Conditions: Peanut Allergy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 148
Healthy volunteers: no

Brief summary:
Primary objective is to assess whether dupilumab as adjunct to AR101 compared to placebo improves desensitization at the completion of up-dosing, defined as an increase in the proportion of participants who pass a post up-dosing double-blind placebo-controlled food challenge (DBPCFC) at visit 16.

Secondary objectives are:

* To assess whether dupilumab as adjunct to AR101 compared to placebo improves desensitization at the completion of up-dosing, defined as an increase in the cumulative tolerated dose (log transformed) of peanut protein during a post up-dosing DBPCFC at visit 16
* To assess whether dupilumab as (indefinite \[continuously\]) adjunct to AR101 compared to placebo maintains desensitization, defined as an increase in the proportion of participants who pass a post maintenance DBPCFC at visit 22
* To assess whether dupilumab as (limited \[previously\]) adjunct to AR101 compared to placebo maintains desensitization, defined as an increase in the proportion of participants who pass a post maintenance DBPCFC at visit 22
* To evaluate the safety and tolerability of dupilumab as adjunct to AR101 compared to placebo
* To assess the effect of dupilumab (compared to placebo) as adjunct to AR101 on the change in peanut-specific Immunoglobulin E (sIgE), Immunoglobulin G (IgG), Immunoglobulin G4 (IgG4), and peanut-specific IgG4/IgE ratio
* To assess if dupilumab increases the tolerability of AR101 as measured by the daily symptoms (electronic diary \[e-diary\]) during the up-dosing phase

Detailed description:

Arms:
arm 1: Participant randomization of a ratio of 2 active dupilumab arms arm 2: Participant randomization of a ratio of 1 placebo arm

Interventions: intervention 1: Dupilumab intervention 2: Placebo matching dupilumab intervention 3: AR101
Intervention descriptions: intervention 1: Dupilumab will be administered subcutaneously (SC) in a single-use, pre-filled glass syringe every two weeks (Q2W) intervention 2: Placebo matching dupilumab is prepared in the same formulation without the addition of protein intervention 3: AR101 will be provided in dose-escalating capsules and then sachets during maintenance phase

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
R668-ALG-16114 Amendment 4 
Regeneron Pharmaceuticals, Inc. 
Page 1 of 118 
CONFIDENTIAL 
IND Number: 18263 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY IN PEDIATRIC SUBJECTS WITH 
PEANUT ALLERGY TO EVALUATE THE EFFICACY AND SAFETY 
OF DUPILUMAB AS ADJUNCT TO AR101 (PEANUT ORAL 
IMMUNOTHERAPY) 
Compound: 
Dupilumab 
Clinical Phase: 
2 
Protocol Number: 
R668-ALG-16114 
Protocol Version: 
R668-ALG-16114 Amendment 4 
Amendment 4 Date of Issue: 
See appended electronic signature page of the 
clean version
Amendment 3 Date of Issue: 
12 May 2020 
Amendment 2 Date of Issue: 
06 Sep 2019 
Amendment 1 Date of Issue: 
Original Date of Issue: 
02 Nov 2018 
07 Jun 2018 
Scientific/Medical Monitor: 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
 
VV-RIM-00116697-1.0 Approved - 23 Jul 2020 GMT-5:00
NCT03682770


Clinical Study Protocol 
 
R668-ALG-16114 Amendment 4 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 118 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 4 
The purpose of this amendment is to define the primary efficacy analysis based on approximately 122 subjects who 
up-dosed AR101 per the original protocol’s 24-week up-dosing schedule (pre-COVID-19 restrictions) and to define a 
modified analysis set to differentiate these subjects. Changes were also made to clarify: rescue and prohibited 
medications, biomarker variables, visit windows, and adverse events of special interest (AESIs). The following table 
outlines changes made to the protocol and the rationale.  
  
Description of Change 
Rationale 
Section Changed 
Updated sample size for the 
primary analysis such that 
approximately 122 subjects who 
undergo the post up-dosing 
double-blind placebo-controlled 
food challenge (DBPCFC) at week 
28 (visit 16) or discontinue from 
study prior to week 28 (visit 16) 
will be included in the primary 
efficacy analysis.  
 
Added a new analysis set to the 
statistical plan to clarify that these 
subjects who up-dosed AR101 per 
the original protocol plan will be 
analyzed in a modified full 
analysis set (mFAS), separate from 
the full analysis set (FAS), which 
includes all randomized subjects.  
To differentiate the analysis 
of subjects who up-dosed 
AR101 per the original 
protocol plan from those 
subjects who attended 
optional visits 15a-f (added 
in amendment 3 to 
accommodate COVID-19 
restrictions), which extended 
up-dosing by up to 12 weeks. 
Subjects who attend optional 
visits will have increased 
duration of exposure to 
AR101 and dupilumab. 
  
 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 11.2 Justification of Sample Size 
Section 11.3.1 Efficacy Analysis Sets 
Section 11.4.1 Subject Disposition 
Section 11.4.3 Efficacy Analyses 
Section 11.4.3.1 Primary Efficacy 
Analysis 
 
Clarified that several treatments 
listed in prohibited medications are 
also considered rescue treatments 
and should result in study 
discontinuation, whereas acute 
treatment with epinephrine and 
certain other medications is 
permitted for the treatment of 
allergic reactions.  
For clarification that certain 
rescue medications will lead 
to study drug discontinuation 
as they may affect study 
outcome. 
Section 8.2 Rescue Treatment 
Section 8.3.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
Section 8.7 Concomitant Medications 
Section 8.7.1 Prohibited Medications and 
Procedures 
Updated biomarker variables to 
include sIgE, sIgG4, and sIgG 
against main peanut protein 
allergen components such as Ara 
h1, Ara h2, and Ara h3. 
To align with emerging data 
in food allergy research that 
suggest IgE-mediated allergic 
reactions to main peanut 
allergen components (eg, Ara 
h1, h2, h3) may correlate 
with clinical sensitivity to 
peanut exposure and the 
outcome of DBPCFC. It is 
important to understand how 
dupilumab as an adjunct to 
AR101 could modulate the 
IgE, IgG, and IgG4 levels 
against different peanut 
Section 5.6 Pharmacodynamic and 
Biomarker Variables 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Table 4 Schedule of Events – 
Maintenance Period and Follow-Up 
Period 
Section 9.2.5 Pharmacodynamic and 
Biomarker Procedures 
 
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Page 3 of 118 
CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
allergen components during 
oral immunotherapy (OIT). 
Extended the visit window for the 
DBPCFCs at visit 16, 22, and 25 to 
up to 7 days before and 30 days 
after the target date for all subjects. 
To address the difficulty 
subjects have encountered in 
scheduling the DBPCFCs 
within the -3 day visit 
window. (In amendment 3, 
the visit window was 
extended to -3/+30 days due 
to COVID-19). 
 
 
Table 4 Schedule of Events – 
Maintenance Period and Follow-Up 
Period 
Section 9.1.2 Footnotes for the Schedule 
of Events Table 4, footnote #14  
Updated the list of AESIs to 
remove malignancy and suicide-
related events. 
For program consistency 
based on regulatory authority 
feedback. 
Section 10.4.3 Other Events that Require 
Accelerated Reporting to Sponsor  
Corrected the language pertaining 
to a secondary endpoint for the 
daily symptom e-diary. 
 
The e-diary uses a numeric 
rather than categorical scale 
to rate symptom severity. 
Clinical Study Protocol Synopsis: 
Endpoints 
Section 4.2 Secondary Endpoints 
Specified that study drug 
administration will be recorded in 
the unscheduled visit folder for 
unscheduled and optional visits. 
 
For clarification. 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Table 4 Schedule of Events – 
Maintenance Period and Follow-Up 
Period 
Section 9.1.1 Footnotes for the Schedule 
of Events Table 3, footnote #15  
Section 9.1.2 Footnotes for the Schedule 
of Events Table 4, footnote # 15  
Clarified procedures in the peanut 
skin prick test (SPT) and Eczema 
Area and Severity Index (EASI). 
For clarification. 
Section 9.2.2.3 Peanut Skin Prick Test 
Section 9.2.2.4 Eczema and Severity 
Index 
Clarified that subjects who do not 
achieve 300 mg/day will still enter 
the 12-week follow-up. 
For clarification. 
Section 6.1 Study Description and 
Duration 
Minor editorial corrections and 
clarifications. 
For clarification. 
Throughout the protocol. 
 
 
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Clinical Study Protocol 
 
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Page 4 of 118 
CONFIDENTIAL 
Amendment 3 
The purpose of this protocol amendment is to protect subject safety and data integrity during the COVID-19 
pandemic by extending the screening and up-dosing periods, and by modifying requirements for FeNO 
(fractional exhaled nitric oxide) and spirometry assessments. All mechanisms utilized and deviations from 
planned study procedures are to be documented as being related to COVID-19 where applicable and will 
remain in effect for the duration of the public health emergency. The following table outlines the changes 
made to the protocol and the rationale.  
Description of Change 
Rationale 
Section Changed 
The up-dosing period for AR101 
peanut protein was permitted to be 
extended an additional 12 weeks for 
subjects impacted by the COVID-19 
pandemic, such that the up-dosing 
period is ideally 28 weeks but may 
be extended to a maximum of 
40 weeks (4 weeks pretreatment, 
22 to 34 weeks up-dosing, and 
2 weeks at maximum dose).  
 
These changes are reflected in the 
Schedule of Events such that all 
subjects will complete up to visit 15, 
then visits 15a-f will be optional to 
reach 300 mg/day AR101 for a 
minimum of 2 weeks.  
 
Subsequently, the on-study double-
blind placebo-controlled food 
challenges (DBPCFCs) were re-
named to reference milestones rather 
than time points for operational 
consideration: 
• 
Screening DBPCFC 
(name unchanged)  
• 
Post up-dosing DBPCFC 
at visit 16 (formerly week 
28) is the first on-study 
food challenge after the 
up-dosing period (week 28 
to week 40). This will be 
considered visit 16 
regardless of whether a 
subject completes optional 
visits 15a-f. 
• 
Post maintenance 
DBPCFC at visit 22 
(formerly week 52) is the 
second on-study food 
challenge at the end of the 
maintenance period (week 
52 to week 64), 24 weeks 
The AR101 up-dosing 
period was extended to 
allow for in-clinic visit 
flexibility and thereby 
protect subject safety 
and data integrity in the 
context of the COVID-
19 pandemic. 
 
The DBPCFCs were 
subsequently re-named 
for clarification, as the 
time points may differ 
for subjects affected by 
COVID-19. 
Clinical Study Protocol Synopsis: 
Objective(s), Study Design, Study Duration, 
Treatment(s), Endpoints, Procedures and 
Assessments, Statistical Plan 
Section 2.1 Primary Objective 
Section 2.2 Secondary Objectives 
Section 3.2.2 Rationale for Study Design 
Section 3.2.3.2 Dose and Regimen for AR101 
Oral Immunotherapy 
Section 4.1 Primary Endpoint 
Section 4.2 Secondary Endpoint 
Section 6.1 Study Description and Duration 
Figure 1 Schematic of Study Design 
Considerations 
Section 6.1.1.2 AR101 Up-Dosing Regimen 
Starting at Week 6 
Table 2 AR101: Bi-Weekly Up-Dosing 
Regimen Starting at Week 6 
Section 6.1.3 Study Design Safety 
Considerations for DBPCFC 
Section 6.2 Planned Interim Analysis 
Section 8.5 Method of Treatment Assignment 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Table 4 Schedule of Events – Maintenance 
Period and Follow-Up Period 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, footnote #14  
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4, footnote #13  
Section 9.1.3 Early Termination Visit 
Section 10.4.1 Adverse Events 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.4 Statistical Methods 
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy Analysis 
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Page 5 of 118 
CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
after the post up-dosing 
DBPCFC  
• 
End of study DBPCFC at 
visit 25 (formerly week 64) 
is the end of study food 
challenge (week 64 to week 
76), 12 weeks after the post 
maintenance DBPCFC  
Section 11.4.3.3 Multiplicity Considerations 
Section 11.4.3.4 Timing of Analyses 
Section 11.4.4.1 Adverse Events 
Appendix 1 Peanut DBPCFC Schedule of 
Dosing Performed at Screening, Visits 16, 22, 
and 25 
Appendix 5 Schematic for Subsequent AR101 
Dose Escalation Days Performed In-Clinic at 
Weeks 6 Through End of Up-Dosing 
(week 28 to 40)  
While screening and enrollment 
have been halted for new subjects 
during COVID-19, the screening 
period duration was extended from 8 
weeks to 16 weeks for current 
subjects in screening. Screening was 
previously day -57 to day -17 and is 
now day -113 to day -17. 
 
The screening period 
was extended to allow 
for in-clinic visit 
flexibility and thereby 
protect subject safety 
and data integrity in the 
context of the COVID-
19 pandemic. 
Clinical Study Protocol Synopsis: Study 
Design 
Section 6.1 Study Description and Duration 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Modifications were made to the 
requirements for FeNO (not required 
at screening or on-study during 
COVID-19, at the discretion of the 
investigator) and spirometry (may 
be replaced with peak flow while 
on-study during COVID-19 at the 
discretion of the investigator, but 
still required at screening).  
FeNO and spirometry 
requirements were 
modified to minimize 
aerosolized exposure 
concerns and thereby 
protect both site staff 
and subject safety 
during the COVID-19 
pandemic. 
 
Section 5.6 Pharmacodynamic and Biomarker 
Variables 
Table 3 Schedule of Events –Screening, 
Baseline, Double-Blind Treatment Period 
Table 4 Schedule of Events – Maintenance 
Period and Follow-Up Period 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, footnote #9.a 
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4, footnote #9.a 
Section 9.2.2.2 Fractional Exhaled Nitrous 
Oxide 
Section 9.2.3.3 Spirometry 
Added language to clarify general 
changes in study conduct in the 
context of the COVID-19 pandemic. 
For clarification.  
Section 3.3 Safety Considerations (Risk-
Benefit) 
Section 8.1 Investigational and Reference 
Treatments 
Section 9.1 Schedule of Events 
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4, footnote #14  
Section 11 Statistical Plan 
Section 13.1 Monitoring of Study Sites 
Provided updated language 
regarding AR101, which is now 
approved in the US as a 
monotherapy for peanut allergy 
(previously listed as investigational). 
For clarification. 
Section 1 Introduction 
Section 3.2.1 Rationale for Study 
Section 3.3.2 Risk-Benefit for Peanut Protein 
Section 23 References 
Minor editorial corrections. 
For clarification. 
Throughout the protocol. 
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CONFIDENTIAL 
Amendment 2 
The following table shows the changes made to the protocol and the sections affected. 
Change 
Section Changed 
Decreased 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, compared to SPT 
negative control, to expand the pool of subjects who may be 
eligible for the study. The previous criteria were too restrictive 
compared to similar oral immunotherapy (OIT) studies and the 
change will still enroll only severely allergic subjects who 
react to screening double-blind peanut challenge at ≤144 mg 
(cumulative). 
Section 7.2.1 Inclusion Criteria, #4  
Changed prohibited use to allow use of systemic (oral, 
intravenous [IV], intramuscular [IM], subcutaneous [SC]) 
corticosteroids during the study for no more than 5 continuous 
days, no more than 15 days in total, or within 2 days prior to 
double-blind placebo-controlled food challenges (DBPCFCs) 
to align with standard of care. 
Section 8.7.1 Prohibited Medications and 
Procedures 
Modified windows for visits W8 to W26 from  
+/- 1 day to +/- 2 days to allow greater flexibility for subject 
scheduling consistent with expected clinical practice and other 
OIT studies. 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period  
The timing of administration of AR101 was changed from at 
least 8 hours before SC study drug administration to at least 8 
hours apart from SC study drug administration to allow greater 
dosing flexibility. 
Clinical Study Protocol Synopsis – Study Design 
Section 3.2.3.1 Dose and Regimen for Dupilumab 
Section 6.1 Study Description and Duration 
Section 6.1.2 Study Design Safety Considerations 
for AR101 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, #1  
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4, #1  
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CONFIDENTIAL 
Change 
Section Changed 
Removed the time restriction of daily dosing in the evening 
with AR101 to align with Aimmune Protocol ARC003 and 
anticipated clinical use of AR101. Daily dosing in the evening 
is recommended but provision for dosing at other times were 
clarified. A statement was added that subjects should be 
monitored for at least 2 hours afterwards. 
Clinical Study Protocol Synopsis – Study Design 
Section 3.2.3.1 Dose and Regimen for Dupilumab 
Section 6.1 Study Description and Duration 
Section 6.1.1.1 AR101 Initial Dose Escalation 
Day at Week 4 
Section 6.1.2.1 Guidance for Home Dosing 
Section 8.1.1 AR101 for Oral Immunotherapy 
and IDED 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, #1 and #2  
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4, #1 and #2  
A positive SPT result determined by averaging maximal 
perpendicular wheal diameters 15 minutes after applying lancet 
was modified from ≥5 to ≥3 mm to be consistent with standard 
guidelines. 
Section 9.2.2.3 Peanut Skin Prick Test 
The start of the 2-week washout period after food challenge 
was revised from the last DBPCFC to after the peanut 
screening DBPCFC day to reduce time to randomization. 
Section 6.1 Study Description and Duration 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, #13  
Revision was made to clarify that all subjects who undergo a 
DBPCFC at week 28 and week 52 for assessment of 
desensitization, dosing with AR101 should continue on the 
days between the 2 parts of the DBPCFC. 
Clinical Study Protocol Synopsis – Study Design 
Section 6.1 Study Description and Duration 
Limited the post-dose observation period to 30 minutes during 
the maintenance phase in clinic to align with Aimmune 
Protocol ARC003 and anticipated clinical practice. 
Section 6.1 Study Description and Duration 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, #8 
Modified vital sign collection time interval at DBPCFC, initial 
dose escalation days, and up-dosing visits from every 
15 minutes to every 15 to 30 minutes to align with other OIT 
studies. Also added that only pulse and blood pressure need to 
be taken for post-dose monitoring. 
Clinical Study Protocol Synopsis – Study Design 
Section 6.1 Study Description and Duration 
Section 6.1.1.2 AR101 Up-Dosing Regimen 
Starting at Week 6 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, #8  
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4, #8  
Section 9.2.3.1 Vital Signs 
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Change 
Section Changed 
Added some background information on pharmacodynamic 
and biomarker variables of Serum Peanut-Specific Antibody 
Assays and Peanut-Reactive Th2A Cells 
Section 5.6 Pharmacodynamic and Biomarker 
Variables 
Clarified that blood samples collected for exploratory research 
will be kept for up to 15 years for studying the allergen 
response ex-vivo.  
Section 5.7 Other Exploratory Research 
(Optional) 
Clarified that DNA sample is recommended to be collected on 
any day after day 1.  
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3, #11  
Section 9.2.6.1 Genomics Analysis (Optional) 
Clarified that subjects who exhibit moderate symptoms may 
have their dose reduced by 1 dose level per visit until the dose 
is tolerated with no or mild symptoms. 
Section 6.1.1.2 AR101 Up-Dosing Regimen 
Starting at Week 6 
Clarified that visit windows should be adhered to strictly as per 
the schedule of assessment. 
Section 6.1 Study Description and Duration 
Clarified that maintenance dose can continue to be taken at 
home on in-clinic maintenance period. 
Section 6.1 Study Description and Duration 
Cumulative column of Table 1 (AR101 Initial Dose Escalation 
Day at Week 4) was removed for clarity. 
Table 1 AR101 Initial Dose Escalation Day at 
Week 4  
Clarified that subjects in the dupilumab treatment group being 
re-randomized 1:1 to placebo or dupilumab are from the up-
dosing phase. Also, that subjects will have an interactive web 
response system transaction to maintain the blind. 
Section 6.1 Study Description and Duration 
Added ‘symptom(s) of reaction due to exposure’ in parentheses 
for clarity. 
Section 7.2.1 Inclusion Criteria, #2  
Deleted ‘investigational’ from the following sentence for 
clarity: Use of other investigational forms of allergen 
immunotherapy (eg, oral, subcutaneous, patch, or sublingual) 
or immunomodulatory therapy (not including corticosteroids) 
within 3 months prior to screening. 
Section 7.2.2 Exclusion Criteria, #10  
Corrected the list of biomarkers to be investigated. 
Section 9.2.5 Pharmacodynamic and Other 
Biomarker Procedures 
Clarified that additional samples will be collected as detailed in 
the schedule of assessments for Future Biomedical Research. 
Section 9.2.6 Future Biomedical Research 
(Optional) 
Removed CODIT as part of descriptor for AR101 Figure 1. 
Figure 1 Schematic of Study Design  
Minor editorial revisions for clarification, consistency, 
corrections, and completeness. 
Throughout 
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Amendment 1 
The following table shows the changes made to the protocol and the sections affected: 
Change 
Section Changed 
Provided greater detail in exclusion criterion for asthma per 
regulatory authority recommendation and added relevant 
references. 
Section 7.2.2 Exclusion Criteria, #7 
Section 23 References 
Specified that subjects should receive all vaccinations for 
measles, mumps, rubella, and varicella at least 3 months prior 
to enrollment into the study, per regulatory authority 
recommendation. 
Section 7.2.2 Exclusion Criteria, #16 
Section 8.7.1 Prohibited Medications and 
Procedures 
Corrected numeric errors about assumptions in the 
justification of sample size per regulatory authority request. 
No change has been made to sample size. 
Clinical Study Protocol Synopsis – Statistical 
Plan 
Section 11.2 Justification of Sample Size 
Expanded monitoring plan for eosinophilic esophagitis (EoE) 
and other gastrointestinal (GI) symptoms per regulatory 
authority request and added Pediatric Eosinophilic 
Esophagitis Symptom Score (PEESS) v2.0 at Early 
Termination visit. 
Section 6.1.2.5 Gastrointestinal Adverse Events 
and Disruption of Dosing 
Table 4 Schedule of Events – Maintenance 
Period and Follow-up Period 
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4 (footnote #10) 
Modified window for screening visits to allow greater 
flexibility and specified that a 2-week washout period is 
required after the screening Double-blind, placebo-controlled 
food challenge (DBPCFC), before visit 2 (randomization 
visit). Added footnote to schedule of events table to clarify 
modified screening window and clarified footnote #10. 
Clinical Study Protocol Synopsis – Study 
Design 
Section 6.1 Study Description and Duration 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Section 9.1.1 Footnotes for Schedule of Events 
Table 3 (footnote #10, #12, #13) 
Added that subjects must meet all eligibility for screening 
visit 1 before proceeding with the DBPCFC in visit 1a. 
Section 6.1 Study Description and Duration 
Section 9.1.1 Footnotes for Schedule of Events 
Table 3 (footnote #12) 
Modified Guidance for Home Dosing to clarify that moderate 
or severe symptoms should be confirmed by the investigator. 
Section 6.1.2.1 Guidance for Home Dosing 
Clarified that escalation during the initial dose escalation day 
is to 6 mg single dose 
Section 6.1.2 Study Design Considerations for 
AR101 
Clarified that the injection log in the e-diary will only 
document compliance with injection of study drug and not 
injection site reactions or concomitant medications, which 
will be collected in the case report form (CRF). Also, that the 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3 (footnote #1, #2) 
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4 (footnotes #1, #2) 
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Change 
Section Changed 
dosing diary will document only compliance with AR101, not 
concomitant medications as these are collected in the CRF. 
Added a statement to schedule of events footnotes from the 
study design that subjects will have a physical assessment 
before each DBPCFC and added a physical examination at 
visit 1a  
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3 (footnote #5) 
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4 (footnote #5) 
Added a paragraph regarding the use of the fractional exhaled 
nitric oxide (FeNO) device in subjects aged 6 years, which 
resulted in the addition of two references. 
Section 9.2.2.2 Fractional Exhaled Nitric Oxide 
Section 23 References 
Included the asthma control questionnaire-interviewer 
administered (ACQ-IA) for children aged 6 to 10 years and 
added a statement regarding validation of the asthma control 
questionnaire (ACQ). 
Section 9.2.2.5 Juniper Asthma Control 
Questionnaire 
Specified that subjects with moderate reaction at 6 mg single 
dose will be discontinued. In addition, the statement “Subjects 
to return for dosing at 6 mg” was removed from the initial 
dose escalation day (IDED) schematic. 
Section 6.1.1.1 AR101 Initial Dose Escalation 
Day at Week 4 
Appendix 4 Schematic for AR101 Initial Dose 
Escalation Day Performed in-Clinic at Week 4. 
Clarified that subjects who experience severe allergic 
reactions in dose escalation of AR101 will discontinue from 
study. 
Section 6.1.1.2 AR101 Up-Dosing Regimen 
Starting at Week 6 
Section 6.1.2 Study Design Safety 
Considerations for AR101 
Appendix 5 Schematic for Subsequent AR101 
Dose Escalation Days Performed In-clinic at 
Weeks 6 through 28 
Specified that biomedical research samples and the DNA 
sample are optional and added a paragraph regarding consent. 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Table 4 Schedule of Events – Maintenance 
Period and Follow-up Period 
Section 9.2.6 Future Biomedical Research 
(Optional) 
Section 9.2.6.1 Genomic Analysis (Optional) 
Removed CODIT as part of descriptor for AR101. 
Throughout (including title) 
Corrections:   
• 
Added “with e-diary” to daily allergy symptoms  
• 
Removed FeNO as a safety variable 
Section 5.2 Efficacy Variables 
Section 5.3 Safety Variables 
Section 5.5 Anti-Drug Antibody Variables 
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CONFIDENTIAL 
Change 
Section Changed 
• 
Updated ADA variables by removing neutralizing 
antibody status 
• 
Abbreviation for peak expiratory flow was updated 
• 
Removed “single day” and “blinded” in IDED 
• 
Stopping rule #5 now reads (a severe allergic reaction 
or” instead of “and” 
• 
Clarified that dose-limiting symptoms should be 
evaluated by the same physician for all DBPCFCs. 
• 
Removed Daily Allergy Symptom Diary at visits 2 
and 3 in schedule of events. 
• 
Footnote #2 in schedule of events tables was revised 
to include “subject/caregiver” instead of “subjects” 
• 
Corrected description of skin prick test (SPT) 
• 
Reference added for spirometry measurements 
• 
Removed the statement that “no formal statistical 
analysis will be performed” for drug concentration 
data. 
• 
Corrections made to analysis of anti-drug antibody 
data by adding “treatment-boosted” 
Section 6.1.1.1 AR101 Initial Dose Escalation 
Day at Week 4 
Section 6.1.2.3 Individual Subject Stopping 
Rules 
Section 8.5.1 Blinding 
Table 3 Schedule of Events – Screening, 
Baseline, Double-Blind Treatment Period 
Section 9.1.1 Footnotes for the Schedule of 
Events Table 3 (footnote #2) 
Section 9.1.2 Footnotes for the Schedule of 
Events Table 4 (footnote #2) 
Section 9.2.2.3 Peanut Skin Prick Test 
Section 9.2.3.3 Spirometry 
Section 11.4.5 Analysis of Drug Concentration 
Data 
Section 11.4.6 Analysis of Anti-Drug Antibody 
Data 
Section 23 References 
Appendix 3 Criteria for Suspected Diagnosis 
and Severity Grading of Anaphylaxis 
Minor editorial corrections 
Throughout 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................28 
1. 
INTRODUCTION ......................................................................................................31 
2. 
STUDY OBJECTIVES ..............................................................................................33 
2.1. 
Primary Objective .......................................................................................................33 
2.2. 
Secondary Objectives .................................................................................................33 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................34 
3.1. 
Hypothesis ..................................................................................................................34 
3.2. 
Rationale .....................................................................................................................34 
3.2.1. 
Rationale for Study .....................................................................................................34 
3.2.2. 
Rationale for Study Design .........................................................................................36 
3.2.3. 
Rationale for Dose Selection ......................................................................................37 
3.2.3.1. 
Dose and Regimen for Dupilumab .............................................................................37 
3.2.3.2. 
Dose and Regimen for AR101 Oral Immunotherapy .................................................38 
3.3. 
Safety Considerations (Risk-Benefit) .........................................................................38 
3.3.1. 
Risk-Benefit for Dupilumab .......................................................................................38 
3.3.2. 
Risk-Benefit for Peanut Protein ..................................................................................39 
4. 
STUDY ENDPOINTS ................................................................................................40 
4.1. 
Primary Endpoint ........................................................................................................40 
4.2. 
Secondary Endpoints ..................................................................................................40 
5. 
STUDY VARIABLES................................................................................................42 
5.1. 
Demographic and Baseline Characteristics ................................................................42 
5.2. 
Efficacy Variables ......................................................................................................42 
5.3. 
Safety Variables ..........................................................................................................42 
5.4. 
Pharmacokinetic Variables .........................................................................................42 
5.5. 
Anti-Drug Antibody Variables ...................................................................................42 
5.6. 
Pharmacodynamic and Biomarker Variables .............................................................42 
5.7. 
Other Exploratory Research (Optional) ......................................................................44 
6. 
STUDY DESIGN .......................................................................................................45 
6.1. 
Study Description and Duration .................................................................................45 
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6.1.1. 
Description of AR101 Dose Escalation, and Study Stopping Rules ..........................50 
6.1.1.1. 
AR101 Initial Dose Escalation Day at Week 4 ..........................................................50 
6.1.1.2. 
AR101 Up-Dosing Regimen Starting at Week 6 ........................................................51 
6.1.2. 
Study Design Safety Considerations for AR101 ........................................................52 
6.1.2.1. 
Guidance for Home Dosing ........................................................................................53 
6.1.2.2. 
Missed Doses AR101 .................................................................................................53 
6.1.2.3. 
Individual Subject Stopping Rules .............................................................................54 
6.1.2.4. 
Anaphylaxis ................................................................................................................54 
6.1.2.5. 
Gastrointestinal Adverse Events and Disruption of Dosing .......................................54 
6.1.3. 
Study Design Safety Considerations for DBPCFC ....................................................55 
6.1.4. 
End of Study Definition ..............................................................................................55 
6.2. 
Planned Interim Analysis ............................................................................................55 
6.3. 
Study Committees .......................................................................................................56 
6.3.1. 
Independent Data Monitoring Committee ..................................................................56 
6.3.2. 
Adjudication Committee .............................................................................................56 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF SUBJECTS ..............57 
7.1. 
Number of Subjects Planned ......................................................................................57 
7.2. 
Study Population .........................................................................................................57 
7.2.1. 
Inclusion Criteria ........................................................................................................57 
7.2.2. 
Exclusion Criteria .......................................................................................................58 
7.3. 
Premature Withdrawal from the Study .......................................................................60 
7.4. 
Replacement of Subjects .............................................................................................60 
8. 
STUDY TREATMENTS............................................................................................61 
8.1. 
Investigational and Reference Treatments ..................................................................61 
8.1.1. 
AR101 for Oral Immunotherapy and IDED ...............................................................61 
8.1.2. 
Peanut for Food Challenges ........................................................................................62 
8.2. 
Rescue Treatment .......................................................................................................62 
8.3. 
Dose Modification and Study Treatment Discontinuation Rules ...............................63 
8.3.1. 
Dose Modification ......................................................................................................63 
8.3.2. 
Study Drug Discontinuation .......................................................................................63 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................63 
8.3.2.2. 
Reasons for Temporary Discontinuation of SC Study Drug ......................................63 
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8.4. 
Management of Acute Reactions ................................................................................64 
8.4.1. 
Acute Injection Reactions ...........................................................................................64 
8.4.1.1. 
Systemic Injection Reactions ......................................................................................64 
8.5. 
Method of Treatment Assignment ..............................................................................64 
8.5.1. 
Blinding ......................................................................................................................65 
8.5.2. 
Emergency Unblinding ...............................................................................................66 
8.6. 
Treatment Logistics and Accountability .....................................................................66 
8.6.1. 
Packaging, Labeling, and Storage ..............................................................................66 
8.6.2. 
Supply and Disposition of Treatments .......................................................................66 
8.6.3. 
Treatment Accountability ...........................................................................................66 
8.6.4. 
Treatment Compliance ................................................................................................67 
8.7. 
Concomitant Medications ...........................................................................................67 
8.7.1. 
Prohibited Medications and Procedures .....................................................................67 
8.7.2. 
Permitted Medications ................................................................................................68 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................69 
9.1. 
Schedule of Events .....................................................................................................69 
9.1.1. 
Footnotes for the Schedule of Events Table 3 ............................................................77 
9.1.2. 
Footnotes for the Schedule of Events Table 4 ............................................................78 
9.1.3. 
Early Termination Visit ..............................................................................................80 
9.1.4. 
Unscheduled Visits .....................................................................................................80 
9.2. 
Study Procedures ........................................................................................................80 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................80 
9.2.2. 
Efficacy Procedures ....................................................................................................80 
9.2.2.1. 
Double-Blind Placebo-Controlled Food Challenge ....................................................80 
9.2.2.2. 
Fractional Exhaled Nitric Oxide .................................................................................81 
9.2.2.3. 
Peanut Skin Prick Test ................................................................................................81 
9.2.2.4. 
Eczema Area and Severity Index ................................................................................81 
9.2.2.5. 
Asthma Control Questionnaire ...................................................................................82 
9.2.2.6. 
Daily Allergy Symptom Diary....................................................................................82 
9.2.2.7. 
Food Allergy Quality of Life Questionnaire ..............................................................82 
9.2.3. 
Safety Procedures .......................................................................................................82 
9.2.3.1. 
Vital Signs ..................................................................................................................82 
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9.2.3.2. 
Physical Examination .................................................................................................83 
9.2.3.3. 
Spirometry ..................................................................................................................83 
9.2.3.4. 
Laboratory Testing ......................................................................................................83 
9.2.3.5. 
Pediatric Eosinophilic Esophagitis Symptom Score Questionnaire ...........................84 
9.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures ..............................................84 
9.2.4.1. 
Drug Concentration Measurements and Samples .......................................................84 
9.2.4.2. 
Anti-Drug Antibody Measurements and Samples ......................................................84 
9.2.5. 
Pharmacodynamic and Other Biomarker Procedures .................................................85 
9.2.6. 
Future Biomedical Research (Optional) .....................................................................85 
9.2.6.1. 
Genomics Analysis (Optional) ...................................................................................85 
10. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................87 
10.1. 
Obligations of Investigator .........................................................................................87 
10.2. 
Obligations of Sponsor ...............................................................................................87 
10.3. 
Definitions ..................................................................................................................87 
10.3.1. 
Adverse Event .............................................................................................................87 
10.3.2. 
Serious Adverse Event ................................................................................................87 
10.3.3. 
Adverse Events of Special Interest .............................................................................88 
10.4. 
Recording and Reporting Adverse Events ..................................................................88 
10.4.1. 
Adverse Events ...........................................................................................................88 
10.4.2. 
Serious Adverse Events ..............................................................................................88 
10.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................89 
10.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................89 
10.4.5. 
Abnormal Laboratory or Vital Signs Results .............................................................90 
10.4.6. 
Follow-Up ...................................................................................................................90 
10.5. 
Evaluation of Severity and Causality .........................................................................90 
10.5.1. 
Evaluation of Severity ................................................................................................90 
10.5.2. 
Evaluation of Causality ...............................................................................................91 
10.6. 
Safety Monitoring .......................................................................................................93 
10.7. 
Investigator Alert Notification ....................................................................................93 
11. 
STATISTICAL PLAN................................................................................................94 
11.1. 
Statistical Hypothesis ..................................................................................................94 
11.2. 
Justification of Sample Size........................................................................................94 
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11.3. 
Analysis Sets ...............................................................................................................95 
11.3.1. 
Efficacy Analysis Sets ................................................................................................95 
11.3.2. 
Safety Analysis Set .....................................................................................................95 
11.3.3. 
Other Analysis Sets .....................................................................................................95 
11.4. 
Statistical Methods ......................................................................................................95 
11.4.1. 
Subject Disposition .....................................................................................................96 
11.4.2. 
Demography and Baseline Characteristics .................................................................96 
11.4.3. 
Efficacy Analyses .......................................................................................................96 
11.4.3.1. 
Primary Efficacy Analysis ..........................................................................................96 
11.4.3.2. 
Secondary Efficacy Analysis ......................................................................................97 
11.4.3.3. 
Multiplicity Considerations ........................................................................................97 
11.4.3.4. 
Timing of Analyses .....................................................................................................97 
11.4.4. 
Safety Analysis ...........................................................................................................98 
11.4.4.1. 
Adverse Events ...........................................................................................................98 
11.4.4.2. 
Other Safety ................................................................................................................98 
11.4.4.3. 
Treatment Exposure ....................................................................................................99 
11.4.4.4. 
Treatment Compliance ................................................................................................99 
11.4.5. 
Analysis of Drug Concentration Data .........................................................................99 
11.4.6. 
Analysis of Immunogenicity Data ............................................................................100 
11.4.7. 
Analysis of Pharmacodynamic Data .........................................................................100 
11.5. 
Additional Statistical Data Handling Conventions ...................................................100 
11.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......101 
12. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................102 
12.1. 
Data Management .....................................................................................................102 
12.2. 
Electronic Systems ....................................................................................................102 
13. 
STUDY MONITORING ..........................................................................................103 
13.1. 
Monitoring of Study Sites .........................................................................................103 
13.2. 
Source Document Requirements ..............................................................................103 
13.3. 
Case Report Form Requirements ..............................................................................103 
14. 
AUDITS AND INSPECTIONS ...............................................................................103 
15. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................104 
15.1. 
Good Clinical Practice Statement .............................................................................104 
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15.2. 
Assent and Informed Consent ...................................................................................104 
15.3. 
Subjects Confidentiality and Data Protection ...........................................................105 
15.4. 
Institutional Review Board .......................................................................................105 
16. 
PROTOCOL AMENDMENTS ................................................................................105 
17. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................106 
17.1. 
Premature Termination of the Study .........................................................................106 
17.2. 
Close-out of a Site ....................................................................................................106 
18. 
STUDY DOCUMENTATION .................................................................................107 
18.1. 
Certification of Accuracy of Data .............................................................................107 
18.2. 
Retention of Records ................................................................................................107 
19. 
DATA QUALITY ASSURANCE ............................................................................107 
20. 
CONFIDENTIALITY ..............................................................................................108 
21. 
FINANCING AND INSURANCE ...........................................................................108 
22. 
PUBLICATION POLICY ........................................................................................108 
23. 
REFERENCES .........................................................................................................109 
24. 
INVESTIGATOR’S AGREEMENT ........................................................................112 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................118 
 
LIST OF TABLES 
Table 1: 
AR101 Initial Dose Escalation Day at Week 4 ..........................................................48 
Table 2: 
AR101: Bi-Weekly Up-Dosing Regimen Starting at Week 6 ....................................51 
Table 3: 
Schedule of Events – Screening, Baseline, Double-Blind Treatment Period .............70 
Table 4: 
Schedule of Events – Maintenance Period and Follow-Up Period .............................75 
 
LIST OF FIGURES 
Figure 1: 
Schematic of Study Design .........................................................................................45 
 
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LIST OF APPENDICES 
APPENDIX 1. PEANUT DBPCFC SCHEDULE OF DOSING PERFORMED AT 
SCREENING, VISITS 16, 22, AND 25...........................................................113 
APPENDIX 2. ALLERGIC REACTION SEVERITY GRADING .........................................114 
APPENDIX 3. CRITERIA FOR SUSPECTED DIAGNOSIS AND SEVERITY 
GRADING OF ANAPHYLAXIS ....................................................................115 
APPENDIX 4. SCHEMATIC FOR AR101 INITIAL DOSE ESCALATION DAY 
PERFORMED IN-CLINIC AT WEEK 4 ........................................................116 
APPENDIX 5. SCHEMATIC FOR SUBSEQUENT AR101 DOSE ESCALATION 
DAYS PERFORMED IN-CLINIC AT WEEKS 6 THROUGH END 
OF UP-DOSING (WEEK 28 TO 40) ...............................................................117 
 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Study in Pediatric Subjects with Peanut Allergy to Evaluate the Efficacy and 
Safety of Dupilumab as Adjunct to AR101 (Peanut Oral Immunotherapy)  
Site Locations 
 
