Clinical trial NCT03793608
Conditions: Peanut Allergy
Sponsor: Regeneron Pharmaceuticals
Start date: 2019-03-12; Completion date: 2021-05-12
Enrollment: 25 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of the study is to assess the tolerability of peanut protein in pediatric patients (6-17 years old) treated with dupilumab monotherapy, in which tolerability is defined as the proportion of patients who safely pass a double-blind placebo-controlled food challenge (DBPCFC) at week 24.

The secondary objectives are:

* To determine whether dupilumab treatment improves peanut tolerability, defined as a change in the cumulative tolerated dose (log transformed) of peanut protein during a DBPCFC
* To evaluate the safety and tolerability of dupilumab treatment in peanut allergic patients
* To evaluate the effects of dupilumab treatment on the levels of peanut-specific Immunoglobulin E (IgE)
* To evaluate the treatment effect of dupilumab on the average wheal size after a titrated skin prick test (SPT), as measured by area under curve (AUC) of the average wheal size induced by peanut extract at different concentrations
* To assess the incidence of treatment-emergent anti-drug antibodies (ADA) to dupilumab in patients over time

Detailed description:

Arms: arm 1: Open label weight base subcutaneous (SC) injection every two (Q2) weeks.
Interventions: intervention 1: Dupilumab
Intervention descriptions: intervention 1: Dupilumab weight-based dosing will be administered subcutaneously (SC) in a single-use, pre-filled syringe every two weeks (Q2W)

Protocol documents:
SAP_002.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 58 
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 and Safety of Dupilumab Monotherapy in Pediatric Patients 
with Peanut Allergy 
Compound: 
Dupilumab (REGN668) 
Protocol Number: 
R668-ALG-1702 Amendment 2 
Clinical Phase:  
Phase 2 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
Clinical Trial Manager: 
Study Medical Director: 
Version/Date:  
Original Statistical Analysis Plan / March 3, 2021 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
CONFIDENTIAL 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
  
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
 
 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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TABLE OF CONTENTS 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objectives .......................................................................................................9 
1.2.2. 
Secondary Objectives ...................................................................................................9 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ..................................9 
1.2.4. 
Revision History for SAP Amendments .......................................................................9 
2. 
INVESTIGATION PLAN ..........................................................................................10 
2.1. 
Study Design and Randomization ..............................................................................10 
2.2. 
Statistical Hypothesis ..................................................................................................10 
2.3. 
Sample Size and Power Considerations .....................................................................10 
2.4. 
Study Plan ...................................................................................................................10 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
The Safety Analysis Set (SAF) ...................................................................................13 
3.2. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................14 
3.3. 
The Immunogenicity Analysis Set..............................................................................14 
3.4. 
Subgroups ...................................................................................................................14 
4. 
ANALYSIS VARIABLES .........................................................................................15 
4.1. 
Demographic and Baseline Characteristics ................................................................15 
4.2. 
Medical History ..........................................................................................................16 
4.3. 
Prior / Concomitant Medication and Procedures ........................................................16 
4.4. 
Rescue Medication/or Prohibited Medication During Study ......................................17 
4.5. 
Efficacy Variable ........................................................................................................18 
4.5.1. 
Primary Efficacy Variable (s) .....................................................................................18 
4.5.2. 
Secondary Efficacy Variable(s) ..................................................................................18 
4.5.3. 
Exploratory Efficacy Variable(s) ................................................................................19 
4.6. 
Safety Variables ..........................................................................................................20 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................20 
4.6.2. 
Adverse Events of Special Interest .............................................................................21 
4.6.3. 
Laboratory Safety Variables .......................................................................................21 
4.6.4. 
Vital Signs ..................................................................................................................23 
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Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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4.6.5. 
Body Weight and Height ............................................................................................23 
4.6.6. 
Physical Examination Variables .................................................................................23 
4.6.7. 
Spirometry ..................................................................................................................23 
4.7. 
Pharmacokinetic (PK) Variables ................................................................................23 
4.8. 
Anti-Drug Antibody Variable .....................................................................................24 
4.9. 
Pharmacodynamic and Biomarker Variables .............................................................25 
5. 
STATISTICAL METHODS .......................................................................................26 
5.1. 
Demographics and Baseline Characteristics ...............................................................26 
5.2. 
Medical History ..........................................................................................................26 
5.3. 
Prior and Concomitant Medications/Procedures ........................................................26 
5.4. 
Patient Disposition ......................................................................................................27 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................28 
5.5.1. 
Measurement of Compliance ......................................................................................28 
5.5.2. 
Exposure to Investigational Product ...........................................................................28 
5.6. 
Analyses of Efficacy Variables ..................................................................................29 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................29 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................29 
5.6.3. 
Analysis of Exploratory Efficacy Analysis ................................................................31 
5.6.4. 
Adjustment for Multiple Comparison .........................................................................31 
5.6.5. 
Subgroup Analysis ......................................................................................................31 
5.7. 
Analysis of Safety Data ..............................................................................................31 
5.7.1. 
Adverse Events ...........................................................................................................31 
5.7.2. 
Analysis of Adverse Events of Special Interest ..........................................................34 
5.7.3. 
Clinical Laboratory Measurements.............................................................................34 
5.7.4. 
Analysis of Vital Signs ...............................................................................................34 
5.7.5. 
Physical Exams ...........................................................................................................35 
5.7.6. 
Spirometry and Peak Expiratory Flow (PEF) .............................................................35 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................36 
5.9. 
Analysis of Immunogenicity Data ..............................................................................36 
5.9.1. 
Analysis of ADA Data ................................................................................................36 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb) Data ......................................................37 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................37 
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Date: March 3, 2021 
 
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5.10.1. 
Immunogenicity and Exposure ...................................................................................37 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................37 
5.11. 
Analysis of Biomarker Data .......................................................................................38 
6. 
DATA CONVENTIONS ............................................................................................39 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................39 
6.2. 
General Data Handling Conventions ..........................................................................39 
6.3. 
Data Handling Convention for Efficacy Variables .....................................................39 
6.4. 
Data Handling Convention for Missing Data .............................................................40 
6.5. 
Visit Windows ............................................................................................................42 
7. 
INTERIM ANALYSIS ...............................................................................................44 
8. 
SOFTWARE ...............................................................................................................45 
9. 
REFERENCES ...........................................................................................................46 
10. 
APPENDIX.................................................................................................................47 
10.1. 
Summary of Statistical Analyses ................................................................................47 
10.2. 
Schedule of Time and Events .....................................................................................49 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................53 
10.4. 
Adverse Event of Special Interest (AESI) ..................................................................57 
 
LIST OF TABLES 
Table 1 
Schedule of Events .....................................................................................................49 
 
LIST OF FIGURES 
Figure 1.  Schematic of Study Design .........................................................................................11 
 
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Date: March 3, 2021 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AD 
Atopic Dermatitis 
ADA 
Anti-Drug Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
BUN 
Blood urea nitrogen 
CoFAR 
Consortium of Food Allergy Research 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
DBPCFC 
Double-blind, placebo-controlled food challenge 
DLS 
Dose limiting symptom 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EoE 
Eosinophilic Esophagitis 
FAQLQ 
Food allergy quality of life questionnaire 
FDA 
Food and Drug Administration 
FeNO 
Fractional Exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume in 1 Second 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
Hep C Ab 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E 
IL-4 
Interleukin 4 
IL-4Rα 
Interleukin 4 Receptor Alpha 
IL-13 
Interleukin 13 
IM 
Intramuscular 
IL 
Interleukin 
IRB 
Institutional Review Board 
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Protocol: R668-ALG-1702 
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Date: March 3, 2021 
 
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IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing antibody 
OIT 
Oral immunotherapy 
PBMC 
Peripheral blood mononuclear cells 
PCSV 
Potentially clinically significant value 
PEFR/PEF 
Peak expiratory flow rate 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
PT 
Preferred term 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
sIgE 
Peanut-specific IgE 
SOC 
System organ class 
SPT 
Skin prick test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
WBC 
White blood cell 
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Date: March 3, 2021 
 
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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-1702 study. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned analyses. 
These revisions will be based on review of the study and data, and a final plan will be issued prior 
to data lock. 
1.1. 
Background/Rationale 
Food allergy is a potentially life-threatening condition that affects up to 8% of young children and 
3% to 5% of the entire United States (US) population (Gupta, 2011) (Sicherer, 2010) 
(Nwaru, 2014). Unlike many other childhood allergies, peanut allergy typically persists into 
adulthood and is associated with a higher incidence of severe anaphylaxis as compared with other 
food allergies (Dyer, 2015). The prevalence of peanut allergy by self-reports in US and European 
Union (EU) children varies from 1.2% to 2.0% (Dunlop, 2018). The current remedies for food 
allergy are food avoidance and treatment with medications such as injectable epinephrine for 
accidental exposures associated with severe allergic symptoms. Although recent progress has been 
made in the treatment of food allergy through allergen-specific oral immunotherapy (OIT), there 
is an unmet need for a new therapy in food allergy. (Jones, 2009) (Anagnostou, 2011) 
(Anagnostou, 2014). The aim of oral immunotherapy (OIT) is to induce desensitization and 
increase the threshold for peanut ingestion and reduce the risks of allergic reactions after accidental 
ingestion. However, many subjects in OIT trials continue to have side effects that can hinder their 
compliance and the overall efficacy of OIT. There is also a subsequent rapid loss of tolerance upon 
cessation of OIT (Vickery, 2014) (Wood, 2017). 
The immune system in the gut actively induces an immune tolerant state to the proteins that are 
normally consumed. Food allergy occurs when the body has a break in this tolerance, which results 
in an abnormal immune reaction to food. It is known that allergic response to food including peanut 
protein is an immunoglobulin E (IgE) mediated event; however, recent data suggest that 
interleukin (IL-4) and IL-13 may also play a significant role in food allergy pathogenesis.  
Dupilumab, a fully human VelocImmune-derived monoclonal antibody directed against 
interleukin-4 receptor alpha (IL-4Rα), blocks the activity of IL-4 and IL-13 and is approved as a 
treatment for atopic dermatitis (AD).  
This phase 2 proof-of-concept (POC) study will explore whether dupilumab has 
immunomodulatory effects on type 2 immune responses, which may result in improved safety and 
tolerance to peanut exposure as determined by the ability to tolerate a higher cumulative peanut 
protein dose level during a double-blind, placebo-controlled food challenge (DBPCFC) after 
24 weeks of monotherapy treatment. In addition, the study will evaluate whether dupilumab 
influences known biomarkers that are important in the allergic response to peanuts such as a 
reduction in allergen-specific IgE and/or increase in allergen-specific IgG4.  
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
The primary objective of this study is to assess the tolerability of peanut protein in pediatric 
patients (6 ot 17 years old) treated with dupilumab monotherapy, in which tolerability is defined 
as the proportion of patients who safely pass a double-blinded placebo-controlled food challenge 
(DBPCFC) at week 24. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study include: 
• To determine whether dupilumab treatment improves peanut tolerability, defined as a 
change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC (up to 2044 mg cumulative) 
• To evaluate the safety and tolerability of dupilumab treatment in peanut allergic 
patients 
• To evaluate the effects of dupilumab treatment on the levels of peanut-specific IgE, 
IgG, IgG4 and peanut-specific IgG4/sIgE ratio, and peanut-specific IgG/sIgE ratio 
• To evaluate the treatment effect of dupilumab on the average wheal size after a titrated 
skin prick test (SPT), as measured by area under the curve (AUC) of the average wheal 
size induced by peanut extract at different concentrations 
• To assess the incidence of treatment-emergent anti-drug antibodies (ADA) to 
dupilumab in patients over time 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
Modifications from protocol amendment 2: 
• Removed the FAS and week 36 FAS for efficacy analysis. This study design is an open-
label, single-arm study, and all patients receive study drug treatment. The SAF includes 
all patients who received any dupilumab that can be applied to either safety or efficacy 
endpoint; Also, the efficacy analyses at week 36 are based on SAF for patients who 
pass a DBPCFC of at least 444 mg (cumulative) of peanut challenge at week 24. 
• The primary analysis for primary and secondary endpoints will be analyzed using 
descriptive statistics instead of inferential statistics. Therfore, the p-value stated in the 
protocol will be removed from analysis. 
1.2.4. 
Revision History for SAP Amendments 
NA 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 2, multicenter, single-arm open-label POC study in pediatric patients aged 6 to 
17 years inclusive who are allergic to peanut, to evaluate the effects of dupilumab on tolerability 
of peanut protein during a DBPCFC. 
2.2. 
Statistical Hypothesis 
The statistical hypothesis is on the primary endpoint, the proportion of patients who achieve a 
cumulative dose of at least 444 mg peanut protein during a DBPCFC at week 24.  
Let μD be the true proportion of patients who achieve a cumulative dose of 444 mg peanut protein 
during a DBPCFC at week 24 for dupilumab. The following hypothesis will be tested at the 2-sided 
5% significance level:  
Null hypothesis H0: μD = 8%, ie, the proportion of patients who achieve a cumulative dose of 
444 mg peanut protein during a DBPCFC at week 24 is 8% (Vickery, 2018).  
Alternative hypothesis Ha: μD ≠ 8%, ie, the proportion of patients who achieve a cumulative dose 
of 444 mg peanut protein during a DBPCFC at week 24 is different from 8%. 
2.3. 
Sample Size and Power Considerations 
The sample size is determined to adequately power the primary endpoint of the proportion of 
patients who pass at least a DBPCFC of 444 mg (cumulative) of peanut protein at week 24. Based 
on assessment of clinical data from Aimmune Therapeutics AR101 phase 3 peanut OIT study 
(ARC003), it is assumed that the rate of a tolerated cumulative dose of at least 444 mg of peanut 
protein on DBPCFC at week 24 is 8% in placebo (Vickery, 2018) and 29% in dupilumab.  
A sample size of 20 patients will have 80% power to detect the 21% difference in tolerated rate at 
the 2-sided 5% significance level. Allowing for a dropout rate of around 15%, approximately 
24 patients will be required. The sample size calculations were done by one-sample Chi-square 
test (normal approximation) using nQuery + nTerim 4.  
2.4. 
Study Plan 
The study consists of 8-week screening period, 24-week open-label treatment period with 
dupilumab, followed by 12-week safety follow-up period (Figure 1). 
The Schedule of Events table is presented in Section 10.2. 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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Figure 1.  
Schematic of Study Design 
 
 
After obtaining informed consent/assent, patients will be assessed for eligibility during a 2-part 
screening period. During screening visit 1 (day -57 to day -43), patients will undergo a medical 
history, physical examination, spirometry, peanut SPT, and laboratory testing (including sIgE) and 
will be evaluated for the study eligibility criteria. During screening visit 1a, under direct study 
investigator monitoring, patients will undergo a DBPCFC to confirm current peanut allergy. This 
will consist of 5 doses of peanut protein with a dose given every 15 to 30 minutes in increasing 
amounts up to a cumulative total of 144 mg of peanut protein. Vital signs will be assessed every 
15 to 30 minutes. If the study team suspects a reaction may be developing, they may exercise their 
clinical judgment to separate doses by up to an additional 30 minutes (1 hour maximum between 
doses). The matching placebo challenge will consist of placebo material (oat protein) given also 
in 5 doses. The food challenges will be performed on different days (1 day placebo [oat] protein, 
1 day peanut protein, with order determined at random) at least 24 hours, but not more than 7 days, 
apart. The doses will be 1, 3, 10, 30, and 100 mg of peanut protein (or placebo). Both food 
challenge days (placebo and peanut) must be done to evaluate eligibility.  
Reactions during DBPCFCs will be scored using the Consortium of Food Allergy Research 
(CoFAR) grading system. The DBPCFC will be stopped when the blinded assessor finds 
symptoms and/or signs that indicate a definite objective allergic reaction has occurred based on 
clinically significant changes in reported symptoms, physical findings, or vital signs that the 
patient is experiencing to the challenge material. The patient will be observed for a minimum of 
2 hours after the final administered dose and discharged only when deemed clinically stable by a 
study physican. If the patient does not experience dose-limiting symptoms at or before the 100 mg 
challenge dose (≤144 mg cumulative) of peanut protein or if he/she experiences symptoms at any 
dose of placebo, he/she will not be enrolled in the study. Investigator/site personnel will be 
unblinded only to the results of the screening food challenge upon completion of the second part 
of the challenge to assess eligibility. A 2-week washout period is needed after the screening 
DBPCFC where peanut was given. All other on-study food challenges in the study will remain 
blinded to the clinic study team. 
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Patients with a history of confirmed peanut allergy signs and symptoms at screening who continue 
to meet eligibility criteria at baseline will be enrolled. Dupilumab will be dosed SC on day 1 at 
least 14 days after the screening DBPCFC and the dose will not be changed regardless of weight 
gain or loss: 
• Patients weighing ≥20 kg and <60 kg will receive dupilumab 200 mg Q2W following 
a loading dose of 400 mg on day 1 
• Patients weighing ≥60 kg will receive dupilumab 300 mg Q2W following a loading 
dose of 600 mg on day 1 
Study drug may be administered in the clinic on day 1 by the study team, patient’s caregiver, or 
patient. The last dose of study drug will be at week 22. For patients under 12 years of age, adult 
caregiver will need to administer the study drug injections. Patients will have monthly clinic visits 
and phone calls in-between visits to collect AEs, concomitant medications and compliance to study 
drug administration. 
At week 24, under intensive monitoring, all patients will undergo a DBPCFC up to 2044 mg peanut 
protein (cumulative) or placebo to assess tolerability.  
All patients who complete or prematurely discontinue the treatment will be assessed for safety, 
laboratory, and clinical assessments 12 weeks after the end of treatment. At the end of the 12-week 
follow-up period, patients who passed a DBPCFC of at least 444 mg (cumulative) at week 24 will 
undergo a final DBPCFC (up to 2044 mg cumulative), under intensive monitoring, at week 36 to 
assess the level of peanut sensitivity after 12 weeks off dupilumab to determine whether there is 
evidence of persistent effects and unresponsiveness.  
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Date: March 3, 2021 
 
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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 Safety Analysis Set (SAF) 
SAF 
includes 
all 
patients 
who 
received 
any 
dupilumab. 
Efficacy, 
treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF.  
Efficacy at week 36 (Subset of SAF at week 36) will be analyzed using SAF patients who pass a 
DBPCFC of at least 444 mg (cumulative) of peanut protein at week 24.  
For safety summaries, three analysis periods are defined as follows for SAF: 
• Treatment period is defined as  
− Day 1 to the date of second DBPCFC at week 24 EOT visit for those patients who 
completed week 24 visit with week 24 visit date present 
− Day 1 to the early terminiation (ET) visit date for those patients who early 
terminated before week 24 visit 
• Follow-up period is defined as  
− The day after the week 24 EOT visit date to the date of the end of study visit for 
those patients who completed week 24 visit with week 24 visit date present 
− The day after the ET visit date during treatment period to the date of the end of 
study visit for those patients who early terminated in the treatment period 
• Overall study period is defined as Day 1 to the date of the end of study visit. 
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Protocol: R668-ALG-1702 
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Date: March 3, 2021 
 
