Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in Children and Adults (PALISADE)
Phase: PHASE3
Conditions: Peanut Allergy
Sponsor: Aimmune Therapeutics, Inc.

 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
ARC003 
Peanut Allergy Oral Immunotherapy Study of AR101 for Desensitization in 
Children and Adults (PALISADE) 
 
 
 
 
Protocol Amendment 4.0 – 31 Jul 2017 
Reference Numbers:  NCT02635776, EudraCT 2015-004257-41 
 
 
 
 
 
 
 
 
 
 
 
Aimmune Therapeutics, Inc. 
8000 Marina Blvd, Suite 300 
Brisbane, CA  94005 
United States 
 
 
 

Aimmune Therapeutics, Inc. 
CONFIDENTIAL 
Page 1 of 126 
Protocol ARC003, Amendment 4.0 
PALISADE 
31 July 2017 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY
OF AR101 FOR DESENSITIZATION IN CHILDREN AND
ADULTS (PALISADE) 
Investigational Drug: 
AR101, Characterized Peanut Allergen 
Protocol Number: 
ARC003 
IND: 
EudraCT: 
15463 
2015-004257-41 
Sponsor: 
Aimmune Therapeutics, Inc. 8000 Marina Blvd, 
Suite 200  
Brisbane, CA 94005 
USA 
Current Version / Approval 
Date: 
Previous Versions: 
Amendment 4.0 (Global) 
31 July 2017 
Amendment 3.0 (North 
America) 
Amendment 2.0 (Europe) 
Amendment 1.0 (Global) 
Original (Global) 
29 August 2016 
25 April 2016 
14 December 2015 
25 August 2015 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from Aimmune Therapeutics, Inc., 
unless it is necessary to obtain informed consent from potential study subjects. 

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Protocol ARC003, Amendment 4.0 
PALISADE 
 
31 July 2017 
 
CLINICAL STUDY PROTOCOL ARC003 
Sponsor Personnel 
Clinical Lead, 
Clinical 
Operations 
Ryan Taylor 
Aimmune Therapeutics, Inc. 
Chief Medical 
Officer 
Daniel C. Adelman, MD 
Aimmune Therapeutics, Inc.  
 
 
 
 
CLINICAL STUDY PROTOCOL ARC003 
Clinical Research Organization (CRO) Personnel 
CRO 
INC Research 
Raleigh, North Carolina 
3201 Beechleaf Court 
Suite 600 
Raleigh, NC 27604-1547 
USA 
 
 
  
CRO Medical 
Monitor 
Anita Maniktala, MD 
INC Research 
 
 
Sponsor Medical 
Monitor 
Brian P. Vickery, MD 
Aimmune Therapeutics, Inc.  
 
 

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Protocol ARC003, Amendment 4.0 
PALISADE 
31 July 2017 
Sponsor Protocol Approval 
Protocol ARC003 
Version / Date:  
Protocol Amendment 4.0 / 31 July 2017 
Sponsor: Aimmune Therapeutics, Inc. 
Short Title: PALISADE 
I have read protocol ARC003, Amendment 4.0 (Global), and I approve it. I agree to 
meet all obligations of the Sponsor as detailed in all applicable regulations and 
guidelines. In addition, I will inform the Principal Investigator and all other 
investigators of all relevant information that becomes available during the conduct of 
this study. 
 Daniel C. Adelman, MD       
 Chief Medical Officer (Print)           
 _______________________________        _______________ 
   Chief Medical Officer (Signature)                Date 
8/3/2017

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Protocol ARC003, Amendment 4.0 
PALISADE 
 
31 July 2017 
Principal Investigator Protocol Approval 
Protocol ARC003 
Version / Date: 
Amendment 4.0 (Global) / 31 July 2017 
IND: 15463 
EudraCT: 2015-004257-41 
Principal Investigator: 
 
Short Title: PALISADE 
I have read protocol ARC003, Amendment 4.0 (Global), and I approve it. As the 
Principal Investigator, I agree to conduct this protocol according to Good Clinical 
Practice (GCP), as delineated in the United States Code of Federal Regulations (CFR) 
– 21 CFR Parts 50, 54, and 312 (Subpart D) and in the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
“Guideline for Good Clinical Practice” E6(R1) 10 June 1996, and according to the 
criteria specified in this protocol. Furthermore, I will conduct this protocol in keeping 
with local, state and federal requirements. 
 
 
_______________________________         _______________ 
Principal Investigator (Print)                      Date 
 
 
_______________________________         _______________ 
Principal Investigator (Signature)                  Date 

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Protocol ARC003, Amendment 4.0 
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31 July 2017 
Synopsis 
Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
Short Title 
PALISADE  
Clinical Phase 
3 
IND 
15463 
EudraCT 
2015-004257-41 
IND Sponsor 
Aimmune Therapeutics, Inc. (formerly Allergen Research Corporation; ARC) 
Number of Subjects 
Approximately 500 peanut-allergic subjects will be randomized 3:1 to peanut oral 
immunotherapy (OIT) versus placebo. At least 80% of the subjects randomized will 
be children. 
Objective 
The primary objective is to demonstrate the efficacy of AR101, a pharmaceutical-
grade peanut allergen formulation, through reduction in clinical reactivity to limited 
amounts of peanut allergen in peanut-allergic children (ages 4-17 years, inclusive). 
The secondary objectives are: 
• 
To demonstrate the safety of AR101 as measured by the incidence of adverse 
events, including serious adverse events in children (ages 4-17 years, 
inclusive). 
• 
To evaluate the immunological effects of peanut OIT therapy in children (ages 
4-17 years, inclusive). 
Study Design 
This is an international, multicenter, randomized, double-blind, placebo-controlled 
study of the efficacy and safety of AR101 in a characterized desensitization OIT 
regimen in peanut-allergic individuals. The study will consist of a screening phase, 
that includes a Screening double-blind, placebo- controlled food challenge 
(DBPCFC), and a double-blind OIT treatment phase that includes an initial 
escalation period, an up-dosing period, and a maintenance period, followed by an 
Exit DBPCFC.  
An open-label safety follow-on study (ARC004) is planned after completion of 
ARC003.  
All eligible subjects will receive escalating doses of either AR101 or placebo. 
Eligible subjects who reach the targeted dose of 300 mg/d and maintain that dose 
for approximately 24 weeks will undergo an Exit DBPCFC. Subjects who do not 
reach 300 mg/d will be considered escalation failures and nonresponders for the 
primary analysis. 
A DBPCFC will be performed for those subjects achieving the target dose of 
300 mg/d and continuing to receive that dose throughout the maintenance period 
(~24 weeks). Each subject will be unblinded when he/she completes the DBPCFC 
at the end of the ~24-week maintenance period, provided regulatory and IRB/EC 
approval for ARC004 have been received, the availability of IP for ARC004, and all 
major data queries for the subject have been resolved. If this is not the case, the 
subject shall remain on blinded treatment until these requirements are satisfied. The 
subject should continue his or her maintenance visits (completed as unscheduled 
visits), every 30 days and complete all protocol procedures at each visit until study 
completion and rollover to ARC004.  
All placebo subjects who complete ARC003 are eligible for rollover into the 
ARC004 protocol. Placebo subjects from ARC003 will, in ARC004, undergo an 
escalation schedule identical to that for active subjects in the ARC003 protocol. All 
subjects on active treatment in ARC003 who pass the DBPCFC at the 300 mg 
(443 mg cumulative) challenge dose level of peanut protein are eligible to proceed 

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31 July 2017 
Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
to ARC004. Those who do not pass DBPCFC at the 300 mg (443 mg cumulative) 
challenge dose level will be considered endpoint failures and nonresponders for the 
primary analysis. They will not be eligible for rollover into the ARC004 protocol 
due to safety concerns. Those subjects who pass DBPCFC at the 300 mg (443 mg 
cumulative) challenge dose level, but fail at the 600 mg (1043 mg cumulative) or 
1000 mg (2043 mg cumulative) challenge dose level, will also be considered 
endpoint failures and nonresponders for the primary analysis for North America or 
Europe, respectively; however, they will be eligible for rollover into the ARC004 
protocol because tolerating a 300 mg (443 mg cumulative) dose of peanut protein is 
considered a clinically relevant level of desensitization in the event of accidental 
exposure. 
A Data Safety Monitoring Committee (DSMC) will be established to monitor the 
study for safety.  
Study Duration 
Approximately 12 months (44 to 68 weeks) 
Primary Endpoint 
North America: The primary clinical efficacy endpoint is the proportion of 
subjects aged 4 to 17 years who tolerate a single highest dose of at least 600 mg 
(1043 mg cumulative) of peanut protein with no more than mild symptoms at the 
Exit DBPCFC 
Europe: The primary clinical efficacy endpoint is the proportion of subjects aged 
4 to 17 years who tolerate a single highest dose of at least 1000 mg (2043 mg 
cumulative) of peanut protein with no more than mild symptoms at the Exit 
DBPCFC 
Secondary Endpoints 
Key Secondary Endpoints, North America   
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest 
dose of at least 300 mg (443 mg cumulative) of peanut protein with no more 
than mild symptoms at the Exit DBPCFC 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest 
dose of at least 1000 mg (2043 mg cumulative) of peanut protein with no more 
than mild symptoms at the Exit DBPCFC 
• 
The maximum severity of symptoms in subjects aged 4 to 17 years occurring at 
any challenge dose of peanut protein during the Exit DBPCFC 
• 
The proportion of subjects aged 18 to 55 years who tolerate a single highest 
dose of at least 600 mg (1043 mg cumulative) of peanut protein with no more 
than mild symptoms at the Exit DBPCFC 
Key Secondary Endpoints, Europe  
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest 
dose of at least 600 mg (1043 mg cumulative) of peanut protein with no more 
than mild symptoms at the Exit DBPCFC 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest 
dose of at least 300 mg (443 mg cumulative) of peanut protein with no more 
than mild symptoms at the Exit DBPCFC 
• 
The maximum severity of symptoms in subjects aged 4 to 17 years occurring at 
any challenge dose of peanut protein during the Exit DBPCFC 
• 
The proportion of subjects aged 18 to 55 years who tolerate a single highest 
dose of at least 1000 mg (2043 mg cumulative) of peanut protein with no more 
than mild symptoms at the Exit DBPCFC 
 
 

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31 July 2017 
Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
Other Secondary Endpoints, North America and Europe 
• 
Maximum dose achieved with no or mild symptoms at Exit DBPCFC in 
subjects aged 4 to 17 years 
• 
Change from baseline in maximum tolerated dose (MTD) of peanut protein at 
DBPCFC in subjects aged 4 to 17 years 
• 
Use of epinephrine as a rescue medication at Exit DBPCFC and comparison to 
its use at Screening DBPCFC in subjects aged 4 to 17 years 
• 
Changes in peanut-specific serum IgE and IgG4 levels in subjects aged 4 to 
17 years 
• 
Changes in peanut skin prick test (SPT) mean wheal diameters in subjects aged 
4 to 17 years  
• 
Quality of life assessment using the food allergy related quality of life 
questionnaire (FAQLQ), and the food allergy independent measure (FAIM) 
questionnaire in subjects aged 4 to 17 years 
Secondary Safety 
Endpoints 
Secondary Safety Endpoints, North America and Europe: 
• 
The safety of peanut OIT based on adverse events (AEs) including serious 
adverse events (SAEs) in the following 5 age groups: 4 to 17 years, 4 to 
11 years, 12 to 17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Use of epinephrine as a rescue medication during OIT (Initial Escalation, 
Up-dosing, and Maintenance Periods) in the following 5 age groups: 4 to 
17 years, 4 to 11 years, 12 to 17 years, 18 to 55 years, and 4 to 55 years, 
inclusive 
• 
Frequency of anaphylaxis during OIT (Initial Escalation, Up-dosing, and 
Maintenance Periods) in the following 5 age groups: 4 to 17 years, 4 to 
11 years, 12 to 17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Frequency of allergic reaction (hypersensitivity) AEs occurring during the 
Up-dosing versus the Maintenance Period, normalized for duration of 
treatment in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 
17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Frequency of accidental ingestions of peanut and other allergenic foods in the 
following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 18 to 
55 years, and 4 to 55 years, inclusive 
• 
Severity of adverse events associated with accidental ingestions of peanut and 
other allergenic foods in the following 5 age groups: 4 to 17 years, 4 to 
11 years, 12 to 17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Frequency of premature discontinuation of dosing due to AEs; and frequency 
of premature discontinuation of dosing due to chronic/recurrent gastrointestinal 
(GI) AEs in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 
17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Assessment of asthma control using the Asthma Control Test questionnaire in 
in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 18 to 
55 years, and 4 to 55 years, inclusive  
Exploratory Endpoints 
Exploratory Endpoints, North America and Europe 
• 
The primary endpoints identified above will be repeated in the following 3 age 
groups: 4 to 11 years, 12 to 17 years, and 4 to 55 years, inclusive   

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31 July 2017 
Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
• 
The first 3 key secondary endpoints and all other secondary endpoints 
identified above will be repeated in the following 4 age groups: 4 to 11 years, 
12 to 17 years, 18 to 55 years, and 4 to 55 years, inclusive  
• 
Treatment satisfaction assessment using the Treatment Satisfaction 
Questionnaire for Medication (TSQM-9), an exit questionnaire, and 
palatability questions 
• 
(North America sites only) Optional mRNA expression patterns in saliva 
obtained longitudinally from peanut-allergic participants undergoing OIT in 
ARC003 (Appendix 6) 
Study Product and 
Dispensing  
AR101 or placebo. Doses characterized and normalized for total protein and 
specific peanut allergen ratios will ascend per the dosing regimen outlined below. 
Study product will be provided in pull-apart capsules formulated to contain 0.5, 1, 
10, 20, and 100 mg of peanut protein. Matching placebo capsules identical to the 
active capsules will be used to maintain double-blinded conditions. For the 
Maintenance Period, 300 mg of peanut protein will be formulated in foil-laminate 
sachets. Matching placebo sachets will be used to maintain the double-blind. Study 
products will be shipped directly to the investigational site or the investigational 
site’s pharmacy, depending on the investigational site’s institutional requirements. 
Trained investigational site personnel will dispense the study product to the subject 
or the subject’s parent or guardian in a manner consistent with the assigned dose 
level. Study product will be dispensed in double-blinded fashion according to 
subject randomization number, using an interactive voice/web response system.  
Inclusion Criteria 
• 
Age 4 through 55 years (inclusive) 
• 
Clinical history of allergy to peanuts or peanut-containing foods 
• 
Serum IgE to peanut of ≥ 0.35 kUA/L [determined by UniCAPTM within the 
past 12 months] and/or a SPT to peanut ≥ 3 mm compared to control 
• 
Experience dose-limiting symptoms at or before the 100 mg challenge dose 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 
• 
Written informed consent from adult subjects 
• 
Written informed consent from parent/guardian for minor subjects 
• 
Written assent from minor subjects as appropriate (eg, above the age of 7 years 
or the applicable age per local regulatory requirements) 
• 
Use of effective birth control by female subjects of child-bearing potential 
• 
Not be residing at the same address as another subject in this or any peanut 
OIT study 
Exclusion Criteria 
• 
History of cardiovascular disease, including uncontrolled or inadequately 
controlled hypertension (see also Section 5.10 Prohibited Medications) 
• 
History of severe or life-threatening episode of anaphylaxis or anaphylactic 
shock within 60 days of Screening DBPCFC 
• 
History of chronic disease (other than asthma, atopic dermatitis, or allergic 
rhinitis) that is, or is at significant risk of becoming, unstable or requiring a 
change in chronic therapeutic regimen 
• 
History of eosinophilic esophagitis (EoE), other eosinophilic gastrointestinal 
disease, chronic, recurrent, or severe gastroesophageal reflux disease (GERD), 

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31 July 2017 
Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
symptoms of dysphagia (eg, difficulty swallowing, food “getting stuck”), or 
recurrent gastrointestinal symptoms of undiagnosed etiology 
• 
Current participation in any other interventional study 
• 
Subject is in “build-up phase” of immunotherapy to another allergen (ie, has 
not reached maintenance dosing) 
• 
Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2) 
• 
Mild or moderate asthma (2007 NHLBI Criteria Steps 1-4), if uncontrolled or 
difficult to control as defined by any of the following: 
o 
Forced expiratory volume in 1 second (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) or 
o 
Inhaled corticosteroid (ICS) dosing of > 500 mcg daily fluticasone (or 
equivalent ICSs based on National Heart, Lung, and Blood Institute 
[NHLBI] dosing chart) or 
o 
One hospitalization in the past year prior to screening for asthma or  
o 
Emergency room (ER) visit for asthma within 6 months prior to 
screening 
• 
History of steroid medication use (via intravenous [IV], intramuscular [IM] or 
oral administration) in any of the following manners:  
o 
History of daily oral steroid dosing for > 1 month during the past year or 
o 
Burst oral (IM or IV) steroid course in the past 3 months prior to 
randomization or 
o 
> 2 burst oral (IM or IV) steroid courses in the past year ≥1 week in 
duration 
• 
Inability to discontinue antihistamines 5 half-lives before the initial day of 
escalation, skin prick testing, or DBPCFC 
• 
Lack of an available palatable vehicle food to which the subject is not allergic 
• 
Use of any therapeutic antibody (eg omalizumab, mepolizumab, reslizumab, 
etc.), any investigational peanut immunotherapy (eg oral, sublingual, 
epicutaneous), or any other immunomodulatory therapy excluding 
corticosteroids within the past 6 months (see also Section 5.10 Prohibited 
Medications)  
• 
Use of beta-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin-receptor blockers (ARB) or calcium channel blockers (see also 
Section 5.10 Prohibited Medications) 
• 
Pregnancy or lactation 
• 
Having the same place of residence as another subject in the study 
• 
Participation in another clinical trial within 30 days or 5 half-lives of the 
investigational product, whichever is longer, prior to randomization 
• 
Developing dose limiting symptoms in reaction to the placebo part of the 
Screening DBPCFC 
• 
History of a mast cell disorder, including mastocytosis, urticaria pigmentosa, 
and hereditary or idiopathic angioedema 
• 
Allergy to oat 
• 
Hypersensitivity to epinephrine and any of the excipients in the product 

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Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
Treatment Description 
Screening/baseline: All eligible subjects will undergo a DBPCFC at the end of the 
screening portion of the study. The Screening DBPCFC will be an abbreviated 
version of the DBPCFC described in the PRACTALL guidelines, progressing only 
up to a top challenge dose of 100 mg (144 mg cumulative) of peanut protein or 
placebo. Additionally, the DBPCFC will progress through the dose levels in an 
unaltered sequence, without repeating any dose. Those subjects who have dose-
limiting symptoms (DLSs) at or before the 100 mg (144 mg cumulative) challenge 
dose of peanut protein (measured as 200 mg of peanut flour) will be randomized 3:1 
to active treatment (AR101) or placebo.  
For each subject, a “blinded” Evaluating Physician is to be designated to assess the 
tolerability of the challenge doses presented in the DBPCFC. The Blinded 
Evaluating Physician (or Blinded Assessor) is not to be involved directly in the 
oversight of study product dosing (neither initial escalation, nor up-dosing, nor 
maintenance), nor the assessment or management of adverse events. To the extent 
practicable, the same Blinded Evaluating Physician who determines DLSs in the 
Screening DBPCFC should determine DLSs in the Exit DBPCFC. 
Initial Escalation (2 days): Eligible subjects will initiate OIT starting at a dose of 
0.5 mg of peanut protein, and then increase the dose incrementally at 20 to 
30 minute intervals over the course of a single day to a maximum dose of 6 mg. 
Subjects who fail to tolerate at least a 3 mg dose will be considered escalation 
failures. Subjects who tolerate both the 3 mg and 6 mg doses of study product, or 
who tolerate the 3 mg, but not the 6 mg dose, will undergo confirmatory testing of 
the tolerability of a 3 mg dose the following day (refer to Initial Escalation Schedule 
at end of synopsis). Therapy details are found in Section 3 and Section 6 of the 
protocol. 
Up-dosing: Subjects will receive daily oral dosing of peanut or placebo OIT for 
about 5 months (20 weeks, if up-dosing proceeds without holding at, or reducing, a 
dose level; 40 weeks, maximum). All escalation doses (see escalation table below) 
will occur in a clinical research center (CRC) or other monitored setting (unless 
required by a specific institution, no distinction will be drawn between an 
investigational site, study center office, clinic, or CRC, provided the capability 
requirements for monitoring and emergency intervention are met by the facility). 
All up-dosing activities will be performed under direct observation. Therapy details 
are found in Section 3 and Section 6 of the protocol.  
Maintenance: Those subjects who reach the target maintenance dose of 300 mg/d of 
study product will enter an approximately 24-week Maintenance Period of 
continued dosing at 300 mg/d.  
Exit DBPCFC: Following completion of the ~24-week Maintenance Period, 
subjects will undergo an Exit DBPCFC (to a cumulative maximum of 2043 mg of 
peanut protein). Subjects who fail to tolerate the Exit DBPCFC at 300 mg (443 mg 
cumulative) of peanut protein will be discontinued from further study (Section 3.3 
for details). 

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Protocol ARC003 Synopsis 
Title 
PEANUT ALLERGY ORAL IMMUNOTHERAPY STUDY OF AR101 FOR 
DESENSITIZATION IN CHILDREN AND ADULTS (PALISADE) 
Study Procedures 
The following procedures will be performed according to the scheduled visits 
tabulated in Appendix 1: 
• 
Informed consent (and assent, as age appropriate) 
• 
Inclusion/exclusion criteria 
• 
Medical/allergy history  
• 
Concomitant medications 
• 
Physical examination, including height and weight 
• 
Vital signs (BP, PR, temperature) 
• 
Spirometry (FEV1) and/or Peak Expiratory Flow Rate (PEFR) 
• 
Pregnancy test 
• 
Diet history 
• 
Blood draw for peanut-specific IgE (including, at screening only, 
determination of Ara h 1, Ara h 2, Ara h 3, Ara h 8 and Ara h 9 IgE 
components) and IgG4 serum levels (immunoglobulin assays) 
• 
Complete blood cell count (CBC), obtained with the same venipuncture as the 
blood draw for the immunoglobulin assays 
• 
Additional blood samples for optional exploratory immune cell 
characterization by the Immune Tolerance Network (ITN). These can be 
obtained with the same venipuncture as the blood draw for the 
immunoglobulin assays (separate informed consent required). 
• 
Optional collection of saliva sample for exploratory biomarker development 
(separate informed consent required) 
• 
Optional post-DBPCFC blood draws for exploratory immune cell 
characterization by the ITN (separate informed consent required) 
• 
Skin prick test (SPT) 
• 
Clinical research center study product administration 
• 
Dispensing of study products for home dosing/Return of unused study products 
• 
Dose assessment to decide appropriateness of up-dosing or maintenance 
• 
Peak Expiratory Flow Rate (PEFR) prior to any DBPCFC 
• 
DBPCFC, performed in accordance with PRACTALL guidelines, but with the 
protocol-specified modifications 
• 
Quality of life assessment using the food allergy related quality of life 
questionnaire (FAQLQ), and the food allergy independent measure (FAIM) 
questionnaire 
• 
Monitoring for dosing compliance 
• 
Adverse event (AE) monitoring 
• 
Assessment of asthma control using the Asthma Control Test questionnaire in 
subjects with asthma 
• 
Assessment of treatment satisfaction using TSQM-9, exit questionnaires and 
palatability questions 
 

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31 July 2017 
Protocol ARC003 Synopsis 
Initial Escalation Period, Day-1, Dosing Schedule 
Day-1 
Dose # 
Study Product Dose 
(mg peanut protein or placebo) 
Cumulative Study Product Dose 
(mg peanut protein or placebo) 
1 
0.5 
0.5 
2 
1 
1.5 
3 
1.5 
3 
4 
3 
6 
5 
6 
12 
Doses will be delivered at 20 to 30 minute intervals. 
Subjects who are unable to tolerate a dose of 3 mg at the end of Day -1 will be considered an initial day 
escalation failure. 
All subjects who tolerate a dose of at least 3 mg on Day -1 will return on Day -2 to receive a single confirmatory 
3 mg dose under direct observation. 
Subjects with either no symptoms or mild, non-dose-limiting symptoms after receiving 3 mg on Day -2 are to 
start 2 weeks of daily dosing at 3 mg. 
Subjects who experience moderate or severe symptoms after receiving the 3 mg dose on Day -2 will be 
considered escalation failures.  
Future dose escalations will occur every 2 weeks with the initial dose increase administered in the clinical 
research center. 

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Protocol ARC003 Synopsis 
Up-dosing Period Dosing Schedule 
Up-dosing 
Dose # 
Study Product Dose 
(mg peanut protein or 
placebo) 
Interval (weeks) 
% Increase 
1 
3 
2 
 
2 
6 
2 
100% 
3 
12 
2 
100% 
4 
20 
2 
67% 
5 
40 
2 
100% 
6 
80 
2 
100% 
7 
120 
2 
50% 
8 
160 
2 
33% 
9 
200 
2 
25% 
10 
240 
2 
20% 
11 
300 
24-Week Maintenance Period 
25% 
Capsules and sachets (introduced during the Maintenance Period) are opened, contents sprinkled over an 
age-appropriate food, and mixed thoroughly. 300 mg capsules will be used for at least the first 2 weeks of dosing 
during the 24-Week Maintenance Period. 

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31 July 2017 
Table of Contents 
1 
BACKGROUND AND RATIONALE........................................................................................22 
1.1 
Background .................................................................................................................................... 22 
1.2 
Peanut OIT ..................................................................................................................................... 24 
1.2.1 
Published Literature on OIT Studies .............................................................................................. 24 
1.2.2 
Clinical Trials Sponsored by Aimmune ......................................................................................... 25 
1.2.2.1 Results of ARC001, A Phase 2 Study ............................................................................................ 25 
1.2.2.2 ARC003, A Phase 3 Study with AR101 ........................................................................................ 28 
1.2.2.3 ARC004, A Phase 3 Follow-on Study with AR101 ....................................................................... 28 
1.3 
Rationale for Selection of Study Population .................................................................................. 28 
1.4 
Rationale for Selection of Study Drug Regimen (Dose and Duration) .......................................... 29 
1.5 
Rationale for the Doses Used for the DBPCFC ............................................................................. 30 
1.6 
Known and Potential Risks and Benefits to Human Participants .................................................. 30 
1.6.1 
Risks............................................................................................................................................... 30 
1.6.2 
Benefits .......................................................................................................................................... 32 
2 
OBJECTIVES .......................................................................................................................32 
2.1 
Primary Objective .......................................................................................................................... 32 
2.2 
Secondary Objective(s) .................................................................................................................. 32 
3 
STUDY DESIGN ...................................................................................................................32 
3.1 
Screening Period ............................................................................................................................ 33 
3.2 
Treatment Phase ............................................................................................................................. 34 
3.3 
Exit DBPCFC ................................................................................................................................ 36 
3.4 
Follow-on Study ARC004 ............................................................................................................. 37 
3.5 
Study Design Safety Considerations .............................................................................................. 37 
3.6 
Primary Efficacy Endpoint ............................................................................................................ 38 
3.6.1 
Primary Efficacy Endpoint, North America .................................................................................. 38 
3.6.2 
Primary Efficacy Endpoint, Europe ............................................................................................... 38 
3.7 
Secondary Endpoints ..................................................................................................................... 38 
3.7.1 
Key Secondary Endpoints .............................................................................................................. 38 
3.7.2 
Other Secondary Endpoints, North America and Europe .............................................................. 39 
3.7.3 
Secondary Safety Endpoints, North America and Europe ............................................................. 39 
3.8 
Exploratory Endpoints, North America and Europe ...................................................................... 40 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................................40 
4.1 
Inclusion Criteria ........................................................................................................................... 40 
4.2 
Exclusion Criteria .......................................................................................................................... 40 
4.3 
Premature Subject Termination from the Study ............................................................................ 42 
4.3.1 
Criteria ........................................................................................................................................... 42 

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4.3.2 
Follow-up of Subjects Who Discontinue Treatment ...................................................................... 43 
5 
STUDY MEDICATION .........................................................................................................44 
5.1 
Formulation, Packaging and Labeling ........................................................................................... 44 
5.2 
Preparation, Administration and Dosage ....................................................................................... 44 
5.3 
Drug Accountability....................................................................................................................... 45 
5.4 
Assessment of Compliance with Study Treatment and Monitoring .............................................. 46 
5.5 
Modification of Study Treatment ................................................................................................... 46 
5.6 
Concomitant Medications .............................................................................................................. 46 
5.7 
Prophylactic Medications ............................................................................................................... 46 
5.8 
Rescue Medications for Acute Allergic Reactions ........................................................................ 46 
5.9 
Symptomatic Treatment for Chronic and/or Recurrent Adverse Events ....................................... 46 
5.10 
Prohibited Medications .................................................................................................................. 47 
6 
STUDY PROCEDURES .........................................................................................................48 
6.1 
Enrollment and Randomization ..................................................................................................... 48 
6.2 
Screening and Baseline .................................................................................................................. 48 
6.2.1 
Optional Post-DBPCFC Blood Draw Visit .................................................................................... 50 
6.3 
Study Treatment Visits .................................................................................................................. 50 
6.3.1 
Initial Escalation ............................................................................................................................ 50 
6.3.1.1 Initial Escalation, Day-1 ................................................................................................................ 50 
6.3.1.2 Initial Escalation, Day -2 ............................................................................................................... 52 
6.3.2 
Up-dosing (also Referred to as Buildup or Escalation) Visits ....................................................... 53 
6.3.3 
Up-dosing Midpoint Visit .............................................................................................................. 55 
6.3.4 
End of Up-dosing / Start of Maintenance Period Visit .................................................................. 56 
6.3.5 
Maintenance Period Visits ............................................................................................................. 57 
6.4 
Unscheduled Visits / Unscheduled Blood Draws .......................................................................... 58 
6.5 
Exit Visit / Early Discontinuation Visit ......................................................................................... 58 
6.6 
Double-Blind, Placebo Controlled Food Challenge (DBPCFC) .................................................... 60 
6.6.1 
Screening Double-Blind, Placebo Controlled Food Challenge (DBPCFC) ................................... 62 
6.6.2 
Exit Double-Blind, Placebo Controlled Food Challenge (DBPCFC) ............................................ 63 
6.7 
Assessment and Treatment of Allergic Reactions to Peanut OIT .................................................. 64 
6.7.1 
Assessment of the Severity of Acute Allergic Reactions to Peanut OIT ....................................... 64 
6.7.2 
Assessment of the Tolerability of an Individual Dose of Study Product ....................................... 64 
6.7.3 
Assessment of the Tolerability of a Dose Level ............................................................................ 66 
6.7.3.1 Assessment of Acute Symptoms Occurring after Dosing .............................................................. 66 
6.7.3.2 Assessment of Chronic / Recurrent Symptoms .............................................................................. 66 
6.7.4 
Treatment of Acute Reactions to Peanut OIT during Initial Escalation ........................................ 67 
6.7.5 
Treatment for Reactions During the Up-dosing Period: Dose Adjustment ................................... 69 
6.7.5.1 Reactions to In-Clinic Dosing ........................................................................................................ 70 
6.7.5.2 Reactions to Dosing at Home ........................................................................................................ 72 

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6.7.5.3 Dose Adjustment in Response to Adverse Events ......................................................................... 75 
6.7.6 
Treatment for Reactions During the Up-dosing Period: Pharmacological and Supportive 
Treatments ..................................................................................................................................... 75 
6.7.7 
Reactions Occurring During the Maintenance Period ................................................................... 77 
6.8 
Missed Peanut OIT (Study Product) Doses during Up-dosing: ..................................................... 77 
6.9 
Skin Prick Test ............................................................................................................................... 78 
6.10 
Assessment of Asthma Control Using the Asthma Control Test Questionnaire ............................ 78 
6.11 
Visit Windows ............................................................................................................................... 78 
6.12 
Study Blinding Procedures ............................................................................................................ 78 
6.12.1 Securing Blinding and Randomization Information ...................................................................... 79 
6.12.2 Requirements for an Unblinding .................................................................................................... 79 
6.12.3 Breaking the Blind ......................................................................................................................... 80 
6.12.4 Documenting and Unblinding ........................................................................................................ 80 
7 
SAFETY MONITORING .......................................................................................................80 
7.1 
Definitions for Recording of Safety Events ................................................................................... 80 
7.2 
Dosing Symptoms as Adverse Events ........................................................................................... 81 
7.3 
Accidental Food Exposures ........................................................................................................... 82 
7.4 
Definitions ..................................................................................................................................... 82 
7.4.1 
Adverse Event (AE) or Medical Event .......................................................................................... 82 
7.4.2 
Serious Events (Serious Adverse Events, Serious Suspected Adverse Reactions or Serious 
Adverse Reactions) ........................................................................................................................ 82 
7.4.3 
AEs of Special Interest ................................................................................................................... 83 
7.4.3.1 Anaphylaxis ................................................................................................................................... 83 
7.4.3.2 Gastrointestinal Adverse Events Resulting in Prolonged Disruption of Dosing ........................... 83 
7.4.4 
Unexpected Adverse Event ............................................................................................................ 85 
7.5 
Adverse Event Monitoring ............................................................................................................. 85 
7.5.1 
Data Safety Monitoring Committee ............................................................................................... 85 
7.5.2 
Adjudication Committee ................................................................................................................ 85 
7.6 
Severity Grading ............................................................................................................................ 85 
7.6.1 
Guidelines for Determining Causality of an Adverse Event .......................................................... 86 
7.7 
Adverse Event Collection Procedures............................................................................................ 86 
7.7.1 
Recording and Reporting Procedures ............................................................................................ 87 
7.7.2 
SAE Recording and Reporting Procedures .................................................................................... 87 
7.7.2.1 Reporting Criteria .......................................................................................................................... 88 
7.8 
Serious Adverse Event Notification ............................................................................................... 88 
7.8.1 
Notifying the Sponsor .................................................................................................................... 88 
7.8.2 
Expedited SAEs Reporting to Regulatory Health Authorities and DSMC .................................... 89 
7.8.3 
Notifying the Data Safety Monitoring Committee ........................................................................ 89 
7.8.4 
Notifying the Institutional Review Board and Ethics Committee ................................................. 89 
7.9 
Other Safety Assessments and Precautions ................................................................................... 89 
7.9.1 
Physical Examination and Vital Signs ........................................................................................... 89 

