Clinical trial NCT03558997
Conditions: Allergic Rhinitis
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-06-07; Completion date: 2019-06-13
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess whether 16 weeks of treatment with dupilumab as an adjunct to Timothy Grass Subcutaneous Immunotherapy (SCIT) improves upon the efficacy of Timothy Grass SCIT to reduce provoked allergic rhinitis symptoms, as measured by Total Nasal Symptom Score (TNSS) after nasal allergen challenge (NAC) with Timothy Grass extract at week 17.

The secondary objectives of the study are:

* To assess whether 16 weeks of treatment with dupilumab as compared to placebo reduces provoked allergic rhinitis symptoms, as measured by TNSS after nasal allergen challenge (NAC) with Timothy Grass extract
* To assess whether 16 weeks of treatment with dupilumab as compared to dupilumab + SCIT reduces provoked allergic rhinitis symptoms, as measured by TNSS after nasal allergen challenge (NAC) with Timothy Grass extract
* To assess changes in serum Timothy-grass-specific immunoglobulin G4 (IgG4), serum Timothy grass-specific immunoglobulin E (IgE), and ratio of serum Timothy Grass-specific IgG4 to IgE over 16 weeks of treatment with dupilumab + SCIT as compared to SCIT monotherapy
* To evaluate the safety and tolerability of 16 weeks of treatment with dupilumab as an adjunct to Timothy Grass SCIT

Detailed description:

Arms: arm 1: Participants received placebo matched to Dupilumab and placebo matched to Timothy grass subcutaneous immunotherapy (SCIT) every 2 weeks (Q2W) for 16 weeks. Both placebo doses were administered with a gap of 1 or 7 days. arm 2: Participants received placebo matched to SCIT and subcutaneous (SC) injections of Dupilumab at a loading dose of 600 milligrams (mg) on Day 1, followed by a 300 mg for Q2W for 16 weeks. Both placebo matched to SCIT and Dupilumab doses were administered with a gap of 1 or 7 days. arm 3: Participants received SCIT titrated up to a 4000 bioequivalent allergy unit (BAU) for 8 weeks followed by maintenance dose of 4000 BAU for following 8 weeks and SC injections of placebo matched to Dupilumab Q2W for 16 weeks. Both SCIT and placebo matched to Dupilumab doses were administered with a gap of 1 or 7 days. arm 4: Participants received SC injections of Dupilumab at a loading dose of 600 mg on Day 1, followed by 300 mg Q2W for 16 weeks and SCIT titrated up to 4000 BAU for 8 weeks followed by maintenance dose of 4000 BAU for following 8 weeks. Both SCIT and Dupilumab doses were administered with a gap of 1 or 7 days.
Interventions: intervention 1: Dupilumab intervention 2: Timothy Grass SCIT intervention 3: Placebo matching dupilumab intervention 4: Placebo matching SCIT
Intervention descriptions: intervention 1: Dupilumab was administered SC in a single-use, pre-filled glass syringe intervention 2: Timothy grass extract was administered SC. intervention 3: Placebo matching dupilumab was prepared in the same formulation without the addition of protein intervention 4: Placebo matching SCIT was prepared in the same formulation (SCIT diluent) without the addition of Timothy grass extract

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
R668-ALG-16115 Amendment 2 
IND Number:  017987 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A STUDY TO EVALUATE THE EFFICACY OF DUPILUMAB AS AN ADJUNCT FOR 
SUBCUTANEOUS GRASS IMMUNOTHERAPY TO REDUCE PROVOKED 
ALLERGIC RHINITIS SYMPTOMS USING THE NASAL ALLERGEN 
CHALLENGE MODEL 
Compound: 
REGN668 (dupilumab) 
Clinical Phase: 
2a 
Protocol Number: 
R668-ALG-16115 
Protocol Version:  
R668-ALG-16115 Amendment 2 
Amendment 2 Date of Issue:  
See appended electronic signature page 
Amendment 1 Date of Issue: 
13 Apr 2018 
Original Date of Issue: 
20 Dec 2017 
Medical/Study Director: 
Associate Director 
Early Clinical Development and Experimental 
Sciences 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
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Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 87 
CONFIDENTIAL 
Amendment 2 
The purpose of this amendment is to respond to feedback received from the FDA. 
The following table outlines the changes made to the protocol and the affected sections: 
Change and Rationale for Change 
Section Changed 
As requested by the FDA, added a secondary endpoint 
which is the “Change and percent change from baseline 
in the TNSS AUC post NAC over the first hour of the 
challenge (0-1 hr post peak TNSS) at week 17 for 
dupilumab + SCIT as compared to dupilumab + placebo 
for SCIT.” 
Clinical Study Protocol Synopsis: Objective(s) and 
Endpoints 
Section 2.2 Secondary Objectives  
Section 4.2.2 Secondary Endpoints 
Added a footnote to clarify that the NAC happens after 
16 weeks of study treatment at week 17. 
Section 5.1.1.2, Figure 1 Study Flow diagram 
Changed text regarding the follow-up of pregnancies in 
dupilumab studies.   
The changes were made based on a decision made by 
the program team, which aligns with the current 
dupilumab label.   
Section 6.2.2 Exclusion Criteria, #33 
Section 9.4.3. Other Events that Require Accelerated 
Reporting to Sponsor 
As requested by the FDA, added text that “The Placebo 
SCIT will have an identical appearance to the Grass 
SCIT” for clarification.  
Section 7.1.2 
Timothy 
Grass 
SCIT: 
Reference 
Treatment 
Added the following footnote to the schedule of events 
table for clarification:  
18. The visit should be conducted as close as possible 
to the designated study schedule date and the window 
for the days used only as needed.   
Section 8.1.1 Footnotes for the Schedule of Events 
Table; footnote #18  
Added text to clarify that treatment with prohibited 
medications is allowed during the study if medically 
necessary as judged by the investigator (ie, as needed 
for allergic symptoms related to SCIT or SCIT placebo 
or related to study procedures).   
Section 7.7.1 
Prohibited 
Medications 
(after 
Randomization) and Procedures 
Added text to clarify the grading of severity of AEs by 
Common Terminology Criteria for Adverse Events 
(CTCAE). 
Section 9.5.1 Evaluation of Severity 
As requested by the FDA, corrected the type-o in the 
statistical hypothesis for superiority testing (ie, 
corrected from “week 24” to “week 17.” 
Section 10.1 Statistical Hypothesis 
Minor editorial changes: 
Section 8.1 Schedule of Events 
Section 10.2 Justification of Sample Size 
 
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Page 3 of 87 
CONFIDENTIAL 
Amendment 1 
The following table outlines the changes made to the protocol for Amendment 1 and the affected 
sections: 
Change and Rationale for Change 
Section Changed 
Change the detailed description of concentrations 
delivered during the NAC (4 BAU, 10 BAU, 40 BAU, 
100 BAU, 400 BAU, 1000 BAU) to incorporate flexible 
language instead, including one highest dose, and refer 
to the Study Operations Manual for the actual dilutions 
that will be given.   
Rationale: This level of detail is better suited to the 
Study Operations Manual because we are finding during 
writing of the Study Operations Manual, that these 
doses will need to be adjusted for ease of dilution 
preparation. One highest dose has been suggested by 
multiple site PIs as has been done in similar studies.  
Section 5.2 Screening 
Clarify that any AEs or SAEs that are related to any 
study procedure, including the NAC procedure, should 
be reported as AEs and SAEs.  
The protocol currently states “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 symptoms that occur in response 
to the NAC on the day of the NAC.  Allergic symptoms 
that occur in response to the NAC are not to be reported 
as AEs, as they will be recorded as outcome measures”. 
The protocol now reads as follows “However, AEs that 
occur in response to the NAC that are outside of 
expected symptoms which are recorded in response to 
the NAC, or SAEs, should be reported as AEs and 
SAEs”.   
Additional 
text 
was 
added 
to 
Section 
9.5.2, 
“Relationship of Adverse Events to Study Procedures” 
Rationale: To clarify that reporting of AEs and SAEs 
related to study procedures.    
Section 9.4.1 Adverse Events 
Section 9.5.2 Evaluation of Causality 
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CONFIDENTIAL 
Change and Rationale for Change 
Section Changed 
Correct typos and make clarifications.  
Rationale: Since the protocol has been circulated to 
study sites, we have received feedback to correct typos 
and inconsistencies 
Synopsis Added study procedures section 
Section 3.2.7 Rationale for Primary Endpoint 
Section 3.2.8.1 Rationale of allergen-Specific IgG4 to 
IgE in Serum 
Section 3.2.8.5 Basophil Sensitivity Test for Timothy 
Grass 
Section 3.2.8.6 Frequency of Circulating Th2A Cells 
Section 3.2.8.7 Type 2 Inflammation in the Nasal 
Mucosa in Response to a NAC as Measured by RNA 
Sequence and Gene Expression Analysis 
Section 5.2 Screening 
Section 5.3.1 Randomization 
Section 6.2.2 Exclusion Criteria, #1, #6, #8 
Table 1 SCIT Up Titration and Maintenance Regimen 
(corrected the sequence in the injection number) 
Table 2 Dosing Schedule for Dupilumab/Placebo with 
Respect to SCIT/Placebo (reference in the footnote) 
Section 7.3.2 Study Drug Discontinuation (Dupilumab 
or Placebo for Dupilumab and SCIT or Placebo for 
SCIT) 
Section 7.7 Concomitant Medications and Procedures 
Table 3 Schedule of Events 
Section 8.1.1 Footnotes for the Schedule of Events 
Section 8.2.1.1 NAC and NAC Assessments:  TNSS, 
TOSS, PNIF, and Total Sneezes 
Section 8.2.1.4 Nasal Brushing 
Section 8.2.2.4 Spirometry 
Section 8.2.2.5 Peak Expiratory Flow 
Section 8.2.2.6 Laboratory Testing 
Section 9.4.2 Serious Adverse Events 
Section 9.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................16 
1. 
INTRODUCTION ......................................................................................................19 
2. 
STUDY OBJECTIVES ..............................................................................................21 
2.1. 
Primary Objective .......................................................................................................21 
2.2. 
Secondary Objectives .................................................................................................21 
2.3. 
Other Objectives .........................................................................................................21 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................22 
3.1. 
Hypothesis ..................................................................................................................22 
3.2. 
Rationale .....................................................................................................................22 
3.2.1. 
Rationale for Study .....................................................................................................22 
3.2.2. 
Rationale for Study Design .........................................................................................22 
3.2.3. 
Rationale for Dose Selection ......................................................................................23 
3.2.3.1. 
Dose and Regimen of Dupilumab...............................................................................23 
3.2.3.2. 
Dose and Regimen of SCIT ........................................................................................23 
3.2.4. 
Rationale for Dose of SCIT and Up-titration Regimen ..............................................24 
3.2.5. 
Rationale for Choice of Allergen and Its Route of Administration ............................24 
3.2.6. 
Rationale for Nasal Allergen Challenge .....................................................................25 
3.2.7. 
Rationale for Primary Endpoint ..................................................................................25 
3.2.8. 
Rationale for Other Endpoints ....................................................................................25 
3.2.8.1. 
Ratio of Allergen-Specific IgG4 to IgE in Serum ......................................................25 
3.2.8.2. 
Nasal: Early-Phase (0–60 min) and Late-Phase (6 hr) Reaction to Nasal 
Allergen Challenge .....................................................................................................26 
3.2.8.3. 
Skin: Early-Phase (0–60 min) and Late-Phase (6 hr) Skin Reaction to 
Allergen Challenge .....................................................................................................27 
3.2.8.4. 
Serum TARC and Total IgE .......................................................................................27 
3.2.8.5. 
Basophil Sensitivity Test for Timothy Grass..............................................................27 
3.2.8.6. 
Frequency of Circulating Th2A Cells .........................................................................28 
3.2.8.7. 
Type 2 Inflammation in the Nasal Mucosa in Response to a NAC as 
Measured by RNA Sequence and Gene Expression Analysis ....................................28 
3.2.8.8. 
Rationale for Study Duration ......................................................................................29 
4. 
STUDY VARIABLES................................................................................................29 
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4.1. 
Demographic and Baseline Characteristics ................................................................29 
4.2. 
Primary and Secondary Endpoints..............................................................................29 
4.2.1. 
Primary Endpoint ........................................................................................................29 
4.2.2. 
Secondary Endpoints ..................................................................................................30 
4.2.3. 
Exploratory Endpoints ................................................................................................30 
4.3. 
Pharmacokinetic Variables .........................................................................................31 
4.4. 
Anti-Drug Antibody Variables ...................................................................................31 
5. 
STUDY DESIGN .......................................................................................................31 
5.1. 
Study Description and Duration .................................................................................31 
5.1.1. 
Dosing and Administration .........................................................................................32 
5.1.1.1. 
Dupilumab or Dupilumab Placebo .............................................................................32 
5.1.1.2. 
SCIT and Placebo Matching SCIT .............................................................................32 
5.2. 
Screening ....................................................................................................................33 
5.3. 
Randomized Treatment Period (16 Weeks) ................................................................35 
5.3.1. 
Randomization ............................................................................................................35 
5.3.2. 
Study Design Safety Considerations for SCIT ...........................................................35 
5.4. 
Post-Treatment Follow-up Period (8 Weeks): ............................................................36 
5.5. 
End of Study Definition ..............................................................................................36 
5.6. 
Planned Interim Analysis ............................................................................................36 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS ..............36 
6.1. 
Number of Subjects Planned ......................................................................................36 
6.2. 
Study Population .........................................................................................................36 
6.2.1. 
Inclusion Criteria ........................................................................................................36 
6.2.2. 
Exclusion Criteria .......................................................................................................37 
6.3. 
Premature Withdrawal from the Study .......................................................................40 
6.4. 
Replacement of Subjects .............................................................................................40 
7. 
STUDY TREATMENTS............................................................................................40 
7.1. 
Investigational and Reference Treatments ..................................................................40 
7.1.1. 
Dupilumab Injection:  Investigational Treatment .......................................................40 
7.1.2. 
Timothy Grass SCIT:  Reference Treatment ..............................................................41 
7.1.3. 
Timing of Dupilumab/placebo and SCIT/placebo ......................................................43 
7.2. 
Rescue Treatments ......................................................................................................44 
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7.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................44 
7.3.1. 
Dose Modification ......................................................................................................44 
7.3.2. 
Study Drug Discontinuation (Dupilumab or Placebo for Dupilumab and 
SCIT or Placebo for SCIT) .........................................................................................44 
7.3.3. 
Reasons for Permanent Discontinuation of Study Drug (Dupilumab or 
Placebo for Dupilumab and SCIT or Placebo for SCIT) ............................................45 
7.3.3.1. 
Reasons for Temporary Discontinuation of Study Drug (Dupilumab or 
Placebo for Dupilumab and SCIT or Placebo for SCIT) ............................................45 
7.4. 
Management of Acute Reactions ................................................................................46 
7.4.1. 
Acute Injection Reactions ...........................................................................................46 
7.4.1.1. 
Systemic Injection Reactions ......................................................................................46 
7.5. 
Method of Treatment Assignment ..............................................................................46 
7.5.1. 
Blinding ......................................................................................................................46 
7.5.2. 
Emergency Unblinding ...............................................................................................47 
7.6. 
Treatment Logistics and Accountability .....................................................................47 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................47 
7.6.2. 
Supply and Disposition of Treatments .......................................................................47 
7.6.3. 
Treatment Accountability ...........................................................................................48 
7.6.4. 
Treatment Compliance ................................................................................................48 
7.7. 
Concomitant Medications and Procedures .................................................................48 
7.7.1. 
Prohibited Medications (After Randomization) and Procedures ................................48 
7.7.2. 
Permitted Medications and Procedures ......................................................................48 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................49 
8.1. 
Schedule of Events .....................................................................................................49 
8.1.1. 
Footnotes for the Schedule of Events Table ...............................................................54 
8.1.2. 
Early Termination Visit ..............................................................................................55 
8.1.3. 
Unscheduled Visits .....................................................................................................55 
8.2. 
Study Procedures ........................................................................................................55 
8.2.1. 
Efficacy Procedures ....................................................................................................55 
8.2.1.1. 
NAC and NAC assessments:  TNSS, TOSS, PNIF, and Total Sneezes .....................55 
8.2.1.2. 
Skin Prick Test with Serial Allergen Titration ...........................................................56 
8.2.1.3. 
Intradermal Allergen Injection ...................................................................................56 
8.2.1.4. 
Nasal Brushing ............................................................................................................57 
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8.2.1.5. 
Nasal Fluid Collection ................................................................................................57 
8.2.2. 
Safety Procedures .......................................................................................................57 
8.2.2.1. 
Vital Signs ..................................................................................................................57 
8.2.2.2. 
Physical Examination .................................................................................................57 
8.2.2.3. 
Electrocardiogram .......................................................................................................58 
8.2.2.4. 
Spirometry ..................................................................................................................58 
8.2.2.5. 
Peak Expiratory Flow .................................................................................................58 
8.2.2.6. 
Laboratory Testing ......................................................................................................58 
8.2.3. 
Drug Concentration and Measurements .....................................................................59 
8.2.4. 
Anti-Drug Antibody Measurements and Samples ......................................................59 
8.2.5. 
Pharmacodynamic and Biomarker Procedures ...........................................................60 
8.2.5.1. 
Biomarker Sample collections ....................................................................................60 
 
 
 
 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................61 
9.1. 
Obligations of Investigator .........................................................................................61 
9.2. 
Obligations of Sponsor ...............................................................................................61 
9.3. 
Definitions ..................................................................................................................62 
9.3.1. 
Adverse Event .............................................................................................................62 
9.3.2. 
Serious Adverse Event ................................................................................................62 
9.4. 
Recording and Reporting Adverse Events ..................................................................62 
9.4.1. 
Adverse Events ...........................................................................................................62 
9.4.2. 
Serious Adverse Events ..............................................................................................63 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................63 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................64 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................64 
9.4.6. 
Follow-up ....................................................................................................................64 
9.5. 
Evaluation of Severity and Causality .........................................................................65 
9.5.1. 
Evaluation of Severity ................................................................................................65 
9.5.2. 
Evaluation of Causality ...............................................................................................65 
9.6. 
Safety Monitoring .......................................................................................................69 
9.7. 
Investigator Alert Notification ....................................................................................69 
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10. 
STATISTICAL PLAN................................................................................................69 
10.1. 
Statistical Hypothesis ..................................................................................................69 
10.2. 
Justification of Sample Size........................................................................................70 
10.3. 
Analysis Sets ...............................................................................................................70 
10.3.1. 
Efficacy Analysis Sets ................................................................................................70 
10.3.2. 
Safety Analysis Set .....................................................................................................70 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................70 
10.3.4. 
Anti-Drug Antibody Analysis Sets .............................................................................70 
10.4. 
Statistical Methods ......................................................................................................71 
10.4.1. 
Subject Disposition .....................................................................................................71 
10.4.2. 
Demography and Baseline Characteristics .................................................................71 
10.4.3. 
Efficacy Analyses .......................................................................................................71 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................71 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................72 
10.4.3.3. 
Multiplicity Considerations ........................................................................................72 
10.4.3.4. 
First-Step Analysis......................................................................................................72 
10.4.4. 
Safety Analysis ...........................................................................................................72 
10.4.4.1. 
Adverse Events ...........................................................................................................72 
10.4.4.2. 
Other Safety ................................................................................................................73 
10.4.4.3. 
Treatment Exposure ....................................................................................................73 
10.4.4.4. 
Treatment Compliance ................................................................................................74 
10.4.5. 
Pharmacokinetics ........................................................................................................74 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................74 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................74 
10.5. 
Additional Statistical Data Handling Conventions .....................................................74 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........75 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS .....................................75 
11.1. 
Data Management .......................................................................................................75 
11.2. 
Electronic Systems ......................................................................................................75 
12. 
STUDY MONITORING ............................................................................................76 
12.1. 
Monitoring of Study Sites ...........................................................................................76 
12.2. 
Source Document Requirements ................................................................................76 
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12.3. 
Case Report Form Requirements ................................................................................76 
13. 
AUDITS AND INSPECTIONS .................................................................................76 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................77 
14.1. 
Good Clinical Practice Statement ...............................................................................77 
14.2. 
Subjects Confidentiality and Data Protection .............................................................78 
14.3. 
Institutional Review Board/Ethics Committee ...........................................................78 
15. 
PROTOCOL AMENDMENTS ..................................................................................78 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................78 
16.1. 
Premature Termination of the Study ...........................................................................78 
16.2. 
Close-out of a Site ......................................................................................................79 
17. 
STUDY DOCUMENTATION ...................................................................................79 
17.1. 
Certification of Accuracy of Data ...............................................................................79 
17.2. 
Retention of Records ..................................................................................................79 
18. 
DATA QUALITY ASSURANCE ..............................................................................80 
19. 
CONFIDENTIALITY ................................................................................................80 
20. 
FINANCING AND INSURANCE .............................................................................80 
21. 
PUBLICATION POLICY ..........................................................................................80 
22. 
REFERENCES ...........................................................................................................81 
23. 
INVESTIGATOR’S AGREEMENT ..........................................................................85 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS .....................................................87 
 
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LIST OF TABLES 
Table 1: 
SCIT Up-Titration and Maintenance Regimen...........................................................42 
Table 2: 
Dosing Schedule for Dupilumab/Placebo with Respect to SCIT/Placebo .................43 
Table 3: 
Schedule of Events .....................................................................................................50 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................33 
 
LIST OF APPENDICES 
Appendix 1. TOXICITY GRADING SCALE FOR GRADING ALLERGIC 
REACTIONS AND ANAPHYLAXIS – COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (CTCAE VERSION 4.0, 
PUBLISHED 28 MAY 2009; V4.03, 14 JUNE 2010) ...............................................86 
 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Study To Evaluate The Efficacy Of Dupilumab As An 
Adjunct For Subcutaneous Grass Immunotherapy To Reduce 
Provoked Allergic Rhinitis Symptoms Using The Nasal 
Allergen Challenge Model 
Site Location(s) 
North America  
Objective(s) 
The primary objective is to assess whether 16 weeks of 
treatment with dupilumab as an adjunct to Timothy Grass 
subcutaneous immunotherapy (SCIT) improves upon the 
efficacy of Timothy Grass SCIT to reduce provoked allergic 
rhinitis symptoms, as measured by Total Nasal Symptom Score 
(TNSS) after nasal allergen challenge (NAC) with Timothy 
Grass extract at week 17. 
The secondary objectives of the study are: 
 To assess whether 16 weeks of treatment with dupilumab 
as compared to placebo reduces provoked allergic rhinitis 
symptoms, as measured by TNSS after nasal allergen 
challenge (NAC) with Timothy Grass extract  
 To assess whether 16 weeks of treatment with dupilumab 
as compared to dupilumab + SCIT reduces provoked 
allergic rhinitis symptoms, as measured by TNSS after 
nasal allergen challenge (NAC) with Timothy Grass 
extract  
 To assess changes in serum Timothy Grass-specific IgG4, 
serum Timothy Grass-specific IgE, and ratio of serum 
Timothy Grass-specific IgG4 to IgE over 16 weeks of 
treatment with dupilumab + SCIT as compared to SCIT 
monotherapy 
 To evaluate the safety and tolerability of 16 weeks of 
treatment with dupilumab as an adjunct to Timothy Grass 
SCIT  
Study Design 
This is a phase 2a, multicenter, randomized, double-blind, 
parallel group, 4-arm study of dupilumab as an adjunct to grass 
SCIT in adult subjects with a history of allergic rhinitis.  The 
entire study will be conducted outside of Timothy Grass allergy 
season.  The 4 arms are: 
1. Timothy Grass SCIT up-titrated to a 4,000 Bioequivalent 
allergy unit (BAU) maintenance dose + dupilumab 
subcutaneous (SC) [300 mg every 2 weeks (Q2W), after 
600 mg loading dose]  
 
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2. Timothy Grass SCIT up-titrated to a 4,000 BAU maintenance 
dose + placebo for dupilumab 
3. Placebo for SCIT plus dupilumab (SC 300 mg Q2W, after 
600 mg loading dose)   
4. Placebo for SCIT plus placebo for dupilumab 
Study Duration 
The duration of the study is approximately 24 weeks excluding 
the screening period, including 16 weeks on study drugs and 
8 weeks follow-up  
End of Study Definition 
The end of study is defined as the last visit of the last subject. 
Population 
Adult subjects with a history of allergic rhinitis  
 
Sample Size: 
Approximately 100 subjects, 25 per treatment group 
 
Target Population: 
Male and female subjects aged 18 to 55 with a history of 
Timothy Grass pollen–induced seasonal allergic rhinitis  
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab 
300 mg SC Q2W after loading dose of 600 mg SC on day 1 
 
Reference Drug 
 
Dose/Route/Schedule: 
Timothy Grass Extract SCIT   
Cluster SCIT up-titration regimen of Timothy Grass extract 
over 8 weeks followed by maintenance SC injections for the 
following 8 weeks (regimen described in Table 1) 
 
Placebo 
 
Route/Schedule: 
Placebo for dupilumab 
SC Q2W with loading dose after placebo loading dose SC on 
Day 1 
 
Placebo 
 
Route/Schedule: 
Placebo for SCIT 
Cluster SCIT up-titration regimen of placebo over 8 weeks 
followed by maintenance SC injections for the following 
8 weeks 
Endpoint(s) 
 
Primary: 
The primary endpoint is the percent change in the area under 
the curve (AUC) for TNSS (0-1 hr post peak TNSS) in response 
to a NAC at week 17 from the pretreatment baseline TNSS 
AUC (0-1 hr post peak TNSS) for dupilumab + SCIT as 
compared to placebo +SCIT monotherapy. 
Secondary 
 Change from baseline in TNSS AUC post NAC over the 
first hour after the challenge (0-1 hr post peak TNSS) at 
week 17 for dupilumab + SCIT as compared to SCIT 
monotherapy 
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 Change and percent change from baseline in TNSS area 
under curve (AUC) post NAC over the first hour of the 
challenge (0-1 hr post peak TNSS) at week 17 for 
dupilumab monotherapy as compared to placebo 
 Change and percent change from baseline in the TNSS 
AUC post NAC over the first hour of the challenge (0-
1 hr post peak TNSS) at week 17 for dupilumab + SCIT 
as compared to dupilumab + placebo for SCIT. 
 Change and percent change from baseline (last 
pretreatment measurement) to week 17 in serum 
Timothy Grass sIgG4 for dupilumab + SCIT as 
compared to SCIT monotherapy 
 Change and percent change from baseline (last 
pretreatment measurement) to week 17 in serum 
Timothy Grass sIgE for dupilumab + SCIT as compared 
to SCIT monotherapy 
 Change from baseline (last pretreatment measurement) 
to week 17 in log transformed value of serum Timothy 
Grass sIgG4 to Timothy Grass sIgE ratio for dupilumab 
+ SCIT as compared to SCIT monotherapy 
 Incidence rates of treatment emergent adverse events 
(TEAEs) and serious TEAEs through end of study  
Procedures and Assessments 
Efficacy will be assessed during the study at specified study site 
visits by the investigator(s) and include measurements of TNSS 
after NAC, TOSS after NAC, PNIF after NAC, intradermal 
skin challenge testing, and SPT with serial allergen titration.  
Safety will be assessed by vital signs, physical examination, 
clinical laboratory tests, ECGs, and clinical evaluations.  All 
AEs that occur from the time of the informed consent until the 
end of the study will be monitored by the investigator.   
Statistical Plan 
Sample Size Consideration: 
It is estimated that with 25 subjects per group, at the 2-sided 
5% significance level, the study will have 80% power to detect 
a difference of 29% between dupilumab plus SCIT and placebo 
plus SCIT monotherapy with respect to percent change from 
baseline in TNSS AUC (0-1 hr) at week 17, assuming that the 
mean percent changes from baseline values are -55% and -26% 
and a common standard deviation of 35% for dupilumab plus 
SCIT and placebo plus SCIT monotherapy, respectively. 
 