Principal Investigator 
Approximately 25 sites in the US 
To be determined 
Objectives 
Primary objective: 
• 
To assess whether dupilumab as adjunct to AR101 compared to 
placebo improves desensitization at the completion of up-dosing, 
defined as an increase in the proportion of subjects who pass a post 
up-dosing 
double-blind 
placebo-controlled 
food 
challenge 
(DBPCFC) at visit 16 
Secondary objectives: 
• 
To assess whether dupilumab as adjunct to AR101 compared to 
placebo improves desensitization at the completion of up-dosing, 
defined as an increase in the cumulative tolerated dose (log 
transformed) of peanut protein during a post up-dosing DBPCFC 
at visit 16 
• 
To assess whether dupilumab as (indefinite [continuously]) 
adjunct to AR101 compared to placebo maintains desensitization, 
defined as an increase in the proportion of subjects who pass a 
post maintenance DBPCFC at visit 22 
• 
To assess whether dupilumab as (limited [previously]) adjunct to 
AR101 compared to placebo maintains desensitization, defined as 
an increase in the proportion of subjects who pass a post 
maintenance DBPCFC at visit 22 
• 
To evaluate the safety and tolerability of dupilumab as adjunct to 
AR101 compared to placebo   
• 
To assess the effect of dupilumab (compared to placebo) as 
adjunct to AR101 on the change in peanut-specific 
immunoglobulin E (sIgE), immunoglobulin G (IgG), 
immunoglobulin G4 (IgG4), and peanut-specific IgG4/IgE ratio 
• 
To assess if dupilumab increases the tolerability of AR101 as 
measured by the daily symptoms (electronic diary [e-diary]) 
during the up-dosing phase 
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Study Design 
This is a phase 2, multicenter, randomized, double-blind, parallel-group, 
2-arm study in subjects aged 6 to 17 years inclusive who are allergic to 
peanut. The study consists of a screening period of up to 16 weeks; a 
28 to 40 week treatment period, which includes 4 weeks of pretreatment 
with dupilumab or placebo followed by 24 to 36 weeks of treatment with 
dupilumab or placebo in combination with a gradual up-dosing of AR101 to 
reach 300 mg/day (ideally 28 weeks in duration, including pretreatment, but 
may be extended to a maximum of 40 weeks to accommodate dose 
reductions and re-escalation as well as COVID-19 restrictions of in-clinic 
visits; a 24-week maintenance phase with 300 mg/day AR101 in 
combination with dupilumab or matching placebo (for subjects who achieve 
300 mg/day AR101 for at least 2 weeks in the up-dosing period), and a 
12-week post-treatment follow-up period. Total duration is between 
64 and 76 weeks, excluding the screening period. 
After obtaining informed consent/assent, subjects will be assessed for 
eligibility during a 2-part screening period. During screening visit 1 (day -
113 to day -17), subjects will undergo a medical history, physical 
examination, spirometry, a standard peanut skin prick test (SPT), and 
laboratory testing (including peanut sIgE) and will be evaluated for the study 
eligibility criteria. Subjects must meet all eligibility for screening visit 1 
before proceeding with the DBPCFC in visit 1a. 
During screening visit 1a (must be before day -15), under direct study 
investigator monitoring, subjects will undergo a DBPCFC to confirm peanut 
allergy. This will consist of 5 doses (1, 3, 10, 30 and 100 mg) of peanut 
protein 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 judgement 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 apart. After the last dose of the 
DBPCFC, the subject will be monitored for 2 hours and then discharged 
from the clinic. Subjects will be considered to have tolerated the DBPCFC 
if they do not experience any objective Grade 1 (mild) reaction on the peanut 
protein days based on the Consortium of Food Allergy Research (CoFAR) 
grading system and will be excluded from the study. 
Double-Blind Treatment Period (28 to 40 weeks duration) 
Subjects with a history of confirmed peanut allergy who continue to meet 
eligibility criteria at baseline will undergo day 1/baseline assessments and 
will be randomized in a 2:1 ratio stratified by screening peanut-specific IgE 
level (≤100 kUA/L or >100 kUA/L) and body weight (<30 kg, ≥30 kg and 
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<60 kg, or ≥60 kg) at randomization into one of 2 treatment arms (n=52 for 
placebo and n=104 for dupilumab). A minimum of 15 subjects for each 
weight group will be enrolled. 
Dupilumab and placebo will be dosed subcutaneously (SC) as follows based 
on weight at randomization and dose will not be changed regardless of 
weight gain or loss: 
• 
subjects weighing <30 kg will receive dupilumab 100 mg every 2 
weeks (Q2W) following a loading dose of 200 mg or matching 
placebo Q2W 
• 
subjects weighing ≥30 kg and <60 kg will receive dupilumab 200 mg 
Q2W following a loading dose of 400 mg or matching placebo Q2W 
• 
subjects weighing ≥60 kg will receive dupilumab 300 mg Q2W 
following a loading dose of 600 mg or matching placebo Q2W 
After the first 4 weeks of pretreatment, subjects will begin AR101 with an 
up-dosing regimen to a maximum of 300 mg/day over the next 
24 to 36 weeks of the study, for a total of 28 to 40 weeks (including 
pretreatment) with 28 weeks being ideal and 40 weeks being the maximum. 
(The flexible up-dosing period is to accommodate dose reductions and 
re-escalation as well as COVID-19 restrictions of in-clinic visits. Thus, the 
up-dosing period will consist of 4 weeks pretreatment, 22 to 34 weeks of 
flexible up-dosing, and at least 2 weeks at the maximum dose of 
300 mg/day). 
During concomitant AR101, study drug will be administered SC at home (at 
least 24 hours after in-clinic AR101 dose escalation and at least 8 hours apart 
from the at-home daily AR101 dose). After ingestion of AR101, subjects 
should be monitored for 2 hours for allergic reaction. All subjects will 
complete up to visit 15. Visits 15a-f will be optional in order to reach 300 
mg/day AR101 for a minimum of 2 weeks. Subjects will undergo a post up-
dosing DBPCFC at visit 16 if they have reached 300 mg/day for at least 2 
weeks (on a day after the last dose of AR101). Dosing with AR101 should 
continue on the days between the two parts of the DBPCFC.  
Placebo Group 
At day 1: Placebo (weight-based dose) Q2W SC for 28 to 40 weeks. 
At week 4: AR101 using a standardized regimen of single initial dose 
escalation day (IDED) from 0.5 mg to a maximum of 6 mg peanut protein 
(12 mg cumulative) over 5 hours in-clinic (home dosing will be 3 mg/day 
AR101 for the next 2 weeks until up-dosing) followed by bi-weekly (Q2W) 
in-clinic up-dosing from the highest tolerated initial day dose to a maximum 
of 300 mg/day at home for 22 to 34 additional weeks. If the scheduled 
bi-weekly up-dosing is not possible, the up-dosing period may be extended 
by up to 12 weeks (visits 15a-f, as needed) to accommodate dose reductions 
and re-escalation as well as COVID-19 restrictions of in-clinic visits. Thus, 
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the up-dosing period will end at week 28 to 40 (including 4 weeks 
pretreatment, 22 to 34 weeks of flexible up-dosing, and at least 2 weeks at 
the maximum dose). 
Dupilumab Group 
At day 1: Dupilumab (weight-based or dose) Q2W SC for 28 to 40 weeks. 
At week 4: AR101 using a standardized regimen of single IDED from 
0.5 mg to a maximum of 6 mg peanut protein (12 mg cumulative) over 
5 hours in-clinic (home dosing will be 3 mg/day AR101 for the next 2 weeks 
until up-dosing) followed by Q2W in-clinic up-dosing from the highest 
tolerated initial day dose to a maximum of 300 mg/day at home for 
22 to 34  additional weeks. If the scheduled bi-weekly up-dosing is not 
possible, the up-dosing period may be extended by up to 12 weeks 
(visits 15a-f, as needed) to accommodate dose reductions and re-escalation 
as well as COVID-19 restrictions of in-clinic visits. Thus, the up-dosing 
period will end at week 28 to 40 (including 4 weeks pretreatment, 
22 to 34 weeks of flexible up-dosing, and at least 2 weeks at the maximum 
dose). 
Double-Blind Maintenance Phase (Only for Subjects Who Reach 
300 mg/Day AR101) 
Subjects who achieve 300 mg/day AR101 for at least 2 weeks during the 
up-dosing period will enter a 24-week maintenance phase in which all 
subjects will continue to receive AR101 300 mg/day at home. Subjects in 
the dupilumab treatment group will be re-randomized (1:1) to receive 
dupilumab or placebo. Subjects who received placebo during the up-dosing 
phase will continue to receive placebo in the maintenance phase. After 24 
weeks of AR101 and dupilumab or placebo, subjects will undergo a post 
maintenance DBPCFC to assess the level of peanut protein sensitivity at 
visit 22. Dosing with AR101 should continue on the days between the two 
parts of the DBPCFC. 
Subjects who do not achieve 300 mg/day AR101 for at least 2 weeks at 
visit 16 are not permitted to enter the maintenance phase and will enter a 
12-week follow-up period. 
Double-Blind, Placebo-Controlled Food Challenge 
At visit 16, all subjects who achieve 300 mg/day AR101 for at least 2 weeks 
in the up-dosing phase will undergo a post up-dosing DBPCFC up to 2044 
mg (cumulative) peanut protein or placebo to assess desensitization. At 
visit 22, all subjects who maintain 300 mg/day AR101 will undergo a post 
maintenance DBPCFC up to 2044 mg (cumulative) peanut protein or 
placebo to assess desensitization. Dosing with AR101 should continue on 
the days between the two parts of the DBPCFC. The subject’s sensitivity to 
peanut allergen is defined as the dose at which the subject experiences 
allergic reactions. The DBPCFC will consist of 8 doses (peanut protein or 
placebo), separated 15 to 30-minute time intervals: 1, 3, 10, 30, 100, 300, 
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600, 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. After the last dose of the DBPCFC, the subject 
will be monitored for 2 hours and then discharged from the clinic. Subjects 
will be considered to have passed the DBPCFC if they do not experience 
any objective mild (Grade 1) reaction by CoFAR grading system. In 
addition, subjects will be considered to have passed the DBPCFC if they do 
not experience any mild subjective symptoms requiring pharmacological 
intervention and/or moderate or severe symptoms. 
Post-Treatment Follow-Up Period (12 weeks) 
All subjects will have a 12-week follow-up period after the end of treatment 
and will undergo safety, laboratory and clinical assessments. 
At the end of the 12-week follow-up period, subjects who passed a 444 mg 
(cumulative) post maintenance DBPCFC at visit 22 will be eligible to 
undergo a final end of study DBPCFC (up to 2044 mg cumulative) under 
intensive monitoring, at visit 25 to assess the level of peanut sensitivity after 
12 weeks off peanut and dupilumab to determine whether there is evidence 
of persistent effects and sustained unresponsiveness. 
Study Duration 
The duration of the study for a subject is approximately 64 to 76 weeks, 
excluding the screening period. 
Population 
 
 
Sample Size: 
Approximately 156 subjects, 104 and 52 for the dupilumab and placebo 
treatment groups, respectively, with a history of confirmed peanut allergy 
will be enrolled at approximately 25 sites in the US. 
 
Target Population: 
Male and female subjects aged 6 to 17 years inclusive with a history of 
peanut allergy confirmed by peanut SPT, peanut-specific IgE and by the 
level of peanut protein safely ingested during a peanut DPBCFC. 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab SC (prefilled syringe):  100 mg Q2W for subjects <30 kg 
following a loading dose of 200 mg on day 1, 200 mg Q2W for subjects ≥30 
to <60 kg following a loading dose of 400 mg on day 1, and 300 mg Q2W 
for subjects ≥60 kg following a loading dose of 600 mg on day 1. 
 
Placebo 
 
Route/Schedule: 
Dupilumab matching placebo SC Q2W following a loading dose on day 1. 
 
Background Treatment 
 
Dose/Route/Schedule: 
AR101 (peanut oral immunotherapy). Initial dose escalation day at week 4: 
0.5, 1, 1.5, 3, and 6 mg (12 mg cumulative) over 5 hours. Then 3 mg/day 
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orally for the next 14 days prior to up-dosing to 300 mg daily over the next 
22 to 34 weeks. The on-study DBPCFCs consist of 8 doses (peanut protein 
or placebo), given every 15 to 30 minutes: 1, 3, 10, 30, 100, 300, 600, 1000 
mg, up to 2044 mg peanut protein (cumulative). 
Endpoints 
 
 
Primary: 
• 
Proportion of subjects treated with dupilumab plus AR101 vs placebo 
plus AR101 who “pass” a post up-dosing DBPCFC with 2044 mg 
(cumulative) peanut protein at visit 16 
 
Secondary: 
• 
Change in the cumulative tolerated dose (log transformed) of peanut 
protein during a DBPCFC from baseline to visit 16 in subjects treated 
with dupilumab plus AR101 vs placebo plus AR101   
NOTE:  Due to the positive skew for the distribution of the 
“cumulative 
amount 
of 
peanut 
protein”, 
a 
log 
transformation will be applied to reduce the skewness 
• 
Proportion of subjects treated with dupilumab plus AR101 vs placebo 
plus AR101 who reach the 300 mg/day dose of AR101 by visit 16 
• 
Time from randomization to the first time when subjects reach the 
300 mg/day dose of AR101 during the up-dosing treatment phase (up to 
visit 16) 
• 
Proportion of subjects (continuously) treated with dupilumab plus 
AR101 vs placebo plus AR101 who “pass” a post maintenance 
DBPCFC with 2044 mg (cumulative) peanut protein at visit 22 
• 
Change in the cumulative tolerated dose (log transformed) of peanut 
protein during a DBPCFC from baseline to visit 22 in subjects 
(continuously) treated with dupilumab plus AR101 vs placebo plus 
AR101  
• 
Proportion of subjects (previously) treated with dupilumab plus AR101 
(and re-randomized to placebo plus AR101) vs placebo plus AR101 
who “pass” a post maintenance DBPCFC with 2044 mg (cumulative) 
peanut protein at visit 22 
• 
Change in the cumulative tolerated dose (log transformed) of peanut 
protein during a DBPCFC from baseline to visit 22 in subjects 
(previously) treated with dupilumab plus AR101 (and re-randomized to 
placebo plus AR101) vs placebo plus AR101  
• 
Percent change from baseline to visit 16 in peanut-specific IgE in 
subjects treated with dupilumab plus AR101 vs subjects treated placebo 
plus AR101   
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• 
Percent change from baseline to visit 22 in peanut-specific IgE in 
subjects (continuously) treated with dupilumab plus AR101 vs subjects 
treated placebo plus AR101 
• 
Percent change from baseline to the end of the study visit 25 in 
peanut-specific IgE in subjects (continuously) treated with dupilumab 
plus AR101 vs subjects treated placebo plus AR101 
• 
Proportion of subjects experiencing allergic symptoms by treatment 
group during the up-dosing phase, mean severity score for each 
symptom by treatment during up-dosing phase, maximum severity 
score for each symptom by treatment during up-dosing phase, and 
difference in mean/median duration of symptoms by treatment group 
during up-dosing phase (all endpoints measured by the daily symptom 
e-diary) 
Procedures and Assessments 
The efficacy of dupilumab will be assessed by 3 DBPCFCs to occur after 
the initial screening DBPCFC:  
• 
Post up-dosing DBPCFC at visit 16 (after reaching 300 mg/day of 
AR101 for at least 2 weeks; week 28 to 40)  
• 
Post maintenance DBPCFC at visit 22 (24 weeks after the 
up-dosing DBPCFC; week 52 to 64) 
• 
End of study DBPCFC at visit 25 (12 weeks after the maintenance 
DBPCFC; week 64 to 76) 
Overall 
safety 
will 
be 
assessed 
by 
monitoring/evaluation 
of 
treatment-emergent adverse events (TEAEs), physical examinations, vital 
signs, and clinical safety laboratory tests at prespecified time points. 
Statistical Plan 
Sample Size 
It is assumed that the proportion of subjects who achieve a cumulative dose 
of 2044 mg of peanut protein during a post up-dosing DBPCFC at visit 16 
in the placebo plus AR101 arm will be 40%, based on the Aimmune 
presentation at the 2018 American Academy of Allergy, Asthma & 
Immunology–World Allergy Organization Joint Congress with the 
proportion of subjects in the dupilumab plus AR101 arm assumed to be 65%, 
which is considered to be clinical meaningful benefit by adding on 
dupilumab treatment. A sample size of approximately 156 subjects (104 in 
dupilumab plus AR101 and 52 in placebo plus AR101) will have 80% power 
to detect a treatment difference of 25% between placebo plus AR101 and 
dupilumab plus AR101 at the 2-sided Fisher exact test with 5% significance 
level (the minimum significant difference is approximately 17.8%).  
Approximately 122 subjects who undergo the post up-dosing DBPCFC at 
week 28 (visit 16 with a window of -7/+30 days) or discontinue from study 
prior to week 28 (visit 16 with a window of -7/+30 days) will be included in 
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the primary efficacy analysis. These subjects receive AR101 dose escalation 
per the original protocol’s 24-week up-dosing schedule. The minimum 
significant difference with approximately 122 subjects is approximately 
20.7% between placebo plus AR101 and dupilumab plus AR101 assuming 
the placebo plus AR101 treatment effect is 40% at the 2-sided Fisher exact 
test with 5% significance level. 
Efficacy Analysis Set 
The full analysis set (FAS) includes all randomized subjects. Efficacy 
analyses will be based on the treatment allocated at randomization (as 
randomized). 
The modified full analysis set (mFAS) includes all FAS subjects who 
undergo the post up-dosing DBPCFC at week 28 (visit 16 with a window of 
-7/+30 days) or discontinue from study prior to week 28 (visit 16 with a 
window of -7/+30 days). 
The mFAS will be used for primary analysis for all efficacy endpoints. 
Analysis of the FAS will also be done for supportive analyses. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized subjects who received 
any study drug; it is based on the treatment received (as treated). Treatment 
compliance/administration and all clinical safety variables will be analyzed 
using the SAF. 
Primary Efficacy Analysis 
The primary endpoint will be analyzed using the Cochran-Mantel-Haenszel 
test adjusted by randomization stratification factors to assess the treatment 
difference in the proportion of responders (ie, those who “pass” a post 
up-dosing DBPCFC with 2044 mg [cumulative] peanut protein at visit 16 
[week 28 with a window of -7/+30 days]) in the mFAS. In addition, the 
primary efficacy endpoint will be performed on the FAS as a supportive 
analysis. 
If a subject does not have available post up-dosing DBPCFC data at visit 16, 
the subject 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 subjects with available visit 16 post up-dosing DBPCFC.  
Subgroup analysis (eg, by baseline weight group) will also be performed. 
Secondary Efficacy Analysis 
All secondary endpoints will be analyzed descriptively at given visits.  
Change in the cumulative tolerated dose (log transformed) of peanut protein 
during a DBPCFC from baseline to the end of the up-dosing period at 
visit 16 will be analyzed using analysis of covariance (ANCOVA) with 
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treatment as the main effect, stratification variables, and baseline tolerated 
cumulative amount of peanut protein DBPCFC as covariates. In addition, a 
non-parametric analysis using the Van Elteren test will be conducted as a 
sensitivity analysis.  
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 by treatment 
group. 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACIP 
Advisory Committee on Immunization Practices 
ACQ 
Asthma Control Questionnaire 
ACT 
Asthma Control Test 
AD 
Atopic Dermatitis 
ADA 
Anti-Drug Antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AR101 
Investigational oral biologic drug for use as oral immunotherapy in peanut-
allergic individuals 
AST 
Aspartate aminotransferase 
BAT 
Basophil Activation Test 
BUN 
Blood urea nitrogen 
CoFAR 
Consortium, of Food Allergy Research 
CPK 
Creatine phosphokinase 
CRF 
Case report form (electronic or paper) 
CSR 
Clinical study report 
DBPCFC 
Double-blind, placebo-controlled food challenge 
DLT 
Dose-limiting toxicity 
EAACI 
European Academy of Allergy and Clinical Immunology 
EASI 
Eczema Area and Severity Index 
EDC 
Electronic data capture 
e-diary 
Electronic diary 
EoE 
Eosinophilic Esophagitis 
EU 
European Union 
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 1 Second 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
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Hep C Ab 
Hepatitis C Antibody 
HDL 
High-density lipoprotein 
HIV  
Human Immunodeficiency Virus 
HPMC 
Hydroxypropyl methylcellulose 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDED 
Initial dose escalation day 
IDMC 
Independent Data Monitoring Committee 
Ig 
Immunoglobulin 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IM 
Intramuscular 
IL 
Interleukin4 
IL-4Rα 
Interleukin-4 Receptor Alpha 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IWRS 
Interactive web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
Modified full analysis set 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
PEESS 
Pediatric Eosinophilic Esophagitis Symptom Score 
PK 
Pharmacokinetic 
PEF 
Peak expiratory flow 
PT 
Preferred term 
QW 
Every week 
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 Software 
SC 
Subcutaneous 
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SOC 
System organ class 
SPT 
Skin prick test 
TEAE 
Treatment-emergent adverse event 
Th1 
Type 1 T-helper cell 
Th2 
Type 2 T-helper cell 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
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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). 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 
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. 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 subjects in OIT trials continue 
to have side effects that can hinder their compliance and the overall efficacy of OIT, which is a 
concern as is the re-sensitization upon cessation of peanut intake. It is known that allergic response 
to food is an IgE-mediated event; however, recent data suggest that IL-4 and IL-13 may also play 
a significant role in food allergy pathogenesis. This clinical study proposes to examine the effect 
of dupilumab, a monoclonal antibody, which blocks the action of these cytokines, to enhance the 
safety, tolerability, and efficacy of AR101 (oral biologic drug) in subjects with significant allergy 
to peanuts. 
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. Peanut allergy is an immunoglobulin E (IgE)-mediated 
hypersensitivity reaction following the ingestion of normally innocuous peanut protein. 
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 Type 2 T-helper cell (Th2) 
cytokine release, which results in eosinophil infiltration and creates a vicious cycle of chronic 
allergic inflammation. Like other forms of allergy immunotherapy, OIT to peanut involves a slow 
up-dosing of exposure to allergen, in this case peanut, over time to desensitize or increase the 
threshold of reactivity to peanut. Once reaching a target level of peanut protein, subjects are 
continued on a maintenance dose of peanut protein to maintain desensitization. Although many 
subjects on a maintenance dose of peanut protein have demonstrated desensitization to peanut 
(ie, the ability to tolerate a level of exposure to peanut without an allergic reaction), up to 80% of 
subjects exhibit related adverse events (AEs) during OIT, with 42% experiencing systemic 
reactions and 49% experiencing gastrointestinal (GI) symptoms; the majority of these are mild and 
decline with prolonged treatment (Virkud, 2016). Up to 20% of subjects, however, are unable to 
complete the up-dosing regimen due to side effects, which are primarily GI related. An additional 
issue with current OIT is its limited ability to induce clinical tolerance when subjects are taken off 
daily peanut intake (Vickery, 2014). In many of the studies with peanut OIT, despite years of 
immunotherapy, subjects never achieve tolerance and are re-sensitized within weeks of halting 
daily peanut intake, with a small percentage (~10%) maintaining a sustained unresponsiveness 
even after 3 months off OIT. 
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Dupilumab, a fully human monoclonal antibody directed against interleukin (IL)-4 receptor alpha 
(IL-4Rα), blocks the activity of IL-4 and IL-13. These 2 cytokines are critical to the induction and 
perpetuation of the Type 2 response and have been implicated in multiple atopic diseases. 
Inhibiting both IL-4 and IL-13 signaling with dupilumab has demonstrated clinical efficacy in 
moderate-to-severe atopic dermatitis (AD), persistent, uncontrolled asthma, nasal polyposis, and 
is currently being investigated in eosinophilic esophagitis (EoE). It is known that oral allergen 
up-dosing during OIT induces up-regulation of IL-4 and IL-13 as well as other Type 2 
inflammatory cytokines and pathway activity, which contribute to dose-limiting side effects of 
OIT such as GI (nausea, vomiting, diarrhea and abdominal pain), respiratory (wheezing and 
shortness of breath), and skin (generalized rash, pruritus, and angioedema) symptoms. In addition, 
IL-4 and IL-13 induce isotype class switching to IgE and production of allergen-specific IgE. 
This study will explore whether dupilumab has the ability to enhance immunomodulatory effects 
of OIT by decreasing Type 2 responses, decreasing production of peanut-specific IgE, which will 
result in improved safety and tolerability of OIT up-dosing as well as improved efficacy as 
determined by the ability to tolerate a higher cumulative dose of peanut protein during a double-
blind, placebo-controlled food challenge (DBPCFC) after 28 weeks of dupilumab therapy 
compared to placebo. In addition, the study will evaluate whether dupilumab influences known 
biomarkers important in the allergic response such as a reduction in allergen-specific 
immunoglobulin sub-class switching to IgE, decrease in basophil activation, and decreased 
Th2 cell activities and the associated cytokine/chemokine levels. A maintenance phase where 
subjects previously treated with dupilumab in the treatment period are randomized to continue to 
receive dupilumab (indefinite [continuously]) with OIT or are re-randomized to placebo (limited 
[previously]) with OIT has been included. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To assess whether dupilumab as adjunct to AR101 compared to placebo improves 
desensitization at the completion of the up-dosing period, defined as an increase in the 
proportion of subjects who pass a post up-dosing double-blind placebo-controlled food 
challenge (DBPCFC) at visit 16  
2.2. 
Secondary Objectives 
• To assess whether dupilumab as adjunct to AR101 compared to placebo improves 
desensitization at the completion of up-dosing, defined as an increase in the cumulative 
tolerated dose (log transformed) of peanut protein during a post up-dosing DBPCFC at 
visit 16  
• To assess whether dupilumab as (indefinite [continuously]) adjunct to AR101 compared to 
placebo maintains desensitization, defined as an increase in the proportion of subjects who 
pass a post maintenance DBPCFC at visit 22  
• To assess whether dupilumab as (limited [previously]) adjunct to AR101 compared to 
placebo maintains desensitization, defined as an increase in the proportion of subjects who 
pass a post maintenance DBPCFC at visit 22  
• To evaluate the safety and tolerability of dupilumab as adjunct to AR101 compared to 
placebo   
• To assess the effect of dupilumab (compared to placebo) as adjunct to AR101 on the change 
in peanut-specific IgE, IgG, IgG4, and peanut-specific IgG4/IgE ratio  
• To assess if dupilumab increases the tolerability of AR101 as measured by the daily 
symptoms (electronic diary [e-diary]) during the up-dosing phase 
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3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
Treatment with dupilumab will improve the efficacy of OIT. 
3.2. 
Rationale  
3.2.1. 
Rationale for Study 
This study will investigate whether addition of dupilumab, a fully human monoclonal antibody 
directed against IL-4Rα, will improve OIT in subjects with peanut allergy. This study will seek to 
demonstrate that addition of dupilumab to AR101 will enhance the safety, tolerability, and efficacy 
of OIT. This will be determined by assessing whether treatment with dupilumab provides an 
enhanced ability to tolerate a higher cumulative dose of peanut protein during a food challenge 
after 6 months of treatment compared to placebo, when given concomitantly with AR101, and 
whether treatment with dupilumab allows for more rapid up-dosing of peanut during 
desensitization. The differences in safety and tolerability will be assessed through an evaluation of 
treatment differences in AEs and study drop-out rates. 
Oral immunotherapy has demonstrated efficacy in desensitizing food-allergic subjects by 
promoting physiologic changes, which suppress an allergic response to the ingested food antigen. 
Desensitization is defined as the ability to tolerate a higher threshold of food allergen without an 
allergic reaction, while consuming the food regularly. The first open-label clinical trial of peanut 
protein OIT showed that OIT could successfully induce desensitization in peanut-allergic subjects, 
with a favorable side-effect profile and low rates of anaphylaxis (Jones 2009). A 20-fold or greater 
improvement in DBPCFC-tolerated peanut dose compared to baseline after up-dosing to 800 mg 
per day over 6 months was demonstrated with minimal responses in placebo-treated subjects 
(Anagnostou 2014). A high proportion of individuals who achieve desensitization develop clinical 
reactivity within 3 months if peanut treatment is stopped (Vickery, 2014) (Syed, 2014). Persistent 
adverse reactions, primarily GI related, lead to OIT termination in 20% of subjects (Narisety, 2015) 
(Virkud, 2016). Three hundred mg/day of peanut protein can be safely ingested by 20 to 34 weeks 
and 1200 mg/day by 30 to 58 weeks. Most AEs occur in the first 12 weeks (76% GI, 
7% respiratory, and 14% skin) delaying up-dosing to 300 mg/day in these subjects for 12 weeks. 
Peanut antigen-specific Th2 cells express the highest levels of IL-4 and IL-13 in subjects with the 
highest rate of allergic AEs (Syed, 2014). 
AR101 (Aimmune) is an immunotherapy that consists of an oral peanut protein formulation that 
was evaluated in a double-blind placebo-controlled phase 2 study in 55 pediatric and adult subjects 
who were highly reactive to peanut. Subjects were started on an oral peanut dose of 3 mg on a 
single day and were then escalated to a maintenance dose of 300 mg/day by approximately 
week 22. After 22 weeks of treatment, 23 of the 29 subjects (79%, intent-to-treat [ITT]) assigned 
to OIT (6 dropped out because of GI side effects) tolerated 443 mg (cumulative) (equivalent to 
approximately 1.5 peanut kernels) of peanut protein, and 18 of the 29 subjects (62%, ITT) were 
able to tolerate 1043 mg (cumulative) (equivalent to 4 peanut kernels). Among the 26 subjects in 
the placebo group, only 5 (19%, ITT) could tolerate 443 mg of peanut protein, and none was able 
to reach the 1043 mg challenge dose (Bird 2015).  
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The open-label follow on study ARC002 evaluated the safety and efficacy of AR101 OIT in 
47 eligible peanut-allergic subjects who participated in the ARC001 originating study. Former 
placebo-treated subjects began AR101 up-dosing to 300 mg/day, followed by 2 weeks of daily 
dosing at 300 mg/day, and a post up-dosing DBPCFC. At the post up-dosing DBPCFC, former 
placebo-treated subjects exhibited a high rate of desensitization, with 20 of 21 subjects (95%) 
tolerating the 443 mg cumulative dose of peanut protein. No moderate or severe AEs were 
reported, and no subject required epinephrine. These findings are consistent with those of the 
originating study exit DBPCFC in AR101-treated subjects. A total of 40 subjects overall, in both 
the former placebo-treated and AR101-treated groups, entered a 12-week maintenance period at 
300 mg/day, followed by a post maintenance DBPCFC. After 9 months of AR101 treatment 
(6 months up-dosing, 3 additional months of 300 mg/day of maintenance), 73% of subjects (ITT) 
tolerated 443 mg (cumulative), 65% tolerated 1043 mg (cumulative) and 44% tolerated 2043 mg 
(cumulative) peanut protein DBPCFC. Moderate or severe AEs were reported in a minority of 
subjects at the 2 highest doses. Two subjects each required a single dose of epinephrine 
(AR101 Investigator Brochure).  
A retrospective cohort analysis was also performed to evaluate the safety and efficacy profile of 
AR101 in relation to baseline peanut-specific IgE. Subjects were grouped by peanut-specific 
IgE levels of ≤100 kUA/L or >100 kUA/L. All subjects in both groups tolerated at least 443 mg 
cumulative of peanut protein. However, the 2 groups had different tolerance to higher doses of 
peanut-specific protein:  1043 mg of cumulative peanut protein was tolerated by 21 subjects (91%) 
in the ≤100 kUA/L group and 15 subjects (88%) in the >100 kUA/L group; 2043 mg of cumulative 
peanut protein was tolerated by 17 subjects (74%) in the ≤100 kUA/L group and 7 subjects (17%) 
in the >100 kUA/L group (Wang 2016). 
In the phase 3 AR101 study (PALISADE) in which the prespecified primary analysis was children 
aged 4 to 17 years (n=496) with peanut allergy, subjects were started on an oral peanut dose of 
3 mg on a single day and were then escalated to a maintenance dose of 300 mg/day during an 
up-dosing period of approximately 6 months, which was followed by a 6 month double-blind 
maintenance phase. The primary endpoint was the proportion of subjects tolerating 1043 mg 
(cumulative) peanut protein in the exit DBPCFC; 67.2% of the 372 subjects (ITT) treated with 
peanut OIT tolerated 1043 mg (cumulative) peanut protein compared to 4.0% of the 124 subjects 
treated with placebo. Those tolerating 2043 mg (cumulative) peanut protein, a key secondary 
efficacy endpoint, were 50.3% and 2.4% for peanut OIT and placebo, respectively. Of the 
AR101-treated subjects, a total of 76 (20.4%) discontinued, with 46 (12.4%) related to AEs. 
Treatment with AR101 was associated with a marked reduction in the IgE/IgG4 ratio from 
approximately 100 to <10, whereas an increase was noted in the subjects treated with placebo. 
Similarly, wheal size in the skin prick test (SPT) was reduced compared to placebo by 
AR101 treatment (PALISADE Group of Clinical Investigators, 2018). 
Other investigator-initiated studies have also demonstrated the safety and efficacy of peanut 
protein OIT. These studies suggest that higher levels of peanut protein tolerated at a maintenance 
dose provide a greater protection in a DBPCFC. For example, a prospective cohort study of peanut 
OIT, in which 22 children received a maintenance dosing of 800 mg/day of peanut protein for 
32 weeks demonstrated a significant increase in peanut challenge threshold, with 86% of subjects 
tolerating up-dosing and 14/22 (64%) tolerating 6600 mg (cumulative) of peanut protein at the 
completion of treatment (Anagnostou 2011). 
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The mechanisms by which OIT leads to clinical protection may include mast cell and basophil 
exhaustion or suppression, development of food-specific IgA and IgG4 blocking antibodies, 
increase in the peanut-specific IgG4/IgE ratio, up-regulation and expansion of Treg cells, a 
skewing from a Th2 to a Type 1 T-helper cell (Th1) profile, and the development of anergy and/or 
exhaustion in Th2 antigen-specific cells (Syed, 2014) (Vickery, 2013) (Gorelik, 2015) 
(Santos, 2015).  
The use of omalizumab (monoclonal anti-IgE antibody) as an adjunct therapy to peanut protein 
OIT has been shown to significantly increase the threshold of reactivity in peanut-allergic subjects 
(MacGinnitie 2016). Omalizumab decreased the allergic response by binding to free circulating 
IgE molecules and reducing IgE-mediated mast cell and basophil degranulation on allergen 
exposure. Omalizumab allows more rapid desensitization to higher doses of peanut but does not 
affect long-term efficacy (MacGinnitie 2016). Therefore, there is an unmet need for a safer, more 
rapid, and more reliable adjunct to OIT treatment of peanut allergy that provides lasting protection. 
3.2.2. 
Rationale for Study Design 
AR101, with and without dupilumab, will be tested in a 2-arm, double-blind, randomized, 
parallel-group study in subjects with confirmed peanut allergy. Pediatric subjects will be enrolled 
as children represent the majority of subjects with peanut allergy and are a greater risk for 
accidental ingestion of peanut. Dupilumab/placebo treatment for 28 to 40 weeks as an adjunct to 
24 to 36 weeks of daily AR101 treatment will be evaluated, followed by maintenance period of 
24 weeks of daily AR101 treatment with concomitant dupilumab or placebo. Two treatment 
groups are required to provide informative controls and minimize bias on clinical endpoints:  
dupilumab plus AR101 and placebo plus AR101. Subjects will be treated for 28 to 40 weeks with 
either Q2W subcutaneous (SC) dupilumab or placebo. After the first 4 weeks of pretreatment, 
subjects will begin a 24 to 36 week up-dosing regimen of daily oral AR101. The study will assess 
an up-dosing regimen up to a maximum of 300 mg/day over the following 24 to 36 weeks of the 
study. If the scheduled bi-weekly up-dosing is not possible, the up-dosing period may be extended 
by up to 12 weeks (optional visits 15a-f) if necessary to accommodate dose reductions and re-
escalation as well as COVID-19 restrictions of in-clinic visits. Thus, the up-dosing period will end 
at week 28 to 40 (including 4 weeks pretreatment, 22 to 34 weeks of flexible up-dosing, and at 
least 2 weeks at the maximum dose). 
Subjects who achieve 300 mg daily dose of AR101 for at least 2 weeks at visit 16 (ie, the end of 
the up-dosing period, week 28 to 40) will enter a 24-week maintenance period. Subjects treated 
with dupilumab during the up-dosing period and who achieve 300 mg/day AR101 for at least 
2 weeks will be re-randomized to 2 groups, AR101 plus dupilumab (indefinite [continuously]) and 
AR101 plus placebo (limited [previously]); this will allow an assessment of a lasting or limited 
effect of dupilumab. Subjects treated with placebo during the up-dosing period and who achieve 
300 mg daily AR101 for at least 2 weeks will continue to be treated with placebo plus AR101 
during the maintenance period. 
This design allows for a direct comparison between adjunct dupilumab plus AR101 to placebo 
plus AR101 during the 28 to 40 week double-blind treatment period. It will also evaluate the effect 
of dupilumab in maintaining the response to AR101, defined as an increase in the proportion of 
subjects who pass a DBPCFC.  
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3.2.3. 
Rationale for Dose Selection 
3.2.3.1. 
Dose and Regimen for Dupilumab 
The approved dosing regimen in the treatment of AD in adults is 300 mg SC Q2W. The doses 
selected for this study are consistent with the approved AD pediatric study plan doses for this age 
group and the doses being tested in the ongoing AD pediatric study, R668-AD-1652 (6 to 
<12 years of age).  
In study R668-AD-1412, 78 children aged 6 to 17 years received doses up to 4 mg/kg SC every 
week (QW) for 4 doses, where exposures similar to those in adults receiving 300 mg SC Q2W 
were achieved. Significant improvements in measures of AD were noted in these children, with an 
acceptable safety profile. As with many monoclonal antibodies, weight is the most significant 
covariate affecting dupilumab pharmacokinetics. The weight-based doses chosen for treatment in 
this study are chosen such that subjects should achieve similar dupilumab exposure in serum to 
that observed at the Food and Drug Administration (FDA)-approved adult dose for 
moderate-severe AD (300 mg SC Q2W), based on pharmacokinetic modeling of the data from 
study R668-AD-1412. 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 30 kg or more but less than 60 kg, will 
receive 200 mg Q2W following a loading dose of 400 mg on day 1. Children weighing less than 
30 kg will receive 100 mg SC Q2W following a loading dose of 200 mg on day 1. Regardless of 
subject weight gain or loss, the dupilumab dosing regimen assigned at randomization on day 1 will 
be maintained throughout the study. 
Subcutaneous study drug will be dosed at home by the subject or by their legal guardian after 
adequate training (for subjects under 12 years old, legal guardian injections will be required) and 
at least 8 hours apart from the AR101 daily dose in order to allow for an accurate attribution of 
AE relatedness to study drug or AR101. In addition, dupilumab/placebo must be given at least 
24 hours after in-clinic AR101 up-dosing. 
The administration of the loading dose of dupilumab will allow systemic concentrations to reach 
steady-state faster. Rapid attainment of target-saturating concentrations may yield a rapid clinical 
response within a 4-week period of dupilumab pretreatment by suppressing Type 2 effector cell 
function, which is believed to be responsible for the allergic GI side effects of OIT. Dupilumab 
blockade of IL4/IL13 in AD, an immune-driven disease, reduced skin lesions and suppressed at 
4 weeks the mRNA expression of genes related to T-cells, dendritic cells, eosinophils, 
inflammatory pathways, and Th2-inducing chemokines, whereas increases or insignificant 
decreases were observed with placebo. The correlation between these mechanistic changes and 
rapid improvement in clinical measures of disease activity in adults with AD, including Eczema 
Area and Severity Index (EASI) and SCORing AD, support an AR101 study design with only 
4 weeks of dupilumab SC pretreatment (Hamilton, 2014). Rapid improvements in forced 
expiratory volume in the first second (FEV1) and FeNO have also been observed within 4 weeks 
in dupilumab studies in adults with asthma (Wenzel, 2013) (Wenzel 2016). The results in other 
indications suggest 4 weeks of dupilumab treatment significantly suppresses Type 2-mediated 
responses. 
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3.2.3.2. 
Dose and Regimen for AR101 Oral Immunotherapy 
Concurrent with dupilumab dosing, subjects in the placebo plus AR101 and the dupilumab plus 
AR101 groups will begin at week 4, with Q2W up-dosing of AR101 beginning at 3 mg/day up to 
a maximum of 300 mg/day over 24 to 36 weeks (Baumert 2017). This 300 mg/day maintenance 
dosing regimen has previously been shown to provide significant clinical efficacy and consistent 
kinetics of the sIgG4 and sIgE response (Bird 2015). The AR101 regimen target of 300 mg/day 
may be clinically effective for desensitization for accidental peanut exposure. The majority of 
allergic side effects (GI) occur during bi-weekly up-dosing at a peanut dose less than 100 mg/day 
(Nadeau et al, POISED Peanut OIT Study; unpublished data). 
3.3. 
Safety Considerations (Risk-Benefit) 
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 often limit its full efficacy in many subjects 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 the role of IL-4 and IL-13 may also play a 
significant role in food allergy pathogenesis. Consequently, dupilumab treatment, either alone or 
as an adjunct treatment to OIT, would be expected to provide benefit by blocking the activity of 
IL-4 and IL-13 and decreasing Type 2 responses, decreasing production of peanut-specific IgE, 
and potentially increasing the peanut-specific IgG4 response.  
Note: Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an 
impact on the conduct of clinical trials, the sponsor does not intend to screen any subjects in this 
study until the impact of the COVID-19 pandemic is deemed manageable and no longer interfering 
with the conduct of trials at individual sites, and subjects can safely participate in this study.  
3.3.1. 
Risk-Benefit for Dupilumab 
At the time of writing this protocol, dupilumab 300 mg SC Q2W had been approved in the US, the 
European Union (EU), and several countries ex-US including Japan for the treatment of adults 
with moderate-to-severe AD. Marketing applications are under review in additional countries. 
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. 
Short term (4 weeks), 12- and 16-week treatment with repeated QW doses of SC dupilumab (75, 
150, or 300 mg) monotherapy was well tolerated in adult patients with moderate-to-severe AD not 
adequately controlled with topical medications. Similar results were observed with dupilumab 300 
mg SC QW administered concomitantly with topical corticosteroid in study R668-AD-1121. 
Dupilumab’s efficacy in adult patients with moderate-to-severe uncontrolled asthma has also been 
demonstrated at doses of 200 mg or 300 mg SC Q2W for 24 weeks (study DRI12544) and 
52 weeks (study EFC13579). Asthma is a common comorbidity of allergy and asthma 
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exacerbations are an important safety concern for immunotherapy. 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 
has been completed. Data generated from this study showed that dupilumab administered as single 
and repeated weekly doses 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 SC dose regimens of dupilumab evaluated (2 mg/kg and 4 mg/kg) showed significant 
clinical benefit in both pediatric age groups.  
As of March 2018, approximately 600 pediatric AD (n=407) and asthma (n=196) patients have 
been exposed to dupilumab in completed and ongoing clinical studies.  
3.3.2. 
Risk-Benefit for Peanut Protein 
AR101 has been approved in the US as a monotherapy for peanut allergy. Based on previously 
published studies, approximately 80%, 15%, and <1% of the subjects are expected to have a 
reversible mild, moderate, or severe allergic symptom, respectively, during dosing with peanut. 
Allergic symptoms may include sneezing, rhinorrhea, urticaria, angioedema, flushing, flares of 
eczema, ocular, nasal, oral and/or throat pruritus, nausea, vomiting, abdominal discomfort, 
stridor/laryngeal edema, cough, wheezing, and/or shortness of breath in addition to severe 
anaphylaxis.  
The only major atypical AE reported in the literature related to OIT has been several reported cases 
of EoE. In adult patients with EoE, treatment with dupilumab has shown clinical improvement of 
dysphagia symptoms and histology. 
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 subjects 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. The anticipated rate of life-threatening anaphylactic reactions is <0.1%. There 
may be a risk that during the study, subjects may decrease their vigilance against accidental food 
allergen ingestion because they believe they are protected from it. Therefore, subjects will be 
warned that they should continue to practice their usual vigilance against accidental ingestion of 
food allergens or food allergen-containing foods and be reminded to carry their epinephrine 
autoinjector at all times. 
The potential benefit of peanut oral immunotherapy to desensitize peanut allergic subjects is 
outlined in Section 3.2.1. 
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4. 
STUDY ENDPOINTS 
4.1. 
Primary Endpoint 
• Proportion of subjects treated with dupilumab plus AR101 vs placebo plus AR101 who 
“pass” a post up-dosing DBPCFC with 2044 mg (cumulative) peanut protein at visit 16  
4.2. 
Secondary Endpoints 
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 16 in subjects treated with dupilumab plus AR101 vs 
placebo plus AR101   
NOTE:  Due to the positive skew for the distribution of the “cumulative amount of peanut protein”, 
a log transformation will be applied to reduce the skewness 
• Proportion of subjects treated with dupilumab plus AR101 vs placebo plus AR101 who 
reach the 300 mg/day dose of AR101 by visit 16 
• Time from randomization to the first time when subjects reach the 300 mg/day dose of 
AR101 during the up-dosing treatment phase (up to visit 16)  
• Proportion of subjects (continuously) treated with dupilumab plus AR101 vs placebo 
plus AR101 who “pass” a post maintenance DBPCFC with 2044 mg (cumulative) 
peanut protein at visit 22  
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (continuously) treated with dupilumab 
plus AR101 vs placebo plus AR101  
• Proportion of subjects (previously) treated with dupilumab plus AR101 (and re-
randomized to placebo plus AR101) vs placebo plus AR101 who “pass” a post 
maintenance DBPCFC with 2044 mg (cumulative) peanut protein at visit 22  
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (previously) treated with dupilumab plus 
AR101 (and re-randomized to placebo plus AR101) vs placebo plus AR101  
• Percent change from baseline to visit 16 in peanut-specific IgE in subjects treated with 
dupilumab plus AR101 vs subjects treated placebo plus AR101   
• Percent change from baseline to visit 22 in peanut-specific IgE in subjects 
(continuously) treated with dupilumab plus AR101 vs subjects treated placebo plus 
AR101 
• Percent change from baseline to the end of the study visit 25 in peanut-specific IgE in 
subjects (continuously) treated with dupilumab plus AR101 vs subjects treated placebo 
plus AR101 
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• Proportion of subjects experiencing allergic symptoms by treatment group during the 
up-dosing phase, mean severity score for each symptom by treatment during up-dosing 
phase, maximum severity score for each symptom by treatment during up-dosing 
phase, and difference in mean/median duration of symptoms by treatment group during 
up-dosing phase (all endpoints measured by the daily symptom e-diary)  
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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 subject. 
5.2. 
Efficacy Variables 
Efficacy variables will include the DBPCFC, the peanut SPT, EASI for subjects with AD, 
asthma control questionnaire (ACQ-5 or Juniper ACQ) for subjects with asthma, daily allergy 
symptoms (recorded in an e-diary), and food allergy quality of life questionnaires. 
5.3. 
Safety Variables 
Safety variables will include vital signs, spirometry (FEV1 and/or peak expiratory flow [PEF]), 
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 
be considered to be trough values (Ctrough.time point) 
5.5. 
Anti-Drug Antibody Variables 
Anti-drug antibody (ADA) variables include ADA status, titer, NAb status, and time point/visit. 
5.6. 
Pharmacodynamic and Biomarker Variables 
Pharmacodynamic and biomarker variables are: 
Serum Total IgE: Serum total IgE is a marker of Type 2 activity. Dupilumab significantly 
suppressed total IgE in studies of adult AD, nasal polyposis, and asthma patients. 
Serum Peanut-Specific Antibody Assays (IgE, IgG, IgG4 against peanut extract and peanut 
protein allergen components): The induction of peanut allergen specific IgG4 during OIT has 
been reported in multiple studies. 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 allergen specific IgE was seen to increase by ~3-fold after 3 months of OIT and 
gradually return to baseline at one year. 
In study R668-AD-1307 and other dupilumab studies in adults, dupilumab suppressed both total 
and allergen-specific IgEs. In general, dupilumab suppresses total IgE by ~50% with 12 to 
16 weeks of treatment. 
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Fractional Exhaled Nitric Oxide: Asthma is a common comorbidity in peanut allergic children, 
reported to be between 40%-60% by different groups. While peanut allergic children often 
outgrow co-existing asthma symptoms, eosinophilic airway inflammation usually persists and is 
directly associated with anaphylactic reactions to peanut. Fractional exhaled nitric oxide is a 
non-invasive marker that has been shown to correlate with allergic airway inflammation and IgE 
sensitization. In a study of 94 peanut-allergic children, elevated FeNO levels (>35 ppb) were found 
in over 75% of the subjects (Hughes, 2010). Additionally, baseline FeNO level (pre-OFC) has 
been reported to be comparable to peanut SPT at predicting clinical outcomes in oral food 
challenge to peanut (Preece, 2014). In a 12-month study enrolling 56 subjects with peanut allergy, 
FeNO 
measurement 
demonstrated 
superior 
reproducibility 
(Intra-class 
Correlation 
Coefficient =0.73) in comparison to peanut SPT (Intra-class Correlation Coefficient =0.51) 
(Percival, 2016). In this study, we aim to use FeNO (pre-DBPCFC) as a measure of persistent 
airway eosinophilic inflammation in peanut-allergic children. In past asthma studies, dupilumab 
significantly lowered FeNO levels in adult and adolescent asthma patients, thus we hypothesize 
that dupilumab treatment will suppress FeNO levels in peanut allergic children. It is highly likely 
that peanut exposure during peanut DBPCFC in these subjects may trigger an increase in FeNO 
levels and asthmatic symptoms. Therefore, on the day of DBPCFC, FeNO levels will be measured 
both before and after the oral challenge to assess whether dupilumab may suppress the airway 
inflammation associated with DBPCFC, as reflected by induction of FeNO after the oral challenge. 
During the COVID-19 pandemic, measurements of FeNO no longer need to be completed (at the 
discretion of the investigator).  
Basophil Sensitivity Test (optional): Basophils are one cell type involved in acute allergic 
reaction. CD203c and CD63 have been shown to be increased in basophils from peanut-allergic 
subjects compared to non-allergic healthy controls. The utility of the Basophil Activation Test 
(BAT) was assessed for diagnosing peanut allergy in a well-characterized population of 
peanut-allergic, peanut-sensitized, and non-sensitized children. The BAT showed high accuracy 
(97%) in diagnosing peanut allergy. In a study of omalizumab (anti-IgE) in peanut allergic 
subjects, CD203c expression in the BAT decreased during treatment and returned to pretreatment 
levels after cessation of treatment (Gernez, 2011). However, as a flow cytometry-based test, the 
CD203c or CD63 median fluorescence intensity reading is intrinsically highly variable. As an 
improvement to the traditional BAT, the basophil sensitivity test measures the minimum amount 
of peanut extract required to activate basophils in subject whole blood, as measured by 
up-regulation of CD203c and CD63. Basophil sensitivity to other allergens may also be tested. 
The results of these exploratory tests will not be presented in the clinical study report (CSR). 
Peanut-reactive Th2A cells (Optional): One important area of investigation is to determine the 
effect of dupilumab on allergic T-cell responses as an adjunct during AR101 treatment. At week 
4 (300 mg QW or Q2W) dupilumab effectively reduced CD3+ T-cells in AD skin lesions and 
suppressed Th2 inflammatory pathway genes (eg CCL13, CCL17 and CCL18), as shown by past 
studies in atopic dermatitis (Hamilton, 2014; Guttman-Yassky, 2019). These data indicate that 
dupilumab has direct suppressive effect on Th2 cells. However, due to the extreme low frequency 
of allergen-specific T-cells in circulation, conventional immunophenotyping of Th2 cells has not 
been successful in capturing changes in allergen-specific T-cells during specific immunotherapy. 
Th2A cells are allergen-specific Th2 cells with characteristic surface marker signatures (CRTH2+, 
CD27-, CD154+, CD161+, CD45RB- and CD49d+) (Wambre, 2017). Using these markers, 
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Wambre et al showed a reduction in the frequency of pro-allergic Th2A cell subsets from subjects 
receiving AR101, but not in the placebo group in Aimmune's Phase II study. Th2A subset of T-
cells were also shown to be secreting higher levels of IL-4, IL-5, and IL-9, and were thus postulated 
to be a key pathogenic driver of allergic-T cell response. Therefore, monitoring peanut-reactive 
Th2A cells may reveal important mechanistic insight into the amelioration of allergic symptoms 
by dupilumab as an adjunct to AR101 (peanut oral immunotherapy). 
5.7. 
Other Exploratory Research (Optional) 
Blood may be obtained for additional exploratory tests such as whole blood stimulation with 
CD3/CD28 in the TruCulture® system and flow cytometry-based immune-phenotyping on type-2 
allergic T-cells. Blood samples collected for exploratory research will be kept for up to 15 years 
for studying the allergen response ex-vivo. In subjects who consent/assent, peripheral blood 
mononuclear cells may be collected for RNA sequencing and RNA expression studies. The results 
of these exploratory tests will not be presented in the CSR. 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a phase 2, multicenter, randomized, double-blind, parallel-group, 2-arm study in subjects 
aged 6 to 17 years inclusive who are allergic to peanut. The study consists of a screening period 
of up to 16 weeks; a 28 to 40 week double-blind treatment period, which includes 4 weeks of 
pretreatment with dupilumab or placebo followed by 24 to 36 weeks of treatment with dupilumab 
or placebo in combination with a gradual up-dosing of AR101; a 24-week maintenance phase with 
300 mg/day AR101 with concomitant dupilumab or matching placebo (for subjects who achieve 
300 mg/day AR101 for at least 2 weeks in the up-dosing period); and a 12-week post-treatment 
follow-up period (Figure 1). Subjects who do not achieve 300 mg/day will still enter the 12-week 
follow-up. Visit windows should be adhered to as per the schedule of events, which contains 
flexibility in the screening and up-dosing periods to accommodate dose reductions and re-
escalation as well as COVID-19 restrictions of in-clinic visits. 
All AR101 dose escalation will need to be done in-clinic. If the scheduled bi-weekly up-dosing is 
not possible, the up-dosing period may be extended by up to 12 weeks (optional visits 15a-f) if 
necessary to accommodate dose reductions and re-escalation as well as COVID-19 restrictions of 
in-clinic visits. If necessary, subjects may continue on a dose beyond the planned 2-week duration 
during the up-dosing period. If a temporary hold on up-dosing of AR101 is needed (current dose 
maintained), the investigator should follow up with the subjects via telephone call to evaluate 
safety and administration at current dose.  
The duration of the study is approximately 64 to 76 weeks, excluding the screening period, for 
subjects who enter the maintenance period, and 40 to 52 weeks, excluding the screening period, 
for subjects who do not achieve 300 mg/day AR101 for at least 2 weeks at visit 16 and do not enter 
the maintenance period. 
Figure 1: 
Schematic of Study Design 
 
