Clinical trial NCT01373242
Conditions: Peanut Hypersensitivity Food Hypersensitivity Food Allergy Peanut Allergy
Sponsor: University of North Carolina, Chapel Hill
Start date: 2011-06-01; Completion date: 2018-04-16
Enrollment: 54 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this study will be to increase the reaction threshold (desensitization) of peanut allergic children using peanut sublingual immunotherapy and to determine if the nonreactive state of the immune system persists after treatment has been discontinued (tolerance).

Detailed description:
Allergy to peanuts and tree nuts affects approximately 1.4% of the population. Allergic reactions to peanut can be severe and life threatening and account for the vast majority of fatalities due to food-induced anaphylaxis. At present, there are no viable treatment options for patients with peanut allergy. The current standard of care is strict dietary elimination and emergency preparedness with an anaphylaxis kit in the event of an accidental reaction.

Our group and others have shown that oral immunotherapy can provide protection from anaphylaxis to a variety of food proteins. In addition, our ongoing research has demonstrated that sublingual immunotherapy to peanut provides a safe, alternative mode of immunotherapy to reduce allergic reaction rates (desensitization) during oral food challenge (OFC) to peanut. The goal of this study will be to desensitize peanut allergic children using peanut sublingual immunotherapy and to determine if the nonreactive state of the immune system persists after treatment has been discontinued (tolerance). Children ages 1-11 years will be enrolled following an entry double blind, placebo controlled food challenge (DBPCFC).

After at least 48 months of peanut SLIT study drug, subjects will undergo a second DBPCFC to 5000 mg of peanut protein to assess desensitization.

* Subjects who are not desensitized are those who are not able to consume more than the MCRT without symptoms, which has been defined as 300 mg of peanut protein. Subjects who consume less than 300 mg of peanut protein without symptoms will stop peanut SLIT and conclude the study. These subjects will not undergo any additional study procedures including the remaining protocol DBPCFCs and will be recommended to resume a strict peanut avoidance diet.
* Subjects who are able to consume more than 300 mg of peanut protein will be randomized to an interval between 1 and 17 weeks during which all peanut including peanut SLIT study drug will be discontinued. This period of avoidance will be followed by a third DBPCFC to 5000 mg of peanut protein to evaluate for the loss of the desensitization effect. After this final DBPCFC, the study will be completed for these subjects. At the primary investigators clinical discretion, they will be recommended to transition to a daily peanut food equivalent to maintain the desensitized effect.

Outcome variables of interest include response to double blind, placebo controlled food challenges, skin prick testing, peanut specific serum immunoglobin E (IgE), immunoglobin G (IgG), and immunoglobin G4 (IgG4) and salivary immunoglobin A (IgA), T and B cell responses, basophil hyporesponsiveness, quality of life, and adverse events.

Arms: arm 1: All subjects will receive peanut SLIT upon enrollment for at least the first 48 months. After the desensitization DBPCFC after at least 48 months of treatment, subjects will be randomized off treatment from 1 to 17 weeks. Subjects will then undergo another DBPCFC.
Interventions: intervention 1: Liquid peanut extract (Peanut SLIT)
Intervention descriptions: intervention 1: Liquid peanut extract will be administered under the tongue

Protocol documents:
Prot_000.pdf: 
PEANUT SUBLINGUAL IMMUNOTHERAPY (SLIT) AND INDUCTION OF 
CLINICAL TOLERANCE IN PEANUT ALLERGIC CHILDREN (TLC) 
Protocol 
 
NCT number NCT01373242 
Document Date 03/02/2016 
 
 
 


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Version 6.0, March 2, 2016                                                                                                             Page 2 of 43 
 
PEANUT SUBLINGUAL IMMUNOTHERAPY (SLIT) AND INDUCTION 
OF CLINICAL TOLERANCE IN PEANUT ALLERGIC CHILDREN (TLC) 
 
Peanut SLIT and Tolerance (TLC) 
 
 
Version 6.0 (March 2, 2016) 
 
 
 
This clinical study is supported by the National Institutes of Allergy and Infectious Diseases 
(NIAID) and conducted in the Allergy, Immunology, and Rheumatology (AIR) Division in 
the Department of Pediatrics at the University of North Carolina at Chapel Hill. 
 
PRINCIPAL INVESTIGATOR   
A. Wesley Burks, MD 
Professor of Pediatrics 
University of North Carolina at Chapel Hill 
Phone: 919-966-4427 
E-mail: wesley.burks@unc.edu 
 
 
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 Dr Burks, unless it is necessary 
to conduct the consent process with potential study participants. 
 
 
 
 


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Protocol Approval 
 
 
 
 
 
 
 
 
UNC IRB#11-2308 
Duke eIRB Protocol# 00029390 
Version/Date: 6.0/March 2, 2016 
IND: 14326 
Principal Investigator:  A. Wesley Burks, MD 
 
Title:  Peanut Sublingual Immunotherapy (SLIT) and Induction of Clinical Tolerance in Peanut Allergic 
Children (TLC) 
 
Short Title:  Peanut SLIT and Tolerance (TLC) 
 
 
I have read the protocol, and I approve it.  As the principal investigator, I agree to conduct this protocol 
according to good clinical practices, which are delineated in the International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use 
“Guidance for Industry: E6 Good Clinical Practice Consolidated Guidance” (May 1996), and according to 
the criteria specified in the protocol. 
 
   _______________________________                                    _______________ 
   Principal Investigator (Print)                                                                Date 
 
 
   _______________________________                                    _______________ 
   Principal Investigator (Signature)                                                          Date 


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Synopsis 
Title 
Peanut Sublingual Immunotherapy and Induction of Clinical Tolerance in Peanut Allergic 
Children (TLC) 
Short Title 
Peanut SLIT and Tolerance 
Clinical Phase 
Phase I/II – Safety and Efficacy 
IND 
14326 
Sponsor 
A. Wesley Burks, MD 
Principal Investigator  
A. Wesley Burks, MD  
Participating Site 
University of North Carolina at Chapel Hill (after March 26, 2012)  
Prior to March 26, 2012: Duke University Medical Center, Durham, NC 
Accrual Objective 
55 subjects to allow for 45 subjects to complete study interventions 
Study Design 
A prospective, randomized open-label study to assess the induction of desensitization after at 
least 48 months of peanut sublingual immunotherapy (SLIT) and the persistence of 
desensitization (sustained unresponsiveness) following a period of up to 17 weeks of peanut 
avoidance. 
Study Duration 
Up to 66 months per subject; Duration varies dependent upon subject’s randomized period of 
study drug withholding. 
Primary Endpoints 
• An estimate of the population sensitization threshold as assessed by the 48th month DBPCFC, 
predicted to provoke reactions in 5% and 10% of the peanut-allergic population. 
• Multiplicative or differential change in the population sensitization threshold as assessed by 
the 48th month DBPCFC with a unit change in covariates. 
• An estimate of time to loss of desensitization for the following events: 
-   Subject's true sensitivity threshold to reduce by half.  
-   Subject's true sensitivity threshold to maintain at the same level of LOAEL.  
-   Subject's true sensitivity threshold to drop by at least one level of LOAEL. 
-   Subject's true sensitivity threshold to remain at or above MCRT. 
• Estimates of the proportion of patients at a fixed time for any of the above events that define 
loss of desensitization.  
• Multiplicative change in hazard of loss of desensitization with a unit change in covariates. 
Secondary Endpoints 
• Comparative estimates of changes in immune parameters over time among subjects who were 
induced with clinical desensitization versus those who failed.  Changes coinciding with the 
loss of desensitization would also be studied. 
• Incidence of all adverse events and serious adverse events during the study. 
• Incidence of all gastrointestinal and possible gastrointestinal eosinophilic adverse events. 
 
Inclusion Criteria 
• Age 1-11 years of either sex, any race, any ethnicity with a convincing clinical history of 
peanut allergy or an in vitro peanut-specific IgE [CAP-FEIA] > 0.35 kUA/L; and,  
• A positive result to 1000 mg peanut protein DBPCFC after enrollment (during screening or 
baseline visit); and,  
• Written consent including assent where indicated 
 
OR 
 
• Duke IRB approved enrollment exception for those subjects from Duke IRB Pro0003579, 
UNC IRB 11-2301, “Sublingual Immunotherapy for Peanut Allergy: A Randomized, Double-
Blind, Placebo-Controlled, Phase I/II Pilot Study with a Whole Peanut Extract, CoFAR 4” 
who did not pass the 164 week (3 years) end of study 10 gm peanut DBPCFC. 


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Exclusion Criteria 
• History of severe anaphylaxis to peanut, defined as hypoxia, hypotension, or neurologic 
compromise (cyanosis or SpO2 < 92% at any stage, hypotension, confusion, collapse, loss of 
consciousness, or incontinence) 
• Participation in any interventional study for the treatment of food allergy in the past 6 
months, unless an exception is IRB approved 
• Known oat, wheat, or glycerin allergy 
• Eosinophilic or other inflammatory (e.g. celiac) gastrointestinal disease 
• Severe asthma (2007 NHLBI Criteria Steps 5 or 6 – Appendix 2) 
• Inability to discontinue antihistamines for skin testing and DBPCFCs 
• Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or 
sublingual) or immunomodulator therapy (not including corticosteroids) or biologic therapy 
within the past year 
• Use of β-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-
receptor blockers (ARB) or calcium channel blockers 
• Significant medical condition (e.g., liver, kidney, gastrointestinal, cardiovascular, 
hematologic, or pulmonary disease) which would put the subject at risk for induction of food 
reactions 
Study Intervention 
Description 
The study is a prospective, randomized, open-label trial based on previous experience at Duke 
University with peanut-allergic subjects.  We will enroll 55 participants to receive at least 48 
months of open label peanut SLIT and continue with study interventions described.   
 
The peanut SLIT study drug Build-Up Phase dosing (approximately 20 weeks) is outlined 
below. 
 
 
After completing the build-up phase, subjects will continue on a daily maintenance dose of 
4000 mcg of peanut protein via SLIT doses.   
 
Following at least 48 months of open SLIT study drug (including the build-up phase), subjects 
will undergo a DBPCFC to verify desensitization (i.e., an increase in reaction threshold while 
receiving peanut SLIT study drug).  
Dose # 
 
Peanut 
Dilution 
 
Pumps 
Dose of 
Peanut 
Protein 
Interval in 
Weeks 
%  Increase 
1 
1/100 
1 
2.5 mcg 
 
- 
2 
1/100 
2 
5 mcg 
1 
100% 
3 
1/100 
4 
10 mcg 
1 
100% 
4 
1/100 
8 
20 mcg 
1 
100% 
5 
1/10 
1 
25 mcg 
1 
25% 
6 
1/10 
2 
50 mcg 
1 
100% 
7 
1/10 
4 
100 mcg 
1 
100% 
8 
1/10 
8 
200 mcg 
1 
100% 
9 
Full 
concentration 
1 
250 mcg 
2 
25% 
10 
Full 
concentration 
2 
500 mcg 
2 
100% 
11 
Full 
concentration 
4 
1000 mcg 
2  
100% 
12 
Full 
concentration 
8 
2000 mcg 
2 
100% 
13 
Full 
concentration 
12 
3000 mcg 
2 
50% 
14 
Full 
concentration 
16 
4000 mcg 
2 
33% 


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• 
Subjects who are unable to consume > (more than) 300 mg of peanut protein without 
symptoms will complete the study and not proceed to further evaluations.  These 
subjects will be recommended to resume strict peanut avoidance. 
• 
Subjects who are able to consume > (greater than or equal to) 300 mg of peanut protein 
without symptoms will be randomized to withhold study drug and all peanut 
consumption for a period between 1 and 17 weeks.  This avoidance period will be 
followed by a DBPCFC to assess persistence of the desensitization effect (sustained 
unresponsiveness). 
After this final DBPCFC, the study will be completed and the subject will be 
recommended to transition to a daily peanut food equivalent. 
Study Procedures 
The following procedures will be performed according to the schedule in Appendix 1: 
• Medical and allergy history (including dietary history) 
• Physical examination 
• Peak flow rates (if capable) 
• Serum analysis for peanut-specific immunoglobulins (ImmunoCAP) 
• Whole blood for basophil activation and T-cell studies 
• Sublingual Immunotherapy (SLIT) 
• Double-blind, placebo-controlled, food challenge (DBPCFC) to peanut 
• Endpoint titration peanut skin prick testing 
• Saliva collection for immunoglobulin studies 
Study Stopping Rules 
• Any death related to study drug dosing. 
• Greater than 2 severe anaphylactic reactions related to study drug dosing at any stage of the 
protocol. 
• Greater than 3 subjects who require more than 1 intramuscular epinephrine injection during 
dose escalation or maintenance dosing of study drug. 
 
If any of the above occurs, enrollment and updosing will be halted until there’s a review by the 
DSMB, FDA, and IRB.   