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3.2. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK population includes all treated patients who received any study drug and who had at least 
1 non-missing drug concetration result following the first dose of study drug. 
3.3. 
The Immunogenicity Analysis Set  
The ADA analysis set consists of all patients who received any study drug and who had at least 1 
non-missing ADA result following the first dose of study drug. 
The NAb analysis set (NAS) includes all patients who received any study drug and who are 
negative in the ADA assay or with at least 1 non-missing result in the NAb assay (patients who 
are ADA negative are set to negative in the NAb analysis set). 
3.4. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as follows. 
Subgroups to be considered for both efficacy and safety analyses: 
• Age group (>=6 to <12 years, >=12 to <=17 years)  
• Sex (Male, Female) 
• Screening peanut-specific IgE level (≤100 kUA/L, >100 kUA/L)  
• Baseline body weight (≥20 kg and <60 kg, ≥60 kg) 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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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 group (≥6 to <12 years; ≥12 to ≤17 years)  
• Sex (Male, Female) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Pacific Islander, Other) 
• Ethnicity (Hispanic/Latino, Not Hispanic or Latino) 
• Baseline weight (kg) 
• Baseline weight category (≥20 kg and <60 kg, ≥ 60 kg) 
• Baseline height (m) 
• Baseline Body Mass Index (BMI) (kg/m2) 
• Baseline Characteristics variables 
• Duration of peanut allergy diagnosis (year) 
• Age at peanut allergy onset (year; <5, ≥5 and <10, ≥ 10 and ≤17) 
• Number of co-morbid atopic diseases (atopic dermatitis, asthma, nasal polyps, allergic 
rhinitis or eosinophilic esophagitis) 
• Baseline Fractional Exhaled Nitric Oxide (FeNO) value 
• Baseline Food Allergy Quality of Life Questionnaire (FAQLQ) score for different 
types of FAQLQ form 
• Screening serum peanut-specific IgE 
• Screening serum peanut-specific IgG4 
• Screening serum total IgE 
• Screening peanut-specific IgE/IgG4 ratio 
• Screening peanut-specific IgE level (≤100 kUA/L, >100 kUA/L) 
• Baseline predicted FEV1 (L) 
• Baseline percent predicted FEV1 (%) 
• Baseline predicted FVC (L) 
• Baseline percent predicted FVC (%) 
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• Maximum tolerated dose of peanut protein at screening DBPCFC 
• Use of epinephrine at screening DBPCFC (Yes, No) 
• Normalized mean peanut wheal diameter at screening SPT 
Note: Normalized mean peanut wheal diameter is defined by mean peanut wheal minus mean 
saline wheal.  
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®) by coding CRO. 
Conditions related to patient's allergic and atopic medical history include peanut allergy, atopic 
dermatitis, asthma, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, 
eosinophilic esophagitis, hives, contact dermatitis, egg allergy, milk allergy, tree nut allergy, fish 
allergy, shellfish allergy, wheat allergy, soy allergy, sesame or mustard seeds allergy, and other 
allergies (food, medications, animals, plants, mold, dust mite, etc.). 
Conditions related to patient's family allergic and atopic medical history include atopic dermatitis, 
asthma, allergic conjunctivitis, allergic rhinitis, chronic rhinosinusitis, nasal polyps, eosinophilic 
esophagitis, food allergy, hives, contact dermatitis, other allergies (medications, animals, plants, 
mold, dust, mite, etc.). 
4.3. 
Prior / Concomitant Medication and Procedures 
Medications/Procedures will be recorded from the day of informed consent/assent until the end-
of-study (EOS) 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). 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. 
Prior medications/procedures: medications taken or procedures performed prior to administration 
of the first dose of study drug. 
Concomitant medications/procedures (CMs/CPs): medications taken or procedures performed 
following the first dose of study drug through the EOS visit. This includes medications/procedures 
that were started before the study and are ongoing during the study. Furthermore, CMs/CPs will 
be categorized according to the analysis periods (as defined in Section 3.1): 
• CMs/CPs during the treatment period 
• CMs/CPs during the follow-up period 
Note: Medications/procedures taken during the treatment period and continued afterwards into 
follow-up period will be counted only once as CMs/CPs during the treatment period. 
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4.4. 
Rescue Medication/or Prohibited Medication During Study 
Prohibited concomitant medications/procedures 
Treatment with the following concomitant medications is prohibited during the study: 
• Treatment with a live (attenuated) vaccine (see protocol Section 8.7.1 for the list of 
vaccine) 
• Treatment with any agents known or likely to interact with epinephrine (e.g., beta 
blockers, ACE-inhibitors, tri-cyclic antidepressants, or other drugs) 
• Treatment with antihistamines within 5 days prior to screening and within 5 days prior 
to SPTs and day 1 of DBPCFCs 
The following concomitant procedures are prohibited during study participation: 
• Major elective surgical procedures 
Rescue Treatment (including both medications and procedures) 
The following concomitant treatments will require permanent study drug discontinuation: 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with immunodulating biologic agents, including anti-IgE 
• Treatment with allergen immunotherapy 
• Treatment with systemic (oral, IV, IM, SC) corticosteroids for a duration of more than 
5 continuous days, more than 15 days in total, or within 2 days prior to DBPCFCs 
The following concomitant treatments of allergic reactions will NOT require permanent study drug 
discontinuation: 
• IM or SC administration of epinephrine 
• Oral antihistamines 
• Short acting inhaled bronchodilators 
• Inhaled corticosteriods 
• Systemic (oral, IV, IM, SC) corticosteroids for a duration of less than 5 continuous 
days, less than 15 days in total, and at least 2 days prior to DBPCFCs 
Treatment of acute-allergic reactions will be categorized as follow, 
• Screening DBPCFC of peanut protein 
• Week 24 DBPCFC of peanut protein 
• Week 36 DBPCFC of peanut protein 
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. 
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4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable (s) 
The primary endpoint in this study is: 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 444 mg 
(cumulative) peanut protein at week 24 
Double-blind placebo-controlled food challenge (DBPCFC) 
At week 24, under intensive monitoring, all patients will undergo a DBPCFC up to 2044 mg peanut 
protein (cumulative) or placebo to assess tolerability. The patient’s sensitivity to peanut allergen 
is defined as the dose at which the patient experiences allergic reactions. All symptoms and signs 
will be evaluated and rated based on a standardized oral food challenge scoring system. Up-dosing 
during the DBPCFC will be stopped when the Principal Investigator (or designee) finds symptoms 
and/or signs that indicate a definite objective allergic reaction (CoFAR grading system) has 
occurred based on clinically significant changes in reported symptoms, physical findings, or vital 
signs that the patient is experiencing to the challenge material. Vtial signs will be measured every 
15 to 30 minutes. The DBPCFC will consist of 8 doses (peanut protein or placebo), with a dose 
given every 15 to 30 minutes: 1, 3, 10, 30, 100, 300, 600, and 1000 mg resulting in a total challenge 
of up to 2044 mg peanut protein (cumulative). The food challenges will be performed on different 
days (1 day placebo [oat] protein, 1 day peanut protein, with order determined at random) at least 
24 hours but not more than 7 days apart and not within 24 hours of a dose of study drug. Patients 
will be considered to have passed the DBPCFC if they do not experience any objective Grade 1 
reaction by the CoFAR garding system.  
Consortium of Food Allergy Research (CoFAR) Grading System 
The CoFAR is a grading system based on clinically significant changes in reported symptoms, 
physical findings, or vital signs that the patient is experiencing to the challenge food material. The 
allergic reaction is measured on a 1-5 scale, with grade 1 being mild, grade 2 being moderate, 
grade 3 being severe, grade 4 being life threatening, and grade 5 as death.  
4.5.2. 
Secondary Efficacy Variable(s) 
The secondary efficacy endpoints include: 
• Change in the cumulative tolerated dose (log transformed) mg of peanut protein during 
a DBPCFC from baseline to measured DBPCFC visits at weeks 24 and 36 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 444 mg 
(cumulative) peanut protein at week 36 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
1044 mg (cumulative) peanut protein at weeks 24 and 36 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
2044 mg (cumulative) peanut protein at weeks 24 and 36 
• Percent change from baseline in sIgE to post-baseline visits (weeks 4, 8, 12, 24, and 
36) 
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• Change from baseline in titrated SPT at week 4, 12, 24, 36 as measured by the average 
wheal size AUC after peanut allergen stimulation at different concentrations 
• Proportion of patients with Grade II or above allergic reactions during the DBPCFC at 
week 24 
• Proportion of patients using epinephrine as a rescue medication during the DBPCFC at 
week 24 
Titrated Skin Prick Test (SPT) 
The titrated SPT is the skin testing for atopic response at different concentrations of peanut extract 
with saline as negative control and histamine as positive controls. The SPTs will be performed 
starting at the following dilutions: neat, 1:20, 1:200, 1:2,000, 1:20,000. Wheal size induced by 
peanut extract at each concentration will be calculated as the average of the largest diameter and 
the perpendicular midpoint diameter.  
The formula used to calculate the average wheal diameter at each concentration described in 
Section 6.3. 
4.5.3. 
Exploratory Efficacy Variable(s) 
• Change from baseline in total FAQLQ score at week 12, week 24, and week 36 for 
different types of FAQLQ form 
• Change from baseline to week 12, week 24, and week 36 in peanut-specific IgE 
• Change and percent change from baseline to week 12, week 24 and week 36 in peanut-
specific IgG 
• Change and percent change from baseline to week 12, week 24 and week 36 in peanut-
specific IgG4 
• Change and percent change from baseline to week 12, week 24 and week 36 in peanut-
specific IgG4/sIgE ratio and sIgG/sIgE ratio 
• Change and percent change from baseline to week 12, week 24, and week 36 in 
basophil sensitivity to peanut allergen, as measured by EC50, which is the 
concentration of peanut protein required to achieve 50% of maximal basophil activation 
• Change and percent change from baseline to week 12, week 24, and week 36 in the 
frequency of peanut-specific T cell subsets (e.g. Th2A cell) 
Food Allergy Quality of Life Questionnaire 
The Food Allergy Quality of Life Questionnaire  (FAQLQ) is a validated food allergy-specific 
health-related quality of life (HRQL) questionnaire, which measures the impact of social and 
dietary limitations and assesses the emontional impact of these restrictions on the lives of patients. 
Patients self-report the impact of food allergy on HRQL using different forms of FAQLQ 
depending on their age; the child form (FAQLQ-CF) is used by patients aged 8 to 12 years and the 
teenager form (FAQLQ-TF) is used for patients aged 13 to 17 years. The parent form (FAQLQ-
PF) is a measure of children’s HRQL that is reported by parent proxy from child’s perspective and 
can be used for patients of ages 0 to 12 years. The FAQLQ will be administered to patients and, 
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when appropriate, parents at time points in Section 10.2. Patients will continue using the FAQLQ 
version first administered at baseline regardless of moving to the next age bracket. 
The number of questions and domains varies by questionnaire administered. Each question is 
scored based on a seven-point scale which ranges from 1 (minimal impairment in HRQL) to 
7 (maximal impairment in HRQL). The total score is the arithmetic average of all non-missing 
answers. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered a study 
drug, which may or may not have a causal relationship with the study drug. 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 wosening (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. 
A Serious Adverse Event is any untoward medical occurrence that at any dose results in death; 
is life-theratening; 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. 
Adverse events and serious adverse events will be collected from the time of informed 
consent/assent signed until the end of the study. However, allergic reactions to the DBPCFC during 
the screening phase, at endpoint challenges (at week 24 and 36) will be recorded since allergic 
signs and symptoms are expected to occur after exposure to allergen.  
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 the latest available version).  
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• 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 and treatment-emergent periods are defined as following: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment-emergent period is defined as the day from first dose of study drug to 
the end of the study. The treatment-emergent period includes the 24-week treatment 
period and follow-up period. 
The pre-treatment AE and treatment-emergent AE (TEAE) are defined as following: 
• Pre-treatment signs and symptoms (Pre-treatment AEs) are AEs that developed or 
worsened in severity during the pre-treatment period. 
• Treatment-emergent adverse events (TEAEs) are defined as those that are not present 
at baseline or represent the exacerbation of a pre-existing condition during the 
treatment period and follow-up period. 
4.6.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) for this study include the following: 
• Anaphylactic reactions 
• Systemic or extensive hypersensitivity reactions 
• Malignancy 
• Helminthic infections 
• Suicide-related events 
• Conjunctivitis (any type or etiology), keratitis or blepharitis (for all these AEs only 
events that are severe or serious or lasting ≥4 weeks will be reported as AESIs) 
Section 10.4 provides a list of AESIs search criteria. 
Anaphylaxis: is defined as a severe, potentially life-threatening systemic hypersensitivity reaction, 
characterized by being rapid in onset with life-threatening airway, breathing, or circulatory 
problems that is usually, though not always, associated with skin and mucosal changes.  
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: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Indirect 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] 
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 
For female patients of childbearing potential, a serum pregnancy test will be performed at 
screening and end of study visits. For other visits where a pregnancy test is scheduled, a urine 
pregnancy test will be performed. 
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4.6.4. 
Vital Signs 
The following vital signs parameters will be collected at predose at every in-clinic visit and the 
unscheduled visit or ET visit: 
• Respiratory rate (bpm) 
• Heart rate (bpm) 
• Sitting systolic and diastolic blood pressure (mmHg) 
• Body temperature (°C) with the measure method 
(oral/tympanic/axillary/rectal/temporal) 
During the DBPCFC, vital signs will be monitored every 15 to 30 minutes. After initial DBPCFC 
dose, only pulse and blood pressure need to be taken as part of safety monitoring.  
4.6.5. 
Body Weight and Height 
Body height is measured at the screening visit 1. Body weight is measured at the screening visit 1, 
and every in-clinic visit (except for screening visit 1a). 
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 screening visits (screening visit 1 and 
visit 1a), week 12, week 24, week 36 or ET visit. Physical examination is performed at each 
DBPCFC day.  
4.6.7. 
Spirometry 
A spirometer that meets the American Thoracic Society (TS) / European Respiratory Society 
(ERS) recommendations will be used to measure FEV1 and/or PEFR. During DBPCFC, 
spirometry should be performed before and after the challenge. FeNO should be done prior to 
spirometry. 
4.7. 
Pharmacokinetic (PK) Variables 
Concentration of functional dupilumab in serum at each time point, obtained prior to dosing, will 
be considered to be trough values (Ctrough.time point). 
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4.8. 
Anti-Drug Antibody Variable 
Anti-drug antibody (ADA) variables include ADA status, titer, NAb status, and timepoint/visit. 
Samples for ADA assessment will be collected at time points according to Section 10.2. Samples 
positive in the ADA assay will be further characterized for ADA titers and for the presence of NAb 
to dupilumab. 
Immunogenicity will be characterized by ADA responses and titers observed in patients. The ADA 
response and titer categories are defined as follows: 
• ADA Negative, defined as a negative response in the dupilumab ADA assay at all time 
points, regardless of any missing samples. 
• 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 of 
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. The treatment-
emergent responses will be further characterized as Persistent, Indeterminate or 
Transient.  
− Persistent Response: Treatment-emergent ADA positive response with two or more 
consecutive ADA positive sampling time points, separated by greater than 12-week 
period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response: Treatment-emergent ADA positive response with only the 
last collected sample positive in the ADA assay, regardless of any missing samples. 
− Transient Response: Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• 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) 
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4.9. 
Pharmacodynamic and Biomarker Variables 
Pharmacodynamic and biomarker variables are: 
• Serum TARC and total IgE 
• Peanut-specific IgE, IgG, IgG4 
• Titrated Skin Prick Test 
• Fractional Exhaled Nitric Oxide (FeNO) 
• Basophil sensitivity to peanut allergen (EC50) 
• Frequency of peanut specific Th2A cells  
Biomarker samples will be collected at time points according to according to Section 10.2. 
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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. 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for SAF. Listing of demographics 
and baseline characteristics will be presented. 
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT based on SAF. The table will be 
sorted by decreasing frequency of SOC followed by PT based on the overall incidence. Medical 
history will be listed based on the SAF. 
Subject allergic/atopic medical history and subject family allergic/atopic medical history will be 
summarized and listed. 
5.3. 
Prior and Concomitant Medications/Procedures  
Number and proportion of patients taking prior/concomitant medications, prohibited medications 
and rescue medications will be summarized for study total based on the SAF by ATC level 2 and 
ATC level 4, sorted by decreasing frequency of ATC level 2 and ATC level 4 based on the overall 
incidence. Patients will be counted only once for each medication class (ATC levels 2 and 4) linked 
to the medication. 
Number and proportion of patients taking prior/concomitant procedures will be summarized for 
study total based on the SAF, sorted by decreasing frequency of SOC and PT based on the overall 
incidence. Patients will be counted only once for each SOC and PT linked to the procedure. 
In addition, the summary of prior/concomitant medications/procedures will be performed for 
patients who were impacted by COVID-19 pandemic and not impacted by COVID-19 pandemic, 
respectively. The summary  will be performed for pre-, during, and post-COVID-19 periods for 
patients impacted by COVID-19 pandemic, if applicable.  
Number and proportion of patients taking at least one epinephrine for treatment of acute-allergic 
reactions will be summarized during the following periods, 
• Screening DBPCFCs of peanut protein 
• Week 24 DBPCFCs of peanut protein 
• Week 36 DBPCFCs of peanut protein 
Kaplan-Meier curves for time to first rescue treatment use will be created. 
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Listing of pre-treatment and concomitant medications will include generic name, ATC levels 2 
and 4, indication, the study day of onset (for medications started before treatment, the study day 
of onset = date of medication start – date of the first dose; for medication started on or after 
treatment, the study day of onset = date of medication start – date of the first dose + 1), the study 
day of medication end date, ongoing status, dose, frequency, and route.  
5.4. 
Patient Disposition 
The following summaries will be provided: 
• The total number of screened patients and the screen failure reasons including screen 
failure at visit 1 and visit 1a 
• The total number of enrolled patients 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study and the reasons for 
discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study treatment permanently and the 
reasons for discontinuation (including COVID-19 related reasons) 
The following listings will be provided: 
• Listing of patients disposition including: date of enrollment, date of first study drug 
injection, date of the last visit, completed study or discontinued by reason 
• Listing of patients enrolled but not treated, and treated but not enrolled 
• Listing of patients prematurely discontinued from the study or study treatment, along 
with reasons for discontinuation  
• A listing of protocol deviations will be provided 
Kaplan-Meier curve for time to withdraw from the study and from the study treatment will be 
created, respectively. 
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5.5. 
Extent of Study Treatment Exposure and Compliance 
5.5.1. 
Measurement of 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) x 100% 
where temporary dose discontinuation is ignored. 
Loading doses for the same patient will be counted as 1.  
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: <80%, and ≥80%. 
Listing of study drug compliance will be presented with study drug, study drug injection date/time, 
study day, injection location, kit number, whether or not the total dose is administered for each 
dose, and compliance rate. 
5.5.2. 
Exposure to Investigational Product 
The duration of treatment exposure during the study in day will be presented and is calculated as:  
(Date of last study drug injection – date of first study drug injection) + 14 days 
Note: the calculations are regardless of temporary dosing interruption.  
Summary of exposure to study drug will include the number of study drug administered and 
duration of exposure. The duration of exposure during the study will be summarized using number 
of patients, mean, SD, median, Q1, Q3, minimum and maximum.  
In addition, the duration of exposure to study drug will be summarized categorically by counts and 
percentages for each of the following categories as well: 
≥14 days , ≥28 days, ≥42 days, ≥56 days, ≥70 days, ≥84 days, ≥ 98 days, ≥112 days, ≥ 126 days, 
≥140 days, ≥154 days, and ≥168 days 
The duration of observation period during the study in day is calculated as: 
(Date of last visit – date of first study drug injection) + 1 day 
The duration of observation period will be summarized descriptively using number of patients, 
mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of patients with 
observation periods will be presented by specific time periods. The time periods of interest are 
specified as:  
<15 days, ≥15 days , ≥29 days, ≥43 days, ≥57 days, ≥71 days, ≥85 days, ≥ 99 days, ≥113 days, ≥ 
127 days, ≥141 days, ≥155 days, and ≥169 days 
Listing of dose administration will be presented with information on administration date/time, 
study day, locations of injections, kit number, and whether or not the total dose is administered for 
each dose will be presented.  
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5.6. 
Analyses of Efficacy Variables 
The primary efficacy analyses for all the efficacy endpoints will be conducted at week 24 using 
the SAF population. The continuous efficacy variables will be summarized using number of 
patients, mean, SD, minimum, median, Q1, Q3 and maximum. The categorical efficacy variable 
will be summarized using patient count and proportion. The analyses of efficacy variables are 
described in the subsections below and summarized in Section 10.1. 
5.6.1. 
Analysis of Primary Efficacy Variable 
The primary endpoint will be analyzed using descriptive statistics. Estimate of proportion and the 
2-sided 95% Clopper-Pearson confidence interval will be provided. The number and percentage 
of patients at each dose level for highest tolerated peanut protein dose at week 24 DBPCFC will 
also be summarized.  
Missing data for week 24 DBPCFC will be handled according to the reason for missingness as 
follows: 
• If a patient misses the week 24 DBPCFC due to COVID-19, the missing data will be 
imputed by multiple imputation (MI) method for 10 times utilizing available week 24 
DBPCFC data. The MI will utilize logistic regression method with baseline tolerated 
cumulative amount of peanut protein DBPCFC. 
• If a patient does not have available DBPCFC data at week 24 due to reasons not related 
to COVID-19, the patient will be considered as a non-responder at week 24. 
Each of complete datasets after the above steps will be summarized with estimated proportions 
and standard errors. The SAS MIANALYZE procedure will be used to generate valid statistical 
inferences by combining results using Rubin’s formula (Rubin, 1987). 
Supportive analysis of the primary endpoint will include an analysis of patients who have available 
week 24 DBPCFC of peanut protein. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
All secondary endpoints will be analyzed descriptively at given visits. SAF will be used for 
efficacy analysis at week 24, and subset of SAF at week 36 will be used for efficacy analysis at 
week 36.  
Continuous Endpoint at week 24 
The change from baseline to week 24 in the cumulative tolerated dose (log transformed) of peanut 
protein during a DBPCFC will be summarized descriptively. Estimate of change from baseline to 
week 24 and the 2-sided 95% confidence interval will be provided. If patients do not tolerate any 
dose level of peanut protein challenge, they will be assigned a cumulative tolerated dose of 1 mg 
prior to converting to the log scale.  
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Missing data for week 24 DBPCFC will be handled according to the reason for missingness as 
follows: 
• If a patient misses the week 24 DBPCFC due to COVID-19, the missing data will be 
imputed by MI method for 10 times utilizing available week 24 DBPCFC data. The MI 
will utilize logistic regression method with baseline tolerated cumulative amount of 
peanut protein DBPCFC. 
• If a patient does not have an available week 24 DBPCFC due to reasons not related to 
COVID-19, the baseline value at screening DBPCFC will be used to impute the missing 
week 24 DBPCFC data. 
Each of the complete datasets after the above steps will be summarized with estimated means and 
standard errors of change from baseline to week 24 in the cumulative tolerated dose (log 
transformed) of peanut protein. The SAS MIANALYZE procedure will be used to generate valid 
statistical inferences by combining results. 
Supportive analysis will include an analysis of patients who have available week 24 DBPCFC of 
peanut protein. 
Binary Endpoint at week 24 
For the below binary endpoints of passing a DBPCFC at week 24, the analysis and imputation 
methods will be similar to the primary analysis. 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
1044 mg (cumulative) peanut protein at week 24  
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
2044 mg (cumulative) peanut protein at week 24  
Proportion of patients with Grade II or above allergic reactions during the DBPCFC at week 24 
will summarized descriptively as well as proportion of patients using ephinephrine as a rescue 
medication during the DBPCFC at week 24. 
Continuous Endpoint at week 36 
Change in the cumulative tolerated dose (log transformed) mg of peanut protein during a DBPCFC 
from baseline to measured DBPCFC at week 36 will be summarized descriptively based on a 
subset of SAF at week 36. 
Binary Endpoints at Week 36 
Proportion of patients treated with dupilumab that pass a DBPCFC with at least 444 mg 
(cumulative) peanut protein at week 36 will be summarized descriptively based on a subset of SAF 
at week 36. Similar binary endpoints at week 36 will be summarized in a similar fashion. 
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5.6.3. 
Analysis of Exploratory Efficacy Analysis 
The analysis of other efficacy variables will be the same as the primary analysis described in 
Section 5.6.1 and Section 5.6.2.  
5.6.4. 
Adjustment for Multiple Comparison 
No adjustments for multiplicity for the secondary endpoints are planned for this study. 
5.6.5. 
Subgroup Analysis 
Subgroup analysis for the primary endpoint and the following secondary endpoints will be 
performed on the SAF. Subgroups are defined in the Section 3.4. 
• Change in the cumulative tolerated dose (log transformed) mg of peanut protein during 
a DBPCFC from baseline to measured DBPCFC visits at week 24 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
1044 mg (cumulative) peanut protein at week 24 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
2044 mg (cumulative) peanut protein at week 24 
The analysis method for the subgroup analysis will be the same as the primary analysis described 
in Section 5.6.1 and Section 5.6.2.  
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.1. 
The safety analysis will be based on the reported AEs and clinical laboratory evaluations, physical 
examination, vital signs and spirometry.  
Thresholds for treatment-emergent Potential Clinically Significant Values (PCSV) 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 baseline when determining treatment-emergent PCSV refers to the baseline value of 
the study. 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
5.7.1. 
Adverse Events  
The number and proportion of patients reporting TEAEs will be summarized for treatment period 
and follow-up period separately, as described in Section 3.1.  
AE incidence tables will be presented for the SAF as well as subgroups. Summary of TEAEs will 
present the number (n) and percentage (%) of patients experiencing an TEAE by SOC and PT, 
sorted by the decreasing frequency of SOC and PT. Multiple occurrences of AEs of the same PT 
(or SOC) in the same patient will be counted only once for that PT (or SOC). For AE tables 
presenting severity, the worst severity will be chosen for patients with multiple instances of the 
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same event. The denominator for computation of percentage is the number of patients for the 
corresponding analysis period as specified in Section 3.1. 
An overall summary of TEAEs will be provided with number and proportion of patients with any: 
• TEAE 
• Serious TEAE 
• TEAE/Serious TEAE leading to death 
• TEAE/Serious TEAE leading to permanent treatment discontinuation 
• Study drug related TEAE/serious TEAE 
• Maximum intensity for TEAE 
Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by primary SOC/PT 
− TEAEs by primary SOC/HLT/PT 
− TEAEs by PT 
− TEAEs by primary SOC/PT with incidence of PT ≥ 5% 
− TEAEs by severity and by primary SOC/PT 
− TEAEs related to study drug as assessed by the investigator by primary SOC/PT 
− Severe TEAEs by primary SOC/PT 
− Severe TEAEs related to study drug as assessed by the investigator by primary 
SOC/PT 
− TEAEs leading to permanent discontinuation of study treatment by primary 
SOC/PT 
• Serious TEAE 
− Serious TEAEs by primary SOC/PT 
− Serious TEAEs related to study drug as assessed by the investigator by primary 
SOC/PT 
− Time to first occurrence of serious TEAEs 
• Death by primary SOC/PT 
Number and proportion of patients reporting pre-treatment adverse events will be tabulated by 
primary SOC and PT. 
The number and proportion of patients with injection site reaction by PT will be summarized. 
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The number and proportion of TEAE per 100 patient-year will be tabulated by primary 
SOC/HLT/PT. The number of patients with at least one event per 100 patient-year will be 
calculated and summarized for the following: 
• TEAE by primary SOC/HLT/PT 
• Severe TEAE by primary SOC/HLT/PT 
• Serious TEAE by primary SOC/HLT/PT 
Listing of TEAEs, serious TEAEs, and TEAEs resulting in death and study drug discontinuation 
will be generated. The following variables will be included in the listing: 
• Patient ID 
• Age/sex/race 
• System Organ Class (SOC) 
• High Level Term (HLT) 
• Preferred Term (PT) 
• Verbatim Term 
• AE start date and end date/ongoing (including both calendar days and study days) 
• AE duration 
• Relationship of AE to study drug: Related or Not Related 
• Action taken with study drug: Dose not changed, Drug interrupted, Drug withdrawn, 
Not applicable, or Unknown 
• Severity: mild, moderate, or severe 
• Outcome: Fatal, Not recovered/not resolved, Recovered/resolved, Recovered/resolved 
with sequelae, Recovering/resolving, or Unknown 
• Impact by COVID-19 pandemic: Yes or No 
In addition, summary of adverse events will be categorized by the status of impact by COVID-19 
pandemic. For patients who were impacted by COVID-19 pandemic, the summary of adverse 
events will include overall summary of adverse event, TEAEs by SOC/PT, serious TEAEs by 
SOC/PT (if applicable), TEAEs of special interest (if applicable), TEAEs leading to 
discontinuation of study treatment by SOC/PT (if applicable). The summary of adverse events for 
patients who were not impacted by COVID-19 pandemic will be summarized similarly. The 
summary of adverse events will be performed for pre-, during-, and post-COVID-19 periods for 
patients impacted by COVID-19 pandemic, if applicable. 
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5.7.2. 
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, it will be summarized by AESI category only.  
The time to first AESIs (AESI by category) will be assessed by Kaplan-Meier estimates. Kaplan-
Meier curves will be provided. The time is defined as the date of first event – date of first dose + 
1. Patients without an event will be censored at the end of study visit.  
The number of anaphylactic reactions, the number and percentage of patients experiencing an 
anaphylactic reaction, the number and percentage of patients experiencing an anaphylactic reaction 
by maximum severity using the Muraro Grading Scale (Muraro 2007), the number of patients 
experiencing an anaphylactic reaction was an SAE, the number of patients experiencing an 
anaphylactic reaction that required use of epinephrine will be summarized during DBPCFCs. 
5.7.3. 
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 treatment-emergent PCSVs. This 
summary will be provided based on all patients in the SAF as well as in the subgroup 
of SAF patients who did not meet the PCSV criterion at baseline 
• 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 ranges, abnormal flag, treatment-emergent PCSV by 
patient, visit and the status of impact by COVID-19 pandemic will be provided. 
In addition, summaries of laboratory variables will be performed for patients who were impacted 
by COVID-19 pandemic and not impacted by COVID-19 pandemic, respectively. The summaries 
will be performed for pre-, during-, and post-COVID-19 periods for patients impacted by COVID-
19, if applicable. 
The graph of mean change and/or percent change from baseline value for lab parameters by visit 
will be provided. 
5.7.4. 
Analysis of Vital Signs 
Summaries of vital sign variables excluding measurements at each challenge level of DBPCFCs 
will include: 
• Descriptive statistics of vital sign variables and change from baseline by visit 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
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Summaries of vital sign variables (only systolic and diastolic blood pressure) at DBPCFCs of 
peanut protein at screening visit 1a, week 24 and week 36 will include: 
• Descriptive statistics of vital sign variables (only systolic and diastolic blood pressue) 
and change from pre-dose by challenge dose level 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
The number (n) and percentage (%) of patients with treatment-emergent PCSV will be 
summarized. This summary will be provided based on all patients in the SAF as well as in the 
subgroup of SAF patients who did not meet the PCSV criterion at baseline. 
Listings will be provided with flags indicating the treatment-emergent PCSVs and the status of 
impact by COVID-19 pandemic, depending on the data. 
In addition, summaries of vital signs will be performed for patients who were impacted by COVID-
19 pandemic and not impacted by COVID-19 pandemic, respectively. The summaries will be 
performed for pre-, during-, and post-COVID-19 period for patients impacted by COVID-19 
pandemic, if applicable. 
The graph of mean change and/or percent change from baseline value for vital sign parameters 
excluding measurements at DBPCFCs by visit will be provided. 
5.7.5. 
Physical Exams 
Shift tables based on baseline normal/abnormal status will be provided for assessments of each 
physical exam category and presented by visit. Only the physical examination on the second 
DBPCFC day at week 24 will be summarized in the shift table. 
5.7.6. 
Spirometry and Peak Expiratory Flow (PEF) 
Summaries of spirometry and PEF variables excluding measurement after DBPCFCs will include: 
• Descriptive statistics of spirometry and PEF variables and change from baseline by 
visit will be presented 
• Spaghetti plots of spirometry and PEF data will be displayed by visit 
Summaries of spirometry and PEF variables for pre- and post-DBPCFCs of peanut protein will 
include: 
• Descriptive statistics of spirometry and PEF variables and change from pre-dose will 
be presented 
• Bar plots of spirometry and PEF data will be displayed  
Summaries of spirometry and PEF variables for post-DBPCFCs of peanut protein by visit will 
include: 
• Descriptive statistics of spirometry and PEF variables and change from post-DBPCFC 
of peanut protein at screening visit 1a by visit will be presented 
• Bar plots of spirometry and PEF data will be displayed 
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Listing of spirometry and PEF data will be provided with flag indicating the status of impact by 
COVID-19 pandemic. 
In addition, summaries of spirometry and PEF will be performed for patients who were impacted 
by COVID-19 pandemic and not impacted by COVID-19 pandemic, respectively. The summaries 
will be performed for pre-, during, and post-COVID-19 periods for patients impacted by COVID-
19 pandemic, if applicable. 
5.8. 
Analysis of Pharmacokinetic Data 
The following analyses will be conducted: 
• Descriptive statistics of functional dupilumab concentrations in serum at each sampling 
time by dose 
• 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 
No formal statistical 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. 
5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA Data 
The immunogenicity variables described in Section 4.8 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA responses and titers observed in patients 
in the ADA analysis set.  
The following will be summarized by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative subjects (pre-existing immunoreactivity 
or negative in the dupilumab ADA assay at all time points) 
• Number (n) and percent (%) of treatment-emergent ADA-positive patients 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA-positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
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5.9.2. 
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. 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.1. 
Immunogenicity and Exposure 
Potential associations between immunogenicity variables and systemic exposure to dupilumab will 
be explored. Plots of individual dupilumab concentration may be provided for analyzing the 
potential impact of treatment-emergent ADA responses, titer (high, moderate or low) and NAb on 
PK profiles.  
5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• Injection site reaction (serious or severe and lasting 24 hours or longer) 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
• Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association between immunogenicity variables and primary efficacy endpoints may be 
explored (e.g. scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following 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 
• Patients with persistent treatment-emergent ADA response 
• NAb positive patients, that is patients who were positive in the NAb assay at any time 
point analyzed 
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• Maximum post-baseline titer level in treatment-emergent or treatment boosted ADA 
positive patients:  
− High,  
− Moderate,  
− Low 
5.11. 
Analysis of Biomarker Data 
All biomarker analyses will be performed on the SAF using all observed data. Descriptive statistics 
for the observed values, change from baseline and percent change from baseline values by visit 
will be provided for the biomarker variables as described in Section 4.9. 
The Wilcoxon signed-rank test will be used to test if the change or percent change from baseline 
value is significantly different from zero. P-value will be reported. 
Correlation of baseline biomarkers [including serum peanut sIgE, sIgG, sIgG4, total IgE, and 
basophil sensitivity to peanut allergen stimulation measured by EC50, frequency of peanut specific 
T-cell subsets (e.g. Th2A cells)], absolute change or percent change at week 24 and 36 from 
baseline in these biomarkers with the following continuous clinical endpoint will be explored using 
Spearman’s rho test. Both Spearman correlation coefficients and p-value will be reported. The 
correlation between post-baseline biomarkers and clinical outcome will only be evaluated at the 
same visit. 
• Change in the cumulative tolerated dose (log transformed) mg of peanut protein during 
a DBPCFC from baseline to measured DBPCFC visits at weeks 24 and 36 
Correlation of baseline biomarkers [including serum peanut sIgE, sIgG, sIgG4, total IgE, and 
basophil sensitivity to peanut allergen stimulation measured by EC50, frequency of peanut specific 
T-cell subsets (e.g. Th2A cells)] with the following binary clinical endpoints will also be explored 
using logistic model. The model will include the responder/non-responder of below clinical 
endpoint as the dependent variable and baseline biomarker as the predictor variable. Model 
coefficients and p-value will be provided to indicate significance of the correlation/association. 
• Proportion of patients treated with dupilumab that pass a DBPCFC with at least 444 mg 
(cumulative) peanut protein at week 24 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. The 
following rules specify the determination of baseline by both date/time information: 
• The date and time of first injection will be used to determine the baseline for the AE, 
lab, PK and ADA data. 
• Only the date of first injection will be used to determine the baseline for other data 
except the AE, lab, PK and ADA data. 
6.2. 
General Data Handling Conventions 
For the laboratory safety variables and biomarker data, if the data are below the lower limit of 
quantification (LLOQ)/limit of linearity, half the lower limit value (i.e., LLOQ/2) will be used for 
quantitative analyses. For data above the upper limit of quantification (ULOQ)/ limit of linearity, 
the upper limit value (i.e., ULOQ) will be used for quantitative analyses.  
6.3. 
Data Handling Convention for Efficacy Variables 
Algorithm for calculation of Area Under the Curve (AUC): 
The AUC for titrated SPT will be calculated using the trapezoidal rule. The AUC will be calculated 
using the formula: 
𝐴𝑈𝐶= [∑(𝑐𝑖
4
𝑖=1
−𝑐𝑖−1) ∗(𝐷𝑖+ 𝐷𝑖−1)/2] /(𝑐4 −𝑐0) 
 