 
 
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Efficacy Analysis Sets: 
The full analysis set includes all randomized subjects. Efficacy 
analyses will be based on the treatment allocated at 
randomization (as randomized).  
The per protocol set includes all subjects in the FAS except for 
those who are excluded because of major protocol violations.  
A major protocol violation is one that may affect the 
interpretation of study results. 
Analysis Methods: 
Primary Efficacy Analyses 
The primary endpoint will be analyzed by using the multiple 
imputation with analysis of covariance (ANCOVA) model.  
Missing data will be imputed 40 times to generate 40 complete 
data sets by using the Statistical Analysis System (SAS) 
procedure MI.  Each of the 40 complete datasets will be 
analyzed using an ANCOVA model with treatment and relevant 
baseline as covariates.  The SAS MIANALYZE procedure will 
then be used to generate valid statistical inferences by 
combining results from the 40 analyses using Rubin’s formula. 
All observed data will be used for analysis.  Sensitivity analysis 
such as ANCOVA model with last observation carry forward 
(LOCF) method will also be conducted.  Additional details on 
sensitivity analyses will be provided in the statistical analysis 
plan. 
Secondary Efficacy Analyses 
The continuous secondary efficacy endpoints will be analyzed 
using the same approach as that used for the analysis of the 
primary endpoint. 
The biomarker related continuous endpoint will be analyzed 
using a rank based ANCOVA model with treatment and 
relevant baseline as covariates.  The LOCF method will be used 
to impute the missing data. 
Safety Analyses 
Safety analysis will be based on the safety analysis set. This 
includes reported TEAEs and other safety information (eg, 
clinical laboratory evaluations, vital signs, and 12-lead ECG 
results). 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
BAU 
Bioequivalent allergy unit 
BUN 
Blood urea nitrogen 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
EC50 
50% of maximal activation 
ECG 
Electrocardiogram 
ECP 
Eosinophil cationic protein 
EDC 
Electronic data capture 
EPR 
Early phase reaction 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
High-density lipoprotein 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon Gamma 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IL-4 
Interleukin 4 
IL-4Rα 
Interleukin 4 receptor alpha 
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IL-5 
Interleukin 5 
IL-13 
Interleukin 13 
ISR 
Injection site reactions   
IRB 
Institutional Review Board 
LABA 
Long-acting beta agonist 
LAMA 
Long-acting muscarinic antagonist 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LPR 
Late phase reaction  
MedDRA 
Medical Dictionary for Regulatory Activities 
NAC 
Nasal allergen challenge 
MI 
Multiple imputation 
NIMP 
Non-investigational Medical Product 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NP 
Nasal polyposis 
PBMC 
Peripheral Blood Mononuclear Cells 
PBO 
Placebo 
PCSV 
Potentially clinically significant value 
PK 
Pharmacokinetic 
PNIF 
Peak nasal inspiratory flow 
POM 
Proof of mechanism 
PT 
Preferred term 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
RNA 
Ribonucleic acid 
sIgE 
Specific immunoglobulin E 
sIgG4 
Specific immunoglobulin G4 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SD 
Standard deviation 
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SLIT 
Sublingual immunotherapy  
SOC 
System organ class 
SPT 
Skin prick test 
SQ 
Standardized Quality 
SUSAR 
Suspected unexpected serious adverse reaction 
TARC 
Thymus and activation-regulated chemokine 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 t-cells 
Th2A 
Th2A are a unique Th2 subcell in allergic individuals 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
WBC 
White blood cell 
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1. 
INTRODUCTION 
Subcutaneous immunotherapy (SCIT) is a disease modifying treatment option for patients with 
allergic rhinitis triggered by aeroallergens (such as pollen, animal dander, or dust).  SCIT is 
recommended when pharmacological therapies are not sufficient to control symptoms.  During 
SCIT, increasing doses of the inciting allergen are administered, followed by a maintenance dose 
for several years, with the goal of inducing immunological changes leading to symptom 
amelioration while on therapy, as well as sustained desensitization off SCIT (immune tolerance). 
The pathobiology of allergic disease is complex, involving many cell types and genetic 
susceptibility.  Data suggest that SCIT results in memory T and B cell responses, 
allergen-specific immunoglobulin shifts from immunoglobulin E (IgE) to immunoglobulin G4 
(IgG4), decreased Type 2 cytokines in tissues, decreased tissue migration of eosinophils and 
decreased mediator release from tissue mast cells, basophils and eosinophils (Akdis, 2011) 
(Larche, 2006).  The increase in allergen-specific IgG4 (sIgG4) titers observed in SCIT may 
inhibit effector cell activation by binding to allergen, thereby blocking binding to high affinity 
IgE pre-loaded on Fc (epsilon) receptors expressed on mast cells and basophils (Flicker, 2003).  
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and 
interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 
and IL-13 receptor complexes.  Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 
cytokine-induced responses, including the release of proinflammatory cytokines, chemokines 
and IgE.  IL-4 and IL-13 play key roles in the pathophysiology of allergic diseases, as 
demonstrated by dupilumab’s efficacy shown in clinical studies in atopic diseases such as atopic 
dermatitis (AD), asthma, nasal polyposis (NP) and eosinophilic esophagitis.  This is the basis for 
the rationale to evaluate whether dupilumab may enhance allergy immunotherapy.  Dupilumab 
has clinically demonstrated down-modulation of the Type 2 pathway and has the potential to 
complement the immunoregulatory mechanisms of allergen immunotherapy.  IL-4 and IL-13 are 
important cytokines that trigger class switching in B-cells (Lundgren M, 1989) and dupilumab 
has been shown to suppress serum total and specific immunoglobulin E (sIgE) over time in all 
studies where measured; serum total IgE decreased by ~30% after 12 weeks of weekly 300 mg 
treatment in AD; for sIgE, studies in AD and asthma patients show a ~40% reduction at week 16 
and ~50% reduction at week 24 (Regeneron unpublished data).  In a post-hoc analysis of a 
dupilumab dose-ranging study in moderate-to-severe asthma patients with comorbid allergic 
rhinitis, patients had a significant reduction in reported rhinitis symptoms with dupilumab 
compared to placebo.  Because of these data and the role of IL-4 and IL-13 in immunoglobulin 
class switching, we anticipate that dupilumab as an adjunct to SCIT, will enhance the change of 
allergen specific IgG4/IgE ratio in SCIT + dupilumab treated subjects as compared to subjects 
treated with SCIT alone.  In patients with AD, dupilumab modulated several Type 2 chemokines, 
including CCL17 (thymus and activation-regulated chemokine [TARC]) in serum and skin 
tissue, therefore we anticipate that dupilumab will modulate Type 2 chemokines and cytokines in 
subjects with a history of allergic rhinitis, which may improve tolerability of SCIT up-dosing 
(Beck, 2014) (Hamilton, 2014).  A reduction in the production of Type 2 cytokines and 
chemokines by dupilumab is also likely to potentiate the reduction of provoked allergic rhinitis 
symptoms by SCIT.  
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There is an unmet need for a more efficacious treatment of allergic disease.  SCIT can provide 
long-lasting protection from allergic disease, but it also carries a risk of adverse reactions, has 
variable efficacy between patients, and can take at least 3 years to induce immune tolerance 
(Durham, 1999) (Durham, 2012) (Leung, 2010) (Durham, 2016).  At the start of SCIT, patients 
receive injections of increasing doses of the allergen at weekly intervals over several weeks to 
months, under tightly monitored medical supervision.  The gradual dose escalation enables 
tolerability to therapy and mitigates risk of severe hypersensitivity reactions related to allergen 
administration.  Side effects occur in 40-50 % of patients ranging from mild reactions 
(eg, swelling, injection site reaction, de novo allergic response, and urticaria) to life-threatening 
reactions (eg, asthma exacerbation and anaphylaxis) (Frew, 2006a).  Asthma is a major risk 
factor for life-threatening systemic reactions to SCIT and therefore moderate-severe asthma is a 
contraindication to SCIT.  Therefore with proper patient selection, risk of severe reactions can be 
mitigated (Frew, 2010) (Frew, 2006a).  Induction of Type 2 pathway cytokines upon SCIT 
initiation can transiently exacerbate allergic symptoms, resulting in SCIT dose limitations during 
up-titration in some patients.  Blockade of these cytokines by dupilumab may improve 
tolerability of the desensitization process, in addition to improving overall safety and efficacy by 
further suppression of IgE production.   
Therefore, dupilumab may: 1) limit symptoms of the desensitization process so that maximal 
SCIT uptitration may be achieved 2) improve the efficacy of the sensitization process via its 
suppressive effect on IgE production, and 3) reduce allergic symptoms directly by other 
mechanisms including the inhibition of allergen specific Type 2 t-cells (Th2) cell number and 
function with downstream effects on mast cells, eosinophils, and basophils.  
This trial is a 4-arm, placebo-controlled, double-blind, randomized, parallel-group, 
proof-of-concept study over a 16 week treatment period followed by an 8 week safety follow-up 
period in approximately 100 subjects with a history of Timothy Grass-induced allergic rhinitis.  
Allergy to Timothy and rye grasses are the most prevalent seasonal allergies and grass 
immunotherapy is the most studied form of allergen immunotherapy (Salo, 2014).  The primary 
objective will be to assess whether dupilumab in combination with SCIT can reduce provoked 
allergic symptoms more than SCIT alone by Total Nasal Symptom Score (TNSS) after nasal 
allergen challenge (NAC) with Timothy Grass allergen.  The entire 17 week study will be 
conducted outside of grass allergy season so that environmental allergens do not interfere with 
the provoked allergy symptoms by the NAC.  TNSS is a patient-reported composite symptom 
assessment of congestion, itching, rhinorrhea and sneezing. Cluster SCIT dosing (multiple 
injections per week) accelerates the onset of efficacy of SCIT.  Therefore, up-titration of SCIT 
over 8 weeks (rather than conventional regimen of 12 weeks) plus 8 weeks of maintenance SCIT 
will be investigated in this study with the goal to show early induction of treatment response.  
We hypothesize that efficacy of SCIT, as measured by an improvement in TNSS in response to 
NAC, will be significantly augmented by dupilumab.  The secondary objectives will assess 
safety and tolerability of dupilumab as an adjunct to SCIT, whether dupilumab monotherapy 
reduces provoked allergic rhinitis symptoms more than placebo, and whether dupilumab in 
combination with SCIT changes Timothy Grass-specific IgG4, Timothy-Grass specific IgE, and 
the ratio of Timothy-grass specific IgG4/IgE more than SCIT alone.  Exploratory objectives will 
assess early-phase (0–1 hr) and late-phase (1-6 h) nasal and skin responses following nasal and 
intradermal allergen administration, Total Ocular Symptom Score (TOSS) after NAC, serum 
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TARC, and total IgE.  Additional biomarkers, to be included in a separate Exploratory 
Biomarker Report, will include basophil sensitivities to grass allergen, allergen-specific Th2A 
cells, and changes in type 2 inflammation in the nasal mucosa after NAC as measured by RNA 
sequencing and nasal fluid cytokine concentration.  
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
 To assess whether 16 weeks of treatment with dupilumab as an adjunct to Timothy 
Grass SCIT improves upon the efficacy of Timothy Grass SCIT to reduce provoked 
allergic rhinitis symptoms, as measured by TNSS after NAC with Timothy Grass 
extract at week 17 
2.2. 
Secondary Objectives 
 To assess whether 16 weeks of treatment with dupilumab as compared to placebo 
reduces provoked allergic rhinitis symptoms, as measured by TNSS after NAC with 
Timothy Grass extract  
 To assess whether 16 weeks of treatment with dupilumab as compared to dupilumab 
+ SCIT reduces provoked allergic rhinitis symptoms, as measured by TNSS after 
nasal allergen challenge (NAC) with Timothy Grass extract  
 To assess changes in serum Timothy-grass-specific IgG4, serum Timothy 
Grass-specific IgE, and ratio of serum Timothy Grass-specific IgG4 to IgE over 
16 weeks of treatment with dupilumab + SCIT as compared to SCIT monotherapy 
 To evaluate the safety and tolerability of 16 weeks of treatment with dupilumab as an 
adjunct to Timothy Grass SCIT  
2.3. 
Other Objectives 
 To assess whether 16 weeks of treatment with dupilumab as an adjunct to Timothy 
Grass SCIT improves upon the efficacy of Timothy Grass SCIT to reduce provoked 
allergic conjunctivitis symptoms, as measured by TOSS after NAC with Timothy 
Grass extract.  
 To assess whether 16 weeks of treatment with dupilumab as compared to placebo 
reduces provoked allergic conjunctivitis symptoms, as measured by TOSS after NAC 
with Timothy Grass extract.  
 To assess the changes in both early-phase (0–1 hr) and late-phase (1-6 hr) skin 
responses following Skin Prick Test with Serial Allergen Titration and intradermal 
administration of Timothy Grass, respectively, over 16 weeks of treatment with 
dupilumab monotherapy (+ placebo for SCIT), SCIT monotherapy (+ placebo for 
dupilumab), dupilumab + SCIT, and placebo for SCIT + placebo for dupilumab 
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 To assess changes in peak nasal inspiratory flow (PNIF) after NAC over 16 weeks of 
treatment with dupilumab monotherapy (+ placebo for SCIT), SCIT monotherapy 
(+ placebo for dupilumab), dupilumab + SCIT, and placebo for SCIT + placebo for 
dupilumab 
 To assess total sneeze count after NAC over 16 weeks of treatment with dupilumab 
monotherapy (+ placebo for SCIT), SCIT monotherapy (+ placebo for dupilumab), 
dupilumab + SCIT, and placebo for SCIT + placebo for dupilumab 
 To assess changes in serum TARC over 16 weeks of treatment with dupilumab 
monotherapy (+ placebo for SCIT), SCIT monotherapy (+ placebo for dupilumab), 
dupilumab + SCIT, and placebo for SCIT + placebo for dupilumab 
 To assess changes in serum total IgE over 16 weeks of treatment with dupilumab 
monotherapy (+ placebo for SCIT), SCIT monotherapy (+ placebo for dupilumab), 
dupilumab + SCIT, and placebo for SCIT + placebo for dupilumab 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Dupilumab in combination with SCIT will reduce provoked allergic rhinitis symptoms, as 
measured by TNSS after NAC, two-fold as compared to SCIT alone.  
3.2. 
Rationale  
3.2.1. 
Rationale for Study 
This study is a double blind, placebo-controlled, parallel design study in grass allergic subjects.  
Four treatment groups are required to provide informative controls and minimize bias on clinical 
endpoints: dupilumab + SCIT, placebo for dupilumab + SCIT, dupilumab + placebo for SCIT 
and placebo for dupilumab + placebo for SCIT.  In addition, this study will allow the evaluation 
of dupilumab monotherapy on clinical rhinitis symptoms and related biomarkers. 
3.2.2. 
Rationale for Study Design 
Dupilumab, with and without SCIT, will be tested in a 4-arm, double-blind, randomized, 
parallel-group, proof-of-concept study of 16 week treatment period in approximately 
100 subjects with a history of Timothy Grass-induced allergic rhinitis using change from 
baseline in TNSS area under curve (AUC) post NAC over the first hour after the challenge (0-1 
hr post peak TNSS) as the primary endpoint.  
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3.2.3. 
Rationale for Dose Selection 
3.2.3.1. 
Dose and Regimen of Dupilumab 
Dupilumab at 300 mg every 2 weeks (Q2W) with a loading dose of 600 mg on day 1 will be used 
in this study, as this regimen is Food and Drug Administration (FDA) approved for AD and is 
effective in asthma.  Based on the pharmacokinetic profile of dupilumab, this dose regimen is 
expected to saturate binding to IL-4Ra, providing maximum inhibition of signaling and hence 
suppression of type 2 inflammation and Ig class switching to IgE.  Moreover, this dose of 
dupilumab significantly reduces sIgE by 12 weeks (Regeneron unpublished data), which should 
improve upon the sIgG4/IgE ratio elicited by SCIT by 17 weeks to therefore improve upon the 
efficacy of SCIT as measured by TNSS in response to NAC after 17 weeks.  Subjects may 
administer the dupilumab at home after receiving the loading dose at the study site (and training 
to self-administer at home), but they will be given the opportunity to receive dupilumab at the 
study site as well.  The loading dose will allow subjects to achieve efficacious concentrations 
quickly for this short study.  Dupilumab will be started one day prior to initiation of the SCIT 
regimen, and for subsequent doses dupilumab will be administered Q2W and will always be 
given on a different day than SCIT to assist with interpretation of adverse effects due to each 
agent.  Dupilumab will be dosed as follows: subjects will be given a loading dose of 600 mg 
dupilumab subcutaneous (SC) or placebo on day 1, followed 2 weeks later by 300 mg Q2W SC, 
and to continue 300 mg Q2W SC for a total of 16 weeks.  In previous studies in patients like 
those expected to be enrolled in this study dupilumab has a safety profile similar to placebo 
except for an increased incidence of injection site reactions.  Other common adverse events 
(AEs) were headache, nasopharyngitis, and upper respiratory tract infection and these were most 
commonly mild to moderate in severity.  In patients with AD, conjunctivitis and Herpes simplex 
were also reported at an increased incidence in patients receiving dupilumab compared to 
placebo (Beck 2014) (Wenzel, 2016) (Bachert 2016). 
3.2.3.2. 
Dose and Regimen of SCIT 
On the day following dupilumab dosing (up to 7 days after dupilumab loading dose), subjects 
will begin an up-titration regimen of Timothy Grass SCIT beginning at 1 bioequivalent allergy 
unit (BAU) up to 4,000 BAU, in a modified cluster regimen over 8 weeks, and then maintained 
on 4,000 BAU for the remaining 8 weeks (Table 1).  This dosing regimen has previously been 
shown to give significant clinical efficacy and consistent kinetics of the sIgG4 and sIgE response 
(Frew, 2006b), (Shamji, 2012).  Using a modified cluster regimen over 8 weeks to reach a 
4,000 BAU maintenance dose, the most common AEs were fatigue, urticaria, wheezing, chest 
tightness and flushing (Ewbank, 2003).  As referenced previously, safety of modified cluster 
uptitration of SCIT versus conventional up-titration appears to have similar local and systemic 
AE profile (Creticos, 1992).  Additionally, as recommended by the American Academy of 
Allergy, Asthma & Immunology and the American College of Allergy, Asthma & Immunology 
to reduce local and systemic AEs during cluster SCIT, subjects will be pre-medicated with an 
oral H1 antihistamine prior to cluster SCIT dosing on all dosing days (Cox, 2011).  However, 
oral H1 antihistamines are never to be administered within 5 days prior to a study visit for NAC 
as antihistamines will interfere with the NAC. 
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3.2.4. 
Rationale for Dose of SCIT and Up-titration Regimen 
Per clinical guidelines, immunotherapy is typically initiated 12-16 weeks before the allergen 
season to treat seasonal allergic rhinitis.  Immunotherapy is often continued for a duration of 3-5 
years to reach greater efficacy and achieve allergen immunotolerance.  In clinical studies, 
efficacy is typically assessed after 8-12 months of treatment (Bachert, 2016) (Scadding, 2017) to 
investigate the maximal efficacy of SCIT on reduction of clinical symptoms during natural 
pollen exposure (Bachert, 2016) or by NAC after ≥ 8-12 months (Scadding, 2017).  SCIT 
reduces symptoms by 25-30% relative to placebo in these studies.  
Few studies have evaluated efficacy at time points earlier than 8 months.  However, the onset of 
symptom relief and increase in sIgG4 levels with SCIT occurs after reaching maintenance dose 
(ie, at the end of the up-titration phase [Ewbank, 2003]).  With conventional SCIT up-titration 
regimens, this can take 8-12 weeks of weekly dosing.  Cluster dosing, multiple injections per 
week, is an alternative to accelerate the onset of efficacy.  In a house dust mite SCIT study, 
6 week cluster dosing showed a marginal, but observable advantage to a 12 week conventional 
up-titration on clinical measures and a 50% more rapid rise in sIgG4.  Adverse events rates were 
slightly lower with the cluster regimen than the conventional up-titrations, 3% and 4%, 
respectively (Tabar, 2005).  A meta-analysis of 567 participants in 8 trials showed that cluster 
SCIT has similar effect in the reduction of both rhinitis symptoms and the requirement for 
anti-allergic medication compared with conventional SCIT.  The safety of cluster SCIT showed 
that no differences existed in the incidence of either local or systemic adverse reaction between 
the cluster group and control group (Feng, 2014).  The current study proposes to evaluate the 
highest recommended dose of SCIT (4,000 BAU) provided in a modified cluster regimen so that 
an observable change in treatment groups can be assessed in 17 weeks.  Efficacy will be assessed 
by changes in rhinitis symptoms after NAC (Section 4.2). 
3.2.5. 
Rationale for Choice of Allergen and Its Route of Administration 
Grass SCIT immunotherapy was selected as an experimental model to test the effect of 
dupilumab on SCIT due to the availability of precedent clinical and biomarker data.  Few 
well-controlled studies have been conducted with other allergens (Canonica, 2013).  Besides 
grass specific immunotherapy sublingual immunotherapy (SLIT) and SCIT, there are limited 
studies of other allergen immunotherapies demonstrating efficacy in a NAC study.  The 
advantage of studying seasonal allergens, (ie, grass pollen), compared to perennial allergens (ie, 
cat, house dust mite), is that pollens induce broader symptomatology, induce sneezing, itchiness 
and nasal congestion, whereas the predominant symptom associated with perennial allergens is 
nasal congestion.  Hence, a study of grass pollen will inform about the efficacy of dupilumab as 
an adjuvant to SCIT treatment on broad rhinitis symptoms.  One limitation of using a seasonal 
allergy is that timing of study and seasonality are key considerations; this study must be 
conducted outside of pollen season to minimize the impact of environmental allergen exposure 
on study results. 
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3.2.6. 
Rationale for Nasal Allergen Challenge 
This study will use the NAC to assess the efficacy of dupilumab with or without SCIT on 
allergic symptoms outside of grass allergy season.  The NAC is a well-recognized nasal 
provocation model that reproduces direct allergen contact of the upper airways in a controlled 
clinical setting allowing for rapid proof-of-mechanism (POM) in smaller numbers of patients 
than natural exposure studies (Eckman, 2010) (Paterniti, 2011).  Intranasal instillation of allergen 
causes local allergic symptoms, such as nasal congestion, itching, sneezing and rhinorrhea, 
which peak within the first hour of the early phase reaction (EPR) (Scadding, 2015a).  Within 
minutes of local allergen exposure, IgE-mediated basophil and tissue mast cell degranulation 
occurs with the release of mediators, which cause blood vessel dilation and vascular leakage 
immediately leading to these nasal symptoms.  Therefore, the change in TNSS score after NAC 
with Timothy Grass extract is selected for POM as a reliable, reproducible, and controlled 
method of measuring allergy symptoms for this study.  Each subject will undergo a baseline 
NAC at screening and a repeat NAC at the end of treatment. 
3.2.7. 
Rationale for Primary Endpoint 
As a primary endpoint, the percent change in the AUC for TNSS (0-1 hr post peak TNSS) in 
response to a NAC at week 17 from the pretreatment baseline TNSS AUC (0-1 hr post peak 
TNSS) will be assessed for dupilumab in combination with SCIT vs SCIT monotherapy 
(+ placebo for dupilumab).  During the up-titration phase of the NAC, TNSS will be measured 
every 10 minutes during the first hour until attainment of a TNSS score ≥ 7, and then TNSS will 
be measured at 5 minutes, 15 minutes, 30 minutes, 45 minutes, one hour, then hourly up to 
6 hours post-NAC.  Peak symptoms occur between 0-1 hours after NAC, therefore the primary 
endpoint will measure the AUC of TNSS over the first hour after peak TNSS is achieved 
(Regeneron unpublished data).  A 20-30% reduction in symptoms is considered a clinically 
meaningful response (Meltzer, 2016) (Pawankar, 2011).  Compared to natural exposure or 
environmental chamber, nasal provocation is a controlled and customized administration of 
allergen, resulting in a more reliable and reproducible assessment of efficacy with a smaller 
sample size.  Additionally, environmental chamber studies are limited to one site as chambers at 
different sites vary considerably by allergen exposure. 
3.2.8. 
Rationale for Other Endpoints 
3.2.8.1. 
Ratio of Allergen-Specific IgG4 to IgE in Serum 
Immunotherapy induces both cellular and humoral regulatory immune mechanisms.  Humoral 
mechanisms involve the induction of allergen specific antibodies, especially of the IgG4 isotype, 
which is thought to have a protective effect against IgE-mediated allergic symptoms.  IgG4 
competes with IgE, blocking IgE-mediated effector cell activation, suppresses histamine release 
and inhibits antigen-presentation of IgE-allergen complex by dendritic and B-cells 
(James, 2012).  The gradual increase in serum allergen-specific IgG4, IgE-blocking factor and 
decrease in allergen-specific IgEs have been associated with clinical desensitization in SCIT for 
grass (Shamji, 2012) and was consistently observed across different studies.  At the start of 
SCIT, serum sIgG4s are low/undetectable.  In response to the initiation of SCIT, a 2-fold 
increase in sIgG4 and a transient increase in sIgE is observed (Scadding, 2017) (Creticos, 1992) 
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(Suarez-Fueyo, 2014).  An approximately 8-fold increase in the ratio of sIgG4/sIgE was 
associated with a reduction in symptoms induced by nasal allergen provocation after 1-year of 
SCIT (Scadding, 2017).  A higher ratio of sIgG4/sIgE in patients tolerant to some allergens 
(eg, birch, 
cat, 
peanut) 
compared 
to 
their 
symptomatic 
controls 
was 
observed 
(Geroldinger-Simic, 2011) (Du Toit, 2013) (Burnett, 2013).  Compared to the individual levels 
of sIgG4 or sIgE, the ratio of sIgG4/IgE is thought to be more reflective of the competition for 
allergen binding between IgG4 and IgE and has so far shown better correlation with clinical 
improvement.  Given that the induction of sIgG4 and the suppression of sIgE is the most well-
known phenomenon associated with immunotherapy and dupilumab has been shown to suppress 
specific IgE in past studies, we aim to test if skewing of sIgG4/IgE ratio will be one of the 
immunological effects of dupilumab as an adjunct to SCIT treatment. 
3.2.8.2. 
Nasal: Early-Phase (0–60 min) and Late-Phase (6 hr) Reaction to Nasal Allergen 
Challenge 
Response to nasal allergen challenge has been used as a surrogate for seasonal symptoms in past 
clinical trials of corticosteroid treatment for allergic rhinitis.  The concentration of 
cytokines/chemokines and other mediators in the nasal fluid were recorded as a measure of 
inflammatory response.  The early phase reaction (EPR) was characterized by the induction of 
tryptase and histamine, which were thought to reflect mast cell activation and degranulation in 
the nasal epithelium.  Existing data from multiple studies consistently reported peak induction of 
tryptase at 5-minutes post challenge, followed by rapidly declining levels within 60 minutes and 
then dropping back to baseline within 2 hours.  The late phase reaction (LPR) is thought to 
reflect type 2 inflammation mediated by Th2-cells and eosinophils that migrate to the site of 
inflammation.  The gradual increase in eosinophil cationic protein (ECP), eotaxin, eotaxin-3, 
IL-4, IL-5, IL-13, IFN IL-9 can be detected at pg/mL to ng/mL concentrations from 1 to 2 hours 
onwards.  Typically, Type 2 cytokine levels in nasal fluid also increase some hours after 
challenge: IL-5 at 6–9 h (Nicholson, 2011) (Linden, 2000); IL-13 at 6–8 h (Erin, 2005a) 
(Nicholson, 2011); and IL-4 at 5–6 h (Wagenmann, 2005).  IL-10 was reported to increase in 
nasal fluid 6 hours post allergen challenge (Bensch, 2002).  IFN-γ levels did not show significant 
induction in published studies, which is consistent with a primarily type 2 mediated 
inflammation following NAC (Scadding, 2012).  
Allergen specific immunotherapy with Timothy Grass has been shown to decrease both the early 
phase and late phase reaction post-NAC, as measured by the decrease of tryptase, eotaxin, IL-9 
and IL-4 in the nasal fluid collected from patients on immunotherapy compared to placebo 
(Scadding, 2015b).  We hypothesize that dupilumab treatment as an adjunct to SCIT treatment 
may further suppress the tissue specific allergic response to allergen challenge, as well as further 
decrease the induction of type-2 cyotkines and chemokines in late phase reactions compared to 
SCIT alone. 
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Two techniques could be used to collect and study mediators in nasal fluid.  Key considerations 
include acceptability to patients, collection of adequate volumes, and adequate concentration to 
allow the planned immunoassays.  Generally, techniques involving direct absorbance from the 
mucosa 
provide 
optimal 
results 
(Klimek, 
1999a) 
(Klimek, 
1999b) 
(Lü, 
2010) 
(Riechelmann, 2003).  In a comparison study by Scadding GW and colleagues, nasal sponges 
were shown to be superior to strip paper method (higher sample volume and statistically 
significant induction of ECP, IL-5, IL-13 were detected post NAC) (Scadding, 2012).  In a 
Regeneron/Sanofi sponsored NP study with dupilumab, sufficient volumes of nasal fluid were 
collected by the sponge method and TARC, ECP and eotaxin-3 levels within detectable range for 
ELISA-based assays (Regeneron/Sanofi unpublished data), which also supports our selection of 
nasal sponge as the method of nasal fluid collection.  
3.2.8.3. 
Skin: Early-Phase (0–60 min) and Late-Phase (6 hr) Skin Reaction to Allergen 
Challenge   
The SPT with serial allergen titration assesses the early phase reaction (EPR) at 0-60 min.  The 
intradermal allergen injection will be performed to assess late phase reaction (LPR) at 6 hours.  
The early phase reaction is characterized by histamine release and is thought to reflect cutaneous 
mast cell degranulation upon allergen exposure.  The allergen-induced cutaneous LPR is 
characterized by an influx of inflammatory cells, including basophils, eosinophils, activated 
CD4+-cells, and neutrophils which arrive at the site of inflammation some hours after 
provocation.  
Allergen specific immunotherapy with Timothy Grass has been shown to decrease both the early 
phase reaction after SPT, and late phase reaction after intra-dermal allergen challenge, as 
measured by the decrease of wheal size post challenge (Scadding, 2015b).  In addition, short 
term grass SCIT treatment (13 weeks) led to significant and lasting reduction of LPR with 
statistical significance 12 months after the end of SCIT (Chaker, 2015a) (Chaker, 2015b).  We 
hypothesize that dupilumab as an adjunct to SCIT treatment may further reduce skin allergic 
response to Timothy Grass and can further decrease LPR compared to SCIT alone.  Based on 
expected reduction of IgE levels 12 weeks after dupilumab treatment in past AD studies, a 
reduction in mast cell activation may result in reduction in EPR and therefore reduced wheal 
sizes may also be expected.  
3.2.8.4. 
Serum TARC and Total IgE 
Serum TARC and total IgE are markers of Type 2 immune activity.  Dupilumab significantly 
suppressed both TARC and total IgE in studies of adult AD, NP, and asthma patients. 
3.2.8.5. 
Basophil Sensitivity Test for Timothy Grass 
The allergen-specific decrease in basophil sensitivity following SCIT has been described for 
olive pollen allergy, birch pollen allergy and Timothy Grass allergy (Gokmen, 2012) 
(Lalek, 2010) (Nopp, 2009).  In a 40-patient, 15-month, placebo-controlled study for allergic 
rhinitis, patients who received either SLIT or SCIT for Timothy Grass, basophil sensitivity for 
Timothy Grass was shown to decrease as early as one month after SCIT treatment and continues 
to decline at 15-months (Aasbjerg, 2014).  In the above study, basophil activation was measured 
by high CD203 expression and high percentage of CD63+ cells.  Basophil sensitivity was 
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measured by the concentration of allergen (ng/mL), sufficient to give a 50% of maximal 
activation (EC50) (Aasbjerg, 2014).  For the current study of dupilumab as an adjunct for grass 
SCIT study, instead of EC50, basophil sensitivity will be measured by the threshold 
concentration of Timothy Grass sufficient to activate basophils in patient whole blood. 
Basophil and mast cell activation are critical steps in mediating immediate allergic symptoms 
upon allergen exposure.  The activation of basophil and mast cells is an IgE-mediated event, 
where cross-linking of grass-specific IgEs bound to high affinity Fc (epsilon) receptors on mast 
cells and basophils trigger immediate degranulation.  In a study investigating the biomarker 
profile of dupilumab in patients with AD (Regeneron unpublished data) as well as other 
dupilumab studies, dupilumab suppressed both total and allergen-specific IgEs.  In general, 
dupilumab suppresses total IgE by ~50% with 12 to 16 weeks of treatment.  Based on the 
anticipated effect of dupilumab in reducing IgE, we hypothesize that dupilumab + grass SCIT 
may further reduce basophil sensitivity over grass SCIT alone.  This improvement could be 
linked to allergic symptom reduction during dupilumab treatment as an adjunct for grass SCIT. 
The exploratory basophil sensitivity testing will not be reported in the clinical study report. 
3.2.8.6. 
Frequency of Circulating Th2A Cells 
One important area of investigation is to determine the effect of dupilumab as an adjunct to SCIT 
treatment on changes in allergic T-cell responses.  At week 4 (300mg/QW or Q2W) dupilumab 
effectively reduced CD3+ T-cells in AD skin lesions and suppressed Th2 inflammatory pathways 
genes (eg, CCL13, CCL17 and CCL18), as shown by past studies in atopic dermatitis 
(Hamilton, 2014).  These data indicate that dupilumab has direct suppressive effect on Th2 cells.  
However, due to the extreme low frequency of allergen-specific T-cells in circulation, 
conventional immunophenotyping of Th2 cells has not been successful in capturing changes in 
allergen-specific T-cells during specific immunotherapy.  Th2A cells are allergen-specific Th2 
cells with a characteristic surface marker signatures (CRTH2+, CD27−, CD154+, CD161+, 
CD45RB−, and CD49d+ (Wambre, 2017).  Using these markers, Wambre et al. reported a 
significant reduction in the frequency of pro-allergic Th2A cell subsets from subjects receiving 
active grass tablets (SLIT) compared to those receiving placebo.  This method has also been 
implemented in assessing changes in allergen specific T-cells in a 2-year longitudinal grass 
immunotherapy study performed by the Immune Tolerance Network, where frequency of 
allergen-specific Th2 cells paralleled clinical outcomes (Renand, 2017) .Therefore, monitoring 
allergen-specific Th2 cells may reveal important mechanistic insight into the amelioration of 
allergic symptoms by dupilumab as an adjunct to SCIT treatment. 
The exploratory Th2A analyses will not be reported in the clinical study report. 
3.2.8.7. 
Type 2 Inflammation in the Nasal Mucosa in Response to a NAC as Measured 
by RNA Sequence and Gene Expression Analysis 
The sponsor hypothesizes that dupilumab may suppress the homing of eosinophils and Th2-cells 
to the tissue, thus reducing the induction of genes and inflammatory pathways associated with 
type 2 inflammation post NAC.  Existing data in the literature suggest that type 2 inflammation 
in asthmatic or allergic rhinitis patients could be detected by gene expression analysis of nasal 
tissue samples, collected either by nasal brushing or nasal curettes.  For instance, RNA 
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expression analysis of type 2-associated genes in nasal brushings from 50 asthmatic patients and 
50 healthy controls have identified "Th2-high" and "Th2-low" subjects differentiated by the 
expression of 70 genes associated with type 2 pathways, including IL-13, IL-5, and periostin. 
The analysis also revealed that Th2-high subjects were more likely to have atopy, atopic asthma, 
higher blood eosinophil counts and rhinitis, compared with Th2-low subjects.  Nasal IL-13 
expression was 3.9-fold higher in asthmatic participants who experienced an asthma 
exacerbation in the past year (Poole, 2014).  In a study of allergic rhinitis patients treated with 
prednisone or placebo, nasal challenge with Timothy Grass was performed.  Eight hours post 
NAC, significant increases in eosinophil related gene-expression were detected in the nasal 
sampling of placebo-treated patients compared to baseline, but not in prednisone-treated patients 
(Leaker, 2017).  These data suggest that transcriptome analysis of nasal brushings could be used 
to assess underlying type 2-driven inflammation. 
The exploratory nasal secretion and brushing analyses will not be reported in the clinical study 
report. 
3.2.8.8. 
Rationale for Study Duration 
The time course of SCIT efficacy is not well established with limited data published regarding 
short-term efficacy endpoints.  Clinical guidelines and experience indicate that symptomatic 
improvement can be demonstrated shortly after the patient reaches a maintenance dose 
(Ewbank, 2003).  It is thought the onset of action could coincide with induction of sIgG4, which 
plateaus after reaching maintenance dose.  While conventional up-dosing schedules require 8-
12 weeks, we propose an 8-week cluster up-titration regimen to accelerate time to maintenance 
dose and onset of action of SCIT.  Dupilumab has resulted in rapid, potent suppression of type 2 
biomarkers within 4-12 weeks of treatment in all indications tested to date.  Thus, a 16 week 
treatment duration is expected to be sufficient to evaluate the effects of dupilumab with and 
without SCIT. 
4. 
STUDY VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, 
co-morbid atopic conditions, years with aeroallergen disease, sex, etc), disease characteristics 
including medical history, and medication history for each subject. 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoint 
The primary endpoint is the percent change in AUC for TNSS (0-1 hr post peak TNSS) in 
response to a NAC at week 17 from the pretreatment baseline TNSS AUC (0-1 hr post peak 
TNSS) for dupilumab + SCIT as compared to placebo +SCIT monotherapy. 
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4.2.2. 
Secondary Endpoints 
 Change from baseline in TNSS AUC post NAC over the first hour after the challenge 
(0-1 hr post peak TNSS) at week 17 for dupilumab + SCIT as compared to SCIT 
monotherapy 
 Change and percent change from baseline in TNSS AUC post NAC over the first 
hour of the challenge (0-1 hr post peak TNSS) at week 17 for dupilumab 
monotherapy as compared to placebo 
 Change and percent change from baseline in the TNSS AUC post NAC over the first 
hour of the challenge (0-1 hr post peak TNSS) at week 17 for dupilumab + SCIT as 
compared to dupilumab + placebo for SCIT. 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgG4 for dupilumab + SCIT as compared to SCIT 
monotherapy 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgE for dupilumab + SCIT as compared to SCIT 
monotherapy 
 Change from baseline (last pretreatment measurement) to week 17 in log-transformed 
value of serum Timothy Grass sIgG4 to Timothy Grass sIgE ratio for dupilumab + 
SCIT as compared to SCIT monotherapy 
 Incidence rates of treatment-emergent adverse events (TEAEs) and serious TEAEs 
through end of study 
4.2.3. 
Exploratory Endpoints 
 Change and percent change from baseline in the peak TNSS at week 17 for 
dupilumab + SCIT as compared to SCIT monotherapy and for dupilumab 
monotherapy as compared to placebo  
 Change and percent change from baseline in TOSS AUC post NAC over the first 
hour of the challenge (0-1 hr post peak TNSS) at week 17 for dupilumab + SCIT as 
compared to SCIT monotherapy and for dupilumab monotherapy as compared to 
placebo  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in Skin Prick Test with Serial Allergen Titration, as measured by AUC of the 
wheal sizes (diameter) over the course of 0 hour to hour 1 after the challenge (early 
phase reaction) 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in the wheal size (diameter) induced by skin Timothy Grass intradermal 
injection 6 hrs after the challenge (late phase reaction)  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in PNIF AUC over the course of 0 hour to hour 1 and hour 1 to hour 6 after 
the challenge (early and late phase reaction) 
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 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in sneeze count AUC over the course of 0 hour to hour 1 and hour 1 to hour 
6 after the challenge (early and late phase reaction) 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum TARC  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum total IgE  
4.3. 
Pharmacokinetic Variables 
Concentration of functional dupilumab in serum at each time point, obtained prior to dosing, will 
be measured (Ctrough) 
4.4. 
Anti-Drug Antibody Variables 
Anti-drug antibody variables include ADA status and titer as follows: 
 Total subjects with treatment emergent response 
 Treatment emergent - defined as a positive response in the ADA assay post first dose 
when baseline results are negative. 
 Total subjects with treatment boosted response 
 Treatment boosted – defined as a positive response in the ADA assay post first dose 
that is greater than or equal to 4-fold over baseline titer levels, when baselines results 
are positive. 
Samples positive in the ADA assay will be assessed for titer: 
 Titer category 
o Low (titer <1,000) 
o Moderate (1,000 ≤ titer ≤10,000) 
o High (titer >10,000) 
5. 
STUDY DESIGN 
5.1. 
Study Description and Duration 
This is a Phase 2a, multicenter, randomized, double-blind, parallel group, 4-arm study of 
dupilumab as an adjunct to grass SCIT and consists of a 12 week screening period, 16 week 
treatment period and a 8 week post treatment follow-up period in subjects with a history of 
allergic rhinitis to grass pollen. 
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5.1.1. 
Dosing and Administration 
5.1.1.1. 
Dupilumab or Dupilumab Placebo 
Dupilumab will be administered SC, as a 600 mg loading dose and then 300 mg Q2W.  
Dupilumab 150 mg/mL:  Each single-use, pre-filled glass syringe with snap-off cap delivers 
2.0 mL of a 150 mg/mL solution (300 mg). 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal antibody). 
After the loading dose, subjects will have the option to administer dupilumab or dupilumab 
placebo (or have a caregiver administer it) outside the study site.  The study staff will train the 
subject/caregiver on preparation and administration of dupilumab or dupilumab placebo on day 1 
and will administer the first 2 injections required for the loading dose.  Subjects will be 
monitored at the study site for a minimum of 30 minutes after the first 2 doses of dupilumab or 
dupilumab placebo (loading dose) and blood pressure and heart rate determined.  The subject (or 
caregiver) will administer dupilumab or dupilumab placebo outside of the study site during 
subsequent weeks of the study. 
Subjects who prefer to have the study site staff administer dupilumab or dupilumab placebo may 
choose to have injections administered in the study site. 
The procedure for preparing the dupilumab or dupilumab placebo dose for SC injection will be 
provided in the pharmacy manual.  Subcutaneous injection sites should be alternated among the 
different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper 
arms, so that the same site is not injected for 2 consecutive weeks.  To allow for adequate 
assessment of possible injection site reactions (ISRs), dupilumab or dupilumab placebo should 
be administered only into areas of normal-looking skin.  Instructions for recording and reporting 
ISRs will be provided in the study reference manual. 
Detailed instructions for transport, storage, preparation, and administration of dupilumab or 
dupilumab placebo will be provided by the site to the subject (or caregiver).  Subjects will 
complete a dosing diary to document compliance with self-injection of dupilumab or dupilumab 
placebo outside the study site. 
5.1.1.2. 
SCIT and Placebo Matching SCIT 
SCIT will be up-dosed for 8 weeks to a 4,000 BAU dose, followed by an 8-week maintenance 
dose.  (See Table 1 for SCIT schedule). 
Placebo matching SCIT is prepared in the same formulation (SCIT diluent) without the addition 
of Timothy Grass extract. 
All SCIT visits will be supervised in an in-clinic study site setting where trained study 
physicians, who are experts in Allergy and Immunology and who are experienced SCIT 
providers, are present.  Subjects will be observed for at least 30 minutes after any SCIT injection.  
Standing orders from a study physician will be provided for all clinical study personnel to 
immediately (ie, prior to study physician notification) initiate treatment of reactions, including 
but not limited to intramuscular administration of epinephrine, based on their own clinical 
judgment.  For all SCIT visits subjects must be pre-medicated with an H1 anti-histamine 
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(loratadine 10 mg orally) 1-6 hours prior to each injection visit, as recommended by clinical 
guidelines to reduce local and systemic reactions during the cluster SCIT.  (Cox, 2011) 
(Nielsen, 1996).  Loratadine will be supplied to study sites as a non-investigational medicinal 
product (NIMP). 
Figure 1: 
Study Flow Diagram 
 