Abbreviations: DBPCFC, double-blind placebo-controlled food challenge; DUP, dupilumab; Exc, exclusion; Inc, inclusion; PBO, 
placebo 
Enroll 2-arms (2:1), up-dose AR101 from week 4 to week 28 to 40. Subjects in DUP (dupilumab) +AR101 group will be re-randomized to 
DUP+AR101 and PBO (placebo) + AR101, but only those subjects who achieve 300 mg/day AR101 for at least 2 weeks will be eligible to 
enter the 24-week maintenance treatment. Subjects who do not achieve 300 mg/day AR101 will enter a 12-week follow-up 
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Screening 
After obtaining informed consent/assent, subjects will be assessed for eligibility during a 2-part 
screening period. During screening visit 1 (day -113 to day -17), subjects will undergo a medical 
history, physical examination, spirometry, peanut SPT, and laboratory testing (including peanut 
sIgE), and will be evaluated for the study eligibility criteria. Subjects must meet all eligibility for 
screening visit 1 before proceeding with the DBPCFC in visit 1a. 
During screening visit 1a (must be before day -15), under direct study-investigator monitoring, 
subjects will undergo a screening DBPCFC to confirm current peanut allergy. This will consist of 
5 doses of peanut protein 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 judgement 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 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. Any subject 
who is assessed to have had dose-limiting symptoms to the placebo part, or both parts, of the 
screening DBPCFC (ie, to oat flour as well as peanut flour) will be considered a screen failure and 
will not be randomized. 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. 
All other food challenges in the study will remain blinded. 
Before each challenge, the subject 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 subject is experiencing to the challenge material. The subject 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 subject has no symptoms related to allergic reactions to the peanut ingestion 
with the DBPCFC ≤144 mg (cumulative) peanut protein or if he/she experiences any symptoms at 
any dose of placebo, he/she will not be enrolled in the study. A 2-week washout period is needed 
after the peanut screening DBPCFC day, before subject can proceed with randomization visit.  
Double-Blind Treatment Period (28 to 40 Weeks Duration) 
Subjects with a history of confirmed peanut allergy signs and symptoms who continue to meet 
eligibility criteria at baseline will undergo day 1/baseline assessments and will be randomized in 
a 2:1 ratio stratified by screening peanut-specific IgE level (≤100 kUA/L or >100 kUA/L) and 
body weight (<30 kg, ≥30 kg and <60 kg, or ≥60 kg) at randomization into 1 of 2 treatment arms 
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(n=52 for placebo and 104 for dupilumab). A minimum of 15 subjects for each weight group will 
be enrolled. 
Dupilumab and placebo will be dosed SC as follows based on weight at randomization and dose 
will not be changed regardless of weight gain or loss: 
• subjects weighing <30 kg will receive dupilumab 100 mg Q2W following a loading dose 
of 200 mg on day 1 or matching placebo Q2W (including doubling the amount on day 1) 
• subjects weighing ≥30 kg and <60 kg will receive dupilumab 200 mg Q2W following a 
loading dose of 400 mg on day 1 or matching placebo Q2W (including doubling the 
amount on day 1) 
• subjects weighing ≥60 kg will receive dupilumab 300 mg Q2W following a loading dose 
of 600 mg on day 1 or matching placebo Q2W (including doubling the amount on day 1) 
After the first 4 weeks of pretreatment, subjects will begin AR101 with an up-dosing regimen to a 
maximum of 300 mg/day over the next 24 to 36 weeks of the study, for a total of 28 to 40 weeks 
(including pretreatment), with 28 weeks being ideal and 40 weeks being the maximum. The 
flexible up-dosing period is to accommodate dose reductions and re-escalation as well as 
COVID-19 restrictions of in-clinic visits. Thus, the 28 to 40 week up-dosing period will consist of 
4 weeks pretreatment, 22 to 34 weeks of flexible up-dosing, and at least 2 weeks at the maximum 
dose of 300 mg/day. 
During concomitant AR101, study drug will be administered SC at home (at least 24 hours after 
in-clinic AR101 dose escalation and at least 8 hours apart from the at-home daily AR101 dose). 
After ingestion of AR101, subject should be monitored for 2 hours for allergic reaction. All 
subjects will complete up to visit 15 of the up-dosing period. Visits 15a-f will be conducted as 
needed in order to achieve 300 mg/day AR101 for 2 weeks. Subjects will undergo a post up-dosing 
DBPCFC at visit 16 if they have reached 300 mg/day for at least 2 weeks (on a day after the last 
dose of AR101). Dosing with AR101 should continue on the days between the 2 parts of the 
DBPCFC.  
Placebo Group 
At day 1: Placebo (weight-based dose) Q2W SC for 28 to 40 weeks. 
At week 4: AR101 using a standardized initial dose escalation day (IDED) regimen of doses of 
0.5 mg to a maximum of 6 mg peanut protein (12 mg cumulative) over 5 hours in-clinic (home 
dosing will be 3 mg/day peanut protein for the next 2 weeks until up-dosing) (Table 1) followed 
by bi-weekly (every 2 weeks) in-clinic up-dosing from the highest tolerated initial day dose to a 
maximum of 300 mg/day at home for 22 to 34 additional weeks. If the scheduled bi-weekly 
up-dosing is not possible, the up-dosing period may be extended by up to 12 weeks to 
accommodate dose reductions and re-escalation as well as COVID-19 restrictions of in-clinic 
visits. Thus, the up-dosing period will end at week 28 to 40 (including 4 weeks pretreatment, 
22 to 34 weeks of flexible up-dosing, and at least 2 weeks at the maximum dose). 
Dupilumab Group 
At day 1: Dupilumab (weight-based dose) Q2W SC for 28 to 40 weeks. 
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At week 4: AR101 using a standardized IDED regimen of doses of 0.5 mg to a maximum of 6 mg 
peanut protein (12 mg cumulative) over 5 hours in-clinic (home dosing will be 3 mg/day peanut 
protein for the next 2 weeks until up-dosing) (Table 1) followed by bi-weekly in-clinic up-dosing 
from the highest tolerated initial day dose to a maximum of 300 mg/day at home for 
22 to 34 additional weeks. If the scheduled bi-weekly up-dosing is not possible, the up-dosing 
period may be extended by up to 12 weeks to accommodate dose reductions and re-escalation as 
well as COVID-19 restrictions of in-clinic visits. Thus, the up-dosing period will end at 
week 28 to 40 (including 4 weeks pretreatment, 22 to 34 weeks of flexible up-dosing, and at least 
2 weeks at the maximum dose). 
Table 1: 
AR101 Initial Dose Escalation Day at Week 4 
Study Week 
Dupilumab/Placebo + AR101 
Week 4 (1 to 5 h) IDED 
Dose protein (mg) 
Q30 min 
0.5 
 
1 
 
1.5 
 
3 
 
6 
Cumulative 
12 
Abbreviations: IDED, initial dose escalation day; Q30, every 30 min 
See Section 6.1.1 for details on peanut protein dose escalation. 
After 28 to 40 weeks of dupilumab treatment and 24 to 36 weeks of AR101, subjects who 
achieve 300 mg/day of AR101 for at least 2 weeks will undergo a DBPCFC to assess the level of 
peanut sensitivity. 
Re-Randomization at Week 28 to 40 for Dupilumab Group 
Subjects in the dupilumab treatment group from the up-dosing phase will be re-randomized 
1:1 placebo or dupilumab regardless of whether they achieve 300 mg/day AR101 for at least 
2 weeks at visit 16 or discontinue. However, only those subjects who achieve 300 mg/day AR101 
at visit 16 will be eligible to enter the maintenance phase. Subjects who do not achieve 300 mg/day 
AR101 for at least 2 weeks will enter a 12-week follow-up period. All subjects will have an 
interactive web response system (IWRS) transaction to maintain the blind. 
Double-Blind Maintenance Phase (Only for Subjects Who Reach 300 mg/Day AR101) 
Subjects who achieve 300 mg/day AR101 for at least 2 weeks during the up-dosing period will be 
eligible to enter a 24-week maintenance phase in which all subjects will continue to receive AR101 
300 mg/day at home. The 24-week maintenance duration will start from when the subject has their 
day 1 of their post up-dosing DBPCFC at visit 16. (Safety analysis of the maintenance period starts 
after the second day of the visit 16 post up-dosing DBPCFC.) Subjects will have a monthly clinic 
visit. If the on-site clinic visit cannot occur, phone visits can take place as long as there are no 
changes to the subject’s AR101 dose. Subjects in the dupilumab treatment group will be randomly 
assigned to either continue dupilumab at the same dose as administered during the up-dosing 
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period or to receive placebo. Subjects who received placebo during the up-dosing phase will 
continue to receive placebo in the maintenance phase. After 24 weeks of AR101 and 24 weeks of 
dupilumab or placebo, subjects will undergo a post maintenance DBPCFC to assess the level of 
peanut sensitivity at the end of the maintenance period. 
Subjects who do not achieve 300 mg/day AR101 for at least 2 weeks at visit 16 and are not 
permitted to enter the maintenance phase, will enter a 12-week follow-up period (see below). The 
procedure for monitoring subjects for safety after in-clinic dosing is the same as for the up-dosing 
visits except that the initial period required for post-dose observation may be shortened to 
30 minutes. 
Double-Blind, Placebo-Controlled Food Challenge 
At visit 16 (the end of up-dosing) under intensive monitoring, all subjects who achieve 300 mg/day 
AR101 during the up-dosing phase for at least 2 weeks will undergo a post up-dosing DBPCFC 
up to 2044 mg (cumulative) peanut protein or placebo (see Appendix 1) to assess desensitization. 
At visit 22 (the end of maintenance period), all subjects who maintain 300 mg/day AR101 will 
undergo a post maintenance DBPCFC up to 2044 mg (cumulative) peanut protein or placebo to 
assess desensitization. Dosing with AR101 should continue on the days between the 2 parts of the 
DBPCFC. The subject’s sensitivity to peanut allergen is defined as the dose at which the subject 
experiences allergic reactions. All symptoms and signs will be evaluated and rated based on a 
standardized oral food challenge scoring system (CoFAR) (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 (Grade 1 [mild]) 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 subject is experiencing to the challenge material. Vital signs will be assessed 
every 15 to 30 minutes. In addition, subjects will be considered to have dose-limiting reactions if 
they experience any mild subjective reactions requiring pharmacologic intervention and/or any 
moderate/severe reaction. The DBPCFC will consist of 8 doses (peanut protein or placebo), given 
every 15 to 30 minutes: 1, 3, 10, 30, 100, 300, 600, 1000 mg resulting in a total challenge of up to 
2044 mg (cumulative) peanut protein. 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. Subjects will be considered to 
have passed the DBPCFC if they do not experience any objective Grade 1 (mild) reaction by 
CoFAR grading system (see Appendix 2). If the subject experiences reactions, he/she will be 
treated with the necessary rescue medications. In addition, subjects will be considered to have 
passed the DBPCFC if they do not experience any mild subjective symptoms requiring 
pharmacological intervention and/or moderate or severe symptoms. 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 subject study visit conduct. When dosing elicits an acute reaction 
characterized by the appearance of only a mild subjective symptom or symptoms, the investigator 
will be required to assess whether the dose was or was not tolerated. The determination of 
tolerability must be made on the basis of clinical judgement. The following are presented as 
guidelines for determining whether a dose associated with the emergence of a mild subjective 
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symptom or symptoms was tolerated. A dose eliciting only mild subjective symptoms may be 
considered to be tolerated if the symptoms are: 
• Isolated to a single organ system except for airway (including tongue) or respiratory 
system 
• Resolve with no pharmaceutical intervention or with a single oral administration of an 
H1 antihistamine  
• Do not require administration of epinephrine  
• Are not worsening in intensity or distribution over time  
• Resolve, or shows definite signs of resolving, in under 1 hour 
On the day following DBPCFC, the site is to make telephone contact with the subject/subject’s 
parent or guardian to inquire if any AEs (including allergic symptoms) occurred subsequent to the 
subject leaving the clinic, and to provide assistance in the recording of any such events. 
Post-Treatment Follow-Up Period (12 Weeks) 
All subjects 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 fall 
below the lower limit of quantification after the last dose of dupilumab. At the end of the 12-week 
follow-up period, subjects who passed a 444 mg (cumulative) peanut protein DBPCFC at visit 22 
(the end of the maintenance period, week 52 to 64 will be eligible to undergo a final DBPCFC (up 
to 2044 mg cumulative), under intensive monitoring, at visit 25 (end of study, week 64 to 76) to 
assess the level of peanut sensitivity after 12 weeks off peanut and dupilumab to determine whether 
there is evidence of persistent effects and sustained unresponsiveness. 
Subjects who do not achieve 300 mg/day peanut protein at visit 16, (ideally week 28, and up to a 
maximum of week 40) will enter a 12 week follow-up period. 
6.1.1. 
Description of AR101 Dose Escalation, and Study Stopping Rules 
6.1.1.1. 
AR101 Initial Dose Escalation Day at Week 4 
The IDED will be done in-clinic at week 4 and consist of AR101 dosing, beginning at 0.5 mg of 
AR101 with graduated doses every 30 minutes up to 6 mg (cumulative 12 mg) over 5 hours (see 
Table 1 and Appendix 4). Subjects must be stable, with stable lung function, FEV1 >80% 
predicted, without evidence of wheezing on exam, or active allergic symptoms such as AD or 
symptoms of allergic rhinitis or any other symptoms that in the clinical judgement of the study 
physician contradicts initial dosing. 
Trained clinical staff will be present at all times during all of the in-clinic AR101 dosing visits and 
will be available to respond within minutes to any allergic reaction. Allergic events (Appendix 2) 
will be monitored for at least 2 hours after the last dose or for at least 2 hours after resolution of 
symptoms prior to discharge from the clinic. Subjects tolerating the escalation dose will continue 
to administer a 3 mg/day dose at home for the next 14 days. Subjects who do not tolerate the 6 mg 
single dose (12 mg cumulative) during IDED, due to moderate or severe allergic reactions 
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(Appendix 4), will be considered treatment failures and will not initiate home AR101 dosing and 
should be early terminated from the study. 
6.1.1.2. 
AR101 Up-Dosing Regimen Starting at Week 6 
Subjects in the placebo and dupilumab treatment groups will have bi-weekly in-clinic visits with 
bi-weekly dose increases of the daily oral home AR101 dose from 3 mg/day up to a maximum of 
300 mg/day by week 24 to 36 (see Table 2) depending on safety (see Appendix 5). Subjects who 
exhibit moderate symptoms (Appendix 2) may have the dose reduced by 1 dose level per visit (ie, 
go back to the previous dose prior to new up-dose) until dose tolerated with no or mild symptoms 
(see Appendix 5). A dose reduction, at the investigator’s discretion, may also be implemented for 
an intercurrent adverse event. Subjects who exhibit severe allergic symptoms (Appendix 2 ) must 
be discontinued from study drug (see Appendix 5). 
Note: As of Amendment 3, the up-dosing period has been extended to accommodate dose 
reductions and re-escalation as well as COVID-19 restrictions of in-clinic visits. This 
extension permits a maximum up-dosing period of 40 weeks, while 28 weeks is ideal 
(consisting of 4 weeks pretreatment, 22 to 34 weeks of up-dosing, and at least 2 weeks at 
the maximum dose.) 
For chronic or recurrent GI symptoms, especially upper GI symptoms, investigators are advised to 
establish a low threshold for instituting a dose reduction and for considering early discontinuation 
of affected subjects from the study due to the potential for EoE (see Section 6.1.2.5) following 
discussion with the medical monitor. 
Each AR101 dosing increase will be administered in-clinic and monitored for adverse allergic 
events for at least 2 hours prior to discharge. If the current dose is maintained (ie, subject remains 
at the same dose and not escalated to the new dose during the clinic visit), then the observation 
period can be shortened to 1 hour with subject being discharged if deemed clinically stable. Vital 
signs will be monitored every 15 to 30 minutes. Subjects/legal guardians will be instructed not to 
exceed the specifically assigned doses at home. They will also be instructed not to introduce any 
new foods to the diet and to avoid accidental ingestions. Subjects/legal guardians will be supplied 
with epinephrine autoinjectors for treatment of allergic reactions and 24-hour access to an 
emergency contact telephone number. 
On the day following in-clinic AR101 up-dosing, the site is to make telephone contact with the 
subject/subject’s parent or guardian to inquire if any AEs (including allergic symptoms) occurred 
subsequent to the subject leaving the clinic, and to provide assistance in the recording of any such 
events in the diary. 
Table 2: 
AR101: Bi-Weekly Up-Dosing Regimen Starting at Week 6  
 