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Table of Contents 
1.1 
BACKGROUND ...................................................................................................................................11 
1.2 
RATIONALE .......................................................................................................................................11 
1.3 
RATIONALE FOR SELECTION OF STUDY POPULATION ...................................................................................12 
1.4 
KNOWN AND POTENTIAL RISKS AND BENEFITS TO HUMAN PARTICIPANTS .......................................................12 
1.4.1 
Risks ........................................................................................................................................12 
1.4.2 
Benefits ...................................................................................................................................13 
2. 
OBJECTIVES .........................................................................................................................................14 
2.1 
PRIMARY AND SECONDARY OBJECTIVES ...................................................................................................14 
STUDY DESIGN............................................................................................................................................16 
2.2 
STUDY ENDPOINTS..............................................................................................................................16 
2.2.1 
Primary Endpoint .....................................................................................................................16 
2.2.2 
Secondary Endpoints ...............................................................................................................17 
2.3 
STUDY STOPPING RULES ......................................................................................................................17 
3. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ..............................................................................18 
3.1 
INCLUSION CRITERIA ...........................................................................................................................18 
3.2 
EXCLUSION CRITERIA ...........................................................................................................................18 
3.3 
PREMATURE INTERVENTION HALTING, TERMINATION OR PARTICIPANT WITHDRAWAL .......................................18 
3.3.1 
Criteria ....................................................................................................................................18 
4. 
STUDY DRUG .......................................................................................................................................20 
4.1 
FORMULATION, PACKAGING, AND LABELING ............................................................................................20 
4.2 
PREPARATION, ADMINISTRATION, AND DOSAGE .......................................................................................20 
4.3 
DRUG ACCOUNTABILITY .......................................................................................................................20 
4.4 
ASSESSMENT OF COMPLIANCE WITH STUDY DRUG DOSING AND MONITORING ................................................20 
4.5 
MODIFICATION OF STUDY DRUG DOSES ..................................................................................................20 
4.6 
CONCOMITANT MEDICATIONS ..............................................................................................................20 
4.7 
RESCUE MEDICATIONS ........................................................................................................................21 
4.8 
PROHIBITED MEDICATIONS ...................................................................................................................21 
5. 
STUDY DEFINITIONS AND PROCEDURES ..............................................................................................22 
5.1 
STUDY DEFINITIONS ............................................................................................................................22 
5.1.1 
Anaphylaxis .............................................................................................................................22 
5.1.2 
Criteria for Diagnosis ...............................................................................................................22 
5.2 
ENROLLMENT ....................................................................................................................................22 
5.3 
SCREENING VISIT ................................................................................................................................22 
5.4 
BASELINE VISIT ..................................................................................................................................23 
5.5 
STUDY DRUG/INTERVENTION VISITS .......................................................................................................23 
5.6 
DOUBLE BLIND PLACEBO CONTROLLED FOOD CHALLENGE (DBPCFC)............................................................24 
5.7 
SKIN PRICK TEST.................................................................................................................................25 
5.8 
VISIT WINDOWS ................................................................................................................................25 


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5.9 
STUDY RANDOMIZATION PROCEDURES....................................................................................................26 
6. 
SAFETY MONITORING .........................................................................................................................27 
6.1 
PROCEDURES AND MONITORING ...........................................................................................................27 
6.2 
DEFINITIONS .....................................................................................................................................27 
6.2.1 
Adverse Event (AE) or Medical Event ........................................................................................27 
6.2.2 
Serious Adverse Event (SAE) .....................................................................................................27 
6.2.3 
Unexpected Adverse Event.......................................................................................................28 
6.3 
TOXICITY GRADING .............................................................................................................................28 
6.3.1 
Relationship to Procedure Definitions ......................................................................................29 
6.4 
ADVERSE EVENTS COLLECTION PROCEDURES ............................................................................................29 
6.4.1 
Recording and Reporting Procedures .......................................................................................30 
6.4.2 
SAE Recording and Reporting...................................................................................................30 
6.5 
SERIOUS ADVERSE EVENT NOTIFICATION .................................................................................................30 
6.5.1 
Notifying the FDA, IRB, and DSMB ...........................................................................................30 
6.5.2 
Reporting Criteria ....................................................................................................................30 
7. 
MECHANISTIC ASSAYS .........................................................................................................................31 
7.1 
SERUM SPECIFIC IGE, IGG, IGG4, AND IGA ..............................................................................................31 
7.2 
SALIVARY SPECIFIC IGA, SECRETORY-IGA, IGG, IGE, AND IGM......................................................................31 
7.3 
CYTOKINE MEASUREMENTS...................................................................................................................32 
7.4 
TREG ASSAY ........................................................................................................................................32 
7.5 
BASOPHIL ACTIVATION ASSAY ...............................................................................................................32 
8. 
STATISTICAL CONSIDERATIONS ...........................................................................................................33 
8.1 
STUDY ENDPOINT ASSESSMENT .............................................................................................................33 
8.1.1 
Primary Endpoint .....................................................................................................................33 
8.1.2 
Secondary Endpoints ...............................................................................................................33 
8.2 
SUBJECT AND DEMOGRAPHIC DATA........................................................................................................34 
8.2.1 
Baseline Characteristics and Demographics .............................................................................34 
8.2.2 
Study Completion ....................................................................................................................34 
8.3 
INTERIM ANALYSES TO ENSURE SAFETY ...................................................................................................34 
9. 
IDENTIFICATION AND ACCESS TO SOURCE DATA ................................................................................35 
9.1 
DATA MANAGEMENT ..........................................................................................................................35 
9.2 
ACCESS TO DATA ................................................................................................................................35 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................36 
10.1 
DATA HANDLING ..............................................................................................................................36 
11. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE .............................37 
11.1 
STATEMENT OF COMPLIANCE ..............................................................................................................37 
11.2 
CONSENT AND ASSENT PROCESS ..........................................................................................................37 
11.3 
PRIVACY AND CONFIDENTIALITY ...........................................................................................................37 


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12. 
RESOURCE SHARING..........................................................................................................................38 
13. 
APPENDIX 1. SCHEDULE OF EVENTS ..................................................................................................40 
14. 
APPENDIX 2. EVALUATION OF ASTHMA ............................................................................................41 
15. 
APPENDIX 3. REFERENCES .................................................................................................................42 
 


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Glossary of Abbreviations 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTC 
Common Toxicity Criteria 
CTRC 
Clinical Translational Research Center 
DBPCFCs = OFC 
Double-Blind, Placebo-Controlled Food Challenges = Oral Food Challenge 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
Enrolled 
Signed consent 
EPIT 
Epicutaneous Immunotherapy 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IDS 
Investigational Drug Service 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
kU/L 
Kilounits per Liter 
MCRT 
Minimal Clinically Relevant Threshold 
NIAID 
National Institute of Allergy and Infectious Diseases 
OIT 
Oral Immunotherapy 
PBMC 
Peripheral Blood Mononuclear Cells 
PI 
Principal Investigator 
PST 
Skin Prick Tests 
SAE 
Serious Adverse Event 
SLIT 
Sublingual Immunotherapy 
SU 
Sustained Unresponsiveness 
TReg 
T regulatory cell 
UNC 
University of North Carolina at Chapel Hill 
 
 
 
 
 
 
 
 


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1. BACKGROUND AND RATIONALE 
 
1.1 
Background 
Approximately 4% of the American population suffers from food allergy [1].  More specifically, 
over 3 million Americans are affected by an allergy to peanuts, tree nuts, or both, and the 
prevalence has continued to rise over the past decade particularly in the pediatric population [2].  In 
addition, peanut allergy is the leading cause of fatal allergic reactions in the United States [3, 4].  
Currently, the standard of care for peanut allergy is a strict avoidance of peanut and ready-access to 
self-injectable epinephrine; however, implementation of an avoidance diet is complex and 
accidental ingestions are common.  In one report, up to 50% of food-allergic patients had an allergic 
reaction during a two-year period [5].  More recent data shows that the annual incidence rate for 
food allergic reactions following accidental exposure is ~15% for children with peanut allergy [6].  
Since only 20% of peanut allergy is estimated to be naturally outgrown, the majority of patients face 
a life-long risk of anaphylaxis and death [7, 8]. 
 
1.2 
Rationale 
Traditional subcutaneous immunotherapy is useful in treating forms of inhalant and venom allergies 
but has proven unsafe in treating food allergy [9, 10].  Oral immunotherapy (OIT) has been reported 
by the Burks research group and others to result in protection from anaphylaxis to a variety of food 
proteins [11-19].  In a recent open-label peanut OIT trial by Jones et al., 27 of 29 subjects receiving 
a daily maintenance dose successfully passed an open food challenge to 3900 mg of peanut protein. 
This and other ongoing studies by the Burks group have demonstrated that OIT induces clinical 
desensitization to peanut, with humoral and cellular changes suggestive of the development of long-
term tolerance [12].   Furthermore, peanut OIT appears to be safe in children with peanut allergy 
treated in a controlled setting by trained personnel [20].   
 
Sublingual immunotherapy (SLIT) has also been proposed as a safe, alternative form of 
immunotherapy to reduce clinical reaction rates during oral food challenge for adults with hazelnut 
[21] or kiwi allergy [22].   Dr. Burks’ research team has shown that 12 months of peanut SLIT is 
able to induce an increase in reaction threshold while receiving the SLIT study drug, i.e., clinical 
desensitization [23].  While clinical desensitization is demonstrated in almost all OIT and SLIT 
studies for food allergy, tolerance, which refers to a non-reactive state of the immune system that 
persists after discontinuation of peanut study drug, has only rarely been tested and requires further 
study.  Recent data presented by Dr. Burks’ research team since the onset of this trial has shown 
that basophils return to their reactive state after the discontinuation of immunotherapy ([24]).  This 
suggests that the effect of OIT and SLIT may be transient with the development of true 
immunological tolerance only a rare occurrence.  On this background, the term sustained 
unresponsiveness (SU) was coined ([25]) to refer to the phenomenon of a non-reactive state that 
persists after discontinuation of therapy but wanes after a period of time. 
 
Various studies of OIT and SLIT have looked at SU but these studies have been small and 


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heterogeneous making it difficult to make generalizations [17, 26, 27].  The loss of SU and the 
desensitization effect has not yet been studied in a systematic fashion within a single population.  
With the FDA approval of food immunotherapy potentially on the horizon, practical questions have 
arisen including questions about the frequency of dosing and the response to missed doses due to 
illness, non-compliance, or other factors.  We hope that an understanding of the characteristics of 
SU will provide important clinical data in anticipation of the broader use of immunotherapy for 
food allergy while giving further insights into the immune mechanisms of desensitization, SU, and 
the loss of SU. 
 
1.3 
Rationale for Selection of Study Population 
We will enroll subjects between 1 and 11 years who have a history of clinical allergy to peanut or 
serologic evidence of allergic sensitization with a specific IgE>0.35 kU/L to peanut.  The age group 
for study was selected based on our ongoing peanut SLIT trial (NCT# 00597727; UNC IRB 11-
2296; Duke Pro00001553) which has demonstrated successful desensitization to peanut in this age 
group.   
 
 
1.4 
Known and Potential Risks and Benefits to Human Participants 
 
1.4.1 Risks 
The build-up and daily maintenance doses of SLIT may cause allergic symptoms including 
sneezing, rhinorrhea, urticaria, angioedema, flushing, flares of eczema, ocular, nasal, oral and/or 
throat pruritus, throat tightness, nausea, vomiting, abdominal discomfort, cough, wheezing, and/or 
shortness of breath in addition to severe anaphylaxis.  The most common symptom associated with 
SLIT dosing is oropharyngeal itching present in 9.3% of all doses.  As of October 24, 2012,no 
subject in our ongoing SLIT study (NCT# 00597727; UNC IRB 11-2296; Duke Pro00001553) has 
had dosing-related anaphylaxis requiring treatment with epinephrine [23].  The likelihood of a 
subject experiencing allergic symptoms will be lessened by starting at small amounts of the peanut 
protein for dosing per this SLIT protocol.   
 
Double-blind, placebo-controlled food challenges (DBPCFC) may induce an allergic response with 
symptoms similar to those described for SLIT dosing.  The risk of a severe allergic reaction is 
reduced by conducting the challenge in a monitored clinic setting, 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 (subjects will have an IV catheter in place during all 
DBPCFCs).  Trained personnel, including a physician, as well as medications and equipment, will 
be immediately available to treat any reaction. 
 
Other risks include those related to blood drawing and skin testing.  Blood drawing may aggravate a 
pre-existing anemic condition, but this risk is minimized by restricting the volume drawn to a 
maximum of 3 ml per kg in accordance with United States Department of Health and Human 
Services recommendations [28].  Additional risks are those attendant to any needle puncture, 
including slight bruising, local infection, or the possibility of the subject fainting.   
 


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Skin prick tests (not intradermal) will be performed by techniques reflecting general standard of 
care and cause discomfort (the sensation of a scratch and a pruritic, transient hive may result).  Such 
tests could theoretically induce a systemic allergic reaction, but this is exceedingly rare.  
 
1.4.2 Benefits  
The immediate benefits for the subject include the possibility of a decrease in clinical reactivity to 
peanut and diminished allergic reaction following an accidental ingestion of peanut, as well as the 
possibility of altering the natural course of the peanut allergy.  Additionally, subjects may develop 
lasting desensitization to peanut off of therapy, which is otherwise not likely to happen.  Should 
persistence of desensitization occur, subjects could have the ability to broaden their diet and 
experience an improved quality of life with less of the restrictions imposed by a life-threatening 
food allergy.  This study will also help to expand the knowledge of food allergy in general and may 
lead to new management and therapeutic protocols for individuals with other food allergies. 


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2. 
OBJECTIVES 
2.1 
Primary and Secondary Objectives 
Our central hypothesis is that peanut SLIT will induce clinical desensitization after at least 48 
months of peanut SLIT that will persist for a period of time after the discontinuation of therapy.  We 
will address our hypothesis through investigations focused on the following objectives:  
Primary Objective:  
First, we aim to estimate the population sensitization threshold, the dose predicted to provoke 
reactions in X% of the peanut-allergic population after at least 48 months of peanut SLIT treatment.  
Second, given the above estimated population sensitization threshold and the administered dose 
levels that it lies between, we would like to characterize the SU curve with respect to time for 
several end points including time for desensitization threshold as assessed by the final DBPCFC to 
reduce by half of the estimated sensitization threshold, to drop by a level of the administered dose 
level, to remain above minimal clinically relevant threshold (MCRT) and finally, to maintain 
threshold constancy. 
 
Purpose and expectations:   
This two-part primary objective is designed to estimate the level of desensitization induced by 
peanut SLIT through determination of the population sensitization threshold and to characterize its 
potential for SU by calculation of a desensitization decay curve.  We expect to demonstrate 
successful desensitization above the MCRT (300 mg peanut protein) for the population and to 
demonstrate SU for a period of time between 1 and 17 weeks after discontinuation of peanut SLIT 
therapy. 
 
The studies under the Primary Objective will determine the level of protection against accidental 
ingestions of peanut provided by peanut SLIT therapy.  These results will further determine whether 
peanut SLIT can be considered a viable option alongside OIT and EPIT for peanut allergy.  In 
addition, the studies will provide data regarding the duration of the desensitization effect which may 
have important clinical ramifications on the optimal dosing interval and the effect of missed 
doses/non-compliance.  These results could also shed further insight into the immune mechanisms 
involved in the development and loss of desensitization. 
 
Secondary Objectives: 
Objective #2: To evaluate the safety of SLIT regimen administered over the study period. 
Purpose and Expectations: 
Through Objective #2, we will determine the percentage of adverse events (AE) and serious adverse 
events (SAE) due to peanut SLIT dosing.  There will be a particular focus on symptoms that require 
treatment and/or hospitalization, symptoms that may lead to poorer compliance, and gastrointestinal 
symptoms suggestive of eosinophilic disease.  We expect that SAEs will be extremely rare.  We 
expect AEs to be more common but to be mostly comprised of transient oropharyngeal itching that 
does not affect compliance.  We expect symptoms of GI and eosinophilic disease to be rare as very 
little peanut is ingested by the GI route with peanut SLIT 
 


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Objective #3: To study the changes in immune parameters over time and compare these changes 
among subjects who were successfully desensitization vs. those who failed.  Changes coinciding 
with the loss of desensitization would also be studied. 
 