*The NAC happens after 16 weeks of study treatment at week 17. 
5.2. 
Screening 
After obtaining informed consent, subjects will be assessed for eligibility during a 3-part 
screening period.  The 3-part screening period is up to 12 weeks.  As this is an off-season study 
that must begin and end outside of grass season, sufficient screening time is necessary so that 
subjects may be enrolled efficiently.  During screening visit 1, subjects with a history of allergic 
rhinitis to grass pollen will undergo a medical history, physical examination, SPT for Timothy 
Grass, and blood draw for Timothy Grass specific IgE.  If the subject meets criteria with a 
positive SPT for Timothy Grass and for Timothy Grass specific IgE as per Inclusion/Exclusion 
criteria, they will be invited for screening visit 2.  At screening visit 2 they will undergo a 
pregnancy test if applicable, spirometry, electrocardiogram (ECG), serologic testing for chronic 
viral infections (Human Immunodeficiency Virus Infection [HIV] and Hepatitis B and C), 
hematology, chemistry, urinalysis, will be evaluated for the study eligibility criteria, and will 
undergo a baseline nasal brushing.  The baseline nasal brushing must occur while TNSS≤2 and it 
must be at least 28 days prior to the screening visit 3/Entry visit, so that the nasal mucosa may 
re-epithelialize and return to a resting state prior to NAC.  If the subject reports nasal symptoms 
and has a TNSS>2 at Screening visit 2, they can be rescheduled for screening visit 2 when they 
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are no longer symptomatic- for re-evaluation by TNSS.  The baseline nasal brushing should not 
be performed if the 28 day waiting period until the NAC will compromise the subject’s ability to 
complete the 16 week treatment period and final week 17 NAC prior to the subsequent allergy 
season (eg, subjects cannot have any expected seasonal or environmental allergic symptoms at 
the week 17 NAC visit).  If however, the full 16 week treatment period and week 17 NAC visit is 
expected to be completed prior to the subsequent allergy season, subjects should undergo 
baseline nasal brushing.  Forgoing the baseline nasal brushing in this case will not be considered 
a protocol deviation, but the event will be recorded and justified.  It is expected that subjects who 
are enrolled in the final month of the enrollment period, as described in the Study Operations 
Manual, will not undergo the baseline nasal brushing. 
At screening visit 3/Entry visit (day -1), subjects may not have taken anti-histamines for at least 
5 days.  If the subject reports having taken anti-histamines within 5 days of Screening visit 3, 
they can be rescheduled for Screening visit 3. 
At screening visit 3/Entry visit, subjects will be observed for approximately 10 minutes and a 
resting/baseline TNSS≤2 must be achieved, signifying that the subject does not have active nasal 
symptoms at rest (due to viral infection, sinusitis, allergies, etc.), prior to NAC.  If the subject 
has a TNSS>2, signifying that they have active nasal symptoms at rest, they can be rescheduled 
for Screening visit 3.  TNSS (measured on a 0-12 scale) is a composite symptom assessment of 
congestion, itching, rhinorrhea (each graded on 0-3 scale, 3 being severe), and sneezing (2 being 
3-4 sneezes and 3 being >5 sneezes).  TNSS report will be included in the Study Operations 
Manual.   
If the subject has a resting/baseline TNSS ≤2 and therefore has no appreciable nasal symptoms at 
rest, a NAC and skin testing for early and late phase reactions will be performed as follows: 
 NAC will be performed using increasing doses of Timothy Grass extract every 
10 minutes up to 1 hour (up-titration phase), or until a TNSS ≥7 is reached.  An 
example of concentrations are as follows:  14 BAU/ml, 41 BAU/mL, 123 BAU/mL, 
370 BAU/mL, 1111 BAU/mL, and 3333 BAU/mL; please refer to the study manual 
for exact concentrations.  
 The peak TNSS will be recorded.   
 The Timothy Grass extract concentration that was used to attain TNSS ≥7 must be 
recorded.   
 Subjects will be observed for the subsequent hour and the TNSS will be recorded at 
5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, and then hourly up to 6 hours.   
 In addition to TNSS, the following will be measured at baseline, approximately every 
10 minutes during the up-titration phase, and during the subsequent hour after peak 
TNSS is achieved (at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 1 hour) and 
hourly up to 6 hours: 
o PNIF; (measured in nasal patency, L/min)  
o Total sneezes  
o TOSS  
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Grass allergic subjects will be eligible for enrollment based on having a TNSS ≤2 prior to the 
screening NAC (time 0), peak TNSS ≥7 within the first hour during the up-titration phase. 
Additionally for eligibility, between the first non-zero dose of and approximately 10 minutes 
after the highest/peak dose, subjects must experience either a >20% drop in PNIF or >/=3 
sneezes must be counted. 
5.3. 
Randomized Treatment Period (16 Weeks) 
5.3.1. 
Randomization 
A total of 100 adult subjects with a history of allergic rhinitis to grass pollen who successfully 
complete screening procedures will be randomized 1:1:1:1 into the 4 treatment arms (n=25 in 
each arm) as follows: 
1. SCIT up-titrated as described up to a 4,000 BAU maintenance dose + dupilumab 
(SC 300 mg Q2W, after 600 mg loading dose)  
2. SCIT up-titrated as described up to a 4,000 BAU maintenance dose + placebo for 
dupilumab 
3. Placebo for SCIT plus dupilumab (SC 300 mg Q2W, after 600 mg loading dose)   
4. Placebo for SCIT plus placebo for dupilumab 
Note:  Randomization (visit 4) must occur within 2 weeks after NAC (visit 3) 
5.3.2. 
Study Design Safety Considerations for SCIT 
 All SCIT visits will be supervised in an in-clinic study site setting where trained study 
physicians are available. 
 Subjects will be observed for at least 30 minutes after any SCIT injection. 
 Standing orders from a study physician will be provided for all clinical study 
personnel to immediately (ie, prior to study physician notification) initiate treatment 
of reactions, including intramuscular administration of epinephrine, based on their 
own clinical judgment. 
 A crash cart will be available in close proximity (within 50 feet) of all patient study 
site rooms. 
 On days when SCIT or placebo SCIT are given, subjects must be pre-medicated with 
an H1 anti-histamine (loratadine 10 mg orally) 1-6 hours prior to each injection visit, 
as recommended by clinical guidelines to reduce local and systemic reactions during 
cluster SCIT (Cox, 2011) (Nielsen, 1996).  Loratadine will be supplied to study sites 
as a NIMP. 
 Patients will be dosed Q2W SC with dupilumab or placebo for dupilumab on separate 
days from the study-site SCIT or placebo for SCIT dose escalation.  
 SCIT dosing related allergic symptoms and adverse events will be captured 
throughout the study. 
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5.4. 
Post-Treatment Follow-up Period (8 Weeks):  
All subjects who complete or prematurely discontinue the treatment will be assessed for safety, 
laboratory, and clinical assessments as noted in the Schedule of Events (Table 3) 8 weeks after 
the end-of-treatment.  
The duration of the 8-week follow-up period is based on the time expected for drug 
concentrations to approach the lower limit of quantification after the last dose of dupilumab. 
5.5. 
End of Study Definition 
The end of study is defined as the last visit of the last subject.   
5.6. 
Planned Interim Analysis 
No interim analysis is planned.  An unblinded first-step analysis may be performed once all 
subjects in the study have completed the 16-week treatment period and performed NAC at 
week 17 as specified in the protocol (visit 16 or earlier for those subjects who are withdrawn 
prematurely from the study).  If performed, this first-step analysis will be considered the final 
analysis for the primary endpoint and secondary efficacy endpoints up to end of treatment NAC 
visit 16 (week 17).  A description of the statistical methods to be employed and blinding 
implications are in Section 10.4.3.4. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS 
6.1. 
Number of Subjects Planned 
Approximately 100 subjects will be randomized (25 per treatment group) at approximately 
20 planned sites in North America in geographies where Timothy Grass is the relevant grass 
species.  
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. Male and female subjects aged 18 to 55  
2. History of grass pollen–induced seasonal allergic rhinitis  
3. Grass pollen allergy confirmed by both:  
a. Positive SPT with Timothy Grass extract (mean wheal diameter at least ≥5 mm 
greater than a negative control) 
b. Positive serum Timothy Grass-specific IgE (≥0.35KU/L) 
4. Positive NAC with Timothy Grass extract at screening with peak TNSS score ≥7 out of 
12 
5. Between the first non-zero dose and approximately 10 minutes after the highest dose of 
NAC, participants must experience either a >20% drop in PNIF or >/=3 sneezes must be 
counted 
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6. Provide informed consent signed by study subject 
7. Able to understand and complete study-related questionnaires 
8. Willing and able to comply with study site visits and study-related procedures 
6.2.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Significant rhinitis (causing TNSS >2), sinusitis, outside of the grass pollen season, or 
due to daily contact with other allergens causing symptoms that is expected to coincide 
with the baseline or the final NAC assessments as assessed by the investigator 
2. Subjects who anticipate major changes in allergen exposure in their home or work 
environments that are expected to coincide with the baseline or the final NAC 
assessments as assessed by the investigator 
3. At screening NAC, current symptoms of, or treatment for, upper respiratory tract 
infection, acute sinusitis, acute otitis media, or other relevant infectious process; serous 
otitis media is not an exclusion criterion.  Participants may be re-evaluated for eligibility 
after symptoms resolve. 
4. Any contraindications to SCIT (ie, severe cardiovascular disease, malignancies, 
autoimmune disease, use of beta blocker, asthma severe enough to require chronic 
medication, acute infection)  
5. Patients with any laboratory findings showing evidence of organ dysfunction or any 
clinically significant deviation from the normal range, as decided by the investigator at 
the screening visit, including but not limited to: 
 Clinically significant/active underlying hepatobiliary disease. 
OR, 
 Alanine aminotransferase (ALT) >3 upper limit of normal (ULN). 
Abnormal laboratory values at screening: 
 Creatine phosphokinase (CPK) >10 ULN 
OR, 
 Platelets <100 000 cells/mm3. 
OR, 
 Eosinophils >1500 cells/mm3. 
6. Use of any concomitant medications within the following time period preceding any 
screening visit or any screening NAC visit (visit 3) including antihistamines (5 days), 
leukotriene inhibitors (7 days), mast cell inhibitors (7 days), intranasal corticosteroids 
and/or inhaled corticosteroids (14 days), oral or topical decongestants (5 days), topical 
calcineurin inhibitors (4 weeks), beta blockers (5 days). Participants may be re-evaluated 
for eligibility after the time period for taking these concomitant medications has passed. 
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7. Use of systemic corticosteroids within 4 weeks of screening visits or any NAC visits 
8. Abnormal lung function as judged by the investigator with FEV1<80% of predicted  
9. A clinical history of asthma requiring chronic medication such as regular inhaled 
corticosteroids for >4 weeks per year  
10. A clinical history of asthma with 2 or more asthma exacerbations requiring 
hospitalizations or systemic corticosteroids in the previous year 
11. History of emergency visit or hospital admission for asthma in the previous 12 months 
12. History of significant recurrent sinusitis, defined as 3 episodes per year for the last 
2 years, all of which required antibiotic treatment 
13. History of chronic sinusitis (with or without nasal polyps) as defined as: 
presence of 2 or more symptoms one of which should be either nasal 
blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip):  
 ± facial pain/pressure;  
 ± reduction or loss of smell; 
 for ≥12 weeks; 
14. Any gross mechanical nasal obstruction, or history of nasal or sinus surgery that would 
interfere with the conduct of the NAC, as per judgment of the investigator 
15. Tobacco smoking (ANY) within the last year   
16. Any history of grade 4 anaphylaxis due to any cause as defined by the Common 
Terminology Criteria for Adverse Events (CTCAE) grading criteria for immunotherapy 
(Appendix 1) 
17. History of chronic obstructive pulmonary disease  
18. History of other chronic disease (other than asthma, atopic dermatitis, allergic rhinitis) 
requiring therapy (eg, heart disease, diabetes, hypertension) that, in the opinion of the 
investigator, would represent a risk to the subject’s health or safety in this study or the 
subject’s ability to comply with the study protocol  
19. History of previous allergy immunotherapy (SCIT, sublingual immunotherapy, or oral 
immunotherapy) in the last 5 years  
20. Any previous exposure to dupilumab 
21. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to screening  
22. Member of the clinical site study team or his/her immediate family  
23. Known or suspected immunosuppression, including history of invasive opportunistic 
infections (eg, tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, 
pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent 
infections of abnormal frequency, or prolonged infections suggesting an 
immune-compromised status, as judged by the investigator 
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24. History of patient-reported alcohol or drug abuse within 6 months prior to screening 
25. History of bleeding disorders or treatment with anticoagulation therapy 
26. Subjects tested positive for HIV antibody, Hepatitis B surface antigen, or Hepatitis C 
antibody  
27. Use of anti-IgE therapy within 6 months prior to screening.  
28. Treatment with a live (attenuated) vaccine within 3 months prior to screening and during 
the study.  
29. Active chronic or acute infection requiring systemic treatment with antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the screening visit. 
NOTE:  subjects may be rescreened after the infection resolves.  
30. History of malignancy within 5 years before the screening visit, except completely 
treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic 
squamous or basal cell carcinoma of the skin.  
31. Established diagnosis of a primary immunodeficiency disorder (eg, Severe Combined 
Immunodeficiency, Wiskott Aldrich Syndrome, DiGeorge Syndrome, X-linked 
Agammaglobulinemia, Common Variable Immunodeficiency), or secondary 
immunodeficiency eg, HIV.  
32. Pregnant or breastfeeding women, women planning to become pregnant or breastfeed 
during the study 
33. Women of child bearing potential* who are not sexually abstinent and are unwilling to 
practice highly effective contraception prior to the initial dose/start of the first treatment, 
during the study, and for at least 12 weeks after the last dose.  Highly effective 
contraceptive measures include: 
a. stable use of combined (estrogen and progestogen containing) hormonal 
contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening;  
b. intrauterine device (IUD); intrauterine hormone releasing system (IUS);  
c. bilateral tubal ligation;  
d. vasectomized partner; 
e. and or sexual abstinence †, ‡. 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to 
be considered of childbearing potential.  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 treatments.  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.  
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‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) 
are not acceptable methods of contraception. Female condom and male condom 
should not be used together.  
34. Subjects unable to understand and comply with clinical protocol  
35. Planned or anticipated use of any prohibited medications and procedures (as detailed 
in Section 7.7.1) during study treatment 
36. Adults lacking capacity to consent themselves into the study. 
6.3. 
Premature Withdrawal from the Study 
A subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a subject from the study if it is no 
longer in the interest of the subject to continue in the study, or if the subject’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a subject does not or cannot follow 
study procedures).  An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of subjects should be avoided. 
Subjects who are withdrawn prematurely from the study treatment will be asked to complete 
study assessments, 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 Subjects 
Subjects prematurely discontinued from study drugs (SCIT or placebo for SCIT and dupilumab 
or placebo for dupilumab) will not be replaced. 
7. 
STUDY TREATMENTS 
7.1. 
Investigational and Reference Treatments 
7.1.1. 
Dupilumab Injection:  Investigational Treatment 
Dupilumab at 300 mg Q2W with loading dose of 600 mg or equivalent placebo will be started on 
the day of randomization.  Dupilumab will be dosed as follows:  subjects will be given a loading 
dose of 600 mg dupilumab SC or placebo, followed by 300 mg Q2W SC for a total of 16 weeks. 
Dupilumab 150 mg/mL: Each single-use, prefilled glass syringe with snap-off cap delivers 
300 mg of study drug (2.0 mL of a 150 mg/mL solution). 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal antibody).  The matching placebo formulation will 
be used:  2 mL placebo matching 300 mg dupilumab formulation. 
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Subcutaneous injection sites of dupilumab or placebo for dupilumab should be alternated among 
the different quadrants of the abdomen (avoiding navel and waist areas), upper thighs, and upper 
arms so that the same site is not injected for 2 consecutive administrations. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.1.2. 
Timothy Grass SCIT:  Reference Treatment 
Timothy Grass SCIT will be given using cluster dose escalation regimen over 8 weeks then 
maintenance therapy will be given described below. SCIT will be started no earlier than 1 day 
after the dupilumab loading dose and up to 1 week after the dupilumab loading dose.  Dosing of 
dupilumab should never be performed on the same day and administration site as SCIT. 
The Grass SCIT protocol will comprise 1-3 SC injections per week visit of allergen following 
the up-titration regimen described below over 8 weeks followed by the maintenance SC 
injections for the following 8 weeks as shown in Table 1.  The recommended target maintenance 
dose for SCIT is 4,000 bioequivalent allergy units (BAU) (Table 1), which is equivalent to 
approximately 20 mcg Phlem Pratense 5 (major Timothy Grass allergen) (Cox, 2011) 
(Frew, 2006b).  During weeks 1-3 of the up-dosing phase, 3 doses of SCIT will be given per 
visit: the first (lowest dose for that visit) will be given, the subject will be monitored for 30 
minutes, and if the dose is well tolerated, the next higher scheduled dose for that visit will be 
given.  The subject will then be monitored for the next 30 minutes, and if the dose is well 
tolerated, the next higher scheduled dose for that visit will be given.  During weeks 4-5 of the 
up-dosing phase, 2 doses of SCIT will be given: the first (lowest dose for that visit) will be 
given, subject will be monitored for 30 minutes, and if the dose is well tolerated, the next higher 
scheduled dose for that visit will be given.  During weeks 6-8 of the up-dosing phase, 1 dose of 
SCIT will be given.  During the maintenance phase, one dose will be given per visit as per 
Table 1.  
Placebo SCIT will be given in the same manner as the Grass SCIT, following the same protocol, 
but instead of active agent, diluent will be given.  The Placebo SCIT will have an identical 
appearance to the Grass SCIT.  The first (lowest dose for that visit) will be given, the subject will 
be monitored for 30 minutes, and if the dose is well tolerated, the next higher scheduled dose for 
that visit will be given. 
On days when SCIT or placebo SCIT are given, subjects must be pre-medicated with an H1 anti-
histamine (loratadine 10 mg orally) 1-6 hours prior to each injection visit, as recommended by 
clinical guidelines to reduce local and systemic reactions during cluster SCIT.  (Cox, 2011) 
(Nielsen, 1996).  Reactions associated with SCIT or SCIT placebo should be recorded as AEs 
(Section 9.5), and attributed to SCIT or SCIT placebo or as interpreted by the study investigator 
(Section 9.5). 
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Table 1: 
SCIT Up-Titration and Maintenance Regimen 
Week No 
Injection No 
Subcutaneous Dose of SCIT 
(BAU) 
1 
1 
1 
1 
2 
4 
1 
3 
10 
2 
4 
20 
2 
5 
40 
2 
6 
70 
3 
7 
100 
3 
8 
150 
3 
9 
250 
4 
10 
400 
4 
11 
700 
5 
12 
1000 
5 
13 
1500 
6 
14 
2000 
7 
15 
3000 
8 
16 
4000 
10 
17 
4000 
13 
18 
4000 
16 
19 
4000 
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7.1.3. 
Timing of Dupilumab/placebo and SCIT/placebo 
Dupilumab dosing starts prior to SCIT dosing as shown in Table 2.  Dupilumab/placebo are 
never to be given on the same day as SCIT/ placebo. 
Table 2: 
Dosing Schedule for Dupilumab/Placebo with Respect to SCIT/Placebo 
Dose 
Dupilumab/Placebo1 
SCIT/Placebo 
NAC 
 
