Phase 2 Oral Desensitization to Peanut in Peanut-Allergic Children and Adults Using Characterized Peanut Allergen Oral Immunotherapy
Phase: PHASE2
Conditions: Peanut Allergy
Sponsor: Aimmune Therapeutics, Inc.

 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
ARC001 
Oral Desensitization to Peanut in Peanut-Allergic Children and Adults Using 
Characterized Peanut Allergen (CPNA) Oral Immunotherapy (OIT) 
 
 
 
 
Protocol Amendment 3 – 14 May 2014 
Reference Numbers:  NCT01987817, EudraCT 2021-002087-47 
 
 
 
 
 
 
 
 
 
 
 
Aimmune Therapeutics, Inc. 
8000 Marina Blvd, Suite 300 
Brisbane, CA  94005 
United States 
 
 
 

Allergen Research Corporation  
CONFIDENTIAL 
Page 1 of 71 
Protocol ARC001 Amendment 3 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
Oral Desensitization to Peanut in Peanut-Allergic Children 
and Adults using Characterized Peanut Allergen (CPNA) 
Oral Immunotherapy (OIT) 
Investigational 
Drug: 
Characterized Peanut Allergen (CPNA) 
Protocol 
Number: 
ARC001 
IND Number: 
IND 15463 
Sponsor: 
Allergen Research Corporation (ARC) 
2000 Alameda de las Pulgas, Suite 161 
San Mateo, CA 94403 
USA 
 
Version: 
Date: 
Amendment 3 
14 May 2014 
 
 
 
 
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 Allergen Research Corporation, 
unless it is necessary to obtain informed consent from potential study subjects. 
 
 
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CONFIDENTIAL 
Page 2 of 71 
Protocol ARC001 Amendment 3 
 
CLINICAL STUDY PROTOCOL ARC001 
Sponsor Personnel 
VP, Clinical 
Operations 
Joseph Suttner, MBA 
ARC 
Chief Medical 
Officer 
Robert Elfont MD, PhD 
ARC 
 
 
 
 
CLINICAL STUDY PROTOCOL ARC001 
Clinical Research Organization (CRO) Personnel 
CRO 
Clinipace Worldwide (CPWW) 
3800 Paramount Pkwy, Suite 100 
Morrisville, NC 27560 
USA 
Medical Monitor Dr. Gilad Gordon, MD 
CPWW 
 
 
 
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CONFIDENTIAL 
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Protocol ARC001 Amendment 3 
Sponsor Protocol Approval 
 
 
Protocol ARC001 
Version/Date: Amendment 3/ 
14 May 2014 
 
Sponsor: Allergen Research Corporation (ARC) 
 
Short Title: CPNA Peanut OIT 
 
I have read protocol ARC001, 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.  
 
 
_______________________________                                    _______________ 
Chief Medical Officer (Print)                                                        Date 
 
 
_______________________________                                    _______________ 
Chief Executive Officer (Signature)                                                Date 
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CONFIDENTIAL 
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Protocol ARC001 Amendment 3 
Principal Investigator Protocol Approval 
Protocol ARC001 
Version/Date: Amendment 3/ 
14 May 2014 
IND: 15463 
Principal Investigator:  
 
Short Title: CPNA Peanut OIT 
 
I have read protocol ARC001, 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, 56 and 312 
and in the International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) “Guidance for Industry: E6 
Good Clinical Practice Consolidated Guidance” (April 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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CONFIDENTIAL 
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Protocol ARC001 Amendment 3 
Synopsis 
Protocol ARC001 Synopsis 
Title 
Oral Desensitization to Peanut in Peanut-Allergic Children and Adults 
using Characterized Peanut Allergen (CPNA) Peanut Oral 
Immunotherapy (OIT) 
Short Title 
CPNA Peanut OIT 
Clinical Phase 
2 
IND 
15463 
IND Sponsor 
Allergen Research Corporation (ARC) 
Number of Subjects 
Approximately 50 peanut allergic subjects will be randomized 1:1 to peanut 
Oral Immunotherapy (OIT) versus placebo.  
Objective 
The primary objective is to demonstrate the efficacy of Characterized Peanut 
Allergen through reduction in clinical reactivity to limited amounts of peanut 
allergen in peanut-allergic children and young adults (ages 4-26 years, 
inclusive). 
The secondary objectives are: 
• To demonstrate the safety of Characterized Peanut Allergen as 
measured by incidence of adverse events and dosing symptoms. 
• To evaluate the immunological effects of peanut OIT therapy. 
• To determine the time course of tolerated up-dosing 
• To evaluate safety based on physician global assessment of disease 
activity 
Study Design 
This is a multicenter, randomized, double-blind placebo-controlled study of 
efficacy and safety of characterized peanut OIT in peanut allergic 
individuals.  The study will consist of a screening period, a double-blind OIT 
treatment (up-dosing and maintenance) period, followed by a double-blind, 
placebo controlled food challenge (DBPCFC).  An open-label safety follow-
up study (ARC002) is planned after completion of ARC001.  
All eligible subjects will receive an escalating dose of either characterized 
peanut allergen or placebo.  Beginning at Week 22, eligible subjects who 
reach the targeted daily dose of 300 mg/day and maintain that dose for 
2 weeks will undergo a DBPCFC.  Subjects who have not reached 
300 mg/day will continue to up-dose as tolerated until they are eligible for 
the DBPCFC (after 2 weeks home dosing with 300 mg/day) or until they 
reach Week 34, at which time they will be considered an escalation failure. 
A DBPCFC will be performed for those subjects achieving the target dose of 
300 mg and continuing to receive that dose for 2 weeks.  Each subject will be 
unblinded when he/she completes the DBPCFC at the end of 2 weeks 
treatment with 300 mg/day. 
All placebo subjects are eligible for rollover into the ARC002 protocol. 
Placebo subjects in ARC002 will undergo an escalation schedule identical to 
that for active subjects in the ARC001 protocol.  All subjects on active 
treatment who pass the DBPCFC are eligible to proceed to ARC002.  Those 
who do not pass will be considered endpoint failures. 
A Data Monitoring Committee (DMC) has been established for the study to 
monitor the study for safety.   
Study Duration 
6 to 9 months 
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Protocol ARC001 Amendment 3 
Protocol ARC001 Synopsis 
Title 
Oral Desensitization to Peanut in Peanut-Allergic Children and Adults 
using Characterized Peanut Allergen (CPNA) Peanut Oral 
Immunotherapy (OIT) 
Primary Endpoint 
The primary clinical efficacy endpoint is the proportion of subjects who 
tolerate at least 300 mg (443 mg cumulative) of peanut protein with no more 
than mild symptoms at the exit DBPCFC 
Secondary Endpoints 
• 
Change from baseline in tolerated dose of peanut protein at 
DBPCFC 
• 
Maximum dose achieved with no or mild symptoms at exit 
DBPCFC 
• 
Physician global assessment: Disease activity as measured on a 
100 mm visual analogue scale (VAS) 
• 
Changes in peanut-specific IgE and IgG4, changes in skin prick test 
(SPT) mean wheal diameters 
• 
The safety of peanut OIT based on dosing symptoms and reported 
adverse events (AEs) including serious adverse events (SAEs) 
Study Product and 
Design 
Characterized Peanut Allergen (CPNA) 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 
break-apart capsules formulated to contain 0.5, 1.0, 10, and 100 mg of 
peanut protein. Matching placebo capsules identical to the active capsules 
will be used to maintain double-blinded conditions. An unblinded clinical 
site pharmacist will dispense the study products to the investigational site in 
a manner consistent with the current dose level and treatment assignment 
without breaking the blind for the subjects and the other study personnel. 
Inclusion Criteria 
• 
Age 4 through 26 years 
• 
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 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 (ie, above the age 
of 7 years) 
• 
Use of birth control by female subjects of child-bearing potential 
• 
Should not be residing in the same address as another subject in this 
study 
• 
Cannot have participated in a clinical trial 30 days prior to 
randomization 
Exclusion Criteria 
• 
History of cardiovascular disease 
• 
History of frequent or repeated, severe or life-threatening episodes 
of anaphylaxis or anaphylactic shock 
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Protocol ARC001 Amendment 3 
Protocol ARC001 Synopsis 
Title 
Oral Desensitization to Peanut in Peanut-Allergic Children and Adults 
using Characterized Peanut Allergen (CPNA) Peanut Oral 
Immunotherapy (OIT) 
• 
History of other chronic disease (other than asthma, atopic 
dermatitis, or rhinitis) requiring therapy (e.g., heart disease, 
diabetes) 
• 
History of eosinophilic gastrointestinal disease 
• 
Current participation in any other interventional study 
• 
Subject is on ‘build-up phase” of immunotherapy to another 
allergen (i.e., has not reached maintenance dosing) 
• 
Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2) 
• 
Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma, if 
uncontrolled as defined by any of the following: 
 Forced expiratory volume in 1 second  (FEV1) < 80% of 
predicted, or FEV1/FVC < 75%, with or without controller 
medications (only for age 6 or greater and able to do 
spirometry) or 
 Inhaled corticosteroid (ICS) dosing of > 500 mcg daily 
fluticasone (or equivalent ICSs based on National Heart, 
Lung, and Blood Institute [NHLBI] dosing chart) or 
 1 hospitalization in the past year for asthma or  
 Emergency Room (ER) visit within 6 months 
• 
History of steroid medication use (via intravenous [IV], 
intramuscular [IM] or oral administration) in any of the following 
manners:  
 daily oral steroid dosing for >1 month during the past year 
or 
 burst or steroid course in the past 3 months or 
 >2 burst oral steroid courses in the past year ≥1 week in 
duration 
• 
Inability to discontinue antihistamines 5 half-lives before the initial 
day of escalation, skin testing or DBPCFC 
• 
Lack of an available palatable vehicle food to which the subject is 
not allergic 
• 
Use of omalizumab within the past 6 months, or current use of other 
investigational forms of allergen immunotherapy (eg, oral or 
sublingual) or immunomodulator therapy (not including 
corticosteroids) 
• 
Use of beta-blockers (oral), angiotensin-converting enzyme (ACE) 
inhibitors, angiotensin-receptor blockers (ARB) or calcium channel 
blockers 
• 
Pregnancy or lactation 
• 
Having the same place of residence as another subject in the study 
• 
Participation in another clinical trial within 30 days prior to 
randomization 
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Protocol ARC001 Amendment 3 
Protocol ARC001 Synopsis 
Title 
Oral Desensitization to Peanut in Peanut-Allergic Children and Adults 
using Characterized Peanut Allergen (CPNA) Peanut Oral 
Immunotherapy (OIT) 
Treatment Description 
Screening/baseline: All eligible subjects will undergo a DBPCFC of up to 
100 mg (143 mg cumulative) peanut protein or placebo during the screening 
portion of the study.  The screening DBPCFC will be an abbreviated version 
of the DBPCFC described in the PRACTALL guidelines using up to 100 mg 
(143 mg cumulative) 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 at or 
before the 100 mg (143 mg cumulative) dose of peanut protein (measured as 
200 mg of peanut flour) will be randomized 1:1 to active treatment or 
placebo.   
Up-dosing OIT treatment: Subjects will receive daily oral dosing of peanut 
or placebo OIT for about 6 to 9 months.  All escalation doses (see escalation 
table below) will occur in a clinical research center or other monitored 
setting.  All up-dosing will be performed under direct observation.  Therapy 
details are found in Section 3 and Section 6 of the protocol.  
Exit DBPCFC: After the subjects have been up-dosed to a 300 mg/day dose 
and have continued to receive that dose for at least 2 weeks, subjects will 
undergo a DBPCFC of up to 600 mg (1043 mg cumulative) peanut protein or 
placebo.   
All placebo subjects are eligible for rollover into the ARC002 protocol. 
Placebo subjects in ARC002 will undergo an escalation schedule identical to 
that for active subjects in the ARC001 protocol.  All subjects on active 
treatment who pass the DBPCFC in ARC001 will be eligible for the 
ARC002 study.  
Study Procedures 
The following procedures will be performed according to the scheduled 
visits tabulated in Appendix 1: 
• 
Informed consent 
• 
Inclusion/exclusion criteria 
• 
Medical/Allergy history  
• 
Concomitant medications 
• 
Physical exam, 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 and IgG4  
• 
Optional blood draw (pre-DBPCFC and 5-10 days post-DBPCFC) for 
exploratory analyses by the Immune Tolerance Network (ITN) 
• 
Skin prick test (SPT) 
• 
Clinical research center drug administration 
• 
Dispensing of study drugs for home dosing/Return of unused drugs 
• 
Dose assessment to decide for maintenance or up-dosing 
• 
Peak Expiratory Flow Rate (PFER) prior to any DBPCFC 
• 
Abbreviated double-blind, placebo controlled food challenge (DBPCFC) 
per PRACTALL guidelines 
• 
Physician Global Assessment of Disease Activity 
• 
Monitoring for dosing compliance and symptoms 
• 
Adverse event (AE) monitoring 
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Protocol ARC001 Amendment 3 
 
Protocol ARC001 Synopsis 
Initial Days 1 to 3 (Visit 01) Escalation Schedule 
Dose # 
Study Product Dose 
(mg peanut protein or placebo) 
Cumulative Study Product Dose 
(mg peanut protein or placebo) 
1 
0.5 
0.5 
2 
1.0 
1.5 
3 
1.5 
3.0 
4 
3.0 
6.0 
5 
6.0 
12 
Doses will be delivered at 20 to 30 minute intervals. 
Subjects who are unable to tolerate a dose of 3.0 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 their maximum tolerated dose (3 mg 
or 6 mg) under direct observation. 
Subjects with either no symptoms or mild symptoms on Day 2 at either 3 mg or 6 mg may start daily dosing at their highest 
tolerated level, and will not be required to return for Day 3. 
Subjects who experience moderate or severe symptoms after receiving a 6 mg dose on Day 2 will return on Day 3 to receive 
the next lower dose (3 mg) under direct observation.  
Subjects with moderate or severe symptoms at 3 mg on either Day 2 or Day 3 will be considered escalation failures.   
Future dose escalations will occur every 2 weeks with the initial dose increase administered in the clinical research center. 
Escalation Dosing 
Dose # 
Study Product Dose 
(mg peanut protein or 
placebo) 
Interval (weeks) 
% Increase 
6 
12 
2 
 