Purpose and Expectations: 
Through Objective #3, we will seek to understand the molecular processes by which SLIT affects 
the immune system through evaluation of immune mechanisms in relationship to clinical findings of 
desensitization.  We will delineate the impact of peanut SLIT on the subsequent cellular and 
humoral responses to peanut protein: 1) peanut specific IgE, IgG, and IgG4 response, 2) peanut 
specific basophil activation, 3) mast cell responses through skin prick testing, and 4) specific T-cell 
cytokine responses and T regulatory cell (TReg) activation.   We anticipate that the effect of peanut 
SLIT will occur by induction of TRegs, conversion of T cells from an allergic (Th2) to a non-allergic 
(Th1) lymphocyte response (measured by cytokines, antibody levels, and skin prick test size), a 
change in peanut-specific basophil activation, or through a combination of the above.   
 
Based on mechanistic studies of subcutaneous immunotherapy for allergic rhinitis[29], OIT for food 
allergies [12], and our previous work with SLIT for peanut allergies[23], our expectation is that the  
immunoglobulin response will change over time resulting in a decrease in peanut-specific IgE and 
an increase in peanut-specific IgG and IgG4.  We anticipate an increase in TReg specific cytokines, 
such as IL-10 and TGF-beta, that will parallel early clinical responses and indicate immune 
deviation toward tolerance.  The conversion from Th2 to Th1 cytokine responses would have a 
similar clinical effect of making a subject less sensitive to peanuts, but this would likely occur 
through an alternative mechanism or a mechanism combining TReg activation with other T cell 
changes.  A change in basophil activation would indicate that subjects would be less sensitive to 
peanut, and we anticipate that response would be in parallel to the finding of clinical desensitization 
but may not indicate clinical tolerance development.  Overall, we will assess these immune 
parameters over time and in conjunction with clinical levels of reactivity to determine which 
mechanism(s) is relevant for effective peanut SLIT in desensitization and ultimately the 
maintenance or loss of desensitization. 
 
Objective #4: To evaluate association of baseline characteristics with desensitization as assessed by 
the 48th month DBPCFC and with loss of desensitization as assessed by the final DBPCFC. 
 
Purpose and Expectations: 
Preliminary data using peanut SLIT suggested a range of responses to treatment.  Through objective 
#4, we will seek to identify characteristics such as demographics and specifics about the subject’s 
allergy history that may predict a positive response to treatment and in the future allow providers to 
target treatment to appropriate patients. 


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STUDY DESIGN 
This SLIT study is a prospective, randomized, open-label study based on previous experience at 
Duke University Medical Center using OIT and SLIT in food allergic subjects.  The study will 
enroll 55 participants with peanut allergy with a goal of 50 children completing protocol 
interventions.  Upon enrollment, all subjects will undergo an entry DBPCFC with 1000 mg of 
peanut protein to confirm the peanut allergy diagnosis and establish a baseline threshold level.  
Following a positive DBPCFC, each subject will begin the study drug with peanut SLIT at a starting 
dose of 1 pump of a 1/100 dilution of peanut concentrate (2500 mcg peanut protein).  During the 
build-up phase which lasts approximately 20 weeks (Table 1), subjects will dose daily and increase 
the number of pumps every 1-2 weeks as per the dosing schedule.  Subjects return to the research 
unit for observed dosing with each change in peanut SLIT dilution (1/100, 1/10, full concentration) 
and with every other dose increase on full concentration until the maintenance dose of 16 pumps of 
full concentration peanut SLIT (4000 mcg peanut protein) is achieved.  Subjects will then continue 
daily administration of the maintenance dose and return every 6 months for follow-up.  
  
After at least 48 months of peanut SLIT study drug, subjects will undergo a second DBPCFC to 
5000 mg of peanut protein to assess desensitization.   
• Subjects who are not desensitized are those who are not able to consume more than the 
MCRT without symptoms, which has been defined as 300 mg of peanut protein.  
Subjects who consume less than 300 mg of peanut protein without symptoms will stop 
peanut SLIT and conclude the study.  These subjects will not undergo any additional 
study procedures including the remaining protocol DBPCFCs and will be recommended 
to resume a strict peanut avoidance diet. 
 
• Subjects who are able to consume more than 300 mg of peanut protein will be 
randomized to an interval between 1 and 17 weeks during which all peanut including 
peanut SLIT study drug will be discontinued.  This period of avoidance will be followed 
by a third DBPCFC to 5000 mg of peanut protein to evaluate for the loss of the 
desensitization effect.  After this final DBPCFC, the study will be completed for these 
subjects.  At the primary investigators clinical discretion, they will be recommended to 
transition to a daily peanut food equivalent to maintain the desensitized effect. 
 
 
2.2 
Study Endpoints  
2.2.1 Primary Endpoint  
 
The primary efficacy endpoints are:  
• An estimate of the dose as assessed by the 48th month DBPCFC, also called population 
sensitization threshold, predicted to provoke reactions in 5% and 10% of the peanut-allergic 
population.  This will also give population level NOAEL and LOAEL that would define 
interval of consecutive administered dose levels within which the population sensitization 
threshold lies. 
• Multiplicative or differential change in the population sensitization threshold as assessed by 
the 48th month DBPCFC with a unit change in covariates. 
• An estimate of time to loss of desensitization for the following events: 


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-   Subject's true sensitivity threshold to reduce by half, also called half-life of sensitivity   
threshold.  
-   Subject's true sensitivity threshold to maintain at the same level of LOAEL.  
-   Subject's true sensitivity threshold to drop by at least one level of LOAEL. 
-   Subject's true sensitivity threshold to remain at or above MCRT. 
• Estimates of the proportion of patients at a fixed time for any of the above events that define 
loss of desensitization (bullet 2).  
• Multiplicative change in hazard of loss of desensitization with a unit change in covariates. 
 
2.2.2 Secondary Endpoints 
 
Secondary efficacy endpoints include: 
• Comparative estimates of changes in immune parameters over time among subjects who 
were induced with clinical desensitization versus those who failed.  Changes coinciding with 
the loss of desensitization would also be studied. 
• Incidence of all adverse events and serious adverse events during the study. 
• Incidence of all gastrointestinal and possible gastrointestinal eosinophilic adverse events. 
 
2.3 
Study Stopping Rules 
Study enrollment and updosing will be put on hold until after review by the Principal Investigator, 
IRB, and Data Safety Monitoring Board (DSMB) if any of the following occurs:  
1.Any death related to study drug dosing 
2.More than 2 severe anaphylactic reactions related to study drug dosing at any stage of the 
protocol 
3.More than 3 subjects who require more than 1 injection of intramuscular epinephrine during 
dose escalation or maintenance dosing of the study drug. 
 


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3. 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
3.1 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for study interventions: 
1. Age 1 to 11 years, either sex, any race, any ethnicity with a convincing clinical history of 
clinical allergy to peanut or an in vitro peanut-specific IgE [CAP-FEIA] > 0.35 kU/L 
2. A positive 1000 mg DBPCFC to peanut protein after enrollment. 
3. Written consent from participant’s parent/guardian, including assent where indicated. 
4. Subjects completing Duke IRB Pro0003579, UNC IRB 11-2301  Sublingual 
Immunotherapy for Peanut Allergy: A Randomized, Double-Blind,Placebo-
Controlled, Phase I/II Pilot Study with a Whole Peanut Extract, CoFAR4 who do not 
pass the 164 week (3 years) end of study 10 gm DBPCFC to peanut.  Duke IRB approved 
this enrollment exception.      
 
3.2 
Exclusion Criteria  
Individuals who meet any of these criteria are not eligible for enrollment as study participants: 
• History of severe anaphylaxis to peanut, defined as hypoxia, hypotension, or neurologic 
compromise (cyanosis or SpO2 < 92% at any stage, hypotension, confusion, collapse, loss of 
consciousness, or incontinence) 
• Participation in any interventional study for the treatment of food allergy in the past 6 
months, unless an exception is IRB approved 
• Known oat, wheat, or glycerin allergy 
• Eosinophilic or other inflammatory (e.g. celiac) gastrointestinal disease 
• Severe asthma (2007 NHLBI Criteria Steps 5 or 6 – Appendix 2) 
• Inability to discontinue antihistamines for skin testing and DBPCFCs 
• Use of omalizumab or other non-traditional forms of allergen immunotherapy (e.g., oral or 
sublingual) or immunomodulator therapy (not including corticosteroids) or biologic therapy 
within the past year 
• Use of β-blockers (oral), angiotensin-converting enzyme (ACE) inhibitors, angiotensin-
receptor blockers (ARB) or calcium channel blockers 
• Significant medical condition (e.g., liver, kidney, gastrointestinal, cardiovascular, 
hematologic, or pulmonary disease) which would make the subject unsuitable for induction 
of food reactions 
 
3.3 
Premature Intervention Halting, Termination or Participant Withdrawal  
3.3.1 Criteria 
No subject initiating SLIT in this trial will be replaced. 
 
Participants may be withdrawn from the SLIT study drug and/or the protocol if: 
• Significant clinical symptoms (respiratory, GI, skin) are experienced at home after taking the 
study drug daily dose  
• Poor control or persistent activation of secondary atopic disease (e.g. atopic dermatitis, asthma) 
• Non-adherence with home dosing protocol (i.e., excessive missed dosing days or missed 
appointments) would be a safety issue warranting discontinuation 


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• Started on Angiotensin II Receptor Blockers ARBs, ACE inhibitors, beta-blockers, or other 
prohibited medications with no alternative options per the prescribing physician, will be 
withdrawn from study 
• Pregnancy.  A serum pregnancy test will be performed at the onset of menses, and a history 
of the menstrual cycle will be obtained at regular intervals.  Urine pregnancy tests will be 
performed prior to DBPCFCs and at any other time point if warranted.   Participants who 
become pregnant will be withdrawn from the study drug and may remain in follow-up.   
• The participant (parent) elects to withdraw consent from all future study activities, including 
follow-up 
• The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts 
to reestablish contact with the participant have failed)  
• 
The participant dies 
 
Participants who prematurely stop study drug interventions (i.e., study drug) for any reason, 
may continue in follow-up.   
 


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4. 
STUDY DRUG 
4.1 
Formulation, Packaging, and Labeling 
The study drug will be liquid peanut extract (5000 mcg/ml peanut protein) manufactured by and 
commercially purchased from Greer Laboratories, Inc. in Lenoir, NC.  Study drug will be delivered 
to the unblinded research technician in the site laboratory (PI, Burks).  A certificate of analysis for 
the peanut extract is on file in Dr. Burks’ laboratory, GMP facility.  Glycerinated saline solution 
will be added to make the appropriate dilutions (Table 1).  The study drug will be distributed to the 
study personnel in 32.6 ml plastic vials with each pump dispensing 50 microliters of study drug.  
Individual vials will be labeled with the dilution and the number of pumps to be dispensed daily. 
After the research technician has delivered the study drug vials to the study coordinator, the study 
coordinator will verify that the dilution and the number of daily pumps matched the participant’s 
current prescription.  The subject’s ID and randomization number will also be confirmed prior to 
giving the vials to the participant or participant’s care provider.  
 
4.2 
Preparation, Administration, and Dosage 
For home dose administration the family will be provided with individual 32.6 ml vials of the 
appropriate dilution along with instructions regarding the number of pumps to dispense.  
Participants will be given an adequate supply for the interval between scheduled visits with an 
additional supply to be used in the event of missed or cancelled study visits.  The pumps are to be 
administered below the tongue and held in place for as long as possible for up to 2 minutes before 
swallowing.  The subjects should have nothing to eat or drink 15 minutes before or 30 minutes after 
dosing.  At least 12 hours should pass between doses.  The participant/parents are instructed to keep 
vials under refrigeration at home.   
 
4.3 
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 (participant-by-participant 
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.  Each 
participant will have a current drug-dispensing log.  This log will contain the identification of each 
participant and the date and quantity of drug dispensed. 
 
4.4 
Assessment of Compliance with Study Drug Dosing and Monitoring 
Families will document daily dosing of the study drug and any reaction from at home dosing by 
diary logs.  Additionally, the families will be instructed to return all empty vials as well as all 
unused study drug at each visit.  Families will be provided 24-hour emergency contact information. 
 
4.5 
Modification of Study Drug Doses 
If the subject is unable to tolerate the scheduled dose, the study physician may choose to delay or 
adjust dose and scheduling. 
 
4.6 
Concomitant Medications  
All subjects may continue their usual medications, including those taken for asthma, allergic rhinitis 
and atopic dermatitis, during the study.  However, participants must be able to temporarily 


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discontinue antihistamines (5 half-lives of the antihistamine) prior to skin prick testing and 
DBPCFCs.  Regular topical steroids use is permitted at the time of skin testing.  Allergen 
maintenance immunotherapy for environmental allergies may be continued during the study.  
 
4.7 
Rescue Medications  
Treatment of individual allergic reactions during peanut SLIT should be with an antihistamine 
and/or epinephrine, along with IV fluids, albuterol, steroids, and H2 blockers as indicated.  All 
subjects and/or family member must have an appropriate self-injectable epinephrine device  
available throughout the study for emergency use.  Subjects and parents will be trained in proper 
use of the device and must be able to demonstrate proper technique.  All subjects are given a food 
allergy action plan to implement in the event of an allergic reaction. 
 
4.8 
Prohibited Medications  
o Omalizumab (Xolair) 
o Systemic corticosteroids of longer than 3 weeks duration at any time during the study 
o Beta-blockers (oral) 
o Angiotensin-converting enzyme (ACE) inhibitors 
o Angiotensin-receptor blockers (ARB) 
o Calcium channel blockers 


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5. 
STUDY DEFINITIONS AND PROCEDURES 
5.1 
Study Definitions 
 
5.1.1 Anaphylaxis 
Anaphylaxis is a generalized allergic reaction that is rapid in onset and may progress to death. 
5.1.2 Criteria for Diagnosis  
Anaphylaxis is likely when any one of the three following sets of criteria is fulfilled: 
1. 
Acute onset of an illness (minutes to hours) with involvement of: 
1.Skin/mucosal tissue (e.g., generalized hives, itch or flush, swollen lips/tongue/uvula)  AND 
2.Skin/mucosal tissue (e.g., generalized hives, itch or flush, swollen lips/tongue/uvula)  AND 
3.Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence) 
2. 
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
subject (minutes to hours): 
1.Skin/mucosal tissue (e.g., generalized hives, itch/flush, swollen lips/tongue/uvula) 
2.Airway compromise (e.g., dyspnea, stridor wheeze/bronchospasm, hypoxia, reduced PEF) 
3.Reduced BP or associated symptoms (e.g., hypotonia, syncope, incontinence) 
4.Persistent GI symptoms (e.g., nausea, vomiting, crampy abdominal pain) 
3. 
Reduced BP after exposure to known allergen for that subject (minutes to hours): 
1.Infants and Children: low systolic BP (age-specific) or > 30% drop in systolic BP* 
2.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. 
 