where  
• 𝐷𝑖 is the normalized mean wheal at concentration 𝑐𝑖 
• 𝑐𝑖 is the concentration for which 𝐷𝑖 is measured, 𝑐0 =
1
20,000 , 𝑐1 =
1
2,000 , 𝑐2 =
1
200 , 𝑐3 =
1
20 , 𝑐4 = 1. 
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6.4. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Rules for handling missing data for primary and secondary efficacy variables are described in 
Section 4.5.1  and Section 4.5.2. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
Adverse event start date 
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will be indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and AE start month is the same as first dose month, then AE start day will 
be imputed using the day of first dose. If this leads to a date after the AE end date, AE end date 
will be used instead. If AE start year is the same as first dose year and AE start month different 
from first dose month, AE start day will be imputed using the first day of the month. If this leads 
to a date before informed consent date, the informed consent date will be used. Imputation flag is 
‘D’. 
If AE start month is missing, and AE start year is not missing: If AE start year is before the first 
dose year, the informed consent day and month will be used. If AE start year is the same as first 
dose year, the first dose day and month will be used. If this leads to a date after AE end date, AE 
end date will be used instead. If AE start year is after the first dose year, January 1st will be used. 
Imputation flag is ‘M’. 
If AE start year is missing: The date of first dose will be used. If this leads to a date after the AE 
end date, AE end date will be used instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for AE start date imputation, to carry through the logic for programming, the following 
intermediate step will be used. Afterwards, only the original character/numeric date recorded in 
CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: AE end date will be imputed 
using the last day of the month. If this leads to a date after end of study follow up date, the end of 
follow up date will be used instead. 
If AE end month is missing, and AE end year is not missing: AE end date will be imputed using 
December 31st as the day and month. If this leads to a date after end of study follow up date, the 
end of follow up date will be used instead.  
If AE end year is missing: AE end date will be imputed using end of follow up date. 
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Prior or concomitant medication 
Medication start and end date missing 
To determine whether a medication is prior medication or concomitant medication or both, the 
missing medication start date is estimated as early as possible, and the missing medication end 
date is estimated as late as possible. If the medication start date is missing, the onset day will not 
be calculated in medication listing.  
Prior medication start date 
If start day is missing, and start month and year are not missing: the start day will be imputed using 
the first day of the month. Imputation flag is ‘D’. 
If start month is missing, and start year is not missing: the day and month will be imputed using 
January 1st. Imputation flag is ‘M’. 
If start year is missing: the start date will be imputed using 2 years before informed consent date. 
Imputation flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, to 
simplify the programming flow, the imputation is proposed to align with protocol which specifices 
to collect up to 2 years prior medication. Since the start date of prior medication will not be used 
in any analysis, the rule will not impact the analysis result.  
Prior medication end date 
If end day is missing, and end month and year are not missing: the end date will be imputed using 
the last day of the month. If this leads to a date on or after first dose intake date, the first dose 
intake date – 1  will be used. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: the end date will be imputed using December 
31st as the day and month. If this leads to a date on or after first dose intake date, the first dose 
intake date – 1 will be used instead. Imputation flag is ‘M’. 
If end year is missing: the end date will be imputed using the first dose intake date – 1. Imputation 
flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: the end date will be imputed using 
the last day of the month. If this leads to a date after end of study follow up date, the end of follow 
up date will be used. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: the end date will be imputed using December 
31st as the day and month. If this leads to a date after end of study follow up date, the end of follow 
up date will be used instead. Imputation flag is ‘M’. 
If end year is missing: the end date will be imputed using the end of follow up date. Imputation 
flag is ‘Y’. 
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Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC 2 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. 
6.5. 
Visit Windows 
Data analyzed by-visit-analysis (including efficacy, laboratory data, vital sign and 
spirometry/PEF) 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 and early termination (ET) visit 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 and ET visits, 
based on the study day: 
Visit 
Target Day (TD) 
Analysis Time Window Based on 
Study Day* 
Screening 1 
-57 to -43 
-57 to -43 
Screening 1a 
-42 to -15 
-42 to -15 
Baseline 
1 
1 
Visit 3 (Week 2)  
15 
[2, 22] 
Visit 4 (Week 4)  
29 
[23, 36] 
Visit 5 (Week 6)  
43 
[37, 50] 
 Visit 6 (Week 8) 
57 
[51, 64] 
Visit 7 (Week 10) 
71 
[65, 78] 
Visit 8 (Week 12)  
85 
[79, 92] 
Visit 9 (Week 14)  
99 
[93, 106] 
 Visit 10 (Week 16) 
113 
[107, 120] 
Visit 11 (Week 18)  
127 
[121, 134] 
Visit 12 (Week 20)  
141 
[135, 148] 
Visit 13 (Week 22)  
155 
[149, 162] 
Visit 14 (Week 24)  
169 
[163, 176] 
Visit 15 (Week 30) 
211 
[177, 232] 
Visit 16 (Week 36) 
253 
≥233 
*Study day is calculated relative to the date of first study drug injection 
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In general, the following order will be used to select the record for analysis at give visit: 
1. Scheduled visit 
2. Early termination (ET) or end of study (EOS), whichever comes first if scheduled visit is 
not available 
3. Unscheduled visit if both scheduled visit and ET/EOT/EOS are not available 
For multiple measurements of the same test in the same window, the following rules will be used 
to select 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 target 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. 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
CONFIDENTIAL 
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7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
Data may be analyzed and reviewed internally by the sponsors. 
A primary analysis may be performed once all patients in the study have completed the 24-week 
treatment period (week 24 visit or earlier for those patients who are withdrawn prematurely from 
the study). If performed, this primary analysis will be considered as the final analysis for the 
primary endpoint and secondary efficacy endpoints up to week 24.  
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
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-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
CONFIDENTIAL 
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9. 
REFERENCES 
1. Anagnostou K, Clark A, King Y, et al. Efficacy and safety of high-dose peanut oral 
immunotherapy with factors predicting outcome. Clin Exp Allergy. 2011 Sep;41(9):1273-81. 
2. Anagnostou K, Islam S, King Y. Assessing the efficacy of oral immunotherapy for the 
desensitisation of peanut allergy in children (STOP II): a Phase 2 randomised controlled trial. 
Lancet 2014; 383 (9925), 1297-1304. 
3. Dunlop J, Keet C. Epidemiology of Food Allergy. Immunol Allergy Clin North Am. 2018 Feb; 
38(1):13-25. 
4. Dyer AA. Epidemiology of Food. Allergy, Asthma Proc, 2015, 36:58-64. 
5. Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of 
childhood food allergy in the United States. Pediatrics 2011; 128, e9–e17. 
6. 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. 
7. 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. 
8. 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. 
9. Jones SM, Pons JL, Roberts AM, et al. Clinical efficacy and immune regulation with peanut 
oral immunotherapy. J Allergy Clin Immunol 2009; 124:292-300. 
10. Muraro A. Roberts G. Clark A. E, et al. The management of anaphylaxis in childhood: position 
paper of the European academy of allergology and clinical immunology. Allergy. 2007; 
62(8):857-871. 
11. Nwaru BI, Hickstein L, Panesar SS, et al. EAACI Food Allergy and Guidelines Group. 
Prevalence of common food allergies in Europe: a systemic review and meta-analysis. Allergy, 
2014; 69;992-1007. 
12. Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons Inc., 
New York. 
13. Sicherer SH, Munoz-Furlong A, Godbold JH, et al. US prevalence of self-reported peanut, tree 
nut, and sesame allergy: 11 year follow-up. JACI, 2010, 125:1322-6. 
14. Vickery BP, Vereda A, Casale TB, et al. AR101 Oral Immunotherapy for Peanut Allergy. N 
Engl J Med. 2018 Nov 22. doi: 10.1056/NEJMoa1812856. Epub 2018 Nov 18. 
15. Vickery BP, Scurlock AM, Kulis M. Sustained unresponsiveness to peanut in subjects who 
have completed peanut oral immunotherapy. JACI 2014; 133 (2), 468 - 475. 
16. Wood R. Oral Immunotherapy for Food Allergy. J Investig Allergol Clin Immunol 2017; 27(3) 
1-23. 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
CONFIDENTIAL 
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10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sensitivity 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Proportion of patients treated with 
dupilumab that pass a DBPCFC 
with at least 444 mg (cumulative) 
peanut protein at week 24 
SAF 
Descriptive statistics/missing data 
as non-responder 
Descriptive statistics with 
available week 24 data 
Yes  
Bar chart 
Secondary Endpoints 
Change in the cumulative tolerated 
dose (log transformed) mg of 
peanut protein during a DBPCFC 
from baseline to measured 
DBPCFC visits at week 24  
SAF 
Descriptive statistics/LOCF 
method 
Descriptive statistics with 
available week 24 data 
Yes 
Bar chart 
Change in the cumulative tolerated 
dose (log transformed) mg of 
peanut protein during a DBPCFC 
from baseline to measured 
DBPCFC visits at week 36 
Subset of SAF 
at week 36 
Descriptive statistics 
No 
No 
Bar chart 
Proportion of patients treated with 
dupilumab that pass a DBPCFC 
with at least 444 mg (cumulative) 
peanut protein at week 36 
Subset of SAF 
at week 36 
Descriptive statistics 
No 
No 
Bar chart 
Proportion of patients treated with 
dupilumab that pass a DBPCFC 
with at least 1044 mg (cumulative) 
peanut protein at week 24 
SAF 
Descriptive statistics/missing data 
as non-responder 
No 
Yes 
Bar chart 
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Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sensitivity 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Proportion of patients treated with 
dupilumab that pass a DBPCFC 
with at least 1044 mg (cumulative) 
peanut protein at week 36 
Subset of SAF 
at week 36 
Descriptive statistics 
No 
No 
Bar chart 
Proportion of patients treated with 
dupilumab that pass a DBPCFC 
with 2044 mg (cumulative) peanut 
protein at week 24 
SAF 
Descriptive statistics/missing data 
as non-responder 
No 
Yes 
Bar chart 
Proportion of patients treated with 
dupilumab that pass a DBPCFC 
with 2044 mg (cumulative) peanut 
protein at week 36 
Subset of SAF 
at week 36 
Descriptive statistics 
No 
No 
Bar chart 
 
Safety Analysis: 
 
Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sensitivity 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Adverse events 
SAF 
Descriptive Statistics and time-to-
event analysis 
No 
Yes, for selected 
AE summary 
No 
Laboratory measures 
SAF 
Desriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
Spirometry 
SAF 
Descriptive Statistics 
No 
No 
No 
 
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10.2. 
Schedule of Time and Events 
Table 1 
Schedule of Events 
Study Procedure 
Screening 
Treatment Period 
Follow-up 
UV 
ET 
Visit 
V1 
V1a 
V2 
Baseline 
V3 phone 
V4 clinic 
V5 phone 
V6 clinic 
V7 phone 
V8 clinic 
V9 phone 
V10 clinic 
V11 phone 
V12 clinic 
V13 phone 
EOT V14 
clinic 
V15 
EOS V16 
if applicable 
 
Day 
-57 
to 
 -43 
-42 
to 
 -15 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
211 
253 
 
Week 
 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 
36 
 
Visit Window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epi injection training 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on Study Drug 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study Drug 
Dispensation/Account 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Phone call to collect AEs, 
Conmeds and IP 
compliance  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Concomitant Meds and Tx 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Efficacy5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DBPCFC2, 3,4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X10 
 
 
Peanut SPT3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Titrated Peanut SPT3,7 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
FAQLQ  
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
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Statistical Analysis Plan 
 
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Study Procedure 
Screening 
Treatment Period 
Follow-up 
UV 
ET 
Visit 
V1 
V1a 
V2 
Baseline 
V3 phone 
V4 clinic 
V5 phone 
V6 clinic 
V7 phone 
V8 clinic 
V9 phone 
V10 clinic 
V11 phone 
V12 clinic 
V13 phone 
EOT V14 
clinic 
V15 
EOS V16 
if applicable 
 
Day 
-57 
to 
 -43 
-42 
to 
 -15 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
211 
253 
 
Week 
 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 
36 
 
Visit Window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Height5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Physical Examination5 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Spirometry6 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Adverse Events5 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Ab, HBsAg, HBcAb, 
Hep C Ab5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology/Chemistry5 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
FeNO Test6 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Pregnancy Test (WOCBP)5 
S 
U 
U 
 
U 
 
U 
 
U 
 
U 
 
U 
 
U 
U 
S 
 
U 
Urinalysis5 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Total IgE5 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Peanut sIgE, sIgG, and 
sIgG45 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
X 
Research Samples 
(serum/plasma)5 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Blood samples for 
additional exploratory5 
research7 
 
  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
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Statistical Analysis Plan 
 
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CONFIDENTIAL 
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Study Procedure 
Screening 
Treatment Period 
Follow-up 
UV 
ET 
Visit 
V1 
V1a 
V2 
Baseline 
V3 phone 
V4 clinic 
V5 phone 
V6 clinic 
V7 phone 
V8 clinic 
V9 phone 
V10 clinic 
V11 phone 
V12 clinic 
V13 phone 
EOT V14 
clinic 
V15 
EOS V16 
if applicable 
 
Day 
-57 
to 
 -43 
-42 
to 
 -15 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
211 
253 
 
Week 
 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 
36 
 
Visit Window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
PK/Drug Concentration 
and ADA Samples8: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Drug conc. sample 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
ADA sample 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Genomic DNA sample9: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Buccal swab samples for 
DNA  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WOCBP = women of childbearing potential 
Footnotes for the Schedule of Events Table 
1. Study drug will be administered in the clinic on day 1 by the study team, patient’s caregiver, or patient. With adequate training, 
study drug may be administered at home Q2W for the remaining injections. Patient/caregiver will complete an injection log to 
document compliance with injection of study drug and to document any AEs and concomitant medications. 
2. During DBPCFC, vital signs will be collected every 15 to 30 minutes. After initial DBPCFC dose, only pulse and blood pressure 
need to be taken as part of safety monitoring. 
3. Patients should not take antihistamines within 5 days prior to SPTs and day 1 of the DBPCFCs. 
4. The food challenges (DBPCFC) will be performed on different days (1 day placebo [oat] protein, 1 day peanut protein, with 
order determined at random) at least 24 hours, but no more than 7 days, apart and not within 24 hours of a dose of study drug. 
After the last dose of the DBPCFC, the patient will be monitored for at least 2 hours and then discharged from the clinic. 
5. Assessments will be performed before the administration of study drug. 
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6. FeNO measurement and spirometry will be performed on the same day, except for visit 1, in which only spirometry is performed. 
If the DBPCFC is scheduled on the day of the visit, then both FeNO measurement and spirometry will be performed twice before 
the patient goes home: once before DBPCFC, once after DBPCFC. FeNO should be done prior to spirometry. 
7.  On the day of the DBPCFCs, blood draws for exploratory research, including TruCulture, basophil sensitivity, and peripheral 
blood mononuclear cells (PBMC) samples will be performed before the DBPCFC is performed. On the day of the DBPCFC, 
titrated SPTs will be performed before the DBPCFC. 
8. Samples for PK and ADA analysis should be collected prior to drug administration. 
9. Two buccal swabs for genomic analysis can be collected on day 1 or any day after day 1. 
10. Only patients who passed a DBPCFC of at least 444 mg (cumulative) at week 24 will undergo a final DBPCFC (up to 2044 mg 
cumulative). 
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Statistical Analysis Plan 
 
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10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Parameter 
Treatment Emergent PCSV 
Comments 
Clinical 
Chemistry 
 
 
Alanine 
Aminotransferas
e  
(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. 
Aspartate 
Aminotransferas
e  
(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. 
Alkaline 
Phosphatase 
(ALP) 
>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. 
Bilirubin (BILI) 
>1.3 ULN and baseline ≤ 1.3 ULN 
 
Must be expressed in ULN, not in µmol/L or 
mg/L. 
Based on normal range: <1 mg/dL, CF = mg x 
1.7 = μmol 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Based on normal ranges: <6 mg/dL (Term 0-1 
day), <8 mg/dL (Term 1-2 days), <12 mg/dL 
(Term 3-5 days), <1 mg/dL (Term >5 days) 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total Bilirubin and 
Total Bilirubin >1.3 ULN) and (Direct 
Bilirubin ≤35% Total Bilirubin or Total 
Bilirubin ≤1.3 ULN) at baseline  
Conjugated bilirubin will be measured when 
the total Bilirubin is above the ULN 
Based on normal range: 0 to 0.4 mg/dL  
(ALT or AST) 
and Bilirubin 
(BILI) 
((ALT > 3 ULN or AST >3 ULN)) and BILI 
>2 ULN) and baseline ((ALT ≤3 ULN and 
AST ≤3 ULN) or BILI ≤2 ULN)  
Concept paper on DILI – FDA draft Guidance 
Oct 2007.  
Creatine Kinase  
(CK) 
>5 ULN and ≤10 ULN and baseline ≤5 ULN 
>10 ULN and baseline ≤10 ULN 
 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
Creatinine 
(CREAT) 
>=30% increase from individual patient 
baseline  
>=60% increase from individual patient 
baseline 
 
Urate (URATE) 
Hyperuricemia  
Hypouricemia 
>=30% increase from individual patient 
baseline 
>=60% increase from individual patient 
baseline 
 
Urea Nitrogen 
(UREAN) 
 
>=30% increase from individual patient 
baseline 
>=60% increase from individual patient 
baseline 
 
 
Chloride (CL) 
Hypochloremia 
Hyperchloremia 
<80 mmol/L and baseline ≥ 80 mmol/L  
>115 mmol/L and baseline ≤ 115 mmol/L 
 
Two independent criteria  
 
 
Sodium 
(SODIUM) 
Hyponatremia 
Hypernatremia 
<129 mmol/L and baseline ≥129 mmol/L 
>150 mmol/L and baseline ≤ 150 mmol/L 
 
Two independent criteria  
 
 
Potassium (K) 
Hypokalemia 
Hyperkalemia 
<3.5 mmol/L and baseline ≥ 3.5 mmol/L  
>5.0 mmol/L and baseline ≤ 5.0 mmol/L 
 
Two independent criteria 
 
Cholesterol 
(Cholesterol) 
>6.20 mmol/L and ≤ 6.20 mmol/L at 
baseline  
 
 
Triglycerides 
(TRIG) 
> 5.64 mmol/L and ≤ 5.64 mmol/L at 
baseline 
 
 
Threshold for therapeutic intervention with 
pharmacotherapy in children. (Expert Panel on 
Integrated Guidelines for Cardiovascular 
Health and Risk Reduction in Children and 
Adolescents; 2011). 
 