7 
20 
2 
67% 
8 
40 
2 
100% 
9 
80 
2 
100% 
10 
120 
2 
50% 
11 
160 
2 
33% 
12 
200 
2 
25% 
13 
240 
2 
20% 
14 
300 
2 
25% 
Capsules are opened, contents sprinkled over an age-appropriate food, and mixed thoroughly. 
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Protocol ARC001 Amendment 3 
Table of Contents 
1. 
BACKGROUND AND RATIONALE ...........................................................................17 
1.1 
BACKGROUND .............................................................................................................. 17 
1.2 
PEANUT OIT ................................................................................................................... 17 
1.3 
RATIONALE FOR SELECTION OF STUDY POPULATION ...................................... 18 
1.4 
RATIONALE FOR SELECTION OF STUDY DRUG REGIMEN ................................ 19 
1.5 
RATIONALE FOR THE DOSE USED FOR THE DBPCFC ......................................... 19 
1.6 
KNOWN AND POTENTIAL RISKS AND BENEFITS TO HUMAN 
PARTICIPANTS .............................................................................................................. 19 
1.6.1 Risks ................................................................................................................................. 19 
1.6.2 Benefits ............................................................................................................................. 20 
2. 
OBJECTIVES ...........................................................................................................20 
2.1 
PRIMARY OBJECTIVE .................................................................................................. 20 
2.2 
SECONDARY OBJECTIVE(S) ....................................................................................... 21 
3. 
STUDY DESIGN .......................................................................................................22 
3.1 
SCREENING PERIOD ..................................................................................................... 22 
3.2 
TREATMENT PERIOD ................................................................................................... 23 
3.3 
EXIT DBPCFC ................................................................................................................. 24 
3.4 
FOLLOW-UP STUDY ARC002 ...................................................................................... 25 
3.5 
STUDY DESIGN SAFETY CONSIDERATIONS .......................................................... 25 
3.6 
PRIMARY EFFICACY ENDPOINT ............................................................................... 25 
3.7 
SECONDARY ENDPOINTS ........................................................................................... 25 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS .....................................................26 
4.1 
INCLUSION CRITERIA ................................................................................................. 26 
4.2 
EXCLUSION CRITERIA ................................................................................................ 26 
4.3 
PREMATURE SUBJECT TERMINATION FROM THE STUDY ................................ 27 
4.3.1 Criteria .............................................................................................................................. 27 
4.3.2 Follow-up of Subjects Who Discontinue Treatment Only ................................................ 28 
5. 
STUDY MEDICATION .............................................................................................28 
5.1 
FORMULATION, PACKAGING AND LABELING ..................................................... 28 
5.2 
PREPARATION, ADMINISTRATION AND DOSAGE................................................ 29 
5.3 
DRUG ACCOUNTABILITY ........................................................................................... 29 
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Protocol ARC001 Amendment 3 
5.4 
ASSESSMENT OF COMPLIANCE WITH STUDY TREATMENT AND 
MONITORING ................................................................................................................. 30 
5.5 
MODIFICATION OF STUDY TREATMENT ................................................................ 30 
5.6 
CONCOMITANT MEDICATIONS ................................................................................ 30 
5.7 
PROPHYLACTIC MEDICATIONS ................................................................................ 30 
5.8 
RESCUE MEDICATIONS ............................................................................................... 30 
5.9 
PROHIBITED MEDICATIONS ...................................................................................... 30 
6. 
STUDY PROCEDURES .............................................................................................31 
6.1 
ENROLLMENT AND RANDOMIZATION ................................................................... 31 
6.2 
SCREENING VISIT (VISIT 00) ...................................................................................... 31 
6.3 
BASELINE VISIT ............................................................................................................ 32 
6.4 
STUDY TREATMENT VISITS ....................................................................................... 32 
6.4.1 Initial Escalation Days 1 to 3 (Visit 01) ............................................................................ 32 
6.4.2 Up-dosing/Escalation visits (Up to 34 weeks post-Visit 01) ............................................ 34 
6.4.3 Visit 02 (after approx. 12 weeks post-Visit 01) ................................................................ 35 
6.5 
VISIT 03 - EXIT VISIT / EARLY DISCONTINUATION VISIT .................................. 35 
6.6 
DOUBLE-BLIND, PLACEBO CONTROLLED FOOD CHALLENGE (DBPCFC) 
IN ACCORDANCE WITH PRACTALL GUIDELINES ................................................ 37 
6.6.1 Screening Double-Blind, Placebo Controlled Food Challenge (DBPCFC) – For All 
Subjects ............................................................................................................................. 37 
6.6.2 Exit Double-Blind, Placebo Controlled Food Challenge (DBPCFC)- For All 
Subjects ............................................................................................................................. 37 
6.7 
PHYSICIAN GLOBAL ASSESSMENT ......................................................................... 38 
6.8 
REACTIONS AND TREATMENT OF REACTIONS .................................................... 38 
6.8.1 Reactions and Treatment of Reactions to Peanut OIT During Initial Escalation ............. 38 
6.8.2 Reactions During Build-up Phase: Preventative and Non-pharmacological 
Interventions ..................................................................................................................... 41 
6.8.3 Treatment for Reactions During the Build-up Phase: Pharmacological and 
Supportive Treatments ...................................................................................................... 45 
6.8.4 Reactions During Maintenance Phase .............................................................................. 46 
6.9 
MISSED PEANUT OIT DOSES AT ANY PHASE OF THE STUDY: .......................... 50 
6.10 
DOUBLE-BLIND PLACEBO CONTROLLED FOOD CHALLENGE ......................... 50 
6.11 
SKIN PRICK TEST .......................................................................................................... 51 
6.12 
VISIT WINDOWS ........................................................................................................... 51 
6.13 
STUDY BLINDING PROCEDURES .............................................................................. 51 
6.13.1 Securing Blinding and Randomization Information ......................................................... 51 
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6.13.2 Requirements for an Unblinding ....................................................................................... 51 
6.13.3 Breaking the Blind ............................................................................................................ 51 
6.13.4 Documenting an Unblinding ............................................................................................. 52 
7. 
SAFETY MONITORING ...........................................................................................52 
7.1 
DEFINITIONS FOR RECORDING OF SAFETY EVENTS .......................................... 52 
7.2 
FOOD ALLERGY EPISODES ........................................................................................ 52 
7.3 
DEFINITIONS .................................................................................................................. 53 
7.3.1 Adverse Event (AE) or Medical Event ............................................................................. 53 
7.3.2 Serious Events (Serious Adverse Events, Serious Suspected Adverse Reactions or 
Serious Adverse Reactions) .............................................................................................. 53 
7.3.3 Unexpected Adverse Event ............................................................................................... 53 
7.4 
DATA MONITORING COMMITTEE ............................................................................ 54 
7.5 
TOXICITY GRADING .................................................................................................... 54 
7.5.1 Guidelines for Determining Causality of an Adverse Event ............................................. 55 
7.6 
ADVERSE EVENTS COLLECTION PROCEDURES ................................................... 55 
7.6.1 Recording and Reporting Procedures ............................................................................... 55 
7.6.2 SAE Recording and Reporting Procedures ....................................................................... 55 
7.6.2.1 Reporting Criteria ............................................................................................................ 56 
7.7 
SERIOUS ADVERSE EVENT NOTIFICATION ........................................................... 57 
7.7.1 Notifying the Sponsor ....................................................................................................... 57 
7.7.2 Notifying the Data Monitoring Committee ....................................................................... 57 
7.7.3 Notifying the Institutional Review Board and Ethics Committee .................................... 57 
7.8 
OTHER SAFETY ASSESSMENTS ................................................................................ 58 
7.8.1 Physical Examination and Vital Signs .............................................................................. 58 
7.8.2 Prior and Concomitant Medications ................................................................................. 58 
7.8.3 Pregnancy Test .................................................................................................................. 58 
7.9 
STOPPING RULES .......................................................................................................... 58 
7.9.1 Overall Stopping Rules ..................................................................................................... 58 
7.9.2 Individual Stopping Rules ................................................................................................ 58 
8. 
MECHANISTIC ASSAYS ..........................................................................................59 
8.1 
PEANUT-SPECIFIC ANTIBODY .................................................................................. 59 
9. 
STATISTICAL CONSIDERATIONS ...........................................................................59 
9.1 
STUDY ENDPOINT ASSESSMENT .............................................................................. 59 
9.1.1 Primary Endpoint .............................................................................................................. 59 
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Protocol ARC001 Amendment 3 
9.1.2 Secondary Endpoints ........................................................................................................ 59 
9.2 
SUBJECT AND DEMOGRAPHIC DATA ...................................................................... 60 
9.2.1 Baseline Characteristics and Demographics ..................................................................... 60 
9.2.2 Use of Medications ........................................................................................................... 60 
9.2.3 Study Completion ............................................................................................................. 60 
9.3 
SAMPLE SIZE AND POWER CALCULATIONS ......................................................... 60 
10. 
IDENTIFICATION AND ACCESS TO SOURCE DATA ................................................61 
10.1 
WEB-BASED DATA COLLECTION AND MANAGEMENT SYSTEM ..................... 61 
10.2 
CERTIFICATION IN THE USE OF WEB-BASED DATA ENTRY SYSTEM ............ 61 
10.3 
DATA MANAGEMENT ................................................................................................. 61 
10.4 
ACCESS TO DATA ......................................................................................................... 61 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ..................................................61 
11.1 
STATEMENT OF COMPLIANCE .................................................................................. 61 
11.2 
INFORMED CONSENT/ASSENT .................................................................................. 62 
11.3 
PRIVACY AND CONFIDENTIALITY .......................................................................... 62 
12. 
RESOURCE SHARING .............................................................................................62 
13. 
PROTOCOL DEVIATIONS .......................................................................................62 
13.1 
MAJOR PROTOCOL DEVIATION (PROTOCOL VIOLATION) ................................ 62 
13.2 
NON-MAJOR PROTOCOL DEVIATION ...................................................................... 63 
13.3 
REPORTING AND MANAGING PROTOCOL DEVIATIONS .................................... 63 
14. 
REFERENCE LIST ...................................................................................................64 
APPENDIX 1: SCHEDULE OF EVENTS .................................................................................66 
APPENDIX 2: EVALUATION OF ASTHMA ...........................................................................68 
APPENDIX 3: ANAPHYLAXIS STAGING SYSTEM ................................................................69 
APPENDIX 4: ALLERGIC REACTION TOXICITY GRADING ................................................70 
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Protocol ARC001 Amendment 3 
List of Figures 
Figure 3–1. 
Study Design ....................................................................................................... 22 
Figure 6–1. 
Schematic for Initial (Visit 01) Day Escalation .................................................. 48 
Figure 6–2. 
Schematic for Build Up Phase Dose Escalation – Day of Symptom ................... 49 
Figure 7–1. 
Reporting Decisions for Adverse Events ............................................................. 56 
 
List of Tables 
Table 3-1. 
Initial Dosing Schedule for Peanut OIT .............................................................. 23 
Table 3-2. 
Escalation Dosing Schedule for Peanut OIT ....................................................... 23 
Table 6-1. 
PRACTALL DBPCFC Doses Using Peanut Flour with 50% Peanut 
Protein Content for Screening DBPCFC ............................................................ 37 
Table 6-2. 
Doses Using Peanut Flour with 50% Peanut Protein Content for Exit 
DBPCFC .............................................................................................................. 38 
 
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Protocol ARC001 Amendment 3 
Glossary of Abbreviations 
Abbreviation 
Definition 
ACE 
Angiotensin-converting enzyme inhibitors 
AE 
Adverse Event 
Ag 
Antigen 
ARB 
Angiotensin-receptor blockers 
ARC 
Allergen Research Corporation 
BP 
Blood Pressure 
CFR 
US Code of Federal Regulations 
CoFAR 
Consortium of Food Allergy Research 
CPNA 
Characterized Peanut Allergen 
CRC 
Clinical Research Center 
CRF 
Case Report Form 
CTC 
Common Toxicity Criteria 
DBPCFCs  
Double-Blind, Placebo-Controlled Food Challenges 
DMC 
Data Monitoring Committee 
EC 
Exposure Challenge 
ELISA 
Enzyme-linked immunosorbent assays 
EoE 
Eosinophilic Esophagitis 
ER 
Emergency Room 
FDA 
US Food and Drug Administration 
FEV1 
Forced Expiratory Volume 
GCP / cGCP 
Good Clinical Practice  / Current Good Clinical Practice 
GI 
Gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HPLC 
High-performance liquid chromatography  
ICH 
International Conference on Harmonisation 
ICS 
Inhaled corticosteroid(s) 
IFNg 
Interferon Gamma 
IgA 
Immunoglobulin A 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IL 
Interleukin 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITN 
Immune Tolerance Network 
IV 
Intravenous 
kUA/L 
Kilounits of Antibody per Liter 
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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes for Health 
OIT 
Oral Immunotherapy 
PEFR 
Peak Expiratory Flow Rate 
PI 
Principal Investigator 
PR 
Pulse Rate 
PRACTALL 
PRACtical issues in ALLergology Joint United States/European Union 
Initiative 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SLIT 
Sublingual Immunotherapy 
SPT 
Skin Prick Test 
SUSAR 
Suspected /Unexpected Serious Adverse Reaction 
Th1 
T Helper 1 
Th2 
T Helper 2 
TLR 
Toll-like Receptor 
Tr1 
T Regulatory 1 
Tregs 
Regulatory T cells 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
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1. 
Background and Rationale 
1.1 
Background 
Peanut allergy is a common and serious condition that disproportionately affects children, 
and is commonly associated with severe reactions, including life-threatening anaphylaxis.  
The current standard of care in management of food allergy is dietary avoidance of the 
food, and education of the subject/family in the acute management of an allergic reaction.  
The burden of avoidance and constant fear of accidental exposure negatively affects the 
health-related quality of life for both subjects and their families.1,2,3 
 
Currently, the only treatment for peanut allergy is a peanut-free diet and ready access to 
self-injectable epinephrine. However, strict avoidance diets can be complicated due to 
difficulty in interpreting food labels4 and by the presence of undeclared or hidden 
allergens in commercially prepared foods.5,6  Accidental ingestions are unfortunately 
common, with up to 50% of food-allergic patients having at least one allergic reaction 
over a two-year period.7  
 
Allergic reactions to peanut can be severe and life-threatening; and peanut and/or tree nut 
allergies account for the vast majority of fatal food-induced anaphylaxis.8  This 
combination of strict avoidance diets, the high incidence of accidental exposures, and the 
risk of severe or even fatal reactions with accidental exposures adds a tremendous burden 
and stress on patients and their families. 
 
Specific immunotherapy for food allergy, in particular for peanut allergy, in the forms of 
oral immunotherapy (OIT) and sublingual immunotherapy (SLIT), has been studied in 
recent years and has demonstrated encouraging safety and efficacy results in early 
clinical trials, including beneficial immunologic changes.9-18  There is evidence that OIT 
may induce desensitization in most subjects, with immunologic changes over time 
indicating progression toward clinical tolerance.15,19-22 
 
The goal of this program is to induce a state of desensitization to peanut protein defined 
as the absence of moderate or severe reaction following ingestion of a specific dose of 
peanut protein.  This state of desensitization should be sufficient to protect a subject with 
peanut allergy from an accidental exposure to a small amount of peanut protein while 
maintaining a peanut restricted diet.  Protection to a whole peanut, approximately 250 mg 
of peanut protein (measured as 500 mg of peanut flour), would afford a meaningful level 
of clinical protection against accidental exposure to peanut protein, since accidental 
exposures are typically to only small amounts of the allergen.23 
 
1.2 
Peanut OIT 
Varshney et al15 conducted a double-blind placebo controlled study of an OIT protocol in 
subjects with severe allergy to peanut protein and consistently demonstrated an increase 
in the dose of allergen tolerated by the subjects versus baseline with a good safety profile. 
 