 
Randomization (V4) 
X2 
 
Week 1 
 
X3, 5 
Week 2 
X4 
X5 
Week 3 
 
X4, 5 
Week 4 
X4 
X5 
Week 5 
 
X4, 5 
Week 6 
X4 
X5 
Week 7 
 
X4, 5 
Week 8 
X4 
X5 
Week 9 
 
 
Week 10 
X4 
X5 
Week 11 
 
 
Week 12 
X4 
 
Week 13 
 
X4, 5 
Week 14 
X4 
 
Week 15 
 
 
Week 16 
X4 
X5 
NAC 
 
 
1. 
Dupilumab/placebo dosing must given ± 3 days of the visit window. 
2. 
Dupilumab or placebo for dupilumab loading dose is given day of randomization.  Subsequent dupilumab/placebo dosing is 
given Q2W 
3. 
SCIT/placebo should be given 1 to 7 days following dupilumab/dupilumab placebo loading dose.  Subsequent SCIT/placebo 
dosing follows dosing regimen as depicted in Table 1.  
4. 
During week 2, week 4, week 6, week 10, and week 16, when both dupilumab/placebo and SCIT/placebo are given in the 
same week, SCIT/placebo and dupilumab/placebo are NOT to be given on the same day (can be 1 day to 7 days apart) AND 
SCIT/placebo and dupilumab/placebo are to be given in a different anatomical location. 
5. 
For SCIT/placebo visits, subjects are to be premedicated with an antihistamine as described in Section 5.1.1.2. 
 
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7.2. 
Rescue Treatments 
If required, subjects who experience allergic reactions will be treated with rescue treatment 
including but not limited to IM or SC administration of epinephrine, as determined by trained 
study staff.  Subjects may also take oral antihistamines as needed for allergic rhinitis symptoms 
during the course of the study, however oral antihistamines may not be used within 5 days prior 
to or during a visit for NAC or skin testing.  If subject uses oral antihistamines within 5 days 
prior to or during a visit for NAC or skin testing they must be rescheduled.   
7.3. 
Dose Modification and Study Treatment Discontinuation Rules 
7.3.1. 
Dose Modification 
Dose modification of dupilumab or dupilumab placebo is not allowed.   
Dose modification/reduction of SCIT is allowed for an individual subject according to the 
following specifications: 
Subjects who develop either local or systemic side effects after an up-dosing visit of SCIT 
may require administration of the same dose at the next visit, a dosage reduction at the next 
visit, or a planned series of visits to achieve the same dose, as determined by the principal 
investigator.  
If subjects develop side effects during the up-dosing phase of SCIT, such as repeated large 
immediate local reactions or grade 1-2 systemic reactions requiring dosage adjustments, the 
principal investigator (PI), in consultation with the medical monitor, may decide to reduce the 
planned maintenance dose of SCIT of 4000 BAU down to between 400 BAU and 4000 BAU but 
no lower than 400 BAU. 
7.3.2. 
Study Drug Discontinuation (Dupilumab or Placebo for Dupilumab and SCIT or 
Placebo for SCIT)  
If one study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT) is 
discontinued, all study drugs (dupilumab or placebo for dupilumab and SCIT or placebo for 
SCIT) must be discontinued. 
Subjects who permanently discontinue from study drug (dupilumab or placebo for dupilumab 
and SCIT or placebo for SCIT) and who do not withdraw from the study will be asked to return 
to the study site within 2 weeks of stopping study drug (dupilumab or placebo for dupilumab and 
SCIT or placebo for SCIT), if possible, to undergo their end of treatment visit, including NAC.  
Anti-histamines may not be taken within 5 days of NAC. 
Subjects who permanently discontinue from study drug (dupilumab or placebo for dupilumab 
and SCIT or placebo for SCIT) and who opt to withdraw from the study will be asked to 
complete study assessments as per end of treatment visit immediately, within 2 weeks of 
stopping study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT), if 
possible, including NAC, per Section 8.1.2.  
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7.3.3. 
Reasons for Permanent Discontinuation of Study Drug (Dupilumab or Placebo 
for Dupilumab and SCIT or Placebo for SCIT) 
Subjects will be permanently discontinued from study treatment in the event of: 
 Anaphylactic reaction to study drug (dupilumab or placebo for dupilumab and SCIT 
or placebo for SCIT) 
 Evidence of pregnancy 
 Any infection that: 
o Requires parenteral treatment with antibiotic, antifungal, antiviral, anti-parasitic, 
or anti-protozoal agent 
o Requires oral treatment with such agents for longer than 2 weeks  
o Is opportunistic, such as tuberculosis and other infections whose nature or course 
may suggest an immunocompromised status 
 Severe laboratory abnormalities, such as: 
o Neutrophil count ≤0.5 x 103/µL 
o Platelet count ≤50 x 103/µL 
o ALT and/or aspartate aminotransferase (AST) values >3 x ULN with total 
bilirubin >2 x ULN, excluding confirmed Gilbert’s Syndrome 
o Confirmed AST and/or ALT >5 x ULN (for more than 2 weeks) 
 Other reasons that may lead to the permanent discontinuation of study treatment 
include: 
o Certain AEs deemed related to the study drug (dupilumab or placebo for 
dupilumab and SCIT or placebo for SCIT) (eg, severe and prolonged ISRs) or 
study procedures 
7.3.3.1. 
Reasons for Temporary Discontinuation of Study Drug (Dupilumab or Placebo 
for Dupilumab and SCIT or Placebo for SCIT) 
Study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT) dosing may be 
temporarily suspended in the event of: 
 Clinically important laboratory abnormalities, such as: 
o Neutrophil count ≤1.0 x 103/µL but >0.5 x 103/µL 
o Platelet count ≤100 x 103/µL but >50 x 103/µL 
o CPK >10 ULN 
 Short-term, self-limiting conditions (eg, infections resolving spontaneously or 
requiring ≤2 weeks of oral anti-infective treatment), with the exception of upper 
respiratory infections 
 Other intercurrent illnesses 
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After the condition leading to suspension of dosing resolves, study treatment may resume. 
A decision to temporarily discontinue study drug (dupilumab or placebo for dupilumab and SCIT 
or placebo for SCIT) and/or to reinstitute study treatment should be discussed with the medical 
monitor.  The investigator may suspend study treatment 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 subject’s best interest.  However, the medical monitor should be 
contacted as soon as possible in any case of study drug discontinuation.  Resumption of study 
treatment after temporary discontinuation requires consultation and agreement between the 
investigator and the medical monitor.  In the case of SCIT or placebo for SCIT, if it was 
temporarily discontinued during the up-dosing phase, the investigator may need to modify the 
up-dosing regimen at his/her discretion and will inform the medical monitor of any modification 
of the up-dosing regimen.  
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 systemic reactions must be reported as AEs (as defined in Section 9.4.1) 
and graded using the grading scales as instructed in Section 9.5.1.   
Acute systemic reactions following injection of either dupilumab/placebo or SCIT/placebo 
should be treated using clinical judgment to determine the appropriate response according to 
typical clinical practice.  
7.5. 
Method of Treatment Assignment 
Approximately 100 subjects will be randomized at baseline in a 1:1:1:1 ratio into one of 
4 treatment arms (n=25/arm) described in Section 5.3.1 according to a central randomization 
scheme provided by an interactive voice response system (IVRS)/interactive web response 
system (IWRS) to the designated study pharmacist (or qualified designee).  
7.5.1. 
Blinding 
With the exception of the designated study pharmacist(s)/designee at the study site who prepares 
and gives the SCIT or SCIT placebo, and the provisions in Section 7.5.2 , this study will remain 
blinded to all individuals until the pre-specified unblinding to conduct the primary analyses. 
The designated study pharmacist(s)/designee at the study site who prepares and gives the SCIT 
or SCIT placebo may not perform the NAC and nasal and skin assessments (outcome measures).  
For dupilumab and placebo for dupilumab, blinded study drug kits coded with a medication 
numbering system will be used.  In order to maintain the blind, lists linking these codes with 
product lot numbers will not be accessible to individuals involved in study conduct.   
Dupilumab anti-drug antibody and drug concentration results will not be communicated to the 
sites, and the sponsor operational team will not have access to results associated with patient 
identification until after the final database lock. 
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7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a subject may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy). 
 If unblinding is required: 
 Only the investigator will make the decision to unblind the treatment assignment. 
 Only the affected subjects will be unblinded. 
 The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator.  If there is no study pharmacist, the 
investigator for the site will unblind the subject 
 The investigator will notify Regeneron and/or designee before unblinding the 
subject, whenever possible 
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.  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. 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
Dupilumab/dupilumab placebo: A medication numbering system will be used to label blinded 
dupilumab/dupilumab placebo.  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. 
SCIT and SCIT placebo (SCIT diluent) will display the product lot number on the label.   
Both study drug dupilumab/ dupilumab placebo, and SCIT/SCIT placebo will be stored at the 
site 
 storage instructions will be provided in the pharmacy manual. 
7.6.2. 
Supply and Disposition of Treatments 
Study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT) will be shipped 
 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 (dupilumab or placebo for dupilumab and SCIT or placebo 
for SCIT) will be returned to the sponsor. 
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7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug (dupilumab or 
placebo for dupilumab and SCIT or placebo for SCIT).  These records should contain the dates, 
quantity, and study medication:  
 dispensed to each subject, 
 returned from each subject (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. 
7.6.4. 
Treatment Compliance 
All study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT) compliance 
records must be kept current and made available for inspection by the sponsor and regulatory 
agency inspectors. 
7.7. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent to the time before the 
administration of study drug (dupilumab or placebo for dupilumab and SCIT or placebo for 
SCIT) will be recorded as pretreatment medication.  Any treatment administered from the first 
dose of study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT) to the 
end of the follow-up period will be considered concomitant medication.  This includes 
medications that were started before the study and are ongoing during the study. 
The NIMP loratadine that is given before each SCIT (or placebo for SCIT) dose will also be 
recorded as a concomitant medication. 
7.7.1. 
Prohibited Medications (After Randomization) and Procedures 
Prohibited medications are not to be used after randomization except as noted in Section 7.2.  
Treatment with prohibited medications is allowed during the study if medically necessary as 
judged by the investigator (ie, as needed for allergic symptoms related to SCIT or SCIT placebo 
or related to study procedures).   
Use of leukotriene inhibitors, mast cell inhibitors, corticosteroids including systemic, intranasal, 
or inhaled corticosteroids, oral or topical decongestants, systemic or topical calcineurin 
inhibitors, beta blockers, long-acting beta agonist (LABA), and long-acting muscarinic 
antagonist (LAMA) will be prohibited for the duration of the study. 
7.7.2. 
Permitted Medications and Procedures 
Use of standard of care medications not listed as prohibited will be allowed.  Antihistamines will 
be allowed during the study with the exception of within 5 days of and including the day of 
NAC.   
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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 3. 
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Table 3: 
Schedule of Events 
Study Procedure 
Screening Period 
 
Treatment Period 
 
 
 
 
 
V1 
V2 
NAC 
V3 
R1 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
EOT 
NAC 
V16 
V17 
Unscheduled 
Visit (if 
applicable)13 
EOS 
V18 
ET 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
92 
113 
120 
141 
 
169 
 
Window in Weeks 
±1 
 
-1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±318 
 
Screening/Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization (R) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPT for Timothy 
Grass 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Timothy 
Grass sIgE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dupilumab/ 
PBO loading2 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dupilumab 300 mg 
q 2 weeks dosing2, 3 
 
 
 
 
 
X 
---------------------------X------------------------------- 
 
 
X 
 
 
Visit for SCIT 
Injections4, 5, 
 
 
 
 
X 
X5 
X 
X5 
X 
X5 
X 
X 
X5 
X 
X5 
 
 
X 
 
 
Premedicate with 
loratadine 10 mg 
orally6 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
Training for Self-
injection 
(dupilumab/PBO) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dupilumab/PBO 
distribution 
 
 
 
X  
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
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Study Procedure 
Screening Period 
 
Treatment Period 
 
 
 
 
 
V1 
V2 
NAC 
V3 
R1 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
EOT 
NAC 
V16 
V17 
Unscheduled 
Visit (if 
applicable)13 
EOS 
V18 
ET 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
92 
113 
120 
141 
 
169 
 
Window in Weeks 
±1 
 
-1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±318 
 
Dupilumab/PBO 
diary review/ 
Accountability7 
 
 
 
 
 
--------------------------------X---------------------------------- 
 
 
X 
 
X 
Subject Dosing 
Diary8 
 
 
 
X  
 
X 
 
X 
 
X 
 
X 
X 
X  
 
 
 
X 
 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TNSS 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
TOSS 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
PNIF 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Intradermal skin 
challenge testing 
(LPR) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Skin Prick Test 
with Serial 
Allergen Titration 
(EPR) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Safety:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Spirometry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Peak expiratory 
flow9 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Ab, HBsAg, 
HBcAb, Hep C Ab,  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
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Study Procedure 
Screening Period 
 
Treatment Period 
 
 
 
 
 
V1 
V2 
NAC 
V3 
R1 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
EOT 
NAC 
V16 
V17 
Unscheduled 
Visit (if 
applicable)13 
EOS 
V18 
ET 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
92 
113 
120 
141 
 
169 
 
Window in Weeks 
±1 
 
-1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±318 
 
Hematology, 
Chemistry 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy Test if 
indicated [in 
WOCBP] 
 
X14 
 
X15 
 
 
 
X15 
 
 
 
X15 
 
X15 
 
X15 
X15 
X15 
X14 
X14 
Nasal mucosal 
brushing10 
 
X16 
X   
 
 
 
 
 
 
 
 
 
 
X17 
 
X 
 
 
 
X 
Nasal fluid 
collection 
 
  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Future Biomedical 
Research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research serum11, 12 
 
 
X 
X 
 
X 
 
X  
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Research plasma11, 
12 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for basophil 
sensitivity assays, 
Th2A profiling and 
PBMC banking11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
SerumTARC11 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
Serum total IgE11 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Serum Timothy 
Grass sIgE11 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
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Study Procedure 
Screening Period 
 
Treatment Period 
 
 
 
 
 
V1 
V2 
NAC 
V3 
R1 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
 
V15 
EOT 
NAC 
V16 
V17 
Unscheduled 
Visit (if 
applicable)13 
EOS 
V18 
ET 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
15 
22 
29 
36 
43 
50 
57 
71 
92 
113 
120 
141 
 
169 
 
Window in Weeks 
±1 
 
-1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±318 
 
Serum Timothy 
Grass sIgG411 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Drug 
Concentration and 
ADA:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Functional 
dupilumab PK11, 12 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
Anti-drug 
antibody11, 12 
(ADA) 
 
 
X 
 
 
  
 
  
 
 
 
  
 
  
 
X 
  
 
X 
X 
 
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8.1.1. 
Footnotes for the Schedule of Events Table 
1. Randomization (V4) must occur within 2 weeks of NAC (V3) 
2. Dupilumab or placebo for dupilumab loading dose is given day of randomization.  
Subsequent dupilumab/placebo dosing is given Q2W.  
3. Dupilumab/placebo dosing must be given ±3 days of the visit window. 
4. SCIT/placebo should be given 1 to 7 days following dupilumab/placebo loading dose.  
Subsequent SCIT/placebo dosing follows dosing regimen as depicted in Table 1.  
5. During week 2, week 4, week 6, week 10, and week 16, when both dupilumab/placebo 
and SCIT/placebo are given in the same week, SCIT/placebo and dupilumab/placebo are 
NOT to be given on the same day (can be 1 day to 7 days apart) AND SCIT/placebo and 
dupilumab/placebo are to be given in a different anatomical location. 
6. For SCIT/placebo visits, subjects are to be premedicated with an antihistamine as 
described in Section 5.1.1.2  
7. Starting at visit 4, study drug will be dispensed to the subject for the dose that will be 
administered before the next dupilumab/placebo distribution visit.  Subjects will return 
the original kit box at each dupilumab/placebo distribution visit for accountability 
8. For subjects who choose to self-administer study drug, counsel subject on proper dosing 
diary completion/reporting of each dose of study drug that is administered outside of the 
study site 
9. Peak expiratory flow will be measured prior to NAC in any subject with a history of 
asthma.  Peak expiratory flow must be >80% predicted to perform the NAC in any 
subject with a history of asthma (please refer to the peak flow meter chart in the Study 
Operations Manual as a reference of predicted peak expiratory flow values) 
10. Collected 6 hours post NAC 
11. Collected pre-NAC 
12. Serum samples to be collected for ADA and PK assessments, prior to dosing of 
dupilumab at timepoints indicated in the Schedule of events 
13. Assessments and procedures at the unscheduled visit are to be performed at the discretion 
of the principal investigator 
14. Serum pregnancy test 
15. Urine pregnancy test 
16. Baseline nasal brushing and nasal brushing on study drug (which is performed at least 28 
days before the final NAC) will not be performed if they interfere with the subject’s 
timely completion of the study (prior to the onset of the subsequent allergy season) as 
outlined in the Study Operations Manual 
17. Should be performed approximately 28 days before the final NAC 
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18. The visit should be conducted as close as possible to the designated study schedule date 
and the window for the days used only as needed.   
8.1.2. 
Early Termination Visit 
Subjects who are withdrawn from the study treatment before the primary endpoint visit 
(week 17) will be asked to return to the study site once for an early termination visit consisting of 
the end of treatment assessments described in Table 3, which includes an end of treatment NAC. 
Subjects should return as soon as possible for the end of treatment assessment, so that the NAC 
assessment may be performed while study drug(s) (dupilumab or placebo for dupilumab and 
SCIT or placebo for SCIT) were recently administered.  Subjects who are withdrawn from the 
study treatment after the primary endpoint visit will be asked to return to the study site for early 
termination assessments, including NAC. 
8.1.3. 
Unscheduled Visits 
All attempts should be made to keep subjects on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reason, as warranted. 
8.2. 
Study Procedures 
8.2.1. 
Efficacy Procedures 
A variety of parameters will be collected during the study to assess efficacy/effectiveness of 
dupilumab monotherapy, SCIT monotherapy, dupilumab + SCIT, and placebo. 
Questionnaires and subject-reported assessments should be administered prior to obtaining 
investigator assessments, safety and laboratory assessments, and study drug (dupilumab or 
placebo for dupilumab and SCIT or placebo for SCIT) administration.  
Please see Study Operations Manual for detailed instructions on the procedures and the 
administration and use of all subject-reported instruments.   
8.2.1.1. 
NAC and NAC assessments:  TNSS, TOSS, PNIF, and Total Sneezes 
The NAC and NAC assessments will be administered by study site personnel as noted in 
Table 3.  
At the week 17 NAC on study drugs (dupilumab or placebo for dupilumab and SCIT or placebo), 
subjects may not have taken anti-histamines for at least 5 days.  If the subject reports having 
taken anti-histamines within 5 days of the final NAC, they can be rescheduled for the week 17 
visit so long as they have not taken anti-histamines within 5 days of the visit. 
TNSS 
At the end of treatment NAC (week 17), subjects will be observed for approximately 10 minutes 
and a resting/baseline TNSS ≤2 must be achieved, signifying that the subject does not have 
active nasal symptoms at rest (due to viral infection, sinusitis, allergies, etc.), prior to NAC.  
TNSS (measured on a 0-12 scale) is a composite symptom assessment of congestion, itching, 
rhinorrhea (each graded on 0-3 scale, 3 being severe), and sneezing (2 being 3-4 sneezes and 
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3 being >5 sneezes.  TNSS report will be included in the Study Operations Manual.  If the 
subject has a resting/baseline TNSS≤2 and therefore has no appreciable nasal symptoms at rest, a 
NAC will be performed.  The NAC will be performed using increasing doses of Timothy Grass 
extract every 10 minutes, with TNSS score recorded approximately every 10 minutes (up-
titration symptom score), up until they reach the concentration of Timothy Grass extract that was 
used to achieve a Total Nasal Symptom Score (TNSS) ≥7 at their baseline NAC visit.  This 
TNSS score will be recorded.  After recording the TNSS attained using concentration of Timothy 
Grass extract that was used to achieve a Total Nasal Symptom Score (TNSS) ≥7 at their baseline 
NAC visit, the subject will be observed for the subsequent hour and the TNSS will be recorded at 
5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, and then hourly up to 6 hours. 
TOSS 
TOSS (measured on a 0-3 scale, 3 being severe) is a composite symptom assessment of ocular 
symptoms (Itchy, Red, tearing [eyes watering], and swelling [puffy eyes] (see TOSS report in 
Study Operations Manual).  The TOSS score will be recorded during the NAC assessments.  The 
TOSS score will be recorded approximately every 10 minutes (up-titration symptom score), up 
until they reach the concentration of Timothy Grass extract that was used to achieve a TNSS ≥7 
at their baseline NAC visit.  This TOSS score will be recorded.  The subject will be observed for 
the subsequent hour and the TOSS score will be recorded at 5 minutes, 15 minutes, 30 minutes, 
45 minutes, 1 hour, and then hourly up to and at 6 hours as noted in Table 3. 
PNIF 
Peak nasal inspiratory flow (measured in nasal patency, L/min) will be measured and recorded 
approximately every 10 minutes during the uptitration phase of the NAC and will be measured 
and recorded during the subsequent hour after peak TNSS is achieved (at 5 minutes, 15 minutes, 
30 minutes, 45 minutes, and 1 hour) and hourly up to an at 6 hours as noted in Table 3. 
Total Sneezes 
Total sneezes will be counted and recorded during the uptitration phase and during the hour after 
peak TNSS is achieved. 
8.2.1.2. 
Skin Prick Test with Serial Allergen Titration 
The SPT with serial allergen titration assesses the early phase reaction at 0-60 minutes.  It will be 
performed as noted in Table 3. 
8.2.1.3. 
Intradermal Allergen Injection 
The intradermal allergen injection assesses late phase reaction from 6-24 hours.  It will be 
performed as noted in Table 3. 
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8.2.1.4. 
Nasal Brushing 
Nasal Brushings at Baseline and at Approximately 12 Weeks on Study Drugs. 
The nasal brushing procedure will be performed at baseline, approximately 28 days prior to the 
initial NAC visit.  The baseline nasal brushing must occur while TNSS ≤2 and it must be at least 
28 days prior to the screening visit 3/Entry visit, so that the nasal mucosa may re-epithelialize 
and return to a resting state prior to NAC.  If the subject reports nasal symptoms and has a 
TNSS2 at Screening visit 2, they can be rescheduled for screening visit 2 when they are no 
longer symptomatic- for re-evaluation by TNSS.  The baseline nasal brushing should not be 
performed if the 28 day waiting period until the NAC will compromise the subject’s ability to 
complete the 16 week treatment period and final 17 week NAC prior to the subsequent allergy 
season (eg, subjects cannot have any expected seasonal or environmental allergic symptoms at 
the week 17 NAC visit).  If however, the full 16 week treatment period and 17 week NAC visit is 
expected to be completed prior to the subsequent allergy season, subjects should undergo 
baseline nasal brushing.  Forgoing the baseline nasal brushing in this case will not be considered 
a protocol deviation, but the event will be recorded and justified.  It is expected that subjects who 
are enrolled in the final month of the enrollment period, as described in the Study Operations 
Manual, will not undergo the baseline nasal brushing.  
Nasal Brushings after NAC:  At Screening Visit 3/Entry Visit Prior to Randomization and 
at Week 17 Visit on Study Drug Must be Performed on All Subjects. 
The required nasal brushings will occur 6 hours after NAC at screening visit 3/Entry visit and 
will occur 6 hours after NAC at the week 17 visit on study drug.   
8.2.1.5. 
Nasal Fluid Collection 
Nasal fluid is collected during the 2 NAC study visits to determine the levels of cytokines and  
chemokines produced in response to NAC.  Nasal fluid is collected (1) at the initial NAC visit: at 
baseline prior to NAC and over the course of 6 hours after NAC and (2) at the 17 week (on study 
drug) NAC visit at baseline prior to NAC and over the course of 6 hours after NAC.   
8.2.2. 
Safety Procedures 
8.2.2.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration will be collected 
predose at time points according to Table 3. 
8.2.2.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 3.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the subject’s medical history. 
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8.2.2.3. 
Electrocardiogram 
A standard 12-lead ECG will be performed at time points according to Table 3.  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. 
8.2.2.4. 
Spirometry 
Spirometry will be performed in all subjects.  If subjects have asthma and use short acting 
medications, the following instructions must be followed: after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, FEV1, forced vital 
capacity (FVC) and forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75) 
will be determined at screening visit 2. 
8.2.2.5. 
Peak Expiratory Flow 
Peak expiratory flow will be measured using a peak flow meter (L/min) in any subject with a 
history of asthma prior to NAC on the day of the NAC.  Peak expiratory flow must be >80% 
predicted to perform the NAC in any subject with a history of asthma.  Detailed instructions for 
peak expiratory flow are included in the Study Operations Manual. 
8.2.2.6. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory.  Detailed instructions for blood sample collection are in the laboratory manual 
provided to study sites. 
Samples for laboratory testing will be collected at visits according to Table 3.  Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase 
(CPK) 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
 