CF = g x 1.14 = mmol 
Glucose 
(GLUC) 
Hypoglycaemia 
Hyperglycaemia 
≤ 2.7 mmol/L  
≥10 mmol/L  
 
Albumin (ALB) 
<25 g/L and ≥25 g/L at baseline 
 
Calcium (CA) 
<2 mmol/L and baseline ≥2 mmol/L   
>2.9 mmol/L and baseline ≤2.9 mmol/L 
 
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Parameter 
Treatment Emergent PCSV 
Comments 
LDL 
Cholesterol 
(LDL) 
>4.91 mmol/L and ≤4.91 mmol/L at baseline 
 
 
Threshold for therapeutic intervention with 
pharmacotherapy in children 
(Expert Panel on Integrated Guidelines for 
Cardiovascular Health and Risk Reduction in 
Children and Adolescents; 2011). 
Hematology 
 
 
Leukocytes 
(WBC) 
<4.0 Giga/L and ≥4.0 Giga/L at baseline 
>13.5 Giga/L and ≤13.5 Giga/L at baseline   
 
Lymphocytes 
(LYM) 
<0.6 Giga/L and ≥0.6 Giga/L at baseline 
>6.0 Giga/L and ≤6.0 Giga/L at baseline  
 
Neutrophils 
(NEUT) 
<1.2 Giga/L and ≥1.2 Giga/L at baseline  
>ULN and baseline ≤ ULN  
 
Monocytes 
(MONO) 
>1.2 Giga/L and ≤ 1.2 Giga/L at baseline 
 
 
Basophils 
(BASO) 
>0.2 Giga/L 
 
Eosinophils 
(EOS) 
(>0.5 Giga/L and >ULN) and (≤ 0.5 Giga/L 
or ≤ ULN at baseline) 
Harrison- Principles of internal Medicine 17th 
Ed., 2008. 
Hemoglobin 
(HGB) 
<100 g/L and ≥100 g/L at baseline or any 
decrease ≥ 20 g/L 
>200 g/L and ≤200 g/L at baseline  
Two criteria are independent 
 
Hematocrit 
(HCT) 
<0.37 v/v and ≥ 0.37 v/v at baseline for 
Male; 
<0.33 v/v and ≥0.33 v/v at baseline for 
Female 
 
>0.52 v/v and ≤0.52 v/v at baseline for 
Male; 
>0.47 v/v and ≤0.47 v/v at baseline for 
Female 
Two criteria are independent 
 
Platelets 
(PLAT) 
<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 (PH) 
<5 or >8 
 
Ketones 
(KETONES) 
Ketonuria 
Presence and absence at baseline 
Semi-quantitative methods 
 
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Date: March 3, 2021 
 
CONFIDENTIAL 
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Parameter 
Treatment Emergent PCSV 
Comments 
Glucose 
(GLUC) 
Glycosuria 
Presence and absence at baseline 
Semi-quantitative methods 
 
Erythrocytes 
(RBC) 
Microscopic 
Hematuria 
> 5 RBCs/ HPF and ≤5 RBCs/ HPF at 
baseline 
 
Semi-quantitative methods 
 
Protein (PROT) 
Proteinuria 
≥ 1+ and <1+ at baseline 
 
Semi-quantitative methods, ≥ 1+ means 
concentration ≥30 mg/dL 
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 
≤90 mmHg and decrease from baseline ≥20 
mmHg 
≥119 mmHg and increase from baseline ≥20 
mmHg. 
 
DBP 
≤54 mmHg and decrease from baseline ≥10 
mmHg 
≥78 mmHg and increase from baseline ≥10 
mmHg 
 
Temperature 
Rectal, Tympanic: >100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary or skin infrared (temporal): >99 
°F/37.2 °C 
 
Respiratory rate 
< 12 per minute and ≥12 per minute at 
baseline 
>20 per minute and ≤20 per minute at 
baseline 
 
Weight 
≥5% weight loss from baseline  
 
Based on identification of trends in the child’s 
growth with a series of visits WHO 
Multicentre Reference Study Group, 2006; 
Center for Disease Control. Growth chart 
2007. 
 
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
CONFIDENTIAL 
Page 57 of 58 
10.4. 
Adverse Event of Special Interest (AESI) 
 
AESI 
Search Criteria 
Anaphylactic reactions  
 
SMQ narrow “Anaphylactic Reactions”  
Systemic hypersensitivity 
reactions  
 
Narrow SMQ for hypersensitivity  
Note: manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Malignancy 
Malignant tumours (SMQ) [Broad or Narrow] 
Helminthic infections 
• 
HLT = Cestode infections 
• 
HLT = Helminthic infections NEC 
• 
HLT = Nematode infections 
• 
HLT = Trematode infections 
Suicidal behavior 
Include the following PTs 
• 
Completed suicide 
• 
Suicidal ideation 
• 
Suicide attempt 
• 
Depression suicidal 
• 
Suicidal behaviour 
• 
Assisted Suicide 
Any type of conjunctivitis 
or blepharitis (severe or 
serious) 
Broad CMQ conjunctivitis PTs (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 (Bacterial blepharitis, blepharitis allergic) 
 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Keratitis 
CMQ Keratitis PTs: 
1. Allergic keratitis  2. Atopic keratoconjunctivitis  3. Diffuse lamellar 
keratitis  4. Exposure keratitis  5. Keratitis  6. Keratitis interstitial          
7. Keratitis sclerosing  8. Keratopathy  9. Keratorhexis  10. 
Keratouveitis  11. Neurotrophic keratopathy  12. Punctate keratitis 13. 
Superior limbic keratoconjunctivitis  14. Ulcerative keratitis  15. Vernal 
keratoconjunctivitis 16. Acanthamoeba keratitis 17. Infectious 
crystalline keratopathy 18. Infective Keratitis  19. Keratitis bacterial   
20. Keratitis fungal  21. Keratitis viral  22. Keratoconjunctivitis measles  
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Protocol: R668-ALG-1702 
Statistical Analysis Plan 
 
Date: March 3, 2021 
 
CONFIDENTIAL 
Page 58 of 58 
 
AESI 
Search Criteria 
23. Varicella keratitis  24. Viral keratouveitis  25.Corneal 
neovascularization  26. Limbal swelling  27. Corneal abrasion  28. 
Corneal abscess  29. Corneal bleeding   30. Corneal defect  31. Corneal 
disorder  32. Corneal epithelium defect    33. Corneal erosion  34. 
Corneal infection  35. Corneal irritation  36. Corneal lesion  37. Corneal 
leukoma  38. Corneal opacity   39. Corneal perforation  40. Corneal scar  
41. Infective corneal ulcer  42. Injury corneal 43. Limbal stem cell 
deficiency 
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 
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Prot_000.pdf: 
Clinical Study Protocol 
R668-ALG-1702 Amendment 2 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 1 of 75 
CONFIDENTIAL 
IND Number:  18263  
EudraCT Number:  2018-003133-15 
Regeneron Pharmaceuticals, Inc. 
 
Clinical Study Protocol 
 
A STUDY TO EVALUATE THE EFFICACY AND SAFETY OF 
DUPILUMAB MONOTHERAPY IN PEDIATRIC PATIENTS WITH 
PEANUT ALLERGY  
 
 
 
Compound: 
REGN668 (Dupilumab) 
 
 
Clinical Phase: 
2 
 
 
Protocol Number: 
R668-ALG-1702 
 
 
Protocol Version: 
R668-ALG-1702 Amendment 2 
Amendment 2 Date of Issue:  
See appended electronic signature page 
Amendment 1 Date of Issue:  
13 Dec 2019 
Original Date of Issue: 
21 Aug 2018 
 
 
Medical /Study Director: 
  
 
 Regeneron Pharmaceuticals, 
Inc. 
777 Old Saw Mill River Road  
Tarrytown, NY 10591 
 
 
 
 
 
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Clinical Study Protocol 
R668-ALG-1702 Amendment 2 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 75 
CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................8 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................20 
2. 
STUDY OBJECTIVES ..............................................................................................21 
2.1. 
Primary Objective .......................................................................................................21 
2.2. 
Secondary Objectives .................................................................................................21 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................21 
3.1. 
Hypothesis ..................................................................................................................21 
3.2. 
Rationale .....................................................................................................................21 
3.2.1. 
Rationale for Study Design .........................................................................................21 
3.2.2. 
Rationale for Dose Selection ......................................................................................22 
3.2.3. 
Rationale for Study Population ...................................................................................23 
3.3. 
Safety Considerations .................................................................................................23 
3.3.1. 
Risk Benefits for Dupilumab ......................................................................................23 
3.3.2. 
Risk for Peanut Protein ...............................................................................................24 
4. 
STUDY ENDPOINTS ................................................................................................25 
4.1. 
Primary and Secondary Endpoints..............................................................................25 
4.1.1. 
Primary Endpoint ........................................................................................................25 
4.1.2. 
Secondary Endpoints ..................................................................................................25 
5. 
STUDY VARIABLES................................................................................................25 
5.1. 
Demographic and Baseline Characteristics ................................................................25 
5.2. 
Efficacy Variables ......................................................................................................25 
5.3. 
Safety Variables ..........................................................................................................26 
5.4. 
Pharmacokinetic Variables .........................................................................................26 
5.5. 
Immunogenicity Variables ..........................................................................................26 
5.6. 
Pharmacodynamic and Biomarker Variables .............................................................26 
6. 
STUDY DESIGN .......................................................................................................27 
6.1. 
Study Description and Duration .................................................................................27 
6.1.1. 
End of Study Definition ..............................................................................................29 
6.1.2. 
Study Design Safety Considerations ..........................................................................30 
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CONFIDENTIAL 
6.1.3. 
Study Stopping Rules .................................................................................................31 
6.1.3.1. 
Individual Patient Stopping Rules (both study drug and food challenge) ..................31 
6.1.3.2. 
Anaphylaxis ................................................................................................................31 
6.2. 
Planned Interim Analysis ............................................................................................31 
6.3. 
Study Committees .......................................................................................................32 
6.3.1. 
Independent Data Monitoring Committee ..................................................................32 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............32 
7.1. 
Number of Patients Planned .......................................................................................32 
7.2. 
Study Population .........................................................................................................32 
7.2.1. 
Inclusion Criteria ........................................................................................................32 
7.2.2. 
Exclusion Criteria .......................................................................................................33 
7.3. 
Premature Withdrawal from the Study .......................................................................35 
7.4. 
Replacement of Patients .............................................................................................35 
8. 
STUDY TREATMENTS............................................................................................35 
8.1. 
Investigational and Reference Treatments ..................................................................35 
8.1.1. 
Peanut for Double-Blind Placebo-Controlled Food Challenge ..................................35 
8.2. 
Rescue Treatments ......................................................................................................35 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................36 
8.3.1. 
Dose Modification ......................................................................................................36 
8.3.2. 
Study Drug Discontinuation .......................................................................................36 
8.3.2.1. 
Reasons for Permanent Discontinuation of Dupilumab and Food Challenge ............36 
8.3.2.2. 
Reasons for Temporary Discontinuation of Dupilumab .............................................36 
8.4. 
Management of Acute Reactions ................................................................................37 
8.4.1. 
Acute Injection Reactions ...........................................................................................37 
8.4.1.1. 
Systemic Injection Reactions ......................................................................................37 
8.4.1.2. 
Local Injection Site Reactions ....................................................................................37 
8.5. 
Method of Treatment Assignment ..............................................................................37 
8.5.1. 
Blinding ......................................................................................................................38 
8.6. 
Treatment Logistics and Accountability .....................................................................38 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................38 
8.6.2. 
Supply and Disposition of Treatments .......................................................................38 
8.6.3. 
Treatment Accountability ...........................................................................................38 
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Clinical Study Protocol 
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CONFIDENTIAL 
8.6.4. 
Treatment Compliance ................................................................................................39 
8.7. 
Concomitant Medications and Procedures .................................................................39 
8.7.1. 
Prohibited Medications and Procedures .....................................................................39 
8.7.2. 
Permitted Medications ................................................................................................40 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................40 
9.1. 
Schedule of Events .....................................................................................................40 
9.1.1. 
Footnotes for the Schedule of Events Table ...............................................................44 
9.1.2. 
Early Termination Visit ..............................................................................................44 
9.1.3. 
Unscheduled Visits .....................................................................................................45 
9.2. 
Study Procedures ........................................................................................................45 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................45 
9.2.2. 
Efficacy Procedures ....................................................................................................45 
9.2.2.1. 
Double-Blind Placebo-Controlled Food Challenge ....................................................45 
9.2.2.2. 
Peanut Skin Prick Test ................................................................................................45 
9.2.2.3. 
Food Allergy Quality of Life Questionnaire ..............................................................46 
9.2.3. 
Safety Procedures .......................................................................................................46 
9.2.3.1. 
Vital Signs ..................................................................................................................46 
9.2.3.2. 
Physical Examination .................................................................................................46 
9.2.3.3. 
Spirometry ..................................................................................................................46 
9.2.3.4. 
Laboratory Testing ......................................................................................................46 
9.2.4. 
Drug Concentration and Measurements .....................................................................48 
9.2.5. 
Immunogenicity Measurements and Samples ............................................................48 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................48 
9.2.6.1. 
Serum Thymus and Activation-Regulated Chemokine and Total IgE .......................48 
9.2.6.2. 
Serum Peanut-Specific Antibody Assays (Peanut-specific IgE, IgG, IgG4) ..............48 
9.2.6.3. 
Fractional Exhaled Nitric Oxide .................................................................................49 
9.2.7. 
Exploratory Research ..................................................................................................49 
9.2.7.1. 
Genomics Analysis .....................................................................................................49 
10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................50 
10.1. 
Obligations of Investigator .........................................................................................50 
10.2. 
Obligations of Sponsor ...............................................................................................50 
10.3. 
Definitions ..................................................................................................................50 
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CONFIDENTIAL 
10.3.1. 
Adverse Event .............................................................................................................50 
10.3.2. 
Serious Adverse Event ................................................................................................50 
10.3.3. 
Adverse Events of Special Interest .............................................................................51 
10.4. 
Recording and Reporting Adverse Events ..................................................................51 
10.4.1. 
Adverse Events ...........................................................................................................51 
10.4.2. 
Serious Adverse Events ..............................................................................................51 
10.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................52 
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................52 
10.4.5. 
Abnormal Laboratory, Vital Signs Results .................................................................53 
10.4.6. 
Follow-up ....................................................................................................................53 
10.5. 
Evaluation of Severity and Causality .........................................................................53 
10.5.1. 
Evaluation of Severity ................................................................................................53 
10.5.2. 
Evaluation of Causality ...............................................................................................54 
10.6. 
Safety Monitoring .......................................................................................................55 
10.7. 
Investigator Alert Notification ....................................................................................55 
11. 
STATISTICAL PLAN................................................................................................55 
11.1. 
Statistical Hypothesis ..................................................................................................55 
11.2. 
Justification of Sample Size........................................................................................56 
11.3. 
Analysis Sets ...............................................................................................................56 
11.3.1. 
Efficacy Analysis Sets ................................................................................................56 
11.3.2. 
Safety Analysis Set .....................................................................................................56 
11.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................56 
11.3.4. 
Immunogenicity Analysis Sets ...................................................................................56 
11.4. 
Statistical Methods ......................................................................................................56 
11.4.1. 
Patient Disposition ......................................................................................................57 
11.4.2. 
Demography and Baseline Characteristics .................................................................57 
11.4.3. 
Efficacy Analyses .......................................................................................................57 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................57 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................57 
11.4.3.3. 
Multiplicity Considerations ........................................................................................58 
11.4.3.4. 
Timing of Analyses .....................................................................................................58 
11.4.4. 
Safety Analysis ...........................................................................................................58 
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CONFIDENTIAL 
11.4.4.1. 
Adverse Events ...........................................................................................................58 
11.4.4.2. 
Other Safety ................................................................................................................59 
11.4.4.3. 
Treatment Exposure ....................................................................................................59 
11.4.4.4. 
Treatment Compliance ................................................................................................60 
11.4.5. 
Analysis of Drug Concentration Data .........................................................................60 
11.4.6. 
Analysis of Immunogenicity Data ..............................................................................60 
11.4.7. 
Analysis of Pharmacodynamics Data .........................................................................60 
11.5. 
Additional Statistical Data Handling Conventions .....................................................61 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .........61 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
12.1. 
Data Management and Electronic Systems ................................................................62 
12.1.1. 
Data Management .......................................................................................................62 
12.1.2. 
Electronic Systems ......................................................................................................62 
13. 
STUDY MONITORING ............................................................................................62 
13.1. 
Monitoring of Study Sites ...........................................................................................62 
13.2. 
Source Document Requirements ................................................................................63 
13.3. 
Case Report Form Requirements ................................................................................63 
14. 
AUDITS AND INSPECTIONS .................................................................................63 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ..........................................64 
15.1. 
Good Clinical Practice Statement ...............................................................................64 
15.2. 
Assent and Informed Consent .....................................................................................64 
15.3. 
Patients Confidentiality and Data Protection ..............................................................65 
15.4. 
Institutional Review Board/Ethics Committee ...........................................................65 
15.5. 
Clinical Study Data Transparency ..............................................................................65 
16. 
PROTOCOL AMENDMENTS ..................................................................................65 
17. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ............................................................................................................................66 
17.1. 
Premature Termination of the Study ...........................................................................66 
17.2. 
Close-out of a Site ......................................................................................................66 
18. 
STUDY DOCUMENTATION ...................................................................................66 
18.1. 
Certification of Accuracy of Data ...............................................................................66 
18.2. 
Retention of Records ..................................................................................................66 
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Clinical Study Protocol 
R668-ALG-1702 Amendment 2 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 7 of 75 
CONFIDENTIAL 
19. 
DATA QUALITY ASSURANCE ..............................................................................67 
20. 
CONFIDENTIALITY ................................................................................................68 
21. 
FINANCING AND INSURANCE .............................................................................68 
22. 
PUBLICATION POLICY ..........................................................................................68 
23. 
REFERENCES ...........................................................................................................69 
24. 
INVESTIGATOR’S AGREEMENT ..........................................................................71 
 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................41 
 
LIST OF FIGURES 
Figure 1: 
Schematic of Study Design .........................................................................................27 
 
LIST OF APPENDICES 
APPENDIX 1. PEANUT DBPCFC SCHEDULE OF DOSING PERFORMED AT 
SCREENING AND WEEKS 24 AND 36..........................................................72 
APPENDIX 2. ALLERGY REACTION SEVERITY GRADING ............................................73 
APPENDIX 3. CRITERIA FOR SUSPECTED DIAGNOSIS AND SEVERITY 
GRADING OF ANAPHYLAXIS ......................................................................74 
 
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Page 8 of 75 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 2 
The purpose of this amendment is to revise the sample size of this study in order to expose the 
minimum number of patients to serial food challenges, thereby reducing the number of patients 
enrolled from 35 to 24. Other minor changes were made for clarification. A detailed list of 
changes and their rationales can be found in the table below.  
Change  
Rationale 
Section Changed  
The statistical hypothesis and sample 
size calculation were re-evaluated. It is 
now assumed that the rate of a tolerated 
cumulative dose of at least 444 mg of 
peanut protein on double-blind placebo-
controlled food challenge (DBPCFC) at 
week 24 is 29% in dupilumab and 8% in 
placebo, based on assessment of clinical 
data from the Aimmune Therapeutics 
AR101 phase 3 study. The number of 
patients enrolled was thus reduced from 
35 to 24. 
In order to expose the 
minimum number of 
patients to serial food 
challenges in this proof of 
mechanism study, the 
power analysis was 
re-evaluated. This allowed 
for enrollment of fewer 
patients to meet study 
endpoints. 
Clinical Study Protocol Synopsis: 
Population; Statistical Plan 
Section 3.2.1 Rationale for Study 
Design 
Figure 1 Schematic of Study Design 
Section 7.1 Number of Patients Planned 
Section 8.5 Method of Treatment 
Assignment 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample 
Size 
Clarified language pertaining to 
dupilumab prefilled syringes, packaging, 
and disposition of treatments. 
For clarification. 
Section 8.1 Investigational and 
Reference Treatments 
Section 8.6.1 Packaging, Labeling, and 
Storage 
Section 8.6.2 Supply and Disposition of 
Treatments 
Text was added to specify that, while this 
is an open-label study, the study team 
will remain blinded to the order of the 
exposure for each DBPCFC at weeks 24 
and 36. 
For clarification. 
Section 6.1 Study Description and 
Duration Appendix 1 Peanut DBPCFC 
Schedule of Dosing Performed at 
screening and weeks 24 and 36  
The text stating that no adjustments for 
multiplicity are planned was specified to 
be “for the secondary endpoints.”  
For clarification. 
Section 11.4.3.3 Multiplicity 
Considerations 
The word “tolerated” was changed to 
“passed” for the DBPCFC. 
For clarification. 
Clinical Study Protocol Synopsis: Study 
Design 
Section 6.1 Study Description and 
Duration 
Section 9.2.2.1 Double-Blind Placebo-
Controlled Food Challenge 
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Regeneron Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Change  
Rationale 
Section Changed  
Specified “at least” 444 mg in the 
description of passing the DBPCFC. 
For clarification. 
Clinical Study Protocol Synopsis: Study 
Design; Procedures and Assessments; 
Statistical Plan 
Section 3.2.1 Rationale for Study 
Design 
Section 6.1 Study Description and 
Duration 
Section 9.1.1 Footnotes for the 
Schedule of Events Table, #10  
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample 
Size 
Section 11.3.1 Efficacy Analysis Sets 
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Clinical Study Protocol 
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Regeneron Pharmaceuticals, Inc. 
 
Page 10 of 75 
CONFIDENTIAL 
Amendment 1 
The purpose of this amendment is to change the 2-arm placebo-controlled study design to single-
arm open-label and to remove the week 12 double-blind placebo-controlled food challenge 
(DBPCFC) as a means of increasing enrollment. Subsequent changes were made to the statistical 
analysis plan (SAP) based on this new study design. Changes were also made to align with the 
most recent dupilumab data. The following table outlines the changes made to the protocol and 
the affected sections: 
 
Change and Rationale for Change 
Section Changed  
This phase 2, multicenter, proof of concept (POC) study 
was amended from a 2-arm randomized double-blind study 
to a single-arm open-label study to increase enrollment. 
The rationale is that an open-label design in which all 
patients have access to dupilumab will decrease barriers to 
enrollment regarding concerns related to the risk of 
anaphylaxis in studying peanut protein tolerability in 
pediatric patients with a history of peanut allergy. This is 
further justified by a low historical placebo effect in peanut 
allergy (less than 8%). 
Clinical Study Protocol Synopsis: Objectives; Study 
Design; Population; Treatments; Endpoints; Statistical 
Plan 
Section 2.1 Primary Objective 
Section 2.2 Secondary Objective 
Section 3.2.1 Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 4.1.1 Primary Endpoint 
Section 4.1.2 Secondary Endpoints 
Section 6.1 Study Description and Duration 
Figure 1 Schematic of Study Design 
Section 6.3  Study Committees 
Section 7.1  Number of Patients Planned 
Section 8.1 Investigational Reference Treatments  
Section 8.3.2.1 Reasons for Permanent Discontinuation 
of Dupilumab and Food Challenge 
Section 8.5 Method of Treatment Assignment 
Section 8.5.1 Blinding 
Table 1 Schedule of Events 
Section 10.2 Obligations of Sponsor 
Section 10.5.2 Evaluation of Causality 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.3 Analysis Sets 
Section 11.4 Statistical Methods 
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Page 11 of 75 
CONFIDENTIAL 
Change and Rationale for Change 
Section Changed  
The week 12 DBPCFC was removed, leaving only the 
DBPCFC at screening, week 24, and potentially at End 
of Study week 36. This prevents an IgE priming effect, 
and further reduces the burden on patients. 
Clinical Study Protocol Synopsis: Statistical Plan 
Section 3.2.1 Rationale for Study Design  
Section 4.1.1 Primary Endpoint 
Section 4.1.2 Secondary Endpoints 
Section 6.1 Study Description and Duration 
Figure 1 Schematic of Study Design 
Table 1  Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events, 
Footnote #1 
Section 10.4.1 Adverse Events 
Section 11.2 Justification of Sample Size 
Section 11.3 Analysis Sets 
Appendix 1 Peanut DBPCFC Schedule of Dosing 
Performed at Screening and Weeks 24 and 36 
The number of patients enrolled was changed to 35 in this 
single-arm study, instead of 48 (24 per group) in the prior 
2-arm study. This change was made because of changes 
in the study design. 
Clinical Study Protocol Synopsis: Population; Statistical 
Plan 
Section 7.1 Number of Patients Planned 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.3 Analysis Sets 
Section 11.4 Statistical Methods 
The dose regimen for this study was changed from 100 
mg every 2 weeks (Q2W) for patients weighing <30 kg, 
to 200 mg Q2W for patients weighing ≥20 kg and <60 
kg. This change was based on recent data from pediatric 
patients (6 to 12 years of age) with atopic dermatitis 
(AD). It was determined that 100 mg Q2W may be a 
suboptimal dose regimen for patients weighing ≥20 and 
<30 kg. 
Clinical Study Protocol Synopsis: Study Design 
Section 3.2.2  Rationale for Dose Selection 
Section 7.2.2 Exclusion Criteria #23 
Section 8.1 Investigational Reference Treatments 
 