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In addition, peanut OIT has been administered under IND (Investigational New Drug 
Application) at Duke and Arkansas and under a separate IND at Stanford.*  A total of 44 
cases from Duke/Arkansas were analyzed and 14 cases from Stanford. Efficacy was 
demonstrated in 26 cases (17 active and 9 placebo) matching the published information. 
Sixteen out of 17 active subjects were escalated to a dose between 2400 and 4000 mg 
over a year. Oral food challenge results were significantly better for the active treatment 
group than the placebo group where both groups tolerated a mean of 12 mg of peanut 
protein at baseline, while at one year the mean for the active treatment group was 
5000mg of protein and for the placebo group 280 mg of peanut protein (P < 0.001 by 
Wilcoxon rank-sum test).15 
 
Dosing symptoms were typical for OIT protocols including rash, wheezing, rhinorrhea, 
sneezing, itching, abdominal pain, nausea, vomiting, and diarrhea. Symptoms were noted 
in both the active treatment and the placebo group.  Of the 39 cases on active treatment, 
4 doses of epinephrine were administered – 2 during dosing and 2 during double-blind, 
placebo controlled food challenges (DBPCFCs).  The Stanford data reported on 
14 subjects who were dosed with peanut OIT and dosing symptoms severity and rate 
were similar to those reported in the Duke/Arkansas data. 
 
These published findings, along with the additional clinical data, are the basis for a 
Phase II trial to investigate peanut OIT for efficacy and safety in desensitizing peanut 
allergic subjects.  Protocol ARC001 is designed to be a double-blinded, placebo-
controlled study establishing the efficacy of CPNA for conducting oral immunotherapy.  
Protocol ARC002 and any additional follow-on studies will be related but separate open-
label protocols designed to demonstrate the safety of daily dosing with CPNA for an 
extended period (months to years), to confirm unblinded the efficacy of OIT with CPNA 
at a dose of 300 mg/d of peanut protein in the former ARC001 placebo population, to 
provide an option to explore unblinded the safety and tolerability of OIT, and to maintain 
any desensitization that may have been achieved by subjects. 
 
1.3 
Rationale for Selection of Study Population 
The study will enroll approximately 50 subjects from 4 to 26 years of age with a history 
of allergy to peanuts or peanut-containing foods.  All subjects enrolled must undergo an 
initial DBPCFC to peanut that must be positive at or before the 100 mg (143 mg 
cumulative) dosing level of peanut protein (measured as 200 mg of peanut flour with 
50% protein content) in accordance with PRACTALL (Practical Issues in Allergology, 
Joint United States/European Union Initiative) consensus guidelines,24 regardless of how 
they were initially diagnosed as peanut allergic. This will enroll subjects who are 
sensitive to peanut exposure and expected to benefit from desensitization to the 
equivalent of a whole peanut, and corresponds to a specific level of allergen exposure 
* Data, provided courtesy of Wesley Burks of the University of North Carolina (formerly of Duke 
University Medical Center), Stacie Jones of University of Arkansas for Medical Sciences, and Kari 
Nadeau of Stanford University School of Medicine, on file at Allergen Research Corporation and 
summarized in a report, “Study Report for Clinical Trial Data Collected Under IND for Peanut Oral 
Immunotherapy,” prepared by a third-party vendor, The EMMES Corporation (Rockville, MD). 
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conducted during the enrollment oral food challenge.  The patients generally most 
severely affected by ingestion of peanut allergen are very young children; however, 
young children have limited ability to reliably follow a study protocol. Thus, 4 years of 
age was selected as the lower cutoff age for this study.25  The upper age limit of 26 years 
was selected to insure that the subjects do not have underlying concomitant conditions 
that could preclude the use of epinephrine in subjects exposed to the risk of anaphylaxis.   
 
1.4 
Rationale for Selection of Study Drug Regimen 
The rationale for dosing builds on the work of the Consortium of Food Allergy Research 
(CoFAR) and its investigators.  The dosing consists of a single-day initial escalation at 
very low doses, followed by a build-up phase of dose escalation, with a single escalation 
occurring every 2 weeks.  This has been demonstrated to be well tolerated and efficacious 
in previous studies and will be used in this current trial.26  
 
1.5 
Rationale for the Dose Used for the DBPCFC 
The study DBPCFC will be conducted in accordance with the recommended 
PRACTALL guidelines although the screening DBPCFC will not exceed the 100 mg 
(143 mg cumulative) dose to assess inclusion criteria, and the exit DBPCFC will not go 
above a 600 mg (1043 mg cumulative) dose to help ensure patient safety.  Additionally, 
the DBPCFCs will progress through the dose levels in an unaltered sequence without 
repeating any dose. 
 
The exit DBPCFC will assess protection against slightly more than 1 peanut’s worth of 
peanut protein 300 mg (≥443 mg cumulative dose) since accidental exposures typically 
occur to limited amounts of allergen.  To assess further desensitization, patients tolerating 
the 300 mg (443 mg cumulative) incremental dose will also be challenged with 600 mg 
(1043 mg cumulative), although not up to the 3000 mg dose (4443 mg cumulative), since 
at this point they will have been up-dosed only to the 300 mg dose level.  
 
Since subjects are enrolled only if they are sensitive to ≤100 mg level (143 mg 
cumulative) peanut protein on the screening DBPCFC, this would represent a 10x 
increase in the incremental dose tolerated (and 10.3x increase in cumulative dose) which 
would be in line with the previous demonstration of a 10x total increase, although this 
was after treatment for 1 year, and to larger amounts of peanut protein. A DBPCFC 
started at a very low dose is conducted to confirm that spontaneous desensitization has 
not occurred.   
 
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. 
 
In subjects with peanut allergy, there have been many oral immunotherapy studies 
performed using procedures and dosing similar to those proposed in this Phase 2 study.  
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In general, safety profile has been very good across the studies, and based on those 
studies, approximately 80%, 15%, and <1% of the subjects are expected to have a mild, 
moderate or severe symptoms, respectively, during some point in their dosing with the 
peanut immunotherapy.  It is important to note that essentially all adverse events have 
been allergy-related, predictable, and reversible.  The major atypical adverse event from 
peanut OIT that has been reported in the literature is a single case of eosinophilic 
esophagitis, reversible upon stopping dosing. 
 
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 characterized peanut 
allergen and by buildup of dosing under observation in a clinical setting until the 
maintenance dose is achieved. 
 
Oral food challenges may induce an allergic response.  Allergic reactions can be severe, 
including life-threatening allergic reactions; however, the risk of an allergic reaction is 
reduced by initiating the challenge with a very small amount of the food, gradually 
increasing the dose, and stopping the challenge at the first sign of a reaction.  If subjects 
have an allergic reaction during the challenges, they may need oral, 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.  The anticipated rate of serious life-
threatening anaphylactic reactions would be < 0.1%. 
 
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 Characterized Peanut Allergen 
through reduction in clinical reactivity to limited amounts of peanut allergen in peanut-
allergic children and young adults (ages 4-26 years, inclusive). 
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2.2 
Secondary Objective(s) 
The secondary objectives are: 
• To demonstrate the safety of Characterized Peanut Allergen as measured by 
incidence of adverse events and dosing symptoms. 
• To evaluate the immunological effects of peanut OIT therapy. 
• To determine the time course of tolerated up-dosing 
• To evaluate safety based on physician global assessment of disease activity 
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3. 
Study Design 
ARC001 is a multi-center, randomized, double-blind placebo-controlled study. The study 
design is illustrated in Figure 3–1. 
Figure 3–1. 
Study Design 
 
 
3.1 
Screening period 
Subjects age 4 to 26 years with 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 will be 
screened.  All eligible subjects will undergo an initial DBPCFC at screening.  The 
DBPCFC will include both a peanut challenge and a placebo challenge.  The screening 
DBPCFC will be an abbreviated version of the DBPCFC described in the PRACTALL 
guidelines using up to 100 mg (143 mg cumulative) peanut protein and placebo. 
 
Those who have dose-limiting symptoms at or before the 100 mg (143 mg cumulative) 
dose of peanut protein (measured as 200 mg of peanut flour) will be enrolled into the 
study, since they would be expected to benefit from protection against limited amounts of 
allergen exposure.  Those who successfully consume a dose of >100 mg or more of 
peanut protein during the screening DBPCFC will be considered to be screen failures and 
will not be randomized. 
 
Any subject who is assessed to have had dose-limiting symptoms to both parts of the 
screening DBPCFC (i.e., to oat flour as well as peanut flour) will be considered to be a 
screen failure and will not be randomized. 
 
Approximately 50 subjects who pass screening will be randomized 1:1 to either active 
peanut protein or placebo using TEMPO™’s password-protected Interactive Web 
Response System (IWRS) provided by Clinipace Worldwide.   
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3.2 
Treatment period 
The treatment build-up phase will start with an initial escalation at the study center, 
followed by up-dosing for approximately 24 weeks.  The treatments will be conducted in 
a double-blind fashion.  An unblinded clinical site pharmacist will prepare the study 
medications at different doses according to each subject’s treatment assignment.  The 
subjects and the rest of the study personnel will be blinded to the treatment assignments. 
 
After the initial escalation visit (comprising 2 or 3 days), subjects will report to the study 
center every 2 weeks to escalate their OIT dose, up to an expected daily dose of 
300 mg/day of peanut protein in subjects able to tolerate the up-dosing. The dosing 
escalation schedule is described in detail in Table 3-1 and Table 3-2. 
Table 3-1. 
Initial Dosing Schedule for Peanut OIT 
Initial Days 1 to 3 (Visit 01) Escalation Schedule 
Dose # 
Study Product Dose 
(mg peanut protein or placebo) 
Cumulative Study Product Dose 
(mg peanut protein or placebo) 
1 
0.5 
0.5 
2 
1.0 
1.5 
3 
1.5 
3.0 
4 
3.0 
6.0 
5 
6.0 
12 
Doses will be delivered at 20 to 30 minute intervals. 
Subjects who are unable to tolerate a dose of 3.0 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 their 
maximum tolerated dose (3 mg or 6 mg) under direct observation. 
Subjects with either no symptoms or mild symptoms on Day 2 at either 3 mg or 6 mg may start daily 
dosing at their highest tolerated level, and will not be required to return for Day 3. 
Subjects who experience moderate or severe symptoms after receiving a 6 mg dose on Day 2 will 
return on Day 3 to receive the next lower dose (3 mg) under direct observation.  
Subjects with moderate or severe symptoms at 3 mg on either Day 2 or Day 3 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. 
Escalation Dosing Schedule for Peanut OIT 
Escalation Dosing 
Dose # 
Study Product Dose 
(mg peanut protein/day  or 
placebo) 
Interval 
(weeks) 
% Increase 
6 
12 
2 
 
7 
20 
2 
67% 
8 
40 
2 
100% 
9 
80 
2 
100% 
10 
120 
2 
50% 
11 
160 
2 
33% 
12 
200 
2 
25% 
13 
240 
2 
20% 
14 
300 
2 
25% 
Capsules are to be opened, contents sprinkled over an age-appropriate food, and mixed thoroughly. 
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All subjects who reach and tolerate 300 mg/day for 2 weeks will undergo an exit 
DBPCFC.  Those unable to achieve a dose of 300 mg/day of peanut protein by 34 weeks 
will be considered escalation failures and will not undergo an exit DBPCFC. 
 
During the treatment period, the subjects will be monitored for tolerability as illustrated 
in Figure 6–1 and Figure 6–2 (see Section 6.8.4).   
 
If a subject is removed from therapy because of failing escalation during the initial 
escalation period (Visit 1; Days 1 to 3), the subject will be followed for safety and asked 
to return to the Clinical Research Center 14 days following their last dose of study 
product to undergo an Early Discontinuation Visit (see  Section 6.5).   
 
If a subject’s up-dosing is halted because of failing subsequent build-up (i.e., after the 
initial escalation period; Visit 1), the subject will continue to be dosed at the last tolerated 
dose level and to be followed for safety biweekly (following their established visit 
schedule) until Week 24, i.e., a maintenance phase (See also Section 6.8.4).  Dosing will 
be stopped after the Week 24 Visit; and the subject will be asked to return to the Clinical 
Research Center 14 days following their last dose of study product to undergo an Early 
Discontinuation Visit (see Section 6.5).   
 
For subjects who halt dose-escalation after Week 24, there will be no maintenance phase.  
Dosing in these subjects will be discontinued when dose-escalation is stopped.  They will 
be followed for safety and asked to return to the Clinical Research Center 14 days 
following their last dose of study product to undergo an Early Discontinuation Visit (see 
Section 6.5).   
 
For subjects who achieve the targeted dose of 300 mg/d by Week 34, the maintenance 
phase comprises the last two weeks of the study. 
 
Subjects who prematurely discontinue treatment before Week 24 for any reason will be 
brought in for an early discontinuation visit 14 days after their last dose. 
 
A Data Monitoring Committee (DMC) has been established and will meet every 
3 months to monitor the study for safety.   
 
3.3 
Exit DBPCFC 
All subjects who reach the targeted daily dose of 300 mg/day and maintain that dose for 
2 weeks will undergo an exit DBPCFC. The exit DBPCFC will be performed in 
accordance with PRACTALL guidelines, but requiring progression in an unaltered 
sequence (Table 6-2), without repeating any dose.   
 
Each subject will be unblinded after he/she completes the DBPCFC. 
 
Subjects who do not reach the target dose by Week 34 are not eligible for the exit 
DBPCFC, and will be considered escalation failures.  They will be unblinded no sooner 
than Week 24. 
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All placebo subjects are eligible for rollover into ARC002.  Placebo subjects enrolled in 
ARC002 will undergo an escalation schedule identical to that for active subjects in the 
ARC001 protocol.  All subjects on active treatment who pass the DBPCFC are eligible to 
proceed to ARC002.  Subjects in the active treatment group who do not pass the 
DBPCFC at the 300 mg (443 mg cumulative) protein level will be considered endpoint 
failures and will not be eligible for rollover into the ARC002 protocol.  
 
3.4 
Follow-up Study ARC002 
All placebo subjects are eligible for rollover into ARC002. Placebo subjects enrolled in 
ARC002 will undergo an escalation schedule identical to that for active subjects in the 
ARC001 protocol. All subjects on active treatment who successfully complete the 
ARC001 DBPCFC are eligible to proceed to ARC002 and continue dosing, with an 
opportunity for additional up-dosing. 
 
3.5 
Study Design Safety Considerations 
The study design considers important safety issues: 
 
• All dose escalations will be supervised in the clinic 
• The peanut OIT will only escalate to a maximum 6 mg single dose during the 
initial escalation on Day 1 
• Dosing symptoms and adverse events 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. 
 