Dupilumab/Placebo  
+ 
AR101 protein 
Planned Study Week 
Dose protein (mg) 
6 
6 
7 
6 
8 
12 
9 
12 
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Dupilumab/Placebo  
+ 
AR101 protein 
Planned Study Week 
Dose protein (mg) 
10 
20 
11 
20 
12 
40 
13 
40 
14 
80 
15 
80 
16 
120 
17 
120 
18 
160 
19 
160 
20 
200 
21 
200 
22 
240 
23 
240 
24 
300 
25 
300 
26 
300 
27 
300 
28  
(up to week 40) 
DBPCFC 
Abbreviations: DBPCFC, double-blind placebo-controlled food challenge. 
Note: As of Amendment 3, the up-dosing period is ideally 28 weeks but may be extended up to 40 weeks if needed 
to accommodate dose reductions and re-escalation as well as COVID-19 restrictions of in-clinic visits. 
6.1.2. 
Study Design Safety Considerations for AR101 
• All up-dosing visits will be supervised in an in-clinic setting where trained study 
physicians are available. Subjects who exhibit moderate allergic symptoms 
(Appendix 2 for grading and treatment) may have the dose reduced to the previous dose 
(see Appendix 5). For chronic or recurrent GI symptoms, especially upper GI 
symptoms, investigators are advised to establish a low threshold for instituting a dose 
reduction and for considering early discontinuation of affected subjects from the study 
due to the potential for EoE. 
• Standing orders from a study physician will be provided for all clinical study personnel 
to immediately (ie, prior to study physician notification) initiate treatment of reactions, 
including IM administration of epinephrine, based on their own clinical judgement. 
• A crash cart with pediatric equipment will be available in close proximity (within 
50 feet) of all subject clinic rooms. 
• A code team will be available. 
• Will only escalate to a maximum 6 mg AR101 single dose during the IDED, which has 
been determined in Aimmune phase 2 and 3 peanut protein OIT trials to be a level 
safely achieved in most subjects. 
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• Subjects will be dosed bi-weekly SC at home with dupilumab or placebo on separate 
days (at least 24 hours) from the in-clinic AR101 dose escalation and at least 8 hours 
apart from ingesting their daily oral AR101 dose. 
• Dosing allergic symptoms and AEs will be captured throughout the study. 
• Subjects will be prescribed an epinephrine autoinjector (if not prescribed by a treating 
clinician previous to study entry) and all subjects/legal guardian will be trained in its 
use. Subjects will be advised to carry the autoinjector with them at all times. 
• Subjects/legal guardians will be cautioned against consuming any peanuts or peanut-
containing foods other than study-supplied food allergen while on study. 
• Subjects/legal guardians will be cautioned against vigorous exercise or hot 
showers/baths within 1 hour prior to and 3 hours after AR101. 
• During the in-clinic dosing days, home dosing of AR101 should not occur. 
• An independent data monitoring committee (IDMC) will have oversight of subject 
safety (see Section 6.3.1 for more details). 
6.1.2.1. 
Guidance for Home Dosing 
The subject should take the AR101 at approximately the same time each day and it should be taken 
as part of a meal. Dosing at evening meal is recommended to permit children to be observed and 
supervised in the home setting by their parents or guardian for several hours after dosing. Subjects 
are to be cautioned against activities likely to increase allergic reactivity (eg, exercising or taking 
hot showers or baths within 3 hours after dosing). Dosing should not occur within 2 hours of 
bedtime. If dosing cannot be done in the evening, then it can be done with other meals as long as 
the subject can be observed for 2 hours for allergic reaction. Additionally, if a subject has been 
engaged in strenuous exercise prior to dosing, dosing should be delayed until signs of a 
hypermetabolic state (eg, flushing, sweating, rapid breathing and/or rapid heart rate) have abated. 
No attempt should be made to make up a missed dose if greater than 6 hours has elapsed from the 
usual time of dosing. 
If moderate or severe allergic symptoms (Appendix 2) occur during home dosing, the subject or 
parent/legal guardian should call the study site and the subject should immediately stop home 
dosing and return to the clinic the next day. Upon confirmation by the investigator of moderate 
symptoms, the next dose will be administered under medical supervision. Upon confirmation by 
the investigator of severe symptoms, subject will discontinue all study drugs (Appendix 5) and 
return to the clinic for follow-up.  
6.1.2.2. 
Missed Doses AR101 
No attempt should be made to make up a missed dose if greater than 6 hours has elapsed from the 
usual time of dosing and the subject should continue with the next scheduled dose, which may be 
at home. If 2 consecutive doses are missed, the subject should continue with the next scheduled 
dose, which may be at home. If 3 to 7 consecutive doses are missed, the subject should return to 
the clinic for the next dose.  
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6.1.2.3. 
Individual Subject Stopping Rules  
1. Missing >2 consecutive doses of study drug (dupilumab or placebo) 
2. Missing >7 consecutive days of AR101 therapy (eg, concurrent illness such as 
gastroenteritis). 
3. Anaphylaxis resulting in severe hypotension (Appendix 3), neurological compromise, or 
mechanical ventilation secondary to OIT dosing or any food challenge. 
4. Subject develops biopsy-documented EoE or other eosinophilic GI disease. 
5. Any subject deemed to have a severe allergic reaction or has a life-threatening reaction at 
any time will be discontinued from further therapy. 
6. Other circumstances including, but not limited to, the following: 
a. Poor control or persistent severe activation of secondary atopic disease (eg, AD, 
asthma) 
b. Started on beta-blockers with no alternative medications available per the prescribing 
physician 
c. Pregnancy 
6.1.2.4. 
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 (2011) and 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. 
6.1.2.5. 
Gastrointestinal Adverse Events and Disruption of Dosing 
At each study visit, the site must solicit specific symptoms from subjects that may indicate the 
development of EoE. These include symptoms of both advanced and early disease such as food 
impaction, dysphagia, and choking or gagging with meals, gastroesophageal reflux, nausea, 
vomiting, and abdominal pain. 
Prolonged disruption of dosing is defined as withholding AR101 for >7 consecutive days and is 
an individual stopping rule that results in permanent discontinuation of dosing (see Section 8.3.2). 
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Subjects that discontinue because of GI AEs will be asked to complete the Pediatric Eosinophilic 
Esophagitis Symptom Score (PEESS™) v2.0 questionnaire (Franciosi, 2011), with the assistance 
of a parent or guardian, as appropriate, every month for 6 months. 
If a subject with chronic/recurrent GI AEs has not experienced complete resolution of symptoms 
within 6 weeks of discontinuation of dosing with the investigational product (peanut), the subject 
should be referred to a (pediatric) gastroenterologist. 
Subjects who discontinue dosing prematurely due to chronic/recurrent GI AEs are to be requested 
to return to the clinic for evaluation monthly for at least 6 months (if the subject is asymptomatic), 
telephone follow-up with a physician investigator may be substituted for an in-clinic visit, at the 
investigator’s discretion. If chronic/recurrent GI AEs persist beyond 6 months, subjects are to 
continue to be followed with monthly clinic visits until the symptoms have resolved or are assessed 
to have stabilized with optimal medical management. 
If a subject is seen by a pediatric gastroenterologist, the investigational site is to procure records 
of the visit, as well as any test results, including those from endoscopy and endoscopic biopsy, if 
performed. These are to be retained with the subject’s source documentation. 
6.1.3. 
Study Design Safety Considerations for DBPCFC 
The DBPCFC during screening and precautions taken are described in Section 6.1 (Screening). 
Similarly, the DBPCFCs at visits 16, 22, and 25, and as the stopping rules are described in 
Section 6.1 (Double-Blind, Placebo-Controlled, Food Challenge). Oral food challenges may 
induce an allergic response. Allergic reactions can be severe, including life-threatening allergic 
reactions; however, the risk of an allergic reaction is reduced 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 subjects have an allergic reaction during the challenges, they may need 
oral, IM, or IV medications. Subjects will have an IV catheter placed before the food challenges if 
they have a medically documented history of anaphylaxis with hypotension requiring IV fluid 
resuscitation. 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. The anticipated rate of life-threatening anaphylactic 
reactions is <0.1%. 
6.1.4. 
End of Study Definition 
The end of study is defined as the last visit of the last subject.  
6.2. 
Planned Interim Analysis 
No interim analysis is planned. An unblinded primary analysis may be performed once all subjects 
in the study have completed the 28 to 40 week up-dosing treatment period as specified in the 
protocol (visit 16 or earlier for those subjects 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 the end of the up-dosing period at visit 16 (week 28 to 40). A 
description of the statistical methods to be employed and blinding implications are in 
Section 11.4.3. 
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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 subject 
safety by conducting formal reviews of accumulated safety data that will be blinded by treatment 
group; if requested, the IDMC may have access to the treatment allocation code or any other 
requested data for the purposes of a risk-benefit assessment. The IDMC will provide Regeneron 
and Sanofi with appropriate recommendations on the conduct of the food allergy clinical studies 
to ensure the protection and safety of the subjects enrolled in these studies.  
All activities and responsibilities of the IDMC are described in the IDMC charter. 
6.3.2. 
Adjudication Committee 
The Adjudication Committee will review reports of specific serious adverse events (SAEs) and 
adverse events of special interest (AESI) to verify appropriate diagnosis as per protocol definitions 
(eg, anaphylaxis) and appropriate determination of event seriousness, severity, and causality. The 
Adjudication Committee will provide a complete assessment of the selected cases to help 
independently validate these reports. Adjudication Committee assessments will be reported in 
addition to the investigator’s assessments. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
SUBJECTS 
7.1. 
Number of Subjects Planned 
Approximately 156 subjects, 104 in the dupilumab treatment arm and 52 in the placebo arm, with 
a history of confirmed peanut allergy will be enrolled at approximately 25 sites in the US.  
7.2. 
Study Population 
Male and female subjects ages 6 to 17 years inclusive with a history of peanut allergy confirmed 
by peanut SPT, peanut-specific IgE and by the level of peanut protein safely ingested during a 
peanut DPBCFC. 
7.2.1. 
Inclusion Criteria 
A subject must meet the following criteria to be eligible for inclusion in the study: 
1. Age 6 to 17 years (inclusive). 
2. Subject 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. 
5. Subjects/legal guardians must be trained on the proper use of the epinephrine autoinjector 
device to be allowed to enroll in the study. 
6. Subjects 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. Willing and able to comply with all clinic visits and study-related procedures. 
8. Written informed consent from parent/guardian for minor subjects. 
9. Written assent from minor subjects as appropriate (eg, above the age of 6 years or the 
applicable age per local regulatory requirements). 
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7.2.2. 
Exclusion Criteria 
A subject 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 subject’s health or safety in this study or the 
subject’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 GI disease 
6. Current participation or participation within 6 months prior to screening in any other 
interventional study. 
7. Asthma at time of enrollment with any of the following: 
1. 
FEV1 <80% of predicted, or ratio of FEV1 to forced vital capacity (FEV1/FVC) 
<75% of predicted with or without controller medications (only for age 6 or 
greater and able to do spirometry; 6 to 8 year old [Wang 1993], 8 to 18 years old 
[Third National Health and Nutrition Examination Survey or NHANES III -see 
Hankinson, 1999]) or  
2. 
Inhaled corticosteroids (ICS) dosing of >500 μg daily fluticasone (or equivalent 
ICS based on National Heart, Lung, and Blood Institute dosing chart) or 
3. 
one hospitalization in the past year for asthma or 
4. 
Emergency room visit for asthma within 6 months prior to screening. 
8. Use of systemic corticosteroids within 2 months prior to screening.  
9. Use of omalizumab within 6 months prior to screening. 
10. 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. 
11. Use of anti-histamines within 5 days prior to screening and within 5 days prior to SPTs and 
day 1 of DBPCFCs. 
12. Use of any agents known or likely to interact with epinephrine (eg, beta-blockers, 
angiotensin converting enzyme-inhibitors, tri-cyclic antidepressants, or other drugs), 
within 3 weeks prior to screening. 
13. Allergy to oat (placebo in DBPCFC). 
14. Hypersensitivity to epinephrine and any of the excipients in the epinephrine product. 
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15. History of a mast cell disorder, including mastocytosis, urticarial pigmentosa, and 
hereditary or idiopathic angioedema. 
16. Treatment with a live (attenuated) vaccine within 3 months prior to screening and during 
the study. All subjects must have received all vaccinations per Advisory Committee on 
Immunization Practices (ACIP) or local guidelines for measles, mumps, rubella, and 
varicella at least 3 months prior to enrollment in the study. 
17. Active chronic or acute infection requiring systemic treatment with antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 2 weeks prior to the baseline visit. 
NOTE:  subjects may be rescreened after the infection resolves. 
18. 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. 
19. 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. 
20. Known history of human immunodeficiency virus (HIV) infection or HIV seropositivity at 
the screening visit 
21. With an established diagnosis of hepatitis B viral infection at the time of screening or is 
positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) at 
the time of screening 
22. Body weight ≤17 kg 
23. Pregnant or breastfeeding women, women planning to become pregnant or breastfeed 
during the study. 
24. 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; intrauterine 
hormone-releasing system; 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 subject. 
‡ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method 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 subject has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a subject from the study if it is no 
longer in the interest of the subject to continue in the study, or if the subject’s continuation in the 
study places the scientific outcome of the study at risk (eg, if a subject does not or cannot follow 
study procedures). An excessive rate of withdrawals would render the study uninterpretable; 
therefore, unnecessary withdrawal of subjects should be avoided. 
Subjects who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 13. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.3.2. 
7.4. 
Replacement of Subjects 
Subjects prematurely discontinued from study will not be replaced. 
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8. 
STUDY TREATMENTS 
8.1. 
Investigational and Reference Treatments 
Dupilumab 150 mg/mL: Each 2.25 mL single-use, prefilled glass syringe with snap-off cap 
delivers 300 mg of study drug (2.0 mL of a 150 mg/mL solution) 
Dupilumab 175 mg/mL: Each 1.14 mL single-use, prefilled glass syringe with snap-off cap 
delivers 200 mg of study drug (1.14 mL of a 175 mg/mL solution). 
Dupilumab 150 mg/ml: Each 0.67 mL single-use, prefilled glass syringe with snap-off cap delivers 
100 mg study drug (0.67 mL of a 150 mg/mL solution). 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal antibody). Three matching placebo formulations 
will be used:   
1. 2 mL placebo matching 300 mg dupilumab formulation 
2. 1.14 mL placebo matching 200 mg dupilumab formulation 
3. 0.67 mL placebo matching 100 mg dupilumab formulation 
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. Direct-to-subject shipment 
of study medication may be possible if clinic visits cannot take place, as long as it is for the 
subject’s current dose of AR101 and SC study drug. 
8.1.1. 
AR101 for Oral Immunotherapy and IDED 
AR101 is characterized peanut allergen in the form of peanut flour, formulated with a bulking 
agent (maize starch, microcrystalline cellulose, and other excipients to prevent clumping) and a 
flow agent in premeasured graduated doses. The AR101 drug product is encapsulated in 
hydroxypropyl methylcellulose (HPMC) capsules. The capsules used in the Initial Escalation 
Period and Up-dosing Period of this study currently include the following strengths: 0.5, 1, 10, 20, 
and 100 mg each of peanut protein. AR101 is characterized by high performance liquid 
chromatography and by specific enzyme-linked immunosorbent assay for key allergenic proteins 
to demonstrate stability and lot-to-lot consistency. 
AR101 0.5 mg: each opaque white HPMC capsule delivers 0.5 mg peanut protein 
AR101 1 mg: each opaque red HPMC capsule (with white bars) delivers 1 mg peanut protein 
AR101 10 mg: each opaque blue HPMC capsule delivers 10 mg peanut protein 
AR101 20 mg: each opaque white HPMC capsule (with grey bars) delivers 20 mg peanut protein 
AR101 100 mg: each opaque Swedish orange HPMC capsule (with grey and black bars) delivers 
100 mg peanut protein 
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AR101 capsules will be provided in prepackaged thermoform blister wallet cards with features to 
allow access to each dose in dosing kits. Appropriate combinations of capsules are used to provide 
the required AR101 doses (eg, one 20 mg capsule and one 100 mg capsule to provide a 120 mg 
dose). For the escalation periods, each individual kit will contain 21 daily doses at a given dose 
level, enough to supply 2 weeks of dosing plus 7-day coverage to accommodate potential visit 
scheduling issues. 
For the maintenance period dosing, a 300 mg AR101 dose will be provided in sealed, foil-laminate 
sachets (1 sachet/day). Sachets will be provided in kits containing 35 individual doses. 
All AR101 will be packaged and labeled at the central packaging facility, then inventoried for 
distribution from a drug depot for shipment to the clinical sites. AR101 will be dispensed, 
according to subject identification number using an IWRS according to site-specific institutional 
policies. AR101 will then be distributed to each subject or parent(s)/guardian(s) by study site 
personnel. 
After 4 full weeks of either dupilumab or placebo treatment, subjects start using a standardized 
regimen of single IDED AR101 (0.5 mg to a maximum of 6 mg, 12 mg cumulative) over 
approximately 5 to 6 hours. Subjects will begin a 3 mg/day oral dose at home for the next 14 days 
followed by bi-weekly up-dosing to a maximum of 300 mg/day AR101 at home. 
AR101 will be stored in a secure location at each study site and kept refrigerated between 2°C and 
8°C. Study site personnel will maintain temperature logs for all refrigerators storing study drug for 
the duration of the study. 
8.1.2. 
Peanut for Food Challenges 
For the DBPCFC, peanut flour mixture (containing ~50% peanut protein) or a placebo (oat) flour 
mixture, mixed in a vehicle food, will be used. The placebo flour mixture will be supplied 
pre-mixed with a small amount of artificial peanut flavor to provide a reasonable degree of 
taste-matching of the final placebo/vehicle food mixture to the peanut/vehicle food mixture. 
Investigational sites will be provided with standardized recipes for preparation of the DBPCFC in 
a separate manual of procedures. 
8.2. 
Rescue Treatment 
The following concomitant treatments will require permanent study drug discontinuation: 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with immunomodulating biologic agents, including anti-IgE and anti-IL-5 
• Treatment with allergen immunotherapy other than AR101 
• 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 
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• Short acting inhaled bronchodilators  
• Inhaled corticosteroids  
• 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  
8.3. 
Dose Modification and Study Treatment Discontinuation Rules 
8.3.1. 
Dose Modification 
Dose modification of dupilumab for an individual subject is not allowed. 
8.3.2. 
Study Drug Discontinuation 
Subjects 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. If dupilumab 
study drug is permanently discontinued, subject will also discontinue AR101 and vice versa. 
Subjects who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete study assessments, per Section 13. 
8.3.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
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 
− Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values 
greater than 3 × upper limit of normal (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 certain rescue medications, as specified in Section 8.2 
• Missing >2 consecutive doses of study drug (dupilumab or placebo) 
8.3.2.2. 
Reasons for Temporary Discontinuation of SC Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• Clinically important laboratory abnormalities such as: 
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− Neutrophil count <1.5 x 103/µL but >0.5 x 103/µL 
− ALT or AST 3 × ULN but ≤5 × ULN  
− Platelet count ≤100 × 103/µL but >50 × 103/µL 
− Creatinine phosphokinase (CPK) >2.5 x ULN 
− Serum creatinine >1.5 x ULN 
− Eosinophils >5000/ µL 
• 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 subject met conditions for 
permanently discontinuing study drug described in Section 8.3. 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 subject’s best interest. 
However, the medical monitor should be contacted as soon as possible in any case of study drug 
discontinuation. Resumption of study treatment after temporary discontinuation 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 should be treated using clinical 
judgement to determine the appropriate response according to typical clinical practice.  
8.5. 
Method of Treatment Assignment 
28 to 40 Week Treatment Phase 
Approximately 156 subjects will be randomized at baseline in a 2:1 ratio into one of 2 treatment 
arms (n=104 to dupilumab and 52 to placebo, in combination with up-dosing of AR101) described 
in Section 6.1 according to a central randomization scheme provided by an IWRS to the designated 
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study pharmacist (or qualified designee). Randomization will be stratified by screening 
peanut-specific IgE level (≤100 kUA/L or >100 kUA/L) and body weight (<30, ≥30 kg and 
<60 kg, or ≥60 kg) at randomization. A minimum of 15 subjects for each weight group will be 
enrolled. 
Maintenance Treatment Phase 
At visit 16 (or at the early termination visit for those who discontinue from study prior to visit 16), 
subjects previously in the dupilumab plus AR101 arm will be re-randomized in a 1:1 ratio into one 
of 2 treatment arms (dupilumab versus placebo, in combination with AR101), according to a 
central randomization scheme provided by IWRS. Randomization will be stratified by whether 
subjects achieve 300 mg/day AR101 for at least 2 weeks by visit 16 (Yes or No). For subjects not 
achieving 300 mg/day AR101 for at least 2 weeks at visit 16 or early discontinued from study 
before visit 16, the re-randomization is used to determine their hypothetical assigned treatment for 
the maintenance phase in order to include them in the intent-to-treatment analysis of visit 22 
endpoints. The 24-week maintenance period will start from day 1 of the post up-dosing DBPCFC 
at visit 16. 
Subjects previously in the placebo plus AR101 arm will continue their treatment of placebo plus 
AR101 in the maintenance phase if they achieve 300 mg/day AR101 for at least 2 weeks at visit 
16. To maintain the blinding of treatment assignment, an IWRS randomization call needs to take 
place for these subjects. 
8.5.1. 
Blinding 
With the exception of the IDMC members and the provisions in Section 8.5.2, this study will 
remain blinded to all individuals until the prespecified unblinding to conduct the primary analyses. 
All study staff and study team will be blinded to all post-screening food challenge results until the 
end of the study (once all subjects study-wide have completed the study and the sites receive 
permission to unblind from the sponsor). 
Blinded study drug kits coded with a medication numbering system will be used. In order to 
maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody and drug concentration results will not be communicated to the sites, and the 
sponsor’s operational team will not have access to results associated with subject identification 
until after the final database lock. 
An unblinded pharmacist or designee will mix the peanut protein or oat protein in the food selected 
for masking taste for administration in the DBPCFC. For each subject, 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 (neither initial escalation, nor up-dosing, nor maintenance 
phase), nor the assessment or management of AEs (for details refer to the Study Manual). The 
principal investigator or sub-investigator involved in subject care should not perform the post-
screening food challenges as this may result in bias. 
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8.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a subject may be necessary due to a medical emergency 
or any other significant medical event (eg, pregnancy). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected subjects will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the subject.  
− The investigator will notify Regeneron and/or designee before unblinding the 
subject, whenever possible. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency. In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
8.6. 
Treatment Logistics and Accountability 
8.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups 
(or companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct. 
Study drug will be stored at the site at a temperature of 2 C to 8 C; 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 2 C to 8 C to the investigator or designee at 
regular intervals or as needed during the study. At specified time points during the study 
(eg, interim site monitoring visits), at the site close-out visit, and following drug reconciliation and 
documentation by the site monitor, all opened and unopened study drug will be destroyed or 
returned to the sponsor or designee. 
8.6.3. 
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 subject/legal guardian, 
• returned from each subject/legal guardian (if applicable), and 
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• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
8.6.4. 
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 
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 
first dose of study drug and are ongoing during the study. This section considers concomitant 
medications that are not considered rescue treatment. See Section 8.2 for a discussion of rescue 
treatments. 
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) 
NOTE:  All subjects must have received all vaccinations per ACIP or local guidelines for 
measles, mumps, rubella, and varicella at least 3 months prior to enrollment in the study. 
• Treatment with any agents known or likely to interact with epinephrine (eg, 
beta blockers, ACE-inhibitors, tri-cyclic antidepressants, or other drugs) 
• Treatment with anti-histamines within 5 days prior to screening and within 5 days prior 
to SPTs and day 1 of the DBPCFCs 
The following concomitant procedures are prohibited during study participation: 
• Major elective surgical procedures 
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NOTE: If a subject requires a prohibited medication or procedure at any time during the study, 
the principal investigator should contact the Regeneron medical monitor (except for illness 
requiring prompt treatment). Based on the discussions, study treatment may be continued or 
temporarily or permanently discontinued.  
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. 
If there is any question regarding whether a concomitant medication may be used during the study, 
the study site should contact the medical monitor. 
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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 3 and Table 4. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct 
and 
oversight 
may 
require 
implementation 
of 
temporary 
or 
alternative 
mechanisms. Examples of such mechanisms may include, but are not limited to, any of the 
following: phone contact, virtual visits, telemedicine visits, online meetings, non-invasive remote 
monitoring devices, use of local clinic or laboratory locations, and home visits by skilled 
staff. Additionally, no waivers to deviate from protocol enrollment criteria due to COVID-19 will 
be granted. All temporary mechanisms utilized, and deviations from planned study procedures in 
response to COVID-19, are to be documented as being related to COVID-19 and will remain in 
effect only for the duration of the public health emergency. 
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Table 3: 
Schedule of Events – Screening, Baseline, Double-Blind Treatment Period 
Study Procedure 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
Study Drug 
Pretreatment 
Study Drug Concomitant Treatment  
AR101 Up-Dosing 
Visit (V) 
V112  
V1a13  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Week (W)14  
-113 
to -17 
before 
-15  
D1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Day (D)14 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
Visit Window (d) 
 
±3d 
±3d 
±3d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF for optional assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on Daily Allergy 
Symptom Diary 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Training on Study Drug 
Administration 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded Study Drug SC Q2W 
Administration1  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Study Drug Injection 
Log1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AR101 Daily Administration2 
 
 
 
 
X 
IDED 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily subject AR101 Dosing 
Diary2 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AR101 Dispensation/Account3 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Epinephrine Autoinjector 
Training 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Con Meds/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DBPCFC5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut Skin Prick Test (SPT)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Procedure 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
Study Drug 
Pretreatment 
Study Drug Concomitant Treatment  
AR101 Up-Dosing 
Visit (V) 
V112  
V1a13  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Week (W)14  
-113 
to -17 
before 
-15  
D1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Day (D)14 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
Visit Window (d) 
 
±3d 
±3d 
±3d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Peanut SPT titrated6 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
EASI for AD, ACQ-5 asthma 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily Allergy Symptom Diary7 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FAQL Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry/Peak Flow9, 9a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ab, HBsAg, HBcAb, Hep 
C Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
FeNO Test9,9a 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
Pregnancy Test (WOCBP 
only) 
S 
 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
Total IgE  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
sIgE, sIgG4, sIgG Against 
Peanut Extract and Peanut 
Allergen Components  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Future Biomedical Research 
Sample (Optional) 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Optional Blood Samples for 
Additional Exploratory 
Research (eg, TruCulture, 
Basophil sensitivity, PBMC, 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
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Page 72 of 118 
CONFIDENTIAL 
Study Procedure 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
Study Drug 
Pretreatment 
Study Drug Concomitant Treatment  
AR101 Up-Dosing 
Visit (V) 
V112  
V1a13  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Week (W)14  
-113 
to -17 
before 
-15  
D1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Day (D)14 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
Visit Window (d) 
 
±3d 
±3d 
±3d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
allergen-specific T-cell 
profiling)10 
DNA Sample (Optional)11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samples4: 
Functional dupilumab PK 
Sample 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-dupilumab Antibody 
Sample 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Abbreviations: S, serum; U, urine; FAQL, Food Allergy Quality of Life; FeNO, fractional exhaled nitric oxide; WOCBP, women of child bearing potential; 
PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic 
 
Study Procedure 
Double-Blind Treatment Period 
 
Study Drug Concomitant Treatment  
AR101 Up-Dosing (if applicable) 
Visit (V) 
V15a 
V15b 
V15c 
V15d 
V15e 
V15f 
 Week (W)14  
W28 
W30 
W32 
W34 
W36 
W38 
 Day (D)14 
197 
211 
225 
239 
253 
267 
Visit Window (d) 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Screening/Baseline: 
 
 
 
 
 
 
Informed Consent/Assent 
 
 
 
 
 
 
ICF for optional assessments 
 
 
 
 
 
 
Inclusion/Exclusion 
 
 
 
 
 
 
Medical History/Demographics 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
Training on Daily Allergy Symptom Diary 
 
 
 
 
 
 
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Page 73 of 118 
CONFIDENTIAL 
Study Procedure 
Double-Blind Treatment Period 
 
Study Drug Concomitant Treatment  
AR101 Up-Dosing (if applicable) 
Visit (V) 
V15a 
V15b 
V15c 
V15d 
V15e 
V15f 
 Week (W)14  
W28 
W30 
W32 
W34 
W36 
W38 
 Day (D)14 
197 
211 
225 
239 
253 
267 
Visit Window (d) 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Training on Study Drug Administration 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
Blinded Study Drug SC Q2W 
Administration1, 15  
X 
X 
X 
X 
X 
X 
Subject Study Drug Injection Log1 
X 
X 
X 
X 
X 
X 
AR101 Daily Administration2 
X 
X 
X 
X 
X 
X 
Daily subject AR101 Dosing Diary2 
X 
X 
X 
X 
X 
X 
AR101 Dispensation/Account3 
X 
X 
X 
X 
X 
X 
Epinephrine Autoinjector Training 
 
 
 
 
 
 
Con Meds/Procedures 
X 
X 
X 
X 
X 
X 
Efficacy4: 
 
 
 
 
 
 
DBPCFC5 
 
 
 
 
 
 
Peanut Skin Prick Test (SPT)6 
 
 
 
 
 
 
Peanut SPT Titrated6 
 
 
 
 
 
 
EASI for AD, ACQ-5 asthma 
X 
X 
X 
X 
X 
X 
Daily Allergy Symptom Diary7 
X 
X 
X 
X 
X 
X 
FAQL Questionnaire 
 
 
 
 
 
 
Safety4: 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
 
 
Spirometry/Peak Flow9, 9a 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Laboratory Testing4: 
 
 
 
 
 
 
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Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 74 of 118 
CONFIDENTIAL 
Study Procedure 
Double-Blind Treatment Period 
 
Study Drug Concomitant Treatment  
AR101 Up-Dosing (if applicable) 
Visit (V) 
V15a 
V15b 
V15c 
V15d 
V15e 
V15f 
 Week (W)14  
W28 
W30 
W32 
W34 
W36 
W38 
 Day (D)14 
197 
211 
225 
239 
253 
267 
Visit Window (d) 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
HIV ab, HBsAg, HBcAb, Hep C Ab 
 
 
 
 
 
 
Hematology, Chemistry 
X 
 
 
 
X 
 
FeNO Test9,9a 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
 
X 
X 
X 
Pregnancy Test (WOCBP only) 
U 
U 
U 
U 
U 
U 
Total IgE  
X 
 
 
 
X 
 
sIgE, sIgG4, sIgG Against Peanut Extract 
and Peanut Allergen Components 
X 
 
 
 
X 
 
Future Biomedical Research Sample 
(Optional) 
X 
 
 
 
X 
 
Optional Blood Samples for Additional 
Exploratory Research (eg, TruCulture, 
Basophil sensitivity, PBMC, allergen-
specific T-cell profiling)10 
 
 
 
 
 
 
DNA Sample (Optional)11 
 
 
 
 
 
 
Functional Dupilumab PK Sample 
 
X 
 
X 
 
X 
Anti-dupilumab Antibody Sample 
 
 
 
 
 
 
Abbreviations: S, serum; U, urine; FAQL, Food Allergy Quality of Life; FeNO, fractional exhaled nitric oxide; WOCBP, women of child bearing potential; 
PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic 
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Page 75 of 118 
CONFIDENTIAL 
Table 4: 
Schedule of Events – Maintenance Period and Follow-Up Period 
Study Procedure 
Maintenance Period12 
Post-Treatment 
Follow-up Period 
Un-
scheduled 
Visit (if 
applicable) 
ET Visit 
(if 
applicable) 
Study drug and 
AR101 Withdrawal 
Visit (V) 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
 
V25   
EOS 
 
 
Week (W)13 
W28-
40 
V16+ 
4wk 
V16+ 
8wk 
V16+ 
12wk 
V16+ 
16wk 
V16+ 
20wk 
W52-
64,  
V16+ 
24wk 
V16+ 
28 wk 
V16+ 
32wk 
W64-
76, 
V16 + 
36wk   
 
 
Visit Window (d) 
-7/ 
+30d14 
±3d 
±3d 
±3d 
±3d 
±3d 
-7/ 
+30d14 
±3d 
±3d 
-7/ 
+30d14 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded Study Drug Q2W SC 
Administration1 
X 
X 
X 
X 
X 
X 
 
 
 
 
X15 
 
Subject Study Drug Injection Log1 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
AR101 Daily Administration1 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Daily Subject AR101 Dosing Diary 2 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
AR101 Dispensation/Account3 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Concomitant Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy4: 
 
 
 
 
 
 
 
 
 
 
 
 
DBPCFC5,14 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Peanut SPT Titrated6 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
EASI for AD, ACQ-5 for asthma 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Daily Allergy Symptom Diary7 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
FAQL Questionnaire 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Safety4: 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
Spirometry/Peak Flow 9, 9a 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEESS Questionnaire10 
 
 
 
 
 
 
 
 
 
 
X 
X 
Laboratory Testing4: 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ab, HBsAg, HBcAb, Hep C Ab 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
FeNO Test9, 9a 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
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Page 76 of 118 
CONFIDENTIAL 
Study Procedure 
Maintenance Period12 
Post-Treatment 
Follow-up Period 
Un-
scheduled 
Visit (if 
applicable) 
ET Visit 
(if 
applicable) 
Study drug and 
AR101 Withdrawal 
Visit (V) 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
 
V25   
EOS 
 
 
Week (W)13 
W28-
40 
V16+ 
4wk 
V16+ 
8wk 
V16+ 
12wk 
V16+ 
16wk 
V16+ 
20wk 
W52-
64,  
V16+ 
24wk 
V16+ 
28 wk 
V16+ 
32wk 
W64-
76, 
V16 + 
36wk   
 
 
Visit Window (d) 
-7/ 
+30d14 
±3d 
±3d 
±3d 
±3d 
±3d 
-7/ 
+30d14 
±3d 
±3d 
-7/ 
+30d14 
 
 
Urinalysis 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Pregnancy Test (WOCBP only) 
U 
U 
U 
U 
U 
U 
U 
 
 
S 
 
U 
Total IgE 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
sIgE, sIgG4, sIgG Against Peanut 
Extract and Peanut Allergen 
Components 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Future Biomedical Research sample 
(Optional) 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Optional Blood Samples for Additional 
Exploratory Research (eg, TruCulture, 
Basophil sensitivity, PBMC)11 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
PK/Drug Concentration and ADA 
Samples4: 
 
 
 
 
 
 
 
 
 
 
 