Changes were made to expand the pool of patients who 
may be eligible for the study by decreasing the level of 
serum peanut specific IgE required for inclusion from 
≥24 kUA/L to ≥10 kUA/L and/or Skin Prick Test (SPT) 
to peanut of ≥10 mm to ≥8 mm. The previous criteria 
were too restrictive compared to similar peanut allergy 
studies and the change will still enroll only severely 
allergic patients who react to screening double-blind 
peanut challenge at ≤144 mg (cumulative). 
Section 3.2.3 Rationale for Study Population  
Section 7.2.1 Inclusion Criteria, #4 
Section 9.2.2.2 Peanut Skin Prick Test 
After day 1, patients or their caregivers may administer 
drug at home with adequate training. Additionally, 
phone visits will be used (for visit # 3, 5, 7, 9, 11 and 13) 
between clinic visits. These changes were made to 
increase enrollment by decreasing the burden of visits. 
Section 6.1 Study Description and Duration 
Table 1  Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events, 
Footnote # 1 
 
   
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CONFIDENTIAL 
Change and Rationale for Change 
Section Changed  
Post-treatment follow-up at week 36 is not optional if 
patients pass DBPCFC at week 24. This change is due to 
the smaller sample size. 
Section 6.1 Study Description and Duration 
 
DNA and research sample are no longer mandated for 
sites who have regulatory or IRB concerns. This change 
was made to comply with regulations in Canada. 
Table 1 Schedule of Events  
Section 9.2.7  Exploratory Research 
Section 9.2.7.1 Genomics Analysis 
The protocol was updated for accuracy to reflect that 
approximately 10 study sites will be used in the United 
States (US) and Canada (CAN), rather than the US and 
European Union (EU). 
Clinical Study Protocol Synopsis: Site Location(s) 
Section 7.1  Number of Patients Planned 
 
Minor changes have been made to align with the most 
recent Investigator’s Brochure for dupilumab, Edition 
13. 
Section 1 Introduction 
Section 3 Hypothesis and Rationale 
Section 3.3 Safety Considerations 
Section 3.3.1 Risk Benefits for Dupilumab 
Other minor changes have been made throughout for 
accuracy, clarity, and to correct errors in spelling or 
grammar. 
Section 5.5 Anti-Drug Antibody Variables 
Section 5.6 Pharmacodynamic and Biomarker Variables 
Section 6.2 Planned Interim Analysis  
Section 7.2.1 Inclusion Criteria 
Section 7.2 Study Population  
Section 8.7.1 Prohibited Medications and Procedures 
Table 1 Schedule of Events 
Section 9.1.1 Footnotes for the Schedule of Events, 
Footnotes # 2, 3, 6, 9 
Section 9.2.2.1 Double-Blind Placebo-Controlled Food 
Challenge  
Section 9.2.2.3 
Food 
Allergy 
Quality 
of 
Life 
Questionnaire 
Section 9.2.3.3 Spirometry 
Section 9.2.6  Pharmacodynamic and Exploratory
Biomarkers Procedures 
Section 9.2.6.3 Fractional Exhaled Nitric Oxide 
Section 10.3.2 Serious Adverse Event 
Section 10.4.3 Other Events that Require Accelerated 
Reporting to Sponsor 
Section 11.3.4 Immunogenicity Analysis Sets 
Section 11.4.6 Analysis of Immunogenicity Data 
Section 15.5 Clinical Study Data Transparency 
Section 23 References 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
Title 
A Study to Evaluate the Efficacy and Safety of Dupilumab Monotherapy in 
Pediatric Patients with Peanut Allergy 
Site Location(s) 
 
Principal Investigator 
Approximately 10 sites in the United States (US) and Canada (CAN).  
Objective(s) 
The primary objective of the study is to assess the tolerability of peanut 
protein in pediatric patients (6 to 17 years old) treated with dupilumab, in 
which tolerability is defined as the proportion of patients who safely pass a 
double-blind placebo-controlled food challenge (DBPCFC) at week 24. 
The secondary objectives are: 
 
To determine whether dupilumab treatment improves peanut 
tolerability, defined as a change in the cumulative tolerated dose 
(log transformed) of peanut protein during a DBPCFC (up to 2044 
mg cumulative)  
 
To evaluate the safety and tolerability of dupilumab treatment in 
peanut allergic patients 
 
To evaluate the effects of dupilumab treatment on the levels of 
peanut-specific IgE 
 
To evaluate the treatment effect of dupilumab on the average wheal 
size after a titrated skin prick test (SPT), as measured by area under 
curve (AUC) of the average wheal size induced by peanut extract 
at different concentrations 
 
To assess the incidence of treatment-emergent anti-drug antibodies 
(ADA) to dupilumab in patients over time 
Study Design 
This is a phase 2, multicenter, single-arm open-label proof-of-concept 
(POC) study in pediatric patients aged 6 to 17 years inclusive who are 
allergic to peanut, to evaluate the effects of dupilumab on allergenic 
tolerance to peanut protein during a DBPCFC. The study consists of an 8-
week screening period, a 24-week treatment period with dupilumab, 
followed by a 12-week safety follow-up period. 
Screening Period: During screening visit 1 (day -57 to day -43), patients 
will undergo a medical history, physical examination, spirometry, standard 
peanut skin prick test (SPT), and laboratory testing (including peanut-
specific IgE [sIgE]) and be evaluated for study eligibility criteria. During 
screening visit 1a (day -42 to day -15), under direct study investigator 
monitoring, patients will undergo a DBPCFC to confirm peanut allergy. 
This will consist of 5 doses (1, 3, 10, 30, and 100 mg) of peanut protein with 
a dose given every 15 to 30 minutes in increasing amounts up to a 
cumulative total of 144 mg of peanut protein. Vital signs will be assessed 
every 15 to 30 minutes. If the study team suspects a reaction may be 
developing, they may exercise their clinical judgment to separate doses by 
up to an additional 30 minutes (1 hour maximum between doses). The 
matching placebo challenge will consist of placebo material (artificially 
peanut flavored oat protein) given also in 5 doses (1, 3, 10, 30, and 100 mg). 
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Both peanut and oat protein will be concealed in a food that masks the taste. 
The food challenges will be performed on different days (1 day placebo [oat] 
protein, 1 day peanut protein, with order determined at random) at least 24 
hours, but not more than 7 days, apart. All food challenges will be performed 
under physician supervision. Only patients, who experience dose-limiting 
symptoms at or before the 100 mg challenge dose of peanut protein, will be 
enrolled in the study. 
Treatment Period: Dupilumab will be dosed subcutaneously (SC) as 
follows based on weight at enrollment and the dose will not be changed 
regardless of weight gain or loss: 
 
patients weighing ≥20 kg and <60 kg will receive dupilumab 200 mg 
Q2W following a loading dose of 400 mg on day 1  
 
patients weighing ≥60 kg will receive dupilumab 300 mg Q2W 
following a loading dose of 600 mg on day 1  
Study drug will be given in the study clinic on day 1 and then, with adequate 
training, study drug may be administered at home Q2W. Study drug can be 
administered in the clinic at patient’s request and Principle Investigator’s 
discretion.  
Patients will have monthly clinic visits and phone calls in-between visits to 
collect adverse events (AEs), concomitant medications and compliance to 
study drug administration.  
Double-Blind Placebo-Controlled Food Challenge: At week 24, under 
intensive monitoring, all patients will undergo a DBPCFC up to 2044 mg 
peanut protein (cumulative) or placebo to assess tolerability. The patient’s 
sensitivity to peanut allergen is defined as the dose at which the patient 
experiences allergic reactions. All symptoms and signs will be evaluated and 
rated based on a standardized oral food challenge scoring system. Up-dosing 
during the DBPCFC will be stopped when the Principal Investigator (or 
designee) finds symptoms and/or signs that indicate a definite objective 
allergic reaction (CoFAR grading system) has occurred based on clinically 
significant changes in reported symptoms, physical findings, or vital signs 
that the patient is experiencing to the challenge material. Vital signs will be 
assessed every 15 to 30 minutes. The DBPCFC will consist of 8 doses 
(peanut protein or placebo), with a dose given every 15 to 30 minutes: 1, 3, 
10, 30, 100, 300, 600 mg, and 1000 mg resulting in a total challenge of up 
to 2044 mg peanut protein (cumulative). Both peanut and oat protein will be 
concealed in a food that masks the taste. The food challenges will be 
performed on different days (1 day placebo [oat] protein, 1 day peanut 
protein, with order determined at random) at least 24 hours but not more 
than 7 days apart and not within 24 hours of a dose of study drug. Patients 
will be considered to have passed the DBPCFC if they do not experience 
any objective Grade 1 reaction by the CoFAR grading system. 
Follow-up Period: All patients who complete or prematurely discontinue 
the treatment will be assessed for safety, laboratory, and clinical assessments 
12 weeks after the end of treatment. At the end of the 12-week follow-up 
period, patients who passed a DBPCFC of at least 444 mg (cumulative) at 
week 24 will undergo a final DBPCFC (up to 2044 mg cumulative), under 
intensive monitoring, at week 36 to assess the level of peanut sensitivity 
after 12 weeks off dupilumab to determine whether there is evidence of 
persistent effects and sustained unresponsiveness. 
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Study Duration 
The duration of the study for a patient is approximately 36 weeks, excluding 
the screening period. 
End of Study Definition 
The end of study for this study is defined as the last visit of the last patient. 
Population 
 
 
Sample Size: 
Approximately 24 patients. 
 
Target Population: 
Male and female pediatric patients ages 6 to 17 years with a history of peanut 
allergy confirmed by peanut SPT, sIgE and by the amount of peanut protein 
(mg) safely ingested during a peanut DBPCFC. 
Treatment(s) 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab 
200 mg or 300 mg SC Q2W (weight based) following a loading dose of 400 
mg or 600 mg, respectively, on day 1. 
Endpoint(s) 
 
 
Primary: 
 
Proportion of patients treated with dupilumab that pass a DBPCFC with 
at least 444 mg (cumulative) peanut protein at week 24 
 
Secondary: 
 
Change in the cumulative tolerated dose (log transformed) mg of peanut 
protein during a DBPCFC from baseline to measured DBPCFC visits 
at weeks 24 and 36. 
 
Proportion of patients treated with dupilumab that pass a DBPCFC with 
at least 444 mg (cumulative) peanut protein at week 36. 
 
Proportion of patients treated with dupilumab that pass a DBPCFC with 
at least 1044 mg (cumulative) peanut protein at weeks 24 and 36. 
 
Proportion of patients treated with dupilumab that pass a DBPCFC with 
2044 mg (cumulative) peanut protein at weeks 24 and 36. 
 
Percent change from baseline in sIgE to post-baseline visits (weeks 4, 
8,12, 24, and 36) 
 
Change from baseline in titrated SPT at week 4, 12, 24, 36 as measured 
by the average wheal size AUC after peanut allergen stimulation at 
different concentrations. 
 
Proportion of patients with Grade II or above allergic reactions during 
the DBPCFC at week 24 
 
Proportion of patients using epinephrine as a rescue medication during 
the DBPCFC at week 24 
Procedures and Assessments 
The efficacy of dupilumab will be assessed by DBPCFC at week 24. Patients 
who passed a DBPCFC of at least 444 mg (cumulative) at week 24 will 
undergo a final DBPCFC (up to 2044 mg cumulative) at week 36. 
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Overall safety will be assessed by monitoring/evaluation of treatment-
emergent adverse events (TEAEs), physical examinations, pulse rate, and 
clinical safety laboratory tests at pre-specified time points. 
Statistical Plan 
Sample Size Considerations: The sample size is determined to adequately 
power the primary endpoint of the proportion of patients who pass at least a 
DBPCFC of 444 mg (cumulative) of peanut protein at week 24. Based on 
assessment of clinical data from Aimmune Therapeutics AR101 phase 3 
study, it is assumed that the rate of a tolerated cumulative dose of at least 
444 mg of peanut protein on DBPCFC at week 24 is 29% in dupilumab and 
8% in placebo. 
A sample size of 20 patients will have 80% power to detect the 29% 
tolerated rate in dupilumab group at the 2-sided 5% significance level. 
Allowing for a dropout rate of around 15%, approximately 24 patients will 
be required. The sample size calculations were done by one-sample 
Chi-square test (normal approximation) using nQuery + nTerim 4. 
Efficacy Analysis Set: The full analysis set (FAS) includes all enrolled 
patients. The week 36 FAS includes patients who pass a DBPCFC of at least 
444 mg (cumulative) of peanut protein at week 24.  
Safety Analysis Set: The safety analysis set (SAF) includes all patients who 
received any study drug; it is based on the treatment received (as treated).  
Treatment compliance/administration and all clinical safety variables will 
be analyzed using the SAF. 
Analysis Methods 
Primary Efficacy Analysis: The FAS will be used for the primary efficacy 
endpoint. The primary endpoint will be analyzed using one-sample Chi-
square test. Estimate of proportion, p-value, and the 2-sided 95% confidence 
interval will be provided. 
If a patient does not have available DBPCFC data at week 24, the patient 
will be considered as a non-responder regardless of reasons for missing data. 
Sensitivity analyses of the primary endpoint will include an analysis of the 
subset of patients with available week 24 DBPCFC. Other sensitivity 
analyses may be proposed in the statistical analysis plan (SAP). 
Subgroup analysis (eg, by dose group) will be performed. 
Secondary Efficacy Analysis: All secondary endpoints will be analyzed 
descriptively at given visits.  
FAS will be used for efficacy analysis at week 24, and week 36 FAS will be 
used for efficacy analysis at week 36. 
For binary endpoints, the analysis and imputation methods will be similar to 
the primary analysis. 
A one-sample t-test will be performed to assess the change from baseline to 
week 24 in the cumulative tolerated dose (log transformed) of peanut protein 
during a DBPCFC. Estimate of change from baseline to week 24, p-value, 
and the 2-sided 95% confidence interval will be provided. If the data is 
extremely skewed, nonparametric method may be applied. Details will be 
provided in the SAP. The missing data will be imputed by the last non-
missing DBPCFC assessment including baseline. 
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For other continuous endpoints, the analysis and imputation methods will be 
applied similarly. 
Sensitivity analysis will include an analysis based on the observed cases. 
Other sensitivity analysis may be proposed in the SAP. 
Safety Analysis: Safety analysis will be based on the SAF.  This includes 
reported TEAEs and other safety data (ie, clinical laboratory evaluations and 
vital signs results).  A descriptive summary of safety results will be 
presented. 
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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 
BUN 
Blood urea nitrogen 
CoFAR 
Consortium of Food Allergy Research 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CRO 
Contract research organization 
CRSwNP 
Chronic rhinosinusitis with nasal polyposis 
DBPCFC 
Double-blind, placebo-controlled food challenge 
DMC 
Data monitoring committee 
DLS 
Dose limiting symptom 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EoE 
Eosinophilic Esophagitis 
FAQLQ 
Food allergy quality of life questionnaire 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FeNO 
Fractional Exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume in 1 Second 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
Hep C Ab 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E 
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IL-4 
Interleukin 4 
IDMC 
Independent Data Monitoring Committee 
IL-4Rα 
Interleukin 4 Receptor Alpha 
IL-13 
Interleukin 13 
IM 
Intramuscular 
IL 
Interleukin 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NAb 
Neutralizing antibody 
OIT 
Oral immunotherapy 
PBMC 
Peripheral blood mononuclear cells 
PCSV 
Potentially clinically significant value 
PEFR/PEF 
Peak expiratory flow rate 
PK 
Pharmacokinetic 
POC 
Proof-of-concept 
PT 
Preferred term 
QW 
Weekly 
Q2W 
Every 2 weeks 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SC 
Subcutaneous 
SCORAD 
Scoring AD 
sIgE 
Peanut-specific IgE 
SOC 
System organ class 
SPT 
Skin prick test 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
Tx 
Treatment 
ULN 
Upper limit of normal 
WBC 
White blood cell 
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1. 
INTRODUCTION 
Food allergy is a potentially life-threatening condition that affects up to 8% of young children and 
3% to 5% of the entire United States (US) population (Gupta, 2011) (Sicherer, 2010) 
(Nwaru, 2014).  Unlike many other childhood allergies, peanut allergy typically persists into 
adulthood and is associated with a higher incidence of severe anaphylaxis as compared with other 
food allergies (Dyer, 2015).  The prevalence of peanut allergy by self-reports in US and European 
Union (EU) children varies from 1.2% to 2.0% (Dunlop, 2018). The current remedies for food 
allergy are food avoidance and treatment with medications such as injectable epinephrine for 
accidental exposures associated with severe allergic symptoms.  Although recent progress has been 
made in the treatment of food allergy through allergen-specific oral immunotherapy (OIT), there 
is an unmet need for a new therapy in food allergy (Jones, 2009) (Anagnostou, 2011) 
(Anagnostou, 2014). The aim of OIT is to induce desensitization and increase the threshold for 
peanut ingestion, and reduce the risks of allergic reactions after accidental ingestion. However, 
many patients in OIT trials continue to have side effects that can hinder their compliance and the 
overall efficacy of OIT. There is also a subsequent rapid loss of tolerance upon cessation of OIT 
(Vickery, 2014) (Wood, 2017).  
The immune system in the gut actively induces an immune tolerant state to the proteins that are 
normally consumed. Food allergy occurs when the body has a break in this tolerance, which results 
in an abnormal immune reaction to food. It is known that allergic response to food including peanut 
protein is an immunoglobulin E (IgE) mediated event; however, recent data suggest that 
interleukin (IL)-4 and IL-13 may also play a significant role in food allergy pathogenesis.  Cross-
linking of peanut-specific IgE (sIgE) bound to high affinity IgE receptors on mast cells and 
basophils triggers immediate degranulation. Subsequent release of a diverse array of inflammatory 
mediators results in severe allergic symptoms such as hives, wheezing, vomiting and, in severe 
cases, anaphylactic shock. Release of these mediators also initiates IL-4 and IL-13 release, which 
results in eosinophil gastrointestinal (GI) tissue infiltration and creates a cycle of chronic Type 2 
allergic inflammation (Wong, 2016). 
Dupilumab, a fully human VelocImmune®-derived monoclonal antibody directed against 
interleukin-4 receptor alpha (IL-4Rα), blocks the activity of IL-4 and IL-13 and is approved as a 
treatment for atopic dermatitis (AD). As of October 2019, dupilumab has been approved for the 
adult atopic dermatitis (AD) indication in over 40 countries worldwide. Additionally, dupilumab 
has been approved for severe asthma with type 2 inflammation in both adult and adolescent 
patients, and recently in adult patients with chronic rhinosinusitis with nasal polyposis (CRSwNP), 
and adolescents with AD. Dupilumab is also under development for a range of type 2 inflammatory 
diseases such as food allergies and eosinophilic esophagitis (EOE) amongst others. 
This phase 2 proof-of-concept (POC) study will explore whether dupilumab has 
immunomodulatory effects on Type 2 immune responses, which may result in improved safety 
and tolerance to peanut exposure as determined by the ability to tolerate a higher cumulative peanut 
protein dose level during a double-blind, placebo-controlled food challenge (DBPCFC) after 
24 weeks of monotherapy treatment. In addition, the study will evaluate whether dupilumab 
influences known biomarkers important in the allergic response to peanuts such as a reduction in 
allergen-specific IgE and/or increase in allergen-specific IgG4. 
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Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective 
The primary objective of the study is to assess the tolerability of peanut protein in pediatric patients 
(6 to 17 years old) treated with dupilumab monotherapy, in which tolerability is defined as the 
proportion of patients who safely pass a double-blind placebo-controlled food challenge 
(DBPCFC) at week 24. 
2.2. 
Secondary Objectives 
The secondary objectives of the study include: 
 To determine whether dupilumab treatment improves peanut tolerability, defined as a 
change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC (up to 2044 mg cumulative) 
 To evaluate the safety and tolerability of dupilumab treatment in peanut allergic 
patients 
 To evaluate the effects of dupilumab treatment on the levels of peanut-specific IgE  
 To evaluate the treatment effect of dupilumab on the average wheal size after a titrated 
skin prick test (SPT), as measured by area under the curve (AUC) of the average wheal 
size induced by peanut extract at different concentrations. 
 To assess the incidence of treatment-emergent anti-drug antibodies (ADA) to 
dupilumab in patients over time 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
In pediatric patients with peanut allergy, treatment with dupilumab will result in inhibition of the 
Type 2 immune response and increase the threshold amount of peanut protein that triggers a 
clinically measurable allergic reaction. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
Dupilumab will be tested in a single-arm open-label POC study of 24 weeks subcutaneous (SC) 
dupilumab (every 2 weeks [Q2W]) treatment period and 12-week safety follow-up period in 
approximately 24 pediatric patients with confirmed peanut allergy. 
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Assessing the proportion of patients who tolerate at least 444 mg (cumulative) peanut protein 
during a DBPCFC before and after 24 weeks of dupilumab therapy will provide clinically relevant 
information about the potential increase in the peanut allergic threshold for protection from 
accidental exposure to approximately 2 peanut kernels. 
The time course of dupilumab efficacy in peanut allergy is not yet established.  It is thought the 
onset of action could coincide with reduction of sIgE and suppression of Type 2 effector cells. 
Dupilumab suppresses Type 2 inflammation, as measured by circulating markers such as 
Chemokine (C-C motif) Ligand 17 (also known as thymus and activation regulated chemokine 
[TARC]), within 4 to 12 weeks of treatment in all indications tested to date. Type 2 T-helper and 
effectors also play a major role in the onset of peanut allergy. In past AD studies, CD3+ T-cell 
infiltration in the skin was shown to significantly decrease from weeks 4 to 16.  This suggests 
dupilumab may suppress the activity of pathogenic Th2 cells effectively in 16 weeks. Thus, a 
24 week study is expected to be sufficient to evaluate the onset of effects of dupilumab on peanut 
protein tolerability. Evaluation of effect at week 36 when the dupilumab concentration should be 
below the lower limit of quantitation will assess the persistence of immune modulation following 
12 weeks off treatment. 
3.2.2. 
Rationale for Dose Selection 
The approved dosing regimen in the US and EU for the treatment of AD in adults is 300 mg Q2W. 
Doses of 300 mg Q2W and 300 mg weekly (QW) were shown to have an acceptable safety profile 
in adult AD patients in 2 phase 3 studies. In addition, 300 mg Q2W had an acceptable safety profile 
in a phase 2b study in adults with persistent asthma (Wenzel, 2016) and in a phase 3 study in 
patients ≥12 years of age with uncontrolled moderate-to-severe asthma (Busse, 2018).  The dose 
justification for pediatric patients aged 6 to <12 years old is based on the efficacy and safety 
observed in the global phase 3 monotherapy studies in adult AD patients (R668-AD-1334 and 
R668-AD-1416) and adolescent patients (R688-AD-1526), together with the observed efficacy, 
safety and PK modeling of data gathered from a study of AD patients aged 6 to 18 years (R668-
AD-1412). In pediatric patients receiving 4 mg/kg QW for 4 doses, exposures similar to those in 
adults receiving 300 mg Q2W dupilumab were achieved in the first study (R668-AD-1412), where 
significant improvement in measures of AD were noted, with an acceptable safety profile. 
Similarly, in the pivotal, phase 3 study in adolescent patients (R668-AD-1526), dupilumab 
monotherapy resulted in significant improvements in measures of AD and had an acceptable safety 
profile. Considering these data, 300 mg Q2W dupilumab is a suitable dose for adolescent and adult 
patients >60 kg with confirmed peanut allergy. The weight-based doses chosen for treatments in 
this study represent the doses of dupilumab, which are modeled to result in exposure to dupilumab 
that is associated with efficacy in AD in adults and adolescents. The dupilumab SC dose will be 
300 mg Q2W in children ≥60 kg following a loading dose of 600 mg on day 1. Children who 
weigh 20 kg or more but less than 60 kg, will receive 200 mg Q2W following a loading dose of 
400 mg on day 1. These dose regimens are also being tested in the pediatric AD studies.  
Bi-weekly dupilumab dosing should allow for adequate drug exposure without adversely 
impacting safety. Study drug may be administered in the clinic or at home by the study team, 
patient’s caregiver, or patient. For patients under 12 years old, caregiver injections will be required. 
The administration of the loading dose of dupilumab is the approach that was used for other 
symptomatic conditions where early onset is appropriate, and the same approach is followed here. 
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3.2.3. 
Rationale for Study Population 
Dupilumab has been well tolerated with a favorable safety profile in pediatric patients in studies 
to date (see below). The lower cutoff of 6 years of age was selected to include only patients with 
sufficient blood volumes to perform the mechanistic and safety studies blood measurements every 
month or per schedule of events (±1 clinic visit). A weight cut off of 20 kg to be compliant with 
Institutional Review Board (IRB) guidelines (ie, for children: 5 mL/kg at any single draw, no more 
than 9.5 mL/kg over an 8-week period; adults: the smaller of 10.5 mL/kg or 550 ml total at any 
single draw). The upper age limit of 17 years was selected because the majority of patients with 
peanut allergy are in the pediatric population. Patients will be enrolled with proven peanut allergy 
with serum IgE to peanut of ≥10 kUA/L and/or an SPT to peanut ≥8 mm compared to a negative 
control. In addition, a clinical reaction during a DBPCFC ≤100 mg peanut protein (144 mg 
cumulative) and no clinical reaction during placebo (oat) will ensure the enrollment of only highly 
reactive patients. 
3.3. 
Safety Considerations 
Unlike many other childhood allergies, peanut allergy typically persists into adulthood and is 
associated with a higher incidence of severe anaphylaxis as compared with other food allergies 
(Dyer, 2015). Although recent progress has been made in the treatment of food allergy through 
allergen-specific OIT, side effects, primarily GI related, often limit its full efficacy in many 
patients and there is an unmet need for a new therapy in food allergy. It is known that allergic 
response to food is an IgE mediated event; however, recent data suggest that non-IgE related, IL-
4/13 mediated Type 2 inflammation may also play a significant role in food allergy pathogenesis 
(Yu, 2016). Consequently, dupilumab treatment would be expected to provide benefit by blocking 
the activity of IL-4 and IL-13 and decreasing Type 2 immune responses and production of peanut-
specific IgE. As of 28 March 2019, dupilumab has been well tolerated in all completed studies, 
including studies in AD, asthma, nasal polyps, EoE, grass allergy and peanut allergy. 
3.3.1. 
Risk Benefits for Dupilumab 
At the time of writing this protocol, dupilumab 300 mg Q2W had been approved in the US, the 
EU, and several other countries including Japan for the treatment of adults with moderate-to-severe 
AD. Marketing applications are under review in additional countries. Dupilumab received 
approval from US Food and Drug Administration (FDA) on 11 March 2019 and from European 
Union European Commission on 1 August 2019 for use in adolescent patients (≥12 years) with 
moderate to severe atopic dermatitis. Review of this indication is ongoing in a number of other 
countries worldwide. Fourteen clinical studies (phases 1 through 3) of repeated-doses of 
dupilumab in AD patients have been completed. Dupilumab has demonstrated robust and 
consistent efficacy in completed clinical trials, across a variety of clinical outcomes, reflecting 
clinically meaningful and statistically significant improvement in AD signs, symptoms and quality 
of life with sustained efficacy demonstrated to 52 weeks. Dupilumab was well tolerated in these 
studies with a favorable safety profile. 
Dupilumab’s efficacy in adult patients with moderate-to-severe uncontrolled asthma has also been 
demonstrated at doses of 200 mg or 300 mg Q2W for 24 weeks (DRI12544) and 52 weeks 
(EFC13579). Dupilumab received approval from US FDA on 19 October 2018 for use in adults 
and adolescents (≥12 years) with moderate-to-severe asthma with an eosinophilic phenotype or 
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corticosteroid dependent asthma. In the European Union, dupilumab received a marketing 
authorization approval from the European Commission on 6 May 2019 for use in adults and 
adolescents (≥12 years) with severe asthma with type 2 inflammation. In Japan, dupilumab 
received approval from Pharmaceuticals and Medical Devices Agency on 26 March 2019 for use 
in adults and adolescents (≥12 years) with severe or refractory bronchial asthma. Asthma is a 
common comorbidity of allergy and asthma exacerbations are an important safety concern for food 
challenges. In these studies, treatment with dupilumab at all doses tested was generally well 
tolerated with a favorable safety profile. 
The first clinical study of dupilumab in pediatric patients aged 6 years to <18 years old with AD 
(R668-AD-1412) has been completed. Data generated from this study showed that dupilumab 
administered as single and repeated weekly doses (up to 4 weeks) was generally well tolerated and 
had an acceptable safety profile similar to that for adults in both pediatric age groups included in 
this study (6 to 11 years and 12 to <18 years). There were no new safety signals detected with 
dupilumab in this pediatric population. Most of the AEs reported were mild in intensity, transient 
in nature and not related to the study drug. Both dose regimens of dupilumab evaluated (2 mg/kg 
and 4 mg/kg) showed significant clinical benefit in both pediatric age groups. In the pivotal, phase 
3 study in adolescent patients (R668-AD-1526) the overall rate of AEs was comparable between 
the dupilumab groups and placebo (72% for dupilumab Q2W, 64% for dupilumab Q4W and 69% 
for placebo). There were no serious adverse events (SAEs) or events leading to treatment 
discontinuation in either dupilumab treatment group. Adverse events that were observed at a higher 
rate with dupilumab included Injection Site Reactions (8.5% for dupilumab Q2W, 6% for 
dupilumab Q4W, compared with 3.5% for placebo) and Conjunctivitis (10% for dupilumab Q2W, 
11% for dupilumab Q4W, compared with 5% for placebo). Skin Infections were numerically lower 
in the dupilumab groups (11% for dupilumab Q2W, 13% for dupilumab Q4W, compared with 
20% for placebo). As of 28 March 2019, the estimated total number of subjects exposed to 
dupilumab in clinical studies was 7781 (218 in healthy volunteer studies, 3931 in AD studies, 3073 
in asthma studies, 470 in CRSwNP studies, 26 EoE studies, and 63 in grass allergy and peanut 
allergy studies). In all completed studies, dupilumab has been well tolerated and has demonstrated 
significant and prolonged efficacy in all Type 2 immune indications investigated to date. 
Additional information can be found in the Investigator’s Brochure. 
3.3.2. 
Risk for Peanut Protein 
Oral food challenges may induce a severe life-threatening allergic reaction; however, the risk can 
be greatly mitigated by conducting the challenges in a highly monitored setting and by initiating 
the challenge with a very small amount of the food, gradually increasing the dose, and stopping 
the challenge at the first sign of a reaction. If patients develop an allergic reaction during the 
challenges, they may need oral, intramuscular (IM), or intravenous (IV) medications. Additionally, 
IV catheters may be placed, at physician discretion for any visit, based on factors such as previous 
reactions, recent clinical history, and clinical status observed at the visit. Trained personnel, 
including a study physician, as well as medications and equipment, will be immediately available 
to treat any reaction. Based on similarly designed previous clinical studies, the anticipated rate of 
life-threatening anaphylactic reactions is <0.1%. There may be a risk that during the study patients 
may decrease their vigilance against accidental food allergen ingestion because they believe they 
are protected from it. Therefore, patients/caregivers will be warned that they should continue to 
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practice their usual vigilance against accidental ingestion of food allergens or food allergen-
containing foods and reminded to carry their epinephrine autoinjector at all times. 
4. 
STUDY ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
 Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
444 mg (cumulative) peanut protein at week 24 
4.1.2. 
Secondary Endpoints 
 Change in the cumulative tolerated dose (log transformed) mg of peanut protein 
during a DBPCFC from baseline to measured DBPCFC visits at weeks 24 and 36. 
 Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
444 mg (cumulative) peanut protein at week 36. 
 Proportion of patients treated with dupilumab that pass a DBPCFC with at least 
1044 mg (cumulative) peanut protein at weeks 24 and 36. 
 Proportion of patients treated with dupilumab that pass a DBPCFC with 2044 mg 
(cumulative) peanut protein at weeks 24 and 36. 
 Percent change from baseline in sIgE to post-baseline visits (weeks 4, 8,12, 24, and 
36) 
 Change from baseline in titrated SPT at week 4, 12, 24, 36 as measured by the 
average wheal size AUC after peanut allergen stimulation at different concentrations. 
 Proportion of patients with Grade II or above allergic reactions during the DBPCFC 
at week 24 
 Proportion of patients using epinephrine as a rescue medication during the DBPCFC 
at week 24 
5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, co-
morbid atopic conditions, years with food allergy disease, sex, etc), disease characteristics 
including medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
Efficacy variables will include the DBPCFC and the peanut SPT. 
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5.3. 
Safety Variables 
Safety variables will include vital signs, spirometry (Forced Expiratory Volume in 1 Second 
[FEV1] and/or peak expiratory flow rate [PEFR]), hematology and chemistry, urinalysis, and AEs. 
5.4. 
Pharmacokinetic Variables 
Concentration of functional dupilumab in serum at each time point, obtained prior to dosing, will 
considered to be trough values (Ctrough time point). 
5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) status, and time-
point/visit. 
5.6. 
Pharmacodynamic and Biomarker Variables 
Serum TARC and Total IgE. Serum TARC and total IgE are markers of Type 2 activity. 
Dupilumab significantly suppressed both TARC and total IgE in studies of adult AD, nasal 
polyposis, and asthma patients. 
Peanut-specific IgE, IgG, IgG4. The induction of peanut-specific IgG4 and IgG during OIT has 
been reported in multiple studies, and is thought to have a protective effect against IgE-mediated 
allergic symptoms. The gradual increase in serum allergen-specific IgG4, and decrease in allergen-
specific IgEs are associated with clinical desensitization to peanut (Glaumann, 2015). In a 5-year 
peanut OIT study of 39 peanut-allergic children, increases in total peanut-specific IgG levels were 
reported during the 12-month up-dosing period (Vickery, 2014). In an open-label study of 29 
peanut-allergic children, peanut-specific IgG4 increased steadily during the first year of treatment, 
reaching 3.5-fold increase over baseline after 3 months of OIT and roughly 10-fold increase at the 
end of first year (Jones, 2009). In the same study, peanut-specific IgE increased by ~3 fold after 
3 months of OIT and gradually returned to baseline at one year. In a study investigating the 
biomarker profile of dupilumab in patients with AD (R668-AD-1307 as well as other dupilumab 
studies), dupilumab suppressed both total and allergen-specific IgEs. In general, dupilumab 
suppresses total serum IgE by ~ 50% with 12 to 16 weeks of treatment. 
Titrated Skin Prick Test. The titrated SPT will assess the atopic response to peanut extract. A 
statistically significant reduction in wheal size has been associated with clinical desensitization for 
peanut allergy in a randomized controlled study of peanut OIT for 12 months (Varshney, 2011). 
Fractional Exhaled Nitric Oxide. Fractional exhaled nitric oxide (FeNO) is a non-invasive 
marker that has been shown to correlate with allergic airway inflammation and IgE sensitization. 
The measurement of FeNO has shown predictive value on the outcome of peanut oral food 
challenge (Preece, 2014) In a 12-month-study enrolling 56 patients with peanut allergy, FeNO 
measurement demonstrated superior reproducibility (ICC=0.73) in comparison to peanut skin 
prick test (ICC=0.51), Ara h2 skin prick test (ICC=0.44) (Percival, 2016). In past studies, 
dupilumab significantly lowered FeNO concentrations in asthma patients. Asthma is a common 
comorbid condition in peanut allergic patients (>50%). It is plausible that peanut exposure during 
DBPCFC in these patients may trigger an increase in FeNO and asthmatic symptoms. Thus, 
dupilumab treatment may suppress FeNO induction after an oral food challenge. Although no 
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manufacturer has validated the FeNO device for children under 7 years old due to inadequate 
exhalation force, there are no contraindications with the use of FeNO for 6-year-old children.  
Additionally, specific guidance and reference ranges are available for collection in children as 
young as 6 years of age (Brody, 2013) (Menou, 2017). As FeNO is an exploratory biomarker, it 
will be collected for children 6 years old unless the investigator declines to collect. FeNO will be 
collected prior to spirometry. 
Other Exploratory Research 
Blood may be obtained for additional exploratory tests research to understand better allergy and 
peanut allergy. Blood samples collected for exploratory research will be kept for up to 15 years 
for studying the allergen response ex vivo. 
The results of exploratory analyses will not be presented in the CSR. 
6. 
Study Design 
6.1. 
Study Description and Duration 
This is a phase 2, multicenter, single-arm open-label POC study in pediatric patients aged 6 to 
17 years inclusive who are allergic to peanut, to evaluate the effects of dupilumab on tolerability 
of peanut protein during a DBPCFC. The study consists of an 8-week screening period, 24-week 
open-label treatment period with dupilumab, followed by a 12-week safety follow-up period 
(Figure 1). 
Figure 1: 
Schematic of Study Design  
 