5.2 
Enrollment 
Up to 55 children may be enrolled in this protocol, including the participant allowed under an 
exception to enroll from the CoFAR 4 Pro0003579 (not counted in the data analysis for this study).  
Accounting for a 10% drop out rate, we anticipate having approximately 45 children eligible for 
randomization during the blinded phase of the study.  
 
5.3 
Screening Visit 
The screening visit will include the following procedures: 
1. Consent and assent – no procedures will occur prior to signed consent.   
2. Diet and allergy questionnaire 
3. Physical examination 
4. Blood draw for peanut-specific IgE measurement if not already available 
5. Skin prick testing to peanut 
6. Blood draw for serum pregnancy test (for females of child-bearing potential) 
 


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5.4 
Baseline Visit 
Subjects who meet eligibility criteria will return for a baseline visit.  This baseline visit may be 
combined with the screening visit in subjects whom the study staff believe will qualify for the 
study.  This visit will include the following procedures: 
1. Physical examination 
2. Endpoint titration skin prick test to peanut 
3. Blood draw for mechanistic studies* 
4. Saliva collection 
5. Peak expiratory flow (if capable)  
6. Qualifying DBPCFC to 1000 mg of peanut 
 
* Mechanistic blood draw may be repeated due to inadequate T and non-T cell separation but not to 
exceed 3 ml/kg per blood draw or 7 ml/kg in a 6-week period.   
 
5.5 
Study Drug/Intervention Visits 
Build-up 
Following the qualifying entry 1000 mg peanut protein DBPCFC, subjects will return to the Clinical 
and Translational Research Center (CTRC) to begin the build-up phase dosing scheme (Table 1).  
The subject will administer one pump of a 1/100 dilution of concentrated peanut protein extract 
(5000 mcg/ml) under the tongue and wait 2 minutes before swallowing.  The subject will be 
observed for a minimum of 30 minutes and those with minimal (e.g., oropharyngeal itching) or no 
symptoms will be discharged.  Those with mild symptoms requiring treatment will be observed for 
at least 2 hours or until symptoms resolve.  Any subject who develops moderate or severe 
symptoms requiring epinephrine will be observed for at least 4 hours or until symptoms resolve.  
Thereafter the dose will be administered at home daily for 1-2 weeks according to the schedule in 
below Table 1.  Visits for build-up doses will occur prior to changing peanut dilutions or every 4 
weeks.  Subjects will be given contact numbers for study personnel, including emergency contact 
information.  Families will be instructed to contact study personnel with any new or significant 
dosing side effects, missed doses, and/or concurrent illnesses. 
 
Table 1. Build-up Escalation 
 
Dose 
# 
 
Peanut 
Dilution 
 
Pumps 
Dose of 
Peanut 
Protein 
Interval 
in Weeks 
%  Increase 
 
Study Visit 
1 
1/100 
1 
2.5 mcg 
 
- 
1.  
2 
1/100 
2 
5 mcg 
1 
100% 
 
3 
1/100 
4 
10 mcg 
1 
100% 
 
4 
1/100 
8 
20 mcg 
1 
100% 
 
5 
1/10 
1 
25 mcg 
1 
25% 
2.  
6 
1/10 
2 
50 mcg 
1 
100% 
 
7 
1/10 
4 
100 mcg 
1 
100% 
 
8 
1/10 
8 
200 mcg 
1 
100% 
 


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Build-up and Maintenance for Crossover Subjects from CoFAR 4 Protocol 
Subjects completing the Sublingual Immunotherapy for Peanut Allergy: A Randomized, Double-
Blind, Placebo-Controlled, Phase I/II Pilot Study with Whole Peanut Extract (Duke IRB 
Pro0003579, UNC IRB 11-2301, CoFAR4) who do not pass the 164 week 10 gm DBPCFC may 
enroll in this Peanut SLIT and Tolerance study.  These subjects will have completed 3 years of 1386 
mcg peanut SLIT maintenance.  Upon completion of the CoFAR 4 study Pro0003579 10 gm 
DBPCFC, subjects may resume an escalation schedule starting with the 2000 mcg dose in this SLIT 
(11-2308, TLC) protocol.  The first dose will be an observed dose the day following the CoFAR4 
10gm DBPCFC1 (study visit*).  The 3000 mcg escalation may be done at home if the subject did not 
experience symptoms (other than oral prutitis)2.  The final 4000 mcg dose escalation will be an 
observed dose in the clinical research unit3(study visit *).  The subjects will then follow the schedule of 
Peanut SLIT and Tolerance in this protocol (11-2308) including the endpoint DBPCFCs.  
 
11-2308 TLC Subjects - Home Maintenance Dosing – Before Desensitization DBPCFC 
After completing the escalation schedule, subjects will continue to administer 4000 mcg of peanut 
SLIT daily at home and return to the clinical research unit for follow-up visits every 6 months or 
more frequently for new or significant symptoms.  All subjects will undergo a 5000 mg peanut 
protein DBPCFC after at least 48 months to verify desensitization which will be defined as a 
reaction threshold > 300 mg of peanut protein. 
 
Sustained Unresponsiveness Assessment by DBPCFC 
All subjects who are desensitized after at least 48 months will be randomized to an interval between 
1 and 17 weeks during which all peanut including peanut SLIT study drug will be discontinued.  
This period of avoidance will be followed by a third DBPCFC to 5000 mg of peanut protein to 
evaluate for the loss of the desensitization effect.   
 
• At the completion of the study, subjects will be given the option to transition to a daily 
peanut food equivalent versus resuming a strict peanut avoidance diet. 
 
5.6 
Double Blind Placebo Controlled Food Challenge (DBPCFC) 
Protocol DBPCFCs will be conducted on the clinical research unit at entry, after at least 48 months, 
and after avoidance of peanut SLIT study drug for a randomly selected interval 1 to 17 weeks.  Prior 
9 
Full 
concentration 
1 
250 mcg 
2 
25% 
3.  
10 
Full 
concentration 
2 
500 mcg 
2 
100% 
 
11 
Full 
concentration 
4 
1000 mcg 
2  
100% 
4.  
12 
Full 
concentration 
8 
2000 mcg1 
2 
100% 
* 
13 
Full 
concentration 
12 
3000 mcg2 
2 
50% 
5.  
14 
Full 
concentration 
16 
4000 mcg3 
2 
33% 
* 


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to the food challenge, subjects will be asked to restrict the use of antihistamines (for 5 half-lives of 
the drug), beta-agonists (12 hours), theophylline (12 hours), and cromolyn (12 hours).   
 
Before each challenge, the subject will have a physical exam and peak expiratory flow 
measurements performed if the subject is able to reproduce reliable peak expiratory flow 
measurements prior to the beginning of the challenges.   
 
The DBPCFC consists of 2 parts.  A representative from Dr. Burks’ laboratory will randomly 
determine the order of the 2 parts and prepare all challenge materials.  One part will consist of 
graded doses of peanut flour given every 10-20 minutes up to a cumulative dose of 1000 mg peanut 
protein (25 mg, 50 mg, 100 mg, 250 mg, 575 mg) during the entry challenge.  The 48 month 
desensitization challenge is 5000 mg (100 mg, 200 mg, 500 mg, 800 mg, 1300 mg, 2100 mg) of 
peanut protein.  The randomly assigned post-avoidance DBPCFC will be identical to the 48 month 
DBPCFC.  The other part of each challenge will consist of identical graded doses of placebo in the 
form of oat flour.   
 
All food challenges will be administered in a graded fashion to assure safety of subjects.  There will 
be a minimum 10 minute observation period between doses to monitor for symptoms.  All food 
challenges will be performed under physician supervision.  The challenge will be administered by a 
nurse or physician who is blinded to the testing material.  The supervising investigator will also be 
blinded to testing material.  
 
After each challenge the subject will be observed for a minimum period of 1 hour.  Reactions will 
be scored using a Food Challenge Symptom Score sheet.  If the subject begins to have clinically 
significant or persistent subjective symptoms, the food challenge will be terminated and the subject 
will be given appropriate treatment.  Subjects who are symptomatic are observed for a minimum of 
2 hours after the challenges are completed before being discharged from the clinical research unit. 
 
5.7 
Skin Prick Test 
Allergy skin prick testing with the peanut allergen will be performed at enrollment and once yearly.  
The skin testing performed will be using the standard peanut extract 1:20 wt/vol (Greer, Inc, Lenoir, 
NC).  The mean wheal diameter will be recorded and is defined as the average of the largest 
diameter and the corresponding midpoint diameter.  All wheals will be outlined in ink on 
transparent tape and then transferred to the permanent record.  
 
5.8 
Visit Windows 
Dosing schedule should be adhered to strictly.  Two days before or seven 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 should take place within 2 weeks of the scheduled visit.  Those 
who are unable to comply with the dosing schedule risk being withdrawn from the study.  As of 
February 22, 2016, a subset of subjects reached the 48 month time point while the protocol was 
being amended.  Published data on SLIT for dust mite allergy [30] and internal data on a separate 
ongoing study of peanut SLIT suggested minimal difference in efficacy between 4 and 5 years of 
treatment.  Thus these subjects deferred the scheduled food challenge and have continued peanut 
SLIT dosing with every 6 month follow-up visits pending the amended protocol and revised 


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informed consent.  Upon approval of the amended protocol, these subjects will be approached in 
order to schedule the 48 month food challenge and randomized avoidance period. 
 
5.9 
Study Randomization Procedures 
The peanut SLIT treatment is open-label for the duration of the study.  At the time of the 48 month 
desensitization DBPCFC, subjects will be randomly assigned an interval from 1 to 17 weeks during 
which peanut SLIT study drug and all other peanut will be strictly avoided.  All DBPCFCs are 
conducted in a double-blind manner.  All randomization is performed using a randomization 
scheme provided by our biostatistician collaborators performed by representatives in Dr. Burks’ 
laboratory and laboratory personnel are unblinded throughout the study. 
 


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6. 
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. 
 
6.1 
Procedures and Monitoring 
All unexpected serious adverse events related to the experimental procedures will be reported to the 
IRB, Food Allergy Initiative DSMB, and FDA in a manner consistent with 21 CFR 312.32.  All 
other adverse events related to the experimental procedures will also be reported to the IRB and 
DSMB in an expedited manner if they are Grade 3 and above in severity. Any participant deaths 
that are likely study related and unexpected would be reported within 24 hours.  The investigator 
will continue to follow or obtain documentation of the resolution course of such an event.  
Reactions to study drug dosing will be recorded on a dosing log and will not be reported separately 
as serious adverse events; allergic symptoms are expected during study drug administration and are 
not unexpected reportable adverse events.  Any reaction that meets the criteria for a serious adverse 
event will be reported both on the dosing log and on an adverse event case report form. 
 
6.2 
Definitions 
6.2.1 Adverse Event (AE) or Medical Event 
An adverse event is a new, undesirable medical event or occurrence or worsening of an existing 
condition (including an abnormal laboratory finding) in a subject that occurs during and throughout 
the study, whether or not it is considered to be study related.  Adverse events or medical events and 
toxicities are treatment emergent signs and symptoms.   
This includes the following: 
1.AEs not previously observed that emerge during the protocol participation, including signs or 
symptoms associated with peanut allergy that were not pre-existing  
2.Complications that occur as a result of protocol-mandated interventions 
3.If applicable, AEs that occur prior to study-group assignment associated with medication 
washout, or other protocol-mandated intervention 
4.Preexisting medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol. 
Potential adverse reactions seen in subjects receiving peanut SLIT and subjects undergoing 
DBPCFC include the following: skin manifestations such as pruritus, urticaria, or angioedema; 
respiratory symptoms such as wheezing, coughing, nasal congestion/rhinorrhea, cough and 
hoarseness; and gastrointestinal symptoms such as vomiting, diarrhea, or abdominal pain.  
Anaphylaxis is a potential risk involving any of the above symptoms plus hypotension and 
circulatory collapse. 
 
6.2.2 Serious Adverse Event (SAE) 
A serious adverse event is defined as any adverse therapy experience occurring at any dose that 
suggests a significant hazard, contraindication, side effect, or precaution will be defined as an SAE.  
This includes, but may not be limited to any of the following events: (This terminology is from 
Section B.2 on the FDA MedWatch form.  For a copy of the current MedWatch Form 3500, see the 
list of PDF forms on the Web at: http://www.fda.gov/opacom/morechoices/fdaforms/cder.html) 


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1. Death: A death occurring during the study, or which comes to the attention of the investigator 
during the protocol-defined follow-up after the study completion whether or not considered 
study related, must be reported. 
2. Life-threatening: Any adverse therapy experience that places the subject or subjects, in the view 
of the investigator, at immediate risk of death from the reaction as it occurred (i.e., it does 
not include a reaction that, had it occurred in a more serious form, might have caused death). 
3. In-patient hospitalizations or prolongation of existing hospitalization. 
4. Persistent or significant disability or incapacity. 
5. Congenital anomaly/birth defect. 
6. An event that required intervention to prevent permanent impairment or damage. 
 
6.2.3 Unexpected Adverse Event 
An adverse event is considered “unexpected” when its nature (specificity) or severity is not 
consistent with applicable product information, such as safety information provided in the protocol 
or consent. 
 
6.3 
Toxicity Grading 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of an AE (as 
in mild, moderate, or severe pain); the event itself may be of relatively minor medical significance 
(such as severe headache).  “Serious” is a regulatory definition and is based on patient or event 
outcome or action criteria usually associated with events that pose a threat to a patient’s life or vital 
functions.  Seriousness (not severity) serves as the guide for defining regulatory reporting 
obligations.   
Toxicity grades are assigned by the study site to indicate the severity of adverse experiences and 
toxicities using the NCI-CTCAE version 3.0.  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 Appendix 2.  The NCI-CTCAE has been reviewed specifically for 
this protocol and is otherwise 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 study drug-related toxicities. 
Adverse events not included in the CTCAE listing should be recorded and graded 1-5 according to 
the General Grade Definition provided below: 
Grade 1 
Mild 
Transient or mild discomforts (< 48 hours), no or minimal 
medical intervention/therapy required, hospitalization not 
necessary (non-prescription or single-use prescription 
therapy may be employed to relieve symptoms, 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, 
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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. 
 