 
Functional Dupilumab PK Sample 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Anti-dupilumab Antibody Sample 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Abbreviations: EOS, end of study; ET, early termination; WOCBP, women of child bearing potential 
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Page 77 of 118 
CONFIDENTIAL 
9.1.1. 
Footnotes for the Schedule of Events Table 3 
1. The subject/legal guardian will administer SC study drug as scheduled on dosing days. 
Subject/legal guardian will complete an injection log (e-diary) to document compliance 
with injection of study drug. On days when both dupilumab/placebo study drug and AR101 
are administered, the study drug will be administered at least 8 hours apart from the AR101 
and at least 24 hours after the start of in-clinic dosing. 
2. The subject/legal guardian will administer AR101 during the days in which no in-clinic 
visit is scheduled. Subject/legal guardian will complete a dosing diary to document 
compliance with AR101. On the day following in-clinic up-dosing, the site is to make 
telephone contact to inquire if any AEs occurred and report appropriately. 
3. Starting at visit 4 (week 4), AR101 will be dispensed at the site to the subject/legal guardian 
for the doses that will be administered before the next clinic visit. 
4. Assessments will be performed before the administration of study drug. 
5. Subject will be observed for a minimum of 2 hours after the final administered dose and 
discharged only when deemed clinically stable by a study doctor. On the day following a 
food challenge, the site must make telephone contact to inquire if the subject experienced 
any AEs and report appropriately. Before each challenge, the subject will have a physical 
assessment performed by a trained physician’s assistant, registered nurse, nurse 
practitioner, and/or physician of the study team who is blinded to the testing material. 
Eczema Area and Severity Index and ACQ only needed be completed once during day 1 
of the food challenge. 
6. Subjects should not take anti-histamines for at least 5 days prior to the SPT. 
7. Site should confirm subject compliance at each clinic visit. 
8. During DBPCFC, vital signs will be collected every 15 to 30 minutes. During maintenance 
phase for in-clinic office visits, the post-dose observation may be shortened to 30 minutes. 
9. Spirometry will be performed in-clinic on the same day whenever FeNO measurement is 
scheduled; however, spirometry will also be performed at other visits when FeNO is not 
collected. Fractional exhaled nitric oxide should be done prior to spirometry. If the 
DBPCFC is scheduled on the day of the visit, then both FeNO measurement and spirometry 
will be performed twice before the subject goes home: once before DBPCFC, once after 
DBPCFC. 
a. During the COVID-19 pandemic, measurements of FeNO no longer need to be 
completed (at the discretion of the investigator). Additionally, if spirometry cannot be 
completed after enrollment, peak flow may be performed instead at the discretion of 
the investigator (although spirometry is still required at screening). 
10. On the day of the DBPCFCs, blood draws for optional exploratory research will be 
performed before the DBPCFC is performed. For the day 1 exploratory research sample, 
the peanut day for the DBPCFC must be ≥15 days before to ensure washout of peanut 
allergen. 
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CONFIDENTIAL 
11. One optional DNA sample for the genomics analyses (buccal swab) can be collected on 
day 1 (visit 2) or any other visit. 
12. Must complete all visit 1 assessments and confirm eligibility before visit 1a. 
13. Visit 1a must occur at least 15 days before visit 2 to allow a 2-week washout after the 
peanut screening DBPCFC. 
14. The time points listed in this table correspond with the bi-weekly up-dosing schedule 
(Table 2). These time points may no longer be accurate following adjustments to the 
planned up-dosing period. As of Amendment 3, the up-dosing period has been permitted 
to be extended to accommodate dose reductions and re-escalation as well as COVID-19 
restrictions of in-clinic visits. This extension permits a maximum up-dosing period of 
40 weeks, while 28 weeks is ideal (consisting of 4 weeks pretreatment, 22 to 34 weeks of 
up-dosing, and at least 2 weeks at the maximum dose).  
15. Study drug administration at unscheduled and/or optional visits 15a-f is to be documented 
in the unscheduled visits folder. 
9.1.2. 
Footnotes for the Schedule of Events Table 4 
1. The subject/legal guardian will administer SC study drug as scheduled on dosing days. 
Subject/legal guardian will complete an injection log (e-diary) to document compliance 
with injection of study drug. On days when both dupilumab/placebo study drug and AR101 
are administered, the study drug will be administered at least 8 hours apart from the AR101 
and at least 24 hours after the start of in-clinic dosing. Both days of the up-dosing DBPCFC 
at visit 16 should be completed before starting the visit 16 SC study drug as part of the 
maintenance phase. 
2. The subject/legal guardian will administer AR101 during the days in which no clinic visit 
is scheduled. Subject/legal guardian will complete a dosing diary to document compliance 
with AR101. 
3. Starting at visit 4 (week 4), site will account for the AR101 that is dispense to the 
subject/legal guardian. 
4. Assessments will be performed before the administration of study drug. 
5. 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 SC study drug. Subject 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. On the day following a food challenge, the 
site must make a telephone contact to inquire if the subject experienced any AEs and report 
appropriately. Before each challenge, the subject will have a physical assessment 
performed by a trained physician’s assistant, registered nurse, nurse practitioner, and/or 
physician of the study team who is blinded to the testing material. Eczema Area and 
Severity Index and ACQ only needed be completed once during day 1 of the food 
challenge. 
6. Subjects should not take anti-histamines for at least 5 days prior to the SPT. 
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CONFIDENTIAL 
7. Site should confirm subject compliance at each clinic visit. 
8. During DBPCFC, vital signs will be collected every 15 to 30 minutes. 
9. Spirometry will be performed in-clinic on the same day whenever FeNO measurement is 
scheduled; however, spirometry will also be performed at other visits when FeNO is not 
collected. Fractional exhaled nitric oxide should be done prior to spirometry. If the 
DBPCFC is scheduled on the day of the visit, then both FeNO measurement and spirometry 
will be performed twice before the subject goes home: once before DBPCFC, once after 
DBPCFC. 
a. During the COVID-19 pandemic, measurements of FeNO no longer need to be 
completed while on study (at the discretion of the investigator). Additionally, if 
spirometry cannot be completed after enrollment, peak flow may be performed instead 
at the discretion of the investigator (although spirometry is still required at screening). 
10. Only for subjects who discontinue for GI AEs. If applicable, after week 64 PEESS will be 
collected by phone. 
11. On the day of the DBPCFCs, blood draws for optional exploratory research will be 
performed before the DBPCFC is performed. 
12. Clinic visits are monthly. However, SC study drug administration is Q2W and dosing 
diaries for AR101 and allergic symptoms are done daily. 
13. The time points listed in this table correspond with the bi-weekly up-dosing schedule 
(Table 2). These time points may no longer be accurate following adjustments to the 
planned up-dosing period. As of Amendment 3, the up-dosing period has been permitted 
to be extended to accommodate dose reductions and re-escalation as well as COVID-19 
restrictions of in-clinic visits. This extension permits a maximum up-dosing period of 
40 weeks, while 28 weeks is ideal (consisting of 4 weeks pretreatment, 22 to 34 weeks of 
up-dosing, and at least 2 weeks at the maximum dose).  
14. If subjects are not able to go into the clinic for the DBPCFC within the target time frame, 
the DBPCFC can be started up to 7 days before and 30 days after the target date for visit 
16, 22, and/or 25. 
15. Study drug administration at unscheduled and/or optional visits 15a-f is to be documented 
in the unscheduled visits folder. 
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CONFIDENTIAL 
9.1.3. 
Early Termination Visit 
Subjects who are withdrawn from the study before the primary endpoint visit (week 28 to 40) will 
be asked to return to the clinic for an early termination visit consisting of study assessments 
described in Table 4. Subjects who are withdrawn from the study after the primary endpoint visit 
will be asked to return to the clinic for early termination assessments only but the DBPCFC will 
not be required. 
9.1.4. 
Unscheduled Visits 
All attempts should be made to keep subjects on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
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: HIV antibody, HBsAg, HBcAb, hepatitis C antibody, 
height. Demographics and medical history will be collected. 
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Double-Blind Placebo-Controlled Food Challenge 
The subject’s sensitivity to peanut allergen is defined as the dose at which the subject 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 principal investigator (or designee) 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 
subject is experiencing to the challenge material. The challenge will consist of 8 doses (peanut 
protein 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 subject will be monitored for at least 2 hours and then discharged from the clinic. 
Subjects will be considered to have tolerated the DBPCFC and passed if they do not experience 
any objective Grade 1 (mild) reaction by CoFAR grading system (see Appendix 2). If the subject 
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.  
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9.2.2.2. 
Fractional Exhaled Nitric Oxide 
Fractional exhaled nitric oxide 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). 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. During the COVID-19 pandemic, measurements of FeNO 
no longer need to be completed (at the discretion of the investigator). 
9.2.2.3. 
Peanut Skin Prick Test 
The standard SPT is performed on the volar surface of the subject’s forearm using standard whole 
peanut extract reagent, 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 3 and Table 4. Testing of peanut extract will be conducted at the 
following dilutions: Neat, 1:20, 1:200, 1:2000, 1:20,000. The longest diameter and longest 
orthogonal diameter will be collected.  
Mean wheal size induced by peanut extract, histamine, and saline at each concentration will be 
calculated by adding the longest diameter to the longest orthogonal diameter and dividing by 2. 
Normalized SPT will be calculated by subtracting mean saline wheal size from mean peanut wheal 
size.  
9.2.2.4. 
Eczema Area and Severity Index 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD (Hanifin, 2001). The EASI is a composite index with scores ranging from 0 to 
72. Four AD disease characteristics (erythema, thickness [induration, papulation, edema], 
scratching [excoriation], and lichenification) will each be assessed for severity by the investigator 
or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of AD involvement 
will be assessed as a percentage by body area of head, trunk, upper limbs, and lower limbs, and 
converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 (1% to 9%), 2 
(10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 100%). The EASI 
will be collected for subjects with AD at screening and at subsequent time points according to 
Table 3 and Table 4. 
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9.2.2.5. 
Asthma Control Questionnaire 
The Asthma Control Questionnaire (ACQ) is a validated questionnaire to evaluate asthma control. 
The questionnaire will be administered only to the subset of subjects with a medical history of 
asthma and who fluently speak a language in which the questionnaire is presented (based on 
availability of validated translations in participating countries), at time points according to Table 3 
and Table 4. The ACQ-5 is for subjects aged 11 years or more and the ACQ-interviewer 
administered (IA) is for subjects aged 6 to 10 years. The ACQ has been fully validated for all 
children 6-17 years when the self-administered adult version is used by children 11 years and older 
and the interviewer-administered version is used for children 6-10 years. Subjects will continue 
using the ACQ version first administered at screening regardless of moving to the next age bracket. 
9.2.2.6. 
Daily Allergy Symptom Diary 
The daily allergy symptom diary is a questionnaire that was designed to capture the daily signs 
and symptoms of peanut OIT. The measure was developed with input from patients currently or 
recently treated with peanut OIT as well as clinicians with experience treating patients with peanut 
OIT. The daily allergy symptom diary has also been cognitively debriefed within the target 
population. In addition to daily allergy symptoms, the e-diary will also collect data on dupilumab 
injections, peanut OIT dosing, use of medications to treat symptoms of peanut OIT, and health 
states. Compliance to e-diary will be tracked closely by sites and should be reviewed via IRT portal 
for follow-up. During clinic visit, sites should review entry and reconcile for missing data. 
9.2.2.7. 
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. 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 subject and, when 
appropriate, parents at time points in accordance with Table 3 and Table 4. Subjects 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 rate will be 
collected pre-dose at time points according to Table 3 and Table 4. During the DBPCFC, IDE and 
up-dosing, vital signs will be monitored every 15 to 30 minutes. For post-dose monitoring, only 
pulse and blood pressure need to be taken as part of safety monitoring. 
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9.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 3. Care should be taken to examine and assess any abnormalities that may be present, as 
indicated by the subject’s medical history. 
9.2.3.3. 
Spirometry 
A spirometer that meets the 2005 American Thoracic Society/European Respiratory Society 
recommendations will be used to measure FEV1 and/or PEF. 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 (Pellegrino, 2005). FeNO 
should be done prior to spirometry. If spirometry cannot be completed after enrollment, peak flow 
may be performed instead at the discretion of the investigator. 
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 3 and Table 4. Tests 
will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
AST 
Uric acid 
Calcium 
ALT 
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 
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Urinalysis 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
For female subjects 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. 
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 monitor 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. 
9.2.3.5. 
Pediatric Eosinophilic Esophagitis Symptom Score Questionnaire 
The Pediatric Eosinophilic Esophagitis Symptom Score PEESS v2.0 measures subject-relevant 
outcomes. The PEESS v2.0 holds promise for being a valuable tool to follow the clinical course 
of EoE or an EoE-like immune-mediated GI syndrome. However, it was not designed to establish 
a diagnosis of EoE and has not been validated for use in subjects with GI symptoms of other 
etiologies. Furthermore, the discriminant validity of the questionnaire has not been reported in 
either longitudinal natural history or interventional studies. For these reasons, the use of the PEESS 
v2.0 to monitor the clinical course of GI symptoms must be considered exploratory. Nevertheless, 
the PEESS v2.0 has shown good content and construct validity (Franciosi, 2011) (Martin, 2015).  
9.2.4. 
Pharmacokinetic and Anti-Drug Antibody Procedures 
9.2.4.1. 
Drug Concentration Measurements and Samples 
Samples for drug concentration will be collected at time points listed in Table 3 and Table 4.  
Any unused samples may be used for exploratory biomarker research. 
9.2.4.2. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected at time points listed in Table 3 and Table 4. 
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9.2.5. 
Pharmacodynamic and Other Biomarker Procedures 
Biomarker samples will be collected at time points according to Table 3 and Table 4. Biomarker 
measurements will be performed in serum or plasma to determine effects on biomarkers of relevant 
physiological and pathogenic processes. 
The biomarkers studied will be ones believed to be relevant to the pathophysiology of peanut 
allergy, mechanism of action of dupilumab, and possible toxicities. Biomarkers studied may 
include but need not be limited to: Total IgE, Thymus and Activation-Regulated Chemokine, 
specific IgE, IgG4, and IgG against peanut extract and main peanut allergen components 
(including but not limited to Ara h1, Ara h2, and Ara h3), blood stimulation in TruCulture 
(supernatant cytokine and chemokine profiling), basophil sensitivity to allergen stimulation and 
peanut-specific T-cell profiling.  
Exploratory biomarker results not required for protocol-defined endpoint analyses will not be 
reported in the CSR. 
9.2.6. 
Future Biomedical Research (Optional) 
Research samples (serum/plasma/peripheral blood mononuclear cells) will be banked for future 
biomedical research related to Type 2/Th2 inflammation, allergic diseases, IL-4/IL-13, dupilumab 
(including mechanism of action, efficacy, toxicity), and circulating factors that inhibit allergen-
specific IgE from binding to allergen (eg, IgE blocking factor). Additional samples will be 
collected as detailed in the schedule of assessments for Future Biomedical Research. The research 
may also include, but is not limited to, the study of allergen epitope diversity recognized by 
allergen-specific antibodies (both IgE and IgG4), T-cell and B-cell receptor repertoire (requires 
DNA/RNA sequencing), and the effects of dupilumab treatment on non-peanut allergies. 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. Any unused samples for study-related research, as well 
as unused PK and ADA samples, will be stored for up to 15 years after the final date of the database 
lock. The unused samples may be utilized for future biomedical research (described below). After 
15 years, any residual samples will be destroyed. Results of these future biomedical research 
analyses will not be reported in the CSR.  
9.2.6.1. 
Genomics Analysis (Optional) 
Parents or legal guardians who agree to participate in the genomics sub-study will be required to 
indicate their consent to participate in the sub-study on the informed consent form (ICF) before 
collection of the samples. Subjects are not required to participate in the genomics sub-study in 
order to enroll in the primary study. Samples for DNA extraction is recommended to be collected 
on day 1/baseline (predose) but may be collected at any study visit. 
DNA samples for the genomics analyses 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. 
These data may be used or combined with data collected from other studies to identify and validate 
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genomic markers related to the study drug or other 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 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) all unanticipated 
problems involving risks to subject. This includes 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, regardless of 
assessed causality. 
10.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will inform health authorities, IRBs, and the 
participating investigators of any suspected unexpected serious adverse reaction occurring in other 
study centers for dupilumab and AR101, and also other studies for dupilumab.  
Any AE not listed as an expected event in the Investigator’s Brochure or in this protocol will be 
considered as unexpected. Any worsening of or new onset of symptoms related to peanut allergy 
which occur during the screening/washout period prior to study drug administration will be 
considered expected. 
In addition, the sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the study drug 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 CSR to health authorities and IECs/IRB as appropriate. 
10.3. 
Definitions 
10.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a subject administered a study drug, which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease, which is 
temporally associated with the use of a study drug, whether or not considered related to the study 
drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
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 subject is a passenger). 
• Is life-threatening – in the view of the investigator, the subject is at immediate risk 
of death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. In-
subject hospitalization is defined as admission to a hospital or an emergency room for 
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longer than 24 hours. Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than was originally anticipated for the event or is prolonged due to 
the development of a new AE as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event - Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events. See Section 10.4 for more 
information on recording and reporting SAEs.  
10.3.3. 
Adverse Events of Special Interest 
An 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/assent is signed until the end of study. However, allergic reactions to the DBPCFC during 
the Screening phase, at endpoint challenges (at visits 16, 22, and 25), during AR101 in-clinic 
dosing visits, and daily home dosing 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 and 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 subject completes the study (ie, the 
follow-up period), the following will apply: 
• If the subject is an early termination from the study, SAE with an onset within 12 weeks 
of last study drug administration 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. 
• For SAEs with an onset day greater than 12 weeks from the last study drug 
administration, only 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: 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study subject, during the study or within 12 
weeks of the last dose of study drug. Any complication of pregnancy affecting a 
female study subject, and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: All AESI, serious and non-serious, 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 dupilumab in this study include the following:   
• Anaphylactic reactions  
• Systemic or extensive hypersensitivity reactions 
• Helminthic infections 
• 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) 
Adverse events of special interest for AR101 in this study include: 
• Anaphylactic reactions 
• Gastrointestinal AEs resulting in prolonged disruption of dosing 
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 subject’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days. 
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Refer to the study reference manual for the procedures to be followed. 
10.4.5. 
Abnormal Laboratory or Vital Signs Results 
Abnormal laboratory or vital signs will be graded according to the FDA September 2007. 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 monitor 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. 
Please refer to FDA Guidance for Industry, Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials for reporting severity of 
laboratory abnormalities: 
(https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInfor
mation/Guidances/Vaccines/ucm091977.pdf) 
10.4.6. 
Follow-Up 
Adverse event information will be collected until the subject’s last study visit. 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable. 
10.5. 
Evaluation of Severity and Causality 
10.5.1. 
Evaluation of Severity 
The severity grading of allergic reactions will be according to the definitions developed the 
CoFAR group (Appendix 2) and the severity of anaphylactic reactions will be graded according to 
the EAACI system for grading the severity of anaphylactic reactions (Appendix 3).  
The severity of other AEs will be graded according to the following scale: 
• Mild:  Does not interfere in a significant manner with the subject normal functioning 
level. It may be an annoyance. Prescription drugs are not ordinarily needed for relief 
of symptoms but may be given because of personality of the subject. 
• Moderate:  Produces some impairment of functioning but is not hazardous to health. 
It is uncomfortable or an embarrassment. Treatment for symptom may be needed. 
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• Severe:  Produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health. Treatment for symptom may be given and/or 
subject hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade): 
• Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of 
erythema or induration that does not interfere with activity 
• Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or 
interferes with activity; discomfort with movement; 5.1 cm to 10 cm erythema or 
induration or induration that interferes with activity 
• Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily 
activity; significant discomfort at rest; >10 cm erythema or induration; prevents daily 
activity; requires emergency room visit or hospitalization; necrosis; or exfoliative 
dermatitis 
10.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the blinded investigator and will be a 
clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study 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 subject’s disease state or clinical condition 
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• 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 subject’s disease state or clinical condition 
• 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 
Relationship of Adverse Events to Background Treatment: 
The relationship of AEs to background treatment, etc. will be assessed by the ("blinded") 
investigator and will be a clinical decision based on all available information. The following 
question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the background treatment, 
etc.? 
The possible answers are: 
Not Related: There is no reasonable possibility that the event may have been caused by the 
background treatment, etc. 
Related: 
There is a reasonable possibility that the event may have been caused by the 
background treatment, etc. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
A list of factors to consider in assessing the relationship of AEs to background treatment, etc. 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 background treatment? 
No: 
• due to subject’s disease state or clinical condition 
• do not follow a reasonable temporal sequence following the background treatment 
• do not reappear or worsen when background treatment is resumed 
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• are not a suspected response to the background treatment 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 subject’s disease state or clinical condition 
• follow a reasonable temporal sequence following the background treatment 
• resolve or improve after discontinuation of background treatment 
• reappear or worsen when background treatment is resumed 
• are known or suspected to be a response to the background treatment based upon 
preclinical data or prior clinical data 
10.6. 
Safety Monitoring 
The investigator will monitor the safety of study subject at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The medical monitor 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 Investigator’s 
Brochure or this protocol, and has a reasonable suspected causal relationship to the study drug). 
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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. 
Handling of missing data or delayed procedures due to COVID-19, and any additional analyses 
required to investigate the impact of COVID-19 to understand estimated treatment effect and 
safety, will be detailed in the SAP. 
11.1. 
Statistical Hypothesis 
The primary efficacy endpoint is the proportion of subjects who achieve a cumulative dose of 
2044 mg peanut protein during a post up-dosing DBPCFC at visit 16. The comparison between 
the dupilumab plus AR101 arm and the placebo plus AR101 arm will be made. 
Let pD (and pP) be the true proportion of subjects who achieve a cumulative dose of 2044 mg of 
peanut protein during a post up-dosing DBPCFC at visit 16 in the treatment arms of dupilumab 
plus AR101 and placebo plus AR101, respectively. The following hypothesis for the superiority 
testing will be tested at the 5% 2-sided significance level: 
H0: pD = pP, ie, the proportion of subjects who achieve a cumulative dose of 2044 mg peanut 
protein during a post up-dosing DBPCFC at visit 16 is the same between dupilumab plus AR101 
arm and the placebo plus AR101 arm 
against the alternative 
Ha: pD ≠ pP, ie, the proportion of subjects who achieve a cumulative dose of 2044 mg peanut protein 
during a post up-dosing DBPCFC at visit 16 are different between the dupilumab plus AR101 arm 
and the placebo plus AR101 arm 
11.2. 
Justification of Sample Size 
It is assumed that the proportion of subjects who achieve a cumulative dose of 2044 mg of peanut 
protein during a post up-dosing DBPCFC at visit 16 in the placebo plus AR101 arm will be 40%, 
based on an Aimmune presentation at the 2018 American Academy of Allergy, Asthma & 
Immunology–World Allergy Organization Joint Congress; with the proportion of subjects in the 
dupilumab plus AR101 arm assumed to be 65%, which is considered to be clinical meaningful 
benefit by adding on dupilumab treatment. A sample size of approximately 156 subjects (104 in 
dupilumab plus AR101 and 52 in placebo plus AR101) will have 80% power to detect the treatment 
difference of 25% between placebo plus AR101 and dupilumab plus AR101 at the 2-sided 5% 
significance level (the minimum significant difference is approximately 17.8%). The sample size 
calculations were done by Fisher exact test using nQuery (7.0).  
Approximately 122 subjects who undergo the post up-dosing DBPCFC at week 28 (visit 16 with 
a window of -7/+30 days) or discontinue from study prior to week 28 (visit 16 with a window of -
7/+30 days) will be included in the primary efficacy analysis. These subjects receive AR101 dose 
escalation per the original protocol’s 24-week up-dosing schedule. The minimum significant 
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difference with approximately 122 subjects is approximately 20.7% between placebo plus AR101 
and dupilumab plus AR101 assuming the placebo plus AR101 treatment effect is 40% at the 2-
sided Fisher exact test with 5% significance level. 
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets 
The full analysis set (FAS) includes all randomized subjects. Efficacy analyses will be based on 
the treatment allocated at randomization (as randomized). 
The modified full analysis set (mFAS) includes all FAS subjects who undergo the post up-dosing 
DBPCFC at week 28 (visit 16 with a window of -7/+30 days) or discontinue from study prior to 
week 28 (visit 16 with a window of -7/+30 days). 
The mFAS will be used for primary analysis for all efficacy endpoints. Analysis of the FAS will 
also be done for supportive analyses. 
11.3.2. 
Safety Analysis Set 
The safety analysis set (SAF) includes all randomized subjects who received any study drug; it is 
based on the treatment received (as treated). Treatment compliance/administration and all clinical 
safety variables will be analyzed using the SAF. 
11.3.3. 
Other Analysis Sets 
The pharmacokinetic population includes all treated subjects who received any study drug and 
who had at least 1 non-missing drug concentration result following the first dose of study drug. 
The ADA analysis set includes all treated subjects 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 treated subjects 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 (subjects 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 subjects 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. 
All data will be summarized by treatment groups as outlined below:   
• Double-blind treatment period with pre-dosing and up-dosing of AR101 (28 to 
40 weeks):  placebo plus AR101 vs dupilumab plus AR101. 
• Double-blind maintenance phase (24 weeks):  continuously on placebo + AR101, 
previously on dupilumab + AR101 and re-randomized to placebo + AR101, 
continuously on dupilumab + AR101. 
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11.4.1. 
Subject Disposition 
The following will be provided: 
• The total number of screened subjects:  met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized subjects:  received a randomization number 
• The total number of subjects in each analysis set (eg, mFAS, FAS defined in 
Section 11.3.1 for all efficacy analysis sets) 
• The total number of subjects who discontinued the study, and the reasons for 
discontinuation 
• A listing of subjects treated but not randomized, subjects randomized but not treated, 
and subjects randomized but not treated as randomized 
• A listing of subjects prematurely discontinued from treatment, along with reasons for 
discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all subjects combined.  
11.4.3. 
Efficacy Analyses 
The primary efficacy analyses for all the efficacy endpoints will be conducted using the mFAS 
population. As supportive evidence, the same analysis approach will be repeated with the FAS 
population. 
11.4.3.1. Primary Efficacy Analysis 
The primary endpoint will be analyzed using the Cochran-Mantel-Haenszel test adjusted by 
randomization stratification factors to assess the treatment difference in the proportion of 
responders (ie, those who “pass” a post up-dosing DBPCFC with 2044 mg [cumulative] peanut 
protein at visit 16 [week 28 with a visit window of -7/+30 days]) in the mFAS. Estimate of 
treatment difference, p-value, and the 2-sided 95 % confidence interval will be provided. 
In addition, the primary efficacy endpoint will be performed on the FAS as a supportive analysis. 
If a subject does not have available post up-dosing DBPCFC data at visit 16, the subject will be 
considered as a non-responder regardless of reasons for missing data.  
Sensitivity analyses will include an analysis of the subset of subjects with available post up-dosing 
DBPCFC data from visit 16. 
Subgroup analysis (eg, by baseline weight group) will also be performed. 
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11.4.3.2. Secondary Efficacy Analysis 
Continuous Endpoints at Visit 16 
Change in the cumulative tolerated dose (log transformed) of peanut protein during a post 
up-dosing DBPCFC from baseline at visit 16 will be analyzed using analysis of covariance 
(ANCOVA) with treatment as the main effect, stratification variables and baseline tolerated 
cumulative amount of peanut protein DBPCFC as covariates. In addition, a non-parametric 
analysis using the Van Elteren test will be conducted to assess the sensitivity to the assumption 
about normality of response variable as required by ANCOVA. 
If a subject does not have an available post up-dosing DBPCFC at visit 16, their baseline value 
will be used to impute the missing DBPCFC data at visit 16 (ie, baseline observation carried 
forward). Sensitivity analysis using complete cases will be conducted to assess the robustness of 
the result, with regard to handling of missing data. Other sensitivity analyses may be conducted 
and will be specified in the SAP. 
Continuous secondary efficacy endpoints that are measured repeatedly over time during the 
28 to 40 week double-blind treatment period (eg, EASI) will be analyzed using ANCOVA in a 
similar way to the endpoint of change in the cumulative tolerated dose of peanut protein. For these 
endpoints, missing data will be imputed by multiple imputations. 
Endpoints at Visit 22 or 25 
Secondary endpoints at visit 22 (the end of the maintenance period) or at visit 25 (the end of study) 
will be analyzed descriptively at given visits. These descriptive analyses may include statistical 
tests depending on the type of data in the same way as described above. 
11.4.3.3. Multiplicity Considerations 
The overall Type-1 error rate of 0.05 (2-sided) will be controlled for the primary endpoint and the 
first secondary endpoint (ie, change in the cumulative tolerated dose [log transformed] of peanut 
protein during a post up-dosing DBPCFC from baseline to visit 16) using a hierarchical testing 
procedure. Inferential conclusions about the first secondary endpoint require statistical 
significance at the 2-sided 0.05 significance level of the primary endpoint.  
11.4.3.4. Timing of Analyses 
A primary analysis may be performed when the last subject completes 28 to 40 weeks of the 
double-blind treatment period as specified in the protocol (visit 16 or earlier for those subjects who 
are withdrawn prematurely from the study). No changes in the conduct of the study will be made 
based on this primary analysis. The assessment of primary and secondary endpoints up to visit 16 
as specified in Section 11.4.3.1  and Section 11.4.3.2  and performed during the analysis will be 
the final analysis of the primary endpoint and the secondary endpoints up to visit 16. Hence there 
will be no need for alpha adjustment due to the primary analysis. If a decision is made to perform 
the primary analysis, in order to maintain study integrity with respect to the maintenance phase 
and the post-treatment follow-up visits, and analyses, a dissemination plan will be written. This 
plan will clearly identify the team (including the statistician) that will perform the primary analysis 
and all related activities, restrict other clinical team members and other sponsor personnel from 
access to individual subject treatment allocation and site level analysis results, and ensure that the 
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dedicated team will not participate in the data review or data decisions for the following 
post-treatment analyses. However, the dedicated team can participate in the analysis following the 
final database lock. In addition, an end of maintenance phase analysis may be performed when the 
last subject completes the maintenance treatment period (week 52 to 64 visit or earlier for those 
who are withdrawn prematurely from the study). If a decision is made to perform the end of 
maintenance phase analysis, measures similar to those taken for the primary analysis will be used 
in order to maintain study integrity with respect to the post-treatment follow-up visits and analyses. 
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 
28 to 40 week up-dosing treatment period, the 24-week maintenance treatment 
period, and the follow-up 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-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. 
Summaries of all TEAEs by treatment group will include: 
• The number (n) and percentage (%) of subjects with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 10.5.1), 
presented by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Deaths and other SAEs will be listed and summarized by treatment group. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized by treatment group. 
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 with descriptive statistics. 
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The number and percentage of subjects with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable. The criteria for treatment-emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of subjects with a treatment-emergent PCSV at any post-randomization 
time point will be summarized for each clinical laboratory test. The criteria for treatment-emergent 
PCSVs will be defined in the SAP. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out of laboratory range values. 
11.4.4.3. Treatment Exposure 
The duration of exposure during the study will be presented by treatment group and calculated as: 
(Date of last study drug injection – date of first study drug injection) + 14 days 
The number (%) of subjects randomized and exposed to double-blind study drug will be presented 
by specific time periods for each treatment group. The time periods of interest will be specified in 
the SAP. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of subjects, means, standard deviation, minimums, Q1, medians, Q3, and 
maximums. 
A summary of the number of doses by treatment group will be provided. 
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 compliance with AR101 will be calculated as follows:   
Treatment Compliance of AR101 = (total actual peanut dose protein [mg] received during 
exposure period)/(total planned dose protein [mg] during exposure period) × 100% 
The treatment compliance of study drug and AR101 will be presented by specific ranges for each 
treatment group. 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. 
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11.4.6. 
Analysis of Immunogenicity Data 
• Listings of pre-existing, treatment-emergent and persistent ADA responses, titers, and 
NAb positivity presented by subject, time point, and dose group will be provided. 
Incidence of treatment-emergent and treatment-boosted ADA will be assessed as 
absolute occurrence (N) and percent of subjects (%), grouped by study cohorts and 
ADA titer level as follows:  
• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, 
with all post-dose ADA results negative, or a positive assay response at baseline, with 
all post-dose ADA assay responses less than 4-fold over baseline titer levels. 
• Treatment-emergent - defined as any post-dose ADA-positive response when baseline 
results are negative or missing. 
− Treatment-emergent ADA response may be further characterized as persistent, 
transient, or indeterminate. 
• Treatment-boosted – defined as any post-dose positive ADA response that is at least 
4-fold over the baseline level when baseline is positive in the ADA assay. 
• Titer category (Maximum ADA titer values) 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤10,000) 
− High (titer >10,000) 
− NAb status for samples that are positive in the ADA assay 
Listings of pre-existing, treatment-boosted, and treatment-emergent ADA responses, ADA titers 
and NAb positivity presented by subject, time point, and dose cohort/group will be provided. 
Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and 
percent of subjects (%), grouped by study cohorts and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.4.7. 
Analysis of Pharmacodynamic Data 
The exploratory biomarker data will be summarized by descriptive statistics. 
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) 
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• 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 nonprotocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings, but not summaries. If more than 1 laboratory value is available for a given 
visit, the first observation will be used in summaries, and all observations will be 
presented in listings. 
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. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
12.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation, cleaning, correcting, releasing) will be maintained and stored at Regeneron. 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an EDC tool. 
12.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IWRS system – randomization, study drug supply 
• EDC system – data capture 
• E-diary 
• Statistical Analysis Software (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• AWARE, Business Objects XI – pharmacovigilance activities (Sanofi) 
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13. 
STUDY MONITORING 
13.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, contract research organization monitor) will visit each site 
prior to enrollment of the first subject, and periodically during the study. Remote monitoring may 
be used if applicable. 
13.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate subject records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
13.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic CRFs within 
the EDC system by trained site personnel. All required CRFs must be completed for each and 
every subject enrolled in the study. After review of the clinical data for each subject, the 
investigator must provide an electronic signature. A copy of each subject CRF casebook is to be 
retained by the investigator as part of the study record and must be available at all times for 
inspection by authorized representatives of the sponsor and regulatory authorities. 
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 files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
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In all instances, the confidentiality of the data must be respected. 
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 
Pediatric Subjects 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB. A copy of the IRB-approved ICF and documentation of 
approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each subject and his/her parent(s) or legal guardian(s) prior to the 
subject’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 subject and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the subject’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, if both are required. The subject may also be required to sign 
and date the assent form, as determined by the IRB and in accordance with the local regulations 
and requirements. 
• Subjects who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Subjects who can understand but who can neither write nor read will have the ICF read 
to them in presence of an impartial witness, who will sign and date the ICF to confirm 
that informed consent was given. 
The original ICF must be retained by the investigator as part of the subject’s study record, and a 
copy of the signed ICF must be given to the subject’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 subjects and their parent(s) or legal guardian(s) 
must be informed of the new information and provide their written consent if they wish the subject 
to continue in the study. The original signed revised ICF must be maintained in the subject’s study 
record and a copy must be given to the subject’s parent(s) or legal guardian(s). 
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15.3. 
Subjects Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
subject will be maintained. Subjects should be identified by their subject identification number, 
only, on CRFs or other documents submitted to the sponsor. Documents that will not be submitted 
to the sponsor (eg, signed ICF) must be kept in strict confidence. 
The subject’s and investigator's personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
15.4. 
Institutional Review Board 
An appropriately constituted IRB, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, assent, ICF, and any other materials to be provided to the subjects 
(eg, advertising) before any subject may be enrolled in the study 
• Any amendment or modification to the study protocol, assent or ICF before 
implementation, unless the change is necessary to eliminate an immediate hazard to 
the subject, in which case the IRB 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 should be informed of any event likely to affect the safety of subjects or the 
continued conduct of the clinical study. 
A copy of the IRB approval letter with a current list of the IRB 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 review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
16. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol, assent, or ICF without an 
IRB-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 subject within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of subjects required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB and Health Authorities must be informed according to applicable 
regulatory requirements, and adequate consideration must be given to the protection of the 
subjects’ interests. 
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18. 
STUDY DOCUMENTATION 
18.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of subject final 
CRF 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 
regulatory authorities. The investigator must consult with the sponsor before discarding or 
destroying any essential study documents 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 and the relevant records will be transferred to a mutually 
agreed-upon destination. 
19. 
DATA QUALITY ASSURANCE 
Authority Inspections.  
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). 
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 subjects are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 13.1). 
All subject 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 
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signing a declaration that accompanies each set of subject 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). 
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, 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. 
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. 
Baumert JL, Taylor SL, Koppelman SJ. Quantitative assessment of the safety benefits associated 
with increasing clinical peanut thresholds through immunotherapy. J Allergy Clin Immunol Pract 
2017 In press. 
Bird J. A, Spergel J, Jones S. M, Rachid, R., Assa’ad A. H, Wang J, and Davis B. (2015). A novel 
characterized peanut allergen formulation (AR101) for oral immunotherapy (OIT) induces 
desensitization in peanut-allergic subjects: a phase 2 clinical safety and efficacy study. Allergy 
2015; 70 (S101): 110. 
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. 
Dyer, Allergy, Asthma, Proc, 2015, 36:58-64 
Franciosi JP, Hommel KA, DeBrosse CW, Greenberg AB, Greenler AJ, Abonia JP, Rothenberg 
ME, Varni JW. Development of a validated patient-reported symptom metric for pediatric 
eosinophilic esophagitis: qualitative methods. BMC Gastroenterol. 2011;11:126. 
Gernez Y, Tirouvanziam R, Yu G, et al. Basophil CD203c Levels Are Increased at Baseline and 
Can Be Used to Monitor Omalizumab Treatment in Subjects with Nut Allergy. Int Arch Allergy 
Immunol 2011;154:318–327. 
Gorelik M, Narisety SD, Guerrerio AL. Suppression of the immunologic response to peanut during 
immunotherapy is often transient. JACI 2015; 135 (5) 1283-1292. 
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. 
Guttman-Yassky E, Bissonnette R, Ungar B, Suarez-Farinas M, Ardeleanu M, et al, Dupilumab 
progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. 
JACI 2019 ;143 (1)-155-172 
Hamilton JD, Suarez-Farinas M, Dhingra, N et al. Dupilumab improves the molecular signature in 
the skin of patients with moderate-to-severe atopic dermatitis. JACI 2014; 134(6): 1293-1300. 
Hanifin JM, Thurston M, Omoto M, et al. The eczema area and severity index (EASI): assessment 
of reliability in atopic dermatitis. Exp Dermatol 2001; 10(1): 11-18. 
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric Reference Values from a Sample of the 
General US Population. Am J Respir Crit Care Med 1999; 169:179-87. 
Hughes JL, Brown T, Edgar JD, Shields MD. Peanut allergy and allergic airways inflammation. 
Pediatr Allergy Immunol. 2010 Dec;21(8):1107-13. 
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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 L, Roberts JL, et al: Clinical efficacy and immune regulation with peanut oral 
immunotherapy. JACI  2009; 124:292–300. 
MacGinnitie AJ, Rachid R, Gragg H, et al. Omalizumab facilitates rapid oral desensitization for 
peanut allergy. JACI  2016 doi: 10.1016/j.jaci.2016.08.010. 
Martin LJ, Franciosi JP, Collins MH, Abonia JP, Lee JJ, Hommel KA, et al. Pediatric Eosinophilic 
Esophagitis Symptom Scores (PEESS v2.0) identify histologic and molecular correlates of the key 
clinical features of disease. J Allergy Clin Immunol. 2015;135(6):1519-1528. 
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. 
Narisety SD, Frischmeyer-Guerrerio PA, Keet CA, et al. A randomized, double-blind, 
placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut 
allergy. JACI 2015; 135: 1275–1282. 
PALISADE Group of Clinical Investigators, Vickery BP, Vereda A, Casale TB, et al. AR101 oral 
immunotherapy for peanut allergy. N Engl J Med. 2018;379(21):1991-2001. 
Pellegrino R, Viegi G, Brusasco V, et al. Interpretative Strategies for Lung Function Tests. Eur 
Respir J 2005; 26:948-968. 
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. 
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, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 
2006;117(2):391-397. 
Santos A, James L, Bahnson H, et al. IgG4 inhibits peanut-induced basophil and mast cell 
activation in peanut-tolerant children sensitized to peanut major allergens. JACI 2015; 1249-56. 
Sicherer, JACI, 2010, 125:1322-6. 
Simons FE, Ardusso LR, Bilò MB, El-Gamal YM, Ledford DK, Ring J, et al.; World Allergy 
Organization. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin 
Immunol. 2011 Mar;127(3):587-93.e1-22. 
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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. 
Syed A, Garcia MA, Lyu SC, et al. Peanut oral immunotherapy results in increased antigen-
induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). JACI 
2014; 133, 500-510. 
Vickery BP, Lin J, Kulis M, et al: Peanut oral immunotherapy modifies IgE and IgG4 responses 
to major peanut allergens. JACI 2013; 131: 128–134. 
Vickery BP, Scurlock AM, Kulis M. Sustained unresponsiveness to peanut in subjects who have 
completed peanut oral immunotherapy. JACI 2014; 133 (2), 468 - 475. 
Virkud Y, Burks W, Steele P, et al. Novel baseline predictors of adverse events during oral 
immunotherapy in children with peanut allergy; JACI 2016; 1-7e. 
Wambre E, Bajzik V,Delong JH, O’Brien K , et al. A phenotypically and functionally distinct 
human Th2 cell subpopulation is associated with allergic disorders. Scien. Trans. Med. 2017; 9 
(401) eaam9171 
Wang J, Vickery B, Vereda A, et al. O056 Baseline peanut specific IgE potentially predicts up 
dose completion and treatment response with AR101 in CODIT. Ann Allergy Asthma Immunol. 
2016;117(5): S18. 
Wang X, Dockery DW, Wypij D, et al. Pulmonary Function Between 6 and 18 Years of Age. 
Pediatr Pulmonol 1993; 15:75-88. 
Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil 
levels. NEJM 2013;368: 2455-2466. 
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. 
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24. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-
BLIND, PLACEBO-CONTROLLED STUDY IN PEDIATRIC SUBJECTS WITH PEANUT 
ALLERGY TO EVALUATE THE EFFICACY AND SAFETY OF DUPILUMAB AS ADJUNCT 
TO AR101 (PEANUT ORAL IMMUNOTHERAPY) 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. 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, VISITS 16, 22, AND 25 
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) 
post-screening (V16, V22, 
and V25) 
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 subject, nor the subject’s legal guardian, 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. 
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APPENDIX 2. ALLERGIC REACTION SEVERITY GRADING 
The 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 one of the 3 following sets of criteria is fulfilled: 
1. Acute onset of an illness (min to h) 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 (min to h): 
• 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 (min to h): 
• 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 mmHg from 1 month to 1 year; less than 
(70 mmHg + [2 x age]) from 1 to 10 years; and < 90 mmHg 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 
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APPENDIX 4. SCHEMATIC FOR AR101 INITIAL DOSE ESCALATION 
DAY PERFORMED IN-CLINIC AT WEEK 4 
 
Oral/pharyngeal pruritus 
Time to next dose: 30 min 
Next dose: advance 
Mild Symptoms 
Time to next dose: 30-60 min; 
Next dose: advance if symptoms resolve
spontaneously or to treatment with no 
more than 2 doses of antihistamine 
Dose-Escalation 
Dose 
Moderate Symptom 
Occurring at ≤6 mg: Treat as indicated 
for moderate reaction; stop escalation
and discontinue from study 
Severe Symptoms  
Treatment as indicated for severe 
reaction, stop escalation and
discontinue from study 
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APPENDIX 5. SCHEMATIC FOR SUBSEQUENT AR101 DOSE 
ESCALATION DAYS PERFORMED IN-CLINIC AT 
WEEKS 6 THROUGH END OF UP-DOSING 
(WEEK 28 TO 40) 
 
Oral/pharyngeal pruritus 
 
advance 
Mild Symptoms 
 
advance if symptoms resolve spontaneously 
or to treatment with no more than 2 doses of 
antihistamine 
Dose-Escalation 
Dose 
Moderate Symptoms 
Reduce dose by 1 dose levels until dose 
tolerated with no or mild symptoms; if mild 
symptoms result, proceed as above 
Severe Symptoms 
 
For severe symptoms, discontinue subject 
from study. 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Scientific/Medical Monitor, 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 PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY IN PEDIATRIC SUBJECTS WITH 
PEANUT ALLERGY TO EVALUATE THE EFFICACY AND SAFETY 
OF DUPILUMAB AS ADJUNCT TO AR101 (PEANUT ORAL 
IMMUNOTHERAPY) 
Protocol Number: 
R668-ALG-16114 
Protocol Version: 
R668-ALG-16114 Amendment 4 
 
See appended electronic signature page 
Sponsor’s Responsible Scientific/Medical Monitor 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Representative 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00116697-1.0 Approved - 23 Jul 2020 GMT-5:00


Signature Page for VV-RIM-00116697 v1.0
Signature Page for VV-RIM-00116697 v1.0 Approved
ESig Approval
23-Jul-2020 00:35:37 GMT+0000
ESig Approval
23-Jul-2020 05:23:45 GMT+0000
ESig Approval
23-Jul-2020 12:34:01 GMT+0000
ESig Approval
23-Jul-2020 13:21:03 GMT+0000
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 86 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: 1.0 
A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study in Pediatric 
Subjects with Peanut Allergy to Evaluate the Efficacy and Safety of Dupilumab as Adjunct 
to AR101 (Peanut Oral Immunotherapy) 
Compound: 
Dupilumab (REGN668) 
Protocol Number:  
R668-ALG-16114 Amendment 4 
Clinical Phase:  
Phase 2 
Sponsor:  
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
 
Study Medical Director: 
 
Version/Date: 
Original Statistical Analysis Plan / MM DD, YR 
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NCT03682770


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 2 of 86 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
 
See appended electronic signature page 
Study Biostatistician  
 
 
 
See appended electronic signature page 
Study Medical Director 
 
 
 
See appended electronic signature page 
Head of BDM or designee 
 
 
 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 3 of 86 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Background/Rationale ..................................................................................................8 
1.2. 
Study Objectives ...........................................................................................................9 
1.2.1. 
Primary Objective .........................................................................................................9 
1.2.2. 
Secondary Objectives .................................................................................................10 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.2.4. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................13 
2.1. 
Study Design and Randomization ..............................................................................13 
2.2. 
Statistical Hypothesis ..................................................................................................13 
2.3. 
Sample Size and Power Considerations .....................................................................14 
2.4. 
Study Plan ...................................................................................................................14 
3. 
ANALYSIS POPULATIONS ....................................................................................18 
3.1. 
The Full Analysis Set (FAS) .......................................................................................18 
3.2. 
The Per Protocol Set (PPS) .........................................................................................18 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................18 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................20 
3.5. 
The Immunogenicity Analysis Sets ............................................................................20 
3.6. 
Subgroups ...................................................................................................................20 
4. 
ANALYSIS VARIABLES .........................................................................................21 
4.1. 
Demographic and Baseline Characteristics ................................................................21 
4.2. 
Medical History ..........................................................................................................22 
4.3. 
Prior / Concomitant Medication and Procedures ........................................................22 
4.4. 
Prohibited or Rescue Medication/Procedure During Study ........................................23 
4.5. 
Efficacy Variable ........................................................................................................24 
4.5.1. 
Primary Efficacy Variable (s) .....................................................................................24 
4.5.2. 
Secondary Efficacy Variable(s) ..................................................................................25 
4.5.3. 
Exploratory Efficacy Variable (s) ...............................................................................26 
4.6. 
Safety Variables ..........................................................................................................30 
4.6.1. 
Adverse Events and Serious Adverse Events .............................................................30 
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Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 4 of 86 
4.6.2. 
Adverse Events of Special Interest .............................................................................31 
4.6.3. 
Laboratory Safety Variables .......................................................................................32 
4.6.4. 
Vital Signs ..................................................................................................................33 
4.6.5. 
Body Weight and Height ............................................................................................33 
4.6.6. 
Physical Examination Variables .................................................................................33 
4.6.7. 
Spirometry ..................................................................................................................33 
4.7. 
Pharmacokinetic (PK) Variables ................................................................................33 
4.8. 
Anti-Drug Antibody Variable .....................................................................................33 
4.9. 
Pharmacodynamic and Biomarkers Variables ............................................................34 
4.10. 
Pediatric Eosinophilic Esophagitis Symptom Score Questionnaire ...........................35 
5. 
STATISTICAL METHODS .......................................................................................36 
5.1. 
Demographics and Baseline Characteristics ...............................................................36 
5.2. 
Medical History ..........................................................................................................36 
5.3. 
Prior and Concomitant Medications/Procedures ........................................................36 
5.4. 
Subject Disposition .....................................................................................................37 
5.5. 
Extent of Study Treatment Exposure ..........................................................................38 
5.5.1. 
Measurement of Compliance ......................................................................................38 
5.5.2. 
Exposure to Investigational Product ...........................................................................39 
5.6. 
Analyses of Efficacy Variables ..................................................................................39 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................40 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................40 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................43 
5.6.4. 
Analysis of Exploratory Efficacy Variables ...............................................................43 
5.6.5. 
Subgroup Analysis ......................................................................................................43 
5.7. 
Analysis of Safety Data ..............................................................................................44 
5.7.1. 
Adverse Events ...........................................................................................................44 
5.7.2. 
Analysis of Adverse Events of Special Interest ..........................................................46 
5.7.3. 
Clinical Laboratory Measurements.............................................................................47 
5.7.4. 
Analysis of Vital Signs ...............................................................................................47 
5.7.5. 
Physical Exams ...........................................................................................................48 
5.7.6. 
Spirometry and Peak Expiratory Flow (PEF) .............................................................48 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................48 
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5.9. 
Analysis of Immunogenicity Data ..............................................................................49 
5.9.1. 
Analysis of ADA Data ................................................................................................49 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb) Data ......................................................50 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................50 
5.10.1. 
Immunogenicity and Exposure ...................................................................................50 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................50 
5.11. 
Analysis of Biomarker Data .......................................................................................51 
5.12. 
Analysis of Daily Allergy Symptom Diary Data ........................................................53 
5.13. 
Analysis of Pediatric Eosinophilic Esophagitis Symptom Score ...............................53 
6. 
DATA CONVENTIONS ............................................................................................54 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................54 
6.2. 
General Data Handling Conventions ..........................................................................54 
6.3. 
Data Handling Convention for Missing Data .............................................................54 
6.4. 
Visit Windows ............................................................................................................56 
7. 
INTERIM ANALYSIS ...............................................................................................60 
8. 
SOFTWARE ...............................................................................................................61 
9. 
REFERENCES ...........................................................................................................62 
10. 
APPENDIX.................................................................................................................63 
10.1. 
Summary of Statistical Analyses ................................................................................63 
10.2. 
Schedule of Time and Events .....................................................................................66 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................76 
10.4. 
Search Criteria for TEAE of Special Interest for Dupilumab .....................................79 
10.5. 
Search Criteria for TEAE of Special Interest for AR101 ...........................................80 
10.6. 
Important Protocol Deviations ....................................................................................80 
 
LIST OF TABLES 
Table 1: 
AR101 Initial Dose Escalation Day at Week 4 ..........................................................16 
Table 2: 
Schedule of Events – Screening, Baseline, Double-Blind Treatment Period .............66 
Table 3: 
 Schedule of Events – Maintenance Period and Follow-Up Period ............................71 
 
LIST OF FIGURES 
Figure 1.  Schematic of Study Design .........................................................................................15 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACQ 
Asthma Control Questionnaire  
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGOT) 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST (SGPT) 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CoFAR 
Consortium, of Food Allergy Research 
CRF 
Case report form 
DBPCFC 
Double-blind, placebo-controlled food challenge 
EASI 
Eczema Area and Severity Index 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
FAQLQ 
Food Allergy Quality of Life Questionnaire  
FAS 
Full analysis set 
mFAS 
Modified Full Analysis Set 
HIV 
Human Immunodeficiency Virus 
HLT 
High Level Term 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IDED 
initial dose escalation day  
IL 
Interleukin 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
LDH 
Lactate dehydrogenase  
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
NAb 
Neutralizing Antibody 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
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PKAS 
Pharmacokinetic analysis set 
PT 
Preferred term 
Q2W 
Once 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 software 
sIgE 
Specific immunoglobulin E 
SC 
Subcutaneous 
SD 
Standard deviation 
SE 
Standard error 
SOC 
System organ class 
SPT 
Skin prick test 
TEAE 
Treatment emergent adverse event 
Th2 
Type-2 T helper cells 
WBC 
White blood cell 
WHODD 
World health organization drug dictionary 
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Statistical Analysis Plan 
 