3.6 
Primary Efficacy Endpoint 
The primary clinical efficacy endpoint is the proportion of subjects in each group who 
tolerate at least 300 mg (443 mg cumulative) of peanut protein with no more than mild 
symptoms at the exit DBPCFC. 
 
3.7 
Secondary Endpoints 
The secondary endpoints are as follows: 
• Change from baseline in tolerated dose of peanut protein at DBPCFC 
• Maximum dose achieved with no or mild symptoms at exit DBPCFC 
• Physician global assessment: Disease activity as measured on a 100-mm visual 
analogue scale (VAS) 
• Changes in peanut-specific IgE and IgG4, changes in SPT mean wheal diameters.  
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• The safety of peanut OIT as measured through dosing symptoms, adverse events 
(AEs), and serious adverse events (SAEs). 
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 26 years  
2. Clinical history of allergy to peanuts or peanut-containing foods 
3. Serum IgE to peanut of > 0.35 kUA/L [determined by the UniCAPTM automated 
immunoassay system within the past 12 months] and/or a SPT to peanut > 3mm 
compared to control 
4. Experience dose-limiting symptoms at or before the 100 mg (143 mg cumulative) 
dose of peanut protein (measured as 200 mg of peanut flour) or on screening 
DBPCFC conducted in accordance with PRACTALL guidelines 
5. Written informed consent from parent/guardian for minor subjects 
6. Written assent from minor subjects as appropriate (e.g., above the age of 7 years) 
7. Use of birth control by female subjects of child-bearing potential 
8. Should not be residing in the same address as another subject in this study 
9. Cannot have participated in a clinical trial 30 days prior to randomization 
 
4.2 
Exclusion Criteria 
Subjects who meet any of these criteria are not eligible for enrollment as study subjects: 
 
1. History of cardiovascular disease 
2. History of frequent or repeated, severe or life-threatening episodes of anaphylaxis 
or anaphylactic shock 
3. History of other chronic disease (other than asthma, atopic dermatitis, or rhinitis) 
requiring therapy (e.g., heart disease, diabetes) 
4. History of eosinophilic gastrointestinal disease 
5. Current participation in any other interventional study 
6. Subject is on ‘build-up phase” of immunotherapy for another allergen (i.e., has 
not reached maintenance dosing) 
7. Severe asthma (2007 NHLBI Criteria Steps 5 or 6, see Appendix 2) 
8. Mild or moderate (2007 NHLBI Criteria Steps 1-4) asthma, if uncontrolled as 
defined by any of the following: 
• FEV1 < 80% of predicted, or FEV1/FVC < 75%, with or without controller 
medications (only for age 6 or greater and able to do spirometry†) or 
† Spirometry is to be attempted in all subjects ≥ 6 years of age. For subjects ages 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. The attempt must be documented, and a clinical assessment is required. 
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• ICS dosing of > 500 mcg daily fluticasone (or equivalent inhaled 
corticosteroids based on NHLBI dosing chart) or 
• 1 hospitalization in the past year for asthma or  
• ER visit within six months 
9. Use of steroid medications (IV, IM or oral) in the following manners: 
• history of daily oral steroid dosing for >1 month during the past year or 
• burst or steroid course in the past 3 months prior to inclusion or 
• >2 burst oral steroid course in the past year of at least one 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 omalizumab within the past six months, or current use of other 
investigational forms of allergen immunotherapy (e.g., oral or sublingual) or 
immunomodulator therapy (not including corticosteroids) 
13. Use of beta-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, 
angiotensin-receptor blockers (ARB) or calcium channel blockers 
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 prior to randomization 
 
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 (i.e., 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 24. 
Any subject may be prematurely terminated from additional allergen exposures for the 
following reasons: 
1. Life-threatening symptoms (CoFAR Grade 4; refer to Table A4-3 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 A4-3 in Appendix 4), 
including, but not limited to, those that require aggressive 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 
3. Poor control or persistent activation of secondary atopic disease (e.g., atopic 
dermatitis, asthma)  
4. Started on ARBs, ACE, beta-blockers, or other prohibited medications, with no 
alternative medications available per the prescribing doctor 
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5. Pregnancy  
6. Circumstances (e.g., concurrent illness, such as gastroenteritis) requiring missed 
peanut OIT maintenance dosing of > 7 consecutive days  
7. Non-adherence with home peanut OIT dosing protocol (excessive missed days; 
i.e., > 3 consecutive days missed on 3 or more occasions) would be a safety issue 
warranting discontinuation 
 
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” (i.e., 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 Only 
Subjects who prematurely discontinue treatment will be brought in for an early 
discontinuation visit 14 days after their last dose of study product.  If possible, subjects 
will be monitored for safety until they come back for their Early Discontinuation Visit. 
 
5. 
Study Medication 
5.1 
Formulation, Packaging and Labeling 
The active study product 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, 1.0, 10 and 100 mg each of peanut protein, with an 
HPLC fingerprint and specific ELISAs performed against key allergenic proteins to 
demonstrate stability and lot-to-lot comparability.  Placebos, containing excipients only, 
will be provided as matching capsules which are identical to the active capsules. 
 
All study products (both peanut allergen and placebos) will be packaged and labeled at 
the central manufacturer.  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 site pharmacist for distribution to the site study 
personnel.  The unblinded clinical site pharmacist will dispense study products to the 
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investigational site in a manner consistent with the current dose level and treatment 
assignment without breaking the blind for the subjects and the other study personnel.  
 
All study products will be stored in a secure location and kept refrigerated between 2°C 
and 8°C. 
 
5.2 
Preparation, Administration and Dosage 
The pre-packaged study product will be provided from the site pharmacy in appropriate 
doses to deliver the specified dose as outlined in Section 3.  The capsules should be 
drawn apart, and gently rolled between finger and thumb, followed by a light tap to 
ensure full delivery of contents.  The contents of the capsules will be mixed with a 
vehicle food, such as apple sauce, yogurt, pudding, or other age-appropriate food.  The 
food may not be heated before consumption, and must also be one to which the subject is 
not additionally allergic.  The product must be consumed promptly after mixing.  If there 
is a delay of more than 24 h in consumption, the product will be discarded and a new 
product dose mixed and consumed.  Every attempt will be made to administer the dose of 
study product at the same time of day.  A target interval of at least 12 h should pass 
between doses.  
 
Active and placebo capsules are identical in appearance but there are slight differences 
between the colors (from off-white to beige) of the contents of the capsule depending on 
the dose.  The unblinded pharmacist will prepare the capsules according to the needed 
dose per subject, and will not transmit the treatment assignment to the study investigator 
or study staff.  The subjects or supervising adult will mix the provided capsule contents 
with the vehicle food. 
 
At each clinic visit, each subject will receive a set of capsules to be taken at home 
according to their specific dose level while maintaining treatment blinding.  The subjects 
should be instructed to document capsules taken at home using diary logs and bring all 
unused capsules back to the clinic at every visit. 
 
5.3 
Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator is 
required to maintain adequate records of the disposition of the investigational agent, 
including the date and quantity of the drug 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.  Families will be provided with 
24-h emergency contact information from each site. 
 
All unused study medication should be brought back to the clinic with each visit for 
reconciliation of remaining capsules.  
 
5.5 
Modification of Study Treatment  
As described in the protocol (Section 6.8), peanut OIT doses may be adjusted by the 
study physician if the subject is unable to tolerate the scheduled dose increase.  If such a 
dose modification occurs, the subject will return all unused capsules of study medication 
during the dose adjustment visit, and be dispensed capsules at the adjusted dose level. 
 
5.6 
Concomitant Medications 
Except as indicate in Section 5.9, 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 5 half-lives prior to the initial 
day of escalation, skin testing and oral food challenges.  Usual topical steroid use is 
permitted at the time of skin testing.   
 
5.7 
Prophylactic Medications 
None 
5.8 
Rescue Medications 
Treatment of individual allergic reactions during peanut OIT therapy should be with 
either an antihistamine and/or epinephrine, along with IV fluids, albuterol, oxygen, 
and/or steroids, as indicated.  Subjects and parents/guardians are likely to already have an 
epinephrine auto-injection device, but for those who do not, an epinephrine auto-injection 
device will be provided.  Subjects and parents will be trained in proper use and will be 
able to demonstrate proper technique with the epinephrine auto-injection device.  
 
5.9 
Prohibited Medications 
1. Omalizumab (Xolair) 
2. Systemic (oral) corticosteroids used for any greater duration than a total of 
3 weeks 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 
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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 study products provided by the unblinded 
site pharmacist or nutritionist.  Those reacting to <100 mg of peanut protein (143 mg 
cumulative) will be randomized in a 1:1 ratio to peanut OIT or placebo.  Those able to 
successfully consume >100 mg of peanut protein during their DBPCFC will not be 
eligible for the study.  Randomization will be done via TEMPO™.  If accrual capacity is 
adequate, each of the expected 8 sites should enroll approximately 6-8 subjects each.  
Because of the requirement for the peanut DBPCFC, the screening and baseline visits 
may be conducted in more than 1 day. 
 
The study procedures are tabulated in Appendix 1 and are listed per visit below. 
 
6.2 
Screening Visit (Visit 00) 
The screening visits which may occur over several days (Visit 00) will include the 
following procedures:  
 
• Informed consent and assent  
• Inclusion/exclusion criteria 
• Medical and allergy history 
• Concomitant medications 
• Physical examination, including weight and height 
• Vital signs (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 
• Diet history 
• Blood draw for peanut-specific IgE and IgG4 measurement (mechanistic assay), 
the amount to be specified by local laboratory guidelines 
• Optional blood draw (pre-DBPCFC and 5-10 days post-DBPCFC) for exploratory 
analysis by the Immune Tolerance Network (ITN).  The amount taken should be 
5 mL/kg in children weighing ≥30 kg, with a maximum of 60 mL in total. 
• Skin prick test to peanut extract 
• An initial double-blind DBPCFC conducted in accordance with PRACTALL 
guidelines as described in Section 6.6. 
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6.3 
Baseline Visit 
Subjects who meet eligibility criteria will return for a baseline visit.  This visit will 
include the following procedures and will take place over several days:  
 
• Repeat review of informed consent 
• Review of inclusion/exclusion criteria 
• Medical and allergy history 
• Concomitant medications 
• Physical examination, including weight and height 
• Vital signs (blood pressure, pulse rate, body temperature) 
• Spirometry (FEV1) and/or 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. 
• Urine pregnancy test, for females of childbearing potential 
• Optional blood draw (pre- and 5-10 days post-DBPCFC) for exploratory analysis 
by ITN.  The amount taken should be 5 mL/kg in children weighing ≥30 kg, with 
a maximum of 60 mL in total. Blood draw should be completed per National 
Institutes for Health (NIH) guidelines. 
• Physician global assessment of disease activity using a 100-mm VAS 
 
6.4 
Study Treatment Visits  
6.4.1 
Initial Escalation Days 1 to 3 (Visit 01) 
The following assessments will be performed at Visit 01 at the Clinical Research Center: 
 
Day 1 Initial Escalation 
• OIT administration of peanut protein or matching placebo on escalation day 
(Visit 01) with dosing beginning at 0.5 mg ,with graduated doses up to 6.0 mg (if 
tolerated). Subjects at the end of Day 1 tolerating less than 3.0 mg single dose will 
be considered an initial day escalation failure.  The schedule for initial day dose 
escalation is shown in Table 3-1. 
• Concomitant medications 
• Physical examination, including weight and height 
• Vital signs (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. 
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• Diet history 
• Monitoring for allergic symptoms (see Section 6.8) 
• Adverse events monitoring 
 
Subjects may have clear liquids or JELL-O during the day of the initial day escalation 
protocol while they are being given the desensitization doses. 
 
If symptoms occur which prevent escalation to 6.0 mg, the highest tolerated dose (at least 
3.0 mg) will be accepted as the “desensitization” dose for further escalation (see  
Figure 6–1 in Section 6.8.4).  The maximum tolerated dose on Day 1 (e.g., 3.0 or 
6.0 mg) will be given on Day 2 as a single dose under medical observation at the Clinical 
Research Center.  If moderate symptoms occur on Day 2, the subject will return to the 
Clinical Research Center on Day 3 for the next lower dose (must be at least 3.0 mg) 
under direct observation.  If symptoms prevent initial escalation desensitization dosing to 
3.0 mg, the subject will be dropped from study treatment due to escalation failure and 
followed longitudinally for safety.  These subjects will be asked to return to the Clinical 
Research Center 14 days following their last dose of study product to undergo an Early 
Discontinuation Visit (see Section 6.5). 
 
A physician will be available at all times during any of the Clinical Research Center 
peanut OIT dosing visits. 
 
Day 2 Initial Escalation 
All subjects will return to the clinic on Day 2 for their next dose.  This dose will be the 
previous day’s dose or the last tolerated dose from the initial day escalation.  The 
maximum dose is 6.0 mg.  The minimum dose for Day 2 is 3.0 mg.  
 
Those subjects administered: 3.0 mg  
• If tolerated, return home on that dose for 2 weeks until the next escalation 
• If not tolerated, the subject is considered an escalation failure, discontinued from 
treatment, and followed for safety until the Early Discontinuation Visit 
 
Those subjects administered: 6.0 mg 
• If tolerated, return home on that dose for 2 weeks until next escalation 
• If not tolerated, return on Day 3 with a 1-step reduction (3.0 mg) 
 
Day 3 Initial Escalation 
Those subjects with moderate symptoms on Day 2 at the 6.0 mg dose will return on Day 
3 for an observed dose.  The maximum dose on Day 3 would be 3.0 mg.  
Those subjects administered 3.0 mg 
• If tolerated, return home on that dose for 2 weeks until next escalation. 
• If not tolerated, the subject is considered an escalation failure, discontinued from 
treatment, and followed for safety until the Early Discontinuation Visit. 
 
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5 to 10 days post-DBPCFC  
• Optional post DBPCFC blood draw for exploratory analysis by ITN.  The amount 
taken should be 5 mL/kg in children weighing ≥30 kg, with a maximum of 60 mL 
in total. Blood draws should be completed per NIH guidelines. 
6.4.2 
Up-dosing/Escalation visits (Up to 34 weeks post-Visit 01) 
The following procedures are scheduled for the up-dosing phase, which will last 
approximately 24 weeks). 
 
• Return to clinic every 2 weeks for up-dosing up to a maximum of 300 mg daily 
dose.  The first dose of study product will be administered at the clinic. 
• Concomitant medications 
• Physical exam, including weight and height 
• Vital signs (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. 
• Return unused capsules to the clinic at each visit 
• Take home capsules for daily dosing until next visit 
• Monitoring for compliance and allergic symptoms (phone contact 1 week after 
each escalation visit) 
• Adverse events monitoring 
Subjects should not take their daily maintenance dose on the day of the clinic visits.  The 
initial up-dose is to be administered at the clinic. 
 