6.3.1 Relationship to Procedure Definitions 
Associated: There is a reasonable possibility that the AE may have been caused by the test product 
and/or procedure.  This definition applies to those adverse events that are considered definitely, 
probably or possibly related to the procedure. 
1. Definitely related: An AE that follows a temporal sequence from administration of the test 
product and/or procedure; follows a known response pattern to the test article and/or 
procedure; and, when appropriate to the protocol, is confirmed by improvement after 
stopping the test product (positive rechallenge: and by reappearance of the reaction after 
repeat exposure [positive rechallenge]); and cannot be reasonably explained by known 
characteristics of the subject’s clinical state or by other therapies. 
2. Probably related: An AE that follows a reasonable temporal sequence from administration of 
the test product and/or procedure; follows a known response pattern to the test product 
and/or procedure, is confirmed by improvement after rechallenge; and cannot be reasonably 
explained by the known characteristics of the participant’s clinical state or other therapies. 
3. Possibly related: An AE that follows a reasonable temporal; sequence from administration of 
the test product and/or procedure and follows a known response pattern to the test product 
and/or procedure, but could have been produced by the participant’s clinical state or by other 
therapies. 
4. Not associated: An AE for which sufficient information exists to indicate that the etiology is 
not related to the test product and/or therapy. 
5. Unrelated: An AE that does not follow a reasonable temporal sequence after administration of 
the test product and/or procedure and most likely is explained by the participant’s clinical 
disease state or by other therapies.  In addition, a negative rechallenge to the test article 
and/or procedure would support an unrelated relationship. 
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-
CTCAE website, http://ctep.cancer.gov/reporting/ctc.html. 
 
6.4 
Adverse Events Collection Procedures 
The study staff is responsible for collecting and recording all clinical data.  As these results are 
collected, all toxicities and adverse events will be identified and reported to the principal 


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investigator.  Adverse events will be reported as described above.  The Principal Investigator will 
determine relationship of the event to the study intervention and decide course of action for the 
study participant. 
6.4.1 Recording and Reporting Procedures 
Monitoring will be conducted via reports to the DSMB.   
 
6.4.2 SAE Recording and Reporting 
Serious adverse events will be recorded on the appropriate case report forms.  
 
6.5 
Serious Adverse Event Notification 
The study staff will notify the principal investigator of any serious adverse event immediately upon 
learning about the event. 
 
6.5.1 Notifying the FDA, IRB, and DSMB 
The sponsor will provide the DSMB with listings of all SAEs.  Furthermore, the sponsor will 
inform the FDA, IRB, and DSMB of serious unexpected study-related events.  
 
6.5.2 Reporting Criteria 
The investigator will ensure the timely dissemination of all AE information, including expedited 
reports, to the IRB in accordance with applicable local regulations and guidelines. 
 


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7. 
MECHANISTIC ASSAYS 
Complementary studies will be performed to measure cellular and humoral immune responses at 
baseline and longitudinally.  These assays have been selected based on hypothesized mechanisms of 
clinical desensitization induction.   
Early data demonstrates that desensitization with peanut SLIT alters both humoral and cellular 
parameters [23].  We anticipate that peanut SLIT will induce clinical tolerance and SU by either (1) 
a conversion from a Th2 to Th1 immune response or (2) the induction of TRegs or (3) a combination 
of both.  Subjects will be followed for changes in immunologic parameters at baseline and then 
yearly with additional studies at the 48 month desensitization DBPCFC and post-avoidance SU 
DBPCFC.  Immunologic assays will focus on peanut specific parameters including: 1) basophil 
activation and skin prick testing; 2) humoral studies - specific IgE, IgG, IgG4, and IgA; and 3) 
cellular studies – Treg activation and T cell-stimulated cytokine production.   
Briefly, PBMC’s will be isolated from blood drawn at yearly time points and cultured with crude 
peanut extract (CPE)[31], tetanus toxin, and Con A to assess cellular proliferation responses.  A 
control proliferation assay using nonstimulated cells will also be performed.  In addition, cultures 
will be set up to assess cytokine production by PBMC’s after stimulation with CPE, tetanus toxin, 
ConA and control.  Culture supernatants will be analyzed yearly for the levels of the following 
cytokines: IFN-γ, IL-4, IL-5, IL-10, IL-13, TGF-β and TNF-α.  Using flow cytometry, we will 
determine the presence of TRegs in the blood sample each year.  Basophil studies will be performed 
annually to examine activation markers.  Salivary and serum peanut specific antibody levels, 
including IgE, IgG, IgG4, and IgA will be assessed annually. 
7.1 
Serum specific IgE, IgG, IgG4, and IgA 
Allergen 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). 
We will collect sera at baseline and then yearly with additional studies at the 48 month 
desensitization DBPCFC and post-avoidance SU DBPCFC.  Samples will be stored at –80°C.  
Peanut-specific IgE, IgG, IgG4, and IgA levels will be measured using the Phadia ImmunoCAP 100 
instrument (Uppsala, Sweden) according to the manufacturer’s instructions.   
7.2 
Salivary specific IgA, Secretory-IgA, IgG, IgE, and IgM 
We will utilize ELISA assays to evaluate host antibody responses to Ara h 2 and whole peanut 
extract in saliva samples collected at the designated time points for serum collection (baseline and 
then yearly with additional studies at the 48 month desensitization DBPCFC and the post-avoidance 
SU DBPCFC).  Ara h 2 is the major allergen found in peanut.  Others have used saliva to measure 
allergen-specific S-IgA responses in allergic children as well as antigen-specific S-IgA induced in 
response to oral immunization with KLH (keyhole limpet hemocyanin) or a cholera vaccine.  Saliva 
samples will be tested at an initial dilution of 1:4 followed by serial 2-fold dilutions until we are 
able to determine an endpoint titer.   An endpoint titer will be calculated as the last sample dilution 
that has an ELISA reading (fluorescent relative light units) 3-fold great than the RLU of the same 
sample tested against ELISA plates that are not coated with antigen.  Once the antigen-specific 


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endpoint titers are calculated, we will quantitate the total concentration (mcg/ml) of IgG, IgE, IgA, 
Secretory-IgA and IgM in each saliva sample and report the antigen-specific responses as a 
“titer/mcg of total antibody”. 
7.3 
Cytokine measurements 
Isolated PBMCs from baseline and then yearly with additional studies at the 48 month 
desensitization DBPCFC and the post-avoidance SU DBPCFC will be cultured in RPMI 1640 
containing 10% fetal bovine serum, 1% penicillin/streptomycin, and 1% glutamine.  Cells will be 
cultured in 24 well plates (4 x106/well/ml) in the presence or absence of CPE (200 mcg/ml), tetanus 
toxin (5 mcg/ml), or Con A (5 mcg/ml).  Supernatants will be collected after 72hrs of culture and 
aliquots will be stored at–80 °C until analyzed.  IFN-γ, IL-4, IL-5, IL-13, IL-10, TGF-β, and TNF-α 
levels will be determined either by ELISA according to the manufacturer’s instructions (R&D 
systems, Minneapolis) or by a Cytokine Bead Array (BD).  The stimulated cells will be collected to 
isolate RNA which will be used to measure GATA-3, T-bet, Foxp3, and Th2 cytokines by qPCR.  
7.4 
TReg assay 
Isolated PBMCs from baseline and then yearly with additional studies at the 48 month 
desensitization DBPCFC and the post-avoidance SU DBPCFC will be cultured with CPE (200 
mcg/ml) or media alone and incubated for 7 days.  Cells will be surface stained for CD4 and CD25, 
then intracellularly stained for FoxP3.  The presence of TRegs will be assessed by flow cytometry 
(CD25+/CD4+/Foxp3+).  
7.5 
Basophil Activation Assay 
Whole blood from baseline and then yearly with additional studies at the final randomly selected 
post-avoidance DBPCFC.will be divided and stimulated in the presence of IL-3 with several 
dilutions of peanut antigen (100 mcg/ml, 10-1 mcg/ml, 10-2 mcg/ml, 10-3 mcg/ml), anti-IgE 
(1mcg/ml), and media alone.  After 30 minutes incubation, RBCs will be lysed and leukocytes will 
be fixed and stored frozen for batch mAb staining and flow cytometric analysis of activation 
markers.  Basophils will be identified as CD123+ CD203c+ lin- (CD3, CD14, CD19, CD41) events 
and activation will be assessed by CD203c (ENPP3) and CD63 (LAMP-3), which are markers for 
piecemeal and classical degranulation, respectively. 
 
 


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8. 
STATISTICAL CONSIDERATIONS 
For full description of statistical considerations, please refer to the statistical analysis plan.  A 
summary of the plan is described below.  Unless otherwise indicated, all statistical tests will be 2 
sided and tested at a significance level of 0.05.  Corresponding 95% confidence intervals will be 
presented for statistical tests. 
 
8.1 
Study Endpoint Assessment 
8.1.1 Primary Endpoint 
The primary endpoint is defined in Section 2.2.1.  First, an Interval-Censoring Survival Analysis 
(ICSA) approach will be used to analyze the 48th month DBPCFC threshold data (Collett, 1993, 
Chapter 9, Taylor et al - 2009).  Parametric (Log-normal, Weibull) and non-parametric dose-
distribution model will be used to estimate the ED10 and the ED05, the doses predicted to provoke 
reactions in 10% and 5%, respectively, of the peanut-allergic population.  Second, for each dose 
interval bounded by the NOAEL and LOAEL of the 48th month DBPCFC, we will conduct survival 
analysis with case-1 censoring (Huang – Wellner lecture notes, Kosorok et al, 1998) to estimate 
time to loss of desensitization. 
Sample size was originally calculated for 80% power of detecting a p-value of 0.05 considering 2:1 
placebo:peanut SLIT randomization and estimating a 50% pass rate for those randomized to placebo 
versus a 90% pass rate for those randomized to continue peanut SLIT .  Adjusting for an estimated 
10% drop out rate resulted in a minimum required sample size of 50 subjects.  The sample size for 
the amended study has not been revised from the estimated minimum required size of 50 subjects 
since the study is in progress with an existing enrollment of 51 subjects.  We intuitively think this 
number is adequate with the amended study design and analytical methods for the revised primary 
outcome of interest.  However, to confirm our understanding, we plan on conducting simulations to 
study the power-sample size curve at 80% power based on study assumptions as discussed in the 
statistical methods section of the statistical analysis plan.  
 
8.1.2 Secondary Endpoints 
Secondary efficacy analyses will be based on the intention to treat (ITT) population only.  
Continuous endpoints will be analyzed using the Mixed Model Repeated Measures (MMRM) 
analysis.  The mean changes from baseline will be analyzed using a restricted maximum likelihood 
(REML) based repeated measures approach.  Analyses will include the fixed, categorical effects of 
population source, center and study week as well as the fixed covariates of baseline score and 
baseline score-by-study week interaction.  An unstructured covariance structure will be used to 
model the within-patient errors.  If this analysis fails to converge, the following structures will be 
tested: first order ante dependence, heterogeneous first order autoregressive, heterogeneous 
compound symmetry and compound symmetry.  The covariance structure converging to the best fit, 
as determined by Akaike’s information criterion, will be used in the analysis (Mallinckrodt et al, 


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2008).  The Kenward-Roger approximation will be used to estimate the denominator degrees of 
freedom. 
8.2 
Subject and Demographic Data 
8.2.1 Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be provided for all 
enrolled participants.  Demographic data will include age, race, sex, body weight, and height; these 
data will be presented in the following manner: 
1. Continuous data (i.e., age, body weight, and height) will be summarized descriptively by mean, 
standard deviation, median, and range.   
2. 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 
study drug group and baseline peanut-specific serum IgE.  Statistical comparison of these groups 
will be performed as summarized above. 
8.2.2 Study Completion 
The percentage of participants 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. 
 
8.3 
Interim Analyses to Ensure Safety 
All adverse event reports will be reviewed by the DSMB in its convened meetings.  The annual 
summary of all adverse events and any audit reports will be reviewed annually by the DSMB. 
 


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9. 
IDENTIFICATION AND ACCESS TO SOURCE DATA 
9.1 
Data Management 
All records generated during the visits will be stored in the Food Allergy database, on the 
immunology server, and in the individual subject’s research study binder.  The subject’s 
information is accessible only to the investigator and his designated colleagues. 
 
9.2 
Access to Data 
The subject’s information is accessible only to the investigator or his designated colleagues by 
individual password or direct viewing of the research record.  The research records will be kept 
locked in the investigator’s research area.  The investigator is required by law (21CFR312.62) to 
keep accurate case records until two years after the IND is marketable or three years after the 
investigation is discontinued (whichever is longer).  Any information placed in the medical record 
will remain in the medical record indefinitely.   
 


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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The sponsor/investigator is required to keep accurate records to ensure that the conduct of the study 
is fully documented.  The sponsor/investigator is responsible for regularly reviewing the conduct of 
the trial, for verifying adherence to the protocol, and for confirming the completeness, consistency, 
and accuracy of all documented data. 
 
10.1 Data Handling 
The investigator is required to ensure that all CRFs are legibly completed for every participant 
entered in the trial.   
 


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11. 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
11.1 Statement of Compliance 
This study will be conducted using good clinical practice (GCP), as delineated in 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 consent documents will be 
reviewed and approved by an appropriate IRB.  Any amendments to the protocol or to the consent 
materials must also be approved before they are implemented. 
11.2 Consent and Assent Process 
The consent process is a means of providing information about the study to a prospective participant 
and/or to the parent/guardian.  The consent process allows for an informed decision about 
participation in the study.  The participant or the parents/legal guardians will be asked to read, sign, 
and date a consent form before entering the study, undergoing any screening procedures (e.g., 
physical exam, food challenge, skin testing), taking study drug, or undergoing any study-specific 
procedures.  Minors will sign assent as appropriate.  The consent form will be revised whenever the 
protocol is amended with a study design change.  A signed copy of the consent will be given to a 
prospective participant and/or parent/guardian for review.  The prospective subject and 
parent/guardian are told that being in the study is voluntary and that he or she may withdraw from 
the study at any time, for any reason. 
 
11.3 Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant 
will be assigned a sequential identification number and these numbers will be used to collect, store, 
and report participant information. 
 


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12. 
RESOURCE SHARING 
Subject information will only be shared using the subject study identification number.  All other 
identifiers of the subject will be removed prior to the release of information.  If the results of the 
trial are published the study number may be used; participants’ names will not be included in 
publications.   
 