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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-16114 study. For subjects impacted by 
the COVID-19 pandemic, the up-dosing period for AR101 protein is permitted to be extended an 
additional 12 weeks such that visit 16 may be extended from week 28 to up to week 40. The 
dosing of study drug is extended as well.  
This SAP will describe the descriptive and inferential statistical analysis for 28 to 40 weeks AR101 
pre-dosing and up-dosing periods. The SAP will also describe the descriptive summary of 24 
weeks AR101 maintenance period and 12-week safety follow-up period. The statistical inference 
may be performed for AR101 maintenance period, if needed. 
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). 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 
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 due to the 
incomplete response to OIT. 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. It is known that allergic response to food 
is an IgE-mediated event; however, recent data suggest that IL-4 and IL-13 may also play a 
significant role in food allergy pathogenesis. For instance,  IL4 andIL13 signaling is involved in 
the increased production of allergen specific IgE and activation of effector cells such as basophils 
and mast cells. This clinical study proposes to examine the effect of dupilumab, a monoclonal 
antibody, which blocks the action of these cytokines, to enhance the safety, tolerability, and 
efficacy of AR101 (investigational oral biologic drug) in subjects with significant allergy to 
peanuts. 
Peanut allergy is an immunoglobulin E (IgE)- mediated hypersensitivity reaction following the 
ingestion of normally innocuous peanut protein. 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 Type 2 T-helper cell (Th2) cytokine release, which results in 
eosinophil infiltration and creates a vicious cycle of chronic allergic inflammation. Like other 
forms of allergy immunotherapy, OIT to peanut involves a slow up-dosing of exposure to allergen, 
in this case peanut, over time to desensitize or increase the threshold of reactivity to peanut. Once 
reaching a target level of peanut protein, subjects are continued on a maintenance dose of peanut 
protein to maintain desensitization. Although many subjects on a maintenance dose of peanut 
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protein have demonstrated desensitization to peanut (i.e., the ability to tolerate a level of exposure 
to peanut without an allergic reaction), up to 80% of subjects exhibit related adverse events (AEs) 
during OIT, with 42% experiencing systemic reactions and 49% experiencing gastrointestinal (GI) 
symptoms; the majority of these are mild and decline with prolonged treatment (Virkud, 2016). 
Up to 20% of subjects, however, are unable to complete the up-dosing regimen due to side effects, 
which are primarily GI related. An additional issue with current OIT is its limited ability to induce 
clinical tolerance when subjects are taken off daily peanut intake (Vickery, 2014). In many of the 
studies with peanut OIT, despite years of immunotherapy, subjects never achieve tolerance and 
are re-sensitized within weeks of halting daily peanut intake, with a small percentage (~10%) 
maintaining a sustained unresponsiveness even after 3 months off OIT. 
Dupilumab, a fully human monoclonal antibody directed against IL-4 receptor alpha (IL-4Rα), 
blocks the activity of IL-4 and IL-13. These 2 cytokines are critical to the induction and 
perpetuation of the Type 2 response and have been implicated in multiple atopic diseases. This 
clinical study proposes to examine the effect of dupilumab, a monoclonal antibody, which blocks 
the action of these cytokines, to enhance the safety, tolerability, and efficacy of AR101 in subjects 
with significant allergy to peanuts. 
This study will explore whether dupilumab has the ability to enhance immunomodulatory effects 
of OIT by decreasing Type 2 responses, decreasing production of peanut-specific IgE, which will 
result in improved safety and tolerability of OIT up-dosing as well as improved efficacy as 
determined by the ability to tolerate a higher cumulative dose of peanut protein during a double 
blind, placebo-controlled food challenge (DBPCFC) after 28 weeks of dupilumab therapy 
compared to placebo. The inhibition of IL-4/IL-13 signaling may reduce immune cell activation 
(e.g. eosinophils, Th2 cells). In addition, by blocking IL-4R and B-cell class switching to IgE, the 
decreased production of serum sIgE may reduce the  IgE receptor on basophil and mast cell surface 
over time, thereby preventing the IgE mediated effector cell activation.  In addition, the study will 
evaluate whether dupilumab influences known biomarkers important in the allergic response such 
as a reduction in allergen-specific immunoglobulin class switching to IgE, decrease in basophil 
activation, and decreased Th2 cell activities and the associated cytokine/chemokine levels. A 
maintenance phase where subjects previously treated with dupilumab in the treatment period are 
randomized to continue to receive dupilumab (indefinite [continuously]) with OIT or are re-
randomized to placebo (limited [previously]) with OIT has been included. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
1.2. 
Study Objectives  
1.2.1. 
Primary Objective 
To assess whether dupilumab as adjunct to AR101 compared to placebo as adjunct to AR101 
improves desensitization at the completion of the up-dosing period, defined as an increase in the 
proportion of subjects who pass a post up-dosing DBPCFC at visit 16  
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1.2.2. 
Secondary Objectives 
• To assess whether dupilumab as adjunct to AR101 compared to placebo as adjunct to 
AR101 improves desensitization at the completion of up-dosing, defined as an increase 
in the cumulative tolerated dose (log transformed) of peanut protein during a post up-
dosing DBPCFC at visit 16  
• To assess whether dupilumab as (indefinite [continuously]) adjunct to AR101 
compared to placebo maintains desensitization, defined as an increase in the proportion 
of subjects who pass a post maintenance DBPCFC at visit 22  
• To assess whether dupilumab as (limited [previously]) adjunct to AR101 compared to 
placebo maintains desensitization, defined as an increase in the proportion of subjects 
who pass a post maintenance DBPCFC at visit 22  
• To evaluate the safety and tolerability of dupilumab as adjunct to AR101 compared to 
placebo  
• To assess the effect of dupilumab (compared to placebo) as adjunct to AR101 on the 
change in peanut-specific IgE, IgG, IgG4, peanut-specific IgG4/IgE ratio, and peanut-
specific IgG/IgE ratio 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
Modifications from protocol amendment 4  
• Added that the data will be summarized by treatment groups during pre-dosing period 
of AR101 (4 weeks) separately. 
• Revised the secondary objective “To assess the effect of dupilumab (compared to 
placebo) as adjunct to AR101 on the change in peanut-specific IgE, IgG, IgG4, and 
peanut-specific IgG4/IgE ratio ” as “To assess the effect of dupilumab (compared to 
placebo) as adjunct to AR101 on the change in peanut-specific IgE, IgG, IgG4, peanut-
specific IgG4/IgE ratio and peanut-specific IgG/IgE ratio”. 
• Removed the last secondary objective “To assess if dupilumab increases the tolerability 
of AR101 as measured by the daily symptoms (e-diary) during the up-dosing phase” 
and corresponding secondary endpoints “Proportion of subjects experiencing allergic 
symptoms by treatment group during the up-dosing phase, mean severity score for each 
symptom by treatment during up-dosing phase, maximum severity score for each 
symptom by treatment during up-dosing phase, and difference in mean/median 
duration of symptoms by treatment group during up-dosing phase (all endpoints 
measured by the daily symptom e-diary)” due to the low compliance of the allergy 
symptoms entry in eDiary. Instead, the following exploratory endpoints are added: 
− Proportion of days with one or more of any peanut allergy symptoms excluding 
food challenge test days during the updosing period up to visit 16 
− Proportion of days with one or more severe form of any peanut allergy symptoms 
(i.e. severity score of 7 or more) excluding food challenge test days during the 
updosing period up to visit 16 
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− Proportion of days with one or more symptoms for each symptom category 
excluding food challenge test days during the updosing period up to visit 16 
• The following exploratory endpoints are added as well: 
− Change in the cumulative tolerated dose (log transformed) of peanut protein during 
a DBPCFC from visit 22 to visit 25  
− Proportion of subjects who “pass” a DBPCFC with 2044 mg (cumulative) peanut 
protein at visit 25  
− Change from baseline in total FAQLQ score at visit 16, visit 22 and visit 25 for 
different types of FAQLQ form  
− Proportion of subjects experiencing none, mild, moderate, severe or higher allergic 
symptoms by treatment group during DBPCFCs of peanut protein at visit 16, visit 
22, and visit 25  
− Change and percent change from baseline to visit 16, visit 22 and visit 25 in peanut-
specific IgG 
− Change and percent change from baseline to visit 16, visit 22, and visit 25 in peanut-
specific IgG4 
− Change and percent change from baseline to visit 16, visit 22, and visit 25 in total 
IgE 
− Change from baseline to visit 16, visit 22, and visit 25 in log- transformed peanut-
specific IgG4/ peanut-specific IgE ratio 
− Change from baseline to visit 16, visit 22, and visit 25 in log- transformed peanut-
specific IgG/ peanut-specific IgE ratio 
− Change from baseline to visit 16, visit 22 and visit 25 in peanut-specific IgE 
− Change from baseline to visit 16, visit 22 and visit 25 in log- transformed peanut-
specific IgE/total IgE ratio 
− Change and percent change from baseline to visit 16, visit 22 and visit 25 in Ara h1 
sIgE, Ara h1 sIgG4, Ara h2 sIgE, Ara h2 sIgG4, Ara h3 sIgE, Ara h3 sIgG4 
− Change from baseline to visit 16, visit 22 and visit 25 in log- transformed Ara h1-
specific IgG4/ Ara h1-specific IgE ratio 
− Change from baseline to visit 16, visit 22 and visit 25 in log- transformed Ara h2-
specific IgG4/ Ara h2-specific IgE ratio 
− Change from baseline to visit 16, visit 22 and visit 25 in log- transformed Ara h3-
specific IgG4/ Ara h3-specific IgE ratio 
− Change from baseline to visit 16, visit 22 and visit 25 in Ara h1-specific IgE/ 
peanut-specific IgE ratio 
− Change from baseline to visit 16, visit 22 and visit 25 in Ara h2-specific IgE/ 
peanut-specific IgE ratio 
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− Change from baseline to visit 16, visit 22 and visit 25 in Ara h3-specific IgE/ 
peanut-specific IgE ratio 
− Change and percent change from baseline to visit 16, visit 22 and visit 25 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 visit 16, visit 22 and visit 25 in the 
frequency of peanut-specific T cell subsets (e.g. Th2A cell)   
1.2.4. 
Revision History for SAP Amendments 
NA 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a Phase 2, multicenter, randomized, double-blind, parallel-group, 2-arm study in subjects 
aged 6 to 17 years inclusive who are allergic to peanut. The study consists of a screening period 
of up to 16 weeks, a 28 to 40-week double-blind treatment period, a 24-week maintenance phase, 
and a 12-week post-treatment follow-up period. In protocol amendment 3 to accommodate 
COVID-19 restrictions, double-blind treatment period was extended from 28 weeks to up to 
40 weeks. Subjects who attend optional visits between week 28 and week 40 will have increased 
duration of exposure to AR101 and dupilumab. 
Approximately 156 subjects will be randomized at baseline in a 2:1 ratio into one of 2 treatment 
arms (n=104 to dupilumab and 52 to placebo, in combination with up-dosing of AR101) according 
to a central randomization scheme provided by an IWRS. Randomization will be stratified by 
screening peanut-specific IgE level (≤100 kUA/L or >100 kUA/L) and body weight (<30 kg, ≥30 
kg and <60 kg, or ≥60 kg) at randomization. A minimum of 15 subjects for each weight group will 
be enrolled. 
At visit 16 (or at the early termination visit for those who discontinue from study prior to visit 16), 
subjects previously in the dupilumab plus AR101 arm will be re-randomized in a 1:1 ratio into one 
of 2 treatment arms (dupilumab versus placebo, in combination with AR101), according to a 
central randomization scheme provided by IWRS. Randomization will be stratified by whether 
subjects achieve 300 mg/day AR101 for at least 2 weeks by visit 16 (Yes or No).  
Subjects previously in the placebo plus AR101 arm will continue their treatment of placebo plus 
AR101 in the maintenance phase if they achieve 300 mg/day AR101 for at least 2 weeks at visit 
16. 
2.2. 
Statistical Hypothesis 
The primary efficacy endpoint is the proportion of subjects who achieve a cumulative dose of 2044 
mg peanut protein during a post up-dosing DBPCFC at visit 16. The comparison between the 
dupilumab + AR101 arm and the placebo + AR101 arm will be made. 
Let pD and pP be the true proportions of subjects who achieve a cumulative dose of 2044 mg of 
peanut protein during a post up-dosing DBPCFC at visit 16 in the treatment arms of dupilumab + 
AR101 and placebo + AR101, respectively. The following hypothesis for the superiority testing 
will be tested at the 5% 2-sided significance level for the up-dosing phase: 
H0: pD = pP, i.e., the proportion of subjects who achieve a cumulative dose of 2044 mg peanut 
protein during a DBPCFC at visit 16 is the same between dupilumab + AR101 arm and the placebo 
+ AR101 arm 
against the alternative 
Ha: pD ≠ pP, i.e., the proportion of subjects who achieve a cumulative dose of 2044 mg peanut 
protein during a DBPCFC at visit 16 are different between the dupilumab + AR101 arm and the 
placebo + AR101 arm 
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2.3. 
Sample Size and Power Considerations 
It is assumed that the proportion of subjects who achieve a cumulative dose of 2044 mg of peanut 
protein during a post up-dosing DBPCFC at visit 16 in placebo plus AR101 arm will be 40%, 
based on an Aimmune presentation at the 2018 American Academy of Allergy, Asthma & 
Immunology–World Allergy Organization Joint Congress; with the proportion of subjects in 
dupilumab plus AR101 arm assumed to be 65%, which is considered to be clinical meaningful 
benefit by adding on dupilumab treatment. A sample size of approximately 156 subjects (104 in 
dupilumab plus AR101 and 52 in placebo plus AR101) will have 80% power to detect the treatment 
difference of 25% between placebo plus AR101 and dupilumab plus AR101 at the 2-sided 5% 
significance level (the minimum significant difference is approximately 17.8%). The sample size 
calculations were done by Fisher exact test using nQuery (7.0). 
Approximately 122 subjects who undergo the post up-dosing DBPCFC at Week 28 (visit 16 with 
a window of -7/+30 days) as per protocol or discontinue from study prior to Week 28 (visit 16 
with a window of -7/+30 days) will be included in the primary efficacy analysis. These subjects 
receive AR101 dose escalation per the original protocol’s 24-week up-dosing schedule. The 
minimum significant difference with approximately 122 subjects is approximately 20.7% between 
placebo plus AR101 and dupilumab plus AR101 assuming placebo plus AR101 treatment effect 
is 40% at the 2-sided Fisher exact test with 5% significance level. 
2.4. 
Study Plan 
The study consists of a screening period of up to 16 weeks, a 28 to 40-week double-blind treatment 
period, which includes 4 weeks of pretreatment with dupilumab or placebo followed by 24 to 36 
weeks of treatment with dupilumab or placebo in combination with a gradual up-dosing of AR101, 
a 24-week maintenance phase with 300 mg/day AR101 with concomitant dupilumab or matching 
placebo (for subjects who achieve 300 mg/day AR101 for at least 2 weeks in the up-dosing period), 
and a 12-week post-treatment follow-up period (Figure 1). Subjects who do not achieve 300 
mg/day will still enter the 12-week follow-up. Excluding the screening period, the duration of the 
study is approximately 64 to 76 weeks for subjects who enter the maintenance period, and 40 to 
52 weeks for subjects who do not achieve 300 mg/day AR101 for at least 2 weeks at visit 16 and 
do not enter the maintenance period. 
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Figure 1.  
Schematic of Study Design 
 
 
During screening visit 1 (Day -113 to day -17), subjects will undergo a medical history, physical 
examination, spirometry, a standard peanut skin prick test (SPT), and laboratory testing (including 
peanut sIgE), and will be evaluated for the study eligibility criteria. Subjects must meet all 
eligibility for Screening Visit 1 before proceeding with the DBPCFC in Visit 1a, which will consist 
of 5 doses of peanut or placebo oat protein given every 15 to 30 minutes in increasing amounts up 
to a cumulative total of 144 mg of peanut protein. The doses will be 1, 3, 10, 30 and 100 mg. 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 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 apart. Both food challenge days (placebo and 
peanut) must be done. Subjects will be considered to have tolerated the DBPCFC if they do not 
experience any objective Grade 1 (mild) reaction by the Consortium of Food Allergy Research 
(CoFAR) grading system to the peanut protein ingestion  ≤144 mg (cumulative) or experience any 
symptoms at any dose of placebo and will be excluded from the study. 
Subjects with a history of confirmed peanut allergy who continue to meet eligibility criteria at 
baseline will undergo Day 1/baseline assessments and will be randomized in a 2:1 ratio stratified 
by screening peanut-specific IgE level (≤100 kUA/L or >100 kUA/L) and body weight (<30 kg, 
≥30 kg and <60 kg, or ≥60 kg) at randomization into one of 2 Treatment Arms (104 for dupilumab 
and 52 for placebo). A minimum of 15 subjects for each weight group will be enrolled. 
Dupilumab and placebo will be dosed subcutaneously (SC) as follows based on weight at 
randomization and dose will not be changed regardless of weight gain or loss: 
• subjects weighing <30 kg will receive dupilumab 100 mg every 2 weeks (Q2W) 
following a loading dose of 200 mg or matching placebo Q2W 
Enroll 2-arms (2:1), up-dose AR101 from week 4 to week 28 to 40. Subjects in DUP (dupilumab) +AR101 group will be re-
randomized to DUP+AR101 and PBO (placebo) + AR101, but only those subjects who achieve 300 mg/day AR101 for at 
least 2 weeks will be eligible to enter the 24-week maintenance treatment. Subjects who do not achieve 300 mg/day AR101-
CODIT will enter a 12-week follow-up. 
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• subjects weighing ≥30 kg and <60 kg will receive dupilumab 200 mg Q2W following 
a loading dose of 400 mg or matching placebo Q2W 
• subjects weighing ≥60 kg will receive dupilumab 300 mg Q2W following a loading 
dose of 600 mg or matching placebo Q2W 
After the first 4 weeks, subjects will begin AR101 with an up-dosing regimen to a maximum of 
300 mg/day over the next 24 to 36 weeks of the study, for a total of 28 to 40 weeks (including 
pretreatment) with 28 weeks being ideal and 40 weeks being the maximum. (The flexible up-
dosing period is to accommodate COVID-19 restrictions of in-clinic visits, as well as dose 
reductions and re-escalation, if necessary). Thus, the up-dosing period will consist of 4 weeks 
pretreatment, 22 to 34 weeks of flexible up-dosing, and at least 2 weeks at the maximum dose of 
300 mg/day. During concomitant AR101, study drug will be administered SC at home (at least 24 
hours after in-clinic AR101 dose escalation and at least 8 hours apart from the at-home daily 
AR101 dose). All subjects will go up to visit 15 (Week 26). Visits 15a-f (Week 28 to 38) will be 
optional in order to reach 300mg/day AR101 for a minimum of 2 weeks. Subjects will undergo a 
post up-dosing DBPCFC at visit 16 if they have reached 300 mg/day for at least 2 weeks (on a day 
after the last dose of AR101). Dosing with AR101 should continue on the days between the two 
parts of the DBPCFC. 
Starting on Day 1, subjects will have weight-based dose of placebo or dupilumab Q2W SC for 28 
to 40 weeks. At Week 4, all subjects will be administrated AR101 using a standardized regimen 
of single initial dose escalation day (IDED) from 0.5 mg to a maximum of 6 mg peanut protein 
(12 mg cumulative) over 5 hours in-clinic (home dosing will be 3 mg peanut protein every evening 
for the next 2 weeks until up-dosing) (Table 1) followed by bi-weekly in-clinic up-dosing from 
the highest tolerated initial day dose to a maximum of 300 mg/day at home for 22 to 34 additional 
weeks. If the scheduled bi-weekly up-dosing is not possible, the up-dosing period may be extended 
by up to 12 weeks to accommodate COVID-19 restrictions of in-clinic visits, as well as dose 
reductions and re-escalation, if necessary. Thus, the up-dosing period will end at Week 28 to 40 
(including 4 weeks pretreatment, 22 to 34 weeks of flexible up-dosing, and at least 2 weeks at the 
maximum dose). 
Table 1: 
AR101 Initial Dose Escalation Day at Week 4 
 
Dupilumab/Placebo + AR101 
Week 4 (1 to 5 h) IDED 
Dose of Protein (mg) 
Q30 min 
0.5 
 
1 
 
1.5 
 
3 
 
6 
Cumulative 
12 
Abbreviations: IDED, initial dose escalation day; Q30, every 30 min 
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At visit 16, subjects who achieve 300 mg/day of AR101 for at least 2 weeks will undergo a post 
up-dosing DBPCFC to assess the level of peanut sensitivity. And all dupilumab group subjects 
will be re-randomized 1:1 to placebo or dupilumab. Only subjects from either treatment group who 
achieve 300 mg/day AR101 at visit 16  will be eligible to enter the maintenance phase, in which 
subjects will continue to receive AR101 300 mg/day for 24 weeks. Subjects who do not achieve 
300 mg/day AR101 for at least 2 weeks will enter a 12-week follow-up period. In the analysis, 
subjects not achieving 300mg for a least 2 weeks are considered as the non-responders in 
DBPCFC. Placebo group subjects will continue to receive placebo in the maintenance phase. At 
visit 22, subjects will undergo a DBPCFC to access the level of peanut sensitivity at the end of 
maintenance period.  
The post up-dosing and post maintenance DBPCFCs will consist of 8 doses (peanut or placebo) 
given every 15 to 30 minutes: 1, 3, 10, 100, 300, 600, 1000 mg resulting in a total challenge of up 
to 2044 mg.  
All subjects will have a 12-week follow-up period after the end of treatment and will undergo 
safety, laboratory, and clinical assessments. At the end of the 12-week follow-up period, subjects 
who passed a 444 mg (cumulative) peanut protein DBPCFC at visit 22 (end of maintenance period, 
Week 52 to 64) will be eligible to undergo a final DBPCFC (up to 2044 mg cumulative) under 
intensive monitoring, at visit 25 (end of study, Week 64 to 76) to assess the level of peanut 
sensitivity after 12 weeks off peanut and dupilumab to determine whether there is evidence of 
persistent effects and sustained unresponsiveness. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis: 
3.1. 
The Full Analysis Set (FAS) 
FAS includes all randomized subjects. Efficacy analyses will be based on the treatment allocated 
by the IWRS at randomization (as randomized).  
The modified full analysis set (mFAS) includes all FAS subjects who undergo bi-weekly in-clinic 
up-dosing as described/specified in the protocol and undergo the post up-dosing DBPCFC at Visit 
16/Week 28 (a window of -7/+30 days).  
The mFAS will be considered as primary analysis set for all efficacy endpoints. The FAS will also 
be done for all efficacy endpoints as supportive analyses. 
FAS-maintenance is a subset of FAS and includes subjects in the FAS who achieve 300 mg/day 
AR101 for at least 2 weeks in the up-dosing phase and re-randomized based on the treatment 
allocated by the IWRS at visit 16. The FAS-maintenance is the primary analysis set for efficacy 
analyses at visit 22. 
3.2. 
The Per Protocol Set (PPS) 
PPS includes all subjects in the mFAS except for those who are excluded because of important 
protocol violations. An important protocol violation is one that may affect the interpretation of 
study efficacy results.  A preliminary list of such important protocol violations is provided in 
Section 10.6 and a final list of subjects excluded from FAS will be generated prior to primary 
analysis database lock. Final determinations of the PPS will be made in the blinded manner before 
data base lock. 
The primary endpoint and first secondary endpoint will be evaluated on the PPS in addition to 
mFAS and FAS.  
3.3. 
The Safety Analysis Set (SAF) 
SAF includes all randomized subjects who receive at least one injection of dupilumab/placebo and 
be analyzed as treated. Treatment assignment will be based on the actual treatment received not 
the treatment assigned by IWRS randomization. Treatment compliance/administration for 
investigational product including both dupilumab/placebo and AR101, as well as all clinical safety 
variables will be summarized based on SAF.  
For the safety analyses during the maintenance period, a subset of SAF which is defined as SAF-
maintenance includes re-randomized subjects at visit 16 who received at least one injection of 
dupilumab/placebo during the maintenance period. Treatment compliance/administration for 
investigational product and all clinical safety variables during maintenance period will be 
summarized based on SAF-maintenance. 
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The actual treatment group as treated is defined by the following rule: 
• For a subject randomized to dupilumab Q2W (any dose level), if the subject received 
all placebo injections, the actual treatment will be assigned as placebo. 
• Regardless of the treatment group a subject is randomized to, if the subject received at 
least 1 dupilumab injection, the actual treatment will be assigned as dupilumab Q2W 
(any dose level). 
For safety summaries, the analysis periods are defined as follows: 
• Pre-dosing period (4 weeks) is defined as:  
− Day 1 to the day before the date of AR101 IDED in the up-dosing period if subjects 
completed the IDED at Week 4 
− Day 1 to early termination (ET) visit date before Week 4 if subjects early terminated 
from the pre-dosing period 
• Up-dosing period (24 to 36 weeks) is defined as: 
− For subjects who entered maintenance period: The date of AR101 IDED to the date 
of second post up-dosing DBPCFC at visit 16.  
− For subjects who did not enter maintenance period: 
▪ The date of AR101 IDED at Week 4 to the date of visit 16  if subjects 
entered follow-up period 
▪ The date of AR101 IDED at Week 4 to the last dose date of 
dupilumab/placebo + 14 days if subjects completed dosing to visit 16  but 
did not enter follow-up period 
▪ The date of AR101 IDED at Week 4 to early termination (ET) visit date 
before visit 16  if subjects did not complete dosing to visit 16  
• Maintenance period (24 weeks) for subjects who entered maintenance period is 
defined as: 
− The day after the date of second post up-dosing DBPCFC at visit 16  to the date of 
second post maintenance DBPCFC at visit 22 if subjects completed the visit 22  
with known visit date 
− The day after the date of second post up-dosing DBPCFC at visit 16 to study day 
365 (52 weeks times 7 days/week + 1 day) if subjects had missing visit 22  date 
− The day after the date of second post up-dosing DBPCFC at visit 16 to ET visit date 
before visit 22 if subjects early terminated from maintenance period 
• Follow-up period (12 weeks) for subjects who entered follow-up period is defined as: 
− For subjects who completed maintenance period: The day after the date of second 
post maintenance DBPCFC at visit 22 to the subject end of study visit date or the 
date of second end of study DBPCFC at visit 25, whichever comes later 
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− For subjects who did not receive 300 mg/day of AR101 for at least two weeks by 
visit 16 : The day after the visit 16 date  to the subject end of study visit date  
− For subjects who early terminated from study treatment in the up-dosing period or 
maintenance period: The day after the last visit date in the treatment period to the 
subject end of study visit date 
• Overall study period is defined as Day 1 to the date of end of study visit. 
The SAF and SAF-maintenance will be the basis for the analyses of the pre-dosing/up-dosing 
period and maintenance period, respectively; however, for the analyses of the follow-up period, 
only a subset of the corresponding safety analysis sets will be included, which is defined as the 
subjects who entered the follow-up period from pre-dosing/up-dosing period and had at least one 
visit after visit 16 (for SAF) or subjects who entered the follow-up period from maintenance period 
and had at least one visit after visit 22 (for SAF-maintenance). 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set includes all treated subjects who received any study drug and 
who had at least one non-missing drug concentration result following the first dose of study drug.  
3.5. 
The Immunogenicity Analysis Sets 
The ADA analysis set (AAS) includes all treated subjects who received any study drug and who 
had at least one non-missing ADA result in the dupilumab ADA assay after first dose of the study 
drug. Subjects will be analyzed according to the treatment actually received. 
The neutralizing antibody (NAb) Analysis Set (NAS) includes all treated subjects who received 
any study drug and who are negative in the dupilumab ADA assay or with at least 1 non-missing 
result in the dupilumab NAb assay. Subjects who are negative in the ADA assay are set to negative 
in the NAb analysis set. Subjects will be analyzed according to the treatment actually received. 
3.6. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as the follows.  
Subgroups to be considered for both efficacy and safety analyses: 
• Age group (>=6 to <12 years, >=12 to <=17 years) 
• Sex (Male, Female) 
• Baseline weight group (<30 kg, ≥30-<60 kg, ≥60 kg) 
• Screening peanut-specific IgE level (≤100 kUA/L or >100 kUA/L) 
• Asthma and non-asthma history for primary and key secondary efficacy 
endpoint only 
•  AD and non-AD history for primary and key secondary efficacy endpoint only 
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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 or Latino, Not Hispanic or Latino) 
− Baseline weight (kg) 
− Baseline weight category (<30 kg, ≥30 kg and <60 kg, ≥ 60 kg) 
− Baseline height (m) 
− Baseline Body Mass Index (BMI) (kg/m2) 
• Baseline characteristics 
− 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 
− History of atopic dermatitis (Yes, No) 
− Duration of atopic dermatitis disease with grouping (year; <=1 and >1) 
− Eczema Area and Severity Index (EASI) score for subjects with atopic dermatitis 
− History of asthma (Yes, No) 
− Asthma Control Questionnaire (ACQ-5) score for subjects with asthma 
− 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 IgG4/sIgE ratio 
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− 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 (%) 
− 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 subject'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 subject'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) at the coding CRO. Subjects 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 dupilumab/placebo. 
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Concomitant medications/procedures (CMs/CPs): medications taken or procedures performed 
following the first dose of dupilumab/placebo through the EOS visit. This includes 
medications/procedures that were started before the study and are ongoing during the study. 
Furthermore, CM/CP will be categorized according to analysis periods (as defined in Section 3.3): 
• CMs/CPs taken during the pre-dosing period 
• CMs/CPs taken during the up-dosing period 
• CMs/CPs taken during the maintenance period 
• CMs/CPs taken during the follow-up period 
4.4. 
Prohibited or Rescue Medication/Procedure 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 immunomodulating biologic agents, including anti-IgE and anti-IL-5 
• Treatment with allergen immunotherapy other than AR101 
• 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 corticosteroids 
• 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  
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Treatment of acute-allergic reactions will be categorized as follows, 
• Screening DBPCFC of peanut protein 
• Post up-dosing DBPCFC of peanut protein 
• Post maintenance DBPCFC of peanut protein 
• End of study DBPCFC of peanut protein 
• Pre-dosing/up-dosing period (excluding post up-dosing DBPCFC) 
• Maintenance period (excluding post maintenance DBPCFC) 
Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency and the potential 
impact of the use of the prohibited medication or procedure. The rescue treatments will be 
adjudicated by the clinical study director and the adjudication procedure will be documented. 
4.5. 
Efficacy Variable 
4.5.1. 
Primary Efficacy Variable (s) 
The primary endpoint in this study is: 
• Proportion of subjects treated with dupilumab plus AR101 vs placebo plus AR101 who 
“pass” a post up-dosing DBPCFC with 2044 mg (cumulative) peanut protein at visit 16 
Double-blind placebo-controlled food challenge (DBPCFC) 
At visit 16, under intensive monitoring, all subjects who achieve 300 mg/day AR101 during the 
up-dosing phase for at least 2 weeks will undergo a post up-dosing DBPCFC up to 2044 mg 
(cumulative) peanut protein or placebo to assess desensitization. At visit 22, all subjects who 
maintain 300 mg/day AR101 will undergo a post maintenance DBPCFC up to 2044 (cumulative) 
peanut protein or placebo to assess desensitization. The subject’s sensitivity to peanut allergen is 
defined as the dose at which the subject experiences allergic reactions. All symptoms and signs 
will be evaluated and rated based on a standardized oral food challenge scoring system (CoFAR). 
Up-dosing during the DBPCFC will be stopped when the principal investigator (or designee) finds 
symptoms and/or signs that indicate a definite objective (Grade 1 [mild]) allergic reaction (CoFAR 
grading system) has occurred based on clinically significant changes in reported symptoms, 
physical findings, or vital signs that the subject is experiencing to the challenge material. Vital 
signs will be assessed every 15 to 30 minutes. In addition, subjects will be considered to have 
dose-limiting reactions if they experience any mild subjective reactions requiring pharmacologic 
intervention and/or any moderate/severe reaction.  
The DBPCFC will consist of 8 doses (peanut protein 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 challenge 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. Subjects will be considered to have passed the DBPCFC if they do not experience any 
objective Grade 1 (mild) reaction by CoFAR grading system. If the subject experiences reactions, 
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he/she will be treated with the necessary rescue medications. In addition, subjects will be 
considered to have passed the DBPCFC if they do not experience any mild subjective symptoms 
requiring pharmacological intervention and/or moderate or severe symptoms. He/she will be 
observed for a minimum of 2 hours after the final administered dose and discharged only when 
deemed clinically stable by study physician. Symptom severity will be adjudicated by an 
independent, blinded assessor who is not involved in performing the baseline food challenge. 
When dosing elicits an acute reaction characterized by the appearance of only a mild subjective 
symptom or symptoms, the investigator will be required to assess whether the dose was or was not 
tolerated. 
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 subject 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 are: 
• Change in cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 16 in subjects treated with dupilumab plus AR101 vs 
placebo plus AR101 
Note: Due to the positive skew for the distribution of the “cumulative amount of peanut protein”, 
a log transformation will be applied to reduce the skewness 
• Proportion of subjects treated with dupilumab plus AR101 vs placebo plus AR101 who 
reach the 300 mg/day dose of AR101 by visit 16 
• Time from randomization to the first-time when subjects reach the 300 mg/day dose of 
AR101 during the treatment phase (up to visit 16) 
• Proportion of subjects (continuously) treated with dupilumab plus AR101 vs placebo 
plus AR101 who “pass” a post maintenance DBPCFC with 2044 mg (cumulative) 
peanut protein at visit 22  
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (continuously) treated with dupilumab 
plus AR101 vs placebo plus AR101 
• Proportion of subject (previously) treated with dupilumab plus AR101 (and 
re-randomized to placebo plus AR101) vs placebo plus AR101 who “pass” a post 
maintenance DBPCFC with 2044 mg (cumulative) peanut protein at visit 22 
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (previously) treated with dupilumab plus 
AR101 (and re-randomized to placebo plus AR101) vs placebo plus AR101 
• Percent change from baseline to visit 16 in peanut-specific IgE in subjects treated with 
dupilumab plus AR101 vs subjects treated with placebo plus AR101 
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• Percent change from baseline to visit 22 in peanut-specific IgE in subjects 
(continuously) treated with dupilumab plus AR101 vs subjects treated with placebo 
plus AR101 
• Percent change from baseline to the end of study visit 25 in peanut-specific IgE in 
subjects (continuously) treated with dupilumab plus AR101 vs subjects treated with 
placebo plus AR101 
4.5.3. 
Exploratory Efficacy Variable (s) 
Exploratory efficacy endpoints include: 
• Proportion of subjects who “pass” an end of study DBPCFC with 2044 mg 
(cumulative) peanut protein at visit 25 
• Change from baseline in total FAQLQ score at visit 16, visit 22, and visit 25 for 
different types of FAQLQ form 
• Proportion of subjects experiencing none, mild, moderate, severe or higher allergic 
symptoms by treatment group during DBPCFCs of peanut protein at visit 16 and visit 
22  
• Change and percent change from baseline to visit 16, visit 22 and visit 25 in peanut-
specific IgG 
• Change and percent change from baseline to visit 16, visit 22 and visit 25 in peanut-
specific IgG4 
• Change and percent change from baseline to visit 16, visit 22 and visit 25 in total IgE 
• Change from baseline to visit 16, visit 22 and visit 25 in log- transformed peanut-
specific IgG4/ peanut-specific IgE ratio 
• Change from baseline to visit 16, visit 22 and visit 25 in log- transformed peanut-
specific IgG/ peanut-specific IgE ratio 
• Change from baseline to visit 16, visit 22 and visit 25 in peanut-specific IgE 
• Change from baseline to visit 16, visit 22 and visit 25 in log- transformed peanut-
specific IgE/total IgE ratio 
• Change and percent change from baseline to visit 16, visit 22 and visit 25 in Ara h1 
sIgE, Ara h1 sIgG4, Ara h2 sIgE, Ara h2 sIgG4, Ara h3 sIgE, Ara h3 sIgG4 
• Change from baseline to visit 16, visit 22 and visit 25 in log- transformed Ara h1-
specific IgG4/ Ara h1-specific IgE ratio 
• Change from baseline to visit 16, visit 22 and visit 25 in log- transformed Ara h2-
specific IgG4/ Ara h2-specific IgE ratio 
• Change from baseline to visit 16, visit 22 and visit 25 in log- transformed Ara h3-
specific IgG4/ Ara h3-specific IgE ratio 
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• Change from baseline to visit 16, visit 22 and visit 25 in Ara h1-specific IgE/ peanut-
specific IgE ratio 
• Change from baseline to visit 16, visit 22 and visit 25 in Ara h2-specific IgE/ peanut-
specific IgE ratio 
• Change from baseline to visit 16, visit 22 and visit 25 in Ara h3-specific IgE/ peanut-
specific IgE ratio 
• Change and percent change from baseline to visit 16, visit 22 and visit 25 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 visit 16, visit 22 and visit 25 in the 
frequency of peanut-specific T cell subsets (e.g. Th2A cell)   
• Proportion of days with one or more of any peanut allergy symptoms excluding food 
challenge test days during the up-dosing period up to visit 16 
• Proportion of days with one or more severe form of any peanut allergy symptoms 
(i.e. severity score of 7 or more) excluding food challenge test days during the up-
dosing period up to visit 16 
• Proportion of days with one or more peanut allergy symptoms for each symptom 
category excluding food challenge test days during the up-dosing period up to visit 16 
Eczema Area and Severity Index (EASI) 
The EASI is a validated measure used in clinical practice and clinical trials to assess the severity 
and extent of AD. The EASI is a composite index with scores ranging from 0 to 72. Four Atopic 
Dermatitis (AD) disease characteristics [erythema (E), thickness (induration, papulation, edema) 
(L), scratching (excoriation) (X), and lichenification (L)] will each be assessed for severity by the 
investigator or designee on a scale of “0” (absent) through “3” (severe). In addition, the area of 
AD involvement will be assessed as a percentage by body area of head, trunk, upper limbs, and 
lower limbs, and converted to a score of 0 to 6. In each body region, the area is expressed as 0, 1 
(1% to 9%), 2 (10% to 29%), 3 (30% to 49%), 4 (50% to 69%), 5 (70% to 89%), or 6 (90% to 
100%).  
For each of major section of the body (head, upper extremities, trunk and lower extremities), EASI 
score = (E+I+X+L) ×Area Score. The EASI score is the weighted total of the section EASI using 
the weights. For subjects of age ≥8 years, the weights are 10% = head, 20% = upper extremities, 
30% = trunk, 40% = lower extremities. For subjects of age <8 years, the weights are 20% = head, 
20% = upper extremities, 30% = trunk, 30% = lower extremities.   
Asthma Control Questionnaire 
The Asthma Control Questionnaire (ACQ) is a validated questionnaire to evaluate asthma control. 
The questionnaire will be administered only to the subset of subjects with a medical history of 
asthma and who fluently speak a language in which the questionnaire is presented (based on 
availability of validated translations in participating countries). The ACQ-5 is for subjects aged 11 
years or more and the ACQ-interviewer administered (IA) is for subjects who aged 6 to 10 years. 
The ACQ has been fully validated for all children 6-17 years when the self-administered adult 
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version is used by children 11 years and older and the interviewer-administered version is used for 
children 6-10 years. Subjects will continue using the ACQ version first administered at screening 
regardless of moving to next age bracket.  
The ACQ-IA consists of 7 questions in which the first 5 questions assess the most common 
asthma symptoms:  
1. Frequency in the past week awoken by asthma during the night 
2. Severity of asthma symptoms in the morning 
3. Limitation of daily activities due to asthma 
4. Shortness of breath due to asthma 
5. Wheeze  
6. Short-acting bronchodilator use 
7. FEV1 (pre-bronchodilator % predicted) 
The response options for all these questions consists of a 0 (no impairment/limitation) to 6 (total 
impairment/limitation) scale.  
The ACQ-5 consists of 5 questions which are the same with the first 5 questions of ACQ-IA. The 
ACQ-5 score is a mean of values recorded for the individual questions. The answer to the first 5 
questions of ACQ-IA will be used to calculate an ACQ-5 score for the analysis of the ACQ-5 
endpoint.  
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 subjects. 
Subjects 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 subjects aged 8 to 12 years and 
the teenager form (FAQLQ-TF) is used for subjects aged 13 to 17. 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 subjects of ages 0 to 12 years. The FAQLQ will be administered to subject and, 
when appropriate, parents at time points in accordance with Table 2 and Table 3. Subjects 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. The total score is the arithmetic average of all non-missing 
answers.  
Daily allergy symptom 
The daily allergy symptom diary is a questionnaire that was designed to capture the daily signs 
and symptoms of peanut OIT. In addition to daily allergy symptoms, the e-diary will also collect 
data on dupilumab injections, peanut OIT dosing, use of medications to treat symptoms of peanut 
OIT. 
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Daily allergy symptom in the peanut symptoms daily e-diary includes, dizziness (spinning feeling), 
rash (red, itchy, bumpy skin), eye swelling (eye puffiness), lip swelling (lip puffiness), swelling in 
your throat (throat feeling like it is tight or closing), nausea (feeling like you might throw up), 
vomiting (throwing up), diarrhea (runny, loose, watery poop), runny or stuffy nose, sneezing, 
stomach pain, itching in and around your mouth (lips, tongue), itching in your throat, skin itching, 
eye itching (itching around the eye or eyelid), trouble breathing, wheezing (noisy, squeaky 
breathing), coughing, pain in your tongue or mouth, pain in your throat, tongue swelling (tongue 
puffiness), itching in or around your nose, hive(s) (lumps on skin). Subjects may experience none 
of the symptoms, any symptom or all symptoms. The severity of each symptom will be rated on a 
scale of 1-10.   
Symptom categories to be generated as follows:  
1. Gastro-Intestinal (GI) 
2. Swelling 
3. Itching 
4. Airway symptoms 
5. Rash/hives 
6. Dizziness 
Symptom 
Symptom category 
Dizziness 
Dizziness 
Rash 
Rash/hives 
Eye Swelling 
Swelling 
Lip Swelling 
Swelling 
Swelling in throat 
Swelling 
Nausea 
GI 
Vomiting 
GI 
Diarrhea 
GI 
Runny or stuffy nose 
Airway 
Sneezing 
Airway 
Stomach pain 
GI 
Itching in or around your mouth 
Itching 
Itching in your throat 
Itching 
Skin itching 
Itching 
Eye itching 
Itching 
Trouble breathing 
Airway 
Wheezing 
Airway 
Coughing 
Airway 
Pain in your tongue or mouth 
GI 
Pain in your throat 
GI 
Tongue swelling 
Swelling 
Itching in or around your nose 
Itching 
Hives (lumps on skin) 
Rash/hives 
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The proportion of days with one or more of any peanut allergy symptoms excluding food challenge 
test days during the up-dosing period for each patient is calculated using the follow 2 methods: 
1. Number of days with symptoms / number of days of the treatment duration of the up-
dosing period 
2. Number of days with symptoms / number of Days with non-missing eDiary data in the 
up-dosing period 
The proportion of days with one or more severe form of any peanut allergy symptoms (i.e. severity 
score of 7 or more) excluding food challenge test days and the proportion of days with one or more 
symptoms for each symptom category excluding food challenge test days will be calculated 
similarly. 
4.6. 
Safety Variables 
4.6.1. 
Adverse Events and Serious Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a subject administered a study 
drug, which may or may not have a causal relationship with the study drug. Therefore, an AE is 
any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or 
disease, which is temporally associated with the use of a study drug, whether or not considered 
related to the study drug.  
An AE also includes any worsening (i.e., any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
A Serious Adverse Event is any untoward medical occurrence that at any dose results in death; 
is life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; 
results in persistent or significant disability/ incapacity; is a congenital anomaly/ birth defect; or is 
an important medical event. 
Adverse events and serious adverse events will be collected from the time of informed 
consent/assent is signed until the end of the study. However, allergic reactions to the DBPCFC 
during the Screening phase, at endpoint challenges (at visits 16, 22, and 25), during AR101 in-
clinic dosing visits, and daily home dosing will be recorded as allergic signs and symptoms since 
they are anticipated to allergen challenge.  
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). 
Abnormal laboratory or vital signs will be graded according to the FDA September 2007. 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 
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• 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 
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 4-week pre-dosing 
treatment period, the 24 to 36-week up-dosing treatment period, the 24-week 
maintenance treatment period, and the follow-up period. 
The pre-treatment AE and treatment-emergent AE (TEAE) is 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-emergent period. 
4.6.2. 
Adverse Events of Special Interest 
Adverse event of special interest (AESI) for dupilumab in this study category includes: 
• Anaphylactic reactions  
• Systemic or severe hypersensitivity reactions  
• Helminthic infections 
• 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) 
Adverse events of special interest for AR101 in this study include: 
• Anaphylactic reactions 
• Gastrointestinal AEs resulting in prolonged disruption of dosing 
 Section 10.4 provides a list of AESIs search criteria. 
Anaphylactic reactions: Anaphylaxis is defined as 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.  
Gastrointestinal adverse events and disruption of dosing: At each study visit, the site must solicit 
specific symptoms from subjects that may indicate the development of EoE. These include 
symptoms of both advanced and early disease such as food impaction, dysphagia, and choking or 
gagging with meals, gastroesophageal reflux, nausea, vomiting, and abdominal pain. Prolonged 
disruption of dosing is defined as withholding AR101 for >7 consecutive days and is an individual 
stopping rule that results in permanent discontinuation of dosing.  
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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: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total bilirubin 
Potassium 
Creatinine 
Total cholesterol* 
Chloride 
Blood urea nitrogen (BUN) 
Triglycerides 
Carbon dioxide 
Aspartate aminotransferase (AST) 
Uric acid 
Calcium 
Alanine aminotransferase (ALT) 
Creatine phosphokinase (CPK) 
Glucose 
Alkaline phosphatase 
 