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7.9.2 
Prior and Concomitant Medications .............................................................................................. 90 
7.9.3 
Pregnancy Testing and Contraception ........................................................................................... 90 
7.9.3.1 Pregnancy Testing .......................................................................................................................... 90 
7.9.3.2 Contraception ................................................................................................................................. 90 
7.10 
Stopping Rules ............................................................................................................................... 90 
7.10.1 Overall Stopping Rules .................................................................................................................. 90 
7.10.2 Individual Stopping Rules .............................................................................................................. 91 
8 
MECHANISTIC ASSAYS ......................................................................................................91 
8.1 
Peanut-Specific Antibody (Immunoglobulin) Assays ................................................................... 91 
8.2 
Optional Immune Cell Characterization ........................................................................................ 92 
8.2.1 
Optional Additional Blood Volume ............................................................................................... 92 
8.2.2 
Optional Post-DBPCFC Blood Draws ........................................................................................... 92 
8.3 
Optional Oral Biomarker Substudy ............................................................................................... 92 
9 
STATISTICAL CONSIDERATIONS........................................................................................93 
9.1 
Analysis Populations ...................................................................................................................... 93 
9.2 
Study Endpoint Assessment ........................................................................................................... 94 
9.2.1 
Primary Endpoint ........................................................................................................................... 94 
9.2.2 
Secondary Endpoints ..................................................................................................................... 94 
9.2.2.1 Analysis of Key Secondary Endpoints........................................................................................... 95 
9.2.2.2 Analysis of Other Selected Secondary Endpoints .......................................................................... 97 
9.2.3 
Supportive Analyses of Primary and Secondary Endpoints .......................................................... 97 
9.3 
Subject and Demographic Data ..................................................................................................... 97 
9.3.1 
Study Disposition ........................................................................................................................... 97 
9.3.2 
Baseline Characteristics and Demographics .................................................................................. 98 
9.3.3 
Use of Medications ........................................................................................................................ 98 
9.4 
Sample Size and Power Calculations ............................................................................................. 98 
10 
IDENTIFICATION AND ACCESS TO SOURCE DATA ..........................................................100 
10.1 
Web-Based Data Collection and Management System ............................................................... 100 
10.2 
Certification in the Use of Web-Based Data Entry System ......................................................... 100 
10.3 
Data Management ........................................................................................................................ 100 
10.4 
Access to Data ............................................................................................................................. 100 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................................101 
11.1 
Statement of Compliance ............................................................................................................. 101 
11.2 
Informed Consent/Assent ............................................................................................................. 101 
11.3 
Privacy and Confidentiality ......................................................................................................... 101 
12 
RESOURCE SHARING .......................................................................................................101 

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13 
PROTOCOL DEVIATIONS .................................................................................................102 
13.1 
Major Protocol Deviation (Protocol Violation) ........................................................................... 102 
13.2 
Nonmajor Protocol Deviation ...................................................................................................... 102 
13.3 
Reporting and Managing Protocol Deviations ............................................................................. 102 
14 
REFERENCE LIST .............................................................................................................103 
 
List of Appendices 
Appendix 1: Schedule of Events ...............................................................................................109 
Appendix 2: Evaluation of Asthma ..........................................................................................112 
Appendix 3: Criteria for Suspected Diagnosis, and Severity Grading, of Anaphylaxis ...........113 
Appendix 4:  Allergic Reaction Severity Grading .....................................................................114 
Appendix 5:  Guidance for Determining When an Episode of Anaphylaxis Should Be 
Reported as a Serious Adverse Event (SAE) .......................................................115 
Appendix 6: (North America sites only) Exploratory Biochemical and Molecular Study of 
Peanut-Allergic Children and Adults with Oral Immunotherapy-Related 
Gastrointestinal Symptoms in ARC003 ...............................................................116 
 
 
List of Tables 
Table 3-1. 
Initial Dosing Schedule for Peanut OIT .................................................................35 
Table 3-2. 
Up-dosing Dosing Schedule for Peanut OIT .........................................................35 
Table 6-1. 
Modified PRACTALL DBPCFC Doses Using Peanut Flour with 50% 
Peanut Protein Content for Screening and Exit DBPCFC .....................................61 
Table 6-2.  
Allergy Symptom Severity and Study Product Dose Tolerability .........................65 
 
List of Figures 
Figure 3–1. 
Study Design…………………………………………………………………......33 
Figure 6–1: 
Schematic for Initial Escalation Day-1…………………………………………..69 
Figure 6–2. 
Schematic for Up-Dosing Period Dose Adjustment……………………………..74 
Figure 7–1. 
Reporting Decisions for Adverse Events………………………………………...88 
 

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Glossary of Abbreviations 
Abbreviation 
Definition 
AC 
Adjudication Committee 
ACE 
angiotensin-converting enzyme inhibitors 
AE 
adverse event 
AESI 
adverse event of special interest 
Ag 
Antigen 
ANCOVA 
analysis of covariance  
ARB 
angiotensin-receptor blockers 
ARC 
Allergen Research Corporation 
BP 
blood pressure 
CBC 
complete blood cell count 
CFR 
US Code of Federal Regulations 
CI 
confidence interval 
CODIT 
Characterized Oral Desensitization Immunotherapy 
CoFAR 
Consortium of Food Allergy Research 
CPNA (AR101) 
characterized peanut allergen 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBPCFCs  
Double-Blind, Placebo-Controlled Food Challenges 
DLS 
dose-limiting symptom 
DSMC 
Data Safety Monitoring Committee 
EAACI 
European Academy of Allergy and Clinical Immunology 
EC 
Ethics Committee 
EDC 
electronic data capture 
EGD 
Esophagogastroduodenoscopy 
ELISA 
enzyme-linked immunosorbent assays 
EoE 
eosinophilic esophagitis 
ER 
emergency room 
FAIM 
Food Allergy Independent Measure  
FAQLQ 
food allergy related quality of life questionnaire 
FDA 
US Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
GCP / cGCP 
Good Clinical Practice / Current Good Clinical Practice 
GERD 
gastroesophageal reflux disease 
GI 
Gastrointestinal 
GLMM 
generalized linear mixed model 

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Abbreviation 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HPLC 
high-performance liquid chromatography  
ICF 
informed consent form 
ICH 
International Council for Harmonisation for Pharmaceuticals for Human 
Use 
ICON 
international consensus 
ICS 
inhaled corticosteroid(s) 
IgA 
immunoglobulin A 
IgE 
immunoglobulin E 
IgG 
immunoglobulin G 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IP 
investigational product 
IRB 
Institutional Review Board 
ITN 
Immune Tolerance Network 
ITT 
intent to treat 
IV 
Intravenous 
kUA/L 
kilounits of antibody per liter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/d 
milligrams per day 
mITT 
modified intent to treat 
MMRM 
mixed models repeated measures 
MTD 
maximum tolerated dose 
NCI  
National Cancer Institute 
NHLBI 
National Heart, Lung, and Blood Institute 
OFC 
oral food challenge 
OIT 
oral immunotherapy 
PCA 
principal components analysis 
PCR 
polymerase chain reaction 
PEESS  
pediatric eosinophilic esophagitis symptom scores 
PEFR 
peak expiratory flow rate 
PI 
Principal Investigator 
PP 
per protocol 
PR 
pulse rate 
PRACTALL 
PRACTical issues in ALLergology Joint United States/European Union 
Initiative 
REB 
Research Ethics Board 
RNA 
ribonucleic acid 

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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
serious adverse reaction 
SLIT 
sublingual immunotherapy 
SPT 
skin prick test 
SUSAR 
suspected unexpected serious adverse reaction 
SVM 
support vector machine 
TEAE 
treatment emergent adverse event 
TSQM-9 
Treatment Satisfaction Questionnaire for Medication 
VAS 
visual analogue scale 
VITAL 
Voluntary Incidental Trace Allergen Labeling 
WHO  
World Health Organization 
 

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1 
BACKGROUND AND RATIONALE 
1.1 
Background 
Peanut allergy is a common and serious condition that often affects children, and is commonly 
associated with severe reactions, including life-threatening anaphylaxis. Peanut and/or tree nut 
allergies account for the majority of fatal food-induced anaphylaxis (Sampson et al., 2005). 
Furthermore, published reports suggest that the prevalence of peanut allergy, like other food 
allergies, has been rising, and is now at high levels, affecting up to 10% of the population. 
(Branum & Lukacs, 2008; Sicherer et al., 2014). Peanut allergy, unlike many other types of food 
allergy, is usually life-long, with approximately 80% of patients remaining peanut-allergic in 
adulthood.  
The current standard of care in management of food allergy is dietary avoidance of the allergenic 
food, and education of the patient/family in the acute management of an allergic reaction. 
Unfortunately, accidental ingestions remain common, with up to 50% of food-allergic patients 
having at least 1 allergic reaction over a 2-year period (Sicherer et al., 1998). Furthermore, strict 
adherence to an avoidance diet can be complicated due to difficulty in interpreting food labels 
(Joshi et al., 2002) and by the presence of undeclared or hidden allergens in commercially 
prepared foods (Altschul et al., 2001; Vierk et al., 2002). The burden of avoidance and constant 
fear of accidental exposure can negatively affect the health-related quality of life for both 
patients and their families (Primeau et al., 2000; Avery et al., 2003; Buchanan et al., 2007; 
Sicherer et al., 2010; Hofmann et al., 2009; Anagnostou et al., 2014). 
Despite efforts at strict peanut avoidance, accidental exposure continues to be a major concern in 
peanut allergy because allergic responses can be triggered after ingestion of just milligram 
quantities of peanut protein. Accidental exposures may result from commercial food product 
mislabeling as well as inattention to, or mistrust of, food warning labels (Vierk et al., 2007). 
Foods prepared outside the home, including those encountered in schools, daycares, restaurants, 
or even the homes of friends and relatives present another ready source of accidental exposures. 
Oftentimes the origin of the accidental exposure remains unknown. The threat of accidental 
exposure and its consequences for patients with peanut allergy and their families continues to 
drive research in the field of food allergy.  
While advances in understanding the causes of food allergy, strategies for food-allergy 
prevention, and the mechanisms underlying tolerance continue to be made, a cure for food 
allergy remains elusive. In the meantime, therapies with the potential to reduce the risk of severe 
allergic reaction in the event of an accidental exposure to an allergenic food continue to be 
developed. An approach that has shown consistently promising results is allergen-specific 
immunotherapy, a therapy that entails administration of increasing amounts of an allergen to 
individuals with IgE-mediated food allergy to raise the threshold and decrease the severity of 
allergic responses to the allergenic food. These allergen-based immunotherapies include 
sublingual, epicutaneous, and most advanced among these, oral immunotherapy (OIT).  
Oral immunotherapy for peanut allergy has been widely studied in recent years and has 
demonstrated encouraging safety and efficacy results in early clinical trials. Additionally, 
beneficial immunologic changes have been shown to occur over time that would tend to indicate 
progression toward a clinical state of sustained desensitization with continued OIT 

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(Oppenheimer et al., 1992; Secrist et al., 1995; Nelson et al., 1997; Kapsenberg et al., 1999; 
Lehrer et al., 1999; Frew et al 2003; Bousquet et al., 2004; Wilson et al., 2005; Skripak et al., 
2008; Jones et al., 2009; Narisety et al., 2009; Blumchen et al., 2010; Kim et al., 2011; 
Varshney et al., 2011). 
The goal of Aimmune Therapeutics’ characterized oral desensitization immunotherapy 
(CODITTM) program for peanut allergy is to induce a state of clinically meaningful 
desensitization to peanut protein, where clinically meaningful desensitization is defined as the 
absence of moderate or severe allergic reaction following ingestion of small, but potentially 
dangerous, amounts of peanut protein. In practical terms, this state of desensitization should be 
sufficient to protect a patient with peanut allergy in case of an accidental exposure to peanut 
while the patient is attempting to maintain a peanut- avoidant diet.  
It is unfortunately inherent in the nature of accidental exposures that the level of exposure is 
typically unknown. Nevertheless, it is generally believed that most clinically relevant accidental 
exposures to peanut protein occur at low levels. In 1 well documented case of accidental peanut 
ingestion, the amount ingested was calculated to be approximately 45 mg (McKenna & Klontz, 
1997). Moreover, work by French researchers that considered the peanut content of a variety of 
foods and the typical amounts of these foods consumed in a serving, showed that accidental 
exposures from peanut-contaminated or mislabeled foods are likely to occur at levels below 
15 mg of peanut protein (Rimbaud et al., 2013). While across the peanut-allergic population the 
threshold levels at which allergic reactions are triggered varies widely, approximately 25% of 
peanut-allergic individuals would be expected to react to 15 mg of peanut protein and 5% to as 
little as 0.5-1.5 mg, based on a cross-study retrospective analysis performed by the Voluntary 
Incidental Trace Allergen Labeling (VITAL) 2.0 study group (Remington 2013; Allen et al., 
2014). Moreover, fully half of the peanut allergic population would be expected to have an 
allergic reaction to no more than 100-150 mg of peanut protein. Accordingly, protection to the 
equivalent of 1 whole peanut kernel, containing approximately 250 to 300 mg of peanut protein, 
should afford a clinically meaningful level of protection against many accidental exposures to 
peanut.  
In its Phase 2 study, ARC001, Aimmune Therapeutics showed that a clinically meaningful level 
of protection, defined as the ability to consume a maximum single dose of 300 mg and a 
cumulative dose of 443 mg in a double-blind, placebo-controlled food challenge (DBPCFC), an 
ethically acceptable model for accidental exposure, was achievable with daily dosing of AR101, 
a highly characterized, pharmaceutical grade formulation of defatted peanut flour, when 
administered in a controlled OIT regimen. As presented in greater detail below, 79% of subjects 
who embarked on the OIT regimen in ARC001 were able to achieve the target dose of 300 mg/d, 
after completing an up-dosing period that lasted, on average, approximately 20 weeks. Following 
just an additional 2 weeks of maintenance therapy at 300 mg/d, all subjects (ie, 23 of the 
29 originally randomized to active treatment) were able to tolerate at least 443 mg cumulative of 
peanut protein with no more than mild symptoms in a DBPCFC.  
It is, however, well known from clinical experience, and documented in clinical trials, that a 
peanut-allergic patient’s threshold sensitivity to peanut can vary day to day by as much as two 
orders of magnitude (Glaumann et al., 2013). Also, accidental exposures of up to 1000 mg can 
occur from taking a single, inadvertent, bite of a peanut-dense food, such as a peanut candy or a 

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peanut butter sandwich. Hence, in the current Phase 3 study, Aimmune has chosen to test if a 
significantly greater proportion of subjects undergoing OIT to a maintenance dose of 300 mg/d 
of peanut protein as AR101, as compared to placebo, will be able to tolerate at least 1043 mg 
cumulative of peanut protein with no more than mild symptoms in a DBPCFC after completing 
approximately 12 months of treatment.  
1.2 
Peanut OIT 
1.2.1 Published Literature on OIT Studies  
A number of clinical trials of OIT for peanut allergy have been completed and their results 
published, including 4 open-label studies (Jones et al., 2009; Hofmann et al., 2009; Blumchen et 
al., 2010; Yu et al., 2012), a randomized, double-blind, placebo-controlled study 
(Varshney et al., 2011), and a randomized, contemporaneous natural history-controlled study 
(Anagnostou et al., 2014). All have shown peanut OIT to induce a clinically meaningful level of 
desensitization and to be overall safe and well-tolerated when performed in a supervised medical 
setting by trained personnel. All of the studies tested for desensitization by oral food challenge 
(OFC) after subjects had gone through a period of up-dosing with increasing amounts of peanut 
protein followed by a period of maintenance therapy. The two randomized controlled studies are 
discussed in greater detail below. 
• 
Varshney et al., 2011 used peanut flour as the desensitizing agent in the first multicenter, 
double-blinded, randomized, placebo-controlled study of OIT as a treatment for peanut 
allergy. The peanut flour used in their trial came from the same manufacturer that 
supplies the starting material for AR101 to Aimmune. They enrolled 28 subjects aged 
1 to 16 years. After completing up-dosing to 4000 mg (a much higher level than is 
proposed in the AR101 trial) over a 44-week period, subjects were maintained at that 
dose for 1 month and then returned at week 48 for a DBPCFC. Three peanut OIT subjects 
withdrew early in the study because of allergic side effects. In the DBPCFC all remaining 
peanut OIT subjects (n = 16) ingested the maximum cumulative dose of 5000 mg of 
peanut protein (approximately 20 peanuts), whereas placebo patients (n = 9) could 
tolerate only a median cumulative dose of 280 mg (range, 0-1900 mg; p < 0.001). In 
contrast with the placebo group, the peanut OIT group showed reductions in skin prick 
test wheal size (p < 0.001) and increases in peanut-specific IgG4 (p < 0.001). Peanut OIT 
subjects had initial increases in peanut-specific IgE (p < 0.01), but this had returned to 
baseline by the time of oral food challenge. 
• 
Anagnostou et al., 2014 (STOP II trial): This single center randomized controlled 
crossover trial in 99 children aged between 7 and 16 years conducted in the UK used 
peanut flour as the desensitizing agent that, like the Varshney et al., 2011 study, came 
from the same manufacturer that supplies the starting material for AR101. The primary 
outcome was desensitization, defined as a negative peanut challenge to 1400 mg 
cumulative of peanut protein in a DBPCFC, after a total of 6 months of OIT and a 
maintenance dose of 800 mg/d of peanut protein. Daily dosing with 800 mg of peanut 
protein was tolerated by 84% of the children. Desensitization, was reported for 62% of 
the children in the active arm and 0% of children in the control arm. Also, quality-of-life 
scores improved (decreased) after OIT (median change –1·61; p < 0.001) relative to 
baseline in within-group comparisons. While this trial used a different dosage regimen 

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than is planned for use with AR101, it provides supportive evidence for the efficacy of a 
peanut flour-based product in OIT for desensitizing children with peanut allergy. 
The results of these controlled studies are consistent with the results from open-label studies 
(Hofmann et al., 2009; Jones et al., 2009; Blumchen et al., 2010; Yu et al., 2012). Dosing 
symptoms typically associated with OIT across the various protocols have included rash, 
wheezing, rhinorrhea, sneezing, itching, abdominal pain, nausea, vomiting, and diarrhea. The 
vast majority of symptoms have been mild and consistent with stimulation of a transient, 
low-grade allergic reaction; and across the trials a trend for symptoms to diminish with 
increasing duration of treatment has been evident. Peanut OIT has consistently been assessed to 
be overall safe and well tolerated in the clinical trial setting, but the authors of even recent 
review articles on the subject conclude that additional work needs to be conducted before OIT 
for peanut allergy is ready for widespread adoption in clinical practice (eg, Campbell 2014; 
Trendelenburg et al., 2014; Nurmatov et al., 2014; Le & Burks, 2014). 
The previously published clinical trial findings from peanut-allergic patients ranging in age from 
1 to 65 years old, provided the basis for the Phase 2 trial, ARC001, conducted by Aimmune 
Therapeutics, to investigate the efficacy and safety of AR101 in desensitizing peanut-allergic 
subjects.  
1.2.2 Clinical Trials Sponsored by Aimmune  
1.2.2.1 Results of ARC001, A Phase 2 Study  
Study design: ARC001 was a multicenter, randomized, double-blind placebo-controlled study of 
efficacy and safety of AR101 (characterized peanut allergen) OIT in peanut-allergic children and 
adults (4 to 21 years of age). ARC001 had a Data Safety Monitoring Committee (DSMC) to 
monitor the study for safety. The study consisted of a screening period, an initial escalation 
period, a double-blind OIT treatment (up-dosing and maintenance) period, followed by a 
double-blind, placebo controlled food challenge (DBPCFC).  
Screening/baseline: All eligible subjects underwent a DBPCFC of up to 100 mg (143 mg 
cumulative) of peanut protein or placebo during the screening portion of the study. The 
Screening DBPCFC was an abbreviated version of the DBPCFC described in the PRACTALL 
guidelines using up to 100 mg (143 mg cumulative) of peanut protein or placebo. Additionally, 
the DBPCFC progressed through the dose levels in an unaltered sequence without repeating any 
dose. Those subjects who had dose-limiting symptoms at or before the 100 mg (143 mg 
cumulative) challenge dose of peanut protein (measured as 200 mg of peanut flour) were 
randomized 1:1 to AR101 or placebo.  
Up-dosing OIT treatment: Subjects received daily oral dosing of AR101 or placebo OIT for 
about 6 to 9 months. All escalation doses occurred in a clinical research center or other 
monitored setting. All up-dosing was performed under direct observation.  
Exit DBPCFC: After the subjects had been up-dosed to a 300 mg/d dose and had continued to 
receive that dose for 2 weeks, subjects underwent a DBPCFC of up to 600 mg (1043 mg 
cumulative) of peanut protein or placebo.  

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All placebo subjects who completed ARC001 were eligible for rollover into the ARC002 
protocol. Placebo subjects in ARC002 underwent an escalation schedule identical to that for 
AR101 subjects in the ARC001 protocol. All subjects on AR101 who passed the DBPCFC by 
tolerating ≥ 443 mg cumulative of peanut protein with no more than mild symptoms were 
eligible to proceed to ARC002. Those who did not pass were considered endpoint failures.  
Efficacy Results:  
In ARC001, 56 subjects were randomized: 29 subjects to AR101 and 27 subjects to placebo. 
Consent for 1 subject was withdrawn after the subject was randomized, but before the first dose 
of study treatment was administered. The intent-to-treat (ITT) population, thus, comprised 
55 subjects in total, 29 in the AR101 and 26 in the placebo arm. The 2 study groups were overall 
well matched for baseline characteristics including baseline sensitivity in the Screening 
DBPCFC. Six subjects in the AR101 arm withdrew from the study prior to the Exit DBPCFC. 
For the primary efficacy analysis conducted in the ITT Population, AR101 was shown to be 
statistically significantly superior to placebo, with 23 of 29 (79%) AR101 desensitization 
responders as compared to 5 of 26 (19%) placebo desensitization responders, resulting in a 
treatment difference of 60% (p < 0.0001 by Fisher’s exact test). 
At the time of the Exit DBPCFC, 100% of the 23 AR101 subjects undergoing the DBPCFC 
(Completer Population) tolerated 300 mg as compared to, 5 of the 26 (19%) placebo study 
completers, resulting in a treatment difference of 81% (p < 0.0001 by Fisher’s exact test). 
It was also found at Exit DBPCFC that 18 of 29 (62%) AR101 subjects in the ITT Population 
tolerated 600 mg while none of placebo subjects tolerated 600 mg, resulting in a treatment 
difference of 62%. Post-hoc analysis by Fisher’s exact test yielded statistical significance at the 
p < 0.0001 level. In the Completer Population, 18 of 23 (78%) AR101-treated subjects and no 
placebo subjects tolerated 600 mg at Exit DBPCFC. 
For the key secondary endpoint of the maximum dose achieved with no or mild symptoms at the 
Exit DBPCFC, analyzed using a discrete hazard model, AR101 treatment was shown to increase 
the probability of tolerating higher maximum doses with no or mild symptoms as compared with 
placebo treatment. The adjusted probability of tolerating 300 mg was 0.82 for AR101 and 
0.14 for placebo; the adjusted probability of tolerating 600 mg was 0.59 for AR101 and 0.01 for 
placebo. Overall, the treatment effect hazard ratio (95% CI) was determined to be 
0.10 (0.04, 0.25) (p < 0.0001), indicating that the risk of failing the Exit DBPCFC in AR101 
subjects was one-tenth the risk as compared to placebo subjects. 
The percentage of subjects with a maximum symptom severity grade of moderate or 
severe/worse was lower in the AR101-treated group than in the placebo-treated group at every 
peanut protein level during the Exit DBPCFC. For AR101 subjects, no subject experienced a 
severe/worse symptom during Exit DBPCFC, and moderate symptoms were not encountered 
until a dose of 600 mg. In contrast, at the time of the Exit DBPCFC, at least 1 placebo subject 
experienced moderate or severe/worse symptoms at each evaluated dose. 
For the key secondary endpoint of change from baseline in maximum tolerated dose of peanut 
protein at Exit DBPCFC analyzed in an analysis of covariance (ANCOVA) model, a treatment 

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difference of 0.912 log10 mg (p < 0.0001) was observed with a change from baseline in tolerated 
dose of 1.254 log10 mg for AR101 and 0.341 log10 mg for placebo. In terms of the ratio of 
maximum tolerated dose (MTD) of peanut protein at the Exit DBPCFC compared to Baseline, 
AR101 subjects were able to tolerate 17.94 times as much peanut protein at the Exit DBPCFC 
compared to Baseline, while placebo subjects were able to tolerate 2.19 times as much peanut 
protein at the Exit DBPCFC compared to Baseline. 
For the secondary endpoints of changes in peanut-specific IgE and peanut-specific IgG4 levels 
and related measures, the relative treatment effect was calculated as a ratio of two ratios (study 
exit result : baseline result in the AR101 group / study exit result : baseline result in the Placebo 
group) The largest relative treatment effect, 4.756, was noted for peanut-specific IgG4, reflecting 
study exit values that were 5-times baseline in the AR101 group compared to levels that were 
nearly unchanged in the Placebo group. The 95% CI around this relative treatment effect 
(3.271, 6.915) excluded the null value of 1.  
For the secondary endpoint of changes in skin prick test (SPT) results, the difference between 
treatments was calculated as the change from baseline to study exit in the AR101 group minus 
the change from baseline to study exit in the Placebo group. At exit visit, a notable difference in 
the change from baseline in maximum peanut SPT wheal diameter was observed between 
treatment groups, with a treatment difference of  -5.2 mm. The 95% CI for this treatment 
difference (-9.2, -1.1) excluded the null value of 0. 
Safety Results:  
AR101 was generally well-tolerated. The overall incidence of treatment-emergent AEs (TEAEs) 
was 97% for the AR101 treatment group and 85% for the placebo group. One subject (3%) in the 
AR101 group experienced a treatment-emergent SAE of anaphylactic reaction related to 
treatment. And 1 subject (4%) in the placebo group experienced an SAE of anaphylaxis related 
to the peanut protein in the Exit DBPCFC, not study product. An additional subject experienced 
a non-treatment-emergent SAE of anaphylactic reaction following the Screening DBPCFC. Four 
(14%) AR101 subjects discontinued due to adverse events, with either hypersensitivity (n = 3) or 
vomiting (n = 1) being the most common adverse events leading to discontinuation. Two 
additional AR101 subjects discontinued due to treatment-related reasons that included GI AEs, 
but not exclusively. No placebo subjects discontinued due to adverse events. The most 
commonly occurring TEAE was hypersensitivity, which was reported in 71% of study subjects. 
The next most commonly reported TEAEs were pyrexia (16%), upper respiratory tract infection 
(13%), headache (11%), and vomiting (11%). 
Treatment-emergent adverse events classified as an allergic reaction by the investigator occurred 
in 71% of subjects. For these treatment-emergent hypersensitivity events, MedDRA coding 
indicated that the most common preferred terms were vomiting (16%) and abdominal pain 
(15%). Treatment-emergent hypersensitivity adverse events were more common in AR101 
subjects than in placebo subjects (90% vs. 50%, respectively), however these events tended to be 
mild or moderate in severity and did not typically lead to study withdrawal. 

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No treatment-specific differences in vital signs were observed. Most physical examination 
findings were normal at baseline and no treatment-specific differences in post-baseline abnormal 
findings were noted. 
In summary, AR101 was safe, generally well-tolerated, and statistically superior to placebo for 
reducing clinical reactivity to peanut allergen in peanut-allergic children and adolescents to 
young adults. AR101 treatment significantly increased the probability of tolerating peanut 
allergen doses ≥ 300 mg and resulted in favorable changes in clinical markers of peanut allergen 
immunoreactivity, most notably peanut-specific IgG4 levels, as compared to placebo. 
1.2.2.2 ARC003, A Phase 3 Study with AR101  
Protocol ARC003 is designed to be a double-blinded, placebo-controlled study to confirm the 
efficacy and safety of AR101 as an oral immunotherapy for desensitizing children and adults 
with peanut allergy.  
1.2.2.3 ARC004, A Phase 3 Follow-on Study with AR101  
Protocol ARC004, an open-label follow-on study from ARC003, will be performed as a separate 
protocol. The study is intended to demonstrate the safety of daily dosing with AR101 for an 
extended period (months to years), with the following objectives: 
• 
To expand, in unblinded fashion, the safety database for AR101; 
• 
To confirm, unblinded, the efficacy of OIT with AR101 up-dosed to a maintenance dose 
of 300 mg/d of peanut protein in the former ARC003 placebo population;  
• 
To provide an opportunity to the ARC003 trial participants to maintain the level of 
desensitization they may have achieved. 
1.3 
Rationale for Selection of Study Population 
The study will enroll approximately 500 subjects from 4 to 55 years of age with a history of 
allergy to peanuts or peanut-containing foods. The sample size has been selected in consideration 
of the need to demonstrate robust efficacy and acquire a sufficiently large safety database to be 
representative of the peanut-allergic population balanced against the risks associated with 
repeated DBPCFC (Section 9.4).  
All subjects enrolled must undergo a Screening DBPCFC to peanut that must be positive at or 
before the 100 mg (144 mg cumulative) dosing level of peanut protein (measured as 200 mg of 
peanut flour with approximately 50% protein content) in accordance with PRACTALL (Practical 
Issues in Allergology, Joint United States/European Union Initiative) consensus guidelines 
(Sampson et al., 2012), regardless of how they were initially diagnosed as peanut allergic. This 
should select for roughly the more sensitive half of the peanut-allergic population 
(Remington 2013; Allen et al., 2014), according to a logistical regression analysis performed by 
the VITAL 2.0 study group using food challenge data from multiple sources.  
The current Phase 3 study will focus on the age group most at risk from accidental exposure, ie, 
ages 4 to 17 years, while allowing for older subjects who are motivated to seek desensitization to 
be included. It is intended that fully 80% of the study population (ie, 400 subjects) will be 

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pediatric, with at least 200 subjects randomized from the 4 to 11 years of age range and 
150 subjects randomized from the 12 to 17 years of age range. 
The lower age limit of 4 years was selected based on epidemiologic child-developmental 
considerations related to feeding behavior (Fallon et al., 1984; Cashdan 1994; Farrow & Blisset, 
2012; American Academy of Pediatrics 2013), as well as practical clinical trial execution 
considerations and safety. Very young children, for example, have limited ability to reliably 
follow a study protocol.  
As only about 20% of children with peanut allergy outgrow the condition, it is important to 
collect safety and efficacy data in adults. The upper age limit of 55 years was selected to reduce 
the chance of enrolling subjects with clinically significant heart disease (Mozaffarian et al., 
2015) who could be at increased risk from the use of epinephrine if needed to treat anaphylaxis. 
This is particularly relevant in the clinical trial setting, where the risk of iatrogenic anaphylaxis is 
increased due to the requirement for repeated DBPCFC.  
In the current study, subjects with severe or life-threatening episodes of anaphylaxis or 
anaphylactic shock will be excluded from enrolling if they have had such an episode in the 
60 days prior to the Screening DBPCFC, but will not otherwise be prohibited from entering the 
study. This is because peanut-allergic subjects who have had prior life-threatening episodes on 
exposure to peanut can be considered at high risk for another such episode, and hence, are 
exactly the type of patients who could benefit from desensitization therapy. 
1.4 
Rationale for Selection of Study Drug Regimen (Dose and Duration) 
For the Phase 3 study, ARC003, the dosing regimen to be used is predicated on the dosing 
regimen successfully used in the Phase 2 study, ARC001. The ARC001 dosing regimen, in turn 
was built on the work of the Consortium of Food Allergy Research (CoFAR) and its 
investigators. The basic structure of the dosing regimen consists of a single-day initial escalation 
at very low doses, followed by a buildup phase of dose escalations, with a single escalation 
occurring every 2 weeks, and then an extended maintenance phase at a fixed daily dose. This 
dosing regimen has been demonstrated to be well tolerated and efficacious in previous studies 
(Burks et al., 2012) and was shown to be similarly well tolerated and efficacious in the Phase 2 
study, ARC001, conducted by Aimmune. 
The total duration of treatment in the current Phase 3 study will be approximately 12 months 
(~6 months escalation and 6 months maintenance at 300 mg/d). Aimmune recognizes that any 
number of up-dosing regimens may be effective in escalating peanut-allergic patients to a daily 
maintenance dose of peanut protein, and the 1 chosen for the current Phase 3 study was selected 
empirically based on its success in Phase 2. 
With respect to the duration of maintenance therapy prior to testing for clinical efficacy by 
DBPCFC in the current Phase 3 study, this too was selected empirically based on successful 
Phase 2 results. The clinical trials published to date for peanut OIT have had maintenance 
periods ranging from 1 to 7 months, and have demonstrated the ability to allow subjects to 
tolerate challenge doses ranging from 1.25 to 16.7 times their maintenance dose (Clark et al., 
2009; Jones et al., 2009; Blumchen et al., 2010; Varshney et al., 2011; Anagnostou et al., 2014; 
Cronin, Wisniewski & Commins, 2014; Vickery et al., 2015). The data from Aimmune’s Phase 2 

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studies indicate that a clinically meaningful level of desensitization is achieved after up-dosing 
and just 2 weeks of maintenance dosing at 300 mg (with > 95% passing DBPCFC at a 
cumulative challenge dose of 443 mg of peanut protein and the majority passing at a 1043 mg 
cumulative challenge) and that extending maintenance dosing from 2 to 14 weeks appears to be 
associated with only a modest improvement in the overall degree of desensitization. 
Accordingly, a blinded maintenance period of 6 months is considered sufficient to demonstrate 
efficacy and assess safety in the Phase 3 study. The ability to convey to patients that they are at a 
therapeutic level of desensitization in a reasonable timeframe is an important consideration. 
Thus, the duration of blinded placebo therapy is limited to 12 months in this study. 
The data from Aimmune’s Phase 2 trials, consistent with previously published studies, indicate 
that the use of a low dose maintenance phase can provide a clinically meaningful level of 
desensitization that is considerably higher than the daily maintenance dose. Three studies in 
particular (Jones et al., 2009; Cronin, Wisniewski, & Commins, 2014; Vickery et al., 2015) have 
specifically reported that daily dosing with 300 mg of peanut protein will allow quantities of 
peanut protein ranging from 2.1 to 5 grams to be tolerated in an oral food challenge.  
1.5 
Rationale for the Doses Used for the DBPCFC 
The study DBPCFCs will be conducted in accordance with the recommended PRACTALL 
guidelines although the Screening DBPCFC will not exceed 100 mg (144 mg cumulative). This 
is to select subjects representative of approximately the more sensitive half of the peanut-allergic 
population (Section 1.3).  The Exit DBPCFC will not go above a 1000 mg (2043 mg cumulative) 
dose to help ensure subject safety. Additionally, the DBPCFCs will progress through the dose 
levels in an unaltered sequence without repeating any dose to provide standardization of the 
amounts of peanut protein subjects are exposed to when being tested in the clinical trial setting. 
The Exit DBPCFC will assess protection against approximately 2-4 peanuts’ worth of peanut 
protein at 600 mg (1043 mg cumulative) dose. To assess further desensitization, patients 
tolerating the 600 mg (1043 mg cumulative) incremental dose will also be challenged with 
1000 mg (2043 mg cumulative), or approximately 4-8 peanut’s worth of peanut protein. 
Additionally, since accidental exposures typically occur to limited amounts of allergen, the 
ability to tolerate 300 mg (443 mg cumulative) of peanut protein will be assessed as a key 
secondary endpoint. As discussed in Section 1.1, all of these challenge dose levels are believed 
to represent amounts of peanut protein in excess of what might typically be encountered in an 
accidental ingestion of peanut. 
1.6 
Known and Potential Risks and Benefits to Human Participants 
1.6.1 Risks  
Peanut is a commonly-consumed food and as such has a well understood safety profile. Except 
for allergic reactions in subjects with peanut allergy, it does not cause discernible side effects in 
humans. 
As noted earlier (Section 1.1), there have been several oral immunotherapy studies performed in 
subjects with peanut allergy using procedures and dosing regimens similar to those used in our 
Phase 2 studies (ARC001 and ARC002) and proposed for the current Phase 3 study. In general, 
the safety profile from the completed Phase 2 study, ARC001, was similar to the safety profiles 