 
 


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Figure 1. Study Design Overview 
 
 
 
 
 
                                                                     
 
      0-48 months open peanut SLIT study drug 
 
 
 
 
Entry   
DBPCFC 
1000 mg 
48+ months 
Desensitization
DBPCFC 
 5000 mg Study 
Post-avoidance 
DBPCFC  
5000 mg  
Randomization 
1-17 weeks 
avoidance 
 Studies: immune 
studies and skin tests 
Assess sustained 
unresponsiveness to peanut 
after random peanut 
avoidance (1o outcome) 
Assess 
desensitization to 
peanut at least 48 
months (1o outcome) 


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13. 
APPENDIX 1. SCHEDULE OF EVENTS 
 
 
Procedure 
 
Screening or 
Baseline 
Visit 
 
Build-Up 
Dosing 
(every month 
until 4000mcg  
is reached) 
 
Maintenance 
Study Visits 
(6, 18, 30, 42 
months) 
 
Maintenance 
Study Visits  
(12, 24, 36 
months) 
 
 
Desensitization 
OFC 48+ months 
 
Randomly 
selected 1-17 
week post-
avoidance 
OFC 
Medical/Allergy 
History 
X 
 
 
 
X 
X 
Physical Exam 
X 
 
 
 
X 
X 
Peak Flow Rate 
X 
X 
X 
X 
X 
X 
Targeted H&P 
 
X 
X 
X 
 
 
SLIT 
administration 
 
X 
 
 
 
 
Prick Skin Tests 
X 
 
 
X 
X 
X 
Blood draw for 
peanut-specific Ig 
measurements 
X 
 
 
X 
X 
X 
Saliva collection 
for peanut-
specific Ig 
measurements 
X 
 
 
X 
X 
X 
Blood draw for 
mechanistic 
studies 
X 
 
 
X 
X 
X 
DBPCFC 
X 
 
 
 
X 
X 
 
 
 
 


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14. 
APPENDIX 2. EVALUATION OF ASTHMA 
The evaluation of asthma severity will be assessed using the NHLBI classification as described in the table below.  
Classification 
Symptoms 
Nighttime 
awakenings 
Lung Function 
Interference with 
normal activity 
Short acting beta-agonist 
use 
Intermittent 
(Step 1) 
1. < 2 days per week 
< 2x /month 
1. Normal FEV1 between 
exacerbations 
2. FEV1>80% predicted 
3. FEV1/FVC normal* 
4. None 
5. <2x /month  
Mild Persistent 
(Step 2) 
1. > 2 days per week but 
not daily 
 
3-4x /month 
1. FEV1 > 80% predicted 
2. FEV1/FVC normal* 
3. Minor limitation 
4. 3-4 x /month 
Moderate Persistent 
(Step 3 or 4) 
1. Daily  
> 1x /week but 
not nightly 
1. FEV1 >60% but <80% 
predicted 
2. FEV1/FVC reduced 
5%* 
3. Some limitation 
4. >1x /week but not nightly 
Severe Persistent 
(Step 5 or 6) 
1. Throughout the day 
Often 7x /week 
1. FEV1<60% predicted 
2. FEV1/FVC reduced 
>5%* 
3. Extremely 
limited 
4. Often 7x /week 
*Normal FEV1/FVC: 8-19 yr = 85%; 20-39 yrs = 80%


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15. 
APPENDIX 3. REFERENCES 
1. 
Sampson, H.A., Update on food allergy. J Allergy Clin Immunol, 2004. 113(5): p. 805-19; quiz 820. 
2. 
Sicherer, S.H., et al., US prevalence of self-reported peanut, tree nut, and sesame allergy: 11-year 
follow-up. J Allergy Clin Immunol, 2010. 125(6): p. 1322-6. 
3. 
Bock, S.A., A. Munoz-Furlong, and H.A. Sampson, Further fatalities caused by anaphylactic 
reactions to food, 2001-2006. J Allergy Clin Immunol, 2007. 119(4): p. 1016-8. 
4. 
Bock, S.A., A. Munoz-Furlong, and H.A. Sampson, Fatalities due to anaphylactic reactions to 
foods. J Allergy Clin Immunol, 2001. 107(1): p. 191-3. 
5. 
Sicherer, S.H., A.W. Burks, and H.A. Sampson, Clinical features of acute allergic reactions to 
peanut and tree nuts in children. Pediatrics, 1998. 102(1): p. e6. 
6. 
Yu, J.W., et al., Accidental ingestions in children with peanut allergy. J Allergy Clin Immunol, 2006. 
118(2): p. 466-72. 
7. 
Hourihane, J.O., S.A. Roberts, and J.O. Warner, Resolution of peanut allergy: case-control study. 
BMJ, 1998. 316(7140): p. 1271-5. 
8. 
Skolnick, H.S., et al., The natural history of peanut allergy. J Allergy Clin Immunol, 2001. 107(2): 
p. 367-74. 
9. 
Nelson, H.S., et al., 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. 
10. 
Oppenheimer, J.J., et al., Treatment of peanut allergy with rush immunotherapy. J Allergy Clin 
Immunol, 1992. 90(2): p. 256-62. 
11. 
Buchanan, A.D., et al., Egg oral immunotherapy in nonanaphylactic children with egg allergy. J 
Allergy Clin Immunol, 2007. 119(1): p. 199-205. 
12. 
Jones, S.M., et al., Clinical efficacy and immune regulation with peanut oral immunotherapy. 
Journal of Allergy and Clinical Immunology, 2009. 124(2): p. 292-300.e97. 
13. 
Meglio, P., et al., A protocol for oral desensitization in children with IgE-mediated cow's milk 
allergy. Allergy, 2004. 59(9): p. 980-7. 
14. 
Niggemann, B., et al., Specific oral tolerance induction in food allergy. Allergy, 2006. 61(7): p. 808-
11. 
15. 
Patriarca, G., et al., Oral specific desensitization in food-allergic children. Dig Dis Sci, 2007. 52(7): 
p. 1662-72. 
16. 
Patriarca, G., et al., Oral desensitizing treatment in food allergy: clinical and immunological results. 
Aliment Pharmacol Ther, 2003. 17(3): p. 459-65. 
17. 
Blumchen, K., et al., Oral peanut immunotherapy in children with peanut anaphylaxis. J Allergy 
Clin Immunol, 2010. 126(1): p. 83-91 e1. 
18. 
Clark, A.T., et al., Successful oral tolerance induction in severe peanut allergy. Allergy, 2009. 64(8): 
p. 1218-20. 
19. 
Skripak, J.M., 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. 
20. 
Hofmann, A.M., et al., Safety of a peanut oral immunotherapy protocol in children with peanut 
allergy. J Allergy Clin Immunol, 2009. 124(2): p. 286-91, 291 e1-6. 
21. 
Enrique, E., et al., Sublingual immunotherapy for hazelnut food allergy: a randomized, double-blind, 
placebo-controlled study with a standardized hazelnut extract. J Allergy Clin Immunol, 2005. 
116(5): p. 1073-9. 
22. 
Kerzl, R., et al., Life-threatening anaphylaxis to kiwi fruit: protective sublingual allergen 
immunotherapy effect persists even after discontinuation. J Allergy Clin Immunol, 2007. 119(2): p. 
507-8. 


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23. 
Kim, E., et al., Sublingual immunotherapy for peanut allergy: clinical and immunologic evidence of 
desensitization. Journal of Allergy and Clinical Immunology, 2011(in press). 
24. 
Kulis, M.D., et al., Basophil Hyporesponsiveness Following Six Months of Peanut Oral 
Immunotherapy (OIT) Is Associated with Suppression of Syk Phosphorylation. J Allergy Clin 
Immunol, 2015. 135(2 Supp): p. AB24. 
25. 
Burks, A.W., et al., Oral immunotherapy for treatment of egg allergy in children. N Engl J Med, 
2012. 367(3): p. 233-43. 
26. 
Fleischer, D.M., et al., Sublingual immunotherapy for peanut allergy: a randomized, double-blind, 
placebo-controlled multicenter trial. J Allergy Clin Immunol, 2013. 131(1): p. 119-27 e1-7. 
27. 
Vickery, B.P., et al., Sustained unresponsiveness to peanut in subjects who have completed peanut 
oral immunotherapy. J Allergy Clin Immunol, 2014. 133(2): p. 468-75. 
28. 
Categories of research that may be reviewed by the institutional review board (IRB) through an 
expedited review procedure. 
29. 
Akdis, M. and C.A. Akdis, Mechanisms of allergen-specific immunotherapy. J Allergy Clin 
Immunol, 2007. 119(4): p. 780-91. 
30. 
Marogna, M., et al., Long-lasting effects of sublingual immunotherapy for house dust mites in 
allergic rhinitis with bronchial hyperreactivity: A long-term (13-year) retrospective study in real life. 
Int Arch Allergy Immunol, 2007. 142(1): p. 70-8. 
31. 
Sen, M., et al., Protein structure plays a critical role in peanut allergen stability and may determine 
immunodominant IgE-binding epitopes. Journal of Immunology, 2002. 169(2): p. 882-7. 
 
 

SAP_001.pdf: 
 
 
PEANUT SUBLINGUAL IMMUNOTHERAPY (SLIT) AND 
INDUCTION OF CLINICAL TOLERANCE IN PEANUT 
ALLERGIC CHILDREN (TLC) 
Statistical Analysis Plan 
 
 
NCT number  
NCT01373242 
Document Date 
02/13/2016 
 
 


 
Protocol: TLC 
 
Page 2 of 22 
SAP Final Version 1.0 
 
CONFIDENTIAL 
 
13-Feb-2016 
 
 
Statistical Analysis Plan 
 
Protocol Title: Peanut Sublingual Immunotherapy and Induction of Clinical Tolerance 
(TLC) in Peanut Allergic Children, Version 6.0  (Dated March 2, 2016) 
Protocol Number: UNC IRB# 11-2308 
Investigational 
Product: 
Peanut SLIT 
IND 14326 
Phase: Phase I/II – Safety and Efficacy 
Sponsor: UNC 
SAP Author: Monica Chaudhari 
UNC, Chapel Hill 
SAP Version: Version 1.0 
SAP Date: February 13, 2016 
CONFIDENTIAL 


 
Protocol: TLC 
 
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SAP Final Version 1.0 
 
CONFIDENTIAL 
 
13-Feb-2016 
DOCUMENT HISTORY 
Version 
Date 
Author 
Description 
1.0 
25-Sept-2015 
Monica Chaudhari 
Abbreviated SAP Initial Draft 
0.1 
31-Jan-2016 
Monica Chaudhari 
First Draft, consolidated comments from 
expert reviewers 
0.2 
10-Feb-2016 
Monica Chaudhari 
Second Draft, consolidated comments 
from expert reviewers 
1.0 
13-Feb-2016 
Monica Chaudhari 
Finalize SAP 
 


 
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SIGNATURE PAGE AND APPROVALS 
 
 
Monica Chaudhari 
 
Biostatistician 
 
Date 
 
 
Michael R. Kosorok 
 
Chair of Biostatistics 
 
Date 
 
 
Edwin Kim 
 
Investigator 
 
Date 


 
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TABLE OF CONTENTS 
DOCUMENT HISTORY...................................................................................................... 3 
SIGNATURE PAGE AND APPROVALS......................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 5 
ABBREVIATIONS................................................................................................................ 7 
1. 
BACKGROUND........................................................................................................ 8 
2. 
OVERVIEW .............................................................................................................. 9 
3. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 9 
3.1 
Study Objectives ............................................................................................. 9 
3.1.1 Primary Objectives ............................................................................. 9 
3.1.2 Secondary Objectives....................................................................... 10 
3.2 
Study Endpoints ............................................................................................ 10 
3.2.1 Efficacy Endpoints ........................................................................... 10 
3.2.2 Safety Endpoints .............................................................................. 11 
3.2.3 Endpoint Definitions ........................................................................ 11 
4. 
OVERALL STUDY DESIGN AND PLAN ......................................................... 11 
4.1 
Selection of Study Population ...................................................................... 12 
4.2 
Double Blind Placebo Controlled Food Challenge (DBPCFC)................. 12 
4.3 
Method of Week Assignment for the Final Challenge and Randomization12 
4.4 
Final Challenge Blinding ............................................................................. 13 
4.5 
Minimization of Missing Data due to Missed Visits during Tolerance Phase
........................................................................................................................ 13 
5. 
ANALYSIS AND REPORTING ........................................................................... 13 
5.1 
Interim Analysis ............................................................................................ 13 
5.2 
Final Analysis ............................................................................................... 13 
6. 
SAMPLE SIZE DETERMINATION................................................................... 14 
7. 
ANALYSIS POPULATIONS ................................................................................ 14 
8. 
GENERAL ISSUES FOR STATISTICAL ANALYSIS ................................... 14 
8.1 
General Statistical Methodology ................................................................. 14 
8.1.1 Statistical Assumptions .................................................................... 15 
8.1.2 Event Censoring ............................................................................... 15 
8.1.3 Data Handling for Patients who withdraw from the Study ........... 16 
8.1.4 Imputation of Missing Data ............................................................. 16 


 
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8.2 
Efficacy Endpoints........................................................................................ 16 
8.2.1 Food Challenge Symptom Score ..................................................... 16 
8.2.2 Change in Immune Parameters........................................................ 16 
9. 
STUDY PATIENTS AND DEMOGRAPHICS .................................................. 16 
9.1 
Disposition of Patients and Withdrawals .................................................... 16 
9.2 
Protocol Violations and Deviations ............................................................. 16 
9.3 
Demographics and Other Baseline Characteristics..................................... 16 
10. 
EFFICACY ANALYSES ....................................................................................... 17 
10.1 
Primary Efficacy Analysis Approach .......................................................... 17 
10.2 
Secondary & Exploratory Efficacy Analysis .............................................. 19 
11. 
REFERENCES ........................................................................................................ 20 
12. 
FIGURES.................................................................................................................. 21 
 


 
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ABBREVIATIONS 
ABBREVIATION DEFINITION OR DESCRIPTION 
AE 
Adverse Event 
AVG 
Average 
BMI 
Body Mass Index 
BOCF 
Baseline Observation Carried Forward 
CFB 
Change from Baseline 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DBPCFC 
Double Blind Placebo Control Food Challenge 
DCSA 
Double Censoring Survival Analysis 
ED10 
Expected Dose predicted to provoke AE in 10% of the population 
FDA 
Food and Drug Administration 
FCSS 
Food Challenge Symptom Score 
ICH 
International Conference on Harmonisation 
ICSA 
Interval Censoring Survival Analysis 
IND 
Investigational New Drug 
ITT 
Intent-to-Treat 
LOAEL 
Lowest-Observed Adverse Event Dose Level 
LOCF 
Last Observation Carried Forward 
LSMean 
Least Squares Mean 
MAR 
Missing at Random 
MCRT 
Minimal Clinically Relevant Threshold 
MI 
Multiple Imputation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
NOAEL 
No-Observed Adverse Event Dose Level 
NRS 
Numeric Rating Scale 
PCS 
Physical Component Score 
PMM 
Pattern Mixture Model 
PROMIS 
Patient Reported Outcomes Measurement Information System  
REML 
Restricted Maximum Likelihood 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SLIT 
Sublingual Immunotherapy 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SU 
Sustained Unresponsiveness 
TLC 
Tolerance 
TLD 
Time to Loss of Desensitization 
 