*(low-density lipoprotein [LDL] and high-density lipoprotein [HDL]) 
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Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
HIV Ab, HBsAg, HBcAb, and Hep C Ab will be performed at screening visit 2.   
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 9.4.5. 
8.2.3. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected at time points listed in Table 3.  
. 
8.2.4. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 3. 
. 
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8.2.5. 
Pharmacodynamic and Biomarker Procedures 
8.2.5.1. 
Biomarker Sample collections 
Biomarker samples will be collected at time points according to Table 2. Biomarker 
measurements (TARC, total IgE, Timothy Grass specific IgE, Timothy Grass specific IgG4) will 
be performed in serum or plasma to determine effects on biomarkers of relevant physiological 
and pathogenic processes. 
Biomarker results will be used to better understand the pathophysiology of Timothy Grass 
allergy, mechanism of action of dupilumab and possible toxicities. In addition to the circulating 
biomarkers above, transcriptome sequencing of nasal mucosa after NAC, cytokine/chemokine 
measurements in nasal secretions, basophil allergen sensitivity and Th2A assays will be 
performed.  
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
   
 
 
 
 
  
 
   
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to subjects, according to local regulations.  This 
may include death from any cause and all serious adverse events (SAEs) related to the use of the 
study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT).  It is 
recommended that all SAEs be reported to the IRB/EC, according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (dupilumab or placebo for 
dupilumab and SCIT or placebo for SCIT) (suspected unexpected serious adverse reaction 
[SUSAR]), to the health authorities, IECs/IRBs as appropriate, and to the investigators (in a 
blinded manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected.  Any worsening of or new onset of 
allergy symptoms related to the nasal allergen challenge which occur during the screening period 
prior to study drug (dupilumab or placebo for dupilumab and SCIT or placebo for SCIT) 
administration will be considered expected (Section 9.4.1). 
In addition, the sponsor will report all other SAEs to the health authorities, according to local 
regulations. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the clinical study report to health authorities and IECs/IRB as appropriate. 
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9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a study drug which may or 
may not have a causal relationship with the study drug.  Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any 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. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (eg, a car accident in which a subject is a passenger). 
 Is life-threatening – in the view of the investigator, the subject is at immediate risk 
of death at the time of the event.  This does not include an AE that had it occurred in 
a more severe form, might have caused death. 
 Requires in-patient hospitalization or prolongation of existing hospitalization.  
In-patient hospitalization is defined as admission to a hospital or an emergency room 
for longer than 24 hours.  Prolongation of existing hospitalization is defined as a 
hospital stay that is longer than was originally anticipated for the event, or is 
prolonged due to the development of a new AE as determined by the investigator or 
treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).   
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
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 symptoms that occur in response to the 
NAC on the day of the NAC.  Allergic symptoms that occur in response to the NAC are not to be 
reported as AEs, as they will be recorded as outcome measures.  However, AEs that occur in 
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response to the NAC that are outside of expected symptoms which are recorded in response to 
the NAC, or SAEs, should be reported as AEs and SAEs.  Information on follow-up for AEs is 
provided in Section 9.4.6.  Laboratory, vital signs, or ECG abnormalities are to be recorded as 
AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drugs (dupilumab or placebo 
for dupilumab and SCIT or placebo for SCIT) or procedures, must be reported to the sponsor (or 
designee) within 24 hours.   
Information not available at the time of the initial report must be documented in a follow-up 
report.  Substantiating data such as relevant hospital or medical records and diagnostic test 
reports may also be requested. 
In the event the investigator is informed of an SAE after the subject completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study or within 30 days of last study 
drug administration if the subject early terminated from the study - the SAE will be 
reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome until the event is considered chronic and/or 
stable. 
 SAE with an onset day greater than 30 days from the end of study/early termination 
visit - only fatal SAEs and those deemed by the investigator to be drug-related SAEs 
will be reported to the sponsor.  The investigator should make every effort to obtain 
follow-up information on the outcome of a drug-related SAE until the event is 
considered chronic and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of 
learning of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 
2 times the intended dose of study drugs within the intended therapeutic window, if 
associated with an AE, 
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 study subject during the study or within 
12 weeks of the last dose of study drugs. Any complication of pregnancy affecting a 
female study subject and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
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Adverse Events of Special Interest (AESIs): All AESI, serious and nonserious, must be 
reported within 24 hours of identification using the same reporting process as for 
SAE reporting, per Section 9.4.2.  Adverse events of special interest for this study 
include the following:  anaphylactic reactions, systemic or severe hypersensitivity 
reactions, malignancy (except in-situ carcinoma of the cervix, non-metastatic 
squamous or basal cell carcinoma of the skin), helminthic infections, suicide-related 
events, any type of conjunctivitis or blepharitis (severe or serious or lasting ≥4 
weeks), keratitis. 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a subject’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
 the test result is associated with accompanying symptoms, and/or 
 the test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 the test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test 
finding should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE.  Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale 
outlined in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the subject’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
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9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
 Mild:  Does not interfere in a significant manner with the patient normal functioning 
level.  It may be an annoyance.  Prescription drugs are not ordinarily needed for relief 
of symptoms but may be given because of personality of the patient. 
 Moderate:  Produces some impairment of functioning but is not hazardous to health.  
It is uncomfortable or an embarrassment.  Treatment for symptom may be needed. 
 Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health.  Treatment for symptom may be given and/or 
patient hospitalized. 
The severity of AEs related to SCIT or SCIT-placebo for SCIT-related-allergic or anaphylactic 
reactions (including AESIs) will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE), Version 4.3, criteria for grading allergic reactions and anaphylaxis 
(Cox, 2010) (Appendix 1).  Not all AEs but only the SCIT or SCIT-placebo-related-allergic or 
anaphylactic reactions (including AESIs) will be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE). 
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 due to study drug (dupilumab or placebo for dupilumab and SCIT or 
placebo for SCIT)   
The severity of injection site reactions will be graded according to the following scale 
(semi-colon indicates “or” within description of grade): 
 Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity 
 Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity 
 Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires ER visit or hospitalization; necrosis or exfoliative dermatitis 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Dupilumab or placebo for dupilumab: 
The relationship of AEs to study drug (dupilumab or placebo for dupilumab) will be assessed by 
the blinded investigator, and will be a clinical decision based on all available information.  The 
following question will be addressed: 
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Is there a reasonable possibility that the AE may have been caused by dupilumab or placebo for 
dupilumab? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by 
the study drug (dupilumab or placebo for dupilumab)  
Related: 
There is a reasonable possibility that the event may have been caused by 
the study drug (dupilumab or placebo for dupilumab)  
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to dupilumab or placebo for 
dupilumab is provided below.  Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by dupilumab or placebo 
for dupilumab? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the subject’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug (dupilumab or placebo for dupilumab)  
 do not reappear or worsen when dosing with study drug (dupilumab or placebo for 
dupilumab) is resumed 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the subject’s disease state or clinical condition 
 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug (dupilumab or placebo for dupilumab)  
 resolve or improve after discontinuation of study drug (dupilumab or placebo for 
dupilumab)  
 reappear or worsen when dosing with study drug (dupilumab or placebo for 
dupilumab)  
 are known or suspected to be a response to the study drug (dupilumab or placebo for 
dupilumab) based upon preclinical data or prior clinical data 
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Relationship of Adverse Events to SCIT or placebo for SCIT: 
The relationship of AEs to SCIT or placebo for SCIT will be assessed by the blinded 
investigator, and will be a clinical decision based on all available information.  The following 
question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by SCIT or placebo for 
SCIT? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by 
SCIT or placebo for SCIT 
Related: 
There is a reasonable possibility that the event may have been caused by 
SCIT or placebo for SCIT 
The sponsor will request prespecified information about the SCIT or placebo for SCIT-related 
AEs; instructions to record this information is in the Study Operations Manual.  
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider in assessing the relationship of AEs to SCIT or placebo for SCIT is 
provided below. Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by SCIT or placebo for 
SCIT? 
No: 
 due to patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following SCIT or placebo for SCIT 
 do not reappear or worsen when SCIT or placebo for SCIT is resumed 
 are not a suspected response to SCIT or placebo for SCIT based upon preclinical data 
or prior clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by patient’s disease state or clinical condition 
 follow a reasonable temporal sequence following SCIT or placebo for SCIT 
 resolve or improve after discontinuation of SCIT or placebo for SCIT 
 reappear or worsen when SCIT or placebo for SCIT treatment is resumed 
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Relationship of Adverse Events to Study Procedures 
The relationship of AEs to study procedures will be assessed by the blinded investigator, and will 
be a clinical decision based on all available information.  The following question will be 
addressed: 
Is there a reasonable possibility that the AE may have been caused by the study procedure? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the study procedure. 
Related: There is a reasonable possibility that the event may have been caused by the study 
procedure. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider in assessing the relationship of AEs to study procedures is provided 
below.  Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by study procedures? 
No: 
 due to the subject’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following study procedure. 
 do not reappear or worsen when the study procedure is resumed 
 are not a suspected response to the study procedure based upon preclinical data or 
prior clinical data 
Yes: 
 could not be explained by environmental factors or other treatment(s) being 
administered 
 could not be explained by the subject’s disease state or clinical condition 
 follow a reasonable temporal sequence following the study procedure. 
 resolve or improve after discontinuation of study drug study procedure. 
 reappear or worsen when the study procedure is resumed 
 are known or suspected to be a response to study procedure based upon preclinical 
data or prior clinical data 
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9.6. 
Safety Monitoring 
The investigator will monitor the safety of study subject at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP).  Any questions or 
concerns should be discussed with the sponsor in a timely fashion.  The sponsor will monitor the 
safety data from across all study sites.  The Medical/Study Director will have primary 
responsibility for the emerging safety profile of the compound, but will be supported by other 
departments (eg, Pharmacovigilance and Risk Management; 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. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the statistical analysis plan (SAP) for the study.  The SAP 
may be revised during the study to accommodate amendments to the clinical study protocol and 
to make changes to adapt to unexpected issues in study execution and data that may affect the 
planned analyses.  The final SAP will be issued before the database is locked. 
Analysis variables are listed in Section 4. 
10.1. 
Statistical Hypothesis 
The primary efficacy endpoint is the percent change from baseline in TNSS AUC (0-1 hr) at 
week 17.  The comparison between dupilumab + SCIT as compared to placebo + SCIT 
monotherapy will be made. 
Let μD (and μP) be the true mean percent change from baseline in in TNSS AUC (0-1 hr) for 
Dupilumab + SCIT and Placebo + SCIT, respectively.  The following hypothesis for the 
superiority testing will be tested at the 5% 2 sided significance level: 
H0: μD = μP, ie, the mean percent change from baseline to week 17 is the same between 
Dupilumab + SCIT and Placebo + SCIT  
against the alternative 
Ha: μD ≠ μP, ie, the mean percent changes from baseline to week 17 are different between 
Dupilumab + SCIT and Placebo + SCIT 
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10.2. 
Justification of Sample Size 
It is estimated that with 25 subjects per group, the study will have 80% power to detect a 
difference of 29% between dupilumab plus SCIT and placebo plus SCIT monotherapy with 
respect to percent change from baseline in TNSS AUC (0-1 hr) at week 17, assuming that the 
mean percent changes from baseline values are -55% and -26% and a common standard 
deviation (SD) of 35% for dupilumab plus SCIT and placebo SCIT monotherapy, respectively. 
The significance level is set to 2-sided, 0.05 level. 
The assumptions used for primary endpoint were based on the study result from the Scadding 
(2017) study.  The Scadding study shows after 1 year treatment, the difference between SCIT 
and placebo is 34% for the percent change in TNSS AUC (0-1 hr) at 1 year.  A similar 
magnitude of improvement by adding dupilumab onto SCIT is assumed for the sample size 
calculation.   
10.3. 
Analysis Sets 
10.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized subjects.  Efficacy analyses will be based on 
the treatment allocated at randomization (as randomized). 
The per protocol set (PPS) includes all subjects in the FAS except for those who are excluded 
because of major protocol violations.  A major protocol violation is one that may affect the 
interpretation of study results. 
All efficacy variables will be evaluated on the FAS; the primary endpoint will also be evaluated 
on the PPS. Analysis on the FAS will be considered to be primary. 
10.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized subjects who received any study drug; it is 
based on the treatment received (as treated).  Treatment compliance/administration and all 
clinical safety variables will be analyzed using the SAF. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The pharmacokinetic (PK) analysis set includes all randomized subjects who received any study 
drug and who had at least 1 non-missing drug concentration result following the first dose of 
study drug. 
10.3.4. 
Anti-Drug Antibody Analysis Sets 
The ADA population includes all treated subjects who had received any amount of dupilumab 
study drug or dupilumab placebo and had at least 1 non-missing anti-drug antibody result 
following the first dose of dupilumab study drug or dupilumab placebo. 
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10.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information:  the 
number of subjects reflected in the calculation (n), mean, median, first quartile (Q1), third 
quartile (Q3), SD, minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Subject Disposition 
The following will be provided: 
 The total number of screened subjects:  met the inclusion criteria regarding the target 
indication and signed the ICF 
 The total number of randomized subjects:  received a randomization number 
 The total number of subjects in each analysis set (eg, FAS, provided in 
Section 10.3.2) 
 The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
 A listing of subjects treated but not randomized, subjects randomized but not treated, 
and subjects randomized but not treated as randomized 
 A listing of subjects prematurely discontinued from treatment, along with reasons for 
discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all subjects combined.   
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The primary endpoint will be analyzed by using the multiple imputation (MI) with analysis of 
covariance (ANCOVA) model.  Missing data will be imputed 40 times to generate 40 complete 
data sets by using the Statistical Analysis System (SAS) procedure MI. Each of the 40 complete 
datasets will be analyzed using an ANCOVA model with treatment group being the main factor 
and baseline value as the covariate. The SAS MIANALYZE procedure will then be used to 
generate valid statistical inferences by combining results from the 40 analyses using Rubin’s 
formula. 
All observed data will be used for analysis. Sensitivity analysis such as ANCOVA model with 
last observation carry forward (LOCF) method will also be conducted. Additional details on 
sensitivity analyses will be provided in the SAP. 
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10.4.3.2. Secondary Efficacy Analysis 
The continuous secondary efficacy endpoints will be analyzed using the same approach as that 
used for the analysis of the primary endpoint. 
The biomarker related continuous endpoint will be analyzed using a rank based ANCOVA 
model with treatment and relevant baseline as covariates. LOCF method will be used to impute 
the missing data. 
10.4.3.3. Multiplicity Considerations 
There is no control for multiplicity on the secondary and exploratory endpoints. 
10.4.3.4. First-Step Analysis 
A first-step analysis may be performed when the last subject completes 16 weeks of the 
treatment period and performed the NAC at week 17 as specified in the protocol (Visit 16 visit or 
earlier for those subjects who are withdrawn prematurely from the study).  No changes in the 
conduct of the study will be made based on this first-step analysis.  The assessment of primary 
and secondary endpoints up to end of treatment NAC Visit 16 (week 17) as specified in 
Section 4.2.1and Section 4.2.2 and performed during the analysis will be the final analysis of the 
primary endpoints and secondary endpoints. If a decision is made to perform the first-step 
analysis, in order to maintain study integrity with respect to the post-treatment follow-up visits, 
safety visits and analyses, a dissemination plan will be written.  This plan will clearly identify the 
team (including the statistician) that will perform the first-step analysis and all related activities, 
restrict other clinical team members and other Sponsor personnel from access to individual 
subject treatment allocation and site level analysis results, and ensure that the dedicated team 
will not participate in the data review or data decisions for the following post treatment analyses.  
However, the dedicated team can participate in the analysis following the final database lock. 
10.4.4. 
Safety Analysis 
10.4.4.1. 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 treatment period is defined as the day from first dose of study drug to end of 
study. The treatment-emergent period includes the 16-week treatment period and 
follow-up period 
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 treatment emergent period. 
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Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®).  Coding will be to lowest level terms.  The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of all TEAEs by treatment group will include: 
 The number (n) and percentage (%) of subjects with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 9.5.1 presented 
by SOC and PT 
 TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
 Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each 
scheduled assessment time with descriptive statistics. 
Number and percentage of subjects with a potentially clinically significant value (PCSV) at any 
postrandomization time point will be summarized for each clinical laboratory test.  
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
10.4.4.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment group and calculated 
as: 
(Date of last study drug injection – date of first study drug injection) + 14 days 
The number (%) of subjects randomized and exposed to double-blind study drug will be 
presented by specific time periods for each treatment group.  The time periods of interest will be 
specified in the SAP. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of subjects, means, SD, minimums, Q1, medians, Q3, and maximums. 
A summary of the number of doses by treatment group will be provided. 
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10.4.4.4. Treatment Compliance 
The compliance with study treatment will be calculated as follows: 
Treatment Compliance of study drug = (Number of study drug injections during exposure 
period)/ (Number of planned study drug injections during exposure period) × 100% 
The treatment compliance will be presented by specific ranges for each treatment group.  The 
ranges of interest will be specified in the SAP. 
10.4.5. 
Pharmacokinetics 
Descriptive statistics will be used to summarize the concentration data at each sampling time.  
No formal statistical analysis will be performed.  
10.4.6. 
Analysis of Anti-Drug Antibody Data 
Listings of treatment-emergent ADA and titers presented by subject, time point, and dose cohort 
will be provided.  Incidence of treatment-emergent and treatment-boosted ADA will be assessed 
as absolute occurrence (N) and percent of subjects (%), grouped by study cohorts and ADA titer 
level.  
Assessment of association of treatment -emergent and treatment boosted ADA with potential 
impact of ADA response on PK, safety and efficacy may be evaluated. 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
The exploratory biomarker data will be summarized by descriptive statistics. 
10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
 The baseline assessment will be the latest, valid pre-first-dose assessment available 
General rules for handling missing data:  
 Rules for handling missing data for assessment (other than efficacy) 
 If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment.  If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be 
imputed; otherwise, the missing day or month by the first day or the first month will 
be imputed.  
 No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
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Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed 
according to the case report form (CRF) assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries.  If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
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 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study 
(including data validation, cleaning, correcting, releasing) will be maintained and stored at 
Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding.  All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with both paper and an electronic data capture 
(EDC) tool. 
11.2. 
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 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
 AWARE, Business Objects XI – pharmacovigilance activities (Sanofi) 
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12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first subject, and periodically during the study.   
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of subjects are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate subject records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF).  Case report forms and source 
documents must be available at all times for inspection by authorized representatives of the 
sponsor and regulatory authorities. 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel.  All required CRFs must be 
completed for each and every subject enrolled in the study.  After review of the clinical data for 
each subject, the investigator must provide an electronic signature.  A copy of each subject CRF 
casebook is to be retained by the investigator as part of the study record and must be available at 
all times for inspection by authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee.  
All changes, including date and person performing corrections, will be available via the audit 
trail, which is part of the EDC system.  For corrections made via data queries, a reason for any 
alteration must be provided. 
13. 
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 
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 Taking all appropriate measures requested by the sponsor to resolve the problems 
found during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, 
CRFs, medical records, correspondence, ICFs, IRB/EC files, documentation of certification and 
quality control of supporting laboratories, and records relevant to the study maintained in any 
supporting pharmacy facilities.  Conditions of study material storage are also subject to 
inspection.  In addition, representatives of the sponsor may observe the conduct of any aspect of 
the clinical study or its supporting activities both within and outside of the investigator's 
institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
14.1. 
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. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC.  A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each subject prior to his/her participation in the study and after 
the aims, methods, objectives, and potential hazards of the study have been explained to the 
subject in language that he/she can understand.  The ICF should be signed and dated by the 
subject and by the investigator or authorized designee who reviewed the ICF with the subject.   
 Subjects who can write but cannot read will have the ICF read to them before signing 
and dating the ICF. 
 Subjects who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the subject's study record, and a 
copy of the signed ICF must be given to the subject. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF 
must be reviewed and updated appropriately.  All study subjects must be informed of the new 
information and provide their written consent if they wish to continue in the study.  The original 
signed revised ICF must be maintained in the subject’s study record and a copy must be given to 
the subject. 
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14.2. 
Subjects Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained.  Subjects should be identified by a subject identification number 
only, on CRFs or other documents submitted to the sponsor.  Documents that will not be 
submitted to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The subject's and investigator's personal data, which may be included in the sponsor database, 
will be treated in compliance with all applicable laws and regulations.  The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third 
party. 
14.3. 
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 subjects 
(eg, advertising) before any subject may be enrolled in the study 
 Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the subject, in 
which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of subjects or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator.  
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB/EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely.  Reasons may include efficacy, 
safety, or futility, among others.  Should the sponsor decide to terminate the study, the 
investigator(s) will be notified in writing. 
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16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at 
least 30 days’ notice.  The final decision should be made through mutual agreement with the 
sponsor.  Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing.  
Reasons may include the following, among others:  
 The investigator has received all items and information necessary to perform the 
study, but has not enrolled any subject within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of subjects required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection 
of the subjects’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator.  This signed declaration accompanies each set of subject final 
eCRFs that will be provided to the sponsor. 
17.2. 
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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18. 
DATA 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 summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of 
the data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, Section 13)   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of subjects are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH 
GCP, and all applicable regulatory requirements (Section 12.1).   
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of subject final CRF (Section 12.3 
and Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
21. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Study To Evaluate The Efficacy Of Dupilumab As An 
Adjunct For Subcutaneous Grass Immunotherapy To Reduce Provoked Allergic Rhinitis 
Symptoms Using The Nasal Allergen Challenge Model, 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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Clinical Study Protocol 
 
R668-ALG-16115 Amendment 2 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 86 of 87 
CONFIDENTIAL 
APPENDIX 1. 
TOXICITY GRADING SCALE FOR GRADING ALLERGIC 
REACTIONS AND ANAPHYLAXIS – COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (CTCAE VERSION 4.0, 
PUBLISHED 28 MAY 2009; V4.03, 14 JUNE 2010) 
The CTCAE descriptive terminology will be utilized for reporting AEs of allergic reactions and 
anaphylaxis. A grading (severity) scale is provided for each AE term.  
Adverse 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 
5 
Allergic 
reaction 
Transient flushing or 
rash, drug fever 
<38 degrees C 
(<100.4 degrees F); 
intervention not 
indicated 
Intervention or 
infusion 
interruption 
indicated; 
responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications 
indicated for 
≤24 hours 
Prolonged (eg, not 
rapidly responsive 
to symptomatic 
medication and/or 
brief interruption of 
infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
clinical sequelae 
(eg, renal 
impairment, 
pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen 
Anaphylaxis 
– 
– 
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
intervention 
indicated; 
allergy-related 
edema/angioedema; 
hypotension 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of 
histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response. 
Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of 
consciousness and may lead to death. 
 