Albumin 
Lactate dehydrogenase (LDH) 
 
* Low-density lipoprotein [LDL] and high-density lipoprotein [HDL] 
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 subjects 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 
Vital signs, including temperature, sitting blood pressure, pulse, and respiration rate will be 
collected pre-dose at screening visit 1, screening visit 1a, every scheduled visit and the 
unscheduled visit or ET visit. During the DBPCFC, IDE and up-dosing, vital signs will be 
monitored every 15 to 30 minutes. For post-dose monitoring, 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 scheduled 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 the screening visits (visit 1 and visit 1a), 
visit 16, visit 22  and visit 25  or ET visits. 
4.6.7. 
Spirometry 
A spirometer that meets the 2005 American Thoracic Society/European Respiratory Society 
recommendations will be used to measure FEV1 and/or PEF. During DBPCFC, spirometry should 
be performed before and after the challenge.  
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 (Cthrough.time point). 
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 in the 
ADA analysis set. 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 
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• 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) 
4.9. 
Pharmacodynamic and Biomarkers Variables  
Pharmacodynamic and biomarker variables are: 
• Serum total IgE 
• Serum peanut-specific antibody assays (IgE, IgG, IgG4 against peanut extract and 
peanut protein allergen components) 
• Fractional Exhaled Nitric Oxide (FeNO) 
• Basophil Sensitivity Test (optional) 
• Peanut-reactive Th2A cells (optional) 
Biomarker samples will be collected at time points according to according to Section 10.2. 
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4.10. 
Pediatric Eosinophilic Esophagitis Symptom Score Questionnaire 
The Pediatric Eosinophilic Esophagitis (EoE) Symptom Score PEESS v2.0 measures subject-
relevant outcomes. The PEESS v2.0 holds promise for being a valuable tool to follow the clinical 
course of EoE or an EoE-like immune-mediated GI syndrome. However, it was not designed to 
establish a diagnosis of EoE and has not been validated for use in subjects with GI symptoms of 
other etiologies. Furthermore, the discriminant validity of the questionnaire has not been reported 
in either longitudinal natural history or interventional studies. For these reasons, the use of the 
PEESS v2.0 to monitor the clinical course of GI symptoms must be considered exploratory.  
Subjects that discontinue because of GI AEs will be asked to complete the PEESS v2.0 
questionnaire, with the assistance of a parent or guardian, as appropriate, every month for 
6 months. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of subjects 
reflected in the calculation (n), mean, standard deviation, median, first quartile (Q1), third quartile 
(Q3), minimum, and maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
All data will be summarized by the following treatment groups in each period: 
1. Double-blind treatment period before dosing with AR101 (4 weeks) 
• Dupilumab 
• Placebo 
2. Double-blind treatment period with up-dosing of AR101 (24 to 36 weeks): 
• Dupilumab + AR101 
• Placebo + AR101 
3. Double-blind maintenance period of AR101 (24 weeks): 
• Continuously on placebo+ AR101 
• Previously on dupilumab + AR101 and re-randomized to placebo + AR101 
(dupilumab + AR101/placebo + AR101) 
• Continuously on dupilumab + AR101 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group for mFAS, FAS 
and SAF. They will be summarized by treatment group for FAS-maintenance and SAF-
maintenance for subjects who entered maintenance period. Listing of demographics and baseline 
characteristics will be presented. 
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT for each treatment group based on 
SAF. The table will be sorted by decreasing frequency of SOC followed by PT based on the overall 
incidence across treatment groups. Medical history will be listed, sorted by treatment groups 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 subjects taking prior/concomitant medications, prohibited medications 
and rescue medications will be summarized for each treatment group and study total based on the 
SAF and SAF-maintenance 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 for the combined treatment groups 
for each study period.  
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Number and proportion of subjects taking prior/concomitant procedures will be summarized for 
each treatment group and study total based on the SAF and SAF-maintenance, sorted by decreasing 
frequency of SOC and PT based on the overall incidence for the combined treatment groups for 
each study period.  
In addition, the summary of prior/concomitant medications/procedures will be performed for 
subjects who were impacted by COVID-19 pandemic and not impacted by COVID-19 pandemic 
in each study period, respectively. The summary will be performed for pre-, during, and post-
COVID-19 periods for subjects impacted by COVID-19, if applicable. 
Number and proportion of subjects taking at least one epinephrine and short-term use of systemic 
corticosteroids for treatment of acute-allergic reactions will be summarized during the following 
periods, 
• Screening DBPCFCs of peanut protein 
• Week 4 IDED 
• Post up-dosing DBPCFCs of peanut protein 
• Post maintenance DBPCFCs of peanut protein 
• End of study DBPCFCs of peanut protein 
The number of episodes of epinephrine use and short-term use of systemic corticosteroids during 
up-dosing period (excluding post up-dosing DBPCFCs) and during maintenance period (excluding 
post maintenance DBPCFCs) will be summarized, respectively.  
Kaplan-Meier curves for time to first rescue treatment use will be created for each study period. 
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. 
Subject Disposition 
The following summaries by table will be provided: 
• The total number of screened subjects and the screen failure reasons: met the inclusion 
criteria regarding the target indication and signed the informed consent form (ICF) 
• The total number of randomized subjects in each study treatment period: received a 
randomization number from IWRS 
• The total number of subjects in each analysis set 
• The total number of subjects who discontinued the study and the reasons for 
discontinuation (including COVID-19 related reasons) 
• The total number of subjects who discontinued the study in each study treatment period 
and the reasons for discontinuation (including COVID-19 related reasons) 
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• The total number of subjects who discontinued the study treatment in each study 
treatment period and the reasons for discontinuation (including COVID-19 related 
reasons) 
• A summary table of protocol deviations 
The following listings will be provided: 
• Listing of subjects disposition including: date of randomization, date of first 
dupilumab/placebo injection, date of re-randomization, date of the last visit, completed 
study or discontinued by reason 
• A listing of subjects randomized but not treated, treated but not randomized, and 
subjects randomized but not treated as randomized, if applicable 
• A listing of subjects prematurely discontinued from the study treatment, along with 
reasons for discontinuation in each study period 
• A listing of protocol deviations will be provided 
Kaplan-Meier curve for time to withdraw from the study and from the study treatment in each 
study treatment period will be created, respectively. 
5.5. 
Extent of Study Treatment Exposure  
5.5.1. 
Measurement of Compliance 
The compliance with study treatment will be calculated separately for dupilumab/placebo injection 
and AR101 oral home dosing for each study period as follows: 
Treatment compliance of dupilumab or placebo = (Number of dupilumab/placebo 
injections during exposure period) / (Number of planned dupilumab/placebo injections 
during exposure period) x 100%;  
For treatment compliance calculation of dupilumab/placebo injection, the two injections including 
one loading dose at the randomization visit 2 will be counted as 1 injection.  
Treatment compliance of home dosing AR101 = (total actual peanut dose protein [mg] 
received during exposure period) / (total of planned dose peanut protein [mg] during 
exposure period) x 100%. 
The treatment compliance will be presented by the following specific ranges for each treatment 
group: <80%, and ≥80%. 
Listing of dupilumab/placebo 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. 
Listing of AR101 compliance for home dosing will be presented with AR101 dose date/time, study 
day, AR101 assigned dose, whether or not the full dose was taken, amount taken for partial dose, 
reasons for partial or missed AR101 dose. 
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5.5.2. 
Exposure to Investigational Product  
The duration of exposure to Dupilumab/Placebo in day will be presented by treatment group for 
each study period and calculated as: 
(Date of last dupilumab/placebo injection in the respective study period – date of first study 
drug injection) + 14 days 
The duration of exposure to AR101 in day for each study period will be calculated as: 
 (Date of last AR101 taken in the respective study period – date of first AR101 taken) + 1 day 
Note: the calculations are regardless of temporary dosing interruption.  
Summary of exposure to study drug will include the number of study drug doses administered and 
duration of exposure. The duration of exposure to dupilumab/placebo and AR101 during the study 
will be summarized by treatment group using number of subjects, mean, SD, minimum, Q1, 
median, Q3, and maximum. These summaries will be provided for each study period separately.  
In addition, the duration of exposure to study drug will be summarized categorically by counts and 
percentages for each of the following categories and cumulatively by these categories as well: ≥ 14 
days,  ≥ 28 days, ≥ 42 days, ≥ 56 days, ≥ 70 days,  ≥ 84 days, ≥ 98 days, ≥ 112 days, ≥ 126 days, 
≥ 140 days, ≥ 154 days, ≥ 168 days, ≥ 182 days, ≥ 196 days, ≥ 210 days , ≥ 224 days, ≥ 238 days, 
≥ 252 days,  ≥ 266 days,  ≥ 280 days, ≥ 294 days, ≥ 308 days, ≥ 322 days, ≥ 336 days, ≥ 350 days, 
and ≥ 364 days. 
The duration of observation period during the study in day is calculated as: 
(Date of the last visit – date of the first study drug injection) +1 day. 
The duration of observation period will be summarized descriptively using number of subjects, 
mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of subjects 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, ≥ 169 days, ≥ 183 days, ≥ 197 days, ≥ 225 
days, ≥ 239 days, ≥ 253 days, ≥ 267 days, ≥ 281 days, ≥ 295 days, ≥ 309 days, ≥ 323 days, ≥ 337 
days, ≥ 351 days, ≥ 365 days, ≥ 379 days, ≥ 393 days, ≥ 407 days, ≥ 421 days, ≥ 435 days, and ≥ 
449 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. 
5.6. 
Analyses of Efficacy Variables 
The primary efficacy analyses for all the efficacy endpoints will be conducted at Week 28 (visit 
16 with a window of -7/+30 days) using the mFAS population. As supportive evidence, the same 
analysis approach will be repeated with the FAS population at visit 16. The efficacy analyses at 
visit 22  will be based on the FAS-maintenance population. The analyses of efficacy variables are 
described in the subsections below and summarized in Section 10.1.  
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5.6.1. 
Analysis of Primary Efficacy Variable 
This primary endpoint will be analyzed using the Cochran-Mantel-Haenszel (CMH) test adjusted 
by randomization stratification factors (screening peanut-specific IgE level [≤100 kUA/L or 
>100 kUA/L] and baseline body weight [<30 kg, ≥30 kg and <60 kg, or ≥60 kg]) to assess the 
treatment difference in the proportion of responders (i.e., those who “pass” a post up-dosing 
DBPCFC with 2044 mg [cumulative] peanut protein at visit 16 [Week 28 with a visit window of -
7/+30 days]) in the mFAS.. Estimate of treatment difference, p-value, and the 2-sided 95% 
confidence interval using CMH test will be provided. The number and percent of subjects at each 
dose level for highest tolerated peanut protein dose at post up-dosing DBPCFC will also be 
summarized. 
The primary estimand of interest for the primary endpoint is described as follows, based on 
intercurrent event(s) strategy and missing data handling methods: 
• The treatment policy strategy will be implemented for the intercurrent event of the 
treatment discontinuation. The data collected after the patient discontinued treatment 
will be included in the analysis. 
• Missing data for post up-dosing DBPCFC at visit 16 will be handled according to the 
reason for missingness as follows: 
− If a subject misses the post up-dosing DBPCFC at visit 16 due to COVID-19, the 
missing data will be imputed by multiple imputation (MI) method for 10 times 
utilizing available post up-dosing DBPCFC data at visit 16. The MI will utilize 
logistic regression method with treatment group and randomization stratification.  
− If a subject does not have available DBPCFC data with peanut protein at visit 16 
due to reasons not related to COVID-19, this subject will be considered as a non-
responder at visit 16. 
Each of complete datasets after the above steps will be analyzed by the CMH test. The SAS 
MIANALYZE procedure will then be used to generate valid statistical inferences by combining 
results using Rubin’s formula (Rubin, 1987). 
Sensitivity analyses will include an analysis of the subset of subjects with available visit 16 
DBPCFC data with peanut protein.  
The supportive analyses based on FAS and PPS will be performed using primary analysis method. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
Continuous Endpoints at visit 16 
Change in the cumulative tolerated dose (log transformed) of peanut protein during a DBPCFC 
from baseline at visit 16 will be analyzed using analysis of covariance (ANCOVA) with treatment 
as the main effect, stratification variables and baseline tolerated cumulative amount of peanut 
protein DBPCFC (log transformed) as covariates. If subjects do not tolerate any dose level, they 
will be assigned a cumulative tolerated dose of 1 mg prior to converting to the log scale. The least-
squares (LS) mean for each treatment group with its corresponding standard error (SE), the LS 
mean difference between treatment group and its corresponding SE and 95% CI, and the p-value 
corresponding to the between-treatment-group difference will be reported. In addition, change the 
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cumulative tolerated dose of peanut protein during a DBPCFC at visit 16 will be based on a non-
parametric analysis using the van Elteren test.  
Missing data for post up-dosing DBPCFC at visit 16 will be handled according to the reason for 
missingness as follows: 
• If a subject misses the post up-dosing DBPCFC at visit 16 due to COVID-19,  the 
missing data will be imputed by MI method for 10 times utilizing available post up-
dosing DBPCFC data at visit 16. The MI will utilize regression method with treatment 
group, randomization stratification, and baseline tolerated cumulative amount of 
peanut protein DBPCFC (log transformed). 
• If a subject does not have an available DBPCFC at visit 16 due to reasons not related 
to COVID-19, the baseline value at screening DBPCFC will be used to impute the 
missing post up-dosing DBPCFC data at visit 16.  
Each of the complete datasets after the above steps will be analyzed by the ANCOVA. The SAS 
MIANALYZE procedure will then be used to generate valid statistical inferences by combining 
results.  
Two sensitivity analyses will be performed as below to assess the robustness of results: 
• Completed cases will be conducted regardless the rescue medication used. 
• MI method: the missing data will be imputed by MI method utilizing available post up-
dosing DBPCFC data at visit 16. The MI will utilize the same regression method as the 
above.  
Continuous secondary efficacy endpoints that are measured repeatedly over time during the 28 to 
40-week treatment period, will be analyzed using ANCOVA with treatment as the main effect, 
stratification variables and relevant baseline. For these endpoints, missing data will be imputed by 
multiple imputations (MI) methods 40 times to generate 40 complete data sets by using the 
Statistical Analysis System (SAS) procedure MI following the 2 steps below: 
Step 1: The monotone missing pattern is induced by Markov Chain Monte Carlo (MCMC) 
method in MI procedure using seed number 68367.  The monotone missing pattern 
means that if a subject has missing value for a variable at a visit, then the values at all 
subsequent visits for the same variable are all missing for the subject. 
Step 2: The missing data at subsequent visits will be imputed using the regression method for 
the monotone pattern with seed number 81807 and adjustment for covariates including 
treatment groups, randomization stratification, and relevant baseline. 
Each of the 40 complete datasets will be analyzed using an ANCOVA model with treatment group 
being the main factor, randomization stratification and baseline value as the covariate. The SAS 
MIANALYZE procedure will then be used to generate valid statistical inferences by combining 
results from the 40 analyses.  
The least-squares (LS) mean for each treatment group with its corresponding standard error (SE), 
the LS mean difference between treatment group and its corresponding SE and 95% CI, and the p-
value corresponding to the between-treatment-group difference will be reported. 
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Last observation carried forward (LOCF) method and worst observation carried forward (WOCF) 
will be employed as additional sensitivity analyses for continuous secondary efficacy endpoints 
that are measured repeatedly over time during the 28 to 40-week treatment period.  
Percent change from baseline to visit 16 in peanut-specific IgE will be analyzed using rank-based 
ANCOVA with treatment as the main effect, stratification variables and baseline peanut-specific 
IgE level as covariates. The missing data will be imputed using MI method above. Last observation 
carried forward (LOCF) method will be employed as sensitivity analysis.  
Binary Endpoints at visit 16 
Proportion of subjects who reach 300 mg/day dose of AR101 by visit 16 will be analyzed using 
the Cochran-Mantel-Haenszel test adjusted by randomization stratification factors to assess the 
treatment difference in the proportion of subjects who reach the 300 mg/day dose of AR101 in the 
FAS. The proportion of subjects who reach the 300 mg/day dose of AR101 and its 95% confidence 
interval will be calculated for each treatment group with Clopper-Pearson confidence limits. 
Estimate of treatment difference, p-value, and the 2-sided 95% confidence interval using normal 
approximation will be provided.  
Time-to-event Endpoint at visit 16 
Time from randomization to the first time when subjects reach 300 mg/day dose of AR101 during 
the 28 to 40-week treatment period will be analyzed using the Cox proportional hazards model 
including treatment and randomization strata as factors. The hazards ratio, its 95% confidence 
interval and p-value will be reported. The Kaplan-Meier plots will be provided. 
Continuous Endpoints at visit 22 and visit 25  
Change in cumulative tolerated dose (log transformed) of peanut protein during a DBPCFC from 
baseline to visit 22  in subjects (continuously) treated with dupilumab plus AR101 vs placebo plus 
AR101, and change in cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22  in subjects (previously) treated with dupilumab plus AR101 
(and re-randomized to placebo plus AR101) vs placebo plus AR101, will be assessed in a similar 
fashion as in visit 16 including missing data imputation and sensitivity analysis.  
Percent change from baseline to visit 22 and visit 25 in peanut-specific IgE in subjects 
continuously treated with dupilumab + AR101 vs placebo + AR101 will be analyzed in a similar 
fashion as in visit 16. 
Binary Endpoints at visit 22 
Proportion of subjects (continuously) treated with dupilumab + AR101 vs placebo + AR10, and 
proportion of subjects (previously) treated with dupilumab + AR101 and re-randomized to placebo 
+ AR101 vs placebo + AR101, who ‘pass’ a post-maintenance DBPCFC with 2044 mg cumulative 
peanut protein at visit 22 will be assessed the same way as for visit 16 including missing data 
imputation and sensitivity analysis.  
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5.6.3. 
Adjustment for Multiple Comparison 
The overall Type-1 error rate of 0.05 (2-sided) will be controlled for the primary endpoint and the 
first secondary endpoint (i.e., change in the cumulative tolerated dose [log transformed] of peanut 
protein during a DBPCFC from baseline to visit 16) using a hierarchical testing procedure. 
Inferential conclusions about the first secondary endpoint require statistical significance at the 2-
sided 0.05 significance level of the primary endpoint. 
No formal hypothesis and adjustment for multiplicity will be undertaken for the maintenance 
phase. 
5.6.4. 
Analysis of Exploratory Efficacy Variables 
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 with the following exceptions. The analysis on biomarker variables 
will be specified in Section 5.11. The analysis on the proportion of days with allergy symptoms 
based on eDiary data will be specified in Section 5.12 . 
5.6.5. 
Subgroup Analysis  
Subgroup analysis for the primary endpoint and the following secondary endpoints will be 
performed on mFAS and FAS-maintenance. Subgroups have been defined in Section 3.6 . 
• Change in cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 16 in subjects treated with dupilumab plus AR101 vs 
placebo plus AR101 
• Proportion of subjects treated with dupilumab plus AR101 vs placebo plus AR101 who 
reach the 300 mg/day dose of AR101 by visit 16 
• Proportion of subjects (continuously) treated with dupilumab plus AR101 vs placebo 
plus AR101 who “pass” a post maintenance DBPCFC with 2044 mg (cumulative) 
peanut protein at visit 22  
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (continuously) treated with dupilumab 
plus AR101 vs placebo plus AR101 
• Proportion of subject (previously) treated with dupilumab plus AR101 (and 
re-randomized to placebo plus AR101) vs placebo plus AR101 who “pass” a post 
maintenance DBPCFC with 2044 mg (cumulative) peanut protein at visit 22 
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (previously) treated with dupilumab plus 
AR101 (and re-randomized to placebo plus AR101) vs placebo plus AR101 
The analysis method for the subgroup will be the same as the primary analysis described in 
Section 5.6.1 and Section 5.6.2. Interactions between the subgroups and treatment groups will be 
tested using the logistic regression model for the binary endpoints and using the ANCOVA model 
for the continuous endpoints. The model will include randomization strata, treatment group, 
subgroup, treatment by randomization strata interaction and treatment by subgroup interaction as 
factors. P-values for interaction term will be reported.  
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Forest plots of above efficacy endpoints across subgroups will be generated. 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF and SAF-maintenance for 
each study period, as defined in Section 3.3. 
The safety analysis will be based on the reported AEs, 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 time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
The summary of safety results will be presented for each study period by treatment received in the 
corresponding period. For safety variables/summaries involving baseline values, e.g., absolute 
change from baseline or shift table, study period specific baselines will be used. Summaries for 
pre-dosing period and up-dosing period will use the study baseline (i.e., the latest available valid 
measurement prior to the first dose of study drug in the study). Summaries for maintenance period 
and follow-up period will use study baseline and visit 16 baseline (i.e., the last available valid 
measurement prior to the first dose of study drug in the maintenance period), respectively. 
5.7.1. 
Adverse Events  
The number and proportion of subjects reporting TEAEs will be summarized for pre-dosing 
period, up-dosing period, maintenance period and follow-up period separately, as described in 
Section 3.3. 
AE incidence tables will be presented by treatment group for the SAF and SAF-maintenance as 
well as subgroups. Summary of TEAEs will present the number (n) and percentage (%) of subjects 
experiencing an TEAE by SOC, and PT, sorted by decreasing frequency of SOC and PT for the 
dupilumab treatment group in the pre-dosing period, dupilumab plus AR101 treatment group in 
the up-dosing period, and continuously on dupilumab plus AR101 treatment group in the 
maintenance period. Multiple occurrences of AEs of the same PT (or SOC) in the same subject 
will be counted only once for that PT (or SOC). For AE tables presenting severity, the worst 
severity will be chosen for subjects with multiple instances of the same event. The denominator 
for computation of percentage is the number of subjects in each treatment group for the 
corresponding analysis period as specified in Section 3.3.  
An overall summary of TEAEs will be provided with number and proportions of subjects with 
any: 
• TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
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• TEAE/Serious TEAE leading to death 
• TEAE/Serious TEAE leading to permanent treatment discontinuation 
• TEAE/Serious TEAE of injection site reaction 
• Study drug related TEAE/serious TEAE 
Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by SOC/PT 
− TEAEs by SOC/HLT/PT 
− TEAEs by PT 
− TEAEs by SOC/PT with incidence of PT ≥5% in any treatment group 
− TEAEs by severity and by SOC/PT 
− Severe TEAEs by SOC/PT 
− TEAEs related to dupilumab/placebo as assessed by the investigator by SOC/PT 
− TEAEs related to AR101 as assessed by the investigator by SOC/PT 
− Severe TEAEs related to dupilumab/placebo as assessed by the investigator by 
SOC/PT  
− Severe TEAEs related to AR101 as assessed by the investigator by SOC/PT 
− TEAE of special interest 
• Serious TEAEs: 
− Serious TEAEs by SOC/PT 
− Serious TEAEs related to dupilumab/placebo as assessed by the investigator by 
SOC/PT  
− Serious TEAEs related to AR101 as assessed by the investigator by SOC/PT  
• TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
• Death by SOC/PT 
Number and proportion of subjects reporting pre-treatment adverse events will be tabulated by 
SOC and 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: 
• Subject ID 
• Treatment group 
• Study phase 
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• 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 dupilumab/placebo: unrelated or related 
• Relationship of AE to AR101: unrelated or related 
• Action taken with dupilumab/placebo: Dose not changed, Drug interrupted, Drug 
withdrawn, Not applicable, or Unknown 
• Action taken with AR101: Dose not changed, Dose reduced, 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 subjects who were impacted by COVID-19 pandemic, the summary of adverse 
events by study period 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 by 
study period for subjects 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 subjects impacted by COVID-19, if applicable. 
5.7.2. 
Analysis of Adverse Events of Special Interest 
The adverse events of special interest (AESI) for dupilumab and AR101 will be summarized by 
AESI category (see Section 10.4 ) and HLT/PT, respectively.  
The time to first AESIs (TEAE by category) or TEAE leading to permanent treatment 
discontinuation will be assessed by Kaplan-Meier estimates. Kaplan-Meier plots will be provided. 
In order to detect any safety signals, the hazard ratio (HR) will be provided together with the 
corresponding 95% confidence interval (CI) for the selected adverse events. Hazard ratios will be 
calculated using a Cox model including factors of treatment group, and randomization strata. The 
time is defined as the date of first event – the date of first dose + 1. Subjects without an event will 
be censored at the end of each study period. Graphs of cumulative incidence rate over time will be 
presented by treatment group. 
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The number of anaphylactic reactions, the number and percent of subjects experiencing an 
anaphylactic reaction, the number and percent of subjects experiencing an anaphylactic reaction 
by maximum severity using the Muraro Grading Scale (Muraro 2007), the number of subjects 
experiencing an anaphylactic reaction was an SAE, the number of subjects experiencing an 
anaphylactic reaction that required use of epinephrine will be summarized for each study period 
and 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 subjects with treatment-emergent PCSVs. This 
summary will be provided based on all subjects in the SAF as well as in the subgroup 
of SAF subjects who did not meet the PCSV criterion at baseline 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listing of all laboratory parameters normal range, abnormal flag, treatment-emergent PCSV by 
subject, visit and the status of impact by COVID-19 pandemic will be provided. 
In addition, summaries of laboratory variables will be performed for subjects who were impacted 
by COVID-19 pandemic and not impacted by COVID-19 pandemic in each study period, 
respectively. The summaries will be performed for pre-, during-, and post-COVID-19 periods for 
subjects impacted by COVID-19, if applicable. 
5.7.4. 
Analysis of Vital Signs 
Summaries of vital sign variables excluding post-dose measurements at AR101 up-dosing visit 
and measurements at DBPCFCs will include: 
• Descriptive statistics of vital sign variables and change from baseline by visit  
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV  
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Summaries of vital sign variables at DBPCFCs of peanut protein will include: 
• Descriptive statistics of vital sign variables and change from pre-dose by challenge 
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 
Listings of vital sign will be provided with flags indicating the treatment-emergent PCSVs and the 
status of impact by COVID-19 pandemic. 
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In addition, summaries of vital signs will be performed for subjects who were impacted by 
COVID-19 pandemic and not impacted by COVID-19 pandemic in each study period, 
respectively. The summaries will be performed for pre-, during-, and post-COVID-19 period for 
subjects impacted by COVID-19, if applicable. 
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. 
5.7.6. 
Spirometry and Peak Expiratory Flow (PEF) 
Summaries of spirometry and PEF variables at visits without DBPCFCs performed 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 
Listing of spirometry and PEV 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 subjects who were impacted 
by COVID-19 pandemic and not impacted by COVID-19 pandemic in each study period, 
respectively. The summaries will be performed for pre-, during, and post-COVID-19 periods for 
subjects impacted by COVID-19, 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 
• Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum 
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 
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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 subjects 
in the ADA analysis set.  
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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 subjects 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
subjects 
− Number (n) and percent (%) of transient treatment-emergent ADA positive subjects 
• Number (n) and percent (%) of treatment-boosted ADA-positive subjects 
Listing of all ADA titer levels will be provided for subjects with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.9.2. 
Analysis of Neutralizing Antibodies (NAb) Data 
The absolute occurrence (n) and percent of subjects (%) with NAb positive or negative status will 
be provided by treatment group for subjects 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 subjects, that is subjects with treatment-emergent or treatment-boosted 
response. 
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• ADA negative subjects, that is subjects with pre-existing immunoreactivity or negative 
in the ADA assay at all time points 
•  Subjects with persistent treatment-emergent ADA response 
• NAb positive subjects, that is subjects who were positive in the NAb assay at any time 
point analyzed.  
• Maximum post-baseline titer level in treatment-emergent or treatment boosted ADA 
positive subjects:  
− High,  
− Moderate,  
− Low 
5.11. 
Analysis of Biomarker Data 
All biomarker analyses will be performed on the mFAS and FAS-maintenance using all observed 
data. Descriptive statistics for the observed values, change from baseline and percent change from 
baseline values by treatment and visit will be provided for the biomarker variables as described in 
Section 4.9. 
The Wilcoxon signed-rank test will be used to test if the change or percentage change from baseline 
value is significantly different from zero. P-value will be reported. 
For up-dosing period, exploratory analyses for the difference between dupilumab + AR101 group 
and placebo + AR101 group on the change from baseline and percent change from baseline values 
will be performed using a rank-based ANCOVA model with treatment group and randomization 
stratification factors as fixed factors, and the relevant baseline values as covariate. Missing value 
will be imputed by LOCF method using available post-baseline data for visits up to visit 16. P-
value for difference between dupilumab +AR101 and placebo + AR101 will be provided. 
For maintenance period, exploratory analyses for the difference between continuously on 
dupilumab + AR101 group and continuously on placebo + AR101 group on the change from 
baseline and percent change from baseline values will be performed using a rank-based ANCOVA 
model with treatment group and randomization stratification factors as fixed factors, and the 
relevant baseline values as covariate. Missing value will be imputed by LOCF method using 
available post-baseline data for visits up to visit 22. P-value for difference between continuously 
on dupilumab + AR101 and continuously on placebo + AR101 will be provided.  
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Correlation of baseline serum peanut sIgE, sIgG, sIgG4, total IgE, absolute change or percent 
change at visit 16, 22 and 25 from baseline in these biomarkers; baseline Ara h1 sIgE, Ara h1 
sIgG4, Ara h2 sIgE, Ara h2 sIgG4, Ara h3 sIgE, Ara h3 sIgG4, absolute change or percent change 
at visit 16 in these biomarkers; baseline in basophil sensitivity to peanut allergen stimulation 
measured by EC50,  frequency of peanut specific T-cell subsets (e.g. Th2A cells), and absolute 
change or percent change at visit 16 in these biomarkers with the following continuous clinical 
endpoints will be explored using the Spearman’s rho test. Both Spearman correlation coefficients 
and p-value will be reported. The correlation between post-baseline biomarkers and clinical 
outcomes will only be evaluated at the same visit.  
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 16 in subjects treated with dupilumab plus AR101 vs 
placebo plus AR101 
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 22 in subjects (continuously) treated with dupilumab 
plus AR101 vs placebo plus AR101 
• Change in the cumulative tolerated dose (log transformed) of peanut protein during a 
DBPCFC from baseline to visit 25 in subjects (continuously) treated with dupilumab 
plus AR101 vs placebo plus AR101 
• Change in the normalized wheal size of titrated skin prick test from baseline to visit 16 
in subjects treated with dupilumab plus AR101 vs placebo plus AR101 
• Change in the normalized wheal size of titrated skin prick test from baseline to visit 22  
in subjects (continuously) treated with dupilumab plus AR101 vs placebo plus AR101 
• Change in the normalized wheal size of titrated skin prick test from baseline to visit 25  
in subjects (continuously) treated with dupilumab plus AR101 vs placebo plus AR101 
• Change in the FeNO from baseline to visit 16 in subjects treated with dupilumab plus 
AR101 vs placebo plus AR101 
• Change in the FeNO from baseline to visit 22 in subjects (continuously) treated with 
dupilumab plus AR101 vs placebo plus AR101 
• Change in the FeNO from baseline to visit 25 in subjects (continuously) treated with 
dupilumab plus AR101 vs placebo plus AR101 
Correlation of baseline serum peanut sIgE, sIgG, sIgG4, total IgE, basophil sensitivity to peanut 
allergen stimulation, and Th2A cell frequency 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, with randomization stratification factors, 
treatment group, baseline biomarker value, and treatment by baseline biomarker interaction as the 
predictor variables. Model coefficients and P-value will be provided to indicate significance of the 
correlation/association. 
• Subjects treated with dupilumab plus AR101 vs placebo plus AR101 who “pass” 2044 
mg (cumulative) peanut protein at visit 16 
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• Subjects treated with dupilumab plus AR101 vs placebo plus AR101 who “pass” 1044 
mg (cumulative) peanut protein at visit 16 
• Subjects treated with dupilumab plus AR101 vs placebo plus AR101 who “pass” 
444 mg (cumulative) peanut protein at visit 16 
5.12. 
Analysis of Daily Allergy Symptom Diary Data  
The daily allergy symptom diary analyses during up-dosing period will be performed on the mFAS 
and FAS using all observed data, respectively.  
The continuous variables of the proportion of days with one or more allergy symptoms and with 
one or more severe allergy symptoms will be analyzed descriptively by treatment group during up-
dosing period, separately. Similarly, the proportion of days with one or more allergy symptoms 
will be summarized descriptively for each symptom category defined in Section 4.5.3 .  
5.13. 
Analysis of Pediatric Eosinophilic Esophagitis Symptom Score  
Listings of pediatric eosinophilic esophagitis symptom scores from parent report age 2-18 years 
and self-report age 8-18 years will be provided, respectively.  
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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 study baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the first administration of study drug. If any randomized 
subjects are not treated, the baseline will be the last value on or prior to the randomization. In 
addition, maintenance period baseline is defined as the last available valid measurement taken 
prior to the first administration of dupilumab/placebo during the maintenance period. 
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 
expect AE, lab, PK and ADA data. 
For the re-screened subjects, all data from the same subject will be used to derive baseline 
regardless if the data is from the screen-failure subject ID or enrolled subject ID. 
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 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. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAE.  If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
Adverse event start date 
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will indicate which date component is missing. 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
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If AE start day is missing, and AE start month and year are not missing:  If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month, then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead.  Otherwise impute the AE start day using the first day of the month.  If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
If AE start month is missing, and AE start year is not missing:  If AE start year is before the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month.  If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January.  Imputation flag is ‘M’. 
If AE start year is missing:  Impute AE start date using the date of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date.  However, since AE end date will be 
used for AE starting date imputation, to carry through the logic for programming, the following 
intermediate step will be used. Afterwards, only the original character/numeric date recorded in 
CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing:  Impute AE end date using 
the last day of the month.  If this leads to a date after end of study follow up date, use end of follow 
up date instead. 
If AE end month is missing, and AE end year is not missing:  Impute AE end date using 
31 December as the day and month.  If this leads to a date after end of study follow up date, use 
the end of follow up date instead. 
If AE end year is missing:  Impute AE end date using the end of follow up date. 
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 listings. 
Prior medication start date  
If start day is missing, and start month and year are not missing:  Impute the start day using the 
first day of the month.  Imputation flag is ‘D’; 
If start month is missing, and start year is not missing:  Impute the day and month using 01 January.  
Imputation flag is ‘M’. 
If start year is missing:  Impute start date using 2 years before inform consent date.  Imputation 
flag is ‘Y’. 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 56 of 86 
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 the protocol which 
specifies to collect up to 2 years prior medication.  Since the start date of prior medication will not 
be used in any analysis, the rule will not impact the analysis result. 
Prior medication end date 
If end day is missing, and end month and year are not missing:  Impute end date using the last day 
of the month.  If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead.  Imputation flag is ‘D’. 
If end month is missing, and end year is not missing:  Impute end date using 31 December as the 
day and month.  If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead.  Imputation flag is ‘M’. 
If end year is missing:  Impute end date using the first dose intake date –1.  Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing:  Impute end date using the last day 
of the month.  If this leads to a date after end of study follow up date, use end of follow up date 
instead.  Imputation flag is ‘D’. 
If end month is missing, and end year is not missing:  Impute end date using 31 December as the 
day and month.  If this leads to a date after end of study follow up date, use the end of follow up 
date instead.  Imputation flag is ‘M’. 
If end year is missing:  Impute date using the end of follow up date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study DM and study MD. 
PCSV 
Subjects who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.4. 
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. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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The following analysis visit windows will be used to map the unscheduled visits and ET visit, 
based on the study day: 
Visit 
Target Day (TD) 
Analysis Time Window Based 
on Study Daya 
Screening 1 
-113 to -17 
-113 to -17 
Screening 1a 
-57 to -15 
-57 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 26) 
183 
[177, 190] 
Following visit 15a – 15f are optional visitsb during up-dosing period  
Visit 15a (Week 28) 
197 
[191, 204] 
Visit 15b (Week 30) 
211 
[205, 218] 
Visit 15c (Week 32) 
225 
[219, 232] 
Visit 15d (Week 34) 
239 
[233, 246] 
Visit 15e (Week 36) 
253 
[247, 260] 
Visit 15f (Week 38) 
267 
[261, 274] 
Following windows only apply to subjects who entered double-blind maintenance period 
Visit 16 (Week 28 to 40) 
Target Day (TD) at last visit 
during up-dosing periodc + 14 
days 
 [Visit 16 TDd - 8 days, Visit 16 
TD + 30 days] 
Visit 17 (V16 + 4 weeks) 
Visit 16 TD + 28 days 
 [Visit 17 TD – 13 days, Visit 17 
TD + 14 days] 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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Visit 18 (V16 + 8 weeks) 
Visit 16 TD + 56 days 
[Visit 18 TD – 13 days, Visit 18 
TD + 14 days] 
Visit 19 (V16 + 12 weeks) 
Visit 16 TD + 84 days 
 [Visit 19 TD – 13 days, Visit 19 
TD + 14 days] 
Visit 20 (V16 + 16 weeks) 
Visit 16 TD + 112 days 
 [Visit 20 TD – 13 days, Visit 20 
TD + 14 days] 
Visit 21 (V16 + 20 weeks) 
Visit 16 TD + 140 days 
 [Visit 21 TD – 13 days, Visit 21 
TD + 14 days] 
Visit 22 (Week 52 to 64, V16 + 
24 weeks) 
Visit 16 TD + 168 days 
 [Visit 22 TD – 13 days, Visit 22 
TD + 14 days] 
Following windows apply to subjects who entered follow-up period  
Visit 23 (V16 + 28 weeks) 
Target Day (TD) at last visit 
in pre-dosing/up-
dosing/maintenance period e + 
28 days 
 [Visit 23 TD – 13 days, Visit 23 
TD + 14 days] 
Visit 24 (V16 + 32 weeks) 
Target Day (TD) at last visit 
in pre-dosing/up-
dosing/maintenance period + 
56 days 
 [Visit 24 TD – 13 days, Visit 24 
TD + 14 days] 
Visit 25 (Week 64 to 76, V16 + 
36 weeks) 
Target Day (TD) at last visit 
in pre-dosing/up-
dosing/maintenance period + 
84 days 
≥ Visit 24 TD + 14 days 
a Study day is calculated relative to the date of first study drug injection. 
b Visit 15a – 15f are optional visits in order to reach 300 mg/day AR101 for at least two weeks. Subjects may reach 
300 mg/day AR101 for at least two weeks at any of the optional visits. 
c The last visit during up-dosing period could be any of visit 15, 15a, 15b, 15c, 15d, 15e, or 15f.  
d Visit 16 target day (TD) is defined as target day at last visit during up-dosing period + 14 days. 
e The target day at last visit in pre-dosing/up-dosing/maintenance period could be any of the following visit: 1) 
visit 15 during up-dosing period; 2) ET visit during up-dosing period; 3) visit 22 during maintenance period; 4) ET 
visit during maintenance period. 
In general, the following order will be used to select the record for analysis at given visit: 
4. Scheduled visit 
5. ET or end of study (EOS), whichever comes first if scheduled visit not available  
6. Unscheduled visit if both scheduled visit and ET/EOT/EOS are not available 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 59 of 86 
For the 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 targeted study day will be selected.  
• 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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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 60 of 86 
7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
An unblinded primary analysis will be performed once all subjects in the study have completed 
the 28 to 40-week treatment period (visit 16 or earlier for those subjects who are withdrawn 
prematurely from the study). If performed, the primary analysis will be considered the final 
analysis for the primary endpoint and secondary efficacy endpoints up to visit 16. 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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9. 
REFERENCES 
1. Dyer, Allergy, Asthma, Proc, 2015, 36:58-64 
2. 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. 
3. 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. 
4. 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. 
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. 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. 
7. Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons 
Inc., New York.  
8. Sicherer, JACI, 2010, 125:1322-6. 
9. Vickery BP, Lin J, Kulis M, et al: Peanut oral immunotherapy modifies IgE and IgG4 
responses to major peanut allergens. JACI 2013; 131: 128–134. 
10. Virkud Y, Burks W, Steele P, et al. Novel baseline predictors of adverse events during oral 
immunotherapy in children with peanut allergy; JACI 2016; 1–7e. 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 63 of 86 
10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analysis: 
Endpoints 
Analysis 
Population 
Primary Statistical Method 
Supportive/Sensitivity 
Statistical Method 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Proportion of subjects treated with 
dupilumab plus AR101 vs placebo 
plus AR101 who “pass” a post up-
dosing DBPCFC with 2044 mg 
(cumulative) peanut protein at visit 16 
mFAS, FAS 
Cochran-Mantel-Haenszel test/ MI for 
missing due to COVID-19, otherwise 
missing data as non-responder 
Cochran-Mantel-
Haenszel test with 
available visit 16 
DBPCFC data 
Yes  
Bar chart 
Secondary Endpoint 
Change in cumulative tolerated dose 
(log transformed) of peanut protein 
during a DBPCFC from baseline to 
visit 16 
mFAS, FAS 
ANCOVA model/ MI for missing due 
to COVID-19, otherwise missing data 
imputed by BOCF method 
ANCOVA model with 
available visit 16  
DBPCFC data; MI 
method; van Elteren 
test with LOCF 
method/with available 
visit 16 DBPCFC data 
for change in 
cumulative tolerated 
dose 
Yes 
Bar chart 
Proportion of subjects treated with 
dupilumab plus AR101 vs placebo 
plus AR101 who reach 300 mg/day 
dose of AR101 by visit 16 
mFAS, FAS 
Cochran-Mantel-Haenszel test 
No 
Yes 
Bar chart 
Time from randomization to the first-
time subjects reach the 300 mg/day 
dose of AR101 during up-dosing 
treatment phase (up to visit 16) 
mFAS, FAS 
Kaplan-Meier estimates; Cox 
regression model 
No 
No 
Kaplan-Meier 
plot 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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Endpoints 
Analysis 
Population 
Primary Statistical Method 
Supportive/Sensitivity 
Statistical Method 
Subgroup 
Analysis 
Other 
Analyses 
Proportion of subjects (continuously) 
treated with dupilumab plus AR101 vs 
placebo plus AR101 who ‘pass’ a 
DBPCFC with 2044 mg (cumulative) 
peanut protein at visit 22 
FAS-
maintenance 
Cochran-Mantel-Haenszel test/ MI for 
missing due to COVID-19, otherwise 
missing data as non-responder 
Cochran-Mantel-
Haenszel test with 
available visit 22  
DBPCFC data 
Yes 
Bar chart 
Change in the cumulative tolerated 
dose (log transformed) of peanut 
protein during a DBPCFC from 
baseline to visit 22  in subjects 
(continuously) treated with dupilumab 
plus AR101 vs placebo plus AR101 
FAS-
maintenance 
ANCOVA model/ MI for missing due 
to COVID-19, otherwise missing data 
imputed by BOCF method 
ANCOVA model with 
available visit 22  
DBPCFC data; MI 
method; van Elteren 
test with LOCF 
method/with available 
visit 22  DBPCFC data 
Yes 
Line plot 
Proportion of subjects (previously) 
treated with dupilumab plus AR101 vs 
placebo plus AR101 who ‘pass’ a 
DBPCFC with 2044 mg (cumulative) 
peanut protein at visit 22   
FAS-
maintenance 
Cochran-Mantel-Haenszel test/ MI for 
missing due to COVID-19, otherwise 
missing data as non-responder 
Cochran-Mantel-
Haenszel test with 
available visit 22  
DBPCFC data 
Yes 
Bar chart 
Change in the cumulative tolerated 
dose (log transformed) of peanut 
protein during a DBPCFC from 
baseline to visit 22  in subjects 
(previously) treated with dupilumab 
plus AR101 vs placebo plus AR101 
FAS-
maintenance 
ANCOVA model/ MI for missing due 
to COVID-19, otherwise missing data 
imputed by BOCF method 
ANCOVA model with 
available visit 22  
DBPCFC data; MI 
method; van Elteren 
test with LOCF 
method/with available 
visit 22  DBPCFC data 
Yes 
Line plot 
Percent change from baseline to visit 
16  in peanut-specific IgE in subjects 
treated with dupilumab plus AR101 vs 
subjects treated with placebo plus 
AR101 
mFAS, FAS 
Rank-based ANCOVA model, missing 
data imputed by MI method 
ANCOVA model with 
LOCF method 
No 
Line plot 
Percent change from baseline to visit 
22  in peanut-specific IgE in subjects 
(continuously) treated with dupilumab 
plus AR101 vs subjects treated with 
placebo plus AR101 
FAS-
maintenance 
Rank-based ANCOVA model, missing 
data imputed by MI method 
ANCOVA model with 
LOCF method 
No 
Line plot 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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Endpoints 
Analysis 
Population 
Primary Statistical Method 
Supportive/Sensitivity 
Statistical Method 
Subgroup 
Analysis 
Other 
Analyses 
Percent change from baseline to visit 
25 in peanut-specific IgE in subjects 
(continuously) treated with dupilumab 
plus AR101 vs subjects treated with 
placebo plus AR101 
FAS-
maintenance 
Rank-based ANCOVA model, missing 
data imputed by MI method 
ANCOVA model with 
LOCF method 
No 
Line plot 
Safety Analyses: 
Endpoint 
Analysis Populations 
Statistical Method 
Supportive Analysis 
Subgroup Analysis 
Other Analyses 
Adverse events 
SAF, SAF-maintenance 
Descriptive statistics  
No 
Yes, for selected AE 
summary 
No 
Laboratory measures 
SAF, SAF-maintenance 
Descriptive statistics 
No 
No 
No 
Vital sign 
SAF, SAF-maintenance 
Descriptive statistics 
No 
No 
No 
Spirometry 
SAF, SAF-maintenance 
Descriptive statistics 
No 
No 
No 
Daily allergy 
symptom diary during 
up-dosing period 
mFAS, FAS 
Descriptive statistics  
No 
No 
No 
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Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
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10.2. 
Schedule of Time and Events 
Table 2: 
Schedule of Events – Screening, Baseline, Double-Blind Treatment Period 
Study Procedure 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
Study Drug 
Pretreatment 
Study Drug Concomitant Treatment  
AR101 Up-Dosing 
Visit (V) 
V112  
V1a13  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Week (W) 14 
-113 
to -17 
before 
-15  
D1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Day (D) 14 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
Visit Window (d) 
 