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reported from previous peanut OIT studies. At the start of the ARC001 study it was anticipated 
that approximately 80%, 15%, and < 1% of the subjects would have at least 1 mild, moderate, or 
severe symptom, respectively, at some point during the course of peanut immunotherapy. At the 
close of ARC001, the actual percentages of subjects treated with AR101 who had experienced a 
least 1 mild, moderate, or severe symptom, were 69%, 28%, and 0%, respectively. It is important 
to note that the vast majority of adverse events reported from our Phase 2 studies or in the 
literature have been allergy-related, predictable, and reversible. Specifically, the buildup and 
daily maintenance doses of peanut OIT may cause allergic symptoms including sneezing, 
rhinorrhea, urticaria, angioedema, flushing, flares of eczema, ocular, nasal, oral and/or throat 
pruritus, nausea, vomiting, abdominal discomfort, cough, wheezing, and/or shortness of breath, 
in addition to severe anaphylaxis. The likelihood of a subject experiencing any allergic 
symptoms is expected to be lessened by initiating dosing at extremely small amounts of AR101 
and by buildup of dosing under observation in a clinical setting until the maintenance dose is 
achieved. 
The major adverse event of concern from peanut OIT, other than anaphylaxis, that has been 
reported in the literature is eosinophilic esophagitis (EoE), reversible upon stopping dosing. In 
the ARC001 study, 6 (20%) of the AR101-treated subjects discontinued dosing prematurely for 
treatment-related reasons associated with GI AEs. One of these subjects subsequently underwent 
endoscopy and was found to have biopsy-proven EoE.  
There is a strong association between IgE-mediated food allergy and EoE (Noel 2004; 
Spergel 2012; Greenhawt 2014). Consequently, patients with IgE-mediated food allergy who 
encounter the food to which they are allergic, such as must occur during OIT, are at increased 
risk for manifesting EoE. As of 2014, at least 20 cases of EoE emerging during the course of OIT 
for food allergy have been reported (Lucendo et al., 2014). At present, it remains unclear 
whether in such cases OIT induces EoE or causes pre-existing subclinical EoE to become 
symptomatic. When EoE occurs spontaneously, the current standard of care treatment generally 
entails removing known or suspected food allergens from the diet. When EoE occurs in the 
setting of OIT, treatment should similarly entail removal of the desensitizing (ie, allergenic) 
agent. As the diagnosis of EoE requires endoscopic biopsy, the true incidence of EoE related to 
OIT is difficult to know, because withdrawal of the offending allergen is typically associated 
with symptomatic recovery, which in turn tends to obviate the need to perform an invasive 
procedure. Given the association between IgE-mediated food allergy and EoE, a high index of 
suspicion for EoE or an EoE-like process should be maintained whenever chronic recurrent GI 
symptoms occur during OIT.  
Oral food challenges are expected to induce an allergic response in food-allergic individuals. 
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 definitive sign of a 
significant reaction. If subjects have an allergic reaction during the challenges, they may need 
oral, intramuscular, or intravenous medications, and will be treated per study center standard of 
care. Trained personnel, including a physician, as well as medications and equipment (per 
PRACTALL recommendations and investigational site standard operating procedures), will be 
immediately available to treat any reaction. With these precautions, the rate of severe, 

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life-threatening, serious adverse events of anaphylaxis due to OIT is anticipated to be < 0.5% 
over the course of the ARC003 study. 
There may be a risk that during participation in the trial the subjects may decrease their vigilance 
against accidental peanut ingestion because they believe they are protected from it. This 
phenomenon has been reported in previous trials. Subjects in the trial and their participating 
family will be warned that they should continue to practice their usual vigilance against 
accidental ingestion of peanuts or peanut-containing foods. 
1.6.2 Benefits  
There is no guarantee that participation in this study will help the subject. The subject may 
receive placebo during the double-blind treatment period of the study. Information from this 
study may help researchers to better understand peanut allergy or to develop future tests or 
treatments to help patients with this condition. 
2 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to demonstrate the efficacy of AR101, a pharmaceutical-grade peanut 
allergen formulation, through reduction in clinical reactivity to limited amounts of peanut 
allergen in peanut-allergic children (ages 4-17 years, inclusive). 
2.2 
Secondary Objective(s) 
The secondary objectives are: 
• 
To demonstrate the safety of AR101 as measured by the incidence of adverse events, 
including serious adverse events in children (ages 4-17 years, inclusive). 
• 
To evaluate the immunological effects of peanut OIT therapy in children (ages 
4-17 years, inclusive). 
3 
STUDY DESIGN 
ARC003 is a multi-center, randomized, double-blind placebo-controlled study. The study design 
is illustrated in Figure 3-1. 

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Figure 3–1. 
Study Design 
 
3.1 
Screening Period 
Subjects aged 4 to 55 years must have a clinical history of peanut allergy, a serum IgE to peanut 
of ≥ 0.35 kUA/L and/or a skin prick test (SPT) to peanut of ≥ 3 mm versus control at the time of 
screening. All eligible subjects will undergo an initial DBPCFC at the end of the screening 
period (refer to Section 6.6.1). This DBPCFC will include both a peanut challenge (defatted 
peanut flour) and a placebo challenge (artificially peanut-flavored oat flour) on separate days. 
The Screening DBPCFC will be an abbreviated version of the DBPCFC described in the 
PRACTALL guidelines, with top challenge doses of 100 mg (144 mg cumulative) of peanut 
protein and placebo. 
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), nor the assessment or management of adverse 
events. To the extent practicable, the same Blinded Evaluating Physician who determines DLSs 
in the Screening DBPCFC should determine DLSs in the Exit DBPCFC. 
Those subjects who have dose-limiting symptoms at or before the 100 mg (144 mg cumulative) 
challenge dose of peanut protein (measured as 200 mg of peanut flour) will be enrolled into the 
study. According to a logistical regression analysis performed by the VITAL 2.0 study group 
using food challenge data from multiple sources, this would select for roughly the more sensitive 
half of the peanut-allergic population (Remington, 2013; Allen et al., 2014). Those who 
successfully consume a 100 mg dose of peanut protein during the Screening DBPCFC, ie, 
without manifesting dose-limiting symptoms, will be considered screen failures and will not be 
randomized. 

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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. 
Approximately 500 subjects who pass screening will be randomized 3:1 to either AR101 (active 
treatment) or placebo using a proprietary password-protected interactive response system. At 
least 80% of the subjects randomized will be children. 
3.2 
Treatment Phase 
The Treatment Phase comprises 3 periods:  
• 
Initial Escalation Period – 2 days in duration; 
• 
Up-dosing Period (also referred to as the Buildup Period) – This is defined as the time 
from the subject’s first home dose of study product at 3 mg to the subject’s first in-clinic 
dose at 300 mg, ideally 20 weeks in duration, but may be extended to a maximum of 
40 weeks to accommodate dose reductions and re-escalations, if necessary; 
• 
Maintenance Period – The Maintenance Period starts with the first home dose of 
300 mg. Ideally, it will be 24 weeks in duration, but it may be extended by up to an 
additional 4 weeks (for a maximum Maintenance Period duration of 28 weeks), or to a 
total Treatment Phase duration of 68 weeks, whichever occurs first, to accommodate dose 
reductions and re-escalations that may occur during the final weeks of the Maintenance 
Period. 
The Treatment Phase starts with an initial escalation at the study center, followed by up-dosing 
for approximately 20 weeks, and then approximately 24 weeks of maintenance dosing at 
300 mg/d. Treatment will be conducted in a double-blind fashion. The study products (AR101 or 
placebo) will be coded according to subject randomization number. The subjects and the 
investigational site personnel will be blinded to treatment assignment. 
After the initial escalation period (comprising dose-escalation to a maximum of 6 mg on Day-1 
and confirmation of the tolerability of a single 3 mg dose on Day-2), subjects will report to the 
study center every 2 weeks to escalate their OIT dose to an expected daily dose of 300 mg of 
peanut protein. This constitutes the Up-dosing Period. The dose-escalation schedule is described 
in detail in Table 3-1 and Table 3-2.  

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Table 3-1. 
Initial Dosing Schedule for Peanut OIT 
Initial Escalation Period, Day-1, Dosing Schedule 
Dose # 
Study Product Dose 
(mg peanut protein or 
Cumulative Study Product Dose 
(mg peanut protein or placebo) 
1 
0.5 
0.5 
2 
1  
1.5 
3 
1.5 
3  
4 
3  
6 
5 
6  
12 
Doses will be delivered at 20 to 30 minute intervals. 
Subjects who are unable to tolerate a dose of 3 mg at the end of Day-1 will be considered an initial day 
escalation failure. 
All subjects who tolerate a dose of at least 3 mg on Day-1 will return on Day-2 to receive a single 
confirmatory 3 mg dose under direct observation. 
Subjects with either no symptoms or mild, non-dose-limiting symptoms after receiving 3 mg on Day-2 
may start 2 weeks of daily dosing at 3 mg. 
Subjects who experience moderate or severe symptoms after receiving the 3 mg dose on Day-2 will be 
considered escalation failures.  
Future dose escalations will occur every 2 weeks with the initial dose increase administered in the 
clinical research center. 
Table 3-2. 
Up-dosing Dosing Schedule for Peanut OIT 
Up-dosing Period Dosing Schedule 
Up-dosing 
Dose # 
Study Product Dose 
(mg peanut protein or 
placebo) 
Interval (weeks) 
% Increase 
1 
3 
2 
 
2 
6 
2 
100% 
3 
12 
2 
100% 
4 
20 
2 
67% 
5 
40 
2 
100% 
6 
80 
2 
100% 
7 
120 
2 
50% 
8 
160 
2 
33% 
9 
200 
2 
25% 
10 
240 
2 
20% 
11 
300 
Enter Maintenance 
Period 
25% 
Capsules and sachets (introduced during the Maintenance Period) are to be opened, contents sprinkled 
over an age-appropriate food, and mixed thoroughly. 300 mg capsules will be used for at least the first 
2 weeks of dosing during the 24-Week Maintenance Period. 

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All subjects who reach and tolerate 300 mg/d will continue at that dose level for the duration of 
the Maintenance Period. The first Maintenance visit occurs 2 weeks after the last Up-Dosing 
visit, with visits every 4 weeks thereafter. Any subject unable to achieve a dose of 300 mg/d of 
peanut protein by 40 weeks will be considered an escalation failure nonresponder and will not 
undergo Exit DBPCFC. 
During the treatment period, the subjects will be monitored for the tolerability of study product, 
as described in Section 6.7.2 and Section 6.7.3, and illustrated in Figure 6-1 and Figure 6-2 
(Section 6.7.5.2).  
If a subject discontinues therapy prematurely for any reason, the subject will be followed for 
safety and asked to return to the CRC 14 days following his or her last dose of study product to 
undergo an Early Discontinuation Visit (Section 6.5). In the event of ongoing AEs, subjects who 
have discontinued therapy should continue to be followed beyond the Early Discontinuation 
Visit until such time as the AE has resolved or is assessed to have reached a chronic stable state 
(a determination that may not be made sooner than 30 days after the Early Discontinuation 
Visit). 
A Data Safety Monitoring Committee (DSMC) will be established and will meet approximately 
every 3 months to monitor the study for safety.  
3.3 
Exit DBPCFC 
All subjects who reach the targeted daily dose of 300 mg and maintain that dose through the 
Maintenance Period will undergo an Exit DBPCFC. The Exit DBPCFC will be performed in 
accordance with PRACTALL guidelines, but starting at a dose of 3 mg of peanut protein (except 
for subjects who reacted to 1 mg in their Screening DBPCFC; these subjects will be required to 
start their Exit challenge at 1 mg; see also Section 6.6.2) and requiring progression in an 
unaltered sequence (Table 6-1), without repeating any dose. Also, the Exit DBPCFC will include 
a 600 mg penultimate challenge dose, and the top challenge dose will be capped at 1000 mg.  
The same vehicle food should be used for the Exit DBPCFC as was used for the Screening 
DBPCFC. 
Each subject will be unblinded after he/she completes the DBPCFC, provided regulatory and 
Institutional Review Board (IRB) / Ethics Committee (EC) approval for ARC004 have been 
received, the availability of IP for ARC004, and all major data queries for the subject have been 
resolved. If this is not the case, the subject shall remain on blinded treatment until these 
requirements are satisfied. The subject should continue his or her maintenance visits (completed 
as unscheduled visits) every 30 days, and complete all protocol procedures at each visit until 
study completion and rollover to ARC004. To maintain the study blind overall, individual 
unblinding information should only be distributed to designated team members on a 
need-to-know basis (refer to Masking Plan for details). 
Subjects who do not reach the target dose by Week 40 are not eligible for the Exit DBPCFC, and 
will be considered escalation failure nonresponders. They will be unblinded no sooner than 
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The ARC003 study will end with the last visit of the last subject. 
3.4 
Follow-on Study ARC004 
All placebo subjects who complete ARC003 are eligible for rollover into the ARC004 protocol. 
Placebo subjects from ARC003 will, in ARC004, undergo an escalation schedule identical to that 
for active subjects in the ARC003 protocol. All subjects on active treatment in ARC003 who 
pass the DBPCFC at the 300 mg (443 mg cumulative) challenge dose level of peanut protein are 
eligible to proceed to ARC004. Those who do not pass DBPCFC at the 300 mg (443 mg 
cumulative) challenge dose level will be considered endpoint failures and nonresponders for the 
primary analysis. They will not be eligible for rollover into the ARC004 protocol due to safety 
concerns. Those subjects who pass DBPCFC at the 300 mg (443 mg cumulative) challenge dose 
level, but fail at the 600 mg (1043 mg cumulative) or 1000 mg (2043 mg cumulative) challenge 
dose level, will be considered endpoint failures and nonresponders for the primary analysis for 
North America or Europe, respectively; however, they will be eligible for rollover into the 
ARC004 protocol because tolerating a 300 mg (443 mg cumulative) dose of peanut protein is 
considered a clinically relevant level of desensitization in the event of accidental exposure. 
Upon successful completion of Study ARC003, all subjects will be eligible to receive AR101 in 
Study ARC004. Subjects who received AR101 in Study ARC003 will continue on their 
maintenance dose of 300 mg/d, and subjects who had previously received placebo in Study 
ARC003 will undergo dose-escalation according to the same schedule and procedures used in 
ARC003, but in open-label fashion. At the end of the up-dosing period followed by a period of 
continued maintenance dosing at 300 mg/d, those subjects will be required to pass a DBPCFC by 
tolerating 300 mg (443 mg cumulative) of peanut protein with no more than mild symptoms to 
continue in the study. All subjects continuing maintenance therapy in ARC004 will be required 
to undergo a DBPCFC after at least 6 months of additional maintenance treatment.  
3.5 
Study Design Safety Considerations 
The study design incorporates the following important safety considerations: 
• 
All dose escalations will be performed under direct observation and medical supervision 
in the CRC 
• 
The peanut OIT will start at 0.5 mg and will only escalate to a maximum single dose of 
6 mg during the initial escalation on Day -1 
• 
Adverse events, including dosing-related allergic symptoms, whether expected or not, 
will be captured throughout the study 
• 
All subjects and/or their participating family (as appropriate for age and home 
circumstances) will be provided with an epinephrine auto-injector and will be trained in 
its use 
• 
Subjects will be strongly cautioned against consuming any peanuts or peanut-containing 
foods other than the study product while on study, and will be instructed to remain on a 
peanut-free diet. 

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3.6 
Primary Efficacy Endpoint 
3.6.1 Primary Efficacy Endpoint, North America  
The primary clinical efficacy endpoint is the proportion of subjects aged 4 to 17 years who 
tolerate a single highest dose of at least 600 mg (1043 mg cumulative) of peanut protein with no 
more than mild symptoms at the Exit DBPCFC. 
3.6.2 Primary Efficacy Endpoint, Europe 
The primary clinical efficacy endpoint is the proportion of subjects aged 4 to 17 years who 
tolerate a single highest dose of at least 1000 mg (2043 mg cumulative) of peanut protein with no 
more than mild symptoms at the Exit DBPCFC. 
3.7 
Secondary Endpoints 
3.7.1 Key Secondary Endpoints 
North America: The key secondary endpoints are as follows: 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 300 mg (443 mg cumulative) of peanut protein with no more than mild symptoms at 
the Exit DBPCFC 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 1000 mg (2043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC 
• 
The maximum severity of symptoms in subjects aged 4 to 17 years occurring at any 
challenge dose of peanut protein during the Exit DBPCFC 
• 
The proportion of subjects aged 18 to 55 years who tolerate a single highest dose of at 
least 600 mg (1043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC 
Europe: The key secondary endpoints are as follows: 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 600 mg (1043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 300 mg (443 mg cumulative) of peanut protein with no more than mild symptoms at 
the Exit DBPCFC 
• 
The maximum severity of symptoms in subjects aged 4 to 17 years occurring at any 
challenge dose of peanut protein during the Exit DBPCFC 
• 
The proportion of subjects aged 18 to 55 years who tolerate a single highest dose of at 
least 1000 mg (2043 mg cumulative) of peanut protein with no more than mild symptoms 
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3.7.2 Other Secondary Endpoints, North America and Europe 
The other secondary endpoints are as follows: 
• 
Maximum dose achieved with no or mild symptoms at Exit DBPCFC in subjects aged 
4 to 17 years 
• 
Change from baseline in maximum tolerated dose of peanut protein at DBPCFC in 
subjects aged 4 to 17 years 
• 
Use of epinephrine as a rescue medication at Exit DBPCFC and comparison to its use at 
Screening DBPCFC in subjects aged 4 to 17 years 
• 
Changes in peanut-specific serum IgE and IgG4 levels in subjects aged 4 to 17 years 
• 
Changes in peanut skin prick test (SPT) mean wheal diameters in subjects aged 4 to 
17 years 
• 
Quality of life assessments using the food allergy related quality of life questionnaire 
(FAQLQ), and the food allergy independent measure (FAIM) questionnaire (van der 
Velde et al., 2010) in subjects aged 4 to 17 years  
3.7.3 Secondary Safety Endpoints, North America and Europe 
• 
The safety of peanut OIT based on adverse events (AEs) including serious adverse events 
(SAEs) in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 18 to 
55 years, and 4 to 55 years, inclusive 
• 
Use of epinephrine as a rescue medication during OIT (Initial Escalation, Up-dosing, and 
Maintenance Periods) in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 
17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Frequency of anaphylaxis during OIT (Initial Escalation, Up-dosing, and Maintenance 
Periods) in in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 
18 to 55 years, and 4 to 55 years, inclusive 
• 
Frequency of allergic reaction (hypersensitivity) AEs occurring during the Up-dosing 
versus the Maintenance Period, normalized for duration of treatment in the following 
5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 18 to 55 years, and 4 to 
55 years, inclusive 
• 
Frequency of accidental ingestions of peanut and other allergenic foods in the following 
5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 18 to 55 years, and 4 to 
55 years, inclusive 
• 
Severity of adverse events associated with accidental ingestions of peanut and other 
allergenic foods in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 
17 years, 18 to 55 years, and 4 to 55 years, inclusive 
• 
Frequency of premature discontinuation of dosing due to AEs; and frequency of 
premature discontinuation of dosing due to chronic/recurrent gastrointestinal (GI) AEs in 
the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 18 to 55 years, 
and 4 to 55 years, inclusive 

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• 
Assessment of asthma control using the Asthma Control Test questionnaire in subjects 
with asthma in the following 5 age groups: 4 to 17 years, 4 to 11 years, 12 to 17 years, 
18 to 55 years, and 4 to 55 years, inclusive 
3.8 
Exploratory Endpoints, North America and Europe 
• 
The primary endpoints identified above will be repeated in the following 3 age groups: 
4 to 11 years, 12 to 17 years, and 4 to 55 years, inclusive 
• 
The first 3 key secondary endpoints and all other secondary endpoints identified above 
will be repeated in the following 4 age groups: 4 to 11 years, 12 to 17 years, 18 to 
55 years, and 4 to 55 years, inclusive 
• 
Treatment satisfaction assessment using the Treatment Satisfaction Questionnaire for 
Medication (TSQM-9), an exit questionnaire and palatability questions 
• 
(North America sites only) Optional mRNA expression patterns in saliva obtained 
longitudinally from peanut-allergic participants undergoing OIT in ARC003 
(Appendix 6; Data will be reported separately) 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment as study subjects: 
1. Age 4 through 55 years (inclusive) 
2. Clinical history of allergy to peanuts or peanut-containing foods 
3. Serum IgE to peanut of ≥ 0.35 kUA/L [determined by UniCAPTM within the past 
12 months] and/or a SPT to peanut ≥ 3 mm compared to control 
4. Experience dose-limiting symptoms at or before the 100 mg challenge dose 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 
5. Written informed consent from adult subjects 
6. Written informed consent from parent/guardian for minor subjects 
7. Written assent from minor subjects as appropriate (eg, above the age of 7 years or the 
applicable age per local regulatory requirements) 
8. Use of effective birth control by female subjects of child-bearing potential 
9. Not be residing at the same address as another subject in this or any peanut OIT study 
4.2 
Exclusion Criteria 
Subjects who meet any of these criteria are not eligible for enrollment as study subjects: 
1. History of cardiovascular disease, including uncontrolled or inadequately controlled 
hypertension (see also Section 5.10 Prohibited Medications) 

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2. History of severe or life-threatening episode of anaphylaxis or anaphylactic shock within 
60 days of Screening DBPCFC 
3. History of chronic disease (other than asthma, atopic dermatitis, or allergic rhinitis) that 
is, or is at significant risk of becoming, unstable or requiring a change in chronic 
therapeutic regimen 
4. History of eosinophilic esophagitis (EoE), other eosinophilic gastrointestinal disease, 
chronic, recurrent, or severe gastroesophageal reflux disease (GERD), symptoms of 
dysphagia (eg, difficulty swallowing, food “getting stuck”), or recurrent gastrointestinal 
symptoms of undiagnosed etiology 
5. Current participation in any other interventional study 
6. Subject is in “build-up phase” of immunotherapy to another allergen (ie, has not reached 
maintenance dosing) 
7. Severe asthma (2007 NHLBI Criteria Steps 5 or 6, Appendix 2) 
8. Mild or moderate asthma (2007 NHLBI Criteria Steps 1-4), if uncontrolled or difficult to 
control as defined by any of the following: 
o 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*) or 
o Inhaled corticosteroids (ICS) dosing of > 500 mcg daily fluticasone (or equivalent 
ICS based on NHLBI dosing chart) or 
o One hospitalization in the past year for asthma or  
o ER visit for asthma within six months prior to screening 
9. History of steroid medication use (via intravenous [IV], intramuscular [IM] or oral 
administration) in any of the following manners: 
o history of daily oral steroid dosing for > 1 month during the past year or 
o burst oral (IM or IV) steroid course in the past 3 months prior to randomization or 
o > 2 burst oral (IM or IV) steroid courses in the past year of at least 1 week duration 
10. Inability to discontinue antihistamines 5 half-lives before the initial day of escalation, 
skin testing or DBPCFC 
11. Lack of an available palatable vehicle food to which the subject is not allergic 
12. Use of any therapeutic antibody (eg omalizumab, mepolizumab, reslizumab, etc.), any 
investigational peanut immunotherapy (eg oral, sublingual, epicutaneous), or any other 
                                                 
* Spirometry is to be attempted in all subjects ≥ 6 years of age. For subjects aged 6-11 years: if valid spirometry 
results are not successfully obtained, the attempt is to be documented. Measures of peak flow will be acceptable 
for the entry criteria if results are > 80% of predicted. For subjects 4 or 5 years of age, peak flow rates are to be 
attempted, but reliable performance is not required for the subject to enter the study or undergo study procedures 
at the investigating physician’s discretion. The attempt must be documented, and a clinical assessment is 
required. 

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immunomodulatory therapy excluding corticosteroids within the past 6 months (see also 
Section 5.10 Prohibited Medications)  
13. Use of beta-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin-receptor blockers (ARB) or calcium channel blockers (see also Section 5.10 
Prohibited Medications) 
14. Pregnancy or lactation 
15. Having the same place of residence as another subject in the study 
16. Participation in another clinical trial within 30 days or 5 half-lives of the investigational 
product, whichever is longer, prior to randomization. 
17. Developing dose limiting symptoms in reaction to the placebo part of the Screening 
DBPCFC 
18. History of a mast cell disorder, including mastocytosis, urticaria pigmentosa, and 
hereditary or idiopathic angioedema 
19. Allergy to oat 
20. Hypersensitivity to epinephrine and any of the excipients in the product 
4.3 
Premature Subject Termination from the Study 
4.3.1 Criteria  
No subject randomized into this trial who discontinues treatment for any reason will be replaced.  
Unless required for safety reasons (ie, medical treatment of SAEs), subjects eligible for an Exit 
DBPCFC will not be unblinded earlier than their scheduled DBPCFC. Subjects who are 
considered escalation failures will be unblinded no sooner than Week 64 (or when the last 
subject completes the Exit DBPCFC). 
Any subject will be prematurely terminated from additional allergen exposures for the following 
reasons: 
1. Life-threatening symptoms (CoFAR Grade 4; refer to Table A4 in Appendix 4), 
including, but not limited to, anaphylaxis resulting in hypotension, neurological 
compromise, or mechanical ventilation secondary to peanut OIT dosing or any peanut 
food challenge 
2. Severe symptoms (CoFAR Grade 3; refer to Table A4 in Appendix 4), including, but not 
limited to, those that require intensive therapy (to be determined by the investigator, but 
may include such interventions as IV epinephrine, intubation, or admission to an 
intensive care unit) or those that are recurrent 
Any subject may be prematurely terminated from additional allergen exposures for the following 
reasons: 
3. Poor control or persistent activation of secondary atopic disease (eg, atopic dermatitis, 
asthma)  

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4. Started on angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) 
inhibitors, beta-blockers, or other prohibited medications, with no alternative medications 
available per the prescribing doctor 
5. Pregnancy  
6. Non-adherence (non-compliance) with home peanut OIT (study product) dosing, as 
indicated by missing > 7 consecutive days on any 1 occasion, or 3 consecutive days on 
3 or more occasions during the Up-dosing Period, as this could constitute a potential 
safety issue 
7. Medically indicated circumstances (eg, as part of the treatment for intercurrent adverse 
events) that require missed peanut OIT (study product) dosing for >14 consecutive days 
Any subject may also be prematurely terminated from the study if: 
8. The subject elects to withdraw consent from all future study activities, including 
follow-up 
9. The subject is “lost to follow-up” (ie, no further follow-up is possible because attempts to 
reestablish contact with the subject have failed) 
10. The subject develops biopsy-documented eosinophilic esophagitis (EoE) 
11. The subject’s continued participation in the study is assessed by the investigator to 
constitute a threat to the safety of the subject or the safe conduct of the study 
12. The subject dies (CoFAR Grade 5) 
Subjects who discontinue study product prematurely due to AEs or other safety concerns should 
be encouraged to continue their participation in follow-up safety assessments. If a subject fails to 
return for scheduled visits, a documented effort must be made to determine the reason. 
4.3.2 Follow-up of Subjects Who Discontinue Treatment 
Subjects who prematurely discontinue treatment will be brought in for an Early Discontinuation 
Visit approximately 14 days after their last dose of study product. To the extent possible, 
subjects will be monitored for safety until they come back for their Early Discontinuation Visit. 
In the event of ongoing AEs, subjects who have discontinued therapy should continue to be 
followed beyond the Early Discontinuation Visit until such time as the AE has resolved or is 
assessed to have reached a chronic stable state (a determination that may not be made sooner 
than 30 days after the Early Discontinuation Visit). 
Subjects under the age of 18 years who discontinue treatment due wholly or in part to GI AEs 
will be instructed to complete the Pediatric Eosinophilic Esophagitis Symptom Scores (PEESSTM 
v2.0) questionnaire (Franciosi et al., 2011) monthly for 6 months (Section 7.4.3.2); adults will be 
given a modified version of the questionnaire. These subjects will also be asked to continue to 
fill out their daily diary for the same 6-month duration. Additional instructions for the follow-up 
of subjects who discontinue treatment due wholly or in part to GI AEs is contained in 
Section 7.4.3.2. 

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5 
STUDY MEDICATION 
5.1 
Formulation, Packaging and Labeling 
The active study product, AR101, is characterized peanut allergen in the form of peanut flour, 
formulated with a bulking agent and a flow agent in pre-measured graduated doses, comprising 
capsules containing 0.5, 1, 10, 20, and 100 mg each of peanut protein. AR101 is characterized by 
its HPLC fingerprint and by specific ELISAs performed against key allergenic proteins to 
demonstrate stability and lot-to-lot comparability. Placebos, containing only excipients that are 
color-matched to the peanut flour, will be provided as matching capsules, identical to the active 
capsules. For maintenance dosing, 300 mg of peanut protein are provided in sealed, foil-laminate 
sachets requiring one sachet/day. Matching placebo containing sachets are also provided. 
Capsules containing study product will be provided in pre-packaged bottles or blister cards 
assembled into dosing kits. Each individual bottle or blister of a blister card will contain a single 
day’s dose of study product; each kit will contain 21 daily doses at a given dose level, enough to 
supply 2 weeks of dosing plus a 7-day overage to accommodate potential visit scheduling issues 
(Section 3).  
All study products (both peanut allergen and placebos) will be packaged and labeled at the 
central packaging facility. The products will then be shipped to a drug depot where they will be 
labeled and inventoried for shipment to the clinical sites. Study products will be shipped by the 
drug depot to the investigational site or the investigational site pharmacy, according to site-
specific institutional policies. Study products will then be distributed to subjects/subjects’ parents 
or guardians by study site personnel. Study products will be dispensed to subjects on the basis of 
matching randomization code to ensure dosing according to their assigned treatment arm and 
dose level, without the blind being broken for the subjects or the study personnel.  
All study products will be stored in a secure location and kept refrigerated between 2°C and 8°C. 
Sites will maintain temperature logs for all refrigerators storing study drug for the duration of the 
study. 
5.2 
Preparation, Administration and Dosage 
The first dose at each new dose level is to be administered in the CRC under the direct 
supervision of an appropriately credentialed healthcare provider and the oversight of a physician. 
This dose, intended for in-clinic administration, is removed from the dosing kit for the assigned 
dose level. Once a dose is removed from a dosing kit, the kit must be dispensed to the subject or 
held at the site for documented destruction or return to the sponsor’s designee (as instructed); 
dosing kits once opened cannot be used for any other dosing interval or any other subject. At 
each clinic visit, subjects will receive a kit of capsules to be taken at home according to their 
specific dose level. The subjects will be instructed to document capsules taken at home using 
electronic diary logs and to bring all unused capsules back to the clinic at the next visit. The 
subjects will be instructed to store the dosing kit in the refrigerator other than when it is removed 
to obtain the daily dose. 
Procedures for preparation and administration of doses given in clinic or at home are the same. 
Dose preparation is to be completed by the subject or supervising adult, as age-appropriate. (For 
in-clinic dosing, dose preparation may be performed by clinic staff or by parent/subject under the 

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direct supervision of clinic staff for the purpose of teaching and reinforcing training.) The 
capsules should be pulled apart, and gently rolled between finger and thumb, followed by a light 
tap to the end of each half of the capsule to ensure full delivery of contents. The contents of the 
capsules are to be mixed with a vehicle food, such as apple sauce, yogurt, pudding, or other 
palatable, age-appropriate, food. Care must be taken not to inhale the powder as this could 
provoke worsening of asthma or induce an allergic reaction. Study product may not be added to 
food heated above room temperature before consumption. The vehicle food must be one to 
which the subject is not additionally allergic. The volume of the vehicle food should be such that 
the entire dose can be consumed in a few spoonfuls. The study product should be consumed as 
promptly after mixing as practicable. If not consumed within 4 hours of mixing into a vehicle, 
the study product-vehicle food mixture should be discarded and a new dose mixed prior to 
consumption. If preparing a new dose is not feasible, the study product may be stored for up to 
24 hours under conditions appropriate for the food matrix in which the study product was 
prepared. If there is a delay of more than 24 hours in consumption, the study product is to be 
discarded and a new study product dose mixed and consumed. It is recommended that each dose 
of study product be taken at a consistent time (within a 4-hour time period) each day. A target 
interval of at least 8 hours should pass between doses.  
Except for in-clinic dosing, the daily home dose should be taken as part of a meal. Dosing at the 
evening meal is recommended to permit children to be observed and supervised in the home 
setting by their parents or guardians 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 h after dosing). Dosing should also not occur within 2 hours of bedtime. 
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. 
Except as may be necessary in the course of treating an adverse event (Section 6.7), it is crucial 
that subjects take their dose every day. No attempt should be made to make up for a missed dose 
if greater than 6 hours have elapsed since usual time of dosing. 
5.3 
Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) and International Council 
for Harmonisation Good Clinical Practice Guideline (ICH E6), the investigator is required to 
maintain adequate records of the disposition of the investigational agent, including the date and 
quantity of the drug (study product) received, to whom the drug was dispensed 
(subject-by-subject accounting), and a detailed accounting of any drug accidentally or 
deliberately destroyed. 
Records for receipt, storage, use, and disposition will be maintained by the study site. A 
drug-dispensing log will be kept current for each subject. This log will contain the identification 
of each subject and the date and quantity of drug dispensed. 
All records regarding the disposition of the investigational product will be available for 
inspection by the clinical trial monitor. 