Screening 
After obtaining informed consent/assent, patients will be assessed for eligibility during a 2-part 
screening period. During screening visit 1 (day -57 to day -43), patients will undergo a medical 
history, physical examination, spirometry, peanut SPT, and laboratory testing (including sIgE) and 
will be evaluated for the study eligibility criteria. 
During screening visit 1a (day -42 to day -15), under direct study investigator monitoring, patients 
will undergo a DBPCFC to confirm current peanut allergy. This will consist of 5 doses of peanut 
protein with a dose given every 15 to 30 minutes in increasing amounts up to a cumulative total of 
144 mg of peanut protein (Appendix 1). Vital signs will be assessed every 15 to 30 minutes. If the 
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study team suspects a reaction may be developing, they may exercise their clinical judgment to 
separate doses by up to an additional 30 minutes (1 hour maximum between doses). The matching 
placebo challenge will consist of placebo material (oat protein) given also in 5 doses. Both peanut 
and oat protein will be concealed in a food that masks the taste. The food challenges will be 
performed on different days (1 day placebo [oat] protein, 1 day peanut protein, with order 
determined at random) at least 24 hours, but not more than 7 days, apart. The doses will be 1, 3, 
10, 30, and 100 mg of peanut protein (or placebo). Both food challenge days (placebo and peanut) 
must be done to evaluate eligibility. 
Before each challenge, the patient will have a physical assessment by a trained physician’s 
assistant, registered nurse, nurse practitioner, and/or physician of the study team who is blinded to 
the testing material. The supervising investigator will also be blinded to testing material. 
Reactions will be scored using the Consortium of Food Allergy Research (CoFAR) grading system 
(see Appendix 2). The DBPCFC will be stopped when the blinded assessor finds symptoms and/or 
signs that indicate a definite objective allergic reaction (CoFAR grading system [see Appendix 2]) 
has occurred based on clinically significant changes in reported symptoms, physical findings, or 
vital signs that the patient is experiencing to the challenge material. The patient will be observed 
for a minimum of 2 hours after the final administered dose and discharged only when deemed 
clinically stable by a study physician. All food challenges will be performed under physician 
supervision. If the patient does not experience dose-limiting symptoms at or before the 100 mg 
challenge dose (≤144 mg cumulative) of peanut protein or if he/she experiences symptoms at any 
dose of placebo, he/she will not be enrolled in the study. Investigator/site personnel will be 
unblinded only to the results of the screening food challenge upon completion of the second part 
of the challenge to assess eligibility. A 2-week washout period is needed after the screening 
DBPCFC where peanut was given. All other on-study food challenges in the study will remain 
blinded to the clinic study team. 
Treatment Period 
Patients with a history of confirmed peanut allergy signs and symptoms at screening who 
continue to meet eligibility criteria at baseline will be enrolled. 
Dupilumab will be dosed SC on day 1 at least 14 days after the screening DBPCFC (this interval 
was selected to ensure that accurate biomarker values at baseline are captured) and the dose will 
not be changes regardless of weight gain or loss: 
 patients weighing ≥20 kg and <60 kg will receive dupilumab 200 mg Q2W following 
a loading dose of 400 mg on day 1  
 patients weighing ≥60 kg will receive dupilumab 300 mg Q2W following a loading 
dose of 600 mg on day 1  
Study drug may be administered in the clinic on day 1 by the study team, patient’s caregiver, or 
patient. Patient and/or caregiver will be trained on how to store, handle, prepare, and administer 
study drug at home Q2W. The last dose of study drug will be at week 22. For patients under 
12 years of age, adult caregiver will need to administer the study drug injections. 
Patients will have monthly clinic visits and phone calls in-between visits to collect AEs, 
concomitant medications and compliance to study drug administration. 
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Double-Blind Placebo-Controlled Food Challenge 
At week 24, under intensive monitoring, all patients will undergo a DBPCFC up to 2044 mg peanut 
protein (cumulative) or placebo (see Appendix 1) to assess tolerability. The patient’s sensitivity to 
peanut allergen is defined as the dose at which the patient experiences allergic reactions. All 
symptoms and signs will be evaluated and rated based on a standardized oral food challenge 
scoring system (see Appendix 2). Up-dosing during the DBPCFC will be stopped when the blinded 
assessor finds symptoms and/or signs that indicate a definite objective allergic reaction (CoFAR 
grading system [see Appendix 2]) has occurred based on clinically significant changes in reported 
symptoms, physical findings, or vital signs that the patient is experiencing to the challenge 
material. Vital signs will be assessed every 15 to 30 minutes. The DBPCFC will consist of 8 doses 
(peanut protein or placebo), with a dose given every 15 to 30 minutes: 1, 3, 10, 30, 100, 300, 600 
mg, and 1000 mg resulting in a total challenge of up to 2044 mg peanut protein (cumulative). Both 
peanut and oat protein will be concealed in a food that masks the taste. The food challenges will 
be performed on different days (1 day placebo [oat] protein, 1 day peanut protein, with order 
determined at random) at least 24 hours but not more than 7 days apart and not within 24 hours of 
a dose of study drug. Patients will be considered to have passed the DBPCFC if they do not 
experience any objective Grade 1 reaction by the CoFAR grading system (see Appendix 2). If the 
patient experiences reactions, he/she will be treated with the necessary rescue medications. He/she 
will be observed for a minimum of 2 hours after the final administered dose and discharged only 
when deemed clinically stable by a study physician. Symptom severity will be adjudicated by an 
independent, blinded assessor who is not involved in patient study visit conduct (Bock, 1988; 
Sampson, 2006). 
Study design safety considerations for DBPCFC are described in Section 3.3.2. 
Post-Treatment Follow-up Period (12 weeks) 
All patients will have a 12-week follow-up period after the end of treatment and will undergo 
safety, laboratory, and clinical assessments.  
The duration of the 12-week follow-up period is based on the time expected for drug levels (to be 
below the lower limit of quantification) after the last dose of dupilumab. At the end of the 12-week 
follow-up period, only patients who passed a DBPCFC of at least 444 mg (cumulative) at week 24 
will undergo a final DBPCFC (up to 2044 mg cumulative), under intensive monitoring, at week 
36 to assess the level of peanut sensitivity after 12 weeks off dupilumab to determine whether there 
is evidence of persistent effects and sustained unresponsiveness. 
6.1.1. 
End of Study Definition 
The end of study is defined as the last visit of the last patient. 
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6.1.2. 
Study Design Safety Considerations 
The design considers important safety issues: 
 All DBPCFC visits will be supervised in-clinic setting where trained study physicians 
are available 
 Standing orders from a medical doctor are provided for all clinical study personnel to 
initiate treatment of reactions immediately (ie, prior to medical doctor notification), 
including IM administration of epinephrine, based on their own clinical judgment 
 A crash cart with pediatric equipment will be available in close proximity (within 
50 feet) of all patient clinic rooms 
 A code team is available 
 Dosing allergic symptoms and AEs will be captured throughout the study 
 Patients will be prescribed an epinephrine auto-injector (if not prescribed by a treating 
clinician previous to study entry) and all patients/Caregivers will be trained in its use. 
Patients will be advised to carry the autoinjector with them at all times. 
 Patients /caregivers will be cautioned against patients consuming any peanuts or 
peanut-containing foods other than the peanut allergen challenge while on study 
 The dupilumab clinical development program in food allergy independent data 
monitoring committee (IDMC) will provide oversight of patient safety. The IDMC 
will provide Regeneron and Sanofi with appropriate recommendations on the conduct 
of the food allergy clinical studies to ensure the protection and safety of the patients 
enrolled in these studies. 
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6.1.3. 
Study Stopping Rules 
6.1.3.1. 
Individual Patient Stopping Rules (both study drug and food challenge) 
1. Missing ≥2 consecutive doses of study drug 
2. Anaphylaxis resulting in severe hypotension (Appendix 3), neurological compromise or 
mechanical ventilation secondary to any food challenge (Simons, 2014). 
3. Patient develops biopsy-documented eosinophilic esophagitis (EoE) or other eosinophilic 
gastrointestinal disease. 
4. Any patient deemed to have severe allergic reactions and who receives aggressive 
therapy (eg, mechanical ventilation, 3 or more repeated doses of epinephrine for a life-
threatening reaction) at any time will be discontinued from further therapy. 
5. Other circumstances including, but not limited to, the following: 
 Poor control or persistent severe activation of secondary atopic disease (eg, AD, 
asthma) 
 Started on beta-blockers with no alternative medications available per the prescribing 
physician 
 Pregnancy 
6.1.3.2. 
Anaphylaxis 
The definition of anaphylaxis that has been adopted for this study is from the 2014 position paper 
by the European Academy of Allergy and Clinical Immunology (EAACI) Food Allergy and 
Anaphylaxis Guidelines Group (Muraro, 2007), that in turn was based on the publications of 
Simons (Simons, 2011) and Johansson (Johansson, 2004), and is consistent with the recently 
published “International consensus on (ICON) anaphylaxis” (Simons, 2014).  Accordingly, 
anaphylaxis is defined as a severe, potentially life-threatening systemic hypersensitivity reaction, 
characterized by being rapid in onset with life-threatening airway, breathing, or circulatory 
problems that is usually, though not always, associated with skin and mucosal changes. 
When the diagnosis of anaphylaxis is made, the basis for having suspected the diagnosis must be 
documented, using the criteria established by the Second Symposium on the Definition and 
Management of Anaphylaxis (Sampson, 2006).  Reports of anaphylaxis will be collected in the 
electronic data capture (EDC).  Reports of non-fatal and non-life-threatening anaphylaxis that do 
not require hospitalization (admitted for over 24 hours) will not require expedited safety reporting, 
as these are clinically anticipated events in the target population.  All reports of anaphylaxis will 
be periodically reviewed to ensure proper patient care and prompt identification of any clinically 
concerning safety issues. 
6.2. 
Planned Interim Analysis 
No formal interim analysis is planned for this study.  
Data may be analyzed and reviewed internally by the sponsors. 
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A primary analysis may be performed once all patients in the study have completed the 24-week 
treatment period as specified in the protocol (week 24 visit or earlier for those patients who are 
withdrawn prematurely from the study). If performed, this primary analysis will be considered the 
final analysis for the primary endpoint and secondary efficacy endpoints up to week 24. A 
description of the statistical methods to be employed is in Section 11.4. 
6.3. 
Study Committees 
6.3.1. 
Independent Data Monitoring Committee 
The dupilumab clinical development program in food allergy IDMC, composed of members who 
are independent from the sponsor and the study investigators, will provide oversight of patient 
safety by conducting formal reviews of accumulated safety data. The IDMC will provide 
Regeneron and Sanofi with appropriate recommendations on the conduct of the food allergy 
clinical studies to ensure the protection and safety of the patients enrolled in these studies.  
All activities and responsibilities of the IDMC are described in the IDMC charter. 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 24 patients with a history of confirmed peanut allergy will be enrolled at 
approximately 10 sites in the US and Canada (CAN).  
7.2. 
Study Population 
Male and female pediatric patients ages 6 to 17 years inclusive with a history of peanut allergy 
confirmed by peanut SPT, sIgE, and by the amount of peanut protein (mg) safely ingested during 
a peanut DBPCFC. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Age 6 to 17 years (inclusive). 
2. Patient has a clinical history of allergy to peanuts or peanut-containing foods 
(symptom[s] of reaction due to exposure). 
3. Experience dose-limiting symptoms at or before the 100 mg challenge dose (≤144 mg 
cumulative) of peanut protein (measured as 200 mg of peanut flour) on screening DBPCFC 
conducted in accordance with PRACTALL (Practical Issues in Allergology, Joint United 
States/European Union Initiative) guidelines. And not experiencing dose limiting symptoms 
to placebo 
4. Serum IgE to peanut of ≥10 kUA/L and/or a SPT to peanut ≥8 mm compared to a 
negative control. 
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5. Patients/legal guardians must be trained on the proper use of the epinephrine autoinjector 
device to be allowed to enroll in the study. 
6. Patients with other known food allergies must agree to eliminate these other food items 
from their diet so as not to confound the safety and efficacy data from the study. 
7. Written informed consent from parent/guardian. 
8. Written assent from minor patients as appropriate (eg, above the age of 6 years or the 
applicable age per local regulatory requirements). 
9. Willing and able to comply with all clinic visits and study-related procedures. 
7.2.2. 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1. Any previous exposure to marketed dupilumab or dupilumab in a clinical trial 
2. Member of the clinical site study team or his/her immediate family 
3. History of other chronic disease (other than asthma, AD, or allergic rhinitis) requiring 
therapy (eg, heart disease, diabetes, hypertension) that, in the opinion of the Principal 
Investigator, would represent a risk to the patient’s health or safety in this study or the 
patient’s ability to comply with the study protocol 
4. History of frequent or recent severe, life-threatening episode of anaphylaxis or 
anaphylactic shock as defined by more than 3 episodes of anaphylaxis within the past 
year and/or an episode of anaphylaxis within 60 days of screening DBPCFC 
5. History of eosinophilic gastrointestinal disease 
6. History of eosinophilic granulomatosis with polyangiitis 
7. Current participation or participation within 6 months prior to screening in any other 
interventional study. 
8. Severe, unstable asthma at time of enrollment or any patient with FEV1 <80% of 
predicted or ACQ >1.5. 
9. Use of systemic corticosteroids within 2 months prior to screening   
10. Use of omalizumab, benralizumab, or mepolizumab within 6 months prior to screening. 
11. Use of other forms of allergen immunotherapy (eg, oral, SC, patch or sublingual) or 
immunomodulatory therapy (not including corticosteroids) within 3 months prior to 
screening. 
12. Use of antihistamines within 5 days prior to screening and within 5 days prior to SPTs 
and day 1 of DBPCFCs. 
13. Use of any agents known or likely to interact with epinephrine (eg, beta blockers, ACE-
inhibitors, tri-cyclic antidepressants, or other drugs), within 3 weeks prior to screening. 
14. Allergy to oat (placebo in DBPCFC). 
15. Hypersensitivity to epinephrine and any of the excipients in the epinephrine product. 
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16. History of a mast cell disorder, including mastocytosis, urticarial pigmentosa, and 
hereditary or idiopathic angioedema. 
17. Treatment with a live (attenuated) vaccine within 3 months before the baseline visit and 
during the study  
18. Active chronic or acute infection requiring systemic treatment with antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit. 
NOTE:  patients may be rescreened after the infection resolves. 
19. 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. 
20. 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. 
21. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity 
at the screening visit. 
22. With an established diagnosis of hepatitis B viral infection at the time of screening or is 
positive for hepatitis surface antigen (HBsAg) or hepatitis core antibody (HBcAb) at the 
time of screening  
23. Body weight <20 kg  
24. Pregnant or breastfeeding women, women planning to become pregnant or breastfeed 
during the study. 
25. Girls at or beyond menarche 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 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; intrauterine device (IUD); 
intrauterine hormone releasing system (IUS); bilateral tubal ligation; vasectomized 
partner; and or sexual abstinence. 
†Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study 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 patient. 
‡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. 
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7.3. 
Premature Withdrawal from the Study 
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patients who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.3.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study will not be replaced. 
8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
Dupilumab 175 mg/mL (200mg dose): Each single-use, prefilled syringe delivers 200 mg of study 
drug (1.14 mL of a 175 mg/mL solution, expellable in 1mL syringe). 
Dupilumab 150 mg/mL (300mg dose): Each single-use, prefilled syringe delivers 300 mg of 
study drug (2.0 mL of a 150 mg/mL solution, expellable in 2.25mL syringe). 
Subcutaneous injection sites of the study drug should be alternated among the different quadrants 
of the abdomen (avoiding navel and waist areas), upper thighs, and upper arms so that the same 
site is not injected for 2 consecutive administrations. 
Instructions on dose preparation are provided in the pharmacy manual. 
8.1.1. 
Peanut for Double-Blind Placebo-Controlled Food Challenge 
For the DBPCFC, peanut flour or placebo food challenge mixture will be administered in a food 
vehicle. Investigational sites will be provided with standardized recipes for preparation of the 
DBPCFC in a separate manual of procedures. 
8.2. 
Rescue Treatments 
If required, patients who experience allergic reactions will be treated with IM or SC administration 
of epinephrine at the discretion of the clinical study personnel based on their own clinical 
judgement. The clinical site will also collect rescue medications taken at home in the event of 
accidental exposure to peanut. For more details, see Section 6.1.2. 
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8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification for an individual patient is not allowed. 
8.3.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug and who do not withdraw from the study 
will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 9.1.2. 
8.3.2.1. 
Reasons for Permanent Discontinuation of Dupilumab and Food Challenge 
Study drug dosing will be permanently stopped in the event of: 
 Anaphylactic reaction or other severe systemic reaction to dupilumab 
 Any infection that is opportunistic, such as active tuberculosis and other infections 
whose nature or course may suggest an immuno-compromised status  
 Severe laboratory abnormalities that are deemed to be related to dupilumab: 
 Neutrophil count ≤0.5 x 103/µL 
 Platelet count ≤50 x 103/µL 
 ALT and/or AST values greater than 3 × ULN with total bilirubin >2 × ULN 
(unless elevated bilirubin is related to confirmed Gilbert’s Syndrome) 
 Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks) 
 Diagnosis of a malignancy during the study 
 Evidence of pregnancy 
 Treatment with any prohibited concomitant medication or procedure 
 Missing ≥2 consecutive doses of study drug (dupilumab) 
8.3.2.2. 
Reasons for Temporary Discontinuation of Dupilumab 
Study drug dosing will be temporarily discontinued in the event of: 
 Clinically important laboratory abnormalities such as: 
 ALT or AST 3 × ULN but ≤5 × ULN 
 CPK >2.5 x ULN 
 Serum creatinine >1.5 x ULN 
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 Severe laboratory abnormalities (as noted in Section 8.3.2.1) where a causal 
relationship to dupilumab can be reasonably excluded (ie, an alternative cause is 
evident). In these cases, study treatment will be discontinued while the clinical 
circumstances are being assessed but it may be resumed when the laboratory 
parameters normalize sufficiently. A decision to resume treatment will be made 
jointly by the investigator and medical monitor. 
 Other intercurrent illnesses or major surgery 
 An infection that requires parenteral treatment with antibiotic, antifungal, antiviral, 
antiparasitic, or antiprotozoal agents, or requires oral treatment with such agents for 
longer than 2 weeks. 
After the condition leading to suspension of dosing normalizes sufficiently, study treatment may 
resume at the discretion of the principal investigator in consultation with the medical monitor. A 
decision to discontinue study drug and/or to reinstitute study treatment should be discussed with 
the medical monitor. Note that dosing may NOT be resumed if patient met conditions for 
permanently discontinuing study drug described in Section 7.3 . 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 patient’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 should always be 
discussed with the medical monitor. 
8.4. 
Management of Acute Reactions  
8.4.1. 
Acute Injection Reactions 
8.4.1.1. 
Systemic Injection Reactions 
Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.4.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to the Food and Drug 
Administration (FDA) September 2007 Guidance for Industry, Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (provided in the 
study Regulatory Binder, also see Section 10.5.1). 
8.5. 
Method of Treatment Assignment 
Approximately 24 patients will be enrolled using an interactive web response system (IWRS). 
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8.5.1. 
Blinding 
This is an open-label study. 
For the DBPCFC, an unblinded pharmacist or designee will mix the peanut protein or oat protein 
in a chocolate food matrix that masks taste for administration in the DBPCFC. For each patient, a 
“blinded” evaluating physician (Blinded Assessor) is to be designated to assess the tolerability of 
the challenge doses presented in the DBPCFC. The blinded evaluating physician is not to be 
involved directly in the oversight of study product dosing or the assessment or management of 
AEs (for details refer to the Masking Plan).  To the extent practicable, the same blinded evaluating 
physician who determines dose limiting symptoms (DLS) in the screening DBPCFC should 
determine DLS in the week 24 and 36 DBPCFCs. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
Packaging, Labeling, and Storage 
Study drug for injection will be provided as open-label kits. Each carton box will contain 1 labeled 
prefilled syringe. The carton box and prefilled syringe label will indicate the protocol number, 
product identity and strength, medication/reference number, batch number, directions for use, 
route of administration, expiry date, sponsor information, and storage conditions, and will 
correspond to all regulatory requirements. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed on site after approval 
from sponsor or designee, or returned to a destruction depot after accountability and reconciliation.  
8.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication 
 dispensed to each patient, 
 returned from each patient (if applicable), and 
 disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
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8.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.7. 
Concomitant Medications and Procedures 
Any treatment administered from the time of the first dose of study drug to the final study visit 
will be considered concomitant medication. This includes medications that were started before the 
study and are ongoing during the study. 
The use of prohibited medications should only be considered when necessary for the patient's care 
and well-being and when there are no other options.  Their use results in permanent treatment 
discontinuation but not discontinuation from study.   
8.7.1. 
Prohibited Medications and Procedures 
Treatment with the following concomitant medications is prohibited during the study: 
 Treatment with a live (attenuated) vaccine; below is a list of examples of such 
vaccines. Refer to study manual for a current, comprehensive list of prohibited 
vaccines 
Chickenpox (Varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (Rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (Vaccinia) 
Yellow fever 
Bacillus Calmette-Guerin 
Rotavirus 
Varicella Zoster (shingles) 
 Treatment with an investigational drug (other than dupilumab) 
 Treatment with immunomodulating biologic agents, including anti-IgE 
 Treatment with allergen immunotherapy 
 Treatment with systemic (oral, IV, IM, SC) corticosteroids for a duration of more 
than 5 continuous days, more than 15 days in total, or within 2 days prior to 
DBPCFCs 
 Treatment with any agents known or likely to interact with epinephrine (eg, beta 
blockers, ACE-inhibitors, tri-cyclic antidepressants, or other drugs) 
 Treatment with antihistamines within 5 days prior to screening and within 5 days 
prior to SPTs and day 1 of DBPCFCs 
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The following concomitant procedures are prohibited during study participation:   
 Major elective surgical procedures 
8.7.2. 
Permitted Medications 
Other than the prohibited medications listed in Section 8.7.1, treatment with concomitant 
medications is permitted during the study. 
Medications used to treat chronic disease other than those listed in Section 8.7.1 are also permitted. 
Patients/parents/caregivers should be advised not to reduce or stop taking medications for 
concomitant conditions throughout the entire study period. If there is any question regarding 
whether a concomitant medication may be used during the study, the study site should contact the 
medical monitor. 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
9.1. 
Schedule of Events  
Study assessments and procedures are presented by study period and visit in Table 1. 
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Table 1: 
Schedule of Events 
Study Procedure 
Screening 
Treatment Period 
Follow-up 
UV 
ET 
Visit 
V1 
V1a 
V2 
Baseline 
V3 phone 
V4 clinic 
V5 phone 
V6 clinic 
V7 phone 
V8 clinic 
V9 phone 
V10 clinic 
V11 phone 
V12 clinic 
V13 phone 
EOT V14 
clinic 
V15 
EOS V16 
if applicable 
 