Subjects who require dosing reduction during the 2-week period will reset their 2-week 
escalation schedule to maintain the new dose for a 2-week period prior to attempting to 
escalate again.  The procedure for setting the new, lower, dose is outlined in 
Section 6.8.2 and depends on the severity of the dose-related symptoms.  Any dose 
escalation attempts may be postponed for 1-2 extra weeks based on clinical judgment.  
An escalation attempt must be made by 4 weeks, unless escalation is to be delayed further 
due to administration of epinephrine as defined in Section 6.8.  Failure to successfully 
escalate for three consecutive attempts will result in the subject being considered an 
escalation failure and dose escalation will be halted at the last tolerated dose level.   
These subjects will be followed for safety biweekly (following their established visit 
schedule) while continuing to be dosed at their last tolerated dose level until Week 24, 
i.e., a maintenance phase (see also Section 6.8.4).  Dosing will be stopped after the 
Week 24 visit; and the subject will be asked to return to the Clinical Research Center 14 
days following their last dose of study product to undergo an Early Discontinuation Visit 
(see Section 6.5).  For subjects who halt dose-escalation after Week 24, there will be no 
maintenance phase.  Dosing in these subjects will be discontinued when dose-escalation 
is stopped.  They will be asked to return to the Clinical Research Center 14 days 
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following their last dose of study product to undergo an Early Discontinuation Visit (see 
Section 6.5).   
 
For any noted symptoms during the maintenance phase, the same study dosing rules for 
build-up phase will be followed.  As noted above, for subjects who halt dose-escalation 
prior to Week 24, the maintenance phase extends to Week 24; and for subjects who halt 
dose-escalation after Week 24, there is no maintenance phase.  For subjects who achieve 
a dose of 300 mg/d by Week 34, the maintenance phase comprises the last two weeks of 
the study.     
 
Subjects will continue to follow a peanut restricted diet for the duration of the study.   
 
Note that all study products to be used in the build-up phase for this study have been 
filled from a single lot, so no reductions based on lot changes should be necessary. 
 
6.4.3 
Visit 02 (after approx. 12 weeks post-Visit 01) 
• Study product administration at clinic 
• Medical/allergy history 
• Concomitant medications 
• Physical exam, including weight and height 
• Vital signs (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. 
• Urine pregnancy test, for females of childbearing potential  
• Diet history 
• Return unused capsules to the clinic at each visit 
• Take home capsules for daily dosing until the next visit 
• Monitoring for compliance and allergic symptoms (phone contact 1 week after 
each escalation visit) 
• Adverse events monitoring 
 
Subjects will continue to follow a peanut-restricted diet for the duration of the study.  For 
any noted symptoms during the maintenance phase, the same study dosing rules for the 
build-up phase will be followed. 
 
6.5 
Visit 03 - Exit Visit / Early Discontinuation Visit 
Subjects who tolerate 300 mg/day and are maintained at this dose for 2 weeks will return 
to the clinic for an Exit visit. For these subjects, the Exit visit will occur at approximately 
6-9 months post-Visit 01. 
 
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Subjects who fail escalation or build-up, 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 or associated optional blood draws.  An Early 
Discontinuation visit is to occur 14 days from the last dose of study product. 
 
The following procedures will be performed at the Exit visit: 
 
• Medical/allergy history 
• Concomitant medications 
• Physical exam, including weight and height 
• Vital signs (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. 
• Urine pregnancy test, for females of childbearing potential 
• Diet history 
• Blood draw for peanut-specific IgE and IgG4 measurement (mechanistic assays), 
the amount to be specified by local laboratory guidelines. 
• Optional blood draw (pre-DBPCFC) for exploratory analysis by ITN.  The 
amount taken should be 5 mL/kg in children weighing ≥30 kg, with a maximum 
of 60 mL in total. Blood draw should be collected per NIH guidelines. 
• Skin prick test to peanut extract 
• Physician global assessment of disease activity using a 100-mm VAS 
• Monitoring for compliance and allergic symptoms  
 
In addition to the procedures listed above, eligible subjects will have an exit DBPCFC 
performed. Eligible subjects are those who tolerate 300 mg/day and are maintained at this 
dose for 2 weeks. 
 
For placebo subjects only:  
• Exit DBPCFC conducted in accordance with PRACTALL guidelines as described 
in Section 6.6.2, then proceed to ARC002 
 
For active-treatment subjects completing DBPCFC only:  
• Proceed to ARC002 
 
Each subject participating in the study will be unblinded when he/she completes the Exit 
visit procedures (including the exit DBPCFC for eligible subjects).   
 
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6.6 
Double-Blind, Placebo Controlled Food Challenge (DBPCFC) in accordance 
with PRACTALL guidelines 
The DBPCFC is performed by feeding gradually increasing amounts of the suspected 
food under physician observation.25,26  A sample of food challenge from the PRACTALL 
guidelines using peanut flour is given in Table 6-1. 
 
Table 6-1. PRACTALL DBPCFC Doses Using Peanut Flour with 50% Peanut 
Protein Content for Screening DBPCFC 
Challenge Doses 
Peanut protein 
(mg) 
Peanut flour with 50% protein content 
(mg) 
3 
6 
10 
20 
30 
60 
100 
200 
 
 
6.6.1 
Screening Double-Blind, Placebo Controlled Food Challenge (DBPCFC) – 
For All Subjects 
The initial DBPCFC for eligibility will consist of ascending levels of the peanut flour 
(containing ~50% peanut protein) or placebo in gradually increasing doses at 20-30 min 
intervals.  The 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 (143 mg 
cumulative) peanut protein or placebo.  The PRACTALL doses as shown in Table 6-1 
will be used, as well as PRACTALL rules for safety, assessment, scoring, and stopping.  
At the investigator’s discretion, a 1 mg dose may be added at the beginning of the 
escalation (for a maximum cumulative dose of 144 mg peanut protein).  In the event that 
the 1 mg dose is added, any rules that apply to subjects based on a cumulative dose of 
143 mg will also apply to subjects based on a cumulative dose of 144 mg. 
 
The DBPCFC is conducted as 2 challenges during a single day visit or over 2 days, using 
a placebo (oat flour) for one challenge and peanut (as peanut flour) for the other.  If 
conducted in a single day, at least 3 h must separate the first half of the challenge from 
the second half of the challenge.  The challenge is performed under double-blind 
conditions so that neither the subject, nor the subject’s caregiver nor the physician knows 
which challenge contains the peanut or the placebo. 
 
6.6.2 
Exit Double-Blind, Placebo Controlled Food Challenge (DBPCFC)- For All 
Subjects 
The exit DBPCFC will be conducted in a manner similar to the screening DBPCFC but 
with a dose increasing up to 600 mg (1043 mg cumulative) peanut protein as shown in 
Table 6-2.  
 
Subjects receiving active treatment will be considered a study success if they are able to 
complete a challenge with 300 mg (443 mg cumulative) peanut protein.  
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Table 6-2. Doses Using Peanut Flour with 50% Peanut Protein Content for Exit 
DBPCFC 
Challenge Doses 
Peanut protein 
(mg) 
Peanut flour with 50% protein content 
(mg) 
3 
6 
10 
20 
30 
60 
100 
200 
300 
600 
600 
1200 
 
6.7 
Physician Global Assessment 
A 100-mm visual analog scale (VAS) will be used by the investigators to assess overall 
disease activity as a marker for safety. 
 
In assessing overall disease activity, the investigator should consider the frequency of 
allergic reactions (both observed and reported), their type, their severity, and the dose 
level at which they have occurred.  With these factors in mind, the investigator is to 
assign a single integrated overall disease activity score.  
 
The investigators will be asked: 
  
“How would you rate the severity of the overall disease activity on a scale of 0, no 
disease activity, to 100, very severe disease activity?” 
 
0  
100 
 
No 
Activity  
Very 
Severe 
 
Investigators are permitted to refer back to previous assessments when making their VAS 
determination of overall disease activity. 
 
Although not validated specifically as an instrument for evaluating food allergies, the 
VAS is, nevertheless, a widely used tool in assessing disease activity, especially in 
inflammatory diseases. 
 
6.8 
Reactions and Treatment of Reactions 
6.8.1 
Reactions and Treatment of Reactions to Peanut OIT During Initial 
Escalation 
The process algorithm for symptoms during the initial escalation protocol is shown in 
Figure 6–1 in Section 6.8.4. 
 
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Subjects may develop symptoms during the initial escalation protocol, similar to those 
seen during other desensitization protocols (e.g., venom immunotherapy, drug 
desensitization).  The severity of the reaction will be determined on the basis of the 
investigator’s judgment, using the definitions in the PRACTALL consensus report on 
DBPCFC as a general guide. The investigator’s judgment will also be required to 
determine the best course of action, with possible actions being the following:  
• Extension of time interval between dosing (up to an additional 30 min) without 
any additional treatment   
• Institution of 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 min of 
last dose, if assessed as safe 
• Treating additionally with epinephrine, beta-agonist, oxygen, IV fluids, and/or 
glucocorticosteroids, and discontinuing dose-escalation 
• Discontinuation of desensitization protocol   
 
For oral/pharyngeal pruritus occurring in isolation – the recommended action is to 
continue the normal dosing in 30 min (though the action taken is, as always, at the 
investigator’s clinical discretion). 
 
For mild symptoms, including, but not limited to: 
• Skin – limited (few) or localized hives, swelling (e.g., mild lip edema), skin 
flushing (e.g., few areas of faint erythema) or pruritus (mild, e.g., causing 
occasional scratching 
• Respiratory – rhinorrhea (e.g., 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 
 
Depending on the investigator’s discretion, the action should be either:  
  
• Advance to next dose in 30–60 min or 
• Treat with antihistamine and then resume dose escalation within 60 min of last 
dose, if symptoms have resolved to the point where the investigator assesses the 
subject as safe to continue dosing (i.e., having no or minimal residual signs or 
symptoms) 
 
If moderate symptoms occur, including, but not limited to: 
• Skin – systemic hives (e.g., numerous or widespread hives), swelling (e.g., 
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 
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• GI – persistent moderate abdominal pain/cramping/nausea, more than a single 
episode of vomiting and/or diarrhea 
 
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 (i.e., up to and including 
3 mg), then the desensitization protocol will be discontinued and the subject considered 
an escalation failure.  The decision to discontinue escalation (at any dose below, or at, 
3 mg) is based solely on the determination that the symptoms of allergic reaction are 
moderate, regardless of whether treatment is instituted or what type of treatment is 
instituted.  If moderate symptoms occur only at the 6 mg dose, then the following day’s 
dose (Day 2 or Day 3) will be reduced to 3 mg.   
 
The Medical Monitor is to be available at all times to answer any questions or to assist in 
any decisions related to the study protocol. 
 
If more severe symptoms occur, including, but not limited to: 
• Skin – severe generalized urticarial/angioedema/erythema  
• Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with 
dyspnea, stridor  
• GI – significant severe abdominal pain/cramping/repetitive vomiting and/or 
diarrhea 
• Neurological – change in mental status 
• Circulatory – clinically significant hypotension (see Appendix 3) 
 
The actions taken should be to discontinue the initial escalation and administer the 
appropriate rescue medications.  The desensitization protocol will be discontinued 
regardless of the dose at which the severe symptom or symptoms occurred, and the 
subject considered an escalation failure. 
 
Summary of Initial Escalation Dosing Requirements (see also Figure 6–1 in 
Section 6.8.4)  
 
In general, if the subject requires one or two doses of antihistamine treatment for mild 
symptoms during the initial escalation protocol, then the initial escalation may be 
continued.  If, however, the subject requires a second medication (e.g., epinephrine, a 
beta-agonist, or other medications) in addition to an antihistamine, or multiple doses of 
antihistamines, the initial escalation is to be terminated and the subject will receive no 
further OIT, even if symptoms are assessed to be mild.   
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In the event of moderate symptoms occurring during the initial escalation, the initial 
escalation is to be terminated and the subject will receive no further OIT, regardless of 
whether treatment is instituted or what type of treatment is instituted.  The only exception 
to this is if the occurrence of moderate symptoms is restricted to the 6 mg dose.  In this 
case, and this case only, may testing be attempted the following day (Day 2 or Day 3) at a 
reduced dose (3 mg).  
 
If the initial escalation is completed with no symptoms or only mild symptoms, subjects 
should have, at a minimum, a 2-h post-protocol observation period before continuing in 
the study.  If the subject experiences moderate to severe symptoms, the observation 
period is to be at least 4 h, and up to 24 h (in an appropriate facility), based on the nature 
and severity of the symptoms and the treatment regimen required to stabilize the subject’s 
condition. 
 
6.8.2 
Reactions During Build-up Phase: Preventative and Non-pharmacological 
Interventions  
The process algorithm for symptoms during the build-up/up-dosing phase is shown in 
Figure 6–2. 
 
Subjects will begin the Clinical Research Center dosing scheme as outlined until 
300 mg/day of peanut protein is reached.  Subjects will return for a supervised dose 
escalation in the clinic every 2 weeks.  It is advised that subjects be called the morning of 
the day after each dose escalation visit to assess for delayed or biphasic allergic reactions.  
Subjects will be called 1 week after each dose escalation visit to assess for dosing 
compliance and dose reactions.  Any dose escalation attempts may be postponed for 1-2 
extra weeks based on clinical judgment.  An escalation attempt must be made by 4 
weeks.  Subjects should withhold their daily home dose on the escalation day but should 
take all other prescribed medications.  Note that the daily home dose should be taken as 
part of a meal.  It is recommended that the dose be taken at a consistent time (within a 4-
hour time period), and it is critical to take the dose every day.  Doses should be separated 
by at least 12 h.   
 
Subjects who require dosing reduction during the 2-week period will reset their 2-week 
escalation schedule to maintain the new dose for a 2-week period prior to attempting to 
escalate again.  
 
With the occurrence of symptoms of a dose-reaction or any allergic reaction, 
subjects/parents (or guardians) are instructed to call the study site.   
 
Should significant systemic symptoms, which may include mild symptoms based on 
physician discretion or moderate or greater symptoms, be reported during the daily home 
dosing, the symptom/dosing algorithm will be followed (see Figure 6–2) to determine 
the best course of action.  The appropriate treatment will depend on the type and severity 
of symptoms (see Section 6.8.3).   
 
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If significant symptoms occur consistently following three attempts to increase the daily 
oral dose in the Clinical Research Center or clinic with each attempt spaced 2-4 weeks 
apart, dosing escalation will be halted at the last tolerated dose and the subject will be 
considered an escalation failure.  These subjects will be followed for safety biweekly 
(following their established visit schedule) while continuing to be dosed at their last 
tolerated dose level until Week 24, i.e., a maintenance phase (See also Section 6.8.4).  
Dosing will be stopped after the Week 24 Visit; and the subject will be asked to return to 
the Clinical Research Center 14 days following their last dose of study product to 
undergo an Early Discontinuation Visit (see Section 6.5).  For subjects who halt dose-
escalation after Week 24, there will be no maintenance phase.  Dosing in these subjects 
will be discontinued when dose-escalation is stopped.  They will be asked to return to the 
Clinical Research Center 14 days following their last dose of study product to undergo an 
Early Discontinuation Visit (see Section 6.5).  No additional DBPCFC will be 
performed.   
 