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5.4 
Assessment of Compliance with Study Treatment and Monitoring 
Families will document daily dosing and any reaction to at-home dosing by diary logs. Central 
monitoring of compliance will be performed by comparing returned unused study product 
against the daily dosing records. Families will be provided with 24-hr emergency contact 
information for the site. 
Doses of study product lost or destroyed at home will also be recorded in the diary logs. All 
unused study product should be brought back to the clinic with each visit for reconciliation of 
remaining capsules/sachets.  
5.5 
Modification of Study Treatment  
As described in the protocol (Section 6.7), peanut OIT doses may be adjusted by the study 
physician if the subject is unable to tolerate the scheduled dose level. If such a dose modification 
occurs, the subject will return all kits and unused capsules/sachets of study product during the 
dose adjustment visit, and be dispensed capsules at the adjusted dose level. 
5.6 
Concomitant Medications 
Except as indicated in Section 5.10, all subjects may continue their usual medications, including 
those taken for asthma, allergic rhinitis, and atopic dermatitis, during the study. However, they 
must be able to discontinue antihistamines and other medications that could interfere with the 
assessment of an allergic reaction 5 half-lives prior to the initial day of escalation, skin prick 
testing (SPT), and oral food challenges. Usual topical steroid use is permitted following SPT.  
5.7 
Prophylactic Medications 
None. 
Although symptomatic treatments for chronic/recurrent AEs are permitted, as for example with 
H-1 or H-2 histamine blockers, proton pump inhibitors, or beta-adrenergic agonists, such 
medications should not be started in advance of symptoms; once started, their use should be 
minimized, and then discontinued, at the earliest medically appropriate opportunity.  
5.8 
Rescue Medications for Acute Allergic Reactions 
Treatment of individual acute allergic reactions during peanut OIT therapy should be with either 
an antihistamine and/or epinephrine, along with IV fluids, beta-adrenergic agonist (eg, albuterol), 
oxygen, and/or steroids, as indicated. Subjects and parents/guardians are likely already to have 
an epinephrine auto-injection device, but for those who do not, an epinephrine auto-injection 
device will be provided. The expiry dates for the epinephrine auto-injectors will be tracked and 
subject/families resupplied as necessary. Study staff must document in each subject’s medical 
record that the subject and parent/guardian have been provided with an epinephrine auto-
injection device and have been trained in its proper usage including injection technique.  
5.9 
Symptomatic Treatment for Chronic and/or Recurrent Adverse Events 
Symptomatic treatment for chronic/recurrent AEs is permitted (except for prohibited medications 
[Section 5.10]), but should be used to supplement dose reduction, not substitute for it. It is 
advised that an attempt to withdraw symptomatic therapy be made prior to dose re-escalation. If 

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unsuccessful, symptomatic therapy may be resumed and dose escalation proceed with the 
symptomatic therapy in place. However, any therapy instituted for treatment of symptoms (AEs) 
related to study product, must be withdrawn by 4 weeks prior to Exit DBPCFC. If a subject is 
unable to tolerate a daily maintenance of 300 mg of study product for at least the last 4 weeks of 
dosing prior to Exit DBPCFC, free of any symptomatic therapy that was initiated during the 
course of OIT, the subject will be considered a nonresponder. 
5.10 
Prohibited Medications 
1. Omalizumab (Xolair) 
2. Systemic (oral) corticosteroids used for any greater duration than a total of 3 consecutive 
weeks throughout the study. If used, subjects must not be up-dosed during the 3 days 
after ceasing the administration of oral steroids 
3. Beta-blockers (oral) 
4. Angiotensin-converting enzyme (ACE) inhibitors 
5. Angiotensin-receptor blockers (ARB) 
6. Calcium channel blockers 
7. Tricyclic antidepressants 
During the course of the study, subjects may be at increased risk for anaphylaxis, which, in 
severe form, can result in a drop in blood pressure. Additionally, the administration of 
epinephrine to treat anaphylaxis can result in a sudden rise in blood pressure. For these reasons, 
the risks accompanying the use of any medication with known cardiovascular side effects must 
be weighed against the potential benefits of peanut OIT. This assessment must be performed for 
any medications being taken at study entry or added during the course of the study. The use of 
medication with known cardiovascular side effects during the course of the study is discouraged; 
but if an investigator deems use necessary, it must be undertaken with caution. It is beyond the 
scope of this protocol to list all drugs with cardiovascular side effects. Classes of drugs with a 
high potential for cardiovascular side effects include antipsychotics, cyclooxygenase 2 inhibitors 
(chronic use), non-steroidal anti-inflammatory drugs (chronic use), antiarrhythmics, 
antihypertensives, and antineoplastics. Before a drug with cardiovascular side effects is used in 
conjunction with OIT, the investigator should discuss its use with 1 of the study’s Medical 
Monitors. 
Immunomodulatory (including immunosuppressive) medications constitute another class of 
drugs whose use during the course of the study is generally prohibited. It is beyond the scope of 
this protocol to list all immunomodulatory drugs; broadly, these include drugs to treat or prevent 
transplant rejection, autoimmune disease, and certain neoplasias - examples include 
cyclosporine, tacrolimus, anti-tumor necrosis alpha drugs, and anti-IgE drugs. If an investigator 
contemplates the use of a potentially immunomodulatory drug during the course of the study, the 
investigator should discuss this with 1 of the study’s Medical Monitors.   

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6 
STUDY PROCEDURES 
6.1 
Enrollment and Randomization 
Subjects will have an initial Screening DBPCFC consisting of both a peanut challenge and a 
placebo challenge before randomization. The peanut and placebo challenges will be conducted in 
a double-blind fashion, using foodstuffs provided by an unblinded site pharmacist, nutritionist, or 
study coordinator. Those subjects reacting to ≤ 100 mg of peanut protein (≤ 144 mg cumulative) 
will be randomized in a 3:1 ratio to AR101 or placebo. Those able to successfully consume the 
100 mg top challenge dose of peanut protein during their DBPCFC, ie, do not develop 
dose-limiting symptoms, will not be eligible for the study. In addition, those reacting with 
dose-limiting symptoms to ≤100 mg of the placebo challenge will not be eligible for the study. 
Because of the requirement for the peanut DBPCFC, the screening and baseline visits will need 
to be conducted over more than 1 day. 
Randomization will be stratified to maintain balance between treatment groups and to ensure 
adequate representation of key demographic sub-populations. Stratification will be by broad 
geographic region (to include at a minimum North America and Europe) and age (children from 
ages 4 to 17, inclusive, and adults to age 55, inclusive). As the Phase 2 studies (ARC001 and 
ARC002) were enrolled exclusively in the United States and only 1 adult subject was enrolled, 
stratifying randomization for age and geographic region will ensure balanced representation of 
potentially relevant subpopulations in ARC003. It is anticipated that approximately 65% of 
subjects will be recruited from North America, 30% from Europe, and potentially up to 5% from 
other regions. Investigational centers from Southern as well as Northern Europe are expected to 
participate. At least 80% of the subjects randomized will be children. Analysis of the ARC001 
data showed no interactive effect of age on treatment effect (ie, desensitization), so stratification 
by age will include only the 2 strata, children and adults. As there is male predominance on the 
order of 2 to 1 in the peanut-allergic population below the age of puberty, randomization may be 
regulated to ensure adequate representation of girls younger than 12 years. But since the 
proportion of males and females randomized to each arm of the ARC001, a relatively small 
study, adequately reflected the literature-reported breakdown of the peanut-allergic population 
by gender, and there was no apparent effect of gender on desensitization, it is assumed that in 
ARC003, a relatively large study, the two arms will be adequately balanced for gender without 
stratifying for this independent variable. Further, although the prevalence of peanut allergy tends 
toward parity between males and females after the age of puberty, social factors can play a 
significant role in clinical trial participation, such that a given clinical trial population may not 
match exactly the disease population. Taking this into account, a target for the proportion of 
males to females recruited from the adolescent and adult peanut-allergic populations is not being 
set.  
Randomization will be performed using an interactive response system. 
The study procedures are tabulated in Appendix 1 and are listed per visit below. 
6.2 
Screening and Baseline 
Screening may occur over several days and will include the following assessments/procedures:  
• 
Informed consent and assent, as age appropriate  

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• 
Inclusion/exclusion criteria review 
• 
Medical and allergy history review 
• 
Concomitant medication review 
• 
Diet (food allergen exposure) history review 
• 
Completion of the food allergy related quality of life questionnaire (FAQLQ), and the 
food allergy independent measure (FAIM) questionnaire. Both questionnaires will be 
completed before the DBPCFC 
• 
Assessment of asthma control using the Asthma Control Test questionnaire in subjects 
with asthma 
• 
Physical examination, including weight and height 
• 
Vital sign measurement (blood pressure, pulse rate, body temperature) 
• 
Spirometry (FEV1) and/or Peak Expiratory Flow Rate (PEFR) prior to any DBPCFC; 
3 attempts of FEV1 are performed and the best value is taken; 3 attempts of PEFR are to 
be performed, and the best value taken. PEFR should be measured at the same time for 
each visit assessment. 
• 
Serum pregnancy test, for females of childbearing potential 
• 
Blood draw to collect samples for:  
o Peanut-specific IgE, component-resolved IgE (including at screening determination 
of Ara h 1, Ara h 2, Ara h 3, Ara h 8 and Ara h 9) peanut IgE, total IgE, and 
peanut-specific IgG4 (immunoglobulin assays) The amount of blood to be taken for 
the immunoglobulin assays will be communicated from the central laboratory and 
included in the manual of procedures.  
o Complete blood cell count (CBC), obtained with the same venipuncture as the blood 
draw for the immunoglobulin assays 
o Optional exploratory immune cell characterization by the Immune Tolerance 
Network (ITN). Note that these samples can be obtained with the same venipuncture 
as the blood draw for the immunoglobulin assays and CBC, but will require an 
addition volume of blood to be collected. Separate informed consent is required.  
The amount of blood to be taken in total for the above assays (required immunoglobulin assays, 
required CBC, and optional immune cell characterization assays) will not exceed a total volume 
of 0.67 mL/kg in children, to a maximum of 50 mL, total, in 8 weeks. Blood draw should be 
collected in compliance with local laboratory guidelines and testing regulations. 
• 
Skin prick test to peanut extract 
• 
DBPCFC conducted in accordance with PRACTALL guidelines, with assessments made 
by a Blinded Evaluating Physician (Blinded Assessor), as described in Section 6.6 
• 
(North America sites only) Optional collection of saliva sample for exploratory 
biomarker development (Appendix 6) 
• 
Monitoring for adverse events (AEs), including allergic symptoms (Section 6.7) 

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• 
Subjects will be instructed to continue to follow a peanut-avoidant diet for the duration of 
the study.  
• 
Subjects and parents or guardians will additionally receive teaching about food/peanut 
allergy according to the investigational site’s established standards. This is to include at a 
minimum the following topics (some or all of which may be addressed in a 
comprehensive anaphylaxis action plan): 
o Recognition of an allergic reaction and of the symptoms of anaphylaxis  
o When and how to administer epinephrine via auto-injector 
o Requirement to go to nearest emergency facility following use of epinephrine auto-
injector 
o Ways to minimize the risk of accidental exposure to peanut in, and outside of, the 
home (may be supplemented by referral to recognized food allergy organizations for 
access to additional learning materials)  
All screening procedures must be completed no later than 28 days from the signing of the 
informed consent/assent form. The Initial Escalation Day-1 visit should occur within 10 days of 
the Screening DBPCFC. 
The laboratory values and clinical findings, including those from the Screening DBPCFC, will 
serve as the baseline measures for comparison to subsequent measures obtained during the 
course of the study. 
6.2.1 Optional Post-DBPCFC Blood Draw Visit 
This visit is only for subjects who consent to participate in the optional post-DBPCFC blood 
draw for exploratory immune cell characterization by the Immune Tolerance Network (ITN).  
The visit is to occur 5-10 days after completion of the Screening DBPCFC and may coincide 
with an Initial Escalation Day Visit (Section 6.3.1).  
The only procedure performed on this day is a blood draw. The amount of blood to be taken for 
the immune cell characterization assays will be provided in the manual of procedures and will be 
such that it will not cause the total blood volume collected to exceed 0.67 mL/kg in children, or 
maximum of 50 mL, total, in 8 weeks. Blood draw should be collected in compliance with local 
laboratory guidelines and testing regulations. 
6.3 
Study Treatment Visits  
6.3.1 Initial Escalation  
6.3.1.1 Initial Escalation, Day-1 
The Initial Escalation Day-1 visit should occur within 10 days of the Screening DBPCFC and 
must occur within 6 weeks from the signing of the informed consent/assent form. If the Initial 
Escalation is not started in this time frame, written approval to rescreen the subject and/or to 
waive any of the screening procedures must be obtained from the Sponsor Medical Monitor. 

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A physician will be available at all times during the CRC peanut OIT dosing visits.  
Subjects must be free from active wheezing or a flare of atopic disease (eg, atopic dermatitis), or 
suspected intercurrent illness prior to initiating study product dose escalation. Additionally, 
subjects must be fully recovered, ie back to their baseline state of health, from any preceding 
illness for at least 3 to 7 days, depending on the investigator-determined severity of the illness.  
The following assessments/procedures will be performed during the Initial Escalation.  
Day-1 visit in the CRC: 
• 
Concomitant medication update 
• 
Physical examination, including weight and height 
• 
Diet (food allergen exposure) history update 
• 
Pre-dose vital sign measurement (blood pressure, pulse rate, body temperature) 
• 
PEFR (3 attempts are to be performed, and the best value taken). PEFR should be 
measured at the same time for each visit assessment. 
• 
Administration of study product (AR101 or matching placebo), with dosing beginning at 
0.5 mg and progressing in graduated doses (if tolerated) of 1, 1.5, 3, and 6 mg. Following 
the first dose, subsequent doses will be delivered at 20- to 30-minute intervals. The 
schedule for initial day dose escalation is also shown in Table 3-1.  
• 
Post-dose vital sign measurements (blood pressure, pulse rate) within 15- to 30-minute 
postdose, and prior to next dose, and at 30 minute intervals thereafter, if the time between 
doses is extended, and for the duration of the postdose observation period. 
• 
Monitoring for adverse events (AEs), including allergic symptoms (Section 6.7 and 
Section 7.2) 
• 
Subjects will be reminded to continue to follow a peanut-avoidant diet for the duration of 
the study.  
Subjects may have clear liquids or flavored gelatin (eg, Jell-O) during the day of the initial day 
escalation procedure while they are being given the desensitization doses. 
At a minimum, subjects must be observed for 90 min. (1½ hours) after completion of dose 
escalation, with vital sign measurements and assessment for signs and symptoms of allergic 
reaction performed every 30 minutes. Any signs or symptoms of allergic reaction will be 
recorded in the CRF on the appropriate Dosing Symptom/AE form. 
If Day-1 dose escalation is completed with no symptoms detected after 1½ hours of post-dose 
observation, the subject may be sent home from the CRC. If the subject exhibited mild 
symptoms, the duration of the observation period should be extended to a minimum of 1 hour 
after resolution of the symptoms. For moderate symptoms, the observation period should be 
extended to a minimum of 2 hours after resolution of the symptoms. And for severe symptoms, 
the subject should be observed for a minimum of 3 hours after resolution of the symptoms, either 
at the CRC or an emergency facility, as appropriate. 

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Any subject deemed to have severe symptoms that include hypoxia, hypotension, or change in 
mental status, stage 3 anaphylaxis defined in Appendix 3, or who receives intensive therapy (to 
be determined by the investigator, but may include such interventions as IV epinephrine, 
intubation, or admission to an intensive care unit) for an allergic reaction at any time should be 
discussed with the Medical Monitor and discontinued from the study. 
If dose-limiting symptoms occur at or before the 3 mg single dose, there will be no further 
dosing of study product, and the subject will be classified as an escalation failure and a 
nonresponder for the purpose of primary and key secondary analyses. The subject will be asked 
to return to the CRC 14 days following the last dose of study product to undergo an Early 
Discontinuation Visit (Section 6.5). The subject will continue to be monitored for safety until the 
Early Discontinuation Visit is completed or any ongoing AEs are resolved, whichever is longer. 
If no dose-limiting symptoms occur during Day-1 dose escalation, or if dose-limiting symptoms 
occur only with the 6 mg single dose, the subject is to return to the CRC on Day-2 to confirm the 
tolerability of a single 3 mg dose of study product. 
6.3.1.2 Initial Escalation, Day -2 
On Day -2, a single confirmatory 3 mg dose will be administered under medical supervision in 
the CRC.  
Subjects must be free from active wheezing, a flare of atopic disease (eg, atopic dermatitis), or 
suspected intercurrent illness prior to continuing with Day -2 of the initial dose escalation. 
Consistent with the rules for missed doses (Section 6.8), Day -2 dosing may not be postponed for 
more than 2 weeks.  
The following assessments/procedures will be performed during the Initial Escalation  
Day -2 visit in the CRC: 
• 
Symptom-directed physical examination 
• 
Pre-dose vital sign measurement (blood pressure, pulse rate, body temperature) 
• 
PEFR (3 attempts are to be performed, and the best value taken). PEFR should, as far as 
possible, be measured at the same time for each visit assessment. 
• 
Oral administration of a single 3 mg dose of study product  
• 
Post-dose vital sign measurements (blood pressure, pulse rate) within 15 to 30 minutes 
postdose, and at 15- to 30- minute intervals thereafter for the postdose observation period 
• 
Monitoring for adverse events (AEs), including allergic symptoms (Section 6.7) 
• 
Subjects will be reminded to continue to follow a peanut-avoidant diet for the duration of 
the study.  
At a minimum, subjects must be observed for 1½ hours after dose administration, with vital sign 
measurements and assessment for signs and symptoms of allergic reaction performed every 

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30 minutes. Any signs or symptoms of allergic reaction will be recorded in the CRF on the 
appropriate Dosing Symptom / AE form. 
If Day -2 dosing is completed with no symptoms detected after 1½ hours of post-dose 
observation, the subject may be sent home from the CRC. If the subject exhibited mild 
symptoms, the duration of the observation period should be extended to a minimum of 1 hour 
after resolution of the symptoms. For moderate symptoms, the observation period should be 
extended to a minimum of 2 hours after resolution of the symptoms. And for severe symptoms, 
the subject should be observed for a minimum of 3 hours after resolution of the symptoms, either 
at the CRC or an emergency facility, as appropriate. 
Any subject deemed to have severe symptoms that include hypoxia, hypotension, or change in 
mental status (stage 3 anaphylaxis defined in Appendix 3), or who receives intensive therapy (to 
be determined by the investigator, but may include such interventions as IV epinephrine, 
intubation, or admission to an intensive care unit) for an allergic reaction at any time should be 
discussed with the Medical Monitor and discontinued from the study. 
If dose-limiting symptoms occur on Day -2, there will be no further dosing of study product, and 
the subject will be classified as an escalation failure and a nonresponder for the purpose of 
primary and key secondary analyses. The subject will be asked to return to the CRC 14 days 
following the last dose of study product to undergo an Early Discontinuation Visit (Section 6.5). 
The subject will continue to be monitored for safety until the Early Discontinuation Visit is 
completed or any ongoing AEs are resolved, whichever is longer. 
Those subjects who tolerate the single 3 mg dose of study product on Day -2 will be dispensed a 
2-week supply of study product at the 3 mg/d dose level. They will be instructed to continue 
daily oral dosing at home, starting the following day (Study Day -3), and to continue daily home 
dosing at that dose level for 2 weeks until next escalation. 
On Day -3, the site is to make telephone contact with the subject/subject’s parent or guardian to 
enquire if any AEs (including allergic symptoms) occurred subsequent to the subject leaving the 
clinic, and to provide assistance in recording of, and responding to, any such events. 
6.3.2 Up-dosing (also Referred to as Buildup or Escalation) Visits  
The Up-dosing Period will last approximately 20 (to a maximum of 40) weeks and comprise 
10 scheduled up-dosing visits (including the first 300 mg dose of the Maintenance Period), with 
the potential for unscheduled visits for assessment of dose tolerability, dose-reduction, dose 
re-escalation, or management of AEs. 
Subjects will return to the clinic every 2 weeks for up-dosing to a maximum daily dose of 
300 mg. The first dose of study product at each new dose level will be administered in the CRC 
under direct observation and medical supervision.  
Subjects must be free from active wheezing, a flare of atopic disease (eg, atopic dermatitis), or 
suspected intercurrent illness prior to any dose escalation. Subjects should be maintained on their 
current, or a reduced, dose level of study product until their flare of asthma, atopic disease, or 
intercurrent illness has resolved.  

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Subjects should withhold their daily home dose of study product on in-clinic dosing days, but 
should take all other prescribed medications as scheduled.  
The following assessments/procedures are scheduled for each up-dosing visit in the CRC: 
• 
Concomitant medication review 
• 
Diet (food allergen exposure) history update 
• 
Return unused capsules to the clinic at each visit 
• 
Symptom-directed physical examination 
• 
Pre-dose vital sign measurement (blood pressure, pulse rate, body temperature) 
• 
PEFR (3 attempts are to be performed, and the best value taken). PEFR should be 
measured at the same time for each visit assessment. 
• 
Study product administration under observation in the clinic 
• 
Post-dose vital sign measurements (blood pressure, pulse rate) within 15 to 30 minutes 
postdose, and at 15- to 30-minute intervals thereafter for the postdose observation period 
• 
Take home capsules for daily dosing until next visit 
• 
Monitoring for compliance  
• 
Monitoring for adverse events, including allergic symptoms (see below and also 
Section 6.7 and Section 7.2) 
• 
Subjects will be reminded to continue to follow a peanut-avoidant diet for the duration of 
the study.  
Subjects enrolled in the optional saliva substudy (North America sites only) who are not 
experiencing gastrointestinal symptoms will have a saliva sample collected on the morning of an 
early up-dosing visit (6 weeks ± 2), according to Table A6 in Appendix 6.  
At a minimum, subjects must be observed for 1½ hours after dose administration, with vital sign 
measurements and assessment for signs and symptoms of allergic reaction performed every 
30 minutes. Any signs or symptoms of allergic reaction will be recorded in the CRF on the 
appropriate Dosing Symptom/AE form. 
If up-dosing is completed with no symptoms detected after 1½ hours of post-dose observation, 
the subject may be sent home from the CRC. If the subject exhibited mild symptoms, the 
duration of the observation period should be extended to a minimum of 1 hour after resolution of 
the symptoms. For moderate symptoms, the observation period should be extended to a 
minimum of 2 hours after resolution of the symptoms. And for severe symptoms, the subject 
should be observed for a minimum of 3 hours after resolution of the symptoms, either at the CRC 
or an emergency facility, as appropriate. 
Any subject deemed to have severe symptoms that include hypoxia, hypotension, or change in 
mental status (stage 3 anaphylaxis defined in Appendix 3), or who receives intensive therapy (to 
be determined by the investigator, but may include such interventions as IV epinephrine, 

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intubation, or admission to an intensive care unit) for an allergic reaction at any time should be 
discussed with the Medical Monitor and discontinued from the study. 
On the day following in-clinic up-dosing, the site is to make telephone contact with the 
subject/subject’s parent or guardian to enquire 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. 
A dose escalation attempt may be postponed 1 to 2 weeks if, in the clinical judgment of the 
investigator, the current dose level has not been sufficiently well tolerated to proceed to the next 
dose level. Further, if an investigator suspects that a subject has not tolerated, or is not tolerating, 
his or her current dose level, the investigator should have the subject return to the clinic to 
determine whether a dose reduction is warranted, and if so, the magnitude of the reduction. 
Guidelines for setting the new, lower, dose are outlined in Section 6.7.5, with the dose 
adjustment depending on the severity of the dose-related symptoms.  
Subjects who require dose reduction during a 2-week dosing period will have their escalation 
schedule reset, as necessary, to maintain the new dose level for a 2-week period prior to 
attempting to re-escalate.  
Following a dose reduction, it is advised that an escalation attempt be made by 4 weeks, unless 
escalation is to be delayed further due to administration of epinephrine, as defined in Section 6.7. 
Failure to successfully escalate after 3 consecutive attempts, with each attempt spaced at least 
2 weeks apart, will result in the cessation of dosing and the subject being considered an 
escalation failure and nonresponder. The subject will be asked to return to the CRC 14 days 
following the last dose of study product to undergo an Early Discontinuation Visit (Section 6.5) 
and is to be followed for safety in the interim. 
For symptoms occurring during the Maintenance Period, the same study dosing rules and 
guidelines that apply for the Up-dosing Period will also apply.  
6.3.3 Up-dosing Midpoint Visit 
The first 80 mg in-clinic dosing visit is the approximate midpoint of the Up-dosing Period. At 
the up-dosing visit for the first administration of the 80 mg dose of study product the following 
procedures are to be performed in addition to those performed at the other up-dosing visits:  
• 
Complete (not just symptom-directed) physical examination, including height and weight 
• 
Assessment of asthma control in asthmatic subjects using the Asthma Control Test 
questionnaire 
• 
Urine pregnancy test, for females of childbearing potential 
• 
Review with subjects and parents or guardians teaching about food/peanut allergy 
according to the investigational site’s established standards. This is to include at a 
minimum the following topics (some or all of which may be addressed in a 
comprehensive anaphylaxis action plan): 
o Recognition of an allergic reaction and of the symptoms of anaphylaxis  

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o When and how to administer epinephrine via auto-injector 
o Requirement to go to nearest emergency facility following use of epinephrine 
auto-injector 
o Ways to minimize the risk of accidental exposure to peanut in, and outside of, the 
home (may be supplemented by referral to recognized food allergy organizations for 
access to additional learning materials)  
6.3.4 End of Up-dosing / Start of Maintenance Period Visit 
The first 300 mg in-clinic dosing visit is the end of the Up-dosing Period; it is also the start of the 
Maintenance Period. At this visit the following procedures are to be performed in addition to 
those performed at the up-dosing visits:  
• 
Complete (not just symptom-directed) physical examination, including height and weight 
• 
Assessment of asthma control in asthmatic subjects using the Asthma Control Test 
questionnaire 
• 
Urine pregnancy test, for females of childbearing potential 
• 
Blood draw to collect samples for:  
o Peanut- and peanut-component specific IgE, total IgE, and peanut- and peanut-
component specific IgG4 (immunoglobulin assays). The amount of blood to be taken 
for the immunoglobulin assays will be communicated from the central laboratory and 
included in the manual of procedures.  
o CBC, obtained with the same venipuncture as the blood draw for the immunoglobulin 
assays 
o Optional exploratory immune cell characterization by the Immune Tolerance 
Network (ITN). Note that these samples can be obtained with the same venipuncture 
as the blood draw for the immunoglobulin assays and CBC, but will require an 
addition volume of blood to be collected. Separate informed consent is required.  
The amount of blood to be taken in total for the above assays (required immunoglobulin assays, 
required CBC, and optional immune cell characterization assays) will not exceed a total volume 
of 0.67 mL/kg in children, to a maximum of 50 mL, total, in 8 weeks. Blood draw should be 
collected in compliance with local laboratory guidelines and testing regulations. 
• 
Skin prick test to peanut extract 
• 
Review with subjects and parents or guardians teaching about food/peanut allergy 
according to the investigational site’s established standards. This is to include at a 
minimum the following topics (some or all of which may be addressed in a 
comprehensive anaphylaxis action plan): 
o Recognition of an allergic reaction and of the symptoms of anaphylaxis  
o When and how to administer epinephrine via auto-injector 

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o Requirement to go to nearest emergency facility following use of epinephrine 
auto-injector 
• 
Ways to minimize the risk of accidental exposure to peanut in, and outside of, the home 
(may be supplemented by referral to recognized food allergy organizations for access to 
additional learning materials)  
For the first 2-week dosing interval at the 300 mg/d maintenance dose, the dose will be 
administered from 300 mg capsules. Thereafter, 300 mg doses may be administered from foil-
laminate sachets. 
6.3.5 Maintenance Period Visits  
The Maintenance Period begins with the first 300 mg in-clinic dosing visit. 
The first visit in the Maintenance Period is to occur 2 weeks after the start of dosing at 300 mg/d; 
thereafter Maintenance Period visits will occur approximately every 4 weeks. 
Subjects should withhold their daily home dose of study product on in-clinic dosing days, but 
should take all other prescribed medications as scheduled.  
The following assessments/procedures are scheduled for each in-clinic dosing Maintenance visit 
in the CRC: 
• 
Concomitant medication review 
• 
Diet (food allergen exposure) history update 
• 
Return unused sachets or capsules to the clinic at each visit 
• 
Symptom-directed physical examination 
• 
Pre-dose vital sign measurement (blood pressure, pulse rate, body temperature) 
• 
PEFR (3 attempts are to be performed, and the best value taken). PEFR should be 
measured at the same time for each visit assessment. 
• 
Study product administration under observation in the clinic 
• 
Postdose vital sign measurements (blood pressure, pulse rate) within 15 to 30 minutes 
postdose, and at 15- to 30-minute intervals thereafter if the postdose observation period is 
prolonged beyond the requisite 30 minutes (see below). 
• 
Take home sachets (or capsules, as appropriate) for daily dosing until next visit 
• 
Monitoring for compliance  
• 
Monitoring for adverse events, including allergic symptoms (Section 6.7 and 
Section 7.2) 
• 
Subjects will be reminded to continue to follow a peanut-avoidant diet for the duration of 
the study.  
In the event that dose reduction from the stable dose of 300 mg/d is required during the last 
weeks of the planned 24-week Maintenance Period, the Maintenance Period may be extended on 

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an individual basis up to an additional 4 weeks (to a maximum of 28 weeks) or to a maximum 
study duration of 68 weeks, whichever is shorter. The Exit DBPCFC must be performed by 
Study Week 68. Additionally, subjects must maintain a dose of 300 mg/d for at least the last 
2 consecutive weeks of the Maintenance Period to qualify for the Exit DBPCFC. Failure to do so 
will result in the subject being discontinued from the study as a maintenance failure 
nonresponder for the primary and key secondary analyses. 
If dosing is discontinued, the subject will be asked to return to the CRC 14 days following their 
last dose of AR101 to undergo an Early Discontinuation Visit (Section 6.5). 
The procedures for dose reduction and re-escalating back to a dose of 300 mg/d in the 
Maintenance Period will follow the same guidelines as for the Up-dosing Period.  
The procedure for monitoring subjects for safety after in-clinic dosing is the same as for up-
dosing visits (Section 6.7.3), except that the initial period of required post-dose observation may 
be shortened to 30 min. 
6.4 
Unscheduled Visits / Unscheduled Blood Draws 
The procedures performed at Unscheduled Visits may include any or all of those performed at 
Up-dosing Visits. 
Additionally, if a subject (subject’s parent/guardian) declares his or her intention to discontinue 
study product dosing, whether at a scheduled visit or an unscheduled visit, a blood draw should 
be performed to obtain a CBC, immunoglobulin assays, and optional exploratory immune cell 
characterization samples (if the subject is participating in the substudy). If a blood draw is 
performed at this time, it will take the place of the Exit Visit / Early Discontinuation Visit blood 
draw (Section 6.5). 
6.5 
Exit Visit / Early Discontinuation Visit 
Subjects who tolerate 300 mg/d and are maintained at this dose for approximately 24 weeks will 
return to the clinic for an Exit Visit. 
Subjects who fail initial escalation or up-dosing, or who prematurely discontinue treatment, will 
return to the site for an Early Discontinuation visit that consists of the same procedures as the 
Exit Visit, but without a DBPCFC. An Early Discontinuation Visit is to occur 14 days from the 
last dose of study product. 
Subjects who withdraw from ARC003 wholly or in part due to intolerable gastrointestinal 
symptoms, who are not enrolled in the optional saliva study, may be approached at the time of 
their early termination visit to provide voluntary consent to enroll and participate in the saliva 
substudy (North America sites only). If this occurs, such subjects will provide a saliva sample 
as part of the early termination visit and then again during post-OIT follow-up (Table A6 in 
Appendix 6). 
The following procedures will be performed at the Exit/ Early Discontinuation Visit: 
• 
Concomitant medication review 

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• 
Diet (food allergen) history  
• 
Completion of the palatability questions  
• 
Completion of the food allergy related quality of life questionnaire (FAQLQ), and the 
food allergy independent measure (FAIM) questionnaire after the completion of the exit 
DBPCFC and unblinding for all the patients  
• 
Completion of the Treatment Satisfaction Questionnaire for Medication (TSQM-9) and 
the exit questionnaire after after the completion of the exit DBPCFC and unblinding for 
all the active subjects  
• 
Assessment of asthma control in asthmatic subjects using the Asthma Control Test 
questionnaire 
• 
Physical examination, including weight and height 
• 
Vital signs (blood pressure, pulse rate, body temperature); if DBPCFC is to be conducted, 
these vital sign measurements should be taken shortly before the first challenge dose 
• 
PEFR (3 attempts are to be performed, and the best value taken). PEFR should, to the 
extent possible, be measured at the same time as for prior visit assessments. 
• 
Urine pregnancy test, for females of childbearing potential 
• 
Blood draw to collect samples for:  
o Peanut-and peanut-component specific IgE, total IgE, and peanut- and peanut-
component specific IgG4 measurement (immunoglobulin assays. The amount of 
blood taken for the immunoglobulin assays will be communicated from the central 
laboratory and included in the manual of procedures.  
o CBC, obtained with the same venipuncture as the blood draw for the immunoglobulin 
assays 
o Optional exploratory immune cell characterization by the Immune Tolerance 
Network (ITN). Note that these can be obtained with the same venipuncture as the 
blood draw for the immunoglobulin assays. Separate informed consent is required. 
The amount of blood to be taken for the above assays (required immunoglobulin assays, required 
CBC, and optional immune cell characterization assays) be will not exceed a total volume of 
0.67 mL/kg in children, to a maximum of 50 mL, total, in 8 weeks. Blood draw should be 
collected in compliance with local laboratory guidelines and testing regulations. (For subjects 
who are withdrawing prematurely from the study due to an AE, the blood draw at the Early 
Discontinuation Visit can be foregone if it was performed at the time that dosing with study 
product ceased.)  
• 
Skin prick test to peanut extract 
• 
Take home sachets (or capsules, as appropriate) for daily dosing until next visit (if 
enrollment in ARC004 does not happen at this visit) 
• 
Monitoring for compliance 
• 
Monitoring for AEs, including allergic symptoms (Section 6.7 and Section 7.2) 