 
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1. BACKGROUND 
This Statistical Analysis Plan (SAP) has been written to address the concerns identified in the 
March 19, 2014 protocol abbreviated Peanut SLIT and Tolerance (UNC IRB#11-2308), which 
included our proposed primary analysis plan aimed at assessing effectiveness of peanut SLIT to 
induce clinical tolerance 6 months after its discontinuation.  
We recognize the investigating team’s concerns regarding the assumption that patients will be 
able to clear the food challenge administered after 6 months of SLIT discontinuation to 
demonstrate clinical tolerance. The team believes this assumption is rather optimistic, less 
supported by prior research and suspects that the current study protocol calls for negligible 
success rate by the end of 6 months of SLIT discontinuation as most of the subjects would fail 
for clinical tolerance.  Since time to loss of desensitization (TLD) is an important dimension that, 
in our knowledge, no prior study has investigated, provides clinically valuable information and 
helps facilitate future study design, this study provides an opportunity and a robust framework to 
study the same. As a result, the revised protocol analyzes a systematic approach to address this 
concern. We believe that with few changes in the study design and efficacy analysis plan, the 
revised protocol will help address new objectives of primary enquiry and will provide greater 
precision to cater to individual’s need.  
With 51 total enrollees, we are midway through the study’s conduct with 24 subjects clearing 48 
months of dose maintenance period and waiting to be administered the 48th month food 
challenge and to be randomized to the placebo or the treatment arm as per the existing protocol. 
The revised study design calls for amendments beyond the 48 months’ period of dose 
maintenance to include 48th month food challenge followed by discontinuation of SLIT for all 
subjects for at most 17 weeks, dissolving the need for a two-arm trial. Subjects will be 
randomized to weekly observed time points during 17 weeks following the 48th month food 
challenge when the final food challenge will be administered to assess individual’s persistent 
desensitization also known as sustained unresponsiveness (SU). The structure of this final food 
challenge will be similar to that of the earlier (48th month) food challenge with similar levels of 
administered drug doses. 
We have incorporated strong steps in the protocol to be implemented during the study’s conduct 
to ensure minimization of bias due to unblinding and of missing data during the off-SLIT period. 
We have created a provision for patients who fail to show up on their randomized final food 
challenge to continue to participate in the clinical trial, providing outcome data during regularly 
scheduled visits.  In addition, multiple analysis techniques are included in this SAP to examine 
the outcomes of interest and the robustness of results. 
In summary, the two-fold objectives are to estimate the population level threshold for 
desensitization and study the TLD given a desensitization dose level and subjects’ 
characteristics. The proposed primary efficacy analyses deal with special cases of interval 
censored data using parametric and semi/non-parametric methods of estimation that have been 
carefully chosen to address the primary questions of interest.  A detailed discussion of the 
primary efficacy analysis approach is presented in Section 10.1. 
 
 


 
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2. OVERVIEW 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for protocol 
Peanut SLIT & TLC (IRB#11-2308: Peanut Sublingual Immunotherapy and Induction of 
Clinical Tolerance in Peanut Allergic Children (TLC)), dated 19 March 2014 (Version 5.0). 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA) and International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use: Guidance on Statistical Principles in Clinical Trials. All work planned and reported for this 
SAP will follow internationally accepted guidelines, published by the American Statistical 
Association and the Royal Statistical Society, for statistical practice. 
The planned analysis identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analysis not 
necessarily identified in this SAP may be performed to further examine study data. Any post-
hoc, or unplanned exploratory analysis performed will be clearly identified as such in the final 
CSR. 
In preparation of this SAP, the following documents were reviewed in addition to the literature 
references cited in this SAP: 
Clinical Research Protocol Peanut SLIT and Tolerance (TLC) Version 5.0 (March 19, 2014) 
Team Comments Dated June 30, 2015 and follow-up  
International Conference on Harmonization (ICH) Guidance on Statistical Principles for 
Clinical Trials (E9). 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant 
to the planned analysis. 
 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 Study Objectives 
3.1.1 Primary Objectives 
The study has two-fold objectives: 
First, we aim to estimate distribution of sensitization threshold predicted to provoke reactions in 
the peanut-allergic population based on the no-observed and lowest-observed adverse effect 
levels (NOAELs and LOAELs) observed for subjects upon administration of 48th month 
DBPCFC; specifically, we would like to know the population sensitization threshold, the dose 
predicted to provoke reactions in X% of the peanut-allergic population.  
Second, given the above estimated population sensitization threshold and the administered dose 
levels that it lies between, we would like to characterize the SU curve with respect to time for 


 
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several end points including time for desensitization threshold as assessed by the final DBPCFC 
to reduce by half of the estimated sensitization threshold, to drop by a level of the administered 
dose level, to remain above minimal clinically relevant threshold (MCRT) and finally, to 
maintain threshold constancy.  This will give insight to the length of time peanut SLIT regimen 
is effective in inducing desensitization at the estimated as well as observed dose level predicted 
to provoke reactions in X% of the peanut-allergic population.  
3.1.2 Secondary Objectives 
The multifold secondary objectives include: 
1. To evaluate the safety of SLIT regimen administered over initial 48 months of the study 
period.  
2. To study the changes in immune parameters over time and compare these changes among 
subjects who were induced with clinical tolerance vs. those who failed. 
3. To evaluate association of baseline characteristics with desensitization as assessed by the 48th 
month DBPCFC and with loss of desensitization as assessed by the final DBPCFC. 
 
3.2 Study Endpoints 
3.2.1 Efficacy Endpoints 
The primary efficacy endpoints are:  
• An estimate of the dose as assessed by the 48th month DBPCFC, also called population 
sensitization threshold, predicted to provoke reactions in 5% and 10% of the peanut-
allergic population. This will also give population level NOAEL and LOAEL that would 
define interval of consecutive administered dose levels within which the population 
sensitization threshold lies. 
• Multiplicative or differential change in the population sensitization threshold as assessed 
by the 48th month DBPCFC with a unit change in covariates. 
• An estimate of time to loss of desensitization for the following events: 
-   Subject's true sensitivity threshold to reduce by half, also called half-life of sensitivity   
threshold.  
-   Subject's true sensitivity threshold to maintain at the same level of LOAEL.  
-   Subject's true sensitivity threshold to drop by at least one level of LOAEL. 
-   Subject's true sensitivity threshold to remain at or above MCRT. 
• Estimates of the proportion of patients at a fixed time for any of the above events that 
define loss of desensitization (bullet 2).  
• Multiplicative change in hazard of loss of desensitization with a unit change in 
covariates. 
 
Secondary efficacy endpoints include: 
• Comparative estimates of changes in immune parameters over time among subjects who 
were induced with clinical desensitization versus those who failed. 


 
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• Incidence of all serious adverse events (SAEs) during the study. 
3.2.2 Safety Endpoints 
Safety is assessed by the monitoring and recording of adverse events (AEs), clinical laboratory 
tests, vital signs and physical examination findings. 
3.2.3 Endpoint Definitions 
• The loss of desensitization is defined as the decline in sensitivity threshold at the final 
DBPCFC from the 48th month DBPCFC.  
 
• NOAEL is the highest dose observed not to produce any adverse effect and LOAEL is 
the lowest dose that is observed to produce an adverse effect. Experimentally determined 
individual’s true sensitivity threshold lie between NOAEL and LOAEL. The 
establishment of individual NOAELs and LOAELs is dependent upon the selection of 
and spacing between doses selected in the clinical challenge trial design. 
 
4. OVERALL STUDY DESIGN AND PLAN 
This is a Phase 2, open label 52-month study designed to evaluate the safety and efficacy of 
peanut SLIT in inducing clinical desensitization among peanut allergic children. 
The study consists of a Screening visit, a Baseline Visit (sometimes combined with the 
Screening Visit), a build-up phase (approximately, 20 weeks), a Maintenance phase (42 months) 
and finally, a Sustained Unresponsiveness phase (17 weeks). The total duration of the study, 
including Screening and the follow-up period, is approximately 225 weeks. We note that all the 
24 subjects that have passed the 48 month time point and have been waiting to be administered 
the 48th month DBPCFC are continuing to dose daily. Because, based on prior evidence, the 
benefit of continued dosing past 48 months is considered to be negligible on the overall 
treatment outcome, a slight extension of maintenance phase is considered negligible for such 
subject. 
Following the qualifying entry 1000 mg peanut protein DBPCFC administered at the baseline, 
subjects will be administered diluted pumps of concentrated peanut protein extract (5000 
mcg/ml) based on the build-up dosing scheme to reach an escalated dose of 4000 mcg.  Visits for 
build-up doses will occur prior to changing peanut dilutions or every 4 weeks.  Subjects 
completing the Duke IRB Pro0003579, UNC IRB 11-2301, CoFAR4 who do not pass the 164 
week 10 gm DBPCFC may enroll in this study and resume an escalation schedule starting with 
the 2000 mcg dose in this SLIT (11-2308, TLC) protocol. This defines the build-up phase. 
After completing the escalation schedule, subjects will continue to be administered 4000 mcg of 
peanut SLIT daily at home and will return to the clinical research unit for follow-up visits every 
6 months or more frequently for new or significant symptoms.  This defines the maintenance 
phase. 
At the 48th month visit, all subjects undergo a 5000 mg peanut protein DBPCFC to verify 
desensitization, defined as a reaction threshold greater than MCRT (300 mg of peanut protein). 
At the same visit, subjects are randomized to one of the 17 weeks of SU phase for administration 


 
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of the final DBPCFC to assess SU. SU is claimed if the final DBPCFC reaction threshold is 
greater than or equal to the larger of MCRT and the 48th month DBPCFC sensitivity threshold. 
Subjects who fail the 48th month DBPCFC, hence not desensitized, will not be administered the 
final challenge. 
4.1 Selection of Study Population 
For a complete list of inclusion and exclusion criteria please refer to Protocol SLIT (11-2308, 
TLC), version 5.0 issued 19-Mar-2014. 
 
4.2 Double Blind Placebo Controlled Food Challenge (DBPCFC) 
Protocol DBPCFCs will be administered on the subject at entry, 48 months and weekly during 
the seventeen-week tolerance phase by a nurse or physician who is blinded to the testing 
material.  The supervising investigator will also be blinded to testing material. Before each 
challenge, the subject will have a physical exam and peak expiratory flow measurements 
performed.  
The DBPCFC consists of two parts that will be randomly ordered. One part will consist of 
graded doses of peanut flour and the other of identical graded doses of placebo in the form of oat 
flour. The doses will be given every 10-20 minutes up to a cumulative dose of 1000 mg (25 mg, 
50 mg, 100 mg, 250 mg, 575 mg) during the entry challenge and up to a cumulative dose of 5000 
mg (100 mg, 200 mg, 500 mg, 800 mg, 1300 mg, 2100 mg) during the 48th month and final 
DBPCFC. There will be a minimum 10 minute observation period between doses to monitor for 
symptoms.   
After administration of the first part of the challenge the subject will be observed for a minimum 
period of 1 hour prior to starting the second part.  Reactions will be scored using a Food 
Challenge Symptom Score (FCSS) sheet.  If the subject begins to have significant objective or 
persistent subjective symptoms, the food challenge will be terminated and the subject will be 
given appropriate treatment.  Subjects who are symptomatic and receive treatment are observed 
for a minimum of 2 hours after the challenges are completed before being discharged from the 
clinical research unit. 
 
4.3 Method of Week Assignment for the Final Challenge and Randomization 
The following criteria must be satisfied in order for the patient to continue to the SU phase of the 
study and be randomized:  
1. The patient achieves MCRT at the 48th month DBPCFC to continue to the SU phase. 
This requires patient to be asymptomatic upon administration of 300 mg dose as assessed 
by Food Challenge Symptom Score sheet. 
2. If subjects are found symptomatic and AEs that occur are considered to be intolerable at 
or below the MCRT, subjects will be refrained from taking the final challenge and will 
be considered to have lost their desensitization at week 0.  
3. No subject will be administered a final challenge dose higher than the NOAEL attained 
at the 48th month DBPCFC. 


 
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Before the start of the SU phase of the study, a computer-generated block randomization 
schedule is prepared such that each subject has an equal probability of being randomized to one 
of the weekly challenges held in initial 6 weeks, between 7-12 weeks and between 13-17 weeks. 
Based on the randomization schedule, three qualified subjects are randomly assigned to one of 
the final DBPCFC administered each week during the study’s 17-week SU phase.  
 
4.4 Final Challenge Blinding  
Although an open-label study, subjects, study coordinators and the primary investigator will 
remain blinded to subject’s schedule of final DBPCFC challenge until 48th month DBPCFC is 
executed. Randomized week assignment for administration of the final challenge will be 
revealed only after the patient has completed the 48th month DBPCFC. Schedule randomization 
will be performed by representatives in Dr. Burk’s laboratory and all laboratory personnel will 
be unblinded to the randomization schedule throughout the study. All DBPCFCs are conducted 
in a double-blind manner. 
 
4.5 Minimization of Missing Data due to Missed Visits during Tolerance Phase 
To ensure minimization of missing data during the SU phase, the trial has been designed to 
encourage patient retention through multiple approaches, including provision of the possibility of 
“re-randomization” if more than one subject of the assigned week miss the visit they are 
scheduled at; or allowing a subject to take the final challenge on the study’s next scheduled visit.  
The importance of minimizing the amount of missing data has been discussed with all study 
investigators, and their awareness of the importance of patient compliance and minimal dropout 
rates is factored into their recruiting plans.  In addition, investigators are advised to contact the 
medical monitor for guidance on available management options when needed to prevent patients 
from withdrawing from the study. 
 
5. ANALYSIS AND REPORTING 
5.1 Interim Analysis 
No interim analysis will be performed. 
 
5.2 Final Analysis 
All final, planned analyses will be performed after the last patient has completed the follow-up 
visit and end-of-study assessments and all relevant study data have been processed and 
integrated into the analysis database. Any post-hoc, exploratory analyses completed to support 
planned study analysis, which were not identified in this SAP, will be documented and reported 
in appendices to the CSR. Any results from these unplanned analyses (post-hoc) will also be 
clearly identified in the text of the CSR. 
 


 
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6. SAMPLE SIZE DETERMINATION 
The sample size for this study has not been revised from the earlier estimated minimum required 
size of 50 subjects since the study is midway through with an existing enrollment of 51 subjects 
which we intuitively think is good enough with the new study design and analytical methods for 
the revised primary outcome of interest. However, to confirm our understanding, we plan on 
conducting simulations to study the power-sample size curve at 80% power based on study 
assumptions as discussed in the statistical methods section. 
 