Day 
-57 
to 
 -43 
-42 
to 
 -15 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
211 
253 
 
Week 
 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 
36 
 
Visit Window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Epi injection training 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on Study Drug 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Drug1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Study Drug 
Dispensation/Account 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Phone call to collect AEs, 
Conmeds and IP 
compliance  
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Concomitant Meds and Tx 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Efficacy5: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DBPCFC2, 3,4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X10 
 
 
Peanut SPT3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Titrated Peanut SPT3,7 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
FAQLQ  
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
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Study Procedure 
Screening 
Treatment Period 
Follow-up 
UV 
ET 
Visit 
V1 
V1a 
V2 
Baseline 
V3 phone 
V4 clinic 
V5 phone 
V6 clinic 
V7 phone 
V8 clinic 
V9 phone 
V10 clinic 
V11 phone 
V12 clinic 
V13 phone 
EOT V14 
clinic 
V15 
EOS V16 
if applicable 
 
Day 
-57 
to 
 -43 
-42 
to 
 -15 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
211 
253 
 
Week 
 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 
36 
 
Visit Window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Height5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Physical Examination5 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Spirometry6 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Adverse Events5 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Laboratory Testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Ab, HBsAg, HBcAb, 
Hep C Ab5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology/Chemistry5 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
FeNO Test6 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Pregnancy Test (WOCBP)5 
S 
U 
U 
 
U 
 
U 
 
U 
 
U 
 
U 
 
U 
U 
S 
 
U 
Urinalysis5 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
Total IgE5 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Peanut sIgE, sIgG, and 
sIgG45 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
 
X 
Research Samples 
(serum/plasma)5 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Blood samples for 
additional exploratory5 
research7 
 
  
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
PK/Drug Concentration 
and ADA Samples8: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Drug conc. sample 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
ADA sample 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
Genomic DNA sample9: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Procedure 
Screening 
Treatment Period 
Follow-up 
UV 
ET 
Visit 
V1 
V1a 
V2 
Baseline 
V3 phone 
V4 clinic 
V5 phone 
V6 clinic 
V7 phone 
V8 clinic 
V9 phone 
V10 clinic 
V11 phone 
V12 clinic 
V13 phone 
EOT V14 
clinic 
V15 
EOS V16 
if applicable 
 
Day 
-57 
to 
 -43 
-42 
to 
 -15 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
211 
253 
 
Week 
 
 
 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
30 
36 
 
Visit Window (days) 
 