Subjects will be free from active wheezing or a flare of atopic dermatitis prior to any dose 
escalation.  Subjects will be maintained on their current dose of study product until their 
flare of asthma or atopic dermatitis resolves.   
 
Subjects will be cautioned against activities likely to increase reactivity (e.g., exercising 
or taking hot showers or baths within 4 h after dosing).   
 
At the physician’s discretion, temporary dose reductions, ranging from a 1-step 
decrement (i.e., to the previous dose) to approximately half of the current dose level (to 
the nearest feasible available whole dose), can be instituted while subjects are suffering 
from symptoms of an upper respiratory infection or influenza, or during menses.  If the 
dose is reduced by more than 1 step or for more than 3 days, the subject is to return to the 
CRC within 7 days of the dose-reduction for dose re-escalation under direct observation.  
If the reduction in dose is maintained for ≤3 days, then the pre-reduction dose may be 
resumed directly.  For dose reductions of 1 dose level maintained for ≤3 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 >3 days, the subject will have his or her 2-week 
escalation schedule reset to maintain the new dose for a 2-week period prior to re-
escalating in a bi-weekly stepwise fashion.   
 
Doses may also be withheld at the investigator’s discretion, in response to an AE, 
whether the AE is assessed to be treatment-related or not.  If doses are withheld for this, 
or any, reason, the rules for missed peanut OIT doses (Section 6.7) apply. 
 
Subjects may develop symptoms during dosing for the build-up phase.  The investigator’s 
judgment will be required to determine the best course of action with possible actions 
being the following:  
• Continue with daily home dosing 
• Continue the same daily dose for the rest of the 2-week interval, with 50% of the 
dose split between doses given 8-12 h apart 
• Return for repeat dosing in Clinical Research Center 
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• Return for dosing of previously tolerated dose (without escalation) in Clinical 
Research Center 
• Discontinuation of dosing  
 
If a subject has a dose escalation in the Clinical Research Center without symptoms, the 
action should be to continue per protocol with daily home dosing of the tolerated dose 
with the next escalation visit to the Clinical Research Center 2 weeks later.   
 
If the subject experiences only oral/pharyngeal pruritus during the administration of the 
daily dose, then the same dose can be repeated the next day at home and continued 
throughout the interval unless other symptoms begin to develop (see below). 
 
For mild symptoms, defined as: 
• Skin – limited (few) or localized hives, swelling (e.g., mild lip edema), skin 
flushing (e.g., few areas of faint erythema) or pruritus (mild, e.g., causing 
occasional scratching) 
• Respiratory – rhinorrhea (e.g., occasional sniffling or sneezing), nasal congestion, 
occasional cough, throat discomfort 
• GI – mild abdominal discomfort (including mild nauseas), minor  vomiting 
(typically a single episode) and/or a single episode of diarrhea 
 
The action should be either to repeat the dose the next day (Day 2) at home or to have the 
subject return to the Clinical Research Center the next day (Day 2) for a repeat of the 
previous day’s dose or the last tolerated dose (at the physician’s discretion).  If the dose is 
tolerated, then the subject will continue on that dose and return at the normal interval.  If 
the dose causes mild symptoms again, then the subject will return to the Clinical 
Research Center (Day 3) and be given the last tolerated dose (i.e., a 1-step dose 
reduction) or a 2-step dose reduction.  If tolerated, the subject will continue on this dose 
for the normal time interval.  If mild symptoms recur, a further 1-2-step reduction should 
be administered the next day (Day 4) in the CRC.  If tolerated then that dose should be 
continued for 2 weeks.  If not tolerated, revert to a lower dose.   
 
If moderate symptoms occur, defined as: 
• Skin – systemic hives (e.g., numerous or widespread hives), swelling (e.g., 
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 
 
The action should be to have the subject return to the Clinical Research Center the next 
day (Day 2) for dosing with the previous day’s dose or the last tolerated dose (at the 
investigator’s discretion) under observation.  If the dose is tolerated, the subject will 
continue on that daily home dose for the normal time interval per protocol.  If the subject 
does not tolerate this dose, the subject should receive the last tolerated dose (i.e., a 1-step 
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dose reduction) or a 2-step dose reduction as their next day’s dose (Day 3) in the Clinical 
Research Center.  If this dose is tolerated, it will be continued as the daily home dose for 
the normal time interval, then escalation attempted in the Clinical Research Center as 
noted below.  If this dose is not tolerated, then the next dose will be a further 1-2-step 
reduction in dosing (per investigator judgment), and the dose will be given in the Clinical 
Research Center (Day 4).  If this next dose is not tolerated, then a discussion with the 
Medical Monitor will ensue to make a decision about whether to continue the subject on 
study-product treatment in the study. 
 
If more severe symptoms occur, defined as: 
• Skin – severe generalized urticarial/angioedema/erythema  
• Respiratory – laryngeal edema, throat tightness with hoarseness, wheezing with 
dyspnea, stridor  
• GI – significant severe abdominal pain/cramping/repetitive vomiting and/or 
diarrhea 
• Neurological – change in mental status 
• Circulatory – clinically significant hypotension (see Appendix 3). 
 
The action should be to treat the subject, and at the physician’s discretion either 1) have 
them return to the Clinical Research Center the next day (Day 2) for dosing with a 2-step 
reduction in dose under observation or 2) discontinue them from the study product 
treatment.  If the subject tolerates the dose reduction, then they will remain on that dose 
for 2 weeks and then return to the Clinical Research Center for the dose escalation.  A 
discussion with the Medical Monitor may ensue to make a decision about whether to 
continue the subject on  study product treatment in the study. 
 
If a subject fails dose escalation after three consecutive attempts (with 2-4 weeks 
between), he/she will be considered an escalation failure and the last tolerated dose will 
be accepted as the maintenance dose (to Week 24).  If the dose escalation is completed 
with no symptoms, subjects should be observed for 30 min.  If the subject exhibits mild 
symptoms, the duration of the observation period should be 1-2 h post-protocol.  For 
moderate to severe symptoms, the observation period should be at least 4 h and up to 24 h 
based on symptoms and the treatment regimen needed to stabilize the subject’s condition. 
 
Any subject deemed to have severe symptoms including hypoxia, hypotension, or change 
in mental status (stage 3 anaphylaxis defined in Appendix 3) or who receives aggressive 
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 study 
product therapy. 
 
For specific questions related to dosing escalation or continuation of the same dose that 
are not answered in the above protocol, the Medical Monitor will be available for 
questions.   
 
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Any subject who discontinues build-up dosing due to repeated allergic reactions to the 
characterized peanut allergen will have his/her mechanistic blood draw (refer to 
Section 8) within approximately 1 week of discontinuation of therapy. 
 
6.8.3 
Treatment for Reactions During the Build-up Phase: Pharmacological and 
Supportive Treatments 
Treatment of individual reactions should be with either an antihistamine and/or 
epinephrine, along with IV fluids, a beta-agonist (e.g., albuterol, by inhaler or nebulizer), 
oxygen, and glucocorticosteroids, as indicated.  Generally, for mild symptoms requiring 
treatment, the subject should receive antihistamines.  Generally, for moderate symptoms 
requiring treatment, the subjects should receive antihistamines and/or epinephrine, as 
indicated.  If severe anaphylaxis (stage 3 anaphylaxis defined in Appendix 3) occurs at 
any time, dose escalation will stop and the dose will be reduced to the last tolerated dose 
and the subject continued on that dose as long-term maintenance without further 
escalation.  
 
Antihistamines 
If a subject receives antihistamines only, the dose escalation can be continued.  If 
symptoms during a build-up day require antihistamines in multiple doses (>2) or in 
combination with other medications (except epinephrine), there should be a dose 
reduction by 1-2 doses with the next dose given in the CRC.  If epinephrine is 
administered, then a different course of action is to be taken (see below).  If dose 
escalation fails or requires treatment after two more escalation attempts, each spaced 2 to 
4 weeks apart, the dose should be reduced to the last tolerated dose and continued long 
term (to Week 24) without further escalation.  The subject will be followed for safety 
biweekly (following their established visit schedule) while continuing to be dosed at their 
last tolerated dose level until Week 24, i.e., a maintenance phase (see also Section 6.8.4).  
Dosing will be stopped after the Week 24 Visit; and the subject will be asked to return to 
the Clinical Research Center 14 days following their last dose of study product to 
undergo an Early Discontinuation Visit (see Section 6.5).  For subjects who halt dose-
escalation after Week 24, there will be no maintenance phase.  Dosing in these subjects 
will be discontinued when dose-escalation is stopped.  They will be asked to return to the 
Clinical Research Center 14 days following their last dose of study product to undergo an 
Early Discontinuation Visit (see Section 6.5).  No additional DBPCFC will be 
performed.  
 
Epinephrine - General 
Any reaction (in clinic or at home) that requires two or more doses of epinephrine will 
halt further dose escalation for this individual. Maintenance on the last tolerated dose is 
to be continued until Week 24.  Dosing will be stopped after the Week 24 Visit; and the 
subject will be asked to return to the Clinical Research Center 14 days following their 
last dose of study product to undergo an Early Discontinuation Visit (see Section 6.5). 
For subjects who halt dose-escalation after Week 24, there will be no maintenance phase.  
Dosing in these subjects will be discontinued when dose-escalation is stopped.  They will 
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be asked to return to the Clinical Research Center 14 days following their last dose of 
study product to undergo an Early Discontinuation Visit (see Section 6.5). 
 
Epinephrine - Clinic 
If a single administration of epinephrine is required during escalation in the clinic, the 
dose of study medication is to be reduced by two increments, or to the last tolerated dose 
(at the physician’s discretion), and dose escalation is to continue. 
 
If a single administration of epinephrine is required a second consecutive time during this 
escalation attempt, the dose should be reduced by two doses, and the subject continued 
on that dose for 6-8 weeks.  After 6-8 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 this 
escalation attempt, the dose should be reduced by two doses and the subject continued on 
that dose as long-term maintenance (to Week 24) without further escalation.  (Note: an 
event requiring 3 consecutive administrations of epinephrine is to be reported within 24 
hours of its occurrence, see Section 7.1 and 7.7.2). The subject will continue to be 
followed for safety biweekly (following their established visit schedule) while continuing 
to be dosed at their last tolerated dose level until Week 24.  Dosing will be stopped after 
the Week 24 Visit; and the subject will be asked to return to the Clinical Research Center 
14 days following their last dose of study product to undergo an Early Discontinuation 
Visit (see Section 6.5).  For subjects who halt dose-escalation after Week 24, there will 
be no maintenance phase.  Dosing in these subjects will be discontinued when dose-
escalation is stopped.  They will be asked to return to the Clinical Research Center 14 
days following their last dose of study product to undergo an Early Discontinuation Visit 
(see Section 6.5).  No additional DBPCFC will be performed. 
 
 
Epinephrine - Home 
If a single administration of epinephrine use occurs during dosing at home, this 
epinephrine use is not counted as one of the uses described above, unless severe 
anaphylaxis is assessed to have occurred at home.  The subject should return to clinic for 
an observed dose prior to resuming any dosing at home. 
 
6.8.4 
Reactions During Maintenance Phase  
This phase consists of the subject receiving the maximum achieved daily dose of peanut 
OIT.   
 
Subjects who fail escalation during the initial escalation period (Visit 1; Days 1 to 3), i.e., 
subjects who do not tolerate a minimum of 3 mg of study product (CPNA or matching 
placebo), will stop dosing and will not enter a maintenance phase.  These subjects will be 
followed for safety and be asked to return to the Clinical Research Center 14 days 
following their last dose of study product to undergo an Early Discontinuation Visit (see, 
Section 6.5). 
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Subjects whose up-dosing is halted because of failing subsequent build-up (i.e., after the 
initial escalation period; Visit 1), will continue to be dosed at the last tolerated dose level 
and to be followed for safety biweekly (following their established visit schedule) until 
Week 24.  The length of time from the cessation of up-dosing to Week 24 will constitute 
the maintenance phase for these subjects.  The maintenance phase, thus, may vary in 
length from subject to subject.  Dosing will be stopped after the Week 24 Visit; and the 
subject will be asked to return to the Clinical Research Center 14 days following their last 
dose of study product to undergo an Early Discontinuation Visit (see, Section 6.5).   
 
There will be no maintenance phase for subjects who halt dose-escalation after Week 24.  
Dosing in these subjects will be discontinued when dose-escalation is stopped.  They will 
be followed for safety and asked to return to the Clinical Research Center 14 days 
following their last dose of study product to undergo an Early Discontinuation Visit (see 
Section 6.5).   
 
Subjects who achieve the targeted dose of 300 mg/d by Week 34 will then enter a 2-week 
maintenance phase.  For these subjects, the maintenance phase will be followed by a 
DBPCFC performed at their Exit Visit (no later than week 36; see, Section 6.5). 
 
All subjects will continue to follow a peanut-restricted diet for the duration of the study.   
 