±3d 
±3d 
±3d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Screening/Baseline: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICF for optional 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History/ 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on Daily 
Allergy Symptom 
Diary 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Training on Study 
Drug Administration 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded Study Drug 
SC Q2W 
Administration1  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Study Drug 
Injection Log1 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AR101 Daily 
Administration2 
 
 
 
 
X 
IDED 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily subject AR101 
Dosing Diary2 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AR101 
Dispensation/Account3 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 67 of 86 
Study Procedure 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
Study Drug 
Pretreatment 
Study Drug Concomitant Treatment  
AR101 Up-Dosing 
Visit (V) 
V112  
V1a13  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Week (W) 14 
-113 
to -17 
before 
-15  
D1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Day (D) 14 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
Visit Window (d) 
 
±3d 
±3d 
±3d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Epinephrine 
Autoinjector Training 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Con Meds/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DBPCFC5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut Skin Prick Test 
(SPT)6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peanut SPT titrated6 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
EASI for AD, ACQ-5 
asthma 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily Allergy 
Symptom Diary7 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FAQL Questionnaire 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spirometry/Peak 
Flow9, 9.a  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing4: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ab, HBsAg, 
HBcAb, Hep C Ab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
Chemistry 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
FeNO Test9, 9a 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 68 of 86 
Study Procedure 
Screening 
Baseline 
Double-Blind Treatment Period 
 
 
Study Drug 
Pretreatment 
Study Drug Concomitant Treatment  
AR101 Up-Dosing 
Visit (V) 
V112  
V1a13  
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Week (W) 14 
-113 
to -17 
before 
-15  
D1 
W2 
W4 
W6 
W8 
W10 
W12 
W14 
W16 
W18 
W20 
W22 
W24 
W26 
Day (D) 14 
1 
15 
29 
43 
57 
71 
85 
99 
113 
127 
141 
155 
169 
183 
Visit Window (d) 
 
±3d 
±3d 
±3d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Pregnancy Test 
(WOCBP only) 
S 
 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
U 
Total IgE  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
sIgE, sIgG4, sIgG 
Against Peanut 
Extract and Peanut 
Allergen Components 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Future Biomedical 
Research Sample 
(Optional) 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Optional blood 
samples for additional 
exploratory research 
(eg, TruCulture, 
Basophil sensitivity, 
PBMC, allergen-
specific T-cell 
profiling)10 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
DNA sample 
(Optional)11 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/Drug Concentration and ADA Samples4: 
Functional dupilumab 
PK sample 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Anti-dupilumab 
antibody sample 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Abbreviations: S, serum; U, urine; FAQL, Food Allergy Quality of Life; FeNO, fractional exhaled nitric oxide; WOCBP, women of child bearing potential; 
PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 69 of 86 
Study Procedure 
Double-Blind Treatment Period 
 
Study Drug Concomitant Treatment  
AR101 Up-Dosing (if applicable) 
Visit (V) 
V15a 
V15b 
V15c 
V15d 
V15e 
V15f 
 Week (W)14  
W28 
W30 
W32 
W34 
W36 
W38 
 Day (D)14 
197 
211 
225 
239 
253 
267 
Visit Window (d) 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Screening/Baseline: 
 
 
 
 
 
 
Informed Consent/Assent 
 
 
 
 
 
 
ICF for optional assessments 
 
 
 
 
 
 
Inclusion/Exclusion 
 
 
 
 
 
 
Medical History/ Demographics 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
Training on Daily Allergy Symptom Diary 
 
 
 
 
 
 
Training on Study Drug Administration 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
Blinded Study Drug SC Q2W Administration1, 
15  
X 
X 
X 
X 
X 
X 
Subject Study Drug Injection Log1 
X 
X 
X 
X 
X 
X 
AR101 Daily Administration2 
X 
X 
X 
X 
X 
X 
Daily subject AR101 Dosing Diary2 
X 
X 
X 
X 
X 
X 
AR101 Dispensation/Account3 
X 
X 
X 
X 
X 
X 
Epinephrine Autoinjector Training 
 
 
 
 
 
 
Con Meds/Procedures 
X 
X 
X 
X 
X 
X 
Efficacy4: 
 
 
 
 
 
 
DBPCFC5 
 
 
 
 
 
 
Peanut Skin Prick Test (SPT)6 
 
 
 
 
 
 
Peanut SPT titrated6 
 
 
 
 
 
 
EASI for AD, ACQ-5 asthma 
X 
X 
X 
X 
X 
X 
Daily Allergy Symptom Diary7 
X 
X 
X 
X 
X 
X 
FAQL Questionnaire 
 
 
 
 
 
 
Safety4: 
 
 
 
 
 
 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 70 of 86 
Study Procedure 
Double-Blind Treatment Period 
 
Study Drug Concomitant Treatment  
AR101 Up-Dosing (if applicable) 
Visit (V) 
V15a 
V15b 
V15c 
V15d 
V15e 
V15f 
 Week (W)14  
W28 
W30 
W32 
W34 
W36 
W38 
 Day (D)14 
197 
211 
225 
239 
253 
267 
Visit Window (d) 
±2d 
±2d 
±2d 
±2d 
±2d 
±2d 
Weight 
X 
X 
X 
X 
X 
X 
Height 
 
 
 
 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
Physical Examination 
 
 
 
 
 
 
Spirometry/Peak Flow9, 9a 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Laboratory Testing4: 
 
 
 
 
 
 
HIV ab, HBsAg, HBcAb, Hep C Ab 
 
 
 
 
 
 
Hematology, Chemistry 
X 
 
 
 
X 
 
FeNO Test9,9a 
X 
 
X 
 
X 
 
Urinalysis 
X 
 
 
X 
X 
X 
Pregnancy Test (WOCBP only) 
U 
U 
U 
U 
U 
U 
Total IgE  
X 
 
 
 
X 
 
sIgE, sIgG4, sIgG Against Peanut Extract and 
Peanut Allergen Components 
X 
 
 
 
X 
 
Future Biomedical Research Sample (Optional) 
X 
 
 
 
X 
 
Optional blood samples for additional 
exploratory research (eg, TruCulture, Basophil 
sensitivity, PBMC, allergen-specific T-cell 
profiling)10 
 
 
 
 
 
 
DNA sample (Optional)11 
 
 
 
 
 
 
Functional dupilumab PK sample 
 
X 
 
X 
 
X 
Anti-dupilumab antibody sample 
 
 
 
 
 
 
Abbreviations: S, serum; U, urine; FAQL, Food Allergy Quality of Life; FeNO, fractional exhaled nitric oxide; WOCBP, women of child bearing potential; 
PBMC, peripheral blood mononuclear cell; PK, pharmacokinetic 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 71 of 86 
Table 3: 
 Schedule of Events – Maintenance Period and Follow-Up Period 
Study Procedure 
Maintenance Period12 
Post-Treatment 
Follow-up Period 
Unschedul
ed Visit (if 
applicable) 
ET Visit 
(if 
applicable) 
Study drug and AR101 
Withdrawal 
Visit (V) 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
EOS 
 
 
Week (W)13 
W28 -
40 
 
V16+ 
4wk 
 
V16+ 
8wk 
 
V16+ 
12wk 
 
V16+ 
16wk 
 
V16+ 
20wk 
W52 -
64, 
Vtar16
+ 24wk 
 
V16+ 
28 wk 
 
V16+ 
32wk 
W64 – 
76, V16 
+ 36wk   
 
 
Visit Window (d) 
-7/+30 
d14 
±3d 
±3d 
±3d 
±3d 
±3d 
-7/+30 
d14 
±3d 
±3d 
-7/+30 
d14 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
Blinded Study Drug Q2W SC Administration
1 
X 
X 
X 
X 
X 
X 
 
 
 
 
X15 
 
Subject Study Drug Injection Log1 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
AR101 Daily Administration2 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Daily Subject AR101 Dosing Diary 2 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
AR101 Dispensation/Account3 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
Concomitant medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:4 
 
 
 
 
 
 
 
 
 
 
 
 
DBPCFC5, 14 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Peanut SPT titrated6 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
EASI for AD, ACQ-5 for asthma 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Daily Allergy Symptom Diary7 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
FAQL Questionnaire 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Safety: 4 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
Spirometry/Peak Flow9,9a  
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PEESS Questionnaire10 
 
 
 
 
 
 
 
 
 
 
X 
X 
Laboratory Testing: 4 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ab, HBsAg, HBcAb, Hep C Ab 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
FeNO Test9, 9a 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 72 of 86 
 
Abbreviations: EOS = End of study; ET = Early termination; WOCBP = Women of child bearing potential 
Footnotes for the Schedule of Events Table 2 
1. The subject/legal guardian will administer SC study drug as scheduled on dosing days.  Subject/legal guardian will complete an 
injection log (e-diary) to document compliance with injection of study drug.  On days when both dupilumab/placebo study drug 
and AR101 are administered, the study drug will be administered at least 8 hours apart from the AR101 and at least 24 hours 
after the start of in-clinic dosing. 
Urinalysis 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Pregnancy Test (WOCBP only) 
U 
U 
U 
U 
U 
U 
U 
 
 
S 
 
U 
Study Procedure 
Maintenance Period 
Post-Treatment 
Follow-up Period 
Unschedul
ed Visit (if 
applicable) 
ET Visit 
(if 
applicable) 
Study drug and AR101 
Withdrawal 
Visit (V) 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
EOS 
 
 
Week (W)13 
W28 -
40 
V16+ 
4wk 
V16+ 
8wk 
V16+ 
12wk 
V16+ 
16wk 
V16+ 
20wk 
W52 -
64, 
V16+ 
24wk 
V16
+ 28 
wk 
V16+ 
32wk 
W64 – 
76, V16 
+ 36wk   
 
 
Visit Window (d) 
-7/+30 
d14 
±3d 
±3d 
±3d 
±3d 
±3d 
-7/+30 
d14 
±3d 
±3d 
-7/+30 
d14 
 
 
Total IgE 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
sIgE, sIgG4, sIgG Against Peanut 
Extract and Peanut Allergen 
Components 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Future Biomedical Research sample 
(Optional) 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
Optional blood samples for additional 
exploratory research (eg, TruCulture, 
Basophil sensitivity, PBMC)11 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
PK/Drug Concentration and ADA 
Samples:4 
 
 
 
 
 
 
 
 
 
 
 
 
Functional dupilumab PK sample 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
Anti-dupilumab antibody sample 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 73 of 86 
2. The subject/legal guardian will administer AR101 during the days in which no in-clinic visit is scheduled.  Subject/legal guardian 
will complete a dosing diary to document compliance with AR101.  On the day following in-clinic up-dosing, the site is to make 
telephone contact to inquire if any AEs occurred and report appropriately. 
3. Starting at visit 4 (week 4), AR101 will be dispensed at the site to the subject/caregiver for the doses that will be administered 
before the next clinic visit. 
4. Assessments will be performed before the administration of study drug. 
5. Subject will be observed for a minimum of 2 hours after the final administered dose and discharged only when deemed clinically 
stable by a study doctor.  On the day following a food challenge, the site must make telephone contact to inquire if the subject 
experienced any AEs and report appropriately. Before each challenge, the subject will have a physical assessment performed by 
a trained physician’s assistant, registered nurse, nurse practitioner, and/or physician of the study team who is blinded to the 
testing material. Eczema Area and Severity Index and ACQ only needed be completed once during day 1 of the food challenge. 
6. Subjects should not take anti-histamines for at least 5 days prior to the SPT. 
7. Site should confirm subject compliance at each clinic visit. 
8. During DBPCFC, vital signs will be collected every 15 to 30 minutes. During maintenance phase for in-clinic office visits, the 
post-dose observation may be shortened to 30 minutes. 
9. Spirometry will be performed in-clinic on the same day whenever FeNO measurement is scheduled; however, spirometry will 
also be performed at other visits when FeNO is not collected.  FeNO should be done prior to spirometry. If the DBPCFC is 
scheduled on the day of the visit, then both FeNO measurement and spirometry will be performed twice before the subject goes 
home: once before DBPCFC, once after DBPCFC. 
a. During the COVID-19 pandemic, measurements of FeNO no longer need to be completed while on study (although FeNO 
is still required at screening). Additionally, if spirometry cannot be completed after enrollment, peak flow may be 
performed instead at the discretion of the investigator (although spirometry is still required at screening). 
10. On the day of the DBPCFCs, blood draws for optional exploratory research will be performed before the DBPCFC is performed. 
For the day 1 exploratory research sample, the last DBPCFC must be ≥15 days before to ensure washout of peanut allergen. 
11. One optional DNA sample for the genomics analyses (buccal swab) can be collected on day 1 (visit 2) or any other visit. 
12. Must complete all visit 1 assessments and confirm eligibility before visit 1a. 
13. Visit 1a must occur at least 15 days before visit 2 to allow a 2-week washout after the peanut screening DBPCFC. 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 74 of 86 
14. The time points listed in this table correspond with the bi-weekly up-dosing schedule. These time points may no longer be 
accurate following adjustments to the planned up-dosing period. As of Amendment 3, the up-dosing period has been permitted 
to be extended to accommodate COVID-19 restrictions of in-clinic visits, as well as dose reductions and re-escalation, if 
necessary. This extension permits a maximum up-dosing period of 40 weeks, while 28 weeks is ideal (consisting of 4 weeks 
pretreatment, 22 to 34 weeks of up-dosing, and at least 2 weeks at the maximum dose.) 
15. Study drug administration at unscheduled and/or optional visits 15a-f is to be documented in the unscheduled visits folder. 
Footnotes for the Schedule of Events Table 3 
1. The subject/legal guardian will administer SC study drug as scheduled on dosing days.  Subject/ legal guardian will complete an 
injection log (e-diary) to document compliance with injection of study drug.  On days when both dupilumab/placebo study drug 
and AR101 are administered, the study drug will be administered at least 8 hours apart from the AR101 and at least 24 hours 
after the start of in-clinic dosing. Both days of the post up-dosing DBPCFC at visit 16 should be completed before starting the 
visit 16 SC study drug as part of the maintenance phase. 
2. The subject/legal guardian will administer AR101 during the days in which no clinic visit is scheduled.  Subject/caregiver will 
complete a dosing diary to document compliance with AR101. 
3. Starting at visit 4 (week 4), AR101 that is dispensed at the site to the subject/legal guardian will be accounted for. 
4. Assessments will be performed before the administration of study drug. 
5. 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 SC study drug.  
Subject 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.  On the day following a food challenge, the site must make a telephone contact to inquire if the 
subject experienced any AEs and report appropriately. Before each challenge, the subject will have a physical assessment 
performed by a trained physician’s assistant, registered nurse, nurse practitioner, and/or physician of the study team who is 
blinded to the testing material. Eczema Area and Severity Index and ACQ only needed be completed once during day 1 of the 
food challenge. 
6. Subjects should not take anti-histamines for at least 5 days prior to the SPT. 
7. Site should confirm subject compliance at each clinic visit. 
8. During DBPCFC, vital signs will be collected every 15 to 30 minutes. 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 75 of 86 
9. Spirometry will be performed in-clinic on the same day whenever FeNO measurement is scheduled; however, spirometry will 
also be performed at other visits when FeNO is not collected. FeNO should be done prior to spirometry. If the DBPCFC is 
scheduled on the day of the visit, then both FeNO measurement and spirometry will be performed twice before the subject goes 
home: once before DBPCFC, once after DBPCFC. 
a. During the COVID-19 pandemic, measurements of FeNO no longer need to be completed while on study (although FeNO 
is still required at screening). Additionally, if spirometry cannot be completed after enrollment, peak flow may be 
performed instead at the discretion of the investigator (although spirometry is still required at screening). 
10. Only for patients who discontinue for GI AEs. If applicable, after week 64 PEESS will be collected by phone. 
11. On the day of the DBPCFCs, blood draws for optional exploratory research will be performed before the DBPCFC is performed. 
12. Clinic visits are monthly.  However, SC study drug administration is Q2W and dosing diaries for AR101 and allergic symptoms 
are done daily. 
13. The time points listed in this table correspond with the bi-weekly up-dosing schedule. These time points may no longer be 
accurate following adjustments to the planned up-dosing period. As of Amendment 3, the up-dosing period has been permitted 
to be extended to accommodate COVID-19 restrictions of in-clinic visits, as well as dose reductions and re-escalation, if 
necessary. This extension permits a maximum up-dosing period of 40 weeks, while 28 weeks is ideal (consisting of 4 weeks 
pretreatment, 22 to 34 weeks of up-dosing, and at least 2 weeks at the maximum dose.) 
14. If subjects are not able to go into the clinic for the DBPCFC within the target time frame, the DBPCFC can be started up to 
7 days before and 30 days after the target date for visit 22 and/or visit 25. 
15. Study drug administration at unscheduled and/or optional visits 15a-f is to be documented in the unscheduled visits folder. 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 76 of 86 
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 or 
AST ≤3 ULN) or BILI ≤2 ULN)  
Concept paper on DILI – FDA draft Guidance 
Oct 2007.  
Creatine Kinase  
(CK) 
>5 ULN and baseline ≤5 ULN 
>10 ULN and baseline ≤10 ULN 
 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 77 of 86 
Creatinine 
(CREAT) 
>=30% increase from individual subject 
baseline  
>=60% increase from individual subject 
baseline 
Benichou C., 1994. 
2 independent criteria  
 
Urate 
(URATE) 
Hyperuricemia  
Hypouricemia 
>=30% increase from individual subject 
baseline 
>=60% increase from individual subject 
baseline 
Harrison- Principles of internal Medicine 17th 
Ed., 2008. 
Two independent criteria 
Urea Nitrogen 
(UREAN) 
 
>=30% increase from individual subject 
baseline 
>=60% increase from individual subject 
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 
 
FDA Feb 2005. 
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 
 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 78 of 86 
LDL 
Cholesterol 
(LDL) 
>4.91 mmol/Land ≤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 >7 
 
Ketones 
(KETONES) 
Ketonuria 
Presence and absence at baseline 
Semi-quantitative methods 
 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 79 of 86 
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 
≥20mmHg 
≥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 skink infrared (temporal): >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  
≥5 % weight gain 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. 
10.4. 
Search Criteria for TEAE of Special Interest for Dupilumab 
 
AESI 
Search Criteria 
Anaphylactic reactions  
 
SMQ narrow “Anaphylactic Reactions”  
Systemic or severe 
hypersensitivity reactions  
 
Hypersensitivity: Narrow SMQ for hypersensitivity excluding preferred 
term equal to dermatitis atopic or eczema 
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 80 of 86 
Helminthic infections2 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infections 
Any type of conjunctivitis 
or blepharitis (severe or 
serious) 
Broad CMQ conjunctivitis (Conjunctivitis, Conjunctivitis allergic, 
Conjunctivitis bacterial, Conjunctivitis viral, Atopic 
keratoconjunctivitis, Blepharitis, Dry eye, Eye irritation, Eye pruritus, 
Lacrimation increased, Eye discharge, Foreign body sensation in eyes, 
Photophobia, Ocular hyperaemia, Conjunctival hyperaemia, 
Xerophthalmia) 
Blepharitis PTs (Blepharitis, blepharitis allergic) 
 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Note: manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock. 
Keratitis 
Any of the following PTs: 
a. Keratitis 
b. Allergic keratitis 
c. Ulcerative keratitis 
d. Atopic keratoconjunctivitis 
e. Herpes ophthalmic  
f. Ophthalmic herpes simplex  
Note: manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock. 
1 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 
10.5. 
Search Criteria for TEAE of Special Interest for AR101 
AESI 
Search Criteria 
Anaphylactic reactions  
 
SMQ narrow “Anaphylactic reactions”  
Gastrointestinal AEs 
resulting in prolonged 
disruption of dosing 
Disruption of AR101 dosing ≥7 consecutive days 
AND 
Any PT under SOC “Gastrointestinal disorders” 
 
10.6. 
Important Protocol Deviations 
*Note: This is a preliminary list and the final list will be generated prior to database lock. 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 81 of 86 
Category 
 
Description of Protocol Deviation 
 
Notes 
Entered study even 
though entry criteria 
was not satisfied 
Male or female Aged 6 to 17 years (inclusive) 
Entered study even 
though entry criteria 
was not satisfied 
Subject has a clinical history of allergy to peanuts or peanut 
containing foods (symptom[s] of reaction due to exposure). 
Entered study even 
though entry criteria 
was not satisfied 
Experience dose-limiting symptoms at or before the 100 mg 
challenge dose (<=144 mg cumulative) of peanut protein on 
screening DBPCFC and not experiencing dose-limiting symptoms 
to placebo or Missing 
 
Entered study even 
though entry criteria 
was not satisfied 
Serum IgE to peanut of >=24 kUA/L and/or a SPT to peanut >=10 
mm compared to a negative control or missing value (up to PA1) 
Entered study even 
though entry criteria 
was not satisfied 
Subjects/legal guardians must be trained on the proper use of the 
epinephrine autoinjector device to be allowed to enroll in the study 
Entered study even 
though entry criteria 
was not satisfied 
Subjects 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 
Entered study even 
though entry criteria 
was not satisfied 
Willing and able to comply with all clinic visits and study-related 
procedures 
Entered study even 
though entry criteria 
was not satisfied 
Written informed consent from parent/guardian for minor subjects 
 
Entered study even 
though entry criteria 
was not satisfied 
Written assent from minor subjects as appropriate (e.g. above the 
age of 6 years or the applicable age per local regulatory 
requirements) 
Entered study even 
though entry criteria 
was not satisfied 
Any previous exposure to marketed dupilumab or dupilumab in a 
clinical trial 
Entered study even 
though entry criteria 
was not satisfied 
Member of the clinical site study team or his/her immediate family 
 
Entered study even 
though entry criteria 
was not satisfied 
History of other chronic disease (other than asthma, AD, or allergic 
rhinitis) requiring therapy (eg, heart disease, diabetes, hypertension) 
Entered study even 
though entry criteria 
was not satisfied 
History of frequent or recent severe, life-threatening episode of 
anaphylaxis or anaphylactic shock as defined by more than 3 
episodes of anaphylaxis 
Entered study even 
though entry criteria 
was not satisfied 
History of eosinophilic GI disease 
Entered study even 
though entry criteria 
was not satisfied 
Current participation or participation within 6 months prior to 
screening in any other interventional study 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 82 of 86 
Category 
 
Description of Protocol Deviation 
 
Notes 
Entered study even 
though entry criteria 
was not satisfied 
Severe unstable asthma at time of enrollment with FEV1 <80% of 
predicted, ACQ >1.5 or missing value (Original protocol and 
accessed at visit 1) 
Entered study even 
though entry criteria 
was not satisfied 
Use of systemic corticosteroids within 2 months prior to screening 
Entered study even 
though entry criteria 
was not satisfied 
Use of omalizumab within 6 months prior to screening 
Entered study even 
though entry criteria 
was not satisfied 
Use of other forms of allergen immunotherapy or 
immunomodulatory therapy within 3 months prior to screening 
Entered study even 
though entry criteria 
was not satisfied 
Use of any agents known or likely to interact with epinephrine 
within 3 weeks prior to screening 
Entered study even 
though entry criteria 
was not satisfied 
Allergy to oat (placebo in DBPCFC) 
Entered study even 
though entry criteria 
was not satisfied 
Hypersensitivity to epinephrine and any of the excipients in the 
epinephrine product 
Entered study even 
though entry criteria 
was not satisfied 
History of a mast cell disorder, including mastocytosis, urticarial 
pigmentosa, and hereditary or idiopathic angioedema 
 
Entered study even 
though entry criteria 
was not satisfied 
Treatment with a live (attenuated) vaccine within 3 months prior to 
screening and during the study 
 
Entered study even 
though entry criteria 
was not satisfied 
Active chronic or acute infection requiring systemic treatment with 
antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals 
within 2 weeks prior to the baseline visit 
Entered study even 
though entry criteria 
was not satisfied 
History of malignancy within 5 years before the screening visit 
Entered study even 
though entry criteria 
was not satisfied 
Established diagnosis of a primary immunodeficiency disorder or 
secondary immunodeficiency 
Entered study even 
though entry criteria 
was not satisfied 
Known history of human immunodeficiency virus (HIV) infection 
or HIV seropositivity at the screening visit 
Entered study even 
though entry criteria 
was not satisfied 
With an established diagnosis of hepatitis B viral infection at the 
time of screening or is positive for hepatitis B surface antigen or 
hepatitis B core antibody at the time of screening 
Entered study even 
though entry criteria 
was not satisfied 
Body weight <=17 kg or missing for screening V1 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 83 of 86 
Category 
 
Description of Protocol Deviation 
 
Notes 
Entered study even 
though entry criteria 
was not satisfied 
Pregnant or breastfeeding women, women planning to become 
pregnant or breastfeed during the study 
Entered study even 
though entry criteria 
was not satisfied 
Girls at or beyond menarche who are not sexually abstinent and are 
unwilling to practice highly effective contraception 
Entered study even 
though entry criteria 
was not satisfied 
Serum IgE to peanut of >=10 kUA/L and/or a SPT to peanut >=8 
mm compared to a negative control (after PA2) 
Entered study even 
though entry criteria 
was not satisfied 
Use of anti-histamines within 5 days prior to screening and within 5 
days prior to SPTs and day 1 of DBPCFCs (SCR only) 
Entered study even 
though entry criteria 
was not satisfied 
Asthma at time of enrollment with any of the following: 
FEV1<80% or predicted, or ratio of FEV1 to forced vital capacity 
(FEV1/FVC) <75% of predicted (PA1 and after) 
Entered study even 
though entry criteria 
was not satisfied 
Asthma at time of enrollment with inhaled corticosteroids dosing of 
> 500 ug daily fluticasone. (PA1 and after) 
 
Entered study even 
though entry criteria 
was not satisfied 
Asthma at time of enrollment with one hospitalization in the past 
year for asthma or Emergency room visit for asthma within 6 
months prior to screening. (PA1 and after) 
 
Inadequate Informed 
Consent administration 
Subject did not sign an ICF (main study, pharmacogenomics, 
photography, imaging, etc…) and study procedures initiated (never 
signed ICF or signed after procedure) 
 
Inadequate Informed 
Consent administration 
Sub-study laboratory sample was collected without signed sub-
study consent 
 
Inadequate Informed 
Consent administration 
Subject did not sign an amended ICF and study procedures initiated 
 
Inadequate Informed 
Consent administration 
Subject confidentiality not maintained 
Inadequate Informed 
Consent administration 
ICF is not in subject’s language 
Inadequate Informed 
Consent administration 
Study Procedures performed after patient withdraws full consent 
Other Treatment 
compliance 
Subject poor treatment compliance to SC study drug (define as 
underdose of 80% of planned doses overall) that significantly 
impacts efficacy outcome 
Other Treatment 
compliance 
Subject poor treatment compliance to SC study drug (define as 
overdose of 110% of planned doses) that significantly impacts 
efficacy outcome 
Other Treatment 
compliance 
Subject poor treatment compliance to AR101 study drug (define as 
underdose of 95% of cumulative planned doses) that significantly 
impacts efficacy outcome during updosing phase 
Other Treatment 
compliance 
Subject poor treatment compliance to AR101 study drug (define as 
underdose of 90% of cumulative planned doses) that significantly 
impacts efficacy outcome during maintenance phase 
Other Treatment 
compliance 
Site staff were unblinded to the food challenge exposure 
(oat/peanut days) at DBPCFC at visit V16, V22 or V25. 
 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 84 of 86 
Category 
 
Description of Protocol Deviation 
 
Notes 
Procedure not 
performed 
Demographics were not collected at Screening V1 
Procedure not 
performed 
Vital Signs were not collected at Screening V1, V1A, V16, V22, 
V25 
 
Procedure not 
performed 
Physical Examination was not collected at Screening V1 
Procedure not 
performed 
Pregnancy Test (serum) was not collected at Screening V1 for 
WOCBP. 
Procedure not 
performed 
Peanut sIgE was not collected at Screening V1 
Procedure not 
performed 
Spirometry was not collected at Screening V1a 
Procedure not 
performed 
Randomization was not collected at Baseline V2 
Procedure not 
performed 
2 or more Blinded Study Drug SC Q2W Administration was not 
collected at Baseline V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, 
V12, V13, V14, V15, V16, V17, V18, V19, V20 or V21 (up to 
PA2) 
Procedure not 
performed 
Pregnancy Test (urine) was not collected at Baseline V2, V3, V4, 
V5, V6, V7, V8, V9, V10, V11, V12, V13, V14, V15, V16, V17, 
V18, V19, V20, V21, V22 or Early Termination Visit for wOCBP 
 
Procedure not 
performed 
Pregnancy Test (serum) was not collected at V25 EOS for WOCBP 
Procedure not 
performed 
Randomization was not collected at V16 
 
Procedure not 
performed 
DBPCFC was not collected at V16 
Procedure not 
performed 
DBPCFC was not collected at V22 
 
Procedure not 
performed 
2 or more Blinded Study Drug SC Q2W Administration was not 
collected at Baseline V2, V3, V4, V5, V6, V7, V8, V9, V10, V11, 
V12, V13, V14, V15, V15a, V15b, V15c, V15d, V15e, V15f, V16, 
V17, V18, V19, V20 or V21  or in USCHED (PA3 and after) 
 
Procedure not 
performed 
Pregnancy Test (urine) was not collected at V15a, V15b, V15c, 
V15d, V15e, V15f for WOCBP (PA3) 
 
Procedure not 
performed 
Weight was not collected at Baseline V2 
 
 
Procedure performed 
outside of window 
Food challenges were not performed either on different day, more 
than 1 day apart or less than 7-days apart during DBPCFC at on-
study visit V16, V22 or V25 EOS 
Randomization Error 
Stratification error 
Randomization Error 
Subject randomized twice 
Received an excluded 
concomitant treatment 
Subject received prohibited medication impacting safety or efficacy 
parameters and assessments treatment with a live (attenuated) 
vaccine per protocol 
Received an excluded 
concomitant treatment 
Treatment with an investigational drug (other than dupilumab) 
 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 85 of 86 
Category 
 
Description of Protocol Deviation 
 
Notes 
Received an excluded 
concomitant treatment 
Treatment with immunomodulating biologics agents, including 
anti-IgE and anti-IL-5 
Received an excluded 
concomitant treatment 
Treatment with allergen immunotherapy other than AR101 
 
Received an excluded 
concomitant treatment 
Treatment with systemic corticosteroids (up to PA1) 
Received an excluded 
concomitant treatment 
Treatment with any agents known or likely to interact with 
epinephrine (eg, betablockers, ACE-inhibitors, tri-cyclic 
antidepressants, or other drugs) 
Received an excluded 
concomitant treatment 
Treatment with antihistamines within 5 days- prior to SPTs and 
Day 1 DBPCFCs (post randomization) 
 
Received an excluded 
concomitant treatment 
Major elective surgical procedures 
Received an excluded 
concomitant treatment 
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 (PA2 and after) 
Received wrong 
treatment or incorrect 
dose 
Subject given study drug but subject not randomized 
Received wrong 
treatment or incorrect 
dose 
Subject received incorrect treatment (wrong kit given, kit dispensed 
without IVRS/IWRS transaction at re-supply visit, wrong order) 
Received wrong 
treatment or incorrect 
dose 
Subject received incorrect treatment or unacceptable IP (expired or 
temperature excursion deemed unacceptable) that would impact 
safety or efficacy 
 
Received wrong 
treatment or incorrect 
dose 
Site level treatment unblinded (to for example Investigator, patient 
or medical monitor) where patient care, decision making, data 
analysis and reporting impacted 
Subject developed 
withdrawal criteria but 
were not withdrawn 
 
Missing >2 consecutive doses of study drug (dupilumab or placebo) 
 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Missing >7 consecutive days of AR101 therapy (eg, concurrent 
illness such as gastroenteritis) 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Anaphylaxis resulting in severe hypotension (Appendix 3), 
neurological compromise, or mechanical ventilation secondary to 
OIT dosing or any food challenge. 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Subject develops biopsy-documented EoE or other eosinophilic GI 
disease 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Any subject deemed to have a severe allergic reaction or has a life-
threatening reaction at any time but continues study treatment 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Other circumstances such as poor control or persistent secondary 
atopic disease or started beta blockers 
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-ALG-16114 
Statistical Analysis Plan 
 
Date: October 16, 2020 
 
CONFIDENTIAL 
Page 86 of 86 
Category 
 
Description of Protocol Deviation 
 
Notes 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Any infection that is opportunistic, such as active tuberculosis and 
other infections whose nature or course may suggest an immuno-
compromised status 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Severe laboratory abnormalities that are deemed to be related to 
dupilumab 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Diagnosis of a malignancy during the study 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Evidence of pregnancy 
Subject developed 
withdrawal criteria but 
were not withdrawn 
Treatment with any prohibited concomitant medication or 
procedure but continued to take study drug 
Visit not performed 
Visit 16 was not performed 
 
Visit not performed 
Week 52 Visit 22 (D365) was not performed 
Visit not performed 
Week 64 Visit 25 EOS (D449) was not performed 
Visit not performed 
Screening visit 1 (D-113 to D-17) was not performed 
Visit not performed 
Screening visit 1A (D1 to D-15) was not performed 
Visit performed out of 
window 
Screening V1 (Day -57 to Day -17) was not performed -57 days of 
Baseline visit 2 (D1) (up to PA2) 
Visit performed out of 
window 
Visit 1A was not performed 15 days before visit 2 
 
Visit performed out of 
window 
Week 28 Visit 16 (D197) was not performed within 196 days (+/- 3 
days) of Baseline V2 (D1) (PA2 and earlier) 
 
Visit performed out of 
window 
Visit 16 was not performed within 189-309 days of Baseline V2 
(D1) (PA4) 
 
 
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02-Nov-2020 16:28:52 GMT+0000
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02-Nov-2020 17:53:27 GMT+0000
                                        VV-RIM-00131540-1.0 Approved - 02 Nov 2020 GMT-5:00