 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
 
Buccal swab samples for 
DNA  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WOCBP = women of childbearing potential 
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9.1.1. 
Footnotes for the Schedule of Events Table 
1. Study drug will be administered in the clinic on day 1 by the study team, patient’s 
caregiver, or patient. With adequate training, study drug may be administered at home 
Q2W for the remaining injections. Patient/caregiver will complete an injection log to 
document compliance with injection of study drug and to document any AEs and 
concomitant medications. 
2. During DBPCFC, vital signs will be collected every 15 to 30 minutes. After initial 
DBPCFC dose, only pulse and blood pressure need to be taken as part of safety 
monitoring. 
3. Patients should not take antihistamines within 5 days prior to SPTs and day 1 of the 
DBPCFCs. 
4. The food challenges (DBPCFC) will be performed on different days (1 day placebo [oat] 
protein, 1 day peanut protein, with order determined at random) at least 24 hours, but no 
more than 7 days, apart and not within 24 hours of a dose of study drug. After the last 
dose of the DBPCFC, the patient will be monitored for at least 2 hours and then 
discharged from the clinic. 
5. Assessments will be performed before the administration of study drug. 
6. FeNO measurement and spirometry will be performed on the same day, except for visit 1, 
in which only spirometry is performed. If the DBPCFC is scheduled on the day of the 
visit, then both FeNO measurement and spirometry will be performed twice before the 
patient goes home: once before DBPCFC, once after DBPCFC. FeNO should be done 
prior to spirometry. 
7. On the day of the DBPCFCs, blood draws for exploratory research, including TruCulture, 
basophil sensitivity, and peripheral blood mononuclear cells (PBMC) samples will be 
performed before the DBPCFC is performed. On the day of the DBPCFC, titrated SPTs 
will be performed before the DBPCFC. 
8. Samples for PK and ADA analysis should be collected prior to drug administration.  
9. Two buccal swabs for genomic analysis can be collected on day 1 or any day after day 1. 
10. Only patients who passed a DBPCFC of at least 444 mg (cumulative) at week 24 will 
undergo a final DBPCFC (up to 2044 mg cumulative). 
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study before the primary endpoint visit (week 24) will be 
asked to return to the clinic for study assessments described in Table 1. Patients who are withdrawn 
from the study after the primary endpoint visit will be asked to return to the clinic for early 
termination assessments only. 
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9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.2. 
Study Procedures 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  peanut SPT, HIV Ab, HBsAg, HBcAb, Hep C Ab, 
height. Demographics and medical history will be collected. 
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Double-Blind Placebo-Controlled Food Challenge 
The patient’s sensitivity to peanut allergen is defined as the dose at which the patient experiences 
allergic reactions. All symptoms and signs will be evaluated and rated based on a standardized oral 
food challenge scoring system (see Appendix 2). Up-dosing during the DBPCFC will be stopped 
when the blinded assessor finds symptoms and/or signs that indicate a definite objective allergic 
reaction (CoFAR grading system (see Appendix 2) has occurred based on clinically significant 
changes in reported symptoms, physical findings, or vital signs that the patient is experiencing to 
the challenge material. The challenge will consist of 8 doses (peanut or placebo), given every 15 
to 30 minutes: 1, 3, 10, 30, 100, 300, 600, 1000 mg, up to 2044 mg peanut protein (cumulative). 
Both peanut and oat protein will be concealed in a food that masks the taste. The food challenges 
will be performed on different days (1 day placebo [oat] protein, 1 day peanut protein, with order 
determined at random) at least 24 hours, but not more than 7 days, apart and not within 24 hours 
of a dose of study drug. After the last dose of the DBPCFC, the patient will be monitored for at 
least 2 hours and then discharged from the clinic.  Patients will be considered to have passed the 
DBPCFC if they do not experience any objective Grade 1 reaction by the CoFAR grading system 
(see Appendix 2). If the patient experiences reactions, they will be treated with the necessary 
rescue medications. Symptom severity will be adjudicated by an independent, blinded assessor 
who is not involved in performing the baseline food challenge. 
9.2.2.2. 
Peanut Skin Prick Test 
The standard SPT is performed on the volar surface of the patient’s forearm using standard whole 
peanut extract, 1:10 w/v (ALK-Abello) and will only be performed at screening. A positive result 
is ≥3 mm determined by averaging maximal perpendicular wheal diameters 15 minutes after 
applying the lancet. The positive control is histamine base, 6 mg/mL (ALK-Abello) and with a 
wheal ≥3 mm indicating a valid test. The negative control is glycerol saline.  
The titrated SPT is the skin testing for atopic response at different concentrations of peanut extract 
with saline as negative control and histamine as positive controls. The test will be performed at 
time points shown in Table 1. The SPTs will be performed starting at the following dilutions: neat, 
1:20, 1:200, 1:2000, 1:20,000. Wheal size induced by peanut extract at each concentration will be 
calculated as the average of the largest diameter and the perpendicular midpoint diameter. 
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9.2.2.3. 
Food Allergy Quality of Life Questionnaire 
The Food Allergy Quality of Life Questionnaire (FAQLQ) is a validated food allergy-specific 
health-related quality of life (HRQL) questionnaire, which measures the impact of social and 
dietary limitations and assesses the emotional impact of these restrictions on the lives of patients.   
Patients self-report the impact of food allergy on HRQL using different forms of FAQLQ 
depending on their age; the child form (FAQLQ-CF) is used by patients aged 8 to 12 years and the 
teenager form (FAQLQ-TF) is used for patients aged 13 to 17 years.  The parent form (FAQLQ-
PF) is a measure of children’s HRQL that is reported by parent proxy from the child’s perspective 
and can be used for patients of ages 0 to 12 years.  The FAQLQ will be administered to patients 
and, when appropriate, parents at time points in accordance with Table 1. Patients will continue 
using the FAQLQ version first administered at baseline regardless of moving to the next age 
bracket. 
9.2.3. 
Safety Procedures 
9.2.3.1. 
Vital Signs 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration will be collected 
at time points according to Table 1. During the DBPCFC, vital signs will be monitored every 15 
to 30 minutes. After initial DBPCFC dose, only pulse and blood pressure need to be taken as part 
of safety monitoring. 
9.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1.  Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the patient’s medical history. 
9.2.3.3. 
Spirometry 
A spirometer that meets the American Thoracic Society (ATS) / European Respiratory Society 
(ERS) recommendations will be used to measure FEV1 and/or PEFR. During DBPCFC, 
spirometry should be performed before and after the challenge. The same spirometer and standard 
spirometric techniques, including calibration, should be used to perform spirometry at different 
visits and, whenever possible, the same person should perform the measurements. FeNO should 
be done prior to spirometry. 
9.2.3.4. 
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 1. Tests will include: 
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Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Indirect 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]) 
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 
For female patients of child-bearing potential, a serum pregnancy test will be performed at 
screening and end of study visits. For other visits where a pregnancy test is scheduled, a urine 
pregnancy test will be performed. 
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Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.   
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 10.4.5. 
9.2.4. 
Drug Concentration and Measurements 
Samples for drug concentration will be collected at time points listed in Table 1. 
Any unused samples may be used for exploratory biomarker research. 
9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 1. 
Detailed instructions for blood sample collection are included in the laboratory manual provided 
to study sites. Any unused samples may be used for exploratory research. 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
Biomarker samples will be collected at time points according to Table 1. Biomarker measurements 
will be performed to determine effects on relevant physiological and pathogenic processes. 
The biomarkers studied will be ones believed to be relevant to the pathophysiology of peanut 
allergy, immunology, mechanism of action of dupilumab and possible toxicities. Biomarkers 
studied may include but need not be limited to: Total IgE, TARC, sIgE, sIgG4, sIgG, TruCulture 
study of ex vivo peanut stimulation of whole blood (supernatant cytokine and chemokine profiling, 
mRNA analyses [including transcriptome sequencing] of the resulting cell pellet), and basophil 
allergen sensitivity to allergen stimulation and peanut-specific T-cell and Th2A subset profiling. 
Additional serum and plasma samples will be banked for research. Any unused samples collected 
for PK, ADA, and biomarkers may also be used for exploratory research. 
Exploratory biomarker results not required for protocol-defined endpoint analyses will not be 
included in the clinical study report. 
9.2.6.1. 
Serum Thymus and Activation-Regulated Chemokine and Total IgE 
Serum TARC and total IgE are markers of Type 2 activity. Dupilumab significantly suppressed 
both TARC and total IgE in studies of adult AD, nasal polyposis, and asthma patients. 
9.2.6.2. 
Serum Peanut-Specific Antibody Assays (Peanut-specific IgE, IgG, IgG4) 
In prior dupilumab studies, dupilumab suppressed both total and allergen-specific IgEs. In general, 
dupilumab suppresses total IgE by ~ 50% within 12 to 16 weeks of treatment initiation. 
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9.2.6.3. 
Fractional Exhaled Nitric Oxide 
Fractional exhaled nitric oxide (FeNO) is a non-invasive marker that has been shown to correlate 
with allergic airway inflammation and IgE sensitization. The measurement of FeNO was reported 
to be predictive of peanut oral food challenge outcome (Preece, 2014). Although no manufacturer 
has validated the FeNO device for children under 7 years old due to inadequate exhalation force, 
there are no contraindications with the use of FeNO for 6-year-old children.  Also, specific 
guidance and reference ranges are available for collection in children as young as 6 years of age 
(Brody, 2013) (Menou, 2017). As FeNO is an exploratory biomarker, it will be collected for 
children 6 years old unless the investigator declines to collect. Fractional exhaled nitric oxide will 
be performed prior to spirometry. 
9.2.7. 
Exploratory Research 
Research samples (whole blood/PBMCs) will be banked, unless there are local regulatory or IRB 
restrictions at the study site, for exploratory research related to immunology of peanut allergy, 
other allergic diseases, IL-4/IL-13-mediated Type 2 inflammation, and dupilumab (including 
mechanism of action, efficacy, toxicity).  Research may also include, T-cell and B-cell receptor 
repertoire analyses, which requires RNA sequencing). The list may be altered or expanded as it is 
recognized that more relevant or novel biomarkers may be discovered during the course of this 
study. Banked research samples (serum/plasma/PBMCs), as well as any unused samples for study-
related research (including PK and ADA samples), will be stored for up to 15 years after the final 
date of the database lock.  The unused samples may be utilized for the scope of research described 
above.  After 15 years, any residual samples will be destroyed. Results of these exploratory 
analyses will not be reported in the CSR. 
9.2.7.1. 
Genomics Analysis 
DNA samples will be collected for the genomics analyses unless there are local regulatory or IRB 
restrictions at the study site. Samples will be single-coded as defined by the International Council 
for Harmonisation (ICH) guideline E15. Samples will be stored for up to 15 years after the final 
date of the database lock and may be used for research purposes. The purpose of the genomic 
analyses is to identify genomic associations with clinical or biomarker response, other clinical 
outcome measures and possible AEs. In addition, associations between genomic variants and 
prognosis or progression of peanut allergy, as well as related diseases may also be studied. Samples 
may also be used as controls in genetic research unrelated to the scientific purposes stated above. 
Patient's genetic data may be used or combined with data collected from other studies to identify 
and validate genomic markers related to the study drug and related diseases. Analyses may include 
sequence determination or single nucleotide polymorphism studies of candidate genes and 
surrounding genomic regions. Other methods, including whole-exome sequencing, whole-genome 
sequencing, DNA copy number variation, and transcriptome sequencing (eg, TruCulture cell 
pellet) may also be performed. The list of methods may be expanded to include novel methodology 
that may be developed during the course of this study or sample storage period. Results from the 
genomic analysis will not be reported in the CSR. 
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10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
10.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/Ethics Committee 
(EC) all unanticipated problems involving risks to patients, according to local regulations. This 
may include death from any cause and all SAEs related to the use of the study drug. It is 
recommended that all SAEs be reported to the IRB/EC, according to local regulations. 
10.2. 
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 (suspected unexpected serious 
adverse reaction [SUSAR]), to the health authorities, IRBs/ECs as appropriate, and to the 
investigators.  
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 
symptoms related to (add underlying condition intended to be studied) which occur during the 
screening/washout period prior to study drug administration will be considered expected. 
In addition, the sponsor will report in 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 IRB/ECs as appropriate. 
10.3. 
Definitions 
10.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
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. 
10.3.2. 
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 patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
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 Requires in-patient hospitalization or prolongation of existing hospitalization.  In-
patient hospitalization is defined as admission to a hospital (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event, or that is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
 Is a congenital anomaly/birth defect 
 Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
10.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 10.4.3). 
10.4. 
Recording and Reporting Adverse Events 
10.4.1. 
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. However, allergic reactions to the DBPCFC during the screening 
phase, at endpoint challenges (at week 24 and 36) will be recorded as allergic signs and symptoms 
since they are anticipated to allergen. Refer to the study reference manual for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 10.4.6. Laboratory, vital signs 
abnormalities are to be recorded as AEs as outlined in Section 10.4.5. 
10.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study reference manual for the procedure to be 
followed. 
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. 
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In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 SAE with an onset within 30 days of the end of study or within 12 weeks of last study 
drug administration if the patient 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. 
10.4.3. 
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: Dupilumab is administered every 14±3 days Q2W. The 
doses of this investigational product must be separated by ≥11 days to avoid overdose. Accidental 
or intentional overdose of at least 2 times the intended dose of study drug 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 during the study or within 12 weeks of the last dose of study drug. Any complication 
of pregnancy affecting a female study patient and/or fetus and/or newborn that meets the SAE 
criteria must be reported as an SAE. Outcome for all pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest: All AESI, serious and nonserious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, per 
Section 10.4.2. Adverse events of special interest for this study include the following:   
 Anaphylactic reactions 
 Systemic or extensive hypersensitivity reactions 
 Malignancy 
 Helminthic infections 
 Suicide-related events 
 Conjunctivitis (any type or etiology), keratitis or blepharitis (for all these AEs only 
events that are severe or serious or lasting ≥4 weeks will be reported as AESIs) 
Refer to the study manual for the procedures to be followed. 
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
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Refer to the study reference manual for the procedures to be followed. 
10.4.5. 
Abnormal Laboratory, Vital Signs 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 10.5.1. 
10.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
10.5. 
Evaluation of Severity and Causality 
10.5.1. 
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 patient’s health.  Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade: 
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Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
10.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Dupilumab: 
The relationship of AEs to study drug will be assessed by the 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 drug? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the study drug 
Related: There is a reasonable possibility that the event may have been caused by the study 
drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below.  
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
 due to external causes such as environmental factors or other treatment(s) being 
administered 
 due to the patient’s disease state or clinical condition 
 do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
 do not reappear or worsen when dosing with study drug is resumed 
 are not a suspected response to the study drug 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 patient’s disease state or clinical condition 
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 follow a reasonable temporal sequence following the time of administration of the 
dose of study drug  
 resolve or improve after discontinuation of study drug  
 reappear or worsen when dosing with study drug  
 are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
10.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments (eg, 
Pharmacovigilance 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. 
10.7. 
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). 
11. 
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 5. 
11.1. 
Statistical Hypothesis 
The statistical hypothesis is on the primary endpoint, the proportion of patients who achieve a 
cumulative dose of at least 444 mg peanut protein during a DBPCFC at week 24. 
Let μD be the true proportion of patients who achieve a cumulative dose of at least 444 mg peanut 
protein during a DBPCFC at week 24 for dupilumab. The following hypothesis for the superiority 
testing will be tested at the 2-sided 5% significance level:  
Null hypothesis H0: μD = 8%, ie, the proportion of patients who achieve a cumulative dose of at 
least 444 mg peanut protein during a DBPCFC at week 24 is 8%.  
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Alternative hypothesis Ha: μD ≠ 8%, ie, the proportion of patients who achieve a cumulative dose 
of at least 444 mg peanut protein during a DBPCFC at week 24 is different from 8%. 
11.2. 
Justification of Sample Size 
The sample size is determined to adequately power the primary endpoint of the proportion of 
patients who pass at least a DBPCFC of at least 444 mg (cumulative) of peanut protein at week 
24. Based on assessment of clinical data from the Aimmune Therapeutics AR101 phase 3 study, 
it is assumed that the rate of a tolerated cumulative dose of at least 444 mg of peanut protein on 
DBPCFC at week 24 is 29% in dupilumab and 8% in placebo (Vickery, 2018). 
A sample size of 20 patients will have 80% power to detect the 29% tolerated rate in dupilumab 
group at the 2-sided 5% significance level. Allowing for a dropout rate of around 15%, 
approximately 24 patients will be required. The sample size calculations were done by one-sample 
Chi-square test (normal approximation) using nQuery + nTerim 4. 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all enrolled patients. The week 36 FAS includes patients who 
pass a DBPCFC of at least 444 mg (cumulative) of peanut protein at week 24. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all patients who received any study drug; it is based on the 
treatment received (as treated). Treatment compliance/administration and all clinical safety 
variables will be analyzed using the SAF. 
11.3.3. 
Pharmacokinetic Analysis Sets 
The PK population includes all treated patients who received any study drug and who had at least 
1 non-missing drug concentration result following the first dose of study drug. 
11.3.4. 
Immunogenicity Analysis Sets 
The ADA analysis set consists of all patients who received any study drug and who had at least 1 
non-missing ADA result following the first dose of study drug.  
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay (patients who are ADA 
negative are set to negative in the NAb analysis set). 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information:  the 
number of patients reflected in the calculation (n), mean, median, first quartile (Q1), third 
quartile (Q3), standard deviation, minimum, and maximum.   
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
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All dupilumab patients, regardless of whether it is 200 mg dupilumab or 300 mg dupilumab, will 
be combined for analysis. 
11.4.1. 
Patient Disposition 
The following will be provided: 
 The total number of screened patients:  met the inclusion criteria regarding the target 
indication and signed the informed consent form (ICF) 
 The total number of enrolled patients 
 The total number of patients in each analysis set (eg, FAS, provided in Section 11.3 
for analysis sets) 
 The total number of patients who discontinued the study, and the reasons for 
discontinuation 
 A listing of patients prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively.   
11.4.3. 
Efficacy Analyses 
Efficacy analyses will be conducted using the FAS population and week 36 FAS population. The 
FAS will be used for efficacy analysis at week 24, and week 36 FAS will be used for efficacy 
analysis at week 36. 
11.4.3.1. Primary Efficacy Analysis 
The FAS will be used for the primary efficacy endpoint. The primary endpoint will be analyzed 
using one-sample Chi-square test. Estimate of proportion, p-value, and the 2-sided 95% 
confidence interval will be provided. 
If a patient does not have available DBPCFC data at week 24, the patient will be considered as a 
non-responder regardless of reasons for missing data. 
Sensitivity analyses of the primary endpoint will include an analysis of the subset of patients 
with available week 24 DBPCFC. Other sensitivity analyses may be proposed in the SAP. 
Subgroup analysis (eg, by baseline weight group) will be performed. 
11.4.3.2. Secondary Efficacy Analysis 
All secondary endpoints (Section 4.1.2) will be analyzed descriptively at given visits. FAS will be 
used for efficacy analysis at week 24, and week 36 FAS will be used for efficacy analysis at week 
36. 
All secondary endpoints will be analyzed descriptively at given visits. FAS will be used for 
efficacy analysis at week 24, and week 36 FAS will be used for efficacy analysis at week 36. For 
binary endpoints, the analysis and imputation methods will be similar to the primary analysis. 
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A one-sample t-test will be performed to assess the change from baseline to week 24 in the 
cumulative tolerated dose (log transformed) of peanut protein during a DBPCFC. Estimate of 
change from baseline to week 24, p-value, and the 2-sided 95% confidence interval will be 
provided. If the data is extremely skewed, nonparametric method may be applied. Details will be 
provided in the SAP. The missing data will be imputed by the last non-missing DBPCFC 
assessment including baseline. 
For other continuous endpoints, the analysis and imputation methods will be applied similarly. 
Sensitivity analysis will include an analysis based on the observed cases. Other sensitivity analysis 
may be proposed in the SAP. 
11.4.3.3. Multiplicity Considerations 
No adjustments for multiplicity for the secondary endpoints are planned for this study. 
11.4.3.4. Timing of Analyses 
A primary analysis may be performed when the last patient completes 24 weeks of the treatment 
period as specified in the protocol (week 24 visit or earlier for those patients who are withdrawn 
prematurely from the study).  No changes in the conduct of the study will be made based on this 
primary analysis.  The analyses of primary and secondary endpoints up to week 24 as specified in 
Section 11.4.3.1 and Section 11.4.3.2 will be the final analysis of the primary endpoint and the 
secondary endpoints up to week 24.   
11.4.4. 
Safety Analysis 
11.4.4.1. 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-emergent period is defined as the day from first dose of study drug to 
the end of the study. The treatment-emergent period includes the 24-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. 
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. 
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Summaries of all TEAEs will include: 
 The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
 TEAEs by severity (according to the grading scale outlined in Section 10.5.1), 
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. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
11.4.4.2. 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 as well as the vital signs 
according to Bock’s scale during the challenge (Appendix 2) 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 patients with a potentially clinically significant value (PCSV) at any 
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. 
11.4.4.3. Treatment Exposure 
The duration of exposure during the study will be presented and calculated as: 
(Date of last study drug injection – date of first study drug injection) + 14 days 
The number (%) of patients exposed to the study drug will be presented by specific time periods. 
The time periods of interest will be specified in the SAP. 
In addition, duration of exposure during the study will be summarized using number of patients, 
means, standard deviation, minimums, Q1, medians, Q3, and maximums. 
A summary of the number of doses will be provided. 
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11.4.4.4. 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 of study drug will be presented by specific ranges. The ranges of interest 
will be specified in the SAP. 
11.4.5. 
Analysis of Drug Concentration Data 
Descriptive statistics will be used to summarize the concentration data at each sampling time. 
No formal statistical analysis will be performed. 
11.4.6. 
Analysis of Immunogenicity Data 
Analysis of ADA will be conducted on samples collected at baseline, week 12, week 24, and week 
36. Samples that are positive in the ADA assay will be further characterized for ADA titers and 
for the presence of an NAb response. 
Anti-drug antibody response categories and titer categories that will be assessed are as follows:   
 Pre-existing immunoreactivity 
 Treatment-emergent response 
The treatment-emergent responses will be further characterized as persistent, 
indeterminate, and transient. 
 Treatment-boosted ADA response  
 Titer value category (tier range) 
 Low (titer <1,000) 
 Moderate (1,000≤ titer ≤10,000) 
 High (titer >10,000)  
 NAb response in ADA positive patients. 
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
and NAb positivity presented by patient, time point, and dose group cohort/group will be provided. 
Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and 
percent of patients (%), grouped by study cohorts dose group and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles may be evaluated.  Assessment of impact of ADA and NAbs on safety and efficacy 
may be provided. 
11.4.7. 
Analysis of Pharmacodynamics Data 
The exploratory biomarker data will be summarized by descriptive statistics. 
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11.5. 
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, vital sign data, or physical examination 
data will be made. 
Visit windows: 
 Assessments taken outside of protocol allowable windows will be displayed 
according to the case report form (CRF) assessment recorded by the investigator. 
Unscheduled assessments: 
 Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries and all observations will be 
presented in listings. 
11.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, only those parameters required for the development 
program and/or reporting to regulatory authorities will be summarized. Investigator and sponsor 
responsibilities surrounding the premature termination of a study are presented in Section 17.1. 
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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are described in this section.   
12.1. 
Data Management and Electronic Systems 
12.1.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) tool. 
12.1.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
 IWRS system – study drug supply 
 EDC system – data capture 
 Statistical Analysis System (SAS) – statistical review and analysis 
 Pharmacovigilance safety database 
13. 
STUDY MONITORING 
13.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization [CRO] monitor) will visit 
each site prior to enrollment of the first patient, and periodically during the study.   
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements 
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13.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient 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. 
13.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic Case Report 
Forms (CRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each and every patient enrolled in the study. After review of the clinical data for 
each patient, the investigator must provide an electronic signature. A copy of each patient CRF 
casebook is to be retained by the investigator as part of the study record and must be available at 
all times for inspection by authorized representatives of the sponsor and regulatory authorities. 
14. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities.  Should this occur, the investigator is responsible for: 
Informing the sponsor of a planned inspection by the authorities as soon as notification is received, 
and authorizing the sponsor’s participation in the inspection 
Providing access to all necessary facilities, study data, and documents for the inspection or audit 
Communicating any information arising from inspection by the regulatory authorities to the 
sponsor immediately 
Taking all appropriate measures requested by the sponsor to resolve the problems found during 
the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
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15. 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1. 
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. 
15.2. 
Assent and Informed Consent 
The principles of informed consent are described in ICH guidelines for Good Clinical Practice. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB/EC -approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each patient and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the patient’s 
parent(s) or legal guardian(s) and the same investigator or designee who explained the ICF. 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required.  
If only 1 parent or guardian signs the consent form, the investigator must document the reason the 
other parent or guardian did not sign. The patient may also be required to sign and date the ICF, 
as determined by the IRB/EC and in accordance with the local regulations and requirements. 
 Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
 Patients who can understand but who can neither write nor read will have the ICF 
read to them in presence of an impartial witness, who will sign and date the ICF to 
confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient’s study record, and a 
copy of the signed ICF must be given to the patient’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately. All study patients and their parent(s) or legal guardian(s) 
must be informed of the new information and provide their written consent if they wish the patient 
to continue in the study. The original signed revised ICF must be maintained in the patient’s study 
record and a copy must be given to the patient’s parent(s) or legal guardian(s). 
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15.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF) must be kept in strict confidence. 
The patient's and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
15.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
 The protocol, assent, ICF, and any other materials to be provided to the patients (eg, 
advertising) before any patient may be enrolled in the study 
 Any amendment or modification to the study protocol, assent or ICF before 
implementation, unless the change is necessary to eliminate an immediate hazard to 
the patient, in which case the IRB/EC should be informed as soon as possible  
 Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB/EC should be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
A copy of the IRB/EC approval letter with a current list of the IRB/EC members and their functions 
must be received by the sponsor prior to shipment of drug supplies to the investigator. The approval 
letter should include the study number and title, the documents reviewed, and the date of the 
review. 
Records of the IRB/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
15.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations.  Treatment codes will be disseminated to each investigation site 
thereafter. 
16. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol, assent or ICF without an 
IRB/EC-approved amendment. 
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17. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
17.1. 
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. 
17.2. 
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 patient within a reasonable period of time 
 The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
 The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB/EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
18. 
STUDY DOCUMENTATION 
18.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of patient 
final CRF/eCRF that will be provided to the sponsor. 
18.2. 
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 
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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.  
19. 
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 12.1.1). 
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 13.1, Section 13.2, Section 14).   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 13.1).   
All 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 patient final CRF (Section 13.3 and 
Section 18.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF (Section 13.2).  
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 18.2).  
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20. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
21. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
22. 
PUBLICATION POLICY 
The publication policy is provided as a separate agreement. 
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23. 
REFERENCES 
Anagnostou K, Clark A, King Y, et al. Efficacy and safety of high-dose peanut oral 
immunotherapy with factors predicting outcome. Clin Exp Allergy. 2011 Sep;41(9):1273-81. 
Anagnostou K, Islam S, King Y. Assessing the efficacy of oral immunotherapy for the 
desensitisation of peanut allergy in children (STOP II): a Phase 2 randomised controlled trial 
Lancet 2014; 383 (9925), 1297-1304. 
Bock SA, Sampson HA, Atkins FM, et al. Double-blind, placebo-controlled food challenge 
(DBPCFC) as an office procedure: a manual.  JACI 1988; 82:986–97. 
Brody D, Zhanh, X, Kit B, Dillon C. Reference values and factors associated with exhaled nitric 
oxide: U.S. youth and adults. Respiratory Medicine (2013) 107, 1682-1691. 
Busse WW, Maspero JF, Rabe KF, et al. Liberty Asthma QUEST: Phase 3 Randomized, Double-
Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Dupilumab Efficacy/Safety in 
Patients with Uncontrolled, Moderate-to-Severe Asthma. Adv Ther. 2018 May 3. doi: 
10.1007/s12325-018-0702-4. [Epub ahead of print]. 
Dunlop J, Keet C. Epidemiology of Food Allergy. Immunol Allergy Clin North Am. 2018 
Feb;38(1):13-25. 
Dyer AA. Epidemiology of Food. Allergy, Asthma Proc, 2015, 36:58-64. 
Glaumann S, Nilsson C, Asarnoj A, et al. IgG4 antibodies and peanut challenge outcome in 
children IgE-sensitized to peanut. Pediatr Allergy Immunol. 2015 Jun;26(4):386-9. doi: 
10.1111/pai.12370. Epub 2015 Apr 21 
Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of 
childhood food allergy in the United States. Pediatrics 2011;  128, e9–e17 
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised 
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the 
World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-836. 
Jones SM, Pons JL, Roberts AM, et al. Clinical efficacy and immune regulation with peanut oral 
immunotherapy. J Allergy Clin Immunol 2009; 124:292-300. 
Menou A, Babeanu H, Paruit H, et al. Normal values of offline exhaled and nasal nitric oxide in 
healthy children and teens using chemiluminescence. J. Breath Res. 11 (2017) 036008. 
Muraro A. Roberts G. Clark A. E, et al. The management of anaphylaxis in childhood: position 
paper of the European academy of allergology and clinical immunology. Allergy. 2007;62(8):857-
871. 
Nwaru BI, Hickstein L, Panesar SS, et al. EAACI Food Allergy and Guidelines Group. Prevalence 
of common food allergies in Europe: a systemic review and meta-analysis. Allergy, 2014;69;992-
1007. 
Percival E, Bhatia R, Preece K, et al. Reproducibility of serum IgE, Ara h2 skin prick testing and 
fraction of exhaled nitric oxide for predicting clinical peanut allergy in children. Allergy Asthma 
Clin Immunol. (2016) 12:35. 
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Preece K, Bhatia R, Belcher J, et al. The fraction of exhaled nitric oxide improves prediction of 
clinical allergic reaction to peanut challenge in children. Clin Exp Allergy. 2014 Mar;44(3):371-
80. 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report--Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. J Allergy Clin Immunol. 2006; 117(2): 391-7. 
Sicherer SH, Munoz-Furlong A, Godbold JH, et al. US prevalence of self-reported peanut, tree 
nut, and sesame allergy: 11 year follow-up. JACI, 2010, 125:1322-6. 
Simons FE, Ardusso LR, Bilò MB, Cardona V, Ebisawa M, El-Gamal YM, et al. International 
consensus on (ICON) anaphylaxis. World Allergy Organ J. 2014;30;7(1):9. 
Simons FE. Anaphylaxis pathogenesis and treatment. Allergy. 2011 Jul;66 Suppl 95:31-4. doi: 
10.1111/j.1398-9995.2011.02629 
Varshney P, Jones SM, Scurlock AM, et al. A randomized controlled study of peanut oral 
immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin 
Immunol 2011; 127(3):654-60. 
Vickery BP, Scurlock AM, Kulis M. Sustained unresponsiveness to peanut in subjects who have 
completed peanut oral immunotherapy. JACI 2014; 133 (2), 468 - 475. 
Vickery BP, Vereda A, Casale TB, et al. AR101 Oral Immunotherapy for Peanut Allergy. N Engl 
J Med. 2018 Nov 22.  doi: 10.1056/NEJMoa1812856. Epub 2018 Nov 18. 
Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled 
persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting 
β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. 
Lancet 2016; 388 (10039): 31-44. 
Wong Y, Hussey-Freeland D, Nadeau K, Food allergy: immune mechanisms, diagnosis and 
immunotherapy. Nat Rev Immun 2016 
Wood R. Oral Immunotherapy for Food Allergy.  J Investig Allergol Clin Immunol 2017; 27(3) 
1-23. 
Yu W, Freeland DMH, Nadeau KC. Food allergy: immune mechanisms, diagnosis and 
immunotherapy. Nat Rev Immunol. 2016 Dec;16(12):751-765. doi: 10.1038/nri.2016.111. Epub 
2016 Oct 31. 
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24. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: “A Study to Evaluate the Efficacy and Safety of Dupilumab 
Monotherapy in Pediatric Patients with Peanut Allergy” 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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APPENDIX 1. PEANUT 
DBPCFC 
SCHEDULE 
OF 
DOSING 
PERFORMED AT SCREENING AND WEEKS 24 AND 36 
Challenge Doses 
 
 
Amount of Peanut 
Protein at Each 
Challenge Dose (mg) 
 
Amount of Peanut 
Flour with 50% 
Protein Content (mg) 
Cumulative 
Amount of 
Peanut Protein 
(mg) at Screening 
Cumulative Amount 
of Peanut Protein 
(mg) on Study 
(Weeks 24 and 36) 
Screening 
1 
2 
1 
1 
Screening 
3 
6 
4 
4 
Screening 
10 
20 
14 
14 
Screening 
30 
60 
44 
44 
Screening 
100 
200 
144 
144 
Endpoint 
300 
600 
- 
444 
Endpoint 
600 
1200 
- 
1044 
Endpoint 
1000 
2000 
 
2044 
Note: The DBPCFC is to be conducted as 2 challenges, each on a separate day using a placebo (artificially peanut-flavored oat 
protein) for one challenge and peanut (as defatted peanut protein) for the other. The oral food challenge is to be performed under 
double-blind conditions so that neither the patient, nor the patient’s caregiver, nor any of the clinic staff (save for the unblinded 
preparer of the challenge foods) knows which challenge contains the peanut or the placebo. The clinic staff may not be unblinded 
as to the order of the 2 parts (peanut and placebo) of the DBPCFC until after completion of the observation period of the second 
part of the challenge for the screening challenge only.  For weeks 24 and 36, the study team will remain blinded to the order of 
the exposure for each challenge date. 
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APPENDIX 2. ALLERGY REACTION SEVERITY GRADING 
The Consortium of Food Allergy Research (CoFAR) grading system for allergic reactions 
 
 
PRACTALL consensus report on DBPCFC, and with the CoFAR grading system for allergic 
reactions, are provided as a general guide. 
Mild Symptoms:  
• Skin – limited (few) or localized hives, swelling (eg, mild lip edema), skin flushing (eg, few areas of faint erythema) or 
pruritus (mild, eg, causing occasional scratching)  
• Respiratory – rhinorrhea (eg, occasional sniffling or sneezing), nasal congestion, occasional cough, throat discomfort  
• Gastrointestinal (GI) – mild abdominal discomfort (including mild nausea), minor vomiting (typically a single episode) 
and/or a single episode of diarrhea  
Moderate Symptoms:  
• Skin – systemic hives (eg, numerous or widespread hives), swelling (eg, significant lip or face edema), pruritus 
causing protracted scratching, more than a few areas of erythema or pronounced erythema  
• Respiratory – throat tightness without hoarseness, persistent cough, wheezing without dyspnea  
• GI – persistent moderate abdominal pain/cramping/nausea, more than a single episode of vomiting and/or diarrhea 
Severe Symptoms:  
• Skin – severe generalized urticaria/angioedema/erythema  
• Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea, stridor  
• GI – severe abdominal pain/cramping/repetitive vomiting and/or diarrhea  
• Neurological – change in mental status  
• Circulatory – clinically significant hypotension  
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APPENDIX 3. CRITERIA 
FOR 
SUSPECTED 
DIAGNOSIS 
AND 
SEVERITY GRADING OF ANAPHYLAXIS 
Anaphylaxis is likely when any 1 of the 3 following sets of criteria is fulfilled: 
1.  Acute onset of an illness (minutes to hours) with involvement of: 
 Skin/mucosal tissue (eg, generalized hives, itch or flush, swollen lips/tongue/uvula) 
AND 
 Airway compromise (eg, dyspnea, stridor, wheeze/ bronchospasm, hypoxia, reduced 
PEF) AND/OR 
 Reduced BP or associated symptoms (eg, hypotonia, syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to the allergen (minutes to 
hours): 
 Skin/mucosal tissue (eg, generalized hives, itch/flush, swollen lips/tongue/uvula) 
 Airway compromise (eg, dyspnea, stridor wheeze/bronchospasm, hypoxia, reduced 
PEF) 
 Reduced BP or associated symptoms (eg, hypotonia, syncope, incontinence) 
 Persistent GI symptoms (eg, nausea, vomiting, crampy abdominal pain) 
3. Reduced BP after exposure to the allergen (minutes to hours): 
 Infants and Children: low systolic BP (age-specific) or >30% drop in systolic BP* 
 Adults: systolic BP <90 mm Hg or >30% drop from their baseline 
* Low systolic BP for children is defined as <70 mm Hg from 1 month to 1 year; less than (70 mm 
Hg + [2 x age]) from 1 to 10 years; and <90 mm Hg from age 11 to 17 years. 
Note: Isolated skin or mucosal lesions following the ingestion of a food constitute a “food-induced 
allergic reaction”. 
Criteria for Severity Grading (Muraro 2007) 
Staging System of Severity of Anaphylaxis 
Stage 
Defined By 
1. Mild (skin & subcutaneous tissues, GI, 
&/or mild respiratory) 
Flushing, urticaria, periorbital or facial angioedema; mild 
dyspnea, wheeze or upper respiratory symptoms; mild 
abdominal pain and/or emesis 
2. Moderate (mild symptoms + 
features suggesting moderate 
respiratory, cardiovascular or GI 
symptoms) 
Marked dysphagia, hoarseness and/or stridor; shortness 
of breath, wheezing & retractions; crampy abdominal 
pain, recurrent vomiting and/or diarrhea; and/or mild 
dizziness 
3. Severe (hypoxia, hypotension, or 
neurological compromise) 
Cyanosis or SpO2 ≤92% at any stage, hypotension, 
confusion, collapse, loss of consciousness; or 
incontinence 
                                        VV-RIM-00101740-1.0 Approved - 30 Mar 2020 GMT-5:00


Clinical Study Protocol 
R668-ALG-1702 Amendment 2 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 75 of 75 
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 and Safety of Dupilumab Monotherapy in 
Pediatric Patients with Peanut Allergy 
Protocol Number: 
R668-ALG-1702 
Protocol Version:  
R668-ALG-1702 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-00101740-1.0 Approved - 30 Mar 2020 GMT-5:00


Signature Page for VV-RIM-00101740 v1.0
Signature Page for VV-RIM-00101740 v1.0 Approved
ESig Approval
-2020 12:47:22 GMT+0000
ESig Approval
20 12:55:10 GMT+0000
ESig Approval
-2020 14:26:28 GMT+0000
ESig Approval
000
                                        VV-RIM-00101740-1.0 Approved - 30 Mar 2020 GMT-5:00