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In addition to the procedures listed above, eligible subjects will have an Exit DBPCFC 
performed. Eligible subjects are those who tolerate 300 mg/d and are maintained at this dose for 
the approximately 24-week Maintenance Period. The Exit DBPCFC is to be conducted in 
accordance with PRACTALL guidelines, with the protocol-specified modifications, as described 
in Section 6.6.2. 
Each subject participating in the study will be unblinded when he/she completes the Exit Visit 
procedures (including the Exit DBPCFC for eligible subjects), provided regulatory and IRB/EC 
approval for ARC004 have been received, the availability of IP for ARC004, and all major data 
queries for the subject have been resolved (Section 3.3). If this is not the case, the subject shall 
remain on blinded treatment until these requirements are satisfied. The subject should continue 
his or her maintenance visits (completed as unscheduled visits), every 30 days, and complete all 
protocol procedures at each visit until study completion and rollover to ARC004. 
The end of the study is defined as the date of the last visit of the last subject. 
All ARC003 placebo subjects who complete the study are eligible for rollover into the ARC004 
protocol. Former ARC003 placebo subjects in ARC004 will undergo an escalation schedule 
identical to that for active subjects in the ARC003 protocol. All subjects on active treatment 
(AR101) in ARC003 who pass the DBPCFC at the 300 mg (443 mg cumulative) challenge dose 
level of peanut protein are eligible to proceed to ARC004. Those who do not pass DBPCFC at 
the 300 mg (443 mg cumulative) challenge dose level will be considered endpoint failures and 
nonresponders for the primary analysis. They will not be eligible for rollover into the ARC004 
protocol due to safety concerns. Those subjects who pass DBPCFC at the 300 mg (443 mg 
cumulative) challenge dose level, but fail at the 600 mg (1043 mg cumulative) or 1000 mg 
(2043 mg cumulative) challenge dose level, will be also be considered endpoint failures and 
nonresponders for the primary analysis for North America or Europe, respectively; however, 
they will be eligible for rollover into the ARC004 protocol because tolerating a 300 mg (443 mg 
cumulative) dose of peanut protein is considered a clinically relevant level of desensitization. 
6.6 
Double-Blind, Placebo Controlled Food Challenge (DBPCFC) 
Prior to performing DBPCFC, the subject must be off antihistamines and other medications that 
could interfere with the assessment of the DBPCFC for an appropriate length of time (5 half-
lives of the antihistamine or other medication in question). Also prior to the DBPCFC, subjects 
will be assessed for an exacerbation of asthma as determined by active wheezing or a PEFR < 
80% of predicted.  
Subjects must be free from active wheezing, a flare of atopic disease (eg, atopic dermatitis), or 
suspected intercurrent illness prior to DBPCFC. Additionally, subjects must be fully recovered, 
ie back to their baseline state of health, from any preceding illness for at least 3 to 7 days, 
depending on the investigator-determined severity of the illness. Subjects should be maintained 
on their current, or a reduced, dose level of study product until their flare of asthma, atopic 
disease, or intercurrent illness has resolved.  
Oral food challenges will be undertaken under direct medical supervision and with emergency 
medications and trained staff immediately available. The DBPCFC is performed by feeding 
gradually increasing amounts of a suspect allergenic food (in this case, peanut, presented as 

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defatted peanut flour) mixed in a vehicle (matrix) food under physician observation 
(Bock & Atkins, 1990; Burks et al., 2012). For this study, a uniform approach to food challenge, 
in accordance with the PRACTALL consensus guidelines for DBPCFC, will be used by all 
investigational sites. According to the PRACTALL guidelines, the challenge doses start at 1 mg 
and increase in semi-log increments to a maximum dose of 3000 mg. The DBPCFC dose 
escalation schedules used in the current study have been modified slightly from the PRACTALL 
recommendations, and are presented in Table 6-1. 
Table 6-1. 
Modified PRACTALL DBPCFC Doses Using Peanut Flour with 50% Peanut 
Protein Content for Screening and Exit DBPCFC 
 
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)  
at Exit 
Screening only 
1 
2 
1 
0 (or 1)* 
Screening and Exit 
3 
6 
4 
3 (or 4) 
Screening and Exit 
10 
20 
14 
13 (or 14) 
Screening and Exit 
30 
60 
44 
43 (or 44) 
Screening and Exit 
100 
200 
144 
143 (or 144) 
Exit only 
300 
600 
- 
443 (or 444) 
Exit only 
600 
1200 
- 
1043 (or 1044) 
Exit only 
1000 
2000 
- 
2043 (or 2044) 
*For explanation of contingent/optional doses indicated in parentheses refer to Section 6.6.2 
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), nor the assessment or management of adverse 
events (for details refer to the Masking Plan). To the extent practicable, the same Blinded 
Evaluating Physician who determines DLSs in the Screening DBPCFC should determine DLSs 
in the Exit DBPCFC. 
Vital signs (blood pressure and pulse rate) are to be measured just prior to each challenge dose of 
the DBPCFC or at 15 to 20 minute intervals post-dose, if the between challenge-dosing interval 
is prolonged. Assessment for signs and symptoms of allergic reaction is to be performed at the 
time that vital signs are checked. 
The DBPCFC is halted when the investigator determines that dose-limiting symptoms have 
occurred. Dose-limiting symptoms, in the setting of the DBPCFC, are any symptoms that, in the 
investigator’s assessment, indicate poor tolerability of the last challenge dose administered, and 
preclude safe advancement to the next challenge dose. 

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Dose-limiting symptoms, typically objective symptoms (signs), indicate a positive reaction and 
termination of dosing. The criteria for determining if symptoms are dose limiting during 
DBPCFC are the same as for determining whether a specific dose during up-dosing is tolerated 
(Section 6.7) with the exception that even mild symptoms, if they require pharmacological 
treatment, will be considered dose-limiting. 
As with up-dosing, severe symptoms will always be assessed as dose limiting; and moderate 
symptoms, with only rare exceptions (requiring a documented explanation), will also be assessed 
as dose limiting. Mild symptoms, on the other hand, may or may not be assessed as dose-limiting 
(Section 6.7). 
In general, if an investigator is unwilling to advance to the next challenge dose in a DBPCFC 
because of the emergence of allergic symptoms, the last symptom-eliciting challenge dose 
should be considered to have been not tolerated due to dose-limiting symptoms. There may, 
however, be exceptions to this, as for example if an emotional reaction to continuing the 
challenge dose escalation interferes with the ability to progress the dose escalation to the point 
where convincingly (typically objective) dose limiting symptoms occur. Any such instances must 
be accompanied by an explanation in the CRF.  
On the days that subjects undergo DBPCFCs (Screening and Exit), they must, at a minimum, be 
observed for 2 hours after administration of the last challenge dose, with vital sign measurements 
and assessment for signs and symptoms of allergic reaction performed every 30 minutes. Any 
signs or symptoms of allergic reaction will be recorded in the CRF on the appropriate Dosing 
Symptom / AE form. 
If DBPCFC is completed with no symptoms detected after 2 hours of observation following the 
last challenge dose, the subject may be sent home from the CRC. If the subject exhibited mild 
symptoms, the duration of the observation period should be extended to a minimum of 1 hour 
after resolution of the symptoms. For moderate symptoms, the observation period should be 
extended to a minimum of 2 hours after resolution of the symptoms. And for severe symptoms, 
the subject should be observed for a minimum of 3 hours after resolution of the symptoms, either 
at the CRC or an emergency facility, as appropriate. 
On the day following DBPCFC, the site is to make telephone contact with the subject/subject’s 
parent or guardian to enquire 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. 
6.6.1 Screening Double-Blind, Placebo Controlled Food Challenge (DBPCFC) 
The initial (Screening) DBPCFC for eligibility will consist of administering gradually increasing 
challenge doses of a peanut flour mixture (containing ~50% peanut protein) or a placebo (oat) 
flour mixture, mixed in a vehicle food, at 20 to 30 min intervals. 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. Additional, non-allergenic, powdered flavoring agents have been added both to the 
peanut and placebo flour mixtures to help further mask the distinctive flavor of peanut. A small 
amount of oat flour has been added to the peanut flour mixture to help match its consistency to 

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the placebo flour mixture. Investigational sites will be provided with standardized recipes for 
preparation of the DBPCFC in a separate manual of procedures. 
The Screening DBPCFC will be performed in accordance with PRACTALL guidelines, but 
requiring progression in an unaltered sequence without repeating any dose. The procedure will 
also be modified in that the top dose will be capped at 100 mg (144 mg cumulative) peanut 
protein or placebo, as shown in Table 6-1. Otherwise, the PRACTALL recommendations for 
maintaining safety and assessing symptom severity serve as useful guidelines. 
The DBPCFC is to be conducted as 2 challenges, each on a separate day, using a placebo 
(artificially peanut-flavored oat flour) for one challenge and peanut (as defatted peanut flour) for 
the other. The 2 challenge days should be scheduled as closely together as practicable and should 
not be scheduled more than 7 days apart. The oral food challenge is to be performed under 
double-blind conditions so that neither the subject, nor the subject’s caregiver, nor any of the 
clinic staff (save for the unblinded preparer of the challenge foods) knows which challenge 
contains the peanut or the placebo. The same vehicle food should be used for both parts of the 
DBPCFC. The clinic staff may not be unblinded as to the order of the two parts (peanut and 
placebo) of the DBPCFC until after completion of the observation period of the second part of 
the challenge. 
6.6.2 Exit Double-Blind, Placebo Controlled Food Challenge (DBPCFC) 
The Exit DBPCFC will be conducted in a manner similar to the Screening DBPCFC, but starting 
at a dose of 3 mg of peanut protein (except for subjects who failed their Screening DBPCFC at 
1 mg), and with the last 3 challenge doses progressing from 300 mg (443 mg cumulative) to 
600 mg (1043 mg cumulative) and then to 1000 mg (2043 mg cumulative) of peanut protein as 
shown in Table 6-1.  
The same vehicle food should be used for the Exit DBPCFC as was used for the Screening 
DBPCFC.  
Dosing with study product should continue on the days between the two parts of the Exit 
DBPCFC, according to the same dosing guidelines that apply throughout the Maintenance 
Period. 
Subjects who failed their Screening DBPCFC at the 1 mg challenge dose of peanut protein will 
be required to start the Exit DBPCFC with a 1 mg dose. At the investigator’s discretion, a 1 mg 
dose may be added at the beginning of the escalation (for a maximum cumulative dose of 2044 
mg peanut protein) of any subject’s Exit DBPCFC. 
Subjects will be considered desensitization responders for the primary endpoint analysis for 
North America or Europe if they are able to tolerate an Exit DBPCFC challenge dose of 600 mg 
(1043 mg cumulative) or 1000 mg (2043 cumulative) of peanut protein with no, or only mild, 
symptoms, respectively.  

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6.7 
Assessment and Treatment of Allergic Reactions to Peanut OIT  
6.7.1 Assessment of the Severity of Acute Allergic Reactions to Peanut OIT  
Subjects may develop allergic symptoms during the course of OIT, similar to those seen during 
other desensitization protocols (eg, venom immunotherapy, drug desensitization, desensitization 
to aeroallergens by subcutaneous injection). The severity of the reaction will be determined on 
the basis of the investigator’s judgment. The following definitions, developed to be consistent 
both with the 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 (Appendix 3) 
6.7.2 Assessment of the Tolerability of an Individual Dose of Study Product 
Determination of the tolerability of any individual dose of study product should be based on an 
assessment of acute symptoms occurring in close temporal succession to dosing. 
In general, the severity of allergic symptoms elicited at a particular dose of study product will 
define the tolerability of that dose of study product. The place where there is the greatest need for 

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clinical judgment in determining the tolerability of a dose is when the dose elicits mild allergic 
symptoms. The following Table 6-2 illustrates the likely combinations of symptom severity and 
tolerability: 
Table 6-2. 
Allergy Symptom Severity and Study Product Dose Tolerability 
Symptom Severity 
Assessed Tolerability 
None 
Tolerated 
Mild, oropharyngeal symptoms only 
Tolerated 
Mild, meeting pre-defined tolerability criteria (Section 6.7.1) 
Tolerated 
Mild, not meeting pre-defined tolerability criteria (Section 6.7.1) 
Not tolerated 
Moderate (except for rare exceptions, Section 6.7.1) 
Not tolerated  
Severe 
Not tolerated 
In general, the severity of an allergic reaction will correspond to the maximum severity of any of 
its symptoms. 
No Symptoms: If a dose elicits no symptoms, the dose will be assessed as tolerated. 
Mild Symptoms: When dosing with study product elicits an acute reaction characterized by the 
appearance of only a mild 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 symptom or symptoms was tolerated. A dose 
eliciting only mild symptoms may be considered to be tolerated if the symptoms are:  
• 
Isolated to a single organ 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 
• 
Do not include objective wheezing 
Based on experience from Phase 2, most acute allergic responses to dosing that are characterized 
by mild symptoms would be anticipated to meet the above criteria. If, however, an allergic 
response to dosing is characterized by mild symptoms that do not meet all of the above criteria 
(eg, has mild symptoms occurring in 2 or more organ systems, requires treatment with 2 doses of 
antihistamine or 1 dose epinephrine, shows progression in severity or distribution over time, is 
protracted in duration, or includes objective wheezing), then even though the allergic symptoms 
may be mild, the dose should be assessed to be not tolerated. If a dose elicits mild symptoms that 
do not fit all of the above criteria and the dose is assessed to be tolerated, then a brief explanation 
as to why the dose was considered tolerated must be recorded in the CRF. 

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Moderate symptoms: In general, if a dose elicits moderate symptoms, the dose will be assessed 
as not tolerated. There may, however, be rare occasions when a dose eliciting moderate 
symptoms could be assessed as tolerated. Generally, this would only be the case for a transient, 
self-limited (requiring no intervention and resolving completely) symptom occurring in a single 
organ system. In addition, typically the symptom would be subjective only. Any dose associated 
with moderate symptoms and assessed as tolerated must be accompanied by a brief explanation 
in the CRF as to why the dose was considered tolerated.  
Severe symptoms: In nearly all cases, if a dose elicits severe symptoms, the dose will be 
assessed as not tolerated. Whenever a dose elicits an allergic response characterized by 1 or more 
severe symptoms, the crucial decision, after adequate treatment for the allergic reaction has been 
administered, will be to determine whether the subject should continue in the study, dosing at a 
reduced dose level, or be discontinued early from the study.  
The determination of tolerability will decide the course of action to be taken in response to dose-
related reactions (Section 6.7.3). 
6.7.3 Assessment of the Tolerability of a Dose Level 
6.7.3.1 Assessment of Acute Symptoms Occurring after Dosing 
The assessment of the tolerability of a single dose forms the foundation for assessing the 
tolerability of a dose level during home-dosing when acute symptoms arise in close temporal 
succession to dosing. With the report of moderate or severe symptoms occurring during 
home-dosing, the dose level should be considered not tolerated and the subject brought to the 
clinic the day after the emergence of such symptoms for administration of the next dose of study 
product under medical supervision. If a dose administered at home is suspected to have been not 
tolerated, even on the basis of mild symptoms, the subject should also return to the CRC for 
dosing under medical supervision.  
The recurrence of a mild symptom or symptoms over the course of several days of home-dosing 
should suggest that the dose level is not tolerated, even if each individual occurrence of 
symptoms could be assessed as tolerated on the basis of the criteria listed above. If the 
investigational site is notified of mild dose-related symptoms on 4 or more occasions during a 
single week, the subject should be brought to the CRC for dosing under direct observation for 
assessment of the tolerability of the dose level. If mild dose-related symptoms are noted on 7 or 
more occasions during a 2-week dosing interval at a given dose level, that dose level should be 
considered not tolerated and appropriate action taken (Section 6.7.5.2).  
Because of the reduced reliability inherent in the second-hand reporting of symptoms, 
investigators are strongly encouraged to have subjects return to the clinic to undergo dosing 
under direct observation whenever acute allergic symptoms associated with dosing are reported.  
6.7.3.2 Assessment of Chronic / Recurrent Symptoms  
GI symptoms were the most common potentially allergic symptoms to occur on a subacute, 
chronic, and/or recurrent basis during Phase 2 clinical trials with AR101. Atopic dermatitis, 
seasonal allergies, or asthma are other potentially non-acute allergic reactions that could be 
brought on or exacerbated by OIT. The absence of a clear temporal relationship between dosing 

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and the emergence of recurrent symptoms may help to distinguish these from acute dosing-
related symptoms.  
If symptoms arise that suggest a chronic/recurrent reaction to study product, the dose level 
should be reduced. As with acute symptoms, the level of the dose reduction should be guided by 
the severity of the symptoms. Symptomatic treatment is permitted (refer to Section 6.7.5), but 
should be used as a supplement to dose reduction, not a substitute for it. 
For chronic/recurrent GI symptoms, especially upper GI symptoms, investigators are advised to 
have a low threshold for instituting a dose reduction and/or for considering early discontinuation 
of affected subjects from the study, owing to the potential for EoE.  
For subjects determined to be having dose-limiting chronic/recurrent GI symptoms up to and 
including the 20 mg/d dose level, it is advised that dosing of study product be suspended for 4 
weeks and resumed at a dose level of 3 mg/day for a minimum of 4 weeks, with the first dose 
given in the CRC under medical supervision. If tolerated, up-dosing may resume, with caution, 
according to the usual schedule, as tolerated, (Note – The 4-week suspension of dosing in 
response to chronic/recurrent GI symptoms occurring up to and including the 20 mg/d level is 
the only protocol-specified exception to the rules for missed OIT delineated in Section 6.8.) 
For subjects who develop dose-limiting chronic/recurrent GI symptoms at the 40 mg/d dose level 
or above, dose reduction and re-escalation is to proceed as described in Section 6.7.5. 
6.7.4 Treatment of Acute Reactions to Peanut OIT during Initial Escalation 
The process algorithm for responding to acute allergic symptoms during OIT is shown in 
Figure 6-1 in Section 6.7.5. 
Investigator judgment will be required to determine the best course of action, with possible 
actions being the following:  
• 
Extending the time interval between dosing (up to an additional 30 min) without any 
additional treatment  
• 
Instituting enhanced clinical monitoring. This could include (though is not limited to) 
more frequent vital sign monitoring (including respiratory rate), auscultation, and/or the 
addition of pulse oximetry  
• 
Treating with antihistamine and then resuming dose escalation within 60 minutes of last 
dose, if assessed as safe 
• 
Treating additionally with epinephrine, beta-agonist, oxygen, IV fluids, and/or 
glucocorticosteroids, as necessary, and discontinuing dose-escalation 
• 
Discontinuation of desensitization protocol  
Mild symptoms: For oral/pharyngeal pruritus occurring in isolation, a specific type and 
commonly occurring mild allergic reaction, the recommended action is to advance to the next 
dose in 30 min (though the action taken is, as always, at the investigator’s clinical discretion). 

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For other mild symptoms, the action to be taken, at the investigator’s discretion, should be to 
either:  
• 
Advance to next dose in 30 to 60 minutes or 
• 
Treat with antihistamine and then resume dose escalation within 60 minutes of last dose, 
provided that symptoms have resolved to the point where the investigator assesses the 
subject to be safe to continue dosing (ie, having no or only minimal residual signs or 
symptoms) 
In general, if a subject requires only 1 or two doses of antihistamine to treat mild symptoms 
occurring during the course of the initial escalation, then the initial escalation may continue. If, 
however, the subject requires a second medication (eg, epinephrine or a beta-agonist) to treat the 
symptoms, or more than 2 doses of an antihistamine, the initial escalation is to be terminated and 
the subject is to receive no further OIT, even if the symptoms were assessed to be mild. Use of 
epinephrine to treat dose-related symptoms, even in the unlikely event that the symptoms are 
graded as mild, will be cause to terminate the initial escalation.  
Moderate symptoms: For moderate symptoms, if the symptoms are not worsening or amassing 
at a rapid pace, then a stepwise approach to treatment may be taken at the discretion of the 
investigator. If the first action undertaken is to implement an observation period, the observation 
period should not exceed 30 min before either the symptoms are noted to be resolving or therapy 
is instituted. Whether treatment is initiated immediately or after an observation period, the 
subject may be treated first with antihistamines or immediately with epinephrine, as deemed 
appropriate by the investigator. Other therapies may be added either sequentially or 
simultaneously, per investigator judgment.  
If moderate symptoms occur at any of the doses below 6 mg (ie, up to and including 3 mg), then 
the desensitization procedure will be discontinued and the subject considered an escalation 
failure and desensitization nonresponder. The decision to discontinue escalation is to be based 
solely on the determination of whether the allergic reaction was of moderate severity. Although 
it is generally the case that some form of treatment will be instituted for moderate symptoms, 
treatment is not a requirement for assessing an allergic reaction as being of moderate severity.  
Severe symptoms: For severe symptoms, the actions taken should be to discontinue the initial 
escalation and administer the appropriate rescue medications. The desensitization procedure will 
be discontinued regardless of the dose at which the severe symptom or symptoms occurred, and 
the subject will be considered an escalation failure and desensitization nonresponder. 
A Medical Monitor (from INC or Aimmune) is to be available at all times to answer any 
questions or to assist in any decisions related to the study protocol. 

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Figure 6-1: 
Schematic for Initial Escalation Day-1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.7.5 Treatment for Reactions During the Up-dosing Period: Dose Adjustment 
If a dose or dose level is assessed as not tolerated, the action taken will depend on the type and 
severity of the dose-related reaction and the investigator’s clinical judgement. The following 
possible actions are at the investigator’s disposal and are considered in greater detail in 
subsequent sections (Section 6.7.5.1, Section 6.7.5.2, and Section 6.7.5.3, and Figure 6-2): 
• 
Dosing the subject under medical supervision in the CRC – this is encouraged whenever 
there is question as to the tolerability of a dose level. It may be performed at the current 
dose level or at a reduced dose level, if there is already a high index of suspicion that the 
current dose level has not been tolerated.  
• 
Holding dose level at current level for an additional 1 to 2 weeks before attempting dose 
escalation – this may be done at the discretion of the investigator if there is concern that 
the current dose level has not been sufficiently well tolerated to attempt up-doing to the 
next dose level.  
• 
Reducing dose by 1 or 2 dose levels and maintaining the reduced dose level for at least a 
2- to 4-week period before attempting dose re-escalation – Generally, this should be the 
Dose-Escalation 
Dose 
Oral/pharyngeal pruritus 
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 
 
Severe Symptoms 
 
 
Moderate Symptoms 
 
Time to next dose: 30 min  
Next dose: advance 
Treatment as indicated for severe 
reaction, stop escalation and 
discontinue from study 
Occurring at 6 mg: Treat as indicated 
for moderate reaction; Subject to 
return for Day-2 dosing at 3 mg 
 
Occurring at ≤3 mg: Treat as indicated 
for moderate reaction; stop escalation 
and discontinue from study 
 
Mild Symptoms 
 

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action taken when a dose that has been observed in the CRC is assessed as not tolerated, 
if a dose elicits moderately severe symptoms, if a single dose of epinephrine has been 
administered to treat a dosing reaction, or if the investigator is convinced of the 
intolerability of the current dose level. In short, it should be considered the default action 
whenever a dose or dose level is assessed as not tolerated.  
• 
Reducing dose level for less than the usual 2-week period – this may be instituted as 
treatment for an intercurrent AE, to aid the investigator in determining if a dose level is 
or is not tolerated, or if a pattern of decreased study product tolerability during menses is 
discerned. The level of the reduction in dose, ranging from a 1-step reduction to a 50% 
reduction will be at the investigator’s discretion, based on clinical judgement. The 
manner in which dose escalation may resume will depend on the level and the duration of 
the dose reduction. 
• 
Temporarily withholding study product dosing – this may be instituted as treatment for 
an intercurrent AE or to aid the investigator in determining if a dose level is or is not 
tolerated, but the duration of withholding study product may not exceed 14 consecutive 
days, or the subject will be discontinued from the study. The manner in which dosing 
may resume after withholding dosing of study product depends on the duration for which 
dosing was withheld.  
• 
Reducing dose by 2 dose levels and maintaining the reduced dose level for at least 
6 weeks – continuing dosing at a reduced dose level for at least 6 weeks prior to 
attempting re-escalation is mandatory if 2 doses of epinephrine are given to treat a single 
AE. 
• 
Stopping dosing and discontinuing the subject early from the study – this is an option that 
the subject may elect at any time and for any reason. The investigator must discontinue 
the subject from further dosing and continuation in the trial under circumstances that 
could jeopardize the health of the subject or the integrity of the trial.  
6.7.5.1 Reactions to In-Clinic Dosing  
If symptoms arise in the clinic after up-dosing, the investigator is to determine whether or not the 
dose was tolerated (Section 6.7.3). The process algorithm for continued dosing after dose-related 
symptoms occur is described below and shown in Figure 6-2. 
If a subject has a dose escalation in the CRC without symptoms, the action should be to continue, 
per protocol, with daily home dosing at the tolerated dose level and return to the CRC for the 
next scheduled dose escalation visit 2 weeks later.  
If the subject experiences only oral/pharyngeal pruritus following the administration of the first 
dose at a new dose level, the dose will generally be assessed as tolerated, and the same dose can 
be repeated the next day at home and continued throughout the 2-week home-dosing interval, 
unless other symptoms begin to develop (see below). 
If other mild symptoms occur with the first dose at a new dose level and the dose is assessed as 
not tolerated, the action taken should be to have the subject return to the CRC the next day for 
dosing at the last tolerated dose (ie, a 1-step dose reduction) under medical supervision (if the 
subject is unable to return to the CRC on the day specified, the investigator may initiate an 

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approximate 1 dose-level reduction at home, with the subject coming to the CRC at the earliest 
date possible). If the reduced dose is assessed as tolerated, the subject is to continue on that daily 
home dose for the ensuing 2 weeks. (Section 6.7.5.2 for actions to be taken in the event that 
symptoms develop during home-dosing.) If the reduced dose is again assessed as not tolerated, 
the subject is to return to the CRC the next day for supervised dosing at a 1- or 2-step reduction 
in dose (per investigator judgment, based on severity of reaction). If this further reduced dose is 
assessed as tolerated, the subject will continue at that dose level for daily home-dosing over the 
ensuing 2 weeks. If, however, the reduced dose is assessed as not tolerated, the subject is to be 
considered an escalation failure nonresponder. 
If mild symptoms occur with the first dose at a new dose level and the dose is assessed as 
tolerated, the action taken should be to repeat the same dose the next day. It is advised that the 
repeat (next day’s) dose be administered in the CRC, but it may be given at home, at the 
investigating physician’s discretion. If the second dose at the new (increased) dose level is 
tolerated without symptoms, then the subject is to continue on that dose level for the requisite 
2 weeks and return to the CRC for up-dosing at the next scheduled visit. If the dose again causes 
mild symptoms, but is assessed as tolerated, the subject may continue at that dose level or return 
to the last tolerated dose (at the investigator’s discretion) and continue dosing at home for the 
next 2 weeks at the investigator-determined dose level. (Section 6.7.5.2 for actions to be taken in 
the event that symptoms develop during home-dosing.) If, following the first dose at a new dose 
level, the second dose at the new (increased) dose level is again accompanied by mild symptoms, 
but is assessed as not tolerated, the procedures outlined in the paragraph above should be 
followed. 
If moderate symptoms occur with the first dose at a new dose level, except for rare instances, the 
dose will be assessed as not tolerated. The action taken should be to have the subject return to 
the CRC the next day for dosing at the last tolerated dose under medical supervision. If this 
reduced dose elicits no allergic symptoms, ie, is well tolerated, the subject will continue on that 
daily home dose level for an additional 2 weeks. If the subject experiences mild symptoms at the 
reduced dose, the procedures for responding to a dose with mild symptoms should be followed 
(see above and Figure 6-2. If the subject experiences moderate symptoms at the reduced dose 
level, the subject should return to the CRC the next day and receive a further 1- or 2-step dose 
reduction (per investigator judgment). If this reduced dose is well tolerated, it will be continued 
as the daily home dose for at least 2 weeks before re-escalation is attempted in the CRC. If the 
dose is not well tolerated, but elicits mild symptoms, then the treatment procedures for 
responding to mild symptoms should be followed (see above, and Figure 6-2. If, however, the 
subject again experiences moderate symptoms at the reduced dose level, a discussion with the 
Medical Monitor is to ensue to reach a decision as to whether to continue the subject in the 
study.  
In the rare instance that a dose eliciting moderate symptoms is assessed as tolerated, then the 
actions taken should be the same as for a dose with mild symptoms assessed as tolerated (see 
above). 
If severe symptoms occur, the action should be to treat the subject for the allergic reaction, and 
then, in consultation with the Medical Monitor, decide whether or not to discontinue the subject 
from the study. If it is determined that it is safe to allow the subject to continue in the study, the 

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subject should return to the CRC the next day for dosing at a 2-step reduction in dose under 
observation. If the subject tolerates the dose reduction (ie, shows no or only mild symptoms that 
are assessed as tolerated), then the subject is to remain at the reduced dose level for at least 
2 weeks before returning to the CRC to attempt dose re-escalation. If the subject does not 
tolerate the reduced dose, then the subject is to be considered an escalation failure nonresponder. 
For specific questions related to dose-escalation or continuation of the same dose that are not 
answered in the above protocol, the Medical Monitor will be available for consultation.  
6.7.5.2 Reactions to Dosing at Home 
With the occurrence of symptoms of an acute reaction to study product after home-dosing, or any 
acute allergic reaction, subjects/parents or guardians are instructed to call the study site. The 
investigator must then determine whether or not the dose was tolerated (Section 6.7.3). Because 
of the reduced reliability inherent in the second-hand reporting of symptoms, investigators are 
strongly encouraged to have subjects return to the clinic to undergo dosing under direct 
observation whenever acute allergic symptoms associated with dosing are reported.  
When symptoms of a dose-related allergic reaction are reported during the course of daily 
home-dosing, the investigator must assess the severity of the reaction and whether the dose 
associated with the reaction was tolerated. The appropriate intervention will depend on the type 
and severity of symptoms (Section 6.7.5.2 and Figure 6-2).  
In general, moderate or severe symptoms will be considered clinically significant, and any dose 
eliciting such symptoms assessed as not tolerated; however, mild symptoms may also be 
considered clinically significant, eg, if affecting multiple organ systems, increasing in intensity, 
occurring with increasing frequency, or affecting a larger area over time, and assessed as not 
tolerated. Whenever there is question as to the clinical significance of mild signs or symptoms, 
the investigator should have the subject return to the CRC for observed dosing under medical 
supervision.  
For home-doses assessed as not tolerated on the basis of acute dose-related symptoms, the same 
procedures described in Section 6.7.5, above, for adjusting up-dosing should be followed.  
The recurrence of mild symptoms over the course of several days of home-dosing should suggest 
that the dose level is not tolerated, even if each individual occurrence of symptoms could be 
assessed as tolerated on the basis of the criteria listed above. In this circumstance, investigator 
judgment will be required to determine the best course of action with the possible actions being 
the following:  
• 
Continue with daily home dosing at the current dose level 
• 
Continue the same daily dose for the rest of the 2-week interval, with the dose split into 
2 fractional doses given 8 to 12 hours apart (the 2 fractional doses need not be equal) 
• 
Return to the CRC for repeat dosing at the current dose level under direct observation to 
confirm whether or not the dose level is tolerated 

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• 
Return to the CRC for dosing of a previously tolerated dose level, either a 1- or 2-step 
reduction (per investigator judgment, based on severity of reaction) and follow the 
procedures described in Section 6.7.5.2 above 
• 
Institute the 4-week hiatus from dosing, with resumption of dosing at the 3 mg/d dose 
level, as permitted for recurrent GI symptoms occurring at or before the 20 mg, as 
described in Section 6.7.3.2. 
• 
Discontinuation of dosing 
Any subject who discontinues build-up dosing due to severe or repeated allergic reactions to 
study product should have his/her mechanistic blood draw and CBC (Section 8) at, or as nearly 
as possible to, the time of the last dose and no later than at their Early Discontinuation Visit. 

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Figure 6-2: 
Schematic for Up-dosing Period Dose Adjustment  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild Symptoms; uncertain if 
dose or dose level tolerated 
Next dose at 
home or in 
CRC, per 
investigator  
Moderate Symptoms 
= NOT tolerated  
(with rare exceptions) 
Mild Symptoms; dose or 
dose level NOT tolerated 
Severe Symptoms = 
NOT tolerated;  
0- 1 dose of epinephrine 
Dose subject under medical 
supervision to determine tolerability 
Split home dose into 2 doses 8-12 h apart  
(only for repeated mild symptoms with 
home-dosing) 
Reduce dose by 1 or 2 dose levels and 
maintain reduced dose for at least 2- to 4-week 
period before attempting dose re-escalation 
Hold current dose level for an additional 1 to 
2 weeks before attempting dose escalation 
Reduce dose by 1 or 2 dose levels until dose 
tolerated with no or mild symptoms; if mild 
symptoms result, proceed as above 
Reduce dose by 2 dose levels; if no or mild 
symptoms (assessed as tolerated) result, proceed 
with dosing at reduced level for at least 2 to 
4 weeks; if moderate or severe symptoms result, 
discontinue dosing  
Next dose 
in CRC 
As for “Severe Symptoms” above, but reduced 
dose level (if tolerated) held for 6 to 8 weeks 
Severe Symptoms = 
NOT tolerated;  
2 doses of epinephrine 
Next dose 
in CRC 
Next dose 
in CRC 
Next dose 
in CRC 
or 
or 
or 

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6.7.5.3 Dose Adjustment in Response to Adverse Events 
At the investigating physician’s discretion, temporary dose reductions, ranging from a 1-step 
decrement (ie, to the previous dose) to approximately half of the current dose level (to the 
nearest feasible available whole dose), can be instituted as part of the treatment regimen for an 
intercurrent AE. Also, if a pattern of decreased tolerability of study product during menses is 
discerned, then a temporary dose reduction can be instituted during this time. Temporary dose 
reductions for intercurrent AEs may be instituted as follows: 
• 
For dose reductions of ≤ 4 consecutive days, whether dose re-escalation is to occur at 
home or in the CRC is at the investigator’s discretion. If the reduction in dose is 
maintained for ≤ 4 consecutive days, then the prereduction dose level may be resumed, 
with the biweekly escalation schedule kept unaltered.  
• 
If a reduction in dose is maintained for 5 to 7 consecutive days, then the subject is to 
return to the CRC to undergo dosing under medical supervision. At the investigator’s 
discretion, the prereduction dose level may be resumed or dosing may continue at the 
reduced dose level. The biweekly escalation should be reset so that the subject receives at 
least 2 consecutive weeks of treatment at the dose level assigned (either the reduced or 
the prereduction dose level). 
• 
If a reduction in dose is maintained for 8 to 14 consecutive days, then the next escalation 
attempted must be conducted in the clinic, and it should only be to 1 dose level above the 
reduced dose. If the escalation is successful, the subject should continue home-dosing for 
a minimum of 2 weeks, with his or her biweekly escalation schedule reset as necessary.  
Doses of study product may also be withheld at the investigator’s discretion, in response to an 
intercurrent AE. Doses withheld as part of the treatment for an AE constitute a special category 
of missed peanut OIT doses (Section 6.8). 
6.7.6 Treatment for Reactions During the Up-dosing Period: Pharmacological and 
Supportive Treatments 
Treatment of acute reactions should be with either an antihistamine and/or epinephrine, along 
with IV fluids, a beta-agonist (eg, albuterol, by inhaler or nebulizer), oxygen, and/or 
glucocorticosteroids, as indicated.  
Many mild acute allergic reactions can be transient and self-limiting, requiring no therapeutic 
intervention. Others, however, may require treatment. Generally, for mild symptoms requiring 
treatment, the subject should receive antihistamines.  
Acute allergic reactions manifesting with moderate symptoms will generally require therapeutic 
intervention, although some, even moderate, symptoms may on rare occasion be so transient as 
to require no specific treatment. Generally, for moderate symptoms requiring treatment, the 
subjects should receive antihistamines and/or epinephrine, as indicated. If there is uncertainty as 
to the severity of the reaction, administering epinephrine would be considered the most 
appropriate course of action.  