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Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 87 of 87 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: 
A Study To Evaluate The Efficacy Of Dupilumab As An Adjunct For 
Subcutaneous Grass Immunotherapy To Reduce Provoked Allergic Rhinitis Symptoms Using 
The Nasal Allergen Challenge Model 
 
Protocol Number: 
R668-ALG-16115 
Protocol Version: 
R668-ALG-16115 Amendment 2 
 
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 Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
 
                                        VV-RIM-00062320-1.0 Approved - 13 Nov 2018 GMT-5:00


Signature Page for VV-RIM-00062320 v1.0
Signature Page for VV-RIM-00062320 v1.0 Approved
ESig Approval
12-Nov-2018 17:12:34 GMT+0000
ESig Approval
12-Nov-2018 18:28:40 GMT+0000
ESig Approval
ement
13-Nov-2018 13:51:50 GMT+0000
ESig Approval
13-Nov-2018 14:20:21 GMT+0000
                                        VV-RIM-00062320-1.0 Approved - 13 Nov 2018 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 66 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
Clinical Study Protocol Title: A Study To Evaluate The Efficacy Of Dupilumab As An Adjunct 
For Subcutaneous Grass Immunotherapy To Reduce Provoked Allergic Rhinitis Symptoms 
Using The Nasal Allergen Challenge Model 
Compound: 
Dupilumab (REGN668) 
Protocol Number: 
R668-ALG-16115 
Clinical Phase:  
Phase 2a 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date:  
Version 1.0/19June2019 
VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00
NCT03558997


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 2 of 66 
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 Bioanalytical Sciences  
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................9 
1.1. 
Background/Rationale ..................................................................................................9 
1.2. 
Study Objectives .........................................................................................................10 
1.2.1. 
Primary Objectives .....................................................................................................10 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Other Objectives .........................................................................................................10 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................11 
1.2.5. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Sample Size and Power Considerations .....................................................................13 
2.3. 
Study Plan ...................................................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................17 
3.1. 
The Full Analysis Set (FAS) .......................................................................................17 
3.2. 
The Per Protocol Set (PPS) .........................................................................................17 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................17 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................18 
3.5. 
The Immunogenicity Analysis Sets ............................................................................18 
3.6. 
Subgroups ...................................................................................................................18 
4. 
ANALYSIS VARIABLES .........................................................................................19 
4.1. 
Demographic and Baseline Characteristics ................................................................19 
4.2. 
Medical History ..........................................................................................................20 
4.3. 
Prior/Concomitant Medications and Procedures ........................................................20 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................20 
4.5. 
Efficacy Variables ......................................................................................................21 
4.5.1. 
Primary Efficacy Variable (s) .....................................................................................21 
4.5.2. 
Secondary Efficacy Variables .....................................................................................21 
4.5.3. 
Exploratory Variables .................................................................................................22 
4.6. 
Safety Variables ..........................................................................................................25 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................25 
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Statistical Analysis Plan 
Date: 19June2019 
 
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4.6.2. 
Adverse Events of Special Interest .............................................................................26 
4.6.3. 
Laboratory Safety Variables .......................................................................................26 
4.6.4. 
Vital Signs ..................................................................................................................27 
4.6.5. 
Body Weight and Height ............................................................................................28 
4.6.6. 
Physical Examination Variables .................................................................................28 
4.6.7. 
12-Lead Electrocardiography (ECG) Variables .........................................................28 
4.6.8. 
Spirometry ..................................................................................................................28 
4.6.9. 
Peak Expiratory Flow .................................................................................................28 
4.7. 
Pharmacokinetic (PK) Variables ................................................................................28 
4.8. 
Immunogenicity Variable ...........................................................................................28 
4.9. 
Biomarkers Variables .................................................................................................29 
5. 
STATISTICAL METHODS .......................................................................................30 
5.1. 
Demographics and Baseline Characteristics ...............................................................30 
5.2. 
Medical History ..........................................................................................................30 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................30 
5.4. 
Rescue/ Prohibited Medications .................................................................................30 
5.5. 
Subject Disposition .....................................................................................................31 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................31 
5.6.1. 
Measurement of Compliance ......................................................................................31 
5.6.2. 
Exposure to Investigational Product ...........................................................................32 
5.7. 
Analyses of Efficacy Variables ..................................................................................32 
5.7.1. 
Analysis of Primary Efficacy Variable .......................................................................32 
5.7.2. 
Analyses of Secondary and Exploratory Efficacy Variables ......................................33 
5.7.3. 
Adjustment for Multiple Comparison .........................................................................34 
5.8. 
Analysis of Safety Data ..............................................................................................34 
5.8.1. 
Adverse Events ...........................................................................................................34 
5.8.2. 
Analysis of Adverse Events of Special Interest ..........................................................35 
5.8.3. 
Clinical Laboratory Measurements.............................................................................36 
5.8.4. 
Analysis of Vital Signs ...............................................................................................36 
5.8.5. 
Physical Exams ...........................................................................................................36 
5.8.6. 
Analysis of 12-Lead ECG ...........................................................................................36 
5.9. 
Analysis of Pharmacokinetic Data ..............................................................................36 
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Statistical Analysis Plan 
Date: 19June2019 
 
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5.10. 
Analysis of Immunogenicity Data ..............................................................................37 
5.10.1. 
Analysis of ADA Data ................................................................................................37 
5.10.2. 
Analysis of Neutralizing Antibodies (NAb) Data ......................................................38 
5.11. 
Analysis of Immunogenicity with Exposure, Safety and Efficacy .............................38 
5.11.1. 
Immunogenicity and Exposure ...................................................................................38 
5.11.2. 
Immunogenicity and Safety and Efficacy ...................................................................38 
5.12. 
Analysis of Biomarker Data .......................................................................................38 
6. 
DATA CONVENTIONS ............................................................................................40 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................40 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................40 
6.3. 
Visit Windows ............................................................................................................43 
6.4. 
Unscheduled Assessments ..........................................................................................44 
7. 
INTERIM ANALYSIS ...............................................................................................45 
8. 
SOFTWARE ...............................................................................................................46 
9. 
REFERENCES ...........................................................................................................47 
10. 
APPENDIX.................................................................................................................48 
10.1. 
Summary of Statistical Analyses ................................................................................48 
10.2. 
Schedule of Time and Events .....................................................................................50 
10.3. 
Analyses of Efficacy Variables Criteria for Potentially Clinically Significant 
Values (PCSV) for Adult Patients ..............................................................................59 
10.4. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome ................................65 
 
 
LIST OF TABLES 
Table 1: 
Dosing Schedule for Dupilumab/Placebo with Respect to SCIT/Placebo .................15 
Table 2: 
SCIT Up-Titration and Maintenance Regimen...........................................................16 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................14 
 
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Statistical Analysis Plan 
Date: 19June2019 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AD 
 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGOT) 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST (SGPT) 
Aspartate aminotransferase 
AUC 
Area under curve 
BAU 
Bioequivalent allergy unit 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
ECG 
Electrocardiogram 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
HIV 
Human Immunodeficiency Virus 
HLT 
High Level Term 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IL 
Interleukin 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
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LDH 
Lactate dehydrogenase  
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NAb 
Neutralizing Antibody 
NAC 
Nasal allergen challenge 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
PNIF 
Peak nasal inspiratory flow 
PT 
Preferred term 
Q2W 
Once every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
sIgE 
Specific immunoglobulin E 
sIgG4 
Specific immunoglobulin G4 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SD 
Standard deviation 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
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SE 
Standard error 
SOC 
System organ class 
SPT 
Skin prick test 
TARC 
Thymus and activation-regulated chemokine 
TEAE 
Treatment emergent adverse event 
Th2 
Type-2 T helper cells 
TNSS 
Total nasal symptom score 
TOSS 
Total ocular symptom score 
WHODD 
World health organization drug dictionary 
 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for R668-ALG-16115 study. 
1.1. 
Background/Rationale 
Subcutaneous immunotherapy (SCIT) is a disease modifying treatment option for patients with 
allergic rhinitis triggered by aeroallergens (such as pollen, animal dander, or dust).  SCIT is 
recommended when pharmacological therapies are not sufficient to control symptoms.  During 
SCIT, increasing doses of the inciting allergen are administered, followed by a maintenance dose 
for several years, with the goal of inducing immunological changes leading to symptom 
amelioration while on therapy, as well as sustained desensitization off SCIT (immune tolerance). 
The pathobiology of allergic disease is complex, involving many cell types and genetic 
susceptibility.  Data suggest that SCIT results in memory T and B cell responses, 
allergen-specific immunoglobulin shifts from immunoglobulin E (IgE) to immunoglobulin G 
(IgG), including IgG4, decreased type 2 cytokines in tissues, decreased tissue migration of 
eosinophils and decreased mediator release from tissue mast cells, basophils and eosinophils. 
Dupilumab is a human monoclonal IgG4 antibody that inhibits interleukin-4 (IL-4) and 
interleukin-13 (IL-13) signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 
and IL-13 receptor complexes.  Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 
cytokine-induced responses, including the release of proinflammatory cytokines, chemokines 
and IgE.  IL-4 and IL-13 play key roles in the pathophysiology of allergic diseases, as 
demonstrated by dupilumab’s efficacy shown in clinical studies in atopic diseases such as atopic 
dermatitis (AD), asthma, nasal polyposis (NP) and eosinophilic esophagitis.  This is the basis for 
the rationale to evaluate whether dupilumab may enhance allergy immunotherapy. In a post-hoc 
analysis of a dupilumab dose-ranging study in moderate-to-severe asthma patients with comorbid 
allergic rhinitis, patients had a significant reduction in reported rhinitis symptoms with 
dupilumab compared to placebo.  Because of these data and the role of IL-4 and IL-13 in 
immunoglobulin class switching, we anticipate that dupilumab as an adjunct to SCIT, will 
enhance the change of allergen specific IgG/IgE ratio, in SCIT + dupilumab treated subjects as 
compared to subjects treated with SCIT alone.    
There is an unmet need for a more efficacious treatment of allergic disease.  SCIT can provide 
long-lasting protection from allergic disease, but it also carries a risk of adverse reactions, has 
variable efficacy between patients, and can take at least 3 years to induce immune tolerance. 
Induction of type 2 pathway cytokines upon SCIT initiation can transiently exacerbate allergic 
symptoms, resulting in SCIT dose limitations during up-titration in some patients.  Blockade of 
these cytokines by dupilumab may improve tolerability of the desensitization process, in addition 
to improving overall safety and efficacy by further suppression of IgE production.   
This trial is a 4-arm, placebo-controlled, double-blind, randomized, parallel-group, proof-of- 
concept  (phase 2a) study over a 16-week treatment period followed by an 8-week safety follow-
up period in approximately 100 adult subjects with a history of Timothy Grass-induced allergic 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
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Page 10 of 66 
rhinitis.  Four treatment groups after 600mg loading dose are required to provide informative 
controls and minimize bias on clinical endpoints:   
 dupilumab + SCIT  
 SCIT  
 dupilumab 
 placebo.  
In addition, this study will allow the evaluation of dupilumab monotherapy on clinical rhinitis 
symptoms and related biomarkers. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of the study is to assess whether 16 weeks of treatment with dupilumab as 
an adjunct to Timothy Grass SCIT improves upon the efficacy of Timothy Grass SCIT to reduce 
provoked allergic rhinitis symptoms, as measured by TNSS after NAC with Timothy Grass 
extract at week 17. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are 
 To assess whether 16 weeks of treatment with dupilumab as compared to placebo 
reduces provoked allergic rhinitis symptoms, as measured by TNSS after NAC with 
Timothy Grass extract  
 To assess whether 16 weeks of treatment with dupilumab as compared to dupilumab 
+ SCIT reduces provoked allergic rhinitis symptoms, as measured by TNSS after 
nasal allergen challenge (NAC) with Timothy Grass extract  
 To assess changes in serum Timothy-grass-specific IgG4, serum Timothy 
Grass-specific IgE, and ratio of serum Timothy Grass-specific IgG4 to IgE over 
16 weeks of treatment with dupilumab + SCIT as compared to SCIT monotherapy 
 To evaluate the safety and tolerability of 16 weeks of treatment with dupilumab as an 
adjunct to Timothy Grass SCIT  
1.2.3. 
Other Objectives 
 To assess whether 16 weeks of treatment with dupilumab as an adjunct to Timothy 
Grass SCIT improves upon the efficacy of Timothy Grass SCIT to reduce provoked 
allergic conjunctivitis symptoms, as measured by TOSS after NAC with Timothy 
Grass extract.  
 To assess whether 16 weeks of treatment with dupilumab as compared to placebo 
reduces provoked allergic conjunctivitis symptoms, as measured by TOSS after NAC 
with Timothy Grass extract.  
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 To assess the changes in both early-phase (0–1 hr) and late-phase (1-6 hr) skin 
responses following Skin Prick Test with Serial Allergen Titration and intradermal 
administration of Timothy Grass, respectively, over 16 weeks of treatment with 
dupilumab, SCIT, dupilumab + SCIT, and placebo  
 To assess changes in peak nasal inspiratory flow (PNIF) after NAC over 16 weeks of 
treatment with dupilumab, SCIT , dupilumab + SCIT, and placebo  
 To assess total sneeze count after NAC over 16 weeks of treatment with dupilumab , 
SCIT, dupilumab + SCIT, and placebo 
 To assess changes in serum TARC over 16 weeks of treatment with dupilumab, 
SCIT, dupilumab + SCIT, and placebo 
 To assess changes in serum total IgE over 16 weeks of treatment with dupilumab , 
SCIT, dupilumab + SCIT, and placebo 
 To assess changes in serum Timothy-grass-specific IgG and ratio of serum Timothy 
Grass-specific IgG to IgE over 16 weeks of treatment with dupilumab + SCIT as 
compared to SCIT 
 To assess whether dupilumab as an adjunct to SCIT improves SCIT 
tolerability, defined as an increase in the proportion of subjects who achieve SCIT 
maintenance dose (4000 BAU), comparing 16 weeks of treatment with dupilumab + 
SCIT and 16 weeks of treatment withSCIT 
 To assess whether dupilumab as an adjunct to SCIT improves SCIT 
tolerability, defined as an increase in the maximal tolerated SCIT dose, comparing 16 
weeks of treatment with dupilumab + SCIT and 16 weeks of treatment withSCIT 
 To evaluate the effects of treatment (dupilumab + SCIT vs  SCIT) on local skin wheal 
size, measured approximately 15 minutes after each SCIT injection.  
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
The following other objectives are added into the SAP. 
 To assess changes in serum Timothy-grass-specific IgG and ratio of serum Timothy 
Grass-specific IgG to IgE over 16 weeks of treatment with dupilumab + SCIT as 
compared to SCIT 
 To assess whether dupilumab as an adjunct to SCIT improves SCIT 
tolerability, defined as an increase in the proportion of subjects who achieve SCIT 
maintenance dose (4000 BAU), comparing 16 weeks of treatment with dupilumab + 
SCIT and 16 weeks of treatment with SCIT. 
 To assess whether dupilumab as an adjunct to SCIT improves SCIT 
tolerability, defined as an increase in the maximal tolerated SCIT dose, comparing 16 
weeks of treatment with dupilumab + SCIT and 16 weeks of treatment with  SCIT. 
 To evaluate the effects of treatment (dupilumab + SCIT vs SCIT) on local skin wheal 
size, measured approximately 15 minutes after each SCIT injection.  
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 To assess change and percent in serum Timothy Grass sIgG subclasses other than 
Timothy Grass sIgG4 over 16 weeks of treatment with dupilumab + SCIT as 
compared to SCIT pending on available data  
The following endpoints are added into the exploratory variables as well. 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgG for dupilumab + SCIT as compared to SCIT  
 Change from baseline (last pretreatment measurement) to week 17 in log-transformed 
value of serum Timothy Grass sIgG to Timothy Grass sIgE ratio for dupilumab + 
SCIT as compared to SCIT  
 Proportion of subjects who achieve SCIT maintenance dose (4000 BAU) during 16 
weeks of treatment with dupilumab + SCIT as compared with SCIT 
 Maximal tolerated SCIT dose during 16 weeks of treatment with dupilumab + SCIT 
as compared with SCIT 
 Local skin wheal size at approximately 15 minutes after each SCIT injection during 
16 weeks of treatment with dupilumab + SCIT as compared with SCIT 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgG subclasses other than Timothy Grass sIgG4 
for dupilumab + SCIT as compared to SCIT pending on available data 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in Skin Prick Test with Serial Allergen Titration, as measured by AUC of the 
average wheal sizes (diameter) over log-transformed allergen concentrations after the 
challenge (early phase reaction) for dupilumab + SCIT as compared to SCIT and for 
dupilumab as compared to placebo  
The following endpoint is revised by removing the AUC over the course of hour 1 to hour 6 (late 
phase reaction) to fix the error in the protocol. 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in sneeze count AUC over the course of 0 hour to hour 1 after the challenge 
(early phase reaction) for dupilumab + SCIT as compared to SCIT and for dupilumab 
as compared to placebo 
1.2.5. 
Revision History for SAP Amendments 
There is no SAP amendment. 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a Phase 2a, multicenter, randomized, double-blind, parallel group, 4-arm study of 
dupilumab as an adjunct to grass SCIT and consists of a 12-week screening period, 16-week 
treatment period, and an 8-week post treatment follow-up period in subjects with a history of 
allergic rhinitis to grass pollen. 
Within 2 weeks after NAC (visit 3), a total of approximately 100 adult subjects with a history of 
allergic rhinitis to grass pollen who successfully complete screening procedures will be 
randomized 1:1:1:1 at Randomization (visit 4) into the 4 treatment arms (n=25 in each arm) as 
defined in Section 1.1. 
2.2. 
Sample Size and Power Considerations 
Approximately 100 patients are planned to be randomized. It is estimated that with 25 subjects 
per group, the study will have 80% power to detect a difference of 29% between dupilumab plus 
SCIT and placebo plus SCIT  with respect to percent change from baseline in TNSS AUC (0-1h) 
at week 17, assuming that the mean percent changes from baseline values are -55% and -26% for 
dupilumab plus SCIT and placebo plus SCIT, respectively, and a common standard deviation 
(SD) of 35%. The significance level is set to 2-sided, 0.05 level. 
The assumptions used for primary endpoint were based on the study result from the Scadding 
(2017) study.  The Scadding study shows after 1-year treatment, the difference between SCIT 
and placebo is 34% for the percent change in TNSS AUC (0-1h) at 1 year.  A similar magnitude 
of improvement by adding dupilumab onto SCIT is assumed for the sample size calculation. 
2.3. 
Study Plan 
The study will consist of the following 3 periods: screening of up to 12 weeks, treatment period 
of 16 weeks, and follow-up of 8 weeks as presented below Figure 1 : 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
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Figure 1: 
Study Flow Diagram 
 
*The NAC happens after 16 weeks of study treatment at week 17. 
After obtaining informed consent, subjects will be assessed for eligibility during a 3-part 
screening period.  The 3-part screening period is up to 12 weeks. During screening visit 1, 
subjects with a history of allergic rhinitis to grass pollen will undergo a medical history, physical 
examination, SPT for Timothy Grass, and blood draw for Timothy Grass specific IgE.  If the 
subject meets criteria with a positive SPT for Timothy Grass and for Timothy Grass specific IgE 
as per Inclusion/Exclusion criteria, they will be invited for screening visit 2.  At screening visit 2 
they will undergo a pregnancy test if applicable, spirometry, electrocardiogram (ECG), serologic 
testing for chronic viral infections (Human Immunodeficiency Virus Infection [HIV] and 
Hepatitis B and C), hematology, chemistry, urinalysis, will be evaluated for the study eligibility 
criteria, and will undergo a baseline nasal brushing.  At screening visit 3/Entry visit, a NAC and 
skin testing for early and late phase reactions will be performed. Grass allergic subjects will be 
eligible for enrollment based on having a TNSS ≤2 prior to the screening NAC (visit 3), peak 
TNSS ≥7 within the first hour during the up-titration phase. In addition, for eligibility, between 
the first non-zero dose of and approximately 10 minutes after the highest/peak dose, subjects 
must experience either a >20% drop in PNIF or >/=3 sneezes must be counted. 
Dupilumab will be administered SC, as a 600 mg loading dose and then 300 mg Q2W.  Placebo 
matching dupilumab is prepared in the same formulation without the addition of protein (ie, 
active substance, anti-IL-4Rα monoclonal antibody). Dupilumab dosing starts prior to SCIT 
dosing as shown in Table 1. Dupilumab/placebo are never to be given on the same day as SCIT/ 
placebo. 
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Table 1: 
Dosing Schedule for Dupilumab/Placebo with Respect to SCIT/Placebo 
Dose 
Dupilumab/Placebo1 
SCIT/Placebo 
NAC 
 