For any noted symptoms during the maintenance phase, the same study dosing rules for 
the build-up phase will be followed. 
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Figure 6–1. 
Schematic for Initial (Visit 01) Day Escalation 
 
 
 
Dose - Escalation 
Dose 
Oral/pharyngeal pruritus 
Time to next dose 30-60 min 
Treatment - antihistamines as    
needed 
Next dose - advance 
 
Severe Symptoms 
 
 
Moderate Symptoms 
 
Time to next dose 30 min  
Next dose - advance 
Treatment as indicated for 
severe reaction, stop 
escalation and further dosing 
Occurring at < 6 mg:  
Treatment - as indicated for 
moderate reaction; for 
moderate reaction 
stop escalation 
 
Occurring at 6 mg: 
Treatment - as indicated for 
moderate reaction; for 
moderate reaction 
decrease next day’s dose to 
3  mg 
 
Mild Symptoms 
 
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Figure 6–2. 
Schematic for Build Up Phase Dose Escalation – Day of Symptom 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose - Challenge Escalation 
Dose  
Oral/pharyngeal Pruritus 
 
Mild Symptoms 
 
Dose – PDD or LTD 
Location - Clinical 
Research Center or home 
 
Severe Symptoms 
 
 
Moderate Symptoms 
  
Dose – PDD  
Location – Home 
with phone follow-up 
Dose – PDD or LTD 
Location – Clinical 
Research Center 
Tolerated 
Dose – Continue on 
dose Escalation at 
normal time interval 
Location - Home 
Not Tolerated 
Dose – LTD or 1-2 
step reduction 
Location – Clinical 
Research Center  
Tolerated 
Dose – Continue the 
reduced dose   
Escalation at normal 
time interval 
Day 1* 
Day 3 
Day 2** 
Tolerated – Symptoms no greater than oral/pharyngeal 
pruritus 
LTD – Last Tolerated Dose 
PDD- Previous Days Dose 
Clinical Research Center or monitored clinic setting 
Failure of dose escalation in 3 consecutive attempts – 
maintain dose at LTD  
Escalation at normal 
time interval 
Not Tolerated 
Dose – 1-2 step 
reduction 
Location – Clinical 
Research Center 
Not Tolerated 
Consult with Medical 
Monitor 
Tolerated 
Dose – Continue on 
dose 
Escalation at normal 
time interval 
Remove from study 
treatment, follow for 
safety 
Physician discretion, consult 
with Medical Monitor 
Dose –2-step 
reduction 
Location – Clinical 
Research Center 
Tolerated  
Dose – Continue on 
the reduced dose 
Escalation at normal 
time interval 
Day 4 
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6.9 
Missed Peanut OIT Doses at any Phase of the Study: 
Missed Peanut OIT doses at any phase of the study can pose a significant risk to the 
enrolled subjects. The algorithm for missed consecutive doses of study product is as 
follows: 
• Miss 1 dose – The next dose would be the current dose and could be given at 
home 
• Miss 2 doses in a row – The next dose would be the current dose 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 observation (Clinical Research Center) 
• Miss 4 doses in a row – The next dose would be the current dose and would be 
given under observation (Clinical Research Center) 
• Miss 5-7 doses in a row –Initiate the next dose as approximately 25% of the last 
tolerated dose.  This would be done under observation (Clinical Research Center).  
Dose escalation would occur in the Clinical Research Center with an escalation no 
sooner than weekly and no longer than every 4 weeks with dose increases of 1-
dose levels at each escalation.  If symptoms occur, the dosing symptom rules in 
the build-up phase would apply 
• Missing >7 consecutive days of therapy constitutes an individual stopping rule 
and the subject would no longer take the study product.  The subject will be asked 
to return to the Clinical Research Center 14 days following their last dose of study 
product to undergo an Early Discontinuation Visit (see Section 6.5) 
• Additionally; excessive missed doses, i.e., > 3 consecutive days missed on 3 
occasions, constitutes an individual stopping rule and the subject would no longer 
take the study product.  The subject will be asked to return to the Clinical 
Research Center 14 days following their last dose of study product to undergo an 
Early Discontinuation Visit (see 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. 
 
6.10 Double-Blind Placebo Controlled Food Challenge  
The subject will be off antihistamines for an appropriate length of time (5 half-lives of 
the antihistamine that is being used).  Oral food challenges will be undertaken under 
direct medical supervision in a Clinical Research Center or food challenge area with 
emergency medications and staff immediately available and will follow established study 
procedures.  Prior to the DBPCFC, subjects will be assessed for an exacerbation of 
asthma as determined by active wheezing or a peak expiratory flow rate < 80% of 
predicted.  A uniform approach for food challenges will be used.  Frequent assessments 
will be made for symptoms affecting the skin, gastrointestinal tract, cardiovascular 
system, and/or respiratory tract.  Dose limiting symptoms, typically objective symptoms 
(signs), indicate a positive reaction and termination of dosing.   
 
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6.11 Skin Prick Test 
Subjects will have skin prick tests performed using study approved procedures for food 
allergens.  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 extract of an allergen 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.   
 
6.12 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. 
 
6.13 Study Blinding Procedures 
The study is double-blinded up to completion of the exit DBPCFC, escalation failure, or 
endpoint failure.  
 
Those who are not eligible for the DBPCFC at Week 34 will be unblinded at this time. 
 
Those who do not pass the DBPCFC at Week 36 will be unblinded at this time. 
 
All food challenges are performed in a double-blind manner. 
 
6.13.1 Securing Blinding and Randomization Information 
ARC or contractor will manufacture, package, label, store, and distribute the study 
product.  During site visits, the site monitor checks the pharmacist or clinic logs to ensure 
that appropriate randomization assignments are received, recorded, and maintained.  
 
6.13.2 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 of unblinding 
will 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 events that require unblinding, the investigator 
will contact the clinical monitor who will coordinate with the sponsor’s representatives. 
 
6.13.3 Breaking the Blind 
In case emergency unblinding is necessary, TEMPO™ allows study personnel with 
appropriate permissions to request unblinding for a specific subject.  An email is then 
sent to appropriate sponsor and CPWW safety designees informing them of the blinding.  
A built-in audit trail documents the unblinding process and the persons involved. 
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6.13.4 Documenting an 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.  
 
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 data system for 
the duration of the study.  Some safety events arising under certain defined conditions are 
recorded on specific forms as follows.   
• Safety events related to accidental food exposure are recorded on a Food Allergy 
Episode form and are not reported on an adverse event form unless the event is 
considered a serious adverse event, as defined below (Section 7.2).   
• Any allergic symptoms due to dosing will be recorded directly on the Escalation 
Dosing form (also referred to as a Study Product Administration form).  
• 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 Coordinating Center within 24 h of its occurrence 
and/or the sites being notified of the event (see also Section 7.7.2), if the event is 
associated with any of the following: 
o An emergency room visit; 
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 and food challenge reactions that occur 
in the clinic are captured on study specific forms and are not reported on an 
adverse event form unless the event is considered a serious adverse event, as 
defined below.  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 one of these procedures. All other safety events that occur 
throughout the study are reported on the AE/SAE form set. 
 
7.2 
Food Allergy Episodes 
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 
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for any adverse event.  The subject may be asked to return to the site.  These events will 
be reported as follows: 
 
• A Food Allergy Episode 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, the AE/SAE form will be completed as well.   
 
7.3 
Definitions 
7.3.1 
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.  
 
7.3.2 
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 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.  
 
7.3.3 
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.   
 
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7.4 
Data Monitoring Committee 
Although the safety of peanut OIT overall is well established, a Data Monitoring 
Committee (DMC) has been established to monitor the study for safety.  The DMC 
Charter is under development and a plan has been drafted. 
 
7.5 
Toxicity Grading  
The study site assigns toxicity grades to indicate the severity of adverse experiences and 
toxicities.  The CoFAR adopted usage of NCI-CTCAE v 4.0 for application in adverse 
event reporting and will likewise be used for this protocol.  The allergic reactions in this 
protocol are defined beyond the NCI-CTCAE system, and include further 
characterization of anaphylaxis.  Anaphylaxis is characterized as mild, moderate, or 
severe in Appendix 3, independent of the toxicity grade associated with the event.  
Toxicity grading for allergic reactions including anaphylaxis is modified from the NCI-
CTCAE system to be more appropriate for this study population, and is displayed in 
Table A4-2 in Appendix 4.   
 
The NCI-CTCAE v 4.0 was specifically reviewed for this protocol and is appropriate for 
this study population.  The purpose of using the NCI-CTCAE system is to provide 
standard language to describe toxicities and to facilitate tabulation and analysis of the 
data and 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.    
 
Record adverse events not included in the NCI-CTCAE listing and grade them 1 to 5 
according to the General Grade Definition provided below:  
 
Grade 1 
Mild 
Transient or mild discomforts (< 48 h), no or minimal 
medical intervention/therapy required, hospitalization not 
necessary (non-prescription or single-use prescription therapy 
may be employed to relieve symptoms, e.g., 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 
 
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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.  
 
7.5.1 
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. 
 
7.6 
Adverse Events 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 30 days after the subject completes study treatment, whichever comes 
first. 
 
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 
7.6.1 
Recording and Reporting Procedures 
A multi-page adverse event form 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 pages within the Internet data entry 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. 
 
7.6.2 
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 h of their occurrence and/or the site’s 
knowledge of the event to the Coordinating Center.  The following attributes will be 
assigned:  
• Description 
• Date of onset and resolution (if known when reported) 
• Severity 
• Assessment of relatedness to test article  
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No 
Yes 
• 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 FDA, the DMC, Institutional Review Board (IRB), or the 
sponsor(s) may suspend further trial treatment or procedures at a site.  The study 
sponsor(s) and the FDA 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. 
 
7.6.2.1 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 (e.g., death certificate, medical notes, etc.). 
Standard Reporting 
(within 5-7 days)  
Use Adverse Event 
Form, and other CRFs  
Submit to Coordinating 
Center 
Expedited Reporting (within  
24 h)  
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:  
• Those due to an accidental food ingestion 
• Those occurring in the clinic during study product administration, 
skin prick test or oral food challenge  
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7.7 
Serious Adverse Event Notification 
7.7.1 
Notifying the Sponsor 
Study investigators will provide the Coordinating 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 h of site awareness of the event. The sponsor’s Medical Monitor will review 
each SAE report and will determine whether the SAE must be reported to FDA on an 
expedited basis.  The final decision for disposition regarding reporting to the FDA rests 
with the sponsor’s Medical Monitor.  The IND Sponsor is responsible for submitting the 
SAE reports to FDA.  The IND Sponsor will provide the DMC and the Coordinating 
Center with copies of any SAE reports submitted to FDA by the sponsor. 
 
The Coordinating Center will provide these expedited reports to the individual site 
investigators.  Events that are serious, related to therapy and unexpected will be reported 
to FDA in 15 days or for deaths and life threatening events in 7 days (per 21 CFR 
312.32). 
 
7.7.2 
Notifying the Data Monitoring Committee 
The Coordinating Center will provide the DMC with listings of all SAEs on an ongoing 
basis.  Furthermore, the DMC will be informed of expedited reports of SAEs. Reports 
from DMC ongoing protocol safety reviews will be sent to the investigators. 
 
Per DMC request, centers are instructed to report episodes of anaphylaxis within 24 h of 
their occurrence and/or the sites being notified of the event to the Coordinating Center 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 Coordinating Center.  The Coordinating Center will then 
relay to the sponsor and DMC 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 Coordinating Center. 
 
7.7.3 
Notifying the Institutional Review Board and Ethics Committee 
The investigator will ensure the timely dissemination of all AE information, including 
expedited reports and DMC safety reviews, to the IRB in accordance with applicable 
local regulations and guidelines. 
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7.8 
Other Safety Assessments 
7.8.1 
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. Vital signs will also be assessed, 
including blood pressure (BP), pulse rate (PR), and body temperature. 
 
7.8.2 
Prior and Concomitant Medications 
Prior and concomitant medications will be duly documented in the CRF.  
 
7.8.3 
Pregnancy Test 
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 
Stopping Rules 
7.9.1 
Overall Stopping Rules 
The study will be suspended at any time such that a treatment-associated death occurs, or 
that the second of two subjects is admitted to the hospital as a direct consequence of 
dosing with study medication. The DMC will also be continually reviewing unblinded 
safety data, and can also recommend, in its judgment, halting the study for any 
substantial imbalance in adverse events, apart from dosing symptoms.  The study will not 
be resumed until this information has been discussed with FDA and the FDA concurs 
with resumption of the study. 
 
Allergen Research Corporation additionally reserves the right to discontinue the study at 
any time for any reason. 
 
7.9.2 
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 three days of dosing are missed.  Seven or more days of missed 
dosing constitutes an individual stopping rule, as does a significant number of episodes of 
missed dosing (ie, three or more days on at least three occasions).  For additional 
individual stopping rules, the reader is referred back to Section 4.3.1. 
 
Failure to accomplish up-dosing after three attempts will result in halting further up-
dosing attempts, with the subject maintained at the previously achieved level.  In 
addition, administration of two or more doses of epinephrine for the treatment of dose-
related allergic reactions will result in halting further up-dosing attempts, with the subject 
maintained at the previously achieved level. 
 
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8. 
Mechanistic Assays  
Complementary studies will be performed to measure humoral immune responses at 
baseline and at 6 months.   
• Measurement of antigen-specific IgE and IgG4 levels 
• SPT to peanut 
 
8.1 
Peanut-Specific Antibody 
Antigen immunotherapy has been shown to induce antigen-specific humoral responses.  
The balance of isotypic response may play a role in allergen sensitivity (e.g., an increase 
of IgG/ IgE).  
 
At each of the mechanistic time points, a sample of plasma will be stored for assessment 
of peanut specific antibody levels.  Total IgE and specific IgE and IgG4 will be measured 
using UniCAP.  Peanut specific IgE and IgG4 blood draws will be measured at screening 
and at Visit 03, with the amount of blood to be drawn determined by individual 
laboratory protocol.  
 
9. 
Statistical Considerations 
This protocol is a randomized evaluation of peanut OIT versus placebo therapy and 
baseline for individuals with peanut allergy.   
 
9.1 
Study Endpoint Assessment 
9.1.1 
Primary Endpoint 
The primary endpoint is the proportion of subjects who achieve desensitization as 
determined by tolerating at least 300 mg (443 mg cumulative) of peanut protein with no 
more than mild symptoms at the exit DBPCFC (ie, responders). 
 
Those who fail to achieve the target maintenance dose of at least 300 mg of study product 
will be considered as non-responders. An intent-to-treat analysis will be performed to test 
for a treatment difference in the response rate. All individuals failing to achieve the 
success definition described above will be considered failures. All individuals who drop 
out of the study or discontinue OIT will be considered failures, unless they have added ad 
libitum peanut consumption to their diet otherwise. Analysis will be via Chi-square test at 
the 0.05 significance level. 
 
9.1.2 
Secondary Endpoints 
The secondary endpoints are defined in Section 3.7.  
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9.2 
Subject and Demographic Data 
9.2.1 
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; these data will be presented in the following manner: 
• Continuous data (i.e., age, body weight and height) will be summarized 
descriptively by mean, standard deviation, median and range.   
• Categorical data (i.e., sex and race) will be presented as enumerations and 
percentages.   
Statistical presentation for baseline and demographic characteristics may be further 
summarized by treatment group and baseline peanut-specific serum IgE. 
 
9.2.2 
Use of Medications 
All medications used will be coded using the World Health Organization (WHO) drug 
dictionary.  The number and percentage of subjects receiving concomitant medications or 
therapies will be presented.  Statistical presentation of concomitant medications or 
therapies may be further summarized by treatment group. 
 
9.2.3 
Study Completion 
The percent of subjects who complete the study, losses to follow-up, times to lost to 
follow-up and reasons for discontinuation (e.g., adverse events) will be presented.  
Statistical presentation of study completion will be further presented via analysis of the 
secondary endpoints summarized.  
 
9.3 
Sample Size and Power Calculations 
While natural history of peanut allergy desensitization is not fully understood, significant 
short-term improvements in consumption amounts are believed to be uncommon.  A true 
placebo response rate of 25% or less among subjects who undergo the exit DBPCFC is 
assumed in this study.  Those individuals who fail to achieve the target daily dose or who 
withdraw prematurely will be treated as non-responders.  We will recruit approximately 
50 subjects. 
 
If 3 subjects in each arm (about 12%) do not undergo the exit DBPCFC, then the 
effective placebo response rate in the ITT analysis is assumed to be 22% or less. With a 
2-tailed 5% level test, there is at least 80% power to detect an effective CPNA response 
rate of 58.7% or more, which corresponds to a CPNA response rate of 66.7% or more 
among those who undergo the exit DBPCFC. 
 