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Generally, severe symptoms will require treatment with epinephrine at a minimum. If severe 
symptoms that qualify as stage 3 anaphylaxis (defined in Appendix 3) occur at any time, dosing 
with study product will stop and the subject will be discontinued from the study as an escalation 
failure nonresponder.  
Antihistamines 
If a subject receives antihistamines only, the dose escalation can be continued. If symptoms 
during a build-up day require administration of more than 2 doses of an antihistamine or of an 
antihistamine in combination with other medications (except epinephrine), there should be a dose 
reduction of 1 or 2 dose levels, with the next dose given in the CRC. If epinephrine is 
administered, then a different course of action is to be taken (see below).  
Epinephrine - General 
Any reaction to study product (in clinic or at home) that requires more than two doses of 
epinephrine will halt all further dosing of study product for the individual. The subject will be 
asked to return to the CRC 14 days following the last dose of study product to undergo an Early 
Discontinuation Visit (Section 6.5). 
Epinephrine - Clinic 
If a single administration of epinephrine is required during, or after, a dose-escalation in the 
clinic, no further dosing of study product is to occur at that visit. The next dose of study product 
is to be reduced by two dose levels and administered in the CRC, but biweekly dose escalation 
should continue. 
If a single administration of epinephrine is required a second consecutive time during, or after, 
1 escalation attempt, the dose should be reduced by two dose levels, and the subject continued at 
that dose level for 6 to 8 weeks. After 6 to 8 weeks at the reduced dose, an escalation attempt 
may be tried in clinic. 
If a single administration of epinephrine is required a third consecutive time during an escalation 
attempt, no further dosing should be attempted. Dosing in these subjects will be discontinued. 
They will be asked to return to the CRC 14 days following their last dose of study product to 
undergo an Early Discontinuation Visit (Section 6.5). 
Epinephrine - Home 
If a single administration of epinephrine is given during dosing at home, this epinephrine use is 
not counted as 1 of the uses described above, unless severe anaphylaxis is assessed to have 
occurred at home. Administration of epinephrine outside of the clinic should be followed 
immediately by the subject being taken to the nearest emergency department. The subject should 
return to clinic for an observed dose under medical supervision prior to resuming any dosing at 
home. 

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6.7.7 Reactions Occurring During the Maintenance Period  
This phase consists of the subject receiving the 300 mg/d dose of study product for 
approximately 24 weeks. For any noted symptoms during the Maintenance Period, the same 
study product dosing guidelines and procedures will be followed as for the Up-dosing Period. 
6.8 
Missed Peanut OIT (Study Product) Doses during Up-dosing: 
Missed doses of study product at any phase of the study can pose a significant risk to the enrolled 
subjects, but the risk is believed to be highest during the Up-dosing Period. The algorithm for 
missed consecutive doses of study product is as follows: 
• 
Miss 1 dose – The next dose would be at the current dose level and could be given at 
home 
• 
Miss 2 doses in a row – The next dose would be the current dose level and could be given 
at home 
• 
Miss 3 doses in a row – The next dose would be the current dose and would be given 
under supervision in the CRC 
• 
Miss 4 doses in a row – The next dose would be the current dose and would be given 
under supervision in the CRC 
• 
Miss 5-7 doses in a row – Initiate the next dose at approximately 50% of the last tolerated 
dose (to the nearest feasible available whole dose that is ≤50% of the last tolerated dose). 
This dose is to be administered under supervision in the CRC. If tolerated, dose 
escalation may resume with dose increases of 1 dose level occurring no more frequently 
than weekly and generally no less frequently than every 4 weeks until the subject has 
returned to the dose level at which the lapse in dosing occurred. If symptoms occur, the 
dosing guidelines for the up-dosing period apply. 
• 
Missing > 7 consecutive days of dosing due to non-compliance, ie, for any reason other 
than treatment of an AE or a study product dispensing error, constitutes an individual 
stopping rule and the subject is to stop taking study product. The subject will be 
considered an escalation failure nonresponder, and will be asked to return to the CRC 14 
days following their last dose of study product to undergo an Early Discontinuation Visit 
(Section 6.5). 
• 
Additionally, excessive missed dosing, defined as 3 consecutive days of missed doses on 
3 occasions during the Up-dosing Period or on 3 occasions during the Maintenance 
Period, for any reason other than treatment of an AE, constitutes an individual stopping 
rule and the subject is to stop taking study product. The subject will be considered an 
escalation failure nonresponder, and will be asked to return to the CRC 14 days following 
their last dose of study product to undergo an Early Discontinuation Visit (Section 6.5). 
• 
If study product has been withheld for 8 to 14 consecutive days as treatment for an AE or 
due to a study product dispensing error, dosing may be reinitiated at approximately 25% 
of the last tolerated dose (to the nearest feasible available whole dose that is ≤ 25% of the 
last tolerated dose) if the lapse in dosing occurred during the Up-dosing Period. If the 
lapse in dosing occurred during the Maintenance Period, dosing may, at the investigator’s 
discretion, be reinitiated at 50% of the last tolerated dose (to the nearest feasible available 

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whole dose that is ≤ 50% of the last tolerated dose). The reduced dose is to be 
administered under supervision in the CRC. If tolerated, dose escalation may resume with 
dose increases of 1 dose level occurring no more frequently than weekly and no less 
frequently than every 4 weeks until the subject has returned to the dose level at which the 
lapse in dosing occurred. If symptoms occur, the dosing guidelines for the Up-dosing 
period apply. 
• 
If study product has been withheld for ≥ 15 consecutive days for any reason, at any point 
in the study (with the exception of a dosing hiatus instituted for chronic/recurrent GI AEs 
at or before the 20 mg dose level, as per Section 6.7.3.2), the subject will be considered 
an escalation failure nonresponder, and will be asked to return to the CRC 14 days 
following their last dose of study product to undergo an Early Discontinuation Visit 
(Section 6.5). 
No attempt should be made to make up for a missed dose if greater than 6 hours have elapsed 
since usual time of dosing. 
6.9 
Skin Prick Test 
Subjects will have skin prick tests performed using investigational site- and sponsor-approved 
procedures for food allergens. Detailed instructions for performance of the SPT will be provided 
in a manual of operating procedures. In brief, while the subject is off antihistamines for an 
appropriate length of time (5 half-lives of the antihistamine that is being used), a skin test probe 
is pressed through a commercial peanut allergen extract into the epidermis. Positive (histamine) 
and negative (saline-glycerin) controls are placed to establish that the response is not blocked 
and to determine if there is dermatographism, respectively.  
6.10 
Assessment of Asthma Control Using the Asthma Control Test Questionnaire 
Subject or subject and parental assessment of asthma control will be performed at the specified 
visits using the Asthma Control Test questionnaire for subjects with asthma. 
6.11 
Visit Windows  
Dosing schedule should be adhered to strictly. Two days before, or 2 days after a planned dosing 
visit, is an acceptable window with continued daily dosing of the current dose level. Study visits 
for scheduled blood draws or DBPCFC should take place within 2 weeks of the scheduled visit. 
Early Discontinuations Visits are to occur 14 days after the last dose of study product. The 
permissible window is minus 3 days to plus 7 days. 
6.12 
Study Blinding Procedures 
This is a double-blind study. The study as a whole will not be unblinded until after the last 
subject exits ARC003 and the database is locked. 
After undergoing the Exit DBPCFC, most subjects will, however, become de facto unblinded to 
their on-study treatment assignment on the basis of their experience with the food challenge; ie, 
subjects who fail 1 part of the Exit DBPCFC early on may reasonably deduce that they had been 
in the placebo arm of the study, and those who tolerate both parts of the Exit DBPCFC (or fail 

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1 part only at the highest dose levels tested) may reasonably deduce that they had been in the 
AR101 arm. Hence, the study is double-blinded on an individual subject basis only up to 
completion of the Exit DBPCFC. It is for this reason that assessment of reactions to DBPCFC 
will be made by a Blinded Evaluating Physician (Blinded Assessor).  
Although the unblinding of subjects after completion of the Exit DBPCFC cannot influence the 
manner in which they are assessed or treated by the investigational site personnel (as their 
participation in ARC003 will have concluded at that time), knowledge of subjects’ treatment 
assignments could potentially influence the investigational site personnel’s conduct toward other 
subjects who have not yet reached the conclusion of the study. The risk of bias being introduced 
into the determination of DLSs during DBPCFCs due to knowledge of the treatment assignments 
of other subjects will be substantially reduced by having the assessment of the DBPCFC results 
made by a Blinded Evaluating Physician (Blinded Assessor) who is not otherwise directly 
involved with the treatment of the subjects he or she is evaluating. Additionally, the duration of 
the study and the anticipated rate of recruitment are such that that enrollment should not be 
influenced by the Exit DBPCFC, as enrollment should be completed before the first subjects 
exits the study. 
Additionally, to ensure that allocation of subjects to their appropriate analysis populations is not 
biased by knowledge of their treatment assignments, specific masking procedures have been put 
in place to shield study team members who could be involved in determining allocation of the 
subjects to the analysis populations from knowing subject treatment assignments (refer to 
Masking Plan). To further ensure that allocation of subjects to their appropriate analysis 
populations is performed in an unbiased way, subjects will not be informed of their on-study 
treatment assignments or rollover into the open-label follow-on study, ARC004, until all major 
data queries, ie queries that could influence allocation to 1 or another analysis population, have 
been resolved (as detailed in the Masking Plan), regulatory and IRB/EC approval for ARC004 
have been received, and IP for ARC004 is available.  
Those subjects who are not eligible for the DBPCFC at Week 68 of their projected up-dosing 
schedule, may be unblinded at this time (their projected study Week 68) or when the last subject 
completes the Exit DBPCFC, provided all major data queries for the subject have been resolved. 
6.12.1 Securing Blinding and Randomization Information 
Aimmune or one or more of its contractors will manufacture, package, label, store, and distribute 
the study products. During site visits, the site monitor will check the clinic and/or pharmacy logs 
to ensure that appropriate randomization assignments are received, recorded, and maintained.  
6.12.2 Requirements for an Unblinding  
Prior to the Exit DBPCFC assessment, a subject can be unblinded only when needed for making 
medical decisions regarding the care of a subject. The decision to unblind should, if at all 
possible, be made in collaboration with the sponsor’s Medical Monitor. If a life-threatening 
event occurs, the subject should be treated as if the subject received active study product. For all 
unscheduled non-life-threatening events that require unblinding, the investigator will contact the 
clinical monitor who will coordinate with the sponsor’s representatives. 

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6.12.3 Breaking the Blind 
Site personnel or other study team members (such as a Medical Monitor) may request emergency 
unblinding as described above. If it is specifically necessary to provide a treatment assignment to 
the Sponsor, this information will be provided to a Medical Monitor and/or Clinical Operations 
Designee. 
In case emergency unblinding is necessary, the interactive response system allows study 
personnel with appropriate permissions to request unblinding for a specific subject. An 
automated notification is then sent to the sponsor and the sponsor’s safety designees to inform 
them of the unblinding. A built-in audit trail documents the unblinding process and the persons 
involved. 
6.12.4 Documenting and Unblinding  
Any premature unblinding requires a full written account by the site study physician of the 
event(s) that necessitated unblinding of the study medication for an individual participant. This 
account includes the reason(s) for unblinding, the name of the sponsor’s medical monitor who 
was notified of the unblinding, the names of the unblinded individual staff members and the date 
and time the unblinding occurred. The treatment assignment is confidential and should not be 
provided to blinded team members, as detailed in the Masking Plan. 
7 
SAFETY MONITORING 
This section defines the types of adverse events that should be reported and outlines the 
procedures for appropriately collecting, grading, recording, and reporting them. 
7.1 
Definitions for Recording of Safety Events 
All safety events observed under this protocol are reported through the electronic data capture 
system for the duration of the study. Some safety events arising under certain defined conditions 
are recorded on specific forms as follows.  
• 
Any allergic symptoms observed during in-clinic dosing will be recorded directly on the 
Escalation / In-Clinic Dosing form (also referred to as a Study Product Administration 
form), and are not recorded on an adverse event form (to avoid duplicate reporting) 
unless the event is considered a serious adverse event. These symptoms are, however, by 
definition, adverse events (Section 7.2) and will be reported as such in the database.  
• 
Safety events related to accidental food exposure are recorded on an Accidental Food 
Exposure form. They are not to be reported on an adverse event form (to avoid duplicate 
reporting) unless the event is considered a serious adverse event, as defined below 
(Section 7.3 and Section 7.4.2).  
• 
For any event occurring after a subject has signed the informed consent form that meets 
the definition of anaphylaxis, an Anaphylaxis Episode form will be completed and 
forwarded to the CRO’s Reporting Center within 24 hours of its occurrence and/or the 
site’s being notified of the event (Section 7.7.2), if the event is associated with any of the 
following: 
o An emergency room visit; 

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o Hospitalization; 
o More than 2 doses of epinephrine being given as treatment for the same episode; 
o Assessment of the anaphylaxis as severe, as defined in Appendix 3.  
• 
If any safety event meets the definition of a serious adverse event (whether or not related 
to dosing), it will also be recorded on an adverse event (AE)/serious adverse event (SAE) 
form.  
• 
Skin prick test reactions are not considered adverse events unless the reaction, or a 
complication from the procedure, is considered a serious adverse event, as defined below 
(Section 7.4.2).  
• 
Food challenge reactions that occur in the clinic are captured on study specific forms and 
are not reported on an adverse event form (to avoid duplicate reporting) unless the event 
is considered a serious adverse event, as defined below (Section 7.4.2).  
o As study product is not used in the DBPCFCs, no AEs occurring from Screening 
DBPCFC can be treatment-related (referring to treatment with study product).  
o For food challenge reactions that occur at the Exit DBPCFC, it will also usually be 
the case that study product was not the cause of the reaction, as study product is not 
used in the challenge. There is, however the possibility that dosing with study product 
in the days prior to Exit DBPCFC could contribute to a reaction encountered during 
the challenge. The investigator must determine if dosing with study product in the 
days prior to Exit DBPCFC likely contributed to any observed reaction. If so, the 
investigator should indicate the level of the relatedness, and provide a brief 
explanation as to the manner in which prior dosing with study product was thought to 
be contributory. 
• 
All serious adverse events are reported on the AE/SAE form set in addition to the Skin 
Prick form or an Oral Food Challenge form if the event occurred during 1 of these 
procedures. All other safety events that occur throughout the study are reported on the 
AE/SAE form set. 
7.2 
Dosing Symptoms as Adverse Events 
Although signs and symptoms of allergic reaction, especially those that are mild in severity, are 
frequent and expected occurrences in response to dose escalation during OIT, they still constitute 
AEs. As such, the start and stop times of dose-related allergic reactions, as well as any 
therapeutic interventions, and relatedness to study product will need to be recorded 
(Section 7.7.1).  
It is common for allergic reactions, especially allergic reactions to food allergens, to manifest 
with multiple symptoms. Investigator sites will record each individual symptom as an AE and 
indicate the symptom is part of an allergic reaction by checking the “allergic reaction” box on the 
AE form. 

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7.3 
Accidental Food Exposures 
In order to report the occurrence of a safety event associated with accidental food ingestion, 
subjects will be instructed to contact the site study coordinator or investigator for any adverse 
event. The subject may be asked to return to the site. These events will be reported as follows: 
• 
Accidental Food Exposure form will be completed for each of these events in addition to 
events where consumption of peanut without a reaction occurs.  
• 
If the accidental food ingestion safety event meets the definition of a serious adverse 
event, as defined below (Section 7.4.2), the AE/SAE form will be completed as well.  
7.4 
Definitions 
7.4.1 Adverse Event (AE) or Medical Event 
An adverse event is any untoward medical occurrence in humans, whether or not considered 
drug related which occurs during the conduct of a clinical trial. Any change in clinical status, 
ECGs, routine labs, x-rays, physical examinations, etc., that is considered clinically significant 
by the study investigator is considered an AE.  
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. A reasonable possibility implies that there is evidence that the 
drug caused the event. 
Adverse reaction is any adverse event caused by the drug.  
7.4.2 Serious Events (Serious Adverse Events, Serious Suspected Adverse Reactions or 
Serious Adverse Reactions)  
A serious adverse event including a serious suspected adverse reaction or serious adverse 
reaction as determined by the investigator or the sponsor is any event that results in any of the 
following outcomes: 
1. Death 
2. Life-threatening AE (Life-threatening means that the study subject was, in the opinion of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred.)  
3. Inpatient hospitalization or prolongation of existing hospitalization  
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5. Congenital abnormality or birth defect 
6. Important medical event that may not result in 1 of the above outcomes, but may 
jeopardize the health of the study subject or require medical or surgical intervention to 
prevent 1 of the outcomes listed in the above definition of serious event.  

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It is anticipated that the most likely cause of SAEs in this study will be anaphylaxis; however, 
not all occurrences of anaphylaxis are necessarily SAEs. Guidance for determining when 
anaphylaxis should be reported as an SAE is provided in Appendix 5. 
7.4.3 AEs of Special Interest 
7.4.3.1 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 et al., 2007), that in turn was based on the publications 
of Simons et al. (2011) and Johansson et al. (2004), and is consistent with the recently published 
“International consensus on (ICON) anaphylaxis” (Simons et al., 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. 
With respect to the inclusion of being “potentially life-threatening” in the definition of 
anaphylaxis and how that relates to the assessment of anaphylaxis as an SAE, reference is made 
to the 2012 FDA Guidance for Industry and Investigators, “Safety Reporting Requirements for 
INDs and BA/BE Studies,” that states, “An adverse event or suspected adverse reaction is 
considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have caused death.” 
Thus, for the reporting of anaphylaxis as an SAE, the severity of the reaction, assessed according 
to the EAACI system for grading the severity of anaphylactic reactions (Muraro et al., 2007), is 
also to be taken into account (Section 7.6 and Appendix 5). 
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 et al., 2006) (Appendix 3). These criteria were again 
affirmed in the recently published “International consensus on (ICON) anaphylaxis” (Simons et 
al., 2014). 
7.4.3.2 Gastrointestinal Adverse Events Resulting in Prolonged Disruption of Dosing  
Gastrointestinal AEs, typically chronic/recurrent GI AEs, that result in a prolonged disruption of 
dosing will be considered AEs of special interest and will be assessed longitudinally according to 
the procedures described below. For the purpose of delineating these AEs of special interest, 
prolonged disruption of dosing is defined as withholding study product for > 7 days. This will 
include 3 categories of subjects: 
• 
Any subject whose dose is withheld for > 7 days due to GI AEs and resumes dosing at a 
reduced dose level (Section 6.7) 
• 
Any subject who develops chronic/recurrent GI AEs at or before reaching the 20 mg dose 
level and resumes dosing after a 30-day dosing hiatus (Section 6.7.3.2); 
• 
Any subject who permanently discontinues dosing who had experienced GI AEs 
(Section 4.3.2).  

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Subjects under the age of 18 years who fall into any of these 3 categories will be asked to fill out 
the PEESSTM v2.0 questionnaire (Franciosi et al., 2011), with the assistance of a parent or 
guardian, as appropriate, every month for 6 months; adults will be given the same questionnaire. 
It should, however, be noted that the PEESSTM v2.0 was not designed to establish a diagnosis of 
EoE, and has not been validated for use in patients 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 
PEESSTM v2.0 to monitor the clinical course of GI symptoms must be considered exploratory. 
Nevertheless, the PEESSTM v2.0 has shown good content and construct validity (Franciosi et al., 
2011; Martin et al., 2015) and so holds promise for being a valuable tool to follow the clinical 
course of EoE or an EoE-like immune-mediated GI syndrome. Thus, the PEESSTM v2.0, could 
reveal trends toward symptomatic improvement or worsening that might otherwise go 
undetected.  
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 substitute for 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 with chronic/recurrent GI AEs has not experienced complete resolution of symptoms 
within 6 weeks of discontinuation of dosing with the investigational product, the subject should 
be referred to a (pediatric) gastroenterologist. 
If a subject who discontinued dosing with the investigational product prematurely due to 
chronic/recurrent GI AEs is unable to discontinue the use of symptomatic therapies that may 
have been initiated to treat the GI AEs (eg, H1 or H2 histamine blockers or proton pump 
inhibitors) by 12 weeks from the time that study product was withdrawn, the subject should be 
referred to a (pediatric) gastroenterologist. 
As is the case for any AE occurring during the study, so it is for chronic/recurrent GI AEs that 
the investigator may, at any time, and at his or her discretion, request consultation from an 
outside physician or additional testing to assist in the diagnosis or management of the AE. 
If a subject is seen by a 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. 
Subjects signing the optional consent to participate in the saliva substudy (North America sites 
only) will provide a saliva sample as close as possible to the time that they complete the first 
PEESSTM v2.0 questionnaire, and another saliva sample at the end of their post-OIT follow up 
period.  

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7.4.4 Unexpected Adverse Event  
An adverse event is “unexpected” when its nature (specificity) or severity is not consistent with 
applicable product information, such as safety information provided in the package insert, the 
investigational plan, the investigator’s brochure or the protocol.  
7.5 
Adverse Event Monitoring  
7.5.1 Data Safety Monitoring Committee 
Although the safety of peanut OIT overall is well established, a Data Safety Monitoring 
Committee (DSMC) will monitor the study for safety. The DSMC will meet periodically to 
review accruing safety data. The committee will consist of individuals with extensive 
multi-center clinical study experience drawn from the fields of clinical immunology (specifically 
food allergies) and biostatistics. These individuals will be entirely independent of the conduct of 
the study. Further details will be provided in the DSMC Charter. 
7.5.2 Adjudication Committee 
The Adjudication Committee (AC) will review reports of specific SAEs and AEs of special 
interest to verify appropriate diagnosis as per protocol definitions (eg, anaphylaxis) and 
appropriate determination of event seriousness, severity, and causality. The AC 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. 
7.6 
Severity Grading  
The investigator is to assign severity grades to adverse events (AEs). Depending on the type of 
AE, different severity grading systems will be used in this study.  
• 
The severity grading of allergic reactions will be according to the definitions developed 
the CoFAR group (Appendix 4).  
• 
The severity of anaphylactic reactions will be graded according to the EAACI system for 
grading the severity of anaphylactic reactions (Appendix 3).  
• 
For grading the severity of all other AEs, the National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) system will be used. The 
purpose of using the NCI-CTCAE system is to provide standard language to describe 
AEs (“toxicities”) and to facilitate tabulation and analysis of the data and for assessment 
of the clinical significance of treatment-related toxicities. The NCI-CTCAE provides a 
term and a grade that closely describes the adverse event. Each participating site will 
receive copies of the grading scales and event descriptions. For additional information 
and a printable version of the NCI-CTCAE v. 4.03 manual, consult the NCI-CTCAE 
website, http://ctep.cancer.gov/reporting/ctc.html.  
For adverse events not included in the NCI-CTCAE listing, they are also to be graded on a scale 
from 1 to 5, according to the General Grade Definition provided below:  

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Grade 1 
Mild 
Transient or mild discomforts (< 48 hours), no or minimal 
medical intervention/therapy required, hospitalization not 
necessary (non-prescription or single-use prescription therapy 
may be employed to relieve symptoms, eg, aspirin for simple 
headache, acetaminophen for post-surgical pain). 
Grade 2 
Moderate 
Mild to moderate limitation in activity, some assistance may 
be needed; no or minimal intervention/therapy required, 
hospitalization possible.  
Grade 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/therapy required, 
hospitalization possible.  
Grade 4 
Life-threatening 
Extreme limitation in activity, significant assistance required; 
significant medical/therapy intervention required, 
hospitalization, or hospice care probable. 
Grade 5 
Death 
Death 
For additional information and a printable version of the NCI-CTCAE v. 4.03 manual, consult 
the NCI-CTCAE website, http://ctep.cancer.gov/reporting/ctc.html.  
7.6.1 Guidelines for Determining Causality of an Adverse Event 
The investigator will use the following question when assessing causality of an adverse event to 
study product: Is there a reasonable possibility that the study product caused the event? 
An affirmative answer designates the event as a suspected adverse reaction. 
7.7 
Adverse Event Collection Procedures 
Any new event or experience that was not present at Screening, or worsening of an event present 
at Screening, is considered to be an AE. Unchanged, chronic conditions are not AE’s and should 
not be recorded on the AE page of the CRF. Adverse events will be evaluated from the onset of 
the event until the time the event is resolved or medically stable, or until 44 days after the subject 
completes study treatment, whichever comes first. Adverse events ongoing at the time that study 
treatment is discontinued may not be determined to be medically stable until 30 days after the 
Exit or Early Discontinuation Visit has been conducted, in which case additional visits after the 
Exit or Early Discontinuation Visit will be required. Investigators should also report AEs 
discovered after cessation of dosing and prior to the Early Discontinuation. 
AEs may be discovered through any of these methods: 
• 
Observing the subject 
• 
Questioning the subject, which should be done in an objective manner 
• 
Receiving an unsolicited complaint from the subject 
• 
Review of medical records/source documents 
• 
Review of home dosing symptom logs (provided to record symptoms between visits) 

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7.7.1 Recording and Reporting Procedures 
A multi-screen adverse event eCRF will be used allowing all adverse events to be submitted 
through a single reporting mechanism. Serious adverse events will require additional information 
reported on additional screens within the electronic data capture (EDC) system. Source 
documents, with subject identifiers redacted, can be scanned and attached to the adverse event 
form as well. The investigator will treat subjects experiencing adverse events appropriately and 
observe them at suitable intervals until their symptoms resolve or their status stabilizes. 
7.7.2 SAE Recording and Reporting Procedures 
Serious adverse events will be recorded on the adverse event case report form (CRF). All centers 
are obligated to report SAEs within 24 hours of their occurrence and/or the site’s knowledge of 
the event to the Reporting Center. The following attributes will be assigned:  
• 
Description 
• 
Date of onset and resolution (if known when reported) 
• 
Severity 
• 
Assessment of relatedness to test article  
• 
Action taken 
The site investigator will apply his/her clinical judgment to determine whether an adverse event 
is of sufficient severity to require that the subject be removed from treatment. If necessary, an 
investigator will suspend any trial procedures and institute the necessary medical therapy to 
protect a subject from any immediate danger. 
Subsequent review by regulatory health authority(ies), the DSMC, IRB/EC, or the sponsor(s) 
may suspend further trial treatment or procedures at a site. The study sponsor(s) and the 
regulatory health authorities retain the authority to suspend additional enrollment and treatments 
for the entire study as applicable. 
A subject may voluntarily withdraw from treatment due to what he/she perceives as an 
intolerable AE, or for any other reason. If voluntary withdrawal is requested, the subject should 
be asked to continue (at least limited) scheduled evaluations, complete a study termination form, 
and be given appropriate care under medical supervision until the symptoms of any AE resolve 
or their condition becomes stable. 
 
 

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No 
Yes 
7.7.2.1 Reporting Criteria  
Figure 7-1: 
Reporting Decisions for Adverse Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Notify the site’s investigator. 
2. Complete and transmit an AE Form through the Internet data entry system. 
Information regarding a SAE report must be recorded in the subject’s medical chart. 
3. SAE follow-up reports should include hospital admittance notes, hospital discharge 
summary, clinical notes, resolution date, treatment and any other pertinent 
information regarding the event. Reporting should not be delayed in order to provide 
these documents. 
4. In the event of a death, the SAE Form must be completed and transmitted along with 
other supporting data (eg, death certificate, medical notes, etc.). 
7.8 
Serious Adverse Event Notification 
7.8.1 Notifying the Sponsor 
Study investigators will provide the Reporting Center with data of all SAEs as defined per the 
protocol on an ongoing basis. 
The CRO Medical Monitor is responsible for notifying the sponsor and will do so simultaneously 
with the reporting to the clinical database. As noted above, this should be within 24 hours of site 
awareness of the event.  
Standard Reporting 
(within 5 to 7 days)  
Use Adverse Event 
Form, and other CRFs  
Submit to the Reporting 
Center 
Expedited Reporting (within  
24 hrs)  
Use the Adverse Event Form  
Submit to Coordinating 
Committee (also notify 
ethics board/IRB) 
Death, Life Threatening,  
or SAE 
Adverse Event Requiring AE Form Submission: 
All serious adverse events 
All adverse events except:  
• In-clinic dosing allergic reactions captured on a separate CRF set 
(these will be merged into the AE database by the data 
management group) 
• Those due to an accidental food ingestion without any symptoms 
• Those occurring during Screening DBPCFC 
• Those occurring during Exit DBPCFC in which the investigator 
assessed exposure to study product in the days prior to the food 
challenged to be non-contributory to the AE 
• Skin prick test reactions (not considered AEs unless resulting in 
SAE)  

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7.8.2 Expedited SAEs Reporting to Regulatory Health Authorities and DSMC  
The sponsor’s Medical Monitor will review each SAE report and will determine whether the 
SAE must be reported to regulatory health authorities on an expedited basis. The final decision 
for disposition regarding expedited reporting to the regulatory health authorities rests with the 
sponsor’s Medical Monitor. The Study Sponsor and Clinical Research Organization (CRO) will 
provide the DSMC and the Reporting Center with copies of any expedited SAE reports 
submitted to regulatory health authorities. 
The Reporting Center will provide these expedited reports to the individual site investigators. 
Events that are serious, related to therapy, and unexpected will be reported to regulatory health 
authorities within 15 days or for deaths and life-threatening events within 7 days (as per 
applicable regulatory reporting requirements). 
7.8.3 Notifying the Data Safety Monitoring Committee 
The Reporting Center will provide the DSMC with listings of all SAEs on an ongoing basis. 
Furthermore, the DSMC will be informed of expedited reports of SAEs. Periodic reports from 
the DSMC as to the overall safety of the ongoing study, and recommendations regarding 
continuation will be sent to the investigators for forwarding to their IRBs/ECs if requested. 
Investigational sites are instructed to report episodes of anaphylaxis within 24 hours of their 
occurrence and/or the sites being notified of the event to the Reporting Center for forwarding to 
the DMSC if the event is associated with any of the following: 
• 
An emergency room visit; 
• 
Hospitalization; 
• 
More than 2 doses of epinephrine being given as treatment for the same episode; 
• 
Assessment of the anaphylaxis as severe, as defined in Appendix 3. 
An initial Anaphylaxis Episode form containing the information known to the site at this time 
will be transmitted to the Reporting Center. The Reporting Center will then relay to the sponsor 
and DSMC the individual anaphylaxis reports as they are obtained. The investigational site will 
supplement the initial Anaphylaxis Episode report with additional information pertaining to an 
event as it becomes available and will forward the information to the Reporting Center. 
7.8.4 Notifying the Institutional Review Board and Ethics Committee 
The investigator will ensure the timely dissemination of all AE information, including expedited 
reports and DSMC safety reviews, to the IRB in accordance with applicable local regulations and 
guidelines. 
7.9 
Other Safety Assessments and Precautions 
7.9.1 Physical Examination and Vital Signs 
Physical examinations will be conducted at visits indicated in Appendix 1 Schedule of Events. 
Height and weight will also be recorded at specified visits. Vital signs will be measured, 
including blood pressure (BP), pulse rate (PR), and body temperature. Except where a full, age 

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appropriate, physical examination is specifically indicated, a symptom-directed physical exam 
may be performed. 
7.9.2 Prior and Concomitant Medications 
Prior and concomitant medications will be duly documented in the CRF.  
7.9.3 Pregnancy Testing and Contraception 
7.9.3.1 Pregnancy Testing  
All female subjects of child-bearing age will undergo a serum pregnancy test at screening and 
then urine pregnancy test at subsequent visits. 
7.9.3.2 Contraception 
Subjects undergoing OIT are at increased risk for experiencing allergic reactions and may be at 
increased risk for experiencing anaphylaxis. Anaphylaxis can cause a dangerous drop in blood 
pressure; and if this were to occur during pregnancy, it could result in compromised placental 
perfusion and significant risk to the fetus. 
Pregnancy is a time when the mother’s immune system undergoes complex and incompletely 
understood changes that are believed to reduce the risk of a maternal immune reaction directed 
against the fetus. It is also a time when the fetus’s immune system is developing. OIT, at its core, 
entails repeated stimulation of the immune system to affect changes in its makeup and function. 
What effects OIT-induced changes in the immune system might have on the course of pregnancy 
or fetal development are currently unknown. Accordingly, female subjects of child-bearing 
potential are required to practice effective birth control for the duration of the current study.  
Female subjects are to use either:  
• 
A highly effective method of birth control, defined as 1 that results in a low failure rate 
(ie, less than 1 percent per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, some intrauterine contraceptive devices 
(IUDs), sexual abstinence, or a vasectomized partner; or 
• 
Alternatively, if a highly effective method of birth control is not used, an effective, 
double barrier method of contraception (eg, male condom with female condom, cervical 
cap, diaphragm, or contraceptive sponge) may be used. 
7.10 
Stopping Rules 
7.10.1 Overall Stopping Rules 
The study will be suspended at any time if a treatment-associated death occurs in a subject on 
active therapy, or that the second of two subjects is admitted to the hospital, within 6 months of 
the first, as a direct consequence of dosing with study product. Suspension of the study will 
entail halting the enrollment of subjects and refraining from any dose increases, but will not 
entail cessation of dosing unless so directed by the FDA or other regulatory agency, or advised 
by the DSMC and agreed to by the sponsor. The suspension will not be lifted and dose escalation 
will not be resumed until the information has been discussed with regulatory authorities and the 

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regulatory authorities either concur with resumption of up-dosing or direct discontinuation of the 
study in their jurisdictions.  
The DSMC will also be continually reviewing safety data, and can also recommend, in its 
judgment, halting the study for any substantial imbalance in adverse events, apart from 
anticipated allergic dosing symptoms.  
Aimmune Therapeutics additionally reserves the right to discontinue the study at any time for 
any reason. The regulatory health authority(ies) and IRBs/ECs will be notified in the event of 
study discontinuation. 
7.10.2 Individual Stopping Rules 
Individuals may stop the study at any time if they experience subjectively intolerable adverse 
events or dosing symptoms. They must halt up-dosing and re-start with a reduced dose if more 
than 3 days of dosing are missed. Seven or more consecutive days of missed dosing due to non-
compliance constitutes an individual stopping rule, as does a significant number of episodes of 
missed dosing (ie, 3 or more consecutive days on at least 3 occasions) during the Up-dosing 
Period. Missing 15 or more consecutive days of dosing for any reason also constitutes an 
individual stopping rule. For additional individual stopping rules, the reader is referred back to 
Section 4.3.1. 
Occurrence of any of the following will result in the cessation of dosing and the subject being 
discontinued from the study as an escalation failure nonresponder:  
• 
Failure to accomplish up-dosing of study product after 3 attempts 
• 
Failure to identify a tolerated dose of study product after 3 attempts at dose reduction  
• 
Administration of 3 or more doses of epinephrine for the treatment of any dose-related 
allergic reaction. 
8 
MECHANISTIC ASSAYS  
Assays will be performed to measure humoral (immunoglobulin; antibody) immune responses at 
Screening/Baseline, at the end of the Up-dosing Period, and at the Exit or Early Discontinuation 
visit. The blood samples for these serum-based assays can and should be collected with the same 
blood draw as the CBC. This is mandatory blood draw is to be performed at Screening, the End 
of Up-dosing / Start of Maintenance Period Visit, and the Exit Visit. 
Additionally, subjects will be asked to participate in an optional substudy to characterize cellular 
immune responses in allergy. The characterization of immune cells, including lymphocytes and 
basophils, based on their surface markers and responses to in vitro stimulation, performed by the 
Immune Tolerance Network (ITN) and consequently will require an additional consent/assent 
form to be signed.  
8.1 
Peanut-Specific Antibody (Immunoglobulin) Assays 
Antigen immunotherapy has been shown to induce antigen-specific humoral responses. The 
balance of isotypic response may play a role in allergen sensitivity (eg, an increase of IgG / IgE).  