 
Randomization (V4) 
X2 
 
Week 1 
 
X3   
Week 2 
X4 
X4 
Week 3 
 
X4  
Week 4 
X4 
X4 
Week 5 
 
X4 
Week 6 
X4 
X4 
Week 7 
 
X4 
Week 8 
X4 
X4 
Week 9 
 
 
Week 10 
X4 
X4 
Week 11 
 
 
Week 12 
X4 
 
Week 13 
 
X4 
Week 14 
X4 
 
Week 15 
 
 
Week 16 
X4 
X4 
NAC 
 
 
1 Dupilumab/placebo dosing must given +/- 3 days of the visit window. 
2 Dupilumab or placebo for dupilumab loading dose is given day of randomization. Subsequent dupilumab/placebo 
dosing is given Q2W. 
3 SCIT/placebo should be given 1 to 7 days following dupilumab/dupilumab placebo loading dose. Subsequent 
SCIT/placebo dosing follows dosing regimen as depicted in Table 2 . 
4 During week 2, week 4, week 6, week 10, and week 6, when both dupilumab/placebo and SCIT/placebo are given 
in the same week, SCIT/placebo and dupilumab/placebo are NOT to be given on the same day (can be 1 day to 7 
days aprat) AND SCIT/placebo and dupilumab/placebo are to be given in a different anatomical location. For 
SCIT/placebo visits, subjects are to be premedicated with an antihistamine. 
SCIT will be up-dosed for 8 weeks to a maximum of 4,000 BAU dose, followed by an 8-week 
maintenance dose.   
If subjects develop side effects during the up-dosing phase of SCIT, such as repeated large 
immediate local reactions or grade 1-2 systemic reactions requiring dosage adjustments, the 
principal investigator (PI), in consultation with the medical monitor, may decide to reduce the 
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planned maintenance dose of SCIT of 4000 BAU down to between 400 BAU and 4000 BAU but 
no lower than 400 BAU. 
Placebo matching SCIT is prepared in the same formulation (SCIT diluent) without the addition 
of Timothy Grass extract. 
Table 2: 
SCIT Up-Titration and Maintenance Regimen 
Week No 
Injection No 
Subcutaneous Dose of SCIT 
(BAU) 
1 
1 
1 
1 
2 
4 
1 
3 
10 
2 
4 
20 
2 
5 
40 
2 
6 
70 
3 
7 
100 
3 
8 
150 
3 
9 
250 
4 
10 
400 
4 
11 
700 
5 
12 
1000 
5 
13 
1500 
6 
14 
2000 
7 
15 
3000 
8 
16 
4000 
10 
17 
4000 
13 
18 
4000 
16 
19 
4000 
All SCIT visits will be supervised in an in-clinic study site setting where trained study 
physicians, who are experts in Allergy and Immunology and who are experienced SCIT 
providers, are present.  Subjects will be observed for at least 30 minutes after any SCIT injection.   
All subjects who complete or prematurely discontinue the treatment will be assessed for safety, 
laboratory, and clinical assessments as noted in the Schedule of Events as noted in Section 10.2. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis. 
3.1. 
The Full Analysis Set (FAS) 
The full analysis set (FAS) includes all randomized patients.  Efficacy analyses will be based on 
the treatment allocated at randomization (as randomized). 
FAS is the primary analysis set for efficacy endpoints.   
3.2. 
The Per Protocol Set (PPS) 
The per-protocol set (PPS) includes all patients in the FAS except for those who are excluded 
because of major protocol violations.  A major protocol violation is one that may affect the 
interpretation of study results.  Final determination of the PPS will be made before data base 
lock. 
The primary endpoint will be evaluated on the PPS in addition to FAS. 
3.3. 
The Safety Analysis Set (SAF) 
The safety analysis set (SAF) includes all randomized patients who receive at least one injection 
of study drug, it is based on the treatment received (as treated).  Treatment 
compliance/administration and all clinical safety variables will be summarized based on the 
SAF. 
The actual treatment group as treated is defined by the following rules: 
1. To determine whether a patient received dupilumab or placebo 
 For a patient randomized to receive dupilumab, if the patient received all placebo 
injections, the actual treatment will be assigned as placebo. 
 For a patient randomized to receive dupilumab, if the patient received at least one 
dupilumab injection, the actual treatment will be same as the planned treatment. 
 For patients randomized to receive placebo but accidentally received dupilumab 
injections, the actual treatment will be assigned as dupilumab. 
2. To determine whether a patient received SCIT or placebo SCIT 
 For a patient randomized to receive SCIT, if the patient received all placebo SCIT 
injections, the actual treatment will be assigned as placebo SCIT. 
 For a patient randomized to receive SCIT, if the patient received at least one SCIT 
injection, the actual treatment will be same as the planned treatment. 
 For patients randomized to receive placebo SCIT but accidentally received SCIT 
injections, the actual treatment will be assigned as SCIT. 
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For safety summaries, three analysis periods are defined as follows.  
 Treatment period is defined as: 
 Day 1 to the Week 17 NAC visit for those patients who completed Week 17 visit 
with Week 17 visit date present 
 Day 1 to the last dose date plus 14 days for the patients who did not complete 
Week 17 visit or had missing or incomplete Week 17 visit date 
 Follow-up period is defined as: 
 The date after the Week 17 visit date (or last dose date plus14 days if the date of 
Week 17 visit is unavailable) to the date of the end of study visit Week 24 
 Overall study period is defined as: 
 Day 1 to the date of the end of study visit Week 24 
The SAF will be the basis for the analyses for the treatment period and overall study period; 
however, for the analyses for the follow-up period, only a subset of SAF will be included, which 
is defined as the patients who enter the follow-up period and have at least one visit after week 17 
NAC visit. 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set includes all randomized patients who received any dupilumab 
and who had at least one non-missing dupilumab drug concentration result following the first 
dose of dupilumab. Patients will be analyzed according to the treatment actually received. 
3.5. 
The Immunogenicity Analysis Sets 
The ADA analysis set (AAS) will consist of all patients who received any study drug and who 
had at least one non-missing ADA result from the dupilumab ADA assay after first dose of the 
study drug.  Patients will be analyzed according to the treatment actually received. 
The neutralizing antibody (NAb) Analysis Set (NAS) will consist of all patients who received 
any study drug and who had at least one non-missing NAb result from dupilumab neutralizing 
antibody assay or who had all samples negative in the dupilumab ADA assay after first dose of 
the study drug. Patients will be analyzed according to the treatment actually received. 
3.6. 
Subgroups 
Subgroups are defined as the following. 
 Age group (≥18 to <40, ≥40 to ≤55) 
 Sex (Male, Female) 
 Race (White, Other) 
 Baseline weight group (<60 kg, ≥60-<100 kg, ≥100 kg) 
 Baseline BMI group (<15 kg/m2, ≥15-<25 kg/m2, ≥25-<30 kg/m2, ≥30 kg/m2) 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
 Demographic variables: Age at screening (year), age (year) group (≥18-<40, ≥40-
<55), sex, ethnicity, race, baseline weight (kg) with grouping (<60; ≥60-<100, ≥100), 
height (m), BMI (kg/m2) with grouping (<15, ≥15-<25, ≥25-<30, ≥30)  
 Baseline characteristics:  
o baseline TNSS AUC post NAC over the first hour after the challenge (0-1 hr 
post peak TNSS) 
o baseline peak TNSS 
o baseline TOSS AUC post NAC over the first hour of the challenge (0-1 hr 
post peak TNSS) 
o baseline Skin Prick Test with Serial Allergen Titration, as measured by AUC 
of the wheal sizes (diameter) over allergen concentrations (early phase 
reaction) 
o baseline Skin Prick Test with Serial Allergen Titration, as measured by AUC 
of the wheal sizes (diameter) over log-transformed allergen concentrations 
(early phase reaction) 
o baseline wheal size (diameter) induced by skin Timothy Grass intradermal 
injection 6 hrs after the challenge (late phase reaction) 
o baseline PNIF AUC over the course of 0 hour to hour 1 and hour 1 to hour 6 
after the challenge (early and late phase reaction) 
o baseline sneeze count AUC over the course of 0 hour to hour after the 
challenge (early phase reaction) 
o baseline serum TARC 
o baseline serum total IgE 
o baseline serum Timothy Grass sIgE 
o baseline serum Timothy Grass sIgG4 
o baseline serum Timothy Grass sIgG 
o baseline subclasses of Timothy Grass sIgG other than sIgG4 (pending on 
available data) 
o baseline log-transformed value of serum Timothy Grass sIgG4 to Timothy 
Grass sIgE ratio 
o baseline log-transformed value of serum Timothy Grass sIgG to Timothy 
Grass sIgE ratio 
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4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA at the 
coding CRO.   
4.3. 
Prior/Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end of study 
visit.  Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD) at the coding CRO. Patients will be counted once in all ATC categories 
linked to the medication. 
Procedures will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA at the 
coding CRO. 
Prior medications/procedures:  medications taken or procedures performed prior to 
administration of the first study drug. 
Concomitant medications/procedures:  medications taken or procedures performed following the 
first dose of study drug through the end of study visit. 
 Concomitant medications/procedures during the treatment period are 
medications/procedures taken after the first dose up to the date of last injection plus 
14 days.  Medications/procedures taken during the treatment period and continued 
afterwards into follow-up period will be counted only once as concomitant 
medications/procedures during the treatment period. 
 Concomitant medications/procedures during the Follow-up period are 
medications/procedures taken after the end of treatment period to end of study. 
4.4. 
Rescue Medication/or Prohibited Medication During Study  
Prohibited concomitant medications/procedures:   
Use of leukotriene inhibitors, mast cell inhibitors, corticosteroids including systemic, intranasal, 
or inhaled corticosteroids, oral or topical decongestants, systemic or topical calcineurin 
inhibitors, beta blockers, long-acting beta agonist (LABA), and long-acting muscarinic 
antagonist (LAMA) will be prohibited for the duration of the study. 
Prohibited medications are not to be used after randomization except as rescue treatments.  
Treatment with prohibited medications is allowed during the study if medically necessary as 
judged by the investigator (ie, as needed for allergic symptoms related to SCIT or SCIT placebo 
or related to study procedures).   
Concomitant treatments for allergies including allowed and rescue treatments (i.e., both 
medications and procedures):  
If medically required, subjects who experience allergic reactions will be treated with rescue 
treatment including but not limited to IM or SC administration of epinephrine, as determined by 
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trained study staff.  Subjects may also take oral antihistamines as needed for allergic rhinitis 
symptoms during the course of the study, however oral antihistamines may not be used within 
5 days prior to or during a visit for NAC or skin testing.  If subject uses oral antihistamines 
within 5 days prior to or during a visit for NAC or skin testing they must be rescheduled. 
Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency and the potential 
impact of the use of the prohibited medication or procedure. The rescue treatments will be 
adjudicated by the clinical study director and the adjudication procedure will be documented. 
4.5. 
Efficacy Variables 
4.5.1. 
Primary Efficacy Variable (s) 
The primary endpoint in the study is: 
 Percent change in AUC for TNSS (0-1 hr post peak TNSS) in response to a NAC at 
week 17 from the pretreatment baseline TNSS AUC (0-1 hr post peak TNSS) for 
dupilumab + SCIT as compared to SCIT  
The algorithm for calculating the area under curve (AUC) is provided in Section 6.2. 
Total Nasal Symptom Score (TNSS) 
The Total Nasal Symptom Score (measured on a 0 to 12 scale) is a patient-reported composite 
symptom assessment of 4 symptoms graded on a 0 (none) to 3 (severe) scale: rhinorrhea, nasal 
congestion, nasal itching, and sneezing. The TNSS will be performed at Screening Visit 2 and 
each NAC visit (Screening Visit 3 and Visit 16). At the end of treatment (EOT) NAC (week 17), 
subjects will be observed for approximately 10 minutes and a resting/baseline TNSS ≤2 must be 
achieved, signifying that the subject does not have active nasal symptoms at rest (due to viral 
infection, sinusitis, allergies, etc.), prior to NAC. The NAC will be performed using increasing 
doses of Timothy Grass extract every 10 minutes, with TNSS score recorded approximately 
every 10 minutes (up-titration symptom score), up until they reach the concentration of Timothy 
Grass extract that was used to achieve a Total Nasal Symptom Score (TNSS) ≥7 at their baseline 
NAC visit. This TNSS score will be recorded. After recording the TNSS attained using 
concentration of Timothy Grass extract that was used to achieve a Total Nasal Symptom Score 
(TNSS) ≥7 at their baseline NAC visit, the subject will be observed for the subsequent hour and 
the TNSS will be recorded at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, and then 
hourly up to 6 hours.  
4.5.2. 
Secondary Efficacy Variables 
The secondary endpoints are: 
 Change from baseline in TNSS AUC post NAC over the first hour after the challenge 
(0-1 hr post peak TNSS) at week 17 for dupilumab + SCIT as compared to SCIT  
 Change and percent change from baseline in TNSS AUC post NAC over the first 
hour of the challenge (0-1 hr post peak TNSS) at week 17 for dupilumab as compared 
to placebo  
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 Change and percent change from baseline in the TNSS AUC post NAC over the first 
hour of the challenge (0-1 hr post peak TNSS) at week 17 for dupilumab + SCIT as 
compared to dupilumab 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgG4 for dupilumab + SCIT as compared to SCIT  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgE for dupilumab + SCIT as compared to SCIT  
 Change from baseline (last pretreatment measurement) to week 17 in log-transformed 
value of serum Timothy Grass sIgG4 to Timothy Grass sIgE ratio for dupilumab + 
SCIT as compared to SCIT  
4.5.3. 
Exploratory Variables 
Exploratory endpoints include: 
 Change and percent change from baseline in the peak TNSS at week 17 for 
dupilumab + SCIT as compared to SCIT and for dupilumab as compared to placebo  
 Change and percent change from baseline in TOSS AUC post NAC over the first 
hour of the challenge (0-1 hr post peak TNSS) at week 17 for dupilumab + SCIT as 
compared to SCIT and for dupilumab as compared to placebo  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in Skin Prick Test with Serial Allergen Titration, as measured by AUC of the 
average wheal sizes (diameter) over allergen concentrations after the challenge (early 
phase reaction) for dupilumab + SCIT as compared to SCIT and for dupilumab as 
compared to placebo  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in Skin Prick Test with Serial Allergen Titration, as measured by AUC of the 
average wheal sizes (diameter) over log-transformed concentrations after the 
challenge (early phase reaction) for dupilumab + SCIT as compared to SCIT and for 
dupilumab as compared to placebo  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in the wheal size (diameter) induced by skin Timothy Grass intradermal 
injection 6 hrs after the challenge (late phase reaction) for dupilumab + SCIT as 
compared to SCIT and for dupilumab as compared to placebo  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in PNIF AUC over the course of 0 hour to hour 1 and hour 1 to hour 6 after 
the challenge (early and late phase reaction) for dupilumab + SCIT as compared to 
SCIT and for dupilumab as compared to placebo  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in sneeze count AUC over the course of 0 hour to hour 1 after the challenge 
(early phase reaction) for dupilumab + SCIT as compared to SCIT and for dupilumab 
as compared to placebo  
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 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum TARC for dupilumab + SCIT as compared to SCIT  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum total IgE for dupilumab + SCIT as compared to SCIT  
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgG for dupilumab + SCIT as compared to SCIT  
 Change from baseline (last pretreatment measurement) to week 17 in log-transformed 
value of serum Timothy Grass sIgG to Timothy Grass sIgE ratio for dupilumab + 
SCIT as compared to SCIT  
 Proportion of subjects who achieve SCIT maintenance dose (4000 BAU) during 16 
weeks of treatment with dupilumab + SCIT as compared with SCIT 
 Maximal tolerated SCIT dose during 16 weeks of treatment with dupilumab + SCIT 
as compared with SCIT 
 Local skin wheal size at approximately 15 minutes after each SCIT injection during 
16 weeks of treatment with dupilumab + SCIT as compared with SCIT 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in serum Timothy Grass sIgG subclasses other than Timothy Grass sIgG4 
for dupilumab + SCIT as compared to SCIT pending on data availability  
Peak TNSS 
The peak TNSS should be the highest TNSS value between 0 hour and hour 1 inclusive. 
Total Ocular Symptom Score (TOSS) 
TOSS (measured on a 0-3 scale, 3 being severe) is a composite symptom assessment of ocular 
symptoms (Itchy, Red, tearing [eyes watering], and swelling [puffy eyes].  The TOSS score will 
be recorded during the NAC assessments (Screening Visit 3 and Visit 16).  The TOSS score will 
be recorded approximately every 10 minutes (up-titration symptom score), up until they reach 
the concentration of Timothy Grass extract that was used to achieve a TNSS ≥7 at their baseline 
NAC visit.  This TOSS score will be recorded.  The subject will be observed for the subsequent 
hour and the TOSS score will be recorded at 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 
hour, and then hourly up to and at 6 hours. 
Peak nasal inspiratory flow (PNIF) 
Peak nasal inspiratory flow (measured in nasal patency, L/min) will be measured and recorded 
approximately every 10 minutes during the uptitration phase of the NAC and will be measured 
and recorded during the subsequent hour after peak TNSS is achieved (at 5 minutes, 15 minutes, 
30 minutes, 45 minutes, and 1 hour) and hourly up to and at 6 hours. The PNIF will be 
performed at each NAC visit (Screening Visit 3 and Visit 16). 
Sneeze Count 
Sneezes will be counted and recorded approximately every 10 minutes during the uptitration 
phase of the NAC and will be measured and recorded during the subsequent hour after peak 
TNSS is achieved (at 5 minutes, 15 minutes, 30 minutes, 45 minutes, and 1 hour) and hourly up 
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to and at 6 hours as noted. The sneezes count will be performed at each NAC visit (Screening 
Visit 3 and Visit 16). 
Skin Prick Test (SPT) with Serial Allergen Titration 
The SPT with serial allergen titration assesses the early phase reaction at 0-60 minutes. The skin 
prick test with serial allergen titration procedure will be performed two times during the study: at 
visit 3 (on the day of the screening NAC) and at the EOT NAC visit (visit16). The procedure 
should be performed over a 30 minute time period (15 min placement of skin pricks, 15 minutes 
(+/- 2 minutes) after placement to evaluate responses) during the last 2 hours of the NAC day 
when the subject is otherwise undergoing hourly assessments. 
The test will be performed in duplicate by titration of Timothy grass extract at six doses ranging 
from 14-10000 BAU. Duplicate probes with a negative control solution and a positive histamine 
control will be administered simultaneously with Timothy grass extract probes. A mean wheal 
diameter 3 mm greater than the negative control is considered a positive test result.  Skin 
responses to the skin prick test with serial allergen titration will be measured 15 minutes after 
placement (+/- 2 minutes). Mean wheal diameters will be calculated by adding the longest 
diameter to the longest orthogonal diameter and dividing by 2.  For each of the duplicate skin 
prick tests, the longest and longest orthogonal diameters should be recorded, and the mean 
diameter of each wheal calculated to two decimal places. The mean wheal diameters from the 
duplicate skin pricks will then be averaged and recorded.   
The formula used to calculate the average wheal diameter AUC over allergen concentrations is 
similar as the one inside Section 6.2, where ti is ci, the concentration (in BAU/ml) for which Di is 
measured. Di is the average wheal diameter obtained at concentration ci, c0= 14, c1= 41, c2= 123, 
c3= 370, c4= 1111, c5= 3333, c6= 10000. The formula used to calculate the average wheal 
diameter AUC over log-transformed allergen concentrations is similar to above, however, ci is 
the log-transformed concentration. 
The change from baseline, percent change from baseline values for the mean wheal diameters 
from measurement 1 and 2 for skin prick test of negative control, positive histamine control, and 
each concentration level of Timothy grass allergen will be also summarized.  
Intradermal Allergen Injection 
The intradermal allergen injection assesses late phase reaction from 6-24 hours. The intradermal 
allergen injection procedure will be performed two times during the study: at visit 3 (on the day 
of the screening NAC) and at the EOT NAC visit (visit16). The intradermal allergen injection 
procedure will be performed on the extensor and volar aspect of the forearm.  The intradermal 
allergen injection will be performed at the beginning of the NAC day, before the NAC begins, as 
described below. The skin response to the intradermal allergen will be evaluated at 
approximately 6 hours after placement- at the end of the NAC day. The mean wheal diameter 
measured at 15 minutes and 6 hours after injection for the Timothy grass allergen extract of 14, 
41, 123 BAU/ml will be collected.  
The maximum mean wheal diameters 6 hours after injection at the EOT NAC visit (visit 16) 
versus the maximum mean wheal diameters 6 hours after injection at the screening NAC visit 
(Visit 3) up to the largest concentration level at EOT NAC visit will be identified. The change 
and percent change between these two values will be calculated and summarized. If the 
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maximum mean wheal diameters are not at the same Timothy grass allergen concentration at 
Visit 3 and EOT/Visit 16, the assessment at the smaller one of the two concentrations will be 
used in the change and percent change analysis. That is, the wheal diameters of Visit 3 and 
EOT/Visit 16 for the change and percent change calculation should be based on the same 
concentration. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study, with the exception of symptoms that 
occur in response to the NAC on the day of the NAC.  Allergic symptoms that occur in response 
to the NAC are not to be reported as AEs, as they will be recorded as outcome measures.  
However, AEs that occur in response to the NAC that are outside of expected symptoms which 
are recorded in response to the NAC, and/or SAEs, should be reported as AEs and SAEs.   
All adverse events are to be coded to a “Preferred Term (PT)”, “High Level Term (HLT)” and 
associated primary “System Organ Class (SOC)” according to the Medical Dictionary for 
Regulatory Activities (MedDRA, latest version). 
An Adverse Event is any untoward medical occurrence in a patient administered a study drug 
which may or may not have a causal relationship with the study drug.  Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease 
which is temporally associated with the use of a study drug, whether or not considered related to 
the study drug. 
AEs also include: any worsening (i.e., 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; 
abnormal laboratory findings considered by the investigator to be clinically significant; and any 
untoward medical occurrence. 
A Serious Adverse Event is any untoward medical occurrence that at any dose results in death; 
is life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; 
results in persistent or significant disability/ incapacity; is a congenital anomaly/ birth defect; or 
is an important medical event. 
The criteria for determining whether an abnormal laboratory, vital sign or ECG finding should be 
reported as an AE are as follows: 
 Test result is associated with accompanying symptoms, and/or 
 Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 Test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy 
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The pre-treatment period is defined as the period from the patient providing informed consent up 
to the first dose of study drug. The pre-treatment AEs are AEs that developed or worsened in 
severity during pre-treatment period. 
The treatment emergent period is defined as the period from the administration of first study 
dose to the EOS visit. The treatment-emergent period consists of the treatment period and 
follow-up period. The definitions of the treatment period and the follow-up period are described 
inside Section 3.3. Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in 
severity compared to the baseline during the treatment emergent period.  As only the worsening 
pre-existing AEs and new AEs reported during the treatment and follow-up period will be 
collected in the study, all AEs collected during the treatment and follow-up period are considered 
as TEAEs. 
4.6.2. 
Adverse Events of Special Interest 
In this study, the adverse event of special interest (AESI) category includes: 
 Anaphylactic reactions  
 Systemic or severe hypersensitivity reactions  
 Malignancy (except in situ carcinoma of the cervix, non-metastatic squamous or basal 
cell carcinoma of the skin) 
 Helminthic infections 
 Suicide-related events  
 Any type of conjunctivitis or blepharitis (severe or serious) 
 Keratitis (any event regardless of severity or seriousness) 
Section 10.4 provides a list of AESIs search criteria. 
4.6.3. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. 
Samples for laboratory testing will be collected according to visit schedule (Section 10.2).  Tests 
will include: 
Serum Chemistry 
Sodium 
Total protein, serum 
Total bilirubin1 
Potassium 
Creatinine 
Total cholesterol2 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK)3 
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Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
1 Direct and indirect bilirubin will be measured when the total bilirubin is above the ULN 
2 Low-density lipoprotein and high-density lipoprotein 
3 CPK isoenzymes will be measured when CPK >5× the ULN 
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
Neutrophils 
Red blood cells (RBCs) 
Lymphocytes 
White blood cells (WBCs) 
Monocytes 
Red cell indices 
Basophils 
Platelet count 
Eosinophils 
Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast  
Other Laboratory Tests 
Serum and urine pregnancy testing will be performed for all female patients of childbearing 
potential at time points according to Section 10.2.  The following tests will be performed at 
screening: HIV Ab, HBsAg, HBsAb, HBcAb, Hepatitis C antibody.  
4.6.4. 
Vital Signs 
The following vital signs parameters will be collected: 
 Respiratory rate (bpm) 
 Pulse (beats/min) 
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 Sitting systolic and diastolic blood pressures (mmHg) 
 Body temperature (oC) 
Vital signs will be collected predose at the time points according to Section 10.2. 
4.6.5. 
Body Weight and Height 
Body weight and height will be measured at time points according to Section 10.2. 
4.6.6. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal. A thorough 
and complete physical examination will be performed at time points according to visit schedule 
(Section 10.2 ). 
4.6.7. 
12-Lead Electrocardiography (ECG) Variables 
Standard 12-Lead ECG parameters include: Ventricular HR, PR interval, QRS interval, corrected 
QT interval (QTc Fridericia [QTcF] =QT/[RR0.33] and QTc Bazett [QTcB]=QT/[RR0.5]) 
ECG status: normal, abnormal not clinical significant or abnormal clinical significant. 
Electrocardiograms should be performed before blood is drawn during visits requiring blood 
draws. A standard 12-lead ECG will be performed at time points according to Section 10.2. 
4.6.8. 
Spirometry 
Spirometry will be performed in all subjects.  If subjects have asthma and use short acting 
medications, the following instructions must be followed: after withholding the last dose of 
salbutamol/albuterol or levosalbutamol/levalbuterol for at least 6 hours, FEV1, forced vital 
capacity (FVC) and forced expiratory flow at 25% to 75% of forced vital capacity (FEF 25-75) 
will be determined at screening visit 2. 
4.6.9. 
Peak Expiratory Flow 
Peak expiratory flow will be measured using a peak flow meter (L/min) in any subject with a 
history of asthma prior to NAC at Screening Visit 2 and each NAC visit (Screening Visit 3 and 
Visit 16). Peak expiratory flow must be >80% predicted to perform the NAC in any subject with 
a history of asthma.   
4.7. 
Pharmacokinetic (PK) Variables  
Serum samples for measuring functional dupilumab concentrations will be collected at time 
points according to Section 10.2.  PK variables consist of functional dupilumab concentration 
and time (both actual and nominal). 
4.8. 
Immunogenicity Variable 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) status, and 
time-point/visit. Serum samples for anti-dupilumab antibody will be collected at time points 
according to schedule (Section 10.2). Samples positive in the dupilumab ADA assay will be 
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further characterized for ADA titers and for the presence of neutralizing antibody (NAb) against 
dupilumab.  
4.9. 
Biomarkers Variables  
Biomarker samples will be collected at time points according to according to Section 10.2. 
Biomarker measurements (TARC, total IgE, Timothy Grass specific IgE, Timothy Grass specific 
IgG4, Timothy Grass specific IgG) will be performed in serum or plasma to determine effects on 
biomarkers of relevant physiological and pathogenic processes. Biomarker results will be used to 
better understand the pathophysiology of Timothy Grass allergy, mechanism of action of 
dupilumab and possible toxicities. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, standard deviation, median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
All data will be summarized by the following 4 treatment groups defined in Section 1.1. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for FAS. 
Listing of demographics and baseline characteristics will be presented. 
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT for each treatment group.  The 
table will be sorted by decreasing frequency of SOC followed by PT based on the overall 
incidence across treatment groups.  Medical history will be listed. 
5.3. 
Prior/Concomitant Medications/Procedures 
Number and proportion of patients taking prior/concomitant medications, prohibited medications 
and rescue medications will be summarized, sorted by decreasing frequency of ATC Level 2 and 
ATC level 4, based on the overall incidence for the combined treatment groups. Patients will be 
counted only once for each medication class (ATC level 2 and 4) linked to the medication. 
Number and proportion of patients taking prior/concomitant procedures will be summarized, 
sorted by decreasing frequency of SOC and PT based on the overall incidence for the combined 
treatment groups. Patients will be counted only once for each SOC and PT linked to the 
procedure. 
Concomitant medications used to treat SCIT related adverse events will be tabulated separately. 
Prior medications or procedures started before screening visit and started between screening visit 
and first injection date will be summarized separately. 
Listing of medications and procedures will be provided. 
5.4. 
Rescue/ Prohibited Medications  
Number and proportion of patients taking prohibited procedures and rescue procedures will be 
summarized, sorted by decreasing frequency of SOC and PT based on the overall incidence for 
the combined treatment groups. Patients will be counted only once for each SOC and PT linked 
to the procedure. 
Concomitant treatments for allergies including allowed and rescue treatments (i.e., both 
medications and procedures) will be analyzed similarly. 
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5.5. 
Subject Disposition 
The following summaries by table will be provided: 
 The total number of screened patients 
 The total number of randomized patients: received a randomization number 
 The total number of patients in each analysis set 
 The total number of patients who completed the study and discontinued the study 
with the reason of discontinuation 
 The total number of patients who completed the study treatment and discontinued the 
study treatment with the reason of discontinuation 
The following listings will be provided: 
 Listing of patient disposition including: date of randomization, date of the last visit, 
received dose, completed study drug or discontinued by reason, completed study or 
discontinued by reason 
 A listing of patients randomized but not treated, and patients randomized but not 
treated as randomized 
 A listing of patients prematurely discontinued from the study or treatment, along with 
reasons for discontinuation 
 Summary table with listing of protocol deviations will be provided 
Time to the discontinuation will be assessed by Kaplan-Meier estimates (K-M plot) for each 
treatment group. 
5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
The compliance with study treatment will be calculated separately for dupilumab injection and 
SCIT injection as follows: 
Treatment Compliance = (Number of study drug injections during exposure period) / (Number of 
planned study drug injections during exposure period) x 100%, where the study drug injections 
can be dupilumab (or placebo dupilumab) injection, or SCIT (or placebo SCIT) injection.  
For treatment compliance calculation of dupilumab injection, the two injections taken at the 
randomization visit 4 will be counted as 1 injection. 
For treatment compliance calculation of SCIT injection, all the injections taken at the same visit 
will be counted as one single injection. Because due to the judgement of investigators to avoid 
patients having intolerable allergic symptoms, patients may not receive all the planned SCIT 
injections for a visit according to protocol.  
Summary of study drug administration will include the number of study drug doses administered 
and treatment compliance.  The treatment compliance will be presented by the following specific 
ranges for each treatment group: <80%, and ≥80%. 
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Listing of dose administration: including date/time, study day, number of injections, locations of 
injections, dosing information, and whether or not the total dose is administered for each dose 
will be presented. 
5.6.2. 
Exposure to Investigational Product 
The duration of treatment exposure during the study in day is calculated as: 
(Date of last study drug injection – date of first study drug injection) + 14 days 
The calculations are regardless of temporary dosing interruption. The duration of exposure 
during the study will be summarized by treatment group using number of patients, means, SD, 
minimums, medians, and maximums. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories and cumulatively by these categories as well:  
≥ 14 days, ≥ 28 days, ≥ 42 days, ≥ 56 days, ≥ 70 days, ≥ 84 days, ≥ 98 days, ≥ 112 days and ≥ 
126 days. 
The duration of observation period during the study in day is calculated as: 
(Date of the last visit – date of the first study drug injection) +1 day. 
The number (%) of patients with observation periods will be presented by specific time periods. 
The time periods of interest are specified as: < 8 days, ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, 
≥36 days, ≥43 days, ≥50 days, ≥ 57 days, ≥ 71 days, ≥92 days, ≥113 days, ≥120 days, ≥141 days, 
and ≥169 days. 
5.7. 
Analyses of Efficacy Variables 
For all efficacy variables, unless specified, the analysis will be comparisons of  
 dupilumab + SCIT versus SCIT  
 dupilumab versus placebo  
 dupilumab + SCIT versus dupilumab for percent change and change in TNSS AUC only 
The efficacy analyses will be based on the FAS Population. All statistical tests will be 2-sided at 
the 5% significance level. All confidence intervals (CIs) will be 2-sided 95% CIs. 
5.7.1. 
Analysis of Primary Efficacy Variable 
The primary endpoint will be analyzed by using the analysis of covariance (ANCOVA) model as 
the primary analysis method. The model will include treatment group being the main factor and 
baseline value as the covariate. The missing AUC value at a visit directly when a patient does not 
have any TNSS score collected at the visit, will be imputed by multiple imputation (MI) methods 
40 times to generate 40 complete data sets by using the Statistical Analysis System (SAS) 
procedure MI following the 2 steps below: 
Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo (MCMC) 
method in MI procedure using seed number 16115.  The monotone missing pattern 
means that if a patient has missing value for a variable at a visit, then the values at 
all subsequent visits for the same variable are all missing for the patient. 
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Step 2: The missing data at subsequent visits will be imputed using the regression method 
for the monotone pattern with seed number 51161 and adjustment for covariates 
including treatment groups and relevant baseline. 
Each of the 40 complete datasets will be analyzed using an ANCOVA model with treatment 
group being the main factor and baseline value as the covariate. The SAS MIANALYZE 
procedure will then be used to generate valid statistical inferences by combining results from the 
40 analyses using Rubin’s formula. The least-squares (LS) mean for each treatment group with 
its corresponding standard error (SE), the LS mean difference between treatment group and its 
corresponding SE and 95% CI, and the p-value corresponding to the between-treatment-group 
difference will be reported. 
In case of missing TNSS scores at one or more time points at a visit, all available TNSS scores 
collected at the visit will be used to calculate the AUC at the visit. The missing TNSS score at 
timepoints will not be imputed. The algorithm for calculation of AUC is provided in Section 6.2. 
Sensitivity analyses: 
 Post-baseline Last Observation Carried Forward (LOCF) approach will be used to impute 
the primary efficacy data at week 17, then the imputed data will be analyzed using 
ANCOVA model. 
 All observed data without imputation will be included for analysis using ANCOVA 
model. 
The primary efficacy analyses will be performed on FAS, as well as on PPS as a supportive 
analysis. 
Subgroup analysis: 
Subgroup analysis for the primary endpoint based on FAS will be performed. Descriptive 
statistics will be displayed for each subgroup for each treatment group. 
5.7.2. 
Analyses of Secondary and Exploratory Efficacy Variables 
The change and percent change from baseline in continuous secondary and exploratory efficacy 
endpoints will be analyzed using the same approach as that used for the analysis of the primary 
endpoint, unless specified otherwise. 
The biomarker related continuous endpoint will be analyzed using a rank based ANCOVA 
model with treatment and relevant baseline as covariates. Post-baseline LOCF method will be 
used to impute the missing data. The comparison will be performed between dupilumab +SCIT 
vs SCIT. 
The proportion of subjects who achieve SCIT maintenance dose (4000 BAU) during 16 weeks of 
treatment will be compared by Chi-square test between dupilumab + SCIT and placebo for 
dupilumab +SCIT groups. The maximal tolerated SCIT dose during 16 weeks of treatment and 
the local skin wheal size at approximately 15 minutes after each SCIT injection during 16 weeks 
of treatment will be summarized descriptively. If the wheel size is too small to measure after the 
SCIT injection, the diameter is set to zero. 
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5.7.3. 
Adjustment for Multiple Comparison 
There is no control for multiplicity. 
5.8. 
Analysis of Safety Data 
The summary of safety and tolerability will be performed based on SAF and presented for each 
treatment group. 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, physical 
examination, vital signs and 12-lead ECG. 
Thresholds for treatment-emergent Potentially Clinically Significant Values (PCSVs) in 
laboratory variables and vital signs are defined in Section 10.3.  Treatment-emergent PCSV is 
any PCSV developed or worsened in severity compared to the baseline during the treatment and 
follow-up period. 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
5.8.1. 
Adverse Events  
Listing of TEAEs, serious TEAEs, and TEAEs resulting in death and study drug discontinuation 
will be generated. 
Number and proportions of patients reporting TEAEs will be summarized for overall during the 
study sorted by decreasing frequency of SOC and PT based on the overall incidence for the 
combined treatment groups. 
Summaries of TEAEs will include: 
 TEAEs 
 TEAEs by SOC/PT 
 TEAEs by SOC/HLT/PT 
 TEAEs by PT 
 Common TEAEs by SOC/PT (incidence with PT ≥2%) 
 TEAEs by severity by SOC/PT 
 Severe TEAEs by SOC/PT 
 Severe TEAEs related to dupilumab or placebo for dupilumab as assessed by the 
investigator by SOC/PT  
 Severe TEAEs related to SCIT or placebo for SCIT as assessed by the investigator 
by SOC/PT  
 Severe TEAEs related to study procedure as assessed by the investigator by 
SOC/PT 
 Serious TEAEs by SOC/PT 
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 Serious TEAEs by SOC/PT 
 Serious TEAEs by SOC/HLT/PT 
 Serious TEAEs related to dupilumab or placebo for dupilumab as assessed by the 
investigator by SOC/PT  
 Serious TEAEs related to SCIT or placebo for SCIT as assessed by the 
investigator by SOC/PT  
 Serious TEAEs related to study procedure as assessed by the investigator by 
SOC/PT 
 TEAEs leading to permanent discontinuation from study treatment by SOC/PT 
 Death by SOC/PT 
In addition, separate summary will be provided for the TEAE caused by SCIT or placebo SCIT 
injection. 
Number of patients with dupilumab/placebo and SCIT/placebo reactions will be summarized as 
follows. 
 Dupilumab/placebo for dupilumab injection reaction:  
o by preferred ISR term  
o by adverse event preferred term.  
 SCIT/Placebo for SCIT injection reactions 
o by preferred ISR term for early local, late phase, and overall study 
o by adverse event preferred term for early local, late phase, and overall study  
 SCIT/placebo for SCIT reactions  
o by reaction type and toxicity grade  
o by adverse event preferred term. 
Number and proportion of patients reporting pre-treatment adverse events will be tabulated by 
SOC and PT. 
Subgroup analysis 
Subgroup analysis will be performed for TEAE except injection reactions. 
5.8.2. 
Analysis of Adverse Events of Special Interest 
The adverse events of special interest (AESI) will be summarized by AESI category (see 
Section 10.4) and HLT/PT.  
In addition, separate summary will be provided for the AESI caused by SCIT or placebo SCIT 
injection. 
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5.8.3. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units.  Summaries of laboratory variables will include: 
 Descriptive statistics of laboratory result and change from baseline by visit 
 The number (n) and percentage (%) of patients with abnormal lab value during study 
whose baseline values are normal (overall and per each lab parameter) 
 The number (n) and percentage (%) of patients with treatment-emergent PCSVs  
 Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listing of all laboratory parameters normal range, abnormal flag and treatment-emergent PCSV 
by patient and visit will be provided. 
5.8.4. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
 Descriptive statistics of vital sign variables and change from baseline by visit 
 The number (n) and percentage (%) of patients with treatment-emergent PCSV  
 Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listings of vital sign will be provided with flags indicating the treatment-emergent PCSVs. 
5.8.5. 
Physical Exams 
The number (n) and percentage (%) of patients with abnormal physical exams will be 
summarized at baseline, end of treatment period and end of study by treatment group.  A 
summary of treatment-emergent abnormal findings will be provided. 
5.8.6. 
Analysis of 12-Lead ECG 
Summaries of 12-lead ECG parameters by treatment group will include: 
 Each ECG parameter and change from baseline 
 The number (n) and percentage (%) of subjects with PCSV, depending on data 
 ECG status (i.e. normal, abnormal) summarized by a shift table 
Listings of ECG will be provided with flags indicating PCSVs. 
5.9. 
Analysis of Pharmacokinetic Data 
The following analyses will be conducted: 
 Descriptive statistics of functional dupilumab concentrations in serum at each 
sampling time by dose 
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 Graphical presentations of median and mean (+/- SD) functional dupilumab 
concentration in serum vs nominal time profiles 
 Graphical presentations of individual functional dupilumab concentration in serum vs 
actual sampling time profiles 
 Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum 
No formal statisitical analysis will be performed.  For the descriptive statistical analysis, 
concentrations below the lower limit of quantitation (LLOQ) will be set to zero.  When plotted 
on semi-log scale, concentrations are imputed as LLOQ/2.  Mean data are presented by nominal 
time. Individual concentrations are presented by actual time. 
5.10. 
Analysis of Immunogenicity Data 
5.10.1. 
Analysis of ADA Data 
Immunogenicity will be characterized by the ADA responses observed in patients in the ADA 
analysis set: 
 Pre-existing immunoreactivity, defined as either an ADA positive response in the 
dupilumab ADA assay at baseline with all post first dose ADA results negative, OR a 
positive response at baseline with all post first dose ADA responses less than 4-fold 
over baseline titer levels 
 Treatment-emergent response, defined as a positive response in the dupilumab ADA 
assay post first dose when baseline results are negative or missing  
 Treatment-boosted response, defined as a positive response in the dupilumab ADA 
assay post first dose that is greater than or equal to 4-fold over baseline titer levels, 
when baseline results are positive 
 Maximum Titer Values (Titer value category) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
The following summaries will be provided: 
 Number (%) of ADA-negative patients (pre-existing immunoreactivity or negative in 
the dupilumab ADA assay at all time points) 
 Number (%) of treatment-emergent ADA-positive patients 
 Number (%) of treatment-boosted ADA-positive patients 
Listing of all ADA titer levels will be provided for treatment-emergent and treatment-boosted 
ADA response patients. 
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5.10.2. 
Analysis of Neutralizing Antibodies (NAb) Data 
The absolute occurrence (n) and percent of patients (%) with NAb positive or negative status will 
be provided by treatment group for patients in the NAb analysis set.   
5.11. 
Analysis of Immunogenicity with Exposure, Safety and Efficacy 
5.11.1. 
Immunogenicity and Exposure 
Associations between ADA and systemic exposure to dupilumab will be explored. Plots of 
dupilumab concentration may be provided for analyzing the potential impact of treatment-
emergent ADA responses and titer (high, moderate or low) on PK.  
5.11.2. 
Immunogenicity and Safety and Efficacy 
Association between ADA and safety may be explored with a primary focus on the following 
safety events during the TEAE period:  
 