If 5 subjects in each arm (about 20%) do not undergo the DBPCFC, then the effective 
placebo response rate in the ITT analysis is assumed to be 20% or less. With a 2-tailed 
5% level test, there is at least 80% power to detect an effective CPNA response rate of 
56.6% or more, which corresponds to a CPNA response rate of 70.75% or more among 
those who undergo the exit DBPCFC. 
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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 h 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 IND 
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 (21 CFR 312.62) to keep accurate case records for at least 2 years after 
acceptance of a licensure application and FDA is notified, and record observations to 
assure the safe conduct of the study. 
 
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 Conference on Harmonisation of Technical Requirements for 
Registration of 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 as well as FDA.  Any amendments 
to the protocol or must also be approved by the sponsor, DMC, IRB and submitted to the 
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FDA before they are implemented.  Any amendments to the consent materials must also 
be approved by the sponsor and IRB before they are implemented. 
 
11.2 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 be comprised of 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 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.  The attending physician, in the presence of a witness, will 
review the consent and answer questions, as well as emphasize the need to avoid allergen 
exposure other than to Characterized Peanut Allergen, and the necessity to continue 
exposure to Characterized Peanut Allergen to maintain de-sensitization.  The prospective 
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. 
 
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 Coordinating Center for storage and 
analysis.  Subject data will be anonymized to maintain subject confidentiality.  All data 
derived from these 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 Coordinating 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 
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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 Non-Major Protocol Deviation 
A non-major 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. 
Reference List 
1. Buchanan AD, Green TD, Jones SM, Scurlock AM, Christie L, et al. Egg oral immunotherapy in 
nonanaphylactic children with egg allergy, J Allergy Clin Immunol 2007, 119:199-205. 
2. Sicherer SH, Wood RA, Stablein D, Burks AW, Liu AH, et al. Immunologic features of infants with 
milk or egg allergy enrolled in an observational study (Consortium of Food Allergy Research) of food 
allergy). J Allergy Clin Immunol 2010, 125:1077-1083 e1078. PMCID: PMC2868273 
3. Hofmann AM, Scurlock AM, Jones SM, Palmer KP, Lokhnygina Y, et al. Safety of a peanut oral 
immunotherapy protocol in children with peanut allergy, J Allergy Clin Immunol 2009, 124:286-291, 
291 e281-286. PMCID: PMC2731305. 
4. Joshi P. Mofidi S, Sicherer SH. Interpretation of commercial food ingredient labels by parents of food-
allergic children. J Allergy Clin Immunol, 2002. 109(6): p. 1019-21. 
5. Altschul AS, Scherrer DL, Muñoz-Furlong A, Sicherer SH. Manufacturing and labeling issues for 
commercial products: relevance to food allergy. J Allergy Clin Immunol, 2001. 108(3): p. 468. 
6. Vierk K, Falci K, Wolyniak C, Klontz KC. Recalls of foods containing undeclared allergens reported 
to the US Food and Drug Administration, fiscal year 1999. J Allergy Clin Immunol, 2002. 109(6): p. 
1022-6. 
7. Sicherer SH, Burks AW, Sampson HA. Clinical features of acute allergic reactions to peanut and tree 
nuts in children. Pediatrics, 1998. 102(1): p. e6 
8. Sampson HA, Muñoz-Furlong A, Bock SA, Schmitt C, Bass R, et al. Symposium on the definition and 
management of anaphylaxis: summary report. J Allergy Clin Immunol, 2005. 115(3): p. 584-91. 
9. Frew AJ. 25. Immunotherapy of allergic disease. J Allergy Clin Immunol, 2003. 111(2 Suppl): p. 
S712-9. 
10. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review 
and meta-analysis. Allergy, 2005. 60(1): p. 4-12. 
11. Lehrer SB, Wild LG, Bost KL, Sorensen RU. Immunotherapy for food allergies. Past, present, future. 
Clin Rev Allergy Immunol, 1999. 17(3): p. 361-81. 
12. Oppenheimer JJ, Nelson HS, Bock SA, Christensen F, Leung DY. Treatment of peanut allergy with 
rush immunotherapy. J Allergy Clin Immunol, 1992. 90(2): p. 256-62. 
13. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by 
immunotherapy with injections of aqueous peanut extract. J Allergy Clin Immunol, 1997. 99(6 Pt 1): p. 
744-51. 
14. Kim  EH, Bird JA, Kulis M, Laubach S, Pons L, et al. Sublingual immunotherapy for peanut allergy: 
clinical and immunologic evidence of desensitization. J Allergy Clin Immunol, 2011. 127(3): p. 640-6 
e1. 
15. Varshney P, Jones SM, Scurlock AM, Perry TT, et al. A randomized controlled study of peanut oral 
immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin 
Immunol, 2011. 127(3): p. 654-60. 
16. Bousquet J. Primary and secondary prevention of allergy and asthma by allergen therapeutic vaccines. 
Clin Allergy Immunol, 2004. 18: p. 105-14. 
17. Kapsenberg ML, Hilkens CM, Wierenga EA, Kalinski P. The paradigm of type 1 and type 2 antigen-
presenting cells. Implications for atopic allergy. Clin Exp Allergy, 1999. 29 Suppl 2: p. 33-6 
18. Secrist H DeKruyff RH, Umetsu DT.  Interleukin 4 production by CD4+ T cells from allergic 
individuals is modulated by antigen concentration and antigen-presenting cell type. J Exp Med, 1995. 
181(3): p. 1081-9. 
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19. Blumchen K, Ulbricht H, Staden U, Dobberstein K, Beschorner J, et al. Oral peanut immunotherapy in 
children with peanut anaphylaxis. J Allergy Clin Immunol, 2010. 126(1): p. 83-91 e1. 
20. Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, et al.  Clinical efficacy and immune regulation 
with peanut oral immunotherapy. J Allergy Clin Immunol, 2009. 124(2): p. 292-300, 300 e1-97. 
21. Narisety, SD, Skripak JM, Steele P, Hamilton RG, Matsui EC, et al. Open-label maintenance after milk 
oral immunotherapy for IgE-mediated cow's milk allergy. J Allergy Clin Immunol, 2009. 124(3): p. 
610-2. 
22. Skripak, JM, Nash SD, Rowley H, Brereton NH, Oh S,et al. A randomized, double-blind, placebo-
controlled study of milk oral immunotherapy for cow's milk allergy. J Allergy Clin Immunol, 2008. 
122(6): p. 1154-60. 
23. McKenna C, Klontz KC. Systemic allergic reaction following ingestion of undeclared peanut flour in a 
peanut-sensitive woman. Ann Allergy, Asthma & Immunol 1997; 79:234-6. 
24. Sampson HA, van Wijk RG, Bindslev-Jensen C, Sicherer S, et al  Standardizing double-blind, placebo-
controlled oral food challenges: American Academy of Allergy, Asthma & Immunology – European 
Academy of Allergy and Clinical Immunology PRACTALL consensus report. J Allergy Clin Immunol 
2012; 130(8):1260-74. 
25. Bock SA, Atkins FM. Patterns of food hypersensitivity during sixteen years of double-blind, placebo-
controlled food challenges. J Pediatr, 1990. 117(4): p. 561-7. 
26. Burks AW, Jones SM, Wood RA, Fleischer DM, Sicherer SH, et al. for the Consortium of Food 
Allergy Research. Oral Immunotherapy for Treatment of Egg Allergy in Children. N Engl J Med, 2012 
July 19; 367:233-243. 
27. Muraro A. Roberts G. Clark A. Eigenmann PA, et al. The management of anaphalaxis in childhood: 
position paper of the European academy of allergology and clinical immunology. Allergy. 2007 
Aug:62(8):857-71. 
28. Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006 
Feb;117(2):391-7. 
 
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Appendix 1: Schedule of Events  
 
Screening 
Blinded Treatment 
Exit/Early 
Discontinuation 
Procedure 
Visit 00 
Screening 
 
Baseline 
Visit 
Visit 01 
Initial 
Escalation  
(Day 1-3)1 
Up-dosing 
visits 
 (approx. 
every 2 wks 
for 24 wks)2 
Visit 02 
(approx. 
12 wks) 
Visit 03 
 
Informed consent 
X 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
Medical/allergy 
history  
X 
X 
 
 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
Physical exam, 
including weight 
and height 
X 
X 
X 
X 
X 
X 
Vital signs (BP, PR, 
temperature) 
X 
X 
X 
X 
X 
X 
Peak flow rate 
(PEFR)3 
X 
X 
X 
X 
X 
X 
Pregnancy test4 
X 
serum 
X 
urine 
 
 
X 
urine 
X 
urine 
Diet history 
X 
 
X 
 
X 
X 
Blood draw for 
peanut specific IgE, 
IgG4  
Pre-
DBPCFC 
 
 
 
 
Pre-DBPCFC 
Optional blood 
draw for ITN 
exploratory 
analysis5 
Pre-
DBPCFC  
 
 
 
 
 
 
Pre-DBPCFC  
5-10 days post-
DBPCFC 
 
 
 
 
Skin prick test 
X 
 
 
 
 
X 
Clinical Research 
Center  study 
product 
administration 
 
 
X 
X 
X 
X 
Dispensing study 
products  for home 
dosing/Return of 
unused products 
 
 
X 
X 
X 
 
Physician Global 
Assessment 
 
X 
 
 
 
X 
Dose assessment to 
decide for 
maintenance or up-
dosing 
 
 
 
 
 
X 
CPNA Peanut OIT 
Final 
14 May  2014 
 

Allergen Research Corporation  
CONFIDENTIAL 
Page 67 of 71 
Protocol ARC001 Amendment 3 
 
 
Screening 
Blinded Treatment 
Exit/Early 
Discontinuation 
Procedure 
Visit 00 
Screening 
 
Baseline 
Visit 
Visit 01 
Initial 
Escalation  
(Day 1-3)1 
Up-dosing 
visits 
 (approx. 
every 2 wks 
for 24 wks)2 
Visit 02 
(approx. 
12 wks) 
Visit 03 
 
Double-blind, 
placebo controlled 
food challenge 
(DBPCFC) 
PRACTALL 
guidelines 
X 
 
 
 
 
X6 
Telephone 
monitoring of 
dosing compliance 
and symptoms7 
 
 
X 
1 wk after 
visit 
X 
X 
X 
Adverse events8 
 
 
X 
X 
X 
X 
1. Visit 01: Escalation to at least 3.0 mg on Day 1, return Day 2, return Day 3 if symptoms present, return for dose 
escalation every 2 weeks. Dose escalation schedule is shown in Table 3-1. 
2. Up-dosing visits: every 2 .weeks at clinic, unless epinephrine is administered as described in Section 6.8.  Dose 
escalation schedule is shown in Table 3-1 
3. Prior to any DBPCFC and at Baseline; 3 attempts, best value taken; should be measured at the same time for each 
visit assessment 
4. For females of childbearing potential 
5. For subjects ≥30kg only, at 5 mL/kg, with a maximum of 60 mL in total; analysis by ITN. 
6. Eligible subjects (up-dose to 300 mg plus 2 weeks on 300 mg) only will undergo a DBPCFC at the exit visit. 
7. Phone calls will occur 1 week after each escalation visit to assess dosing compliance and symptoms. Schematic for 
symptoms is described in Figure 6–1 and Figure 6–2. 
8. 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. 
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Final 
14 May  2014 
 

Allergen Research Corporation  
CONFIDENTIAL 
Page 68 of 71 
Protocol ARC001 Amendment 3 
 
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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Allergen Research Corporation  
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Protocol ARC001 Amendment 3 
 
Appendix 3: Anaphylaxis Staging System 
Staging System of Severity of Anaphylaxis27 
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 
 
Criteria for Diagnosis28 
Anaphylaxis is likely when any one of the three following sets of criteria is fulfilled: 
1. Acute onset of an illness (min to h) with involvement of: 
• 
Skin/mucosal tissue (e.g., generalized hives, itch or flush, swollen lips/tongue/uvula) 
AND 
• 
Airway compromise (e.g., dyspnea, stridor, wheeze/ bronchospasm, hypoxia, reduced 
PEF) AND/OR 
• 
Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to the allergen (min to h): 
• 
Skin/mucosal tissue (e.g., generalized hives, itch/flush, swollen lips/tongue/uvula) 
• 
Airway compromise (e.g., dyspnea, stridor wheeze/bronchospasm, hypoxia, reduced 
PEF) 
• 
Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence) 
• 
Persistent GI symptoms (e.g., nausea, vomiting, crampy abdominal pain) 
3. Reduced BP after exposure to the allergen (min to h): 
• 
Infants and Children: low systolic BP (age-specific) or > 30% drop in systolic BP* 
• 
Adults: systolic BP < 90 mm Hg or > 30% drop from their baseline 
 
* 
Low systolic BP for children is defined as < 70 mmHg from 1 month to 1 year; less 
than (70 mmHg + [2 x age]) from 1-10 years; and < 90 mmHg from age 11-17 years. 
Note: Isolated skin or mucosal lesions following the ingestion of a food constitute a 
“food-induced allergic reaction”. 
 
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Final 
14 May  2014 
 

Allergen Research Corporation  
CONFIDENTIAL 
Page 70 of 71 
Protocol ARC001 Amendment 3 
 
Appendix 4: Allergic Reaction Toxicity Grading 
Current NCI-CTCAE v. 4.03 grading system for allergic reactions defined as a disorder 
characterized by an adverse local or general response from exposure to an allergen.  
 
Table A4-1: Current NCI-CTCAE v. 4.03 Grading System for Allergic Reactions 
Grade 1 - 
Mild 
Grade 2 - Moderate 
Grade 3 – Severe 
Grade 4 – 
Life-
Threatening 
Grade 5 – 
Death 
Transient 
flushing or 
rash, 
drug fever <38 
degrees C 
(<100.4 
degrees F); 
intervention 
not indicated 
Intervention or 
infusion 
interruption indicated; 
responds promptly to 
symptomatic treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics); 
prophylactic 
medications indicated 
for 
<=24 hrs 
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
clinical sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Current NCI-CTCAE v. 4.03 grading system for anaphylaxis reactions defined as a 
disorder characterized by an acute inflammatory reaction resulting from the release of 
histamine and histamine-like substances from mast cells, causing a hypersensitivity 
immune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, 
cyanosis and loss of consciousness and may lead to death. 
 
Table A4-2: Current NCI-CTCAE v. 4.03 Grading System for Anaphylaxis Reactions 
Grade 1 - 
Mild 
Grade 2 - 
Moderate 
Grade 3 - Severe 
Grade 4 – Life-
Threatening 
Grade 5- 
Death 
- 
- 
Symptomatic 
bronchospasm, 
with or without urticaria; 
parenteral intervention 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
These tables will be replaced with the CoFAR specific grading system for allergic 
reactions as displayed in Table A4-3.  
 
 
CPNA Peanut OIT 
Final 
14 May  2014 
 

Allergen Research Corporation  
CONFIDENTIAL 
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Protocol ARC001 Amendment 3 
 
Table A4-3: 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 h), 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 
 
CPNA Peanut OIT 
Final 
14 May  2014