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The blood sample for antibody analysis should be collected with the same blood draw as the 
CBC. Collection of a sample for antibody analysis, like the CBC, is mandatory. 
At each of the specified points, a sample of serum will be stored for assessment of peanut 
specific antibody levels (immunoglobulin assays). Total IgE and specific IgE and IgG4 will be 
measured using UniCAPTM. Peanut specific IgE and IgG4 (included in the immunoglobulin 
assays) will be measured at Screening/Baseline, the end of the Up-dosing Period, and the 
Exit/Early Discontinuation visit. Additionally, as part of the Screening/Baseline immunoglobulin 
assays, component-resolved (Ara h1, Ara h2, Ara h3, Ara h8, and Ara h9) peanut IgE testing will 
be performed. The amount of blood to be drawn will be determined on the basis of the 
requirements of the test and individual laboratory protocols, in compliance with local 
regulations.  
8.2 
Optional Immune Cell Characterization 
This exploratory characterization of the mechanism of action of OIT at the cellular level will be 
conducted by the Immune Tolerance Network (ITN). Immune cells, including lymphocytes, 
monocytes, and potentially basophils, and eosinophils, will be analyzed for their cell surface 
markers by flow cytometry. Additionally, in vitro stimulation of lymphocytes and potentially 
basophils, or other immune cell types will be performed. 
8.2.1 Optional Additional Blood Volume 
Subjects who consent to participate in the optional substudy to characterize immune cell 
responses, conducted by the ITN, will have an additional volume of blood collected at the same 
time as the immunoglobulin assay blood draws (Section 8.1; full procedures will be provided in 
the manual of procedures). Participation in the substudy to characterize immune cell responses 
does not require an additional venipuncture. 
8.2.2 Optional Post-DBPCFC Blood Draws 
Additionally, subjects will be given the option to volunteer for to characterize immune cell 
changes following an allergic reaction, the optional post-DBPCFC blood draw. Participation 
would require 2 additional venipunctures, 1 after the Screening DBPCFC and 1 after the Exit 
DBPCFC (the blood draw after the Exit DBPCFC will be included in the ARC004 protocol). The 
same types of in vitro assays will be performed on these samples as will be performed in the 
immune cell characterization substudy, but on cells collected after a controlled allergic 
challenge. Because participation requires 2 additional blood draws, separate informed consent is 
required.  
8.3 
Optional Oral Biomarker Substudy  
Subjects will also be given the option to participate in a companion substudy to examine the 
relationship between food allergy and other gastrointestinal disorders. The study, coordinated by 
researchers at Cincinnati Children’s Hospital Medical Center, will involve the collection of 
saliva to measure gene expression products (including ribonucleic acids) that may reflect 
susceptibility to eosinophilic esophagitis or other potentially IgE-related GI diseases. This 
substudy will require subjects/parents to undergo a separate informed consent (and assent, as age 
appropriate) process. 

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9 
STATISTICAL CONSIDERATIONS 
This section outlines the major statistical consideration for the ARC003 study, a randomized 
evaluation of peanut OIT versus placebo therapy and baseline for individuals with peanut 
allergy. A comprehensive statistical analysis plan (SAP) will be finalized prior to the first subject 
undergoing Exit DBPCFC.  
Data will be summarized descriptively by treatment arm and overall. The descriptive summary 
for the categorical variables will include counts and percentages. The descriptive summary for 
the continuous variables will include means, medians, standard deviations and minimum and 
maximum values.  
All data will be listed for all subjects. 
9.1 
Analysis Populations 
The ITT population (ie, the Full Analysis Set) will consist of all randomized subjects who 
received at least 1 dose of randomized study treatment. Subjects will be analyzed according to 
randomized treatment. The ITT population will be used as the primary analysis population for all 
analyses of efficacy endpoints. 
The Completer population includes all subjects in the ITT population who complete treatment 
and have an evaluable Exit DBPCFC, where an evaluable Exit DBPCFC is defined as 
completion of at least the peanut part of the food challenge. Sensitivity analyses and supportive 
analyses of the primary endpoint, and key secondary endpoints, and other secondary endpoints 
will be performed using the Completer population. These supportive analyses are considered 
important because they will provide the basis for informing patients and their families of their 
chances of achieving a clinically relevant level of desensitization if Up-dosing and maintenance 
therapy are achieved. 
The Per Protocol (PP) population will be a subset of the Completer population, limited to 
subjects who have no major protocol deviations that may influence the desensitization response. 
Additional criteria to exclude subjects from the PP population may be added. Any changes will 
be documented in a SAP amendment or other supporting document.  Exclusions will be 
determined by blinded review before database lock and overall study unblinding. Subjects will 
be analyzed according to randomized treatment.  
The Safety population will consist of all subjects who receive randomized study treatment. The 
Safety population will be used for summaries of safety parameters. Subjects will be analyzed 
according to treatment received.  
The modified ITT (mITT) population will consist of all randomized subjects who received at 
least one dose of randomized study treatment and who have sufficient data to assess treatment 
success or failure for the primary efficacy endpoint. Subjects who withdraw early for reasons 
unrelated to treatment success or failure will be excluded as there are no data to suggest they are 
a treatment success or failure. Withdrawals for escalation failure, treatment-related AEs, and 
deaths will not be excluded and these will be counted as treatment failures. Exclusions will be 
determined by blinded review prior to database lock and overall study unblinding. Subjects will 
be analyzed according to randomized treatment. The mITT population may be used for 

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sensitivity analyses of the primary and key secondary endpoints if the mITT population differs 
from ITT population by > 5% in either treatment arm. Sensitivity analyses of selected endpoints 
may, however, be performed if the mITT population differs from the ITT population by ≤ 5% in 
both treatment arms.   
The decision to conduct analyses in the mITT population and other subsets of the ITT population 
will be made before database lock and overall study unblinding. 
9.2 
Study Endpoint Assessment 
9.2.1 Primary Endpoint 
North America: The primary endpoint is the proportion of subjects aged 4 to 17 years who 
achieve desensitization as determined by tolerating a single highest dose of at least 600 mg 
(1043 mg cumulative) of peanut protein with no more than mild symptoms at the Exit DBPCFC 
(ie, responders). 
The primary efficacy analysis will test for a treatment difference in the response rate in the ITT 
population. All individuals failing to achieve the success definition described above will be 
considered treatment failures, as will subjects who fail to achieve and maintain a 300 mg daily 
dose of study product (escalation failure nonresponders). All individuals who drop out of the 
study or discontinue OIT prior to undergoing the Exit DBPCFC will be considered treatment 
failures (ie Missing = Failure). The Farrington-Manning test will be used to test that the 
difference in response rates (AR101 minus Placebo) is not equal to 0.15 at the 0.05 significance 
level. AR101 is considered to have met primary efficacy endpoint if the lower bound of the 
corresponding test-based 95% confidence interval is greater than the pre-specified margin of 
0.15. 
Europe: The primary endpoint is the proportion of subjects aged 4 to 17 years who achieve 
desensitization as determined by tolerating a single highest dose of at least 1000 mg (2043 mg 
cumulative) of peanut protein with no more than mild symptoms at the Exit DBPCFC 
(ie, responders). 
The primary efficacy analysis will test for a treatment difference in the response rate in the ITT 
population. All individuals failing to achieve the success definition described above will be 
considered treatment failures, as will subjects who fail to achieve or maintain a 300 mg daily 
dose of study product (escalation failure or nonresponders, respectively). All individuals who 
drop out of the study or discontinue OIT prior to undergoing the Exit DBPCFC will be 
considered treatment failures (ie Missing = Failure). The Farrington-Manning test will be used to 
test that the difference in response rates (AR101 minus Placebo) is not equal to 0 at the 
0.05 significance level. AR101 is considered to have met primary efficacy endpoint if the lower 
bound of the corresponding test-based 95% confidence interval is greater than 0. 
9.2.2 Secondary Endpoints 
The secondary endpoints are defined in Section 3.7, and a full description of the analyses 
planned for each will be provided in the statistical analysis plan (SAP). A brief description of the 
planned analyses for the key secondary endpoints and other selected secondary endpoints is 
provided below. 

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9.2.2.1 Analysis of Key Secondary Endpoints 
North America: 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 300 mg (443 mg cumulative) of peanut protein with no more than mild symptoms at 
the Exit DBPCFC: The statistical analysis to be conducted for this key secondary 
endpoint will be similar to that used for the primary endpoint. 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 1000 mg (2043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC: The statistical analysis to be conducted for this key secondary 
endpoint will be similar to that used for the primary endpoint.  
• 
The maximum severity of symptoms in subjects aged 4 to 17 years occurring at any 
challenge dose of peanut protein during the Exit DBPCFC: The objective of analysing 
this key secondary endpoint is to show that subjects from the AR101 group will have less 
chance of developing more severe levels of symptom severity compared to subjects from 
the placebo group. Symptom severity will be recorded at 4 levels: 0-None, 1-Mild, 2-
Moderate, 3-Severe or higher. Symptom severity data will be collected at each challenge 
dose of peanut protein during the Exit DBPCFC – 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 
600 mg, and 1000 mg; the maximum severity at any dose will be used for each subject in 
the analysis.  
The analysis of this key secondary endpoint will be conducted in the ITT population. The 
number and percent of subjects by maximum severity at the Exit DBPCFC will be 
tabulated by treatment arm. The Cochran-Mantel-Haenszel statistic (with equally spaced 
scores) will be used to test for a treatment difference. The test will be stratified by region. 
Subjects without an Exit DBPCFC will have their maximum severity during the 
Screening DBPCFC used, which equates to no change from screening.  
• 
The proportion of subjects aged 18 to 55 years who tolerate a single highest dose of at 
least 600 mg (1043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC. The statistical analysis to be conducted for this key secondary 
endpoint will be similar to that used for the primary endpoint. 
The key secondary endpoints will be tested in the ITT population in the hierarchical order 
specified in Section 3.7.1. If the primary efficacy analysis is significant at the 0.05 level, then the 
proportion of subjects who tolerate a single highest dose of at least 300 mg (443 mg cumulative) 
of peanut protein with no more than mild symptoms at Exit DBPCFC will be tested with a Type I 
error rate of 0.05; if this test is significant, then the proportion of subjects who tolerate a single 
highest dose of at least 1000 mg (2043 mg cumulative) of peanut protein with no more than mild 
symptoms at Exit DBPCFC will be tested with a Type 1 error rate of 0.05; if this test is 
significant, then the maximum severity of symptoms occurring at any challenge dose of peanut 
protein during the Exit DBPCFC will be tested with a Type I error rate of 0.05. This closed 
testing procedure maintains the overall Type I error rate at 0.05 (EMEA CPMP, 2002; 
Cook et al., 2008).  

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Europe: 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 600 mg (1043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC: The statistical analysis to be conducted for this key secondary 
endpoint will be similar to that used for the primary endpoint. 
• 
The proportion of subjects aged 4 to 17 years who tolerate a single highest dose of at 
least 300 mg (443 mg cumulative) of peanut protein with no more than mild symptoms at 
the Exit DBPCFC: The statistical analysis to be conducted for this key secondary 
endpoint will be similar to that used for the primary endpoint.  
• 
The maximum severity of symptoms in subjects aged 4 to 17 years occurring at any 
challenge dose of peanut protein during the Exit DBPCFC: The objective of analysing 
this key secondary endpoint is to show that subjects from the AR101 group will have less 
chance of developing more severe levels of symptom severity compared to subjects from 
the placebo group. Symptom severity will be recorded at 4 levels: 0-None, 1-Mild, 
2-Moderate, 3-Severe or higher. Symptom severity data will be collected at each 
challenge dose of peanut protein during the Exit DBPCFC – 3 mg, 10 mg, 30 mg, 
100 mg, 300 mg, 600 mg, and 1000 mg; the maximum severity at any dose will be used 
for each subject in the analysis.  
The analysis of this key secondary endpoint will be conducted in the ITT population. The 
number and percent of subjects by maximum severity at the Exit DBPCFC will be 
tabulated by treatment arm. The Cochran-Mantel-Haenszel statistic (with equally spaced 
scores) will be used to test for a treatment difference. The test will be stratified by region. 
Subjects without an Exit DBPCFC will have their maximum severity during the 
Screening DBPCFC used, which equates to no change from screening.  
• 
The proportion of subjects aged 18 to 55 years who tolerate a single highest dose of at 
least 1000 mg (2043 mg cumulative) of peanut protein with no more than mild symptoms 
at the Exit DBPCFC. The statistical analysis to be conducted for this key secondary 
endpoint will be similar to that used for the primary endpoint. 
The key secondary endpoints will be tested in the ITT population in the hierarchical order 
specified in Section 3.7.1. If the primary efficacy analysis is significant at the 0.05 level, then the 
proportion of subjects who tolerate a single highest dose of at least 600 mg (1043 mg 
cumulative) of peanut protein with no more than mild symptoms at Exit DBPCFC will be tested 
with a Type I error rate of 0.05; if this test is significant, then the proportion of subjects who 
tolerate a single highest dose of at least 300 mg (443 mg cumulative) of peanut protein with no 
more than mild symptoms at Exit DBPCFC will be tested with Type 1 error rate of 0.05; if this 
test is significant, then the maximum severity of symptoms occurring at any challenge dose of 
peanut protein during the Exit DBPCFC will be tested with a Type I error rate of 0.05. This 
closed testing procedure maintains the overall Type I error rate at 0.05 (EMEA CPMP, 2002; 
Cook et al., 2008).  

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9.2.2.2 Analysis of Other Selected Secondary Endpoints  
• 
Maximum dose achieved with no or mild symptoms at Exit DBPCFC: The probability 
estimates for tolerating each challenge dose or higher of the Exit DBPCFC will be 
calculated based on the discrete hazards model in the ITT population with terms for 
treatment group effect, region (North America and Europe) and the MTD at the 
Screening DBPCFC (baseline) in the log10 scale (Chinchilli et al., 2005). The extreme 
value hazard function will be used for the model. The probability estimates will be 
tabulated by treatment group and adjusted for their Screening MTD. The values for MTD 
for subjects who do not undergo the Exit DBPCFC will be imputed using the maximum 
doses of peanut protein tolerated in their Screening DBPCFC. The treatment effect 
hazard ratio and its 95% confidence interval (95% CI) and p-value will be based on the 
Wald statistic.  
• 
Change from baseline in maximum tolerated dose (MTD) of peanut protein at DBPCFC: 
Analyses of change from baseline MTD will be performed using change calculated on the 
log10 scale. An analysis of covariance (ANCOVA) model of change from baseline MTD 
at Exit DBPCFC (log10 mg) will be fit with terms for treatment group, region, and the 
MTD at baseline (log10 mg). The values for MTD for subjects who do not undergo the 
Exit DBPCFC will be imputed using the maximum doses of peanut protein tolerated in 
their Screening DBPCFC. The baseline adjusted least squares means with 95% CIs by 
treatment group and for the treatment group difference will be tabulated. The p-value is 
based on the F-test for treatment group effect adjusted for the MTD at baseline (log10 
mg). Residuals for ANCOVA will be assessed for non-normality using the Shapiro-Wilk 
test. If significant at the 0.05 level, then the Wilcoxon rank sum statistic will be used to 
test for a treatment group difference to examine the robustness of the ANCOVA F-test. 
The statistical methods used for testing the remaining secondary endpoints are described in the 
Statistical Analysis Plan (SAP). 
9.2.3 Supportive Analyses of Primary and Secondary Endpoints 
All analyses described in Sections 9.2.1 and 9.2.2 will be repeated in the Completers and Per 
Protocol (PP) populations. Sensitivity analyses, using different methods to handle missing data, 
will be described in the SAP. In addition, a tipping point analysis to determine at what point may 
a variation in missing data handling overturn the primary efficacy analysis will be conducted. 
Details will be described in the SAP.  
9.3 
Subject and Demographic Data 
9.3.1 Study Disposition 
The number and percent of subjects in each analysis population will be summarized. The number 
of subjects who complete the study, discontinue prematurely, and their reason for study 
discontinuation will be tabulated. Total duration on treatment and total duration on study will 
also be summarized.  

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9.3.2 Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be provided for 
all enrolled subjects. Demographic data will include age, race, sex, body weight and height. 
Baseline characteristics include total IgE, peanut-specific IgE, peanut-specific IgG4, 
peanut-specific IgE/IgG4 ratio, results from SPT, and MTD of peanut protein at Screening 
DBPCFC. 
Baseline and demographic characteristics may also be summarized by baseline peanut-specific 
serum IgE level and by baseline SPT peanut wheal size. 
9.3.3 Use of Medications 
All medications used will be coded using the World Health Organization drug dictionary. The 
number and percentage of subjects receiving concomitant medications or therapies will be 
summarized by treatment group. 
9.4 
Sample Size and Power Calculations 
As of the writing of Amendment 4, 554 subjects, 495 of which are between the ages of 4 and 
17 years, have been enrolled and enrollment has been completed. 
The sample size of 495 subjects between the ages of 4 and 17 years, randomized at a ratio of 3:1, 
provides sufficient power to detect a treatment effect for the primary efficacy analysis. The set of 
assumptions and calculations that follow are provided to show this sample size is adequate to 
demonstrate the AR101 response rate is significantly higher than placebo with at least a 15% 
margin for the primary efficacy endpoint analysis in North America, and the sample size is 
adequate to demonstrate the AR101 response rate is significantly higher than placebo for the 
primary efficacy endpoint analysis in Europe. Additionally, with a trial of this size, there would 
be an 80% probability of observing at least 1 AE among 375 subjects assigned to AR101 when 
the background rate of the AE is 4.3 per 1,000 subjects. With the completion of the ARC004 
study and the ongoing ARC002 study (for a total of approximately 550 subjects treated with 
AR101), it is estimated that there would be an 80% probability of observing at least 1 AE when 
the background rate of the AE is 2.9 per 1,000 subjects.  
While natural history of peanut allergy desensitization is not fully understood, significant 
short-term improvements in consumption amounts are believed to be uncommon. Nevertheless, 
the sensitivity thresholds to peanut allergen are known to vary day to day based on numerous 
intrinsic and extrinsic factors. The inherent variability in the sensitivity threshold for allergic 
reaction to peanut as measured by oral food challenge has been demonstrated in peanut-allergic 
patients not undergoing immunotherapy (Glaumann et al., 2013), as well as in the placebo arms 
of several peanut immunotherapy trials (Sampson et al., 2011; Varshney et al., 2011; Fleischer et 
al., 2013; Sampson et al., 2015). The publication by Glaumann et al. (2013) showed that the 
threshold for responding in oral food challenge can vary up or down by two orders of magnitude. 
The placebo response rates reported across therapeutic trials also vary widely, ranging anywhere 
from 11 to 55%, and are dependent on multiple factors, including the level of peanut protein set 
as a target response, the specific procedures for oral food challenge employed, the dose level of 
maintenance therapy, and the duration of immunotherapy. 

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The literature on peanut OIT, though sparse, also suggests that there could be a high degree of 
variability in the magnitude of the treatment effect. Only 2 randomized controlled trials of peanut 
OIT (Varshney et al., 2011; Anagnostou et al., 2014) have been reported to date, and these 
employed significantly different study designs. In the Varshney study, 16 of 19 (84%) subjects 
randomized to active treatment demonstrated a high degree of desensitization (although baseline 
sensitivity to peanut had not been established). This stands in contrast to the Anagnostou study, 
wherein only 24 of 49 (49%) subjects randomized to active treatment achieved the predefined 
level of desensitization.  
North America: In the Phase 2 ARC001 study the primary endpoint was determined at the 
300 mg (443 mg cumulative) level of peanut protein in the Exit DBPCFC, whereas in the current 
Phase 3 study, ARC003, the primary endpoint will be determined at the 600 mg (1043 mg 
cumulative) dose level of peanut protein in the Exit DBPCFC, a level that was studied as an 
additional endpoint in ARC001. For the purpose of calculating statistical power for the ARC003 
study, the response rates at both the 443 mg (primary) and 1043 mg (additional) cumulative dose 
endpoints from ARC001 have been taken into consideration. 
In the Phase 2 ARC001 study, the placebo response rate for the primary endpoint in the ITT 
population of tolerating 443 mg cumulative of peanut protein at Exit DBPCFC was 19% 
(95% CI of 7% to 39%), and it was 0% (95% CI of 0% to 13%) in the post-hoc analysis of 
tolerating 1043 mg cumulative of peanut protein at Exit DBPCFC. Thus, the Phase 2 results 
suggest that the point estimate for the placebo response rate in the primary endpoint of ARC003 
is likely to fall between 0 and 19% (based on point estimates), although it could be as high as 
13 to 39% (based on upper bound of the 95% CIs). Taking into account the wide range of 
placebo response rates evident from the literature, a placebo response rate of 20% for the primary 
endpoint is assumed for power calculations in this study. 
The response rate in the AR101 arm of the ARC001 study was 79% (95% CI of 60% to 92%) 
and 62% (95% CI of 42% to 79%) for endpoints based on tolerating 443 mg and 1043 mg 
cumulative of peanut protein, respectively, at Exit DBPCFC in the ITT population. Thus, the 
Phase 2 results suggest that the point estimate for the active treatment response rate at the 
primary endpoint in ARC003 is likely to fall between 62 and 79% (based on point estimates), 
although it could be as low as 42 to 60% (based on lower bound of 95% CIs). Given that 
dropouts accounted for the majority of desensitization failures in ARC001, a 6-month study, and 
the opportunity for dropout increases as the duration of the trial increases, a 50% AR101 
response rate at the primary endpoint is assumed for the purpose of power calculation for 
ARC003, a 12 month study. This approach is consistent with published recommendations for 
adjusting assumptions about Phase 3 response rates based on Phase 2 results (Wang, Hung, & 
O'Neill, 2006; Kirby et al., 2012).  
An additional 15% margin in the separation between the placebo response and the response to 
AR101 will be included in defining the success criteria for the primary endpoint. This will help 
to ensure that the number of peanut-allergic patients spared moderate or severe allergic reactions 
at Exit DBPCFC (a model for accidental exposure) after treatment with AR101 represents a 
clinically meaningful benefit, and not just a statistically significant non-zero difference from 
placebo. The primary efficacy analysis is based on the Farrington-Manning test with a two-sided 
alternative hypothesis at the 5% level of significance (Farrington and Manning, 1990). Given 

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placebo response rates of at most 20%, a 2-tailed 5% level test would have approximately 89% 
power to detect an AR101 response rate of at least 50% and rule out treatment differences 
(AR101 minus placebo) that are 15% or less for the primary endpoint. 
Europe: Based on preliminary data from ARC002, 40 out of 55 subjects treated in ARC001 and 
ARC002 with AR101 underwent an Exit DBPCFC with a single dose of 1000 mg (2043 mg 
cumulative) of peanut protein after approximately 12 or more weeks of maintenance dosing at 
300 mg/d. Of these, 24 subjects tolerated a single dose of 1000 mg (2043 mg cumulative) of 
peanut with no more than mild symptoms. This corresponds to an AR101 response rate of 44% 
(95% CI of 30% to 58%). We assume a placebo response rate of 15% at a single dose of 
1000 mg (2043 mg cumulative) of peanut protein (two-thirds of what we assumed for the 
placebo response rate at a single dose of 600 mg [1043 mg cumulative]). A sample size of 
495 children, aged 4 to 17 years, provides at least 93% power to detect an AR101 response rate 
of at least 30% at a single dose of 1000 mg (2043 mg cumulative) of peanut protein when the 
placebo response rate is at most 15%. 
10 
IDENTIFICATION AND ACCESS TO SOURCE DATA  
10.1 
Web-Based Data Collection and Management System 
Data collection will occur via a web-based data entry system to allow easy access to enrollment 
24 hours a day, 7 days a week. Upon enrollment, a form submission schedule is generated for 
each subject and displayed as a grid of forms by study visit that permits direct access to each 
electronic CRF for data entry. As data are entered, they are validated through range and 
within-form consistency checks. The investigator must ensure that all web-based CRFs are 
completed in a timely fashion for each subject in the study. 
10.2 
Certification in the Use of Web-Based Data Entry System 
The clinic and laboratory staff will be trained in the use of the data entry and specimen-tracking 
systems. Once certified, users are permitted to enter data into the production system. Access is 
password controlled. Certification for use of the web-based data entry system will be completed 
via telephone and/or web-cast training. 
10.3 
Data Management 
Information regarding the subject’s history, laboratory tests, nutritional intake, evaluation of 
allergic response and follow-up status will be stored and processed through the data center. 
Quality control procedures and a feedback system between the data center and the sites will be 
instituted to ensure the accuracy and completeness of the data collected. 
10.4 
Access to Data 
The investigational sites shall periodically permit authorized representatives of the Study 
sponsor, and/or regulatory health authorities to examine clinical records and other source 
documents for the purpose of safety monitoring, quality assurance reviews, audits and evaluation 
of the study progress throughout the entire study period. The investigator is required by law and 
applicable guideline (21 CFR 312.62, EU Clinical Trials Directive 2001/20/EC and ICH E6) to 
keep accurate case records for at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing application in an ICH 

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region. These documents should be retained for a longer period however if required by the 
applicable local regulatory requirements or by an agreement with the sponsor. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Statement of Compliance 
This study will be conducted using good clinical practice (GCP), as delineated in the United 
States Code of Federal Regulations (CFR) – 21 CFR Parts 50, 54, 56 and 312 and in the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) “Guidance for Industry: E6 Good Clinical Practice Consolidated Guidance”, 
and according to the criteria specified in this study protocol. Before study initiation, the protocol 
and the informed consent documents will be reviewed and approved by an appropriate 
IRB/EC and other applicable health authorities. Any amendments to the protocol must also be 
approved by Aimmune Therapeutics, IRB/EC and other applicable health authorities before they 
are implemented. Any amendments to the consent materials must also be approved by Aimmune 
Therapeutics and IRB/EC before they are implemented. 
11.2 
Informed Consent/Assent 
The informed consent/assent form is a means of providing information about the study to a 
prospective adult subject or a pediatric subject’s parent/guardian and allows for an informed 
decision about participation in the study. Because the study population will comprise a 
significant percentage of children, parents or legal guardians will be asked to read, sign and date 
a consent form before a child enters the study, takes study product, or undergoes any 
study-specific procedures. Children will sign an assent as appropriate. Consent materials for 
parents/guardians who do not speak or read English will be translated into the appropriate 
language. The informed consent/assent form will be evaluated for revision whenever the protocol 
is amended. A copy of the informed consent/assent will be given to a prospective adult subject or 
a pediatric subjects’ parent/guardian for review. The investigator (or designee), will review the 
consent/assent and answer questions, as well as emphasize the need to avoid allergen exposure 
other than to AR101, and the necessity to continue exposure to AR101 to maintain 
desensitization. The prospective adult subject or a pediatric subject’s parent/guardian will be told 
that being in the study is voluntary and that he or she may withdraw his/her child from the study 
at any time, for any reason. 
In the optional saliva substudy (North America sites only) in which samples will be obtained 
noninvasively from ARC003 participants, only subjects enrolled in ARC003 and providing 
additional consent for this substudy are eligible to participate (Appendix 6). 
11.3 
Privacy and Confidentiality 
A subject’s privacy and confidentiality will be respected throughout the study. Each subject will 
be assigned a sequential identification number and these numbers rather than names will be used 
to collect, store and report subject information. 
12 
RESOURCE SHARING 
All data derived from this study will be sent to the Reporting Center for storage and analysis. 
Subject data will be anonymized to maintain subject confidentiality. All data derived from these 

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studies will be published in peer-reviewed scientific journals in a timely manner. The sponsor 
will review all manuscripts prior to submission to journals for publication and all abstracts prior 
to submission to national and international meetings. All data sets will be archived by the 
Reporting Center and may be made available to interested, outside investigators with the 
approval by the sponsor.  
13 
PROTOCOL DEVIATIONS 
The investigators and site staff will conduct the study in accordance to the protocol. Any change, 
divergence, or departure from the study design or procedures constitutes a protocol deviation. 
Whenever applicable, corrective actions will be developed by the site and implemented promptly 
as a result of protocol deviations.  
13.1 
Major Protocol Deviation (Protocol Violation) 
A Protocol Violation is a deviation from the IRB approved protocol that may affect the subject's 
rights, safety, or well-being and/or the completeness, accuracy and reliability of the study data. 
In addition, protocol violations include willful or knowing breaches of human subject protection 
regulations, or policies, any action that is inconsistent with medical, and ethical principles, and a 
serious or continuing noncompliance with federal, state, local or institutional human subject 
protection regulations, policies, or procedures. 
13.2 
Nonmajor Protocol Deviation 
A nonmajor protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that does not have a major impact on the subject's rights, safety 
or well-being, or the completeness, accuracy and reliability of the study data.  
13.3 
Reporting and Managing Protocol Deviations 
Non-major protocol deviations related to data entry or visit adherence are captured within the 
data system and are not additionally reported on a separate CRF. 
The study site Principal Investigator has the responsibility to identify, document and report 
protocol violations/deviations and appropriate corrective action plans which are described above. 
However, protocol violations/deviations may also be identified during site monitoring visits or 
during other forms of study conduct review. All protocol violations will be reported in the data 
system on a specific CRF. 

