 
drug and subsequent BAT assay samples are to be collected prior to the respective EEU 
challenges. 
32. Samples are to be collected prior to the administration of study drug and prior to EEU 
challenges, when applicable.  
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Regeneron Pharmaceuticals, Inc. 
Protocol: R5713-5714-5715-ALG-21111 Amendment 1 
Statistical Analysis Plan 
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REGENERON CONFIDENTIAL 
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33. Nasal fluid samples may be collected from a subset of participants. It is recommended to 
collect these samples in the same participants from whom BAT assay samples were collected. 
It will be collected in approximately 100 randomized participants at visits 2, 6, 8, 13, and 14 
(subset of the total enrolled population at one or both EEU sites; additional samples may be 
collected at the screening EEU visit to account for potential screen failures). At each visit, the 
nasal fluid samples will be collected at 2 time points, prior to the start of the EEU challenge 
and then at 6 hours after completion of the challenge. 
34. Medical, surgical, allergy and medication history, demographic and social history may be 
obtained from historical data for participants who have available source documentation of 
these within 6 months prior to screening. At screening, all historical data should be reviewed/ 
confirmed for accuracy and completeness with addition of any other relevant missing and/or 
interval changes since that last historical assessment. Eligibility criteria must be reviewed 
during screening to ensure that all inclusion criteria are met, and no exclusion criteria are met. 
35. Skin prick testing data for allergens using standard diagnostic concentrations of allergen 
extracts [except birch, other trees (birch-related or unrelated), or grasses] may be obtained 
from historical data for participants who have source documentation of prior SPT performed 
within 6 months prior to screening.  
Note: Appropriate source documentation (eg, tape transfer method) must be available to calculate and 
verify the mean wheal diameter as per study requirements. Participants who do not have 
historical data for any of the other SPTs as specified in the study reference manual within 6 
months prior to screening will need to perform them during the screening period. All participants 
are required to have an SPT for birch, other trees (birch-related or unrelated), and grasses during 
the study screening period regardless of the availability of historical data.  
36. Pharmacokinetic (drug concentration) and immunogenicity (ADA) samples are to be 
collected prior to the administration of study drug. In the event of suspected serious adverse 
events (SAEs), such as anaphylaxis or systemic hypersensitivity, additional samples for the 
analysis of ADA as well as REGN5713, REGN5714, and REGN5715 drug concentration may 
be collected as close to the event as practically possible. 
37. Pharmacogenomics sub-study is optional for all participants enrolling in the main study. One 
DNA sample is to be collected on day 1/randomization prior to receiving the study drug, but 
if this sample collection was omitted at baseline, it can be collected at any subsequent visit.  
38. Unscheduled visit procedures may be performed per PI discretion based on the reason for the 
visit. 
39. Allergen-specific IgE should be drawn prior to administration of study drug at the 
randomization visit (visit 4). 
40. Day 57 and/or day 85 EEU challenges may not be performed in participants who have a high 
symptom burden assessed due to tree pollens.  
41. Visit 10 may not be performed in participants if they are expected to be dosed within 3 weeks 
after the prior EEU visit. If visit 10 is not performed, then all visit 10 assessments (without 
any duplication) should be performed at the last prior EEU visit (including serum pregnancy 
test, e-diary, dispensing rescue medications, etc)  
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Statistical Analysis Plan 
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REGENERON CONFIDENTIAL 
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14.3. 
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 – United States Food and Drug 
Administration (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  
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  
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Statistical Analysis Plan 
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REGENERON CONFIDENTIAL 
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Parameter 
PCSV 
Comments 
Sodium 
≤129 mmol/L  and baseline > 129 mmol/L  
≥160 mmol/L  and baseline < 160 mmol/L  
Two independent criteria 
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 
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. 
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REGENERON CONFIDENTIAL 
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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 
 
Temperature 
>= 100.4 °F/38.0 °C 
 
14.4. 
Search Criteria for TEAE of Special Interest 
AESI 
Search Criteria 
Systemic or severe 
hypersensitivity 
reactions  
Narrow SMQ for hypersensitivity  
Note:  Anaphylaxis will be prospectively analyzed using the criteria discussed in the 
statement paper from the Second Symposium on the definition and Management of 
Anaphylaxis (Sampson, 2006).   
This would include manual adjudication of relevant PTs performed by the 
study medical monitor, before database lock 
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Statistical Analysis Plan 
Date: May 31, 2023 
 
REGENERON CONFIDENTIAL 
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14.5. 
Sensitization Status by SPT or sIgE 
Sensitization status will be determined by SPT and sIgE testing. For SPT, a negative control (such 
as saline/diluent), and positive control (histamine) will be included. The SPT and sIgE tests used 
to evaluate sensitization status (including definitions of birch, birch-related, and unrelated 
allergens) are provided in the table below. 
Summary of SPT and sIgE Tests Used to Evaluate Sensitization Status 
Type 
Group 
Allergen 
Tests 
Birch Allergens 
Tree pollens 
European White Birch 
SPT, sIgE 
Bet v 1 
sIgE 
Bet v 2 
sIgE 
Birch-Related 
Allergens 
Tree pollens 
White Alder  
SPT 
Grey Alder 
sIgE 
American Hazel 
SPT 
Red Oak  
SPT, sIgE  
Unrelated  
Allergens 
Tree pollens 
Sugar Maple 
SPT 
White Poplar 
SPT 
American Elm 
SPT 
Mountain Cedar 
SPT 
White Ash 
SPT 
Grass pollens 
Grass mix1 
SPT 
Timothy grass 
sIgE 
Weed pollens 
Short Ragweed  
SPT, sIgE 
Animal 
Cat 
SPT, sIgE 
Dog 
SPT, sIgE 
House dust mite 
House Dust Mite Mix2 
SPT 
Dermatophagoides farinae 
sIgE 
Dermatophagoides pteronyssinus 
sIgE 
Mold 
Mold mix3 
SPT 
Alternaria 
sIgE 
[1] Grass Mix: Kentucky Bluegrass, Meadow Fescue, Orchard Grass, Perennial Ryegrass, Redtop, Sweet Vernal 
Grass, Timothy Grass. 
[2] House Dust Mite Mix: D. farinae, D. pteronyssinus. 
[3] Mold Mix: Alternaria alternata, Aspergillus niger, Bipolaris sorokiniana; Cladosporium sphaerospermum, 
Penicillium chrysogenum var. chrysogenum 
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REGENERON CONFIDENTIAL 
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Several distinct definitions of sensitization status (by either SPT or sIgE) will be used and are 
defined below.  
• Mono-sensitization: defined as sensitization to birch and birch-related allergens only. 
• Poly-sensitization: defined as sensitization to birch and birch-related allergens and 
sensitization to any unrelated allergen and specifically the following groups will be 
described based on sensitizations 
− Sensitization to non-tree pollens: defined as sensitization to either grass or weed 
pollens. 
− Sensitization to unrelated tree pollens: defined as sensitization to any unrelated 
tree pollen 
− Indoor perennial allergen sensitization: defined as sensitization to any of house 
dust mite, cat or dog.  
Note: 
• Sensitization by SPT: defined as a mean wheal diameter of at least 3 mm or greater 
versus negative control. The eligibility criterion for birch sensitization by SPT 
requires a mean wheal diameter at least 5 mm greater versus negative control. SPT 
mean wheal diameter is defined as ([longest diameter + longest perpendicular]/2). 
• Sensitization by sIgE: defined as serum sIgE of 0.35 kUa/L or greater. 
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