Injection site reaction (serious or severe and lasting 24 hours or longer) 
 
Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 
Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Association between ADA and primary efficacy endpoints may be explored (e.g. scatter plot or 
spaghetti plot).  
The above mentioned safety and efficacy analyses will be conducted using the following ADA 
response categories: 
 ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response, 
 ADA negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points 
 NAb positive patients, that is patients who were positive in the NAb assay at any time 
point analyzed.  
 Maximum post-baseline titer level in treatment emergent or treatment boosted ADA 
positive patients:  
 High,  
 Moderate,  
 Low 
5.12. 
Analysis of Biomarker Data 
All biomarker analyses will be performed on the FAS using all observed data. Descriptive 
statistics for the observed values, change from baseline and percent change from baseline values 
by treatment and visit will be provided for the biomarker variables. 
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The Wilcoxon signed-rank test will be used to test if the change or percentage change from 
baseline value is significantly different from zero. P-value will be reported. 
Exploratory analyses for the difference between dupilumab groups and placebo on the change 
from baseline and percent change from baseline values will be performed using a rank-based 
ANCOVA model with treatment group and the relevant baseline values as covariate.  Missing 
value will be imputed by LOCF method for visits between post-baseline to week 17.  After week 
17, no imputation will be made. P-value for difference between dupilumab +SCIT and SCIT will 
be provided. 
Correlation of baseline serum Timothy Grass sIgE, Timothy Grass specific IgG, sIgG4, TARC 
and total IgE, absolute change or percent change at weeks 4, 8, and 17 from baseline in these 
biomarkers; with the following clinical endpoints will be explored using the Spearman’s rho test.  
Both Spearman correlation coefficients and p-value will be reported. Correlation of baseline 
serum Timothy Grass sIgE, Timothy Grass specific IgG, sIgG4, TARC and total IgE with the 
following clinical endpoints will also be analyzed by the ANCOVA model with the clinical 
endpoint as the dependent variable and the baseline biomarker as the covariate, treatment group, 
and treatment group by baseline biomarker interaction as the factors. The missing values will be 
imputed using post-baseline LOCF. Similar correlation analysis will be performed for the 
subclasses of Timothy Grass sIgG other than sIgG4 pending on available data.  
 Change and percent change from baseline in TNSS AUC post NAC over the first 
hour after the challenge (0-1 hr post peak TNSS) at week 17 
 Change and percent change from baseline in TOSS AUC post NAC over the first 
hour after the challenge (0-1 hr post peak TNSS) at week 17 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in Skin Prick Test with Serial Allergen Titration, as measured by AUC of the 
average wheal sizes (diameter) after the challenge (early phase reaction) 
 Change and percent change from baseline (last pretreatment measurement) to 
week 17 in the wheal size (diameter) induced by skin Timothy Grass intradermal 
injection 6 hrs after the challenge (late phase reaction)  
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment of the study for all measurements will be the 
latest available valid measurement taken prior to the first administration of study drug.  If any 
randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization.  The baseline of TNSS is defined in Section 4.5.1.  
The following rules specify the determination of baseline by both date/time information: 
 For the AE, lab, PK and ADA data, both date and time of the measurement will be 
used to determine baseline by comparing with the first injection date and time. 
 For other data except AE, lab, PK or ADA, only date of the measurement will be used 
to determine baseline by comparing with the first injection date. 
For the rescreened patients, all data from the same patient will be used to derive baseline 
regardless if the data is from the screen-failure subject ID or enrolled subject ID. 
6.2. 
Data Handling Convention for Efficacy Variables  
Algorithm for calculation of area under curve (AUC) 
The AUC will be calculated using trapezoid rule. For example, the AUC within 1 hour will be 
calculated using  formula 
𝐴𝑈𝐶[0−1ℎ] = [∑(𝑡𝑖
5
𝑖=1
−𝑡𝑖−1) ∗(𝐷𝑖+ 𝐷𝑖−1)/2]/(𝑡5 −𝑡0) 
Where  
 Di is the TNSS value obtained at time ti 
 ti is the time (in hours) for which Di is measured, such as t0 = 0;t1 = 1/12 hour for 5 
minutes, t2 = 0.25 hour for 15 minutes, t3 = 0.5 hour for 30 minutes, t4 = 0.75 hour for 
45 minutes and t5 = 1 for 1 hour. 
In case of missing TNSS scores at one or more time points at a visit, all available TNSS scores 
collected at the visit will be used to calculate the AUC at the visit. The missing TNSS score at 
timepoints will not be imputed.  
For example, if there is one missing timepoint value within 1 hour, then the AUC within 1 hour 
at the visit will be calculated using the 5 available TNSS scores. These 5 scores will be 
numbered as D0, D1, D2, D3, D4, at timepoints t0, t1, t2, t2, t4, the AUC will be calculated as     
𝐴𝑈𝐶[0−1ℎ] = [∑(𝑡𝑖
4
𝑖=1
−𝑡𝑖−1) ∗(𝐷𝑖+ 𝐷𝑖−1)/2]/(𝑡4 −𝑡0) 
Data Handling Convention for Missing Data 
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Statistical Analysis Plan 
Date: 19June2019 
 
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Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 5.7.1  and Section 5.7.2.  
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAE.  If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation 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 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 the AE start month is the same as the first dose month) then impute 
AE start day using the day of first dose. If this leads to a date after the AE end date, use AE end 
date instead.  Otherwise impute the AE start day using the first day of the month.  If this leads to 
a date before informed consent, 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 less than the 
first dose year, use the informed consent day and month. If AE start year is equal to the first dose 
year, use the first dose day and month.  If this leads to a date after the AE end date, use AE end 
date instead. If AE start year is after the first dose year, use 01 January.  Imputation flag is ‘M’. 
If AE start year is missing:  Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date 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 starting date imputation, In order 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:  Impute AE end date 
using the last day of the month.  If this leads to a date after end of study follow up date, use end 
of follow up date instead. 
If AE end month is missing, and AE end year is not missing:  Impute AE end date using 
31 December as the day and month.  If this leads to a date after end of study follow up date, use 
the end of follow up date instead. 
If AE end year is missing:  Impute AE end date using the end of follow up date. 
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 listings. 
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Statistical Analysis Plan 
Date: 19June2019 
 
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Prior medication start date  
If start day is missing, and start month and year are not missing:  Impute the start day using the 
first day of the month.  Imputation flag is ‘D’; 
If start month is missing, and start year is not missing:  Impute the day and month using 
01 January.  Imputation flag is ‘M’. 
If start year is missing:  Impute start date using 2 years before inform consent date.  Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute.  However 
in order to simplify the programming flow, the imputation is proposed to in line with the 
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:  Impute end date using the last 
day of the month.  If this leads to a date on or after first dose intake date, use first dose intake 
date -1 instead.  Imputation flag is ‘D’. 
If end month is missing, and end year is not missing:  Impute end date using 31 December as the 
day and month.  If this leads to a date on or after first dose intake date, use first dose intake 
date -1 instead.  Imputation flag is ‘M’. 
If end year is missing:  Impute end date using the first dose intake date –1.  Imputation flag 
is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing:  Impute end date using the last 
day of the month.  If this leads to a date after end of study follow up date, use end of follow up 
date instead.  Imputation flag is ‘D’. 
If end month is missing, and end year is not missing:  Impute end date using 31 December as the 
day and month.  If this leads to a date after end of study follow up date, use the end of follow up 
date instead.  Imputation flag is ‘M’. 
If end year is missing:  Impute date using the end of follow up date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs.  However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
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6.3. 
Visit Windows 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, and ECG) will be 
summarized by the study scheduled visits described in the study protocol and SAP, “Schedule of 
Event”.  The analysis visit windows will be exhaustive so that all available values obtained from 
unscheduled visits, early termination (ET) visit and end of treatment (EOT)/end of study (EOS) 
have the potential to be summarized.  No analysis visit windows will be applied for the study 
scheduled visits. 
The following analysis visit windows will be used to map the unscheduled visits, ET and 
EOT/EOS visits, based on the study day: 
Visit 
Target Day 
Analysis Time Window 
Based on Study day* 
Screening 
<1 
<1 
Baseline 
1 
1 
Week 1 
8 
[2,11] 
Week 2 
15 
[12,18] 
Week 3 
22 
[19,25] 
Week 4 
29 
[26, 32] 
Week 5 
36 
[33, 39] 
Week 6 
43 
[40, 46] 
Week 7 
50 
[47, 53] 
Week 8 
57 
[54, 64] 
Week 10 
71 
[65, 81] 
Week 13 
92 
[82, 102] 
Week 16 
113 
[103, 116] 
Week 17 
120 
[117, 130] 
Week 20 
141 
[131, 155] 
Week 24 
169 
>=156 
*Study day is calculated relative to the date of first study drug injection. 
In general, the following order will be used to select the record for analysis at given visit: 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
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1. Scheduled visit 
2. Early termination (ET) or end of study (EOS), whichever comes first if scheduled visit 
not available  
3. Unscheduled visit if both scheduled visit and ET/EOT/EOS are not available 
For the multiple measurements of the same test in the same window, the following rules will be 
used to pick up the analysis value: 
 If multiple valid values of a variable within an analysis visit window, the closest from 
the target study day will be selected.  
 If the difference is a tie, the value after the targeted study day will be used.  
 If multiple available values of a variable exist within a same day, then the first value 
of the day will be selected. 
6.4. 
Unscheduled Assessments 
Both scheduled and unscheduled measurements will be considered for determining 
abnormal/PCSV values from laboratory, vital sign or ECG as well as the baseline values. 
 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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7. 
INTERIM ANALYSIS 
There is no interim analysis. 
 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 47 of 66 
9. 
REFERENCES 
ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and  content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for clinical 
trials (E9). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
 
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Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensiti
vity Statistical 
Method 
Subgroup 
Analysis 
TNSS 
percent change and absolute 
change from baseline in AUC 
for TNSS (0-1 hr post peak 
TNSS) at week 17 
ANCOVA model, missing data 
imputed by Multiple Imputation 
(MI) 
Yes  
Yes  
TOSS 
percent change and absolute 
change from baseline in AUC 
for TOSS (0-1 hr post peak 
TNSS) at week 17 
ANCOVA model, missing data 
imputed by Multiple Imputation 
(MI) 
No 
No 
Skin Prick Test with 
Serial Allergen 
Titration 
percent change and absolute 
change from baseline in AUC 
for wheal sizes (diameter) (0-1 
hr post peak TNSS) at week 17 
ANCOVA model, missing data 
imputed by Multiple Imputation 
(MI) 
No 
No 
skin Timothy Grass 
intradermal injection 
percent change and absolute 
change from baseline in wheal 
size (diameter) induced by skin 
Timothy Grass intradermal 
injection 6 hrs after the 
challenge) at week 17 
ANCOVA model, missing data 
imputed by Multiple Imputation 
(MI) 
No 
No 
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Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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Parameter(s) 
Endpoints 
Primary Statistical Method 
Supportive/Sensiti
vity Statistical 
Method 
Subgroup 
Analysis 
PNIF 
percent change and absolute 
change from baseline in PNIF 
AUC (0-1 hr post peak TNSS, 
and 1-6hr post peak TNSS) at 
week 17 
ANCOVA model, missing data 
imputed by Multiple Imputation 
(MI) 
No 
No 
sneeze count 
percent change and absolute 
change from baseline in sneeze 
count AUC (0-1 hr post peak 
TNSS, and 1-6hr post peak 
TNSS) at week 17 
ANCOVA model, missing data 
imputed by Multiple Imputation 
(MI) 
No 
No 
 
Safety Analyses: 
Endpoint 
Analysis Populations 
Statistical Method 
Supportive Analysis 
Subgroup Analysis 
Other Analyses 
Adverse Events 
SAF 
Descriptive statistics  
No 
Yes for selected AE 
summary 
No 
Laboratory 
Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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10.2. 
Schedule of Time and Events 
 
Schedule of Events – Screening, Baseline and Treatment Periods 
Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Screening/Bas
eline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Excl
usion 
X 
X 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
(R) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPT for 
Timothy Grass 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Timothy 
Grass sIgE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dupilumab/ 
PBO loading2 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dupilumab 300 
mg q 2 weeks 
dosing2, 3 
 
 
 
 
 
X 
---------------------------X-----------------------
--------  
 
 
X 
 
 
Visit for SCIT 
Injections4, 5, 
 
 
 
 
X 
X
5 
X 
X5 
X 
X5 
X 
X 
X5 
X 
X5 
 
 
X 
 
 
Premedicate 
with loratadine 
10 mg orally6 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Training for 
Self-injection 
(dupilumab/PB
O) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dupilumab/PB
O distribution 
 
 
 
X  
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Dupilumab/PB
O diary review/ 
Accountability7 
 
 
 
 
 
--------------------------------X--------------------------
--------  
 
 
X 
 
X 
Subject Dosing 
Diary8 
 
 
 
X  
 
X 
 
X 
 
X 
 
X 
X 
X  
 
 
 
X 
 
X 
Concomitant 
Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TNSS 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
X 
TOSS 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
PNIF 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Intradermal 
skin challenge 
testing (LPR) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Skin Prick Test 
with Serial 
Allergen 
Titration (EPR) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Safety:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
Examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Spirometry 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Peak expiratory 
flow9 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
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Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Laboratory 
Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Ab, 
HBsAg, 
HBcAb, Hep C 
Ab,  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Hematology, 
Chemistry 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy Test 
if indicated [in 
WOCBP] 
 
X1
4 
 
X1
5 
 
 
 
X1
5 
 
 
 
X1
5 
 
X1
5 
 
X15 
X1
5 
X15 
X14 X1
4 
Nasal mucosal 
brushing10 
 
X1
6 
X   
 
 
 
 
 
 
 
 
 
 
X1
7 
 
X 
 
 
 
X 
Nasal fluid 
collection 
 
  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
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Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Future 
Biomedical 
Research: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research 
serum11, 12 
 
 
X 
X 
 
X 
 
X  
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Research 
plasma11, 12 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
 
  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarker: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for 
basophil 
sensitivity 
assays, Th2A 
profiling and 
PBMC 
banking11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 56 of 66 
Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
 
SerumTARC11 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
Serum total 
IgE11 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Serum Timothy 
Grass sIgE11 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Serum Timothy 
Grass sIgG411 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Drug 
Concentration 
and ADA:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 57 of 66 
Study 
Procedure 
Screening 
Period 
 
Treatment Period 
 
 
 
 
 
V
1 
V
2 
NA
C 
V3 
R1 
V
4 
V
5 
V
6 
V
7 
V8 V9 
V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
 
V1
5 
EO
T 
NA
C 
V1
6 
V1
7 
Unschedu
led Visit 
(if 
applicabl
e)13 
EO
S 
V1
8 
E
T 
Week (W) 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
10 
13 
16 
17 
20 
 
24 
 
Study Day 
+1 to -84 
1 
8 
1
5 
22 29 
36 
43 
50 
57 
71 
92 
11
3 
120 
14
1 
 
169 
 
Window in 
Weeks 
±1 
 
-1 
±
1 
±
1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
 
±31
8 
 
Functional 
dupilumab 
PK11, 12 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
Anti-drug 
antibody11, 12 
(ADA) 
 
 
X 
 
 
  
 
  
 
 
 
  
 
  
 
X 
  
 
X 
X 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 58 of 66 
Footnotes for the Schedule of Events Table 
1. Randomization (V4) must occur within 2 weeks of NAC (V3) 
2. Dupilumab or placebo for dupilumab loading dose is given day of randomization.  
Subsequent dupilumab/placebo dosing is given Q2W.  
3. Dupilumab/placebo dosing must be given ±3 days of the visit window. 
4. SCIT/placebo should be given 1 to 7 days following dupilumab/placebo loading dose.  
Subsequent SCIT/placebo dosing follows dosing regimen as depicted in Table 2.  
5. During week 2, week 4, week 6, week 10, and week 16, when both dupilumab/placebo 
and SCIT/placebo are given in the same week, SCIT/placebo and dupilumab/placebo are 
NOT to be given on the same day (can be 1 day to 7 days apart) AND SCIT/placebo and 
dupilumab/placebo are to be given in a different anatomical location. 
6. For SCIT/placebo visits, subjects are to be premedicated with an antihistamine as 
described in the protocol Section 5.1.1.2  
7. Starting at visit 4, study drug will be dispensed to the subject for the dose that will be 
administered before the next dupilumab/placebo distribution visit.  Subjects will return 
the original kit box at each dupilumab/placebo distribution visit for accountability 
8. For subjects who choose to self-administer study drug, counsel subject on proper dosing 
diary completion/reporting of each dose of study drug that is administered outside of the 
study site 
9. Peak expiratory flow will be measured prior to NAC in any subject with a history of 
asthma.  Peak expiratory flow must be >80% predicted to perform the NAC in any 
subject with a history of asthma (please refer to the peak flow meter chart in the Study 
Operations Manual as a reference of predicted peak expiratory flow values) 
10. Collected 6 hours post NAC 
11. Collected pre-NAC 
12. Serum samples to be collected for ADA and PK assessments, prior to dosing of 
dupilumab at timepoints indicated in the Schedule of events 
13. Assessments and procedures at the unscheduled visit are to be performed at the discretion 
of the principal investigator 
14. Serum pregnancy test 
15. Urine pregnancy test 
16. Baseline nasal brushing and nasal brushing on study drug (which is performed at least 28 
days before the final NAC) will not be performed if they interfere with the subject’s 
timely completion of the study (prior to the onset of the subsequent allergy season) as 
outlined in the Study Operations Manual 
17. Should be performed approximately 28 days before the final NAC 
18. The visit should be conducted as close as possible to the designated study schedule date 
and the window for the days used only as needed.  
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 59 of 66 
10.3. 
Analyses of Efficacy Variables Criteria for Potentially Clinically 
Significant Values (PCSV) for Adult Patients 
 
Parameter 
Treatment Emergent 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 
Enzyme activity must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Each category is calculated 
independently. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. 
If it is desirable to get the distribution 
across the different PCSV levels, 
additional shift table on ≤3, >3 to ≤5, > 
5 to ≤10, >10 to ≤20, and > 20 category 
for baseline vs. post baseline may be 
provided  
AST* 
>3 and ≤ 5 ULN and baseline ≤ 3 
ULN* 
>5 and ≤ 10 ULN and baseline ≤ 5 
ULN 
>10 and ≤ 20 ULN and baseline ≤ 10 
ULN 
>20 ULN and baseline ≤ 20 ULN 
Enzyme activity 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. 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 60 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
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 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total Bilirubin 
and Total Bilirubin >1.5 ULN) and 
(Direct Bilirubin <=35% Total 
Bilirubin or Total Bilirubin 
<=1.5 ULN) at baseline 
Conjugated bilirubin dosed on a case-
by-case basis. 
ALT and Total 
Bilirubin 
(ALT>3 ULN and TBILI>2 ULN) and 
baseline (ALT <=3 ULN or TBILI 
<=2 ULN) 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 
3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* 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 ≤3, >3 to ≤10, and > 10 category for 
baseline vs. post baseline may be 
provided 
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  
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 61 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 μmol/L at 
baseline 
<120 μmol/L and >= 120 μmol/L at 
baseline 
Harrison- Principles of internal 
Medicine 17th Ed., 2008. 
Two independent criteria 
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L at 
baseline 
Two independent criteria 
Chloride 
Hypochloremia 
Hyperchloremia 
 
<80 mmol/L and baseline ≥ 80 
mmol/L  
>115 mmol/L and baseline ≤ 115 
mmol/L  
Two independent criteria  
Sodium 
Hyponatremia 
Hypernatremia 
 
≤129 mmol/L and baseline > 129 
mmol/L  
≥160 mmol/L and baseline <160 
mmol/L  
Two independent criteria 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 mmol/L  
≥5.5 mmol/L and baseline <5.5 
mmol/L  
FDA Feb 2005. 
Two independent criteria 
Total 
Cholesterol 
≥7.74 mmol/L and < 7.74 mmol/L at 
baseline 
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at 
baseline 
Threshold for therapeutic intervention. 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and (>3.9 
mmol/L or >=LLN) at baseline 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) and < 11.1 mmol/L 
(unfasted); <7 mmol/L (fasted) at 
baseline 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% and <= 8% at baseline 
 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 62 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
CRP 
>2 ULN or >10 mg/L (if ULN not 
provided) and 
<=2 ULN or <=10 mg/L (if ULN not 
provided) at baseline 
 FDA Sept 2005. 
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. 
 
 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>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. 
FDA criteria. 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline  
Basophils 
>0.1 Giga/L <= 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. 
 
 
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). 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 63 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
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 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L  
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for 
particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
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 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
Two independent criteria 
Vital signs 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
To be applied for all positions 
(including missing) except STANDING. 
SBP 
≤95 mmHg and decrease from 
baseline ≥20mmHg 
≥160 mmHg and increase from 
baseline ≥20 mmHg 
To be applied for all positions 
(including missing) except STANDING. 
DBP 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
≥110 mmHg and increase from 
baseline ≥10 mmHg 
To be applied for all positions 
(including missing) except STANDING. 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 64 of 66 
Parameter 
Treatment Emergent PCSV 
Comments 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
 
PR 
≥220 ms and increase from baseline 
≥20 ms 
 
QRS 
≥120 ms & < 120 ms at baseline 
 
QTc 
Borderline 
Prolonged* 
Additional 
Absolute values (ms)  
Borderline: 
 431-450 ms and < 431ms at baseline 
for Male; 451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to <500 ms and <= 450 ms at 
baseline for Male;  
 >470 to <500 ms and <= 470 ms at 
baseline for Female 
 ≥500 ms and < 500 ms at baseline 
 
Increase from baseline 
Borderline: Increase from baseline 30-
60 ms 
Prolonged: Increase from baseline >60 
ms 
To be applied to any kind of QT 
correction formula.  
 
 
 
*QTc prolonged and QTc>60 ms are 
the PCSA to be identified in individual 
subjects/patients listings. 
 
5 independent criteria 
 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 65 of 66 
10.4. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome 
 
AESI 
Search Criteria 
Anaphylactic reactions  
 
For SMQ “anaphylactic reaction” An algorithmic approach will 
be used. A case must include either:  
1. A narrow term (a term from Category A);  
2. Patient with both a term from Category B AND a term from 
Category C;  
3. Patient with a term from Category D AND { a term from 
Category B -  OR a term from Category C } 
For bullets 2 and 3, the search terms that are included under the 
SMQ for a particular event need to have the same start date (for 
e.g. if search shows cough (category B term) occurring at day 3 
and urticaria (category C term) occurring at day 7, this event is not 
adjudicated as anaphylactic reaction as this is inconsistent with the 
clinical presentation of anaphylaxis as an acute event with 
simultaneous involvement of 2 or more body systems. 
For SCIT anaphylactic reactions, only those with toxicity grade 3 
will be included into this category. 
Note:  manual adjudication of relevant PTs will be required by the 
study medical monitor, before database lock 
Systemic or severe 
hypersensitivity reactions  
 
Hypersensitivity: Narrow SMQ for hypersensitivity  
For systemic hypersensitivity, events in which 2 or more body 
systems are involved (as defined by System Organ Class) would 
be considered for adjudication based on further medical 
judgement 
For severe hypersensitivity, an additional search will be done; 
- HLT = Injection site reactions 
- Severity = “severe”  
The SCIT anaphylactic reactions will also be counted in this 
category regardless of toxicity grade. 
Note:  manual adjudication of relevant PTs will be required by the 
study medical monitor, before database lock 
Malignancy 
 SMQ “Malignant tumours” 
 SMQ “Tumours of unspecified malignancy” 
Helminthic infections2 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-ALG-16115 
Statistical Analysis Plan 
Date: 19June2019 
 
CONFIDENTIAL 
Page 66 of 66 
Suicidal behavior 
Include the following PTs 
 Completed suicide 
 Suicidal ideation 
 Suicide attempt 
 Depression suicidal 
 Suicidal behavior 
Any type of 
conjunctivitis or 
blepharitis (severe or 
serious) 
broad CMQ conjunctivitis (Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Atopic 
keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye 
pruritus, Lacrimation increased, Eye discharge, Foreign body 
sensation in eyes, Photophobia, Ocular hyperaemia, Conjunctival 
hyperaemia, Xerophthalmia) 
Blepharitis PTs (Blepharitis, blepharitis allergic) 
 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Note: manual adjudication of relevant PTs will be required by the 
study medical monitor, before database lock. 
Keratitis 
Any of the following PTs: 
a. Keratitis 
b. Allergic keratitis 
c. Ulcerative keratitis 
d. Atopic keratoconjunctivitis 
e. Herpes ophthalmic  
f. − Ophthalmic herpes simplex  
Note: manual adjudication of relevant PTs will be required by the 
study medical monitor, before database lock. 
The search criteria are meant to assist the process of identification of TEAE of Special 
Interest/TEAE Syndrome.  However, since these criteria might not be exhaustive in some cases 
or may not be specific in other cases. Hence an additional blinded review of all PTs in the 
database may be performed by the Medical monitor, based on medical judgement, to identify any 
TEAE of Special Interest/TEAE Syndrome that might have been missed by the criteria or to 
identify any TEAE may been inaccurately assigned as AESI by the algorithmic search. 
 
 
                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00


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                                        VV-RIM-00081352-1.0 Approved - 24 Jun 2019 GMT-5:00