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14 
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31 July 2017 
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Appendix 1: Schedule of Events 
Visit 
Screening/ 
Baseline  
Initial 
Escalation 
 
Up-dosing Period 
Maintenance Period 
 
Un- 
scheduled c  
CRC Dosing Interim (80 
mg) Visit 
End of Period 
(300 mg) Visit CRC Dosing 
Exit/Early 
Discontinuation 
Visit 
 
 
Days 1-2a 
5-10 days 
post-
DBPCFC 
~every 2 
weeks for 20-
40 weeksb 
Approx. 
Week 10 
≤ Week 40 
At 2 wks & 
every 4 wks 
thereafter 
for ~24 wks 
 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion  
X 
 
 
 
 
 
 
 
 
Medical/allergy history  
X 
 
 
 
 
 
 
 
 
Diet (food allergen) history 
X 
X 
 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 
X 
X 
Physical examd 
X 
X 
 
X 
X 
X 
X 
X 
X 
Vital signs (BP, PR, temp) 
X 
X 
 
X 
X 
X 
X 
X 
X 
Spirometry (FEV1) or PEFRe 
X 
X 
 
X 
X 
X 
X 
X 
X 
Pregnancy testf 
Serum 
 
 
 
Urine 
Urine 
 
Urine 
 
FAQLQ & FAIM questionnaires 
Xp 
 
 
 
 
 
 
Xp 
 
Palatability questions 
 
 
 
 
 
 
 
Xq 
 
TSQM-9 and Exit questionnaire 
 
 
 
 
 
 
 
Xr 
 
Blood 
draw 
Peanut-specific IgE, IgG4g  
X 
 
 
 
 
X 
 
X 
X 
CBC 
X 
 
 
 
 
X 
 
X 
X 
Optional extra vol. for ITNh 
X 
 
 
 
 
X 
 
Xi 
X 
Optional saliva collection, and 
packaging/shipping 
         No GI symptoms (controls) 
              GI symptoms (cases) 
 
 
X 
X 
 
 
 
 
Xj 
Xj 
 
 
X 
 
 
 
 
X 
 
Optional additional blood draw for post-
DBPCFC ITN sample  
 
 
Xk 
 
 
 
 
 
 
Skin prick test 
X 
 
 
 
 
X 
 
X 
 
Administration of OIT at site 
 
X 
 
X 
X 
X 
X 
 
X 
Dispense / return unused study drug 
 
X 
 
X 
X 
X 
X 
X 
X 
DBPCFC (2 parts within 7 days) 
Xl 
 
 
 
 
 
 
Xm 
 
Monitor AEs / allergic symptomsn 
X 
X 
 
X 
X 
X 
X 
X 
X 
Monitor for compliance 
 
 
 
X 
X 
X 
X 
X 
X 

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Visit 
Screening/ 
Baseline  
Initial 
Escalation 
 
Up-dosing Period 
Maintenance Period 
 
Un- 
scheduled c  
CRC Dosing Interim (80 
mg) Visit 
End of Period 
(300 mg) Visit CRC Dosing 
Exit/Early 
Discontinuation 
Visit 
 
 
Days 1-2a 
5-10 days 
post-
DBPCFC 
~every 2 
weeks for 20-
40 weeksb 
Approx. 
Week 10 
≤ Week 40 
At 2 wks & 
every 4 wks 
thereafter 
for ~24 wks 
 
 
Assessment of Asthma 
X 
 
 
 
X 
X 
 
X 
 
Subject reminder to avoid all peanut 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Telephone Follow-upo 
 
X 
 
X 
X 
X 
 
 
X 
PEESSTM v2.0 questionnaire 
 
 
 
 
 
 
 
 
Xs 
Footnotes: 
a) 
The Initial Escalation Visit will be scheduled within 10 days after the Screening DBPCFC. See Table 3-1 for dose escalation schedule. Subjects will begin home 
dosing at dose 3 mg/d.  
Day-1: Escalation to at least 3 mg or 6 mg, as tolerated (subjects who cannot tolerate 3 mg are escalation failures). 
Day-2: Confirm tolerance of 3 mg. 
b) Subjects return to clinic every 2 weeks for up-dosing to a maximum of 300 mg, following the dose escalation schedule in Table 3-2 , unless up-dosing is delayed 
due to allergic reaction. 
c) Any of the procedures performed at CRC Dosing Visits may be performed at Unscheduled Visits. 
d) Physical exam to include height and weight. At the investigator’s discretion, symptom-directed physical exams may be completed at up-dosing visits 
during the Up-dosing Period, and CRC Dosing visits during the Maintenance Period. Full physical exams are to be conducted at the Screening/Baseline, 
the first 80 mg up-dosing, the first 300 mg up-dosing, and the Exit/Early Discontinuation (Termination) visits.  
e) 
Peak expiratory flow rate (PEFR): To be conducted prior to any DBPCFC, 3 attempts should be made with the best value recorded. PEFR should be measured at the 
same time for each visit assessment. If a subject’s pulmonary status is in question at any time during the study, performance of pulmonary function testing (spirometry) is 
suggested. 
f) 
For females of childbearing potential. 
g) 
Blood for peanut specific IgE, IgG4 is to be drawn prior to DBPCFC.  
h) 
Optional blood draw for subjects ≥ 30 kg only. No more than 5 mL/kg may be drawn, up to a maximum of 50 mL total; analysis by Immune Tolerance Network (ITN).  
i) 
Blood draw to be collected prior to the Exit DBPCFC (a second draw, 5-10 days post-DBPCFC, will be collected in ARC004; for subjects not continuing to ARC004, 
specimen collection should be as an Unscheduled ARC003 visit). 
j) 
Subjects withdrawing early from ARC003 with GI symptoms who were not already enrolled in the optional saliva substudy will be allowed to enroll upon early 
termination (North America sites only).  
k) 
Blood draw to be collected 5-10 days after the Screening DBPCFC. 
l) 
Eligible subjects, those who satisfy all other screening requirements, will undergo a DBPCFC at the end of the Screening Period to a maximum challenge dose of 100 
mg.  
m) Eligible subjects, those who up-dose to 300 mg and maintain for ~24 weeks, will undergo a DBPCFC at the end of Maintenance Period Visit to a maximum challenge 
dose of 1000 mg.  
n) 
AEs will be evaluated from the onset until the event is resolved or medically stable, or until 30 days after the subject completes study treatment, whichever comes first. 
o) 
Phone calls will occur 1 day after each escalation visit to inquire about allergic symptoms and promote compliance 
p) 
FAQLQ and FAIM to be filled up prior to screening DBPCFC and after exit DBPCFC and unblinding  
q) 
Palatability questions to be answered before the exit DBPCFC for all patients  
r) 
TSQM-9 and Exit questionnaire to be answered after exit DBPCFC and unblinding for all active patients  

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s) 
Subjects under the age of 18 years who fall into any of these 3 categories will be asked to fill out the PEESSTMv2.0 questionnaire (Franciosi et al., 2011), with the 
assistance of a parent or guardian, as appropriate, every month for 6 months: 
• 
Any subject whose dose is withheld for > 7 days due to GI AEs and resumes dosing at a reduced dose level (Section 6.7) 
• 
Any subject who develops chronic/recurrent GI AEs at or before reaching the 20 mg dose level and resumes dosing after a 30-day dosing hiatus 
(Section 6.7.3.2) 
• 
Any subject who permanently discontinues dosing who had experienced GI AEs (Section 4.3.2) 
Note: BP = blood pressure; PR = pulse rate; temp = body temperature; OIT = oral immunotherapy; DBPCFC = double-blind, placebo-controlled food challenge 
 
 

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Appendix 2: Evaluation of Asthma 
The evaluation of asthma severity will be assessed using the NHLBI classification published 
August 28, 2007 as described in the table below. 
Classification 
Symptoms 
Nighttime 
awakenings 
Lung Function 
Interference 
with normal 
activity 
Short acting 
beta-agonist use 
Intermittent 
(Step 1) 
≤ 2 days per 
week 
≤ 2x /month 
Normal FEV1 
between 
exacerbations 
FEV1 > 80% 
predicted 
FEV1/FVC 
normal* 
None 
≤ 2 days /week 
Mild 
Persistent 
(Step 2) 
> 2 days per 
week but not 
daily 
3-4x /month 
FEV1 ≥ 80% 
predicted 
FEV1/FVC 
normal* 
Minor 
limitation 
> 2 days /week 
but not > 1x/day 
Moderate 
Persistent 
(Step 3 or 4) 
Daily 
> 1x /week 
but not 
nightly 
FEV1 ≥ 60% but 
< 80% predicted 
FEV1/FVC 
reduced 5%* 
Some 
limitation 
Daily 
Severe 
Persistent 
(Step 5 or 6) 
Throughout the 
day 
Often  
7x /week 
FEV1 < 60% 
predicted 
FEV1/FVC 
reduced > 5%* 
Extremely 
limited 
Several times per 
day 
*Normal FEV1/FVC: 8-19 yr = 85%; 20-39 yrs = 80 
 

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Appendix 3: Criteria for Suspected Diagnosis, and Severity Grading, of Anaphylaxis  
Criteria for Suspected Diagnosis 
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: 
o Skin/mucosal tissue (eg, generalized hives, itch or flush, swollen lips/tongue/uvula) 
AND 
o Airway compromise (eg, dyspnea, stridor, wheeze/ bronchospasm, hypoxia, reduced 
PEF) AND/OR 
o 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): 
o Skin/mucosal tissue (eg, generalized hives, itch/flush, swollen lips/tongue/uvula) 
o Airway compromise (eg, dyspnea, stridor wheeze/bronchospasm, hypoxia, reduced 
PEF) 
o Reduced BP or associated symptoms (eg, hypotonia, syncope, incontinence) 
o Persistent GI symptoms (eg, nausea, vomiting, crampy abdominal pain) 
3. Reduced BP after exposure to the allergen (min to h): 
o Infants and Children: low systolic BP (age-specific) or > 30% drop in systolic BP* 
o 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 et al., 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:  Allergic Reaction Severity Grading 
The CoFAR grading system for allergic reactions as displayed in Table A4.  
Table A4: 
CoFAR Specific Grading System for Allergic Reactions 
Grade 1 - Mild 
Grade 2 - 
Moderate 
Grade 3 – Severe 
Grade 4 - Life 
Threatening 
Grade 5 
– Death 
Transient or mild 
discomforts 
(< 48 hours), no 
or minimal 
medical 
intervention/ther
apy required. 
These symptoms 
may include 
pruritus, swelling 
or rash, 
abdominal 
discomfort or 
other transient 
symptoms. 
Symptoms that 
produce mild to 
moderate limitation 
in activity some 
assistance may be 
needed; no or 
minimal 
intervention/therapy 
is required. 
Hospitalization is 
possible. These 
symptoms may 
include persistent 
hives, wheezing 
without dyspnea, 
abdominal 
discomfort/ 
increased vomiting 
or other symptoms 
Marked limitation in 
activity, some 
assistance usually 
required; medical 
intervention/therapy 
required, 
hospitalization is 
possible Symptoms 
may include 
Bronchospasm with 
dyspnea, severe 
abdominal pain, 
throat tightness with 
hoarseness, transient 
hypotension among 
others. Parenteral 
medication(s) are 
usually indicated. 
Extreme limitation in 
activity, significant 
assistance required; 
significant 
medical/therapy. 
Intervention is required; 
hospitalization is 
probable. Symptoms may 
include persistent 
hypotension and/or 
hypoxia with resultant 
decreased level of 
consciousness associated 
with collapse and/or 
incontinence or other life-
threatening symptoms. 
Death 
 
 

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Appendix 5:  Guidance for Determining When an Episode of Anaphylaxis Should Be 
Reported as a Serious Adverse Event (SAE) 
For an episode of anaphylaxis to be considered an SAE, Aimmune advises that the event satisfy 
one of the outcome-based definitions of SAE specified in Section 7.4.2 of the 
Protocol, with the stipulations (denoted in italics) indicated. These stipulations follow from, and 
are consistent with, the criteria for DSMC reporting (Section 7.7.2): 
1. Death – No further stipulation. 
2. Life-threatening AE (Life-threatening means that the study subject was, in theopinion of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred.): 
For anaphylaxis to be considered life-threatening it should be assessed to have been 
severe, as defined in Appendix 3 and of a Grade 4 allergic reaction, as defined in 
Table A4 of Appendix 4. 
3. Inpatient hospitalization or prolongation of existing hospitalization: The hospital 
admission should not have been solely for the sake of providing an extended period of 
observation, as, for example, might be implemented to watch for a delayed or biphasic 
reaction. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions: No further stipulation. 
5. Congenital abnormality or birth defect: No further stipulation. 
6. Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study subject or require medical or surgical intervention to 
prevent one of the outcomes listed in the above definition of serious event: 
o In general, for an anaphylactic episode to be classified as an SAE on the basis of 
being an “important medical event,” it should have resulted in an emergency room 
visit, and the emergency room visit should have been associated with intensive 
therapy. What constitutes intensive therapy is to be determined by the investigator, 
but may include such interventions as IV epinephrine, intubation, or admission to an 
intensive care unit. 
o One or 2 intramuscular injections of epinephrine should ordinarily not be construed 
as intensive therapy 
o If an investigator assesses an episode of anaphylaxis to be an “important medical 
event” when the episode was of mild or moderate severity and did not require 
intensive therapy, the rationale for the assessment must be explained in detail in the 
narrative of the event. 
 
 

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Appendix 6: (North America sites only) Exploratory Biochemical and Molecular Study of 
Peanut-Allergic Children and Adults with Oral Immunotherapy-Related 
Gastrointestinal Symptoms in ARC003 
Background 
A strong association exists between food allergy and eosinophilic esophagitis (EoE) (Noel 2004; 
Spergel 2012; Greenhawt 2014). Instituting an elemental diet free of potential allergens is the 
most reliably effective treatment for spontaneously occurring EoE (Arias 2014; Wechsler 2014). 
In some cases of EoE, if a specific allergy-provoking food can be identified, then dietary 
avoidance of the offending food can result in resolution of the esophageal symptoms 
(Spergel 2012). Alternatively, elimination from the diet of the most common food allergens, 
including milk, egg, peanut/tree nuts, soy, wheat, and shellfish/fish, can also result in resolution 
of the esophagitis (Kagalwalla 2006; Gonsalves 2012). When reintroduction of a suspected 
allergenic food is associated with the return of symptoms, this strongly implicates the food as a 
likely causative agent of the EoE (Gonsalves 2012).  
IgE-mediated hypersensitivity to food allergens, but also aeroallergens (Alpan 2012; 
Ridolo 2012; Wolf 2013; Rea 2014), figures prominently in the pathogenesis of EoE, but other 
factors besides the induction of an immediate hypersensitivity reaction also appear important. 
One circumstance in which multiple factors pertaining to food exposure are controlled at the time 
that EoE becomes symptomatic is when EoE occurs in the setting of oral immunotherapy (OIT). 
The inciting food is known, as is the amount and timing of its consumption. Moreover, EoE 
occurs only in a minority of patients undergoing OIT. Thus, studying EoE when it arises during 
the course of OIT may provide a unique opportunity to gain insights into its pathogenesis.  
In OIT studies, gastrointestinal (GI) adverse events (AEs) are typically prominent 
(Anagnostou 2014; Yu 2012; Blumchen 2010; Jones 2009) and account for a substantial 
proportion of premature discontinuations of study treatment (Burks 2012; Varshney 2011; 
Jones 2009; Vickery 2011). This was also observed in the completed ARC001 study and the 
ongoing ARC002 study. In the ARC001 study, 6 out of 29 subjects (21%) receiving active 
treatment discontinued prematurely. Four of the early discontinuations were attributed by the 
principal investigators to have been the consequence of recurrent GI AEs; and in one of these 
cases the diagnosis of EoE was subsequently established by endoscopic biopsy. In the other two 
discontinuations, at least one GI AE had occurred in each subject. In the ongoing ARC002 study, 
an open-label follow-on to the ARC001 study, 6 of the 26 subjects (22%) who had been assigned 
to the placebo group in ARC001 discontinued therapy prematurely. Four of these early 
discontinuations were due to recurrent GI AEs and two were due to study visit scheduling 
difficulties.  
Repeated bouts of abdominal pain and vomiting are common to both EoE and chronic/recurrent 
OIT-related GI symptoms, suggesting a common, or at least a similar, etiology in at least a 
proportion of patients. To date, at least 20 occurrences of OIT-related GI AEs have been 
confirmed histopathologically to be EoE as reported in the medical literature (Hofmann 2009; 
Vickery 2011; Wasserman, 2011; Sánchez-García 2012; Lucendo 2014), and in still other cases 
the symptomatology and clinical course (with or without concomitant blood eosinophilia) have 
been highly suggestive of EoE (Narisety 2009; Vickery 2011; Stein 2012). A recent review of 

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the literature (Lucendo, 2014) has indicated that the incidence of confirmed EoE in OIT is on the 
order of 3% (ranging from approximately 1% to 5%), but the incidence of suspected EoE on 
clinical grounds may be in the vicinity of 15 to 25%. 
Establishing the association between OIT and the subsequent development of EoE is not always 
straight forward. The time to onset of EoE during the course of OIT may vary depending on the 
allergen and OIT regimen. Many (Vickery 2011; Wasserman 2011), though not all 
(Hofmann 2009), of the reported cases of EoE with peanut OIT had developed GI symptoms 
early in the course of oral desensitization, whereas with milk OIT the occurrence of EoE has 
tended to be after reintroduction of milk into the diet (Sánchez-García 2012; Maggadottir 2014; 
Nowak-Wegrzyn 2014). Not all EoE occurring during OIT is necessarily caused by the OIT, 
however. Food allergies often occur to more than one type of food and allergies to foods often 
coexist with allergies to airborne and contact allergens.  
Chronic GI AEs affecting participants in ARC003 have been designated as Adverse Events of 
Special Interest (AESI) in the ARC003 protocol document, Amendment 1. The goal of the 
current substudy is to explore the biology of these GI AESIs occurring during our Phase 3 trial 
using a readily available and noninvasive sampling method (saliva) in an attempt to overcome 
some of the difficulties in assessing intolerable GI AEs in subjects undergoing OIT.  
Rationale for the Proposed Study 
The overall aims of this substudy are to collect biospecimens through a noninvasive technique, 
and to analyze them to develop a better understanding of the biochemical and molecular changes 
that occur when OIT participants develop GI adverse events significant enough to require 
discontinuation of the OIT protocol. We will obtain preliminary information regarding these 
biological changes in biospecimens from symptomatic individuals, as well as controls, using 
methods that have been developed for the study of eosinophilic GI disorders at Cincinnati 
Children’s Hospital Medical Center, Cincinnati, OH, USA.  
Specifically, this substudy of ARC003, Amendment 3 will enroll all willing volunteers at 
screening, prior to dosing, in ARC003 and then collect further information from those subjects 
who go on to experience GI side effects during OIT and controls. To overcome the obstacles 
limiting traditional EoE evaluations in this context (eg, performance of an 
esophagogastroduodenoscopy [EGD]), an easily collected biospecimen will be analyzed to 
determine whether patterns can be detected that correlate with patterns seen in other subjects 
with known bona fide EoE. As there are no known clinical predictors of EoE, all ARC003 
participants will be approached about participating in this substudy. Further analyses will be 
conducted on those subjects who develop GI symptoms during the course of OIT and controls 
who do not develop GI symptoms. While all subjects will provide baseline saliva specimens 
(collected at screening), we will be opportunistic about the collection of esophageal specimens, 
which may provide additional supportive data. Specifically, if subjects in the study withdraw 
from OIT and undergo a clinically-indicated EGD, we will, whenever possible, collect biopsy 
material from the site for further analysis, as per the ARC003 protocol.  
In addition to addressing the detection of biomolecular signatures in subjects having adverse 
events, it is possible that specific biomolecular signatures could emerge from the planned study 

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that associate with treatment success or treatment withdrawal. Thus, a possibility exists that the 
proposed biospecimen testing could yield biomarkers predictive of an individual subject’s 
response to OIT and the collection of biospecimens in this substudy could facilitate these future 
analyses. 
Known and Potential Risks and Benefits to Human Participants 
Risks  
The principal potential risk associated with this substudy is the potential for emotional or 
psychological distress related to the discovery of uncertain information that is not itself 
diagnostic but may suggest a new clinical diagnosis (ie, EoE). To mitigate against this risk, and 
because the assays run in this substudy are experimental, exploratory, and not part of standard 
care EoE diagnostics, the results of these studies will not be shared with participants. Clinical 
management of these individuals will be at the judgment of the site investigator, per the current 
standard of care. The ARC003 protocol document also contains specific recommendations about 
the clinical follow-up of subjects developing AESIs. All study candidates entering ARC003 will 
undergo an informed consent procedure detailing the potential risk of OIT-associated 
gastrointestinal symptoms, including the possibility of EoE.  
There are no known physical risks to the saliva collection procedure.  
Benefits  
Individual subjects are not expected to benefit from participation in this study. Information from 
this study may help researchers to better understand peanut allergy and its relationship to EoE or 
to develop future tests or treatments to help patients with one or both of these conditions. 
Objectives 
Primary Objective 
The primary objective is to analyze biomolecular expression patterns in saliva samples obtained 
longitudinally from peanut-allergic participants undergoing OIT in ARC003. These studies will 
target the salivary RNA transcriptome, and if necessary further validate, with molecular-, 
cellular-, and/or protein-based approaches, the expression profile of gene pathways that are likely 
relevant to intolerable GI side effects in ARC003 subjects. 
Secondary Objectives 
The key secondary objective is to examine the relationship of the RNA expression profile to 
selected clinical variables from ARC003, including: 
• 
The frequency and severity of AEs related to the gastrointestinal tract 
• 
The frequency of dosing interruptions (reductions and/or discontinuations) directly 
related to GI AEs 
• 
Peripheral blood eosinophil counts 

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• 
PEESS v2.0 scores  
• 
Immunoglobulin levels (IgE, IgG4, and their subclasses) 
Further secondary objectives include the correlation of salivary RNA transcriptome data to 
histopathologic and molecular analyses of the esophagus, when available. 
Substudy Design 
This is an optional substudy in which samples will be obtained from ARC003 participants 
according to the Schedule of Events in Table A6. Only subjects enrolled in ARC003 and 
providing additional consent for this substudy are eligible to participate. Subjects enrolled in 
both ARC003 and this substudy will undergo saliva collection coordinated at the designated 
ARC003 study visits. Otherwise these subjects will be treated according to the ARC003 study 
protocol. 
Table A6: 
Schedule of Events 
 
Screening 
Early 
Build-Up 
Visit 
At PEESS 
v2.0 #1 
End of Up-
Dosing Visit 
Post-OIT 
Follow-upb 
Study Weeka 
0 
6 (±2 wk) 
varies 
20 
Varies 
Informed consent/assent 
X 
 
Xc 
 
 
Eligibility assessment  
X 
 
 
 
 
Saliva collection and 
packaging/shipping: 
 
 
 
 
 
No GI symptoms (controls) 
X 
X 
 
X 
 
GI symptoms (cases) 
X 
 
Xc 
 
X 
a 
Minimum study weeks are shown. Actual duration may be longer depending on subject’s actual up-
dosing in ARC003.  
b 
For subjects who terminate dosing and enter observational follow-up, as per Section 7.4.3.2 of the 
ARC003 protocol. This sample is to be collected at the sixth monthly visit after study withdrawal or as 
close as practicable.  
c 
Subjects withdrawing early from ARC003 with GI symptoms that were not already enrolled in this 
substudy will be consented to enroll upon early termination. 
Subjects in this substudy will undergo 3 protocol-specified collections of saliva. All subjects will 
have a baseline saliva sample collected at Screening (before the Screening DBPCFC). Because 
the GI adverse events of special interest are unpredictable and treatment-emergent, the approach 
to sampling post-randomization will differ by treatment response. Subjects who develop 
GI-predominant adverse events that prompt their withdrawal from ARC003 or a protracted 
disruption of dosing with study product will be considered “cases” in this substudy. The second 
saliva sample will be collected from cases when the first PEESSV2.0 is completed. The final 
saliva sample for cases will be collected at the end of the protocol-defined 6-month follow-up 
period for subjects that withdraw from therapy. 

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 “Controls” in this substudy will be defined as ARC003 participants receiving OIT (active and 
placebo) who do not develop intolerable GI symptoms. Following the baseline collection, 
asymptomatic subjects will provide saliva samples at the 6-week up-dosing visit and again at the 
end of the updosing period.  
This substudy will principally involve: collection, shipment, and banking of saliva samples at 
specified time points; gene expression analysis of selected salivary biospecimens; and correlation 
with basic biometric data (eg, peripheral blood eosinophils, clinical symptom reports/PEESSv2.0 
scores) obtained as necessary, and clinical outcome per the ARC003 protocol. Biochemical 
detection of eosinophil activation products or metabolites may also be possible from collected 
samples. 
Subject participation will consist of signing an informed consent form (ICF) approved by the 
institutional review board (IRB), ethics committee (EC), research ethics board (REB), or like 
authority, and age-appropriate assent form, when indicated, as per local guidelines, and the 
provisions for biospecimen collection and handling (further detailed in Section 4.3). 
Case Definition: ARC003 Events Triggering PEESS v2.0  
The following passage is taken from Section 7.4.3.2 of the ARC003 Protocol, Amendment 1 and 
serves to identify the case definition in this substudy; eg, the ARC003 subjects who develop the 
GI AESIs requiring further evaluation.  
GI AEs, typically chronic/recurrent GI AEs, that result in a prolonged disruption of 
dosing will be considered AEs of special interest and will be assessed longitudinally 
according to the procedures described below. For the purpose of delineating these AEs of 
special interest, prolonged disruption of dosing is defined as withholding study product 
for > 7 days. This will include 3 categories of subjects: 
o Any subject whose dose is withheld for > 7 days due to GI AEs and resumes dosing at 
a reduced dose level (Section 6.7 of the ARC003 protocol) 
o Any subject who develops chronic/recurrent GI AEs at or before reaching the 20 mg 
dose level and resumes dosing after a 30-day dosing hiatus (Section 6.7.3.2 of the 
ARC003 protocol); 
o Any subject who permanently discontinues dosing who had experienced GI AEs 
(Section 4.3.2 of the ARC003 protocol). 
Subjects under the age of 18 years who fall into any of these 3 categories will be asked to 
fill out the PEESS v2.0 questionnaire (Franciosi et al., 2011), with the assistance of a 
parent or guardian, as appropriate, every month for 6 months; adults will be given the 
same version of the questionnaire. It should, however, be noted that the PEESS v2.0 was 
not designed to establish a diagnosis of EoE, and has not been validated for use in 
patients 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 et al., 2011; Martin et al., 2015) 

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and so holds promise for being a valuable tool to follow the clinical course of EoE or an 
EoE-like immune-mediated GI syndrome. Thus, the PEESS v2.0, could reveal trends 
toward symptomatic improvement or worsening that might otherwise go undetected. 
Exploratory Endpoints 
All endpoints in this substudy are considered exploratory. The primary objective is to 
characterize RNA expression patterns in salivary specimens collected from peanut-allergic 
subjects who participated in a study of peanut OIT and developed intolerable GI adverse events 
that interfered with treatment (ie, resulted in reducing, holding, or discontinuing OIT dose 
levels). ARC003 subjects who do not develop limiting GI symptoms will also be studied as 
control specimens. Secondarily we will also examine the associations of the salivary RNA 
expression changes with selected clinical variables as listed in Section 3.6 and Section 3.7 and 
explore the within-subject correlation to RNA expression patterns observed in esophageal 
specimens, when available.  
Bioinformatic analysis plan for primary and secondary objectives  
The bioinformatic analysis plan for the primary and secondary objectives of this study include: 
• 
Quality control of the genome-wide RNA sequencing data 
• 
Expression filter and statistical filter 
• 
Clustering analysis with known clinical outcomes 
• 
Develop an algorithm (similar to Wen et al., 2013) to quantify the oral sample signature 
to correlate with the PEESSTM v2.0 
• 
Use a portion of the samples as a training set for machine learning, then carry out the 
support vector machines (SVMs) to predict the rest of the samples. SVM is a supervised 
learning model with associated learning algorithms that analyze data and recognize 
patterns.  
• 
Principle Component Analysis (PCA) will be employed to globally categorize the 
samples, reduce the dimensionality for signature quantification and aid the graphical 
presentation of the data 
Additional exploratory endpoints may include qualitative and/or quantitative comparisons to the 
patterns of biomolecular and biochemical expression seen in subjects with spontaneously 
occurring EoE or other esophageal pathologies (historical controls). These control specimens 
will be obtained under separate protocols at the investigative laboratory.  
Criteria for Study Participation 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment as study subjects: 
• 
Participation in the ARC003 study 

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• 
Written informed consent from adult subjects 
• 
Written informed consent from parent/guardian for minor subjects 
• 
Written assent from minor subjects as appropriate (ie, above the age of 7 years) 
Exclusion Criteria 
1. Otherwise ineligible for ARC003 
Subject Termination from the Substudy 
After enrollment, subjects may withdraw consent from this substudy at any time. Subjects may 
also be withdrawn by the Investigator for reasons of safety or compliance.  
Study Product  
No study product will be administered in the substudy.  
Study Procedures 
The following procedures will be performed:  
1. Enrollment and Permissions  
o Obtain subject/parental signatures on IRB-approved informed consent/assent form. 
2. Subject Information  
o Confirm subject eligibility 
3. Sample Collection, Handling and Analysis Procedures 
o Saliva is the principal biospecimen to be collected in this study with the aid of a 
commercially available kit designed expressly for salivary RNA research purposes. 
Specific details for saliva collection will be provided to sites in a manual of 
procedures.  
o Blood samples for CBC, already collected in ARC003, will also be included in 
analyses relating to the secondary objectives of this substudy. 
o Biospecimens may be temporarily stored at investigational sites to facilitate batch 
shipping and receiving. All biospecimens will be packaged and transported to the 
investigative laboratory in a manner compliant with all local, state, and federal laws 
and regulations, as per standard operating procedures of the shipping and receiving 
facilities. 
o Analyses will include one or more of the following:  
- 
Transcriptome analysis 
- 
EoE diagnostic panel comprising a 96-gene quantitative polymerase chain 
reaction array 
- 
Profiling of local cytokine expression  

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- 
Targeted analysis of expression of previously identified specific candidate genes 
- 
Analysis of single nucleotide polymorphisms in previously identified specific 
candidate genes 
- 
Inflammatory pathway analysis (Ingenuity, Toppfun or David) 
- 
qPCR analysis 
- 
Immunohistochemistry or other protein detection methods (eg ELISA, Western 
blot, etc.). 
- 
Mass spectrometry 
- 
Flow cytometry 
Lead Investigative Laboratory 
The lead investigative laboratory is the following: 
Wen Lab – Cincinnati Children’s Hospital Medical Center 
S6.405 S Building 
240 Albert Sabin Way, 
Cincinnati, OH 45242 
USA. 
Permission to obtain samples of esophageal tissue from the residua (if any) of biopsy 
specimens obtained during the performance of routine clinical endoscopic biopsy will 
be requested for subjects who undergo this procedure.  
4. Study Blinding Procedures 
This substudy will be unblinded after ARC003 is unblinded. The precautions relating to 
maintenance of blinding are detailed in the ARC003 Masking Plan. In order to 
understand the clinical significance of the bioassays performed in this substudy, 
information about the clinical history (including history during participation in ARC003) 
and treatment assignment in ARC003 will be analyzed. However, ARC003 treatment 
assignments will not be provided to any individual directly involved in performance of 
laboratory assays until all assays are completed. Subject identification will be known 
only to the personnel at the investigational site obtaining informed consent, and 
potentially the site monitor(s) and auditors. Subject identification will be kept 
confidential.  
5. Safety Monitoring 
As the study entails no treatment, there can be no treatment-emergent or treatment-related 
adverse events (AEs) in this substudy. As outlined in Section 1.3, the principal risk 
associated with a genetic-based study is the potential for emotional reactions upon 
learning that the subject or a subject’s family member does or does not carry or express a 
gene associated with a particular condition. 

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6. Statistical Considerations 
This substudy is a pilot characterization of biochemical and biomolecular markers in 
relation to GI side effects arising during peanut OIT in ARC003 subjects. The analyses to 
be conducted in this substudy are all considered exploratory in nature. As such, 
descriptive statistical techniques will be utilized to characterize demographic and basic 
clinical variables, with standard assessments for normality and adjustments as necessary. 
Measures of correlation and longitudinal repeated measures will be assessed with 
appropriate techniques (eg regression modeling) as necessary. Statistical testing for 
differences between treatment groups or time points may be assessed, but specific 
hypotheses are not pre-specified.  
7. Study Endpoint Assessment 
All endpoints in this study are considered exploratory and are defined in Section 3.8.  
8. Subject and Demographic Data 
Baseline Characteristics, Demographics, and Safety Data 
Baseline and demographic characteristics may be reported for each subject enrolled in the 
present study as they were obtained in ARC003. Demographic data could include age, 
race, sex, body weight and height. Other analyses involving safety data may also be 
performed.  
Use of Medications 
There will be no medications used in this substudy. Data from concomitant medication 
use in ARC003 related to AEs may be analyzed as part of this substudy.  
9. Sample Size Calculations 
This is an exploratory and hypothesis-generating study involving minimal risk to 
subjects. No specific sample size calculations have been performed.  
Identification and Access to Source Data  
Data Management 
Information regarding the subject’s history, laboratory tests, nutritional intake, evaluation of 
allergic response and follow-up status will be stored and processed through the ARC003 clinical 
trial database. All participating laboratories will collect data in a manner that allows independent 
verification of the results and their communication to the Sponsor. All participating laboratories 
will maintain study records for at least 2 years after acceptance of a licensure application for 
AR101. Quality control procedures and a feedback system between Aimmune and the 
investigational laboratory site(s) may be instituted to ensure the accuracy and completeness of 
the data collected and transmitted. 

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Access to Data 
The investigational sites shall periodically permit authorized representatives of the Study 
sponsor, and/or regulatory health authorities to examine clinical records and other source 
documents for the purpose of safety monitoring, quality assurance reviews, audits and evaluation 
of the study progress throughout the entire study period. The investigator is required by law and 
applicable guideline (21 CFR 312.62, EU Clinical Trials Directive 2001/20/EC and ICH E6) to 
keep accurate case records for at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing application in an ICH 
region. These documents should be retained for a longer period, however, if required by the 
applicable local regulatory requirements or by an agreement with the sponsor. 
Quality Control and Quality Assurance 
Statement of Compliance 
This study will be conducted using good clinical practice (GCP), as delineated in the United 
States Code of Federal Regulations (CFR) – 21 CFR Parts 50, 54, 56 and 312 and in the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) “Guidance for Industry: E6 Good Clinical Practice Consolidated Guidance”, 
and according to the criteria specified in this study protocol. Before study initiation, the protocol 
and the informed consent documents will be reviewed and approved by an appropriate 
IRB/EC and other applicable health authorities. Any amendments to the protocol must also be 
approved by Aimmune Therapeutics, IRB/EC and other applicable health authorities before they 
are implemented. Any amendments to the consent materials must also be approved by Aimmune 
Therapeutics and IRB/EC before they are implemented. 
Changes to assay details and laboratory information will not require a protocol amendment, but 
will be reflected in amendments to consent materials and other accessory documents as 
appropriate. 
The participating laboratory will cooperate with the Sponsor in complying with additional 
requests from the appropriate IRB/EC and the applicable regulatory health authority of the 
countries in which ARC003 is conducted.  
Informed Consent/Assent 
The informed consent form is a means of providing information about the study to a prospective 
subject’s parent/guardian and allows for an informed decision about participation in the study. 
Because the study population will include children, parents or legal guardians will be asked to 
read, sign and date a consent form before a child enters the study, takes study product, or 
undergoes any study-specific procedures. Children will sign an assent as appropriate. Consent 
materials for parents/guardians who do not speak or read English will be translated into the 
appropriate language. The informed consent form will be revised whenever the protocol is 
amended. A copy of the informed consent will be given to a prospective parent/guardian for 
review. Appropriately trained study personnel, in the presence of a witness, will review the 
consent and answer questions. The prospective parent/guardian will be told that being in the 

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study is voluntary, that he or she is under no obligation to enter the study, and that he or she may 
withdraw his/her child from the study at any time, for any reason. 
Privacy and Confidentiality 
A subject’s privacy and confidentiality will be respected throughout the study. Subject data will 
be anonymized by use of subject identification numbers assigned in ARC003. These numbers 
will be used to collect, store and report subject information. 
Resource Sharing 
All data derived from this study will be sent to the investigational laboratory for storage and 
analysis and will also be provided to the Sponsor. Subject data will be coded as described above 
to maintain subject confidentiality. The Sponsor and laboratory will review all data 
communications (including but not limited to abstracts, presentations, and manuscripts) prior to 
external submission. All data sets will be archived by the laboratory and may be made externally 
available after approval by the Sponsor.