7. ANALYSIS POPULATIONS 
The following analysis populations are planned for this study: 
• Safety Population (SAFETY): all patients who receive at least 1 dose of investigational 
product. All safety analyses and demographic/baseline characterization will be performed 
using this population, analyzed as treated. 
• Intention-To-Treat Population (ITT): all patients who are randomized for assessment 
of clinical desensitization and SU. This population is primary for efficacy and all efficacy 
analyses will be performed using this population. 
 
8. GENERAL ISSUES FOR STATISTICAL ANALYSIS 
8.1 General Statistical Methodology 
Descriptive summaries will be provided where appropriate for each of the primary and secondary 
variables.  
Baseline characteristic and safety tables will be completed for the Safety Population unless 
otherwise specified. Baseline values are defined as the last non-missing measurement prior to the 
first dose of study drug.  Change from baseline will be defined as the post-baseline visit value 
minus the baseline value.   
Continuous, quantitative, variable summaries will include the number of patients (N) with non-
missing values, mean and standard deviation, median, minimum, and maximum. Categorical, 
qualitative, variable summaries will include the frequency and percentage of patients who are in 
the particular category.  In general the denominator for the percentage calculation will be based 
upon the total number of patients in the study population unless otherwise specified.  
Efficacy tables will be presented for the ITT Population for each of the primary objectives. First, 
the number and proportion of subjects for each interval of NOAEL and LOAEL observed at the 
48th month DBPCFC will be reported. This will be broken by baseline and other clinical 
characteristics. Non-parametric Kaplan-Meier estimates of NOAEL distribution with interval 
censoring will be used to report expected proportion of subjects within each interval of NOAEL 
and LOAEL, overall and by patient groups. Second, for each interval of NOAEL and LOAEL 
observed at the 48th month DBPCFC, Kaplan-Meier product limit estimates of the probabilities 
of loss of tolerance (as defined by the latter three efficacy outcomes in section 3.2.1 bullet 2) 
using interval censoring, will be plotted against time (17 weeks), overall and for various patient 
groups. The “expected” number of patients with loss of tolerance and the “P values” derived 


 
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from univariate log rank tests for interval censored data will be reported for each 48th month 
DBPCFC NOAEL.  
Unless otherwise indicated, all statistical tests will be 2 sided and tested at a significance level of 
0.05. Corresponding 95% confidence intervals will be presented for statistical tests. 
8.1.1 Statistical Assumptions 
Time to Loss of Desensitization (TLD) requires more rigorous mathematical framework of 
stochastic process. However, a good approximation could be achieved using Interval Censoring 
framework for the latter three events defined in section 3.2.1 (bullet 3). The framework uses 
following assumptions: 
• Desensitization is monotonically decreasing with time. NOAEL(final DBPCFC) <= 
NOAEL(48th month DBPCFC) 
• Subject's true sensitivity threshold at the 48th month DBPCFC is approximated by his/her 
NOAEL.  
• Subjects with the final DBPCFC NOAEL higher than the 48th month DBPCFC NOAEL 
will be regarded as exceptions. Their final DBPCFC NOAEL will be considered equal to 
the 48th month DBPCFC NOAEL for conservative time to loss of desensitization 
estimates. 
 
• Subjects with 48th month LOAEL < MCRT will also fail at LOAEL administered at the 
final DBPCFC that are less than MCRT, thereby un-necessitating the need for the final 
DBPCFC. 
• Since the final DBPCFC observation times are randomized, subject’s unobserved time to 
loss of desensitization and the baseline covariates are independent of his/her final 
DBPCFC observation time. 
8.1.2 Event Censoring  
• For efficacy endpoint in section 3.2.1 bullet 1 (population sensitization threshold), an 
individual’s true threshold is  
- left censored if individual fails on the smallest dose administered 
- right censored if no adverse effect is observed on the largest dose administered 
- interval censored in all other cases. 
 
• For the latter three time to loss of desensitization efficacy endpoints defined in section 
3.2.1 bullet 2, censoring is defined as below: 
-  Subjects with 48th month LOAEL < MCRT who are not administered the final 
DBPCFC have their time to loss of desensitization assumed to be zero.  
-  Subjects with the final DBPCFC NOAEL equal to the highest administered dose level 
are assumed to have their LOAEL beyond the observed time. 
-  For subjects who do not show up for the final DBPCFC until the 17th week of 
randomization will be removed from the analysis. A separate analysis will be conducted 
to predict drop-outs.  
No censoring will occur on safety endpoints.  


 
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8.1.3 Data Handling for Patients who withdraw from the Study 
Such subjects will be considered intolerant and failing at time 0. 
8.1.4 Imputation of Missing Data 
No missing safety data will be imputed. For efficacy data with intermittent missingness, a subject 
will be considered failed at the first time when missingness is encountered. 
 
8.2 Efficacy Endpoints 
8.2.1 Food Challenge Symptom Score   
Total number of symptoms for a given individual and proportion of a specific symptom among 
all subjects. Clear objective or persistent subjective symptoms are typically reasons to stop and 
treat a patient.  
8.2.2 Change in Immune Parameters 
There are numerous parameters: peanut specific IgE, peanut specific IgG4, skin test size, 
basophil reactivity, TH2 cytokine release, and T regulatory levels. These were drawn annually 
and at the final challenge(s).  
 
9. STUDY PATIENTS AND DEMOGRAPHICS 
9.1 Disposition of Patients and Withdrawals 
The numbers and percentage of patients enrolled, completing the 48th month and final 
DBPCFCs, and withdrawing from the study, along with reasons for withdrawal, will be 
tabulated. In addition, the number of patients discontinuing during the SU phase will be 
summarized. The number and percentage of patients in each analysis population will be reported. 
This summary will be based on all patients who have data entered into the database.  
 
9.2 Protocol Violations and Deviations 
Protocol violations and deviations will be checked on complete data for all patients. The final 
decision regarding inclusion and exclusion of patients from the analysis populations will be 
based on a listing of protocol violations and deviations. This will be determined during a 
(blinded) data review meeting before database lock and the final analysis with input from 
Clinical and statistical teams. 
Protocol violations and deviations will be summarized by type for the Safety population. 
Individual patients with protocol deviations or violations will be listed. 
 
9.3 Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be completed 
for all enrolled patients in the study population, unless otherwise specified. 


 
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Descriptive summaries of demographic and other baseline conditions will include: 
• Demographics 
- Age at onset of study (1-11yrs) 
- Sex (M/F) 
- Age at introduction of peanut (0-11yrs) 
- Daycare (Y/N) 
• History  
- Concurrent eczema (Y/N) 
- Concurrent asthma (Y/N) 
- Concurrent allergic rhinitis (Y/N) 
- Parental history of atopic disease (Non/Mother/Father/Both) 
- C-section (Y/N) 
- Breastfeeding (Y/N) 
- Milk allergy (Y/N) 
- Egg allergy (Y/N) 
• Clinical 
- Initial peanut skin test size (3mm-30mm) 
- Initial peanut IgE level (0.35-100kU/L) 
 
Medical History will be coded using the latest version of MedDRA (version 16.0) and 
summarized by SOC and Preferred Term using frequency counts. Physical exam data will be 
presented in listings. 
 
10. EFFICACY ANALYSES 
10.1 Primary Efficacy Analysis Approach 
To begin with, our primary analysis will comprise of two parts.  
First, an Interval-Censoring Survival Analysis (ICSA) approach will be used to analyze the 48th 
month DBPCFC threshold data (Collett, 1993, Chapter 9, Taylor et al - 2009). The methodology 
is appropriate when the exact dose that provokes a reaction in an individual is not known but it is 
known to fall into a particular interval. Using ICSA, if an individual had an objective reaction at 
the first dose in a challenge trial, then left-censoring occurred, and the NOAEL was set to zero 
with the LOAEL set as that first dose. If an individual did not experience an objective reaction 
after the largest challenge dose, then right-censoring occurred, and the NOAEL was set to that 
largest challenge dose (if a subjective response occurred at that largest dose, this was also 
considered as the objective NOAEL), while the LOAEL was set to infinity. In all other cases, 
interval-censoring occurs bounded by the NOAEL and LOAEL. Parametric (Log-normal, 
Weibull) and non-parametric dose-distribution model will be used to estimate the ED10 and the 
ED05, the doses predicted to provoke reactions in 10% and 5%, respectively, of the peanut-
allergic population.  
Second, for each dose interval bounded by the NOAEL and LOAEL of the 48th month DBPCFC, 
we will conduct survival analysis with case-1 censoring (Huang – Wellner lecture notes, 
Kosorok et al, 1998) to estimate time to loss of desensitization. We will assume exponential 


 
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distribution with log link for the decay of sensitivity threshold for those who take the final 
challenge. This assumption of exponential decay will be validated using semi/non-parametric 
analysis with an option for modeling with a more flexible semi-parametric distribution.  The 
analyses will be performed with and without the effect of baseline and other clinical covariates.   
This analysis will provide an initial insight into effectiveness of peanut SLIT in longevity of 
induced clinical desensitization and SU.  
To illustrate, we introduce the following notation. Let Xd be the time to loss of desensitization 
with distribution Fd for a given NOAEL, d, administered at the 48th month DBPCFC (d = 100, 
200, 500, 800, 1300, 2100 mg). Let T be an observation time (in weeks), t = 0, 1…17 with 
distribution G. Because the assignment time is randomized, the time of interest Xd and baseline 
covariates will be independent of T. We also assume that the clinically induced desensitization is 
monotonically decreasing such that the subject’s NOAEL is either decreased or stays constant by 
observation time T. In other words, the true time to loss of desensitization from the 48th month 
DBPCFC, which is unknown, is either less or equal to the observation time. This could 
mathematically be represented as a problem of case-1 interval censoring wherein, we observe n 
i.i.d observations of (T, I{Xd ≤ T}| d) = (T, ∆d) for a given NOAEL, d. Further, we assume Xd = 
0 for those subjects who do not meet MCRT (d < MCRT) at the 48th month DBPCFC. Let π 
define the probability that Xd = 0, and let the baseline and clinical covariates be represented by 
Z. Then, in order to derive the likelihood of Fd, we need to solve the following optimization 
problem to find the MLE: 
sup
𝐹𝐹∈ℱ
𝐿𝐿𝑛𝑛(𝐹𝐹) 
 , where ℱ is a class of distribution functions and  
𝐿𝐿𝑛𝑛(𝐹𝐹)
=
ෑ𝑃𝑃(𝛽𝛽, 𝛾𝛾, 𝑍𝑍𝑖𝑖, 𝑡𝑡)
𝑖𝑖=1..𝑛𝑛
 
𝑃𝑃(𝛽𝛽, 𝛾𝛾, 𝑍𝑍𝑖𝑖, 𝑡𝑡)
=
{𝑃𝑃(𝑋𝑋𝑖𝑖𝑖𝑖= 0) 𝐼𝐼(𝑋𝑋𝑖𝑖𝑖𝑖= 0)} ∗{𝑃𝑃(𝑋𝑋𝑖𝑖𝑖𝑖> 0)𝐼𝐼(𝑋𝑋𝑖𝑖𝑖𝑖> 0)} 
∗{𝑃𝑃(𝑋𝑋𝑖𝑖𝑖𝑖=  t, Δ = 0|𝑑𝑑, 𝑋𝑋𝑖𝑖𝑖𝑖> 0)} ∗{𝑃𝑃(𝑋𝑋𝑖𝑖𝑖𝑖=  t, Δ = 1|𝑑𝑑, 𝑋𝑋𝑖𝑖𝑖𝑖> 0)} 
              
=
ቈ
𝑒𝑒𝛾𝛾′𝑍𝑍𝑖𝑖
1 + 𝑒𝑒𝛾𝛾′𝑍𝑍𝑖𝑖቉
𝑦𝑦𝑖𝑖
∗൤
1
1 + 𝑒𝑒𝛾𝛾′𝑍𝑍𝑖𝑖൨
1−𝑦𝑦𝑖𝑖
∗ൣ൫1 −𝐹𝐹𝑑𝑑(𝑡𝑡)൯𝑔𝑔(𝑡𝑡)൧
1−𝛿𝛿𝑖𝑖∗ [𝐹𝐹𝑑𝑑(𝑡𝑡)𝑔𝑔(𝑡𝑡)]𝛿𝛿𝑖𝑖 
 
=
ቈ
𝑒𝑒𝛾𝛾′𝑍𝑍𝑖𝑖
1 + 𝑒𝑒𝛾𝛾′𝑍𝑍𝑖𝑖቉
𝑦𝑦𝑖𝑖
∗൤
1
1 + 𝑒𝑒𝛾𝛾′𝑍𝑍𝑖𝑖൨
1−𝑦𝑦𝑖𝑖
∗൫1 −𝐹𝐹𝑑𝑑(𝑡𝑡)൯
1−𝛿𝛿𝑖𝑖∗ 𝐹𝐹𝑑𝑑(𝑡𝑡)𝛿𝛿𝑖𝑖𝑔𝑔(𝑡𝑡) 
𝑦𝑦𝑖𝑖=  𝐼𝐼(𝑋𝑋𝑖𝑖𝑖𝑖= 0); 𝛿𝛿𝑖𝑖=  𝐼𝐼(Δ𝑖𝑖= 1);  𝐹𝐹𝑑𝑑(𝑡𝑡) = 1 −𝑒𝑒−𝜆𝜆𝑖𝑖𝑡𝑡; 𝜆𝜆𝑖𝑖(𝑡𝑡, 𝑍𝑍𝑖𝑖) = 𝜆𝜆0𝑒𝑒𝛽𝛽′𝑍𝑍𝑖𝑖 
Maximizing the above likelihood will provide estimates of 𝛽𝛽 & 𝛾𝛾 towards estimating distribution 
of time to loss of desensitization. 
The results from preliminary analyses will help support implementation of advanced and more 
precise methods to study decrease in threshold using Double Censoring Survival Analysis 
(DCSA) (Sun et al, 2004) in a stochastic framework to account for changes with time. This will 
allow estimation of the distribution of decrease in desensitization as a function of time giving an 
opportunity to estimate population half-life and association between the hazard of loss of 
desensitization and baseline and clinical covariates.  


 
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10.2 Secondary & Exploratory Efficacy Analysis 
Secondary efficacy analyses will be based on the ITT population only. Continuous endpoints will 
be analyzed using the MMRM analysis. The mean changes from baseline will be analyzed using 
a restricted maximum likelihood (REML) based repeated measures approach.  Analyses will 
include the fixed, categorical effects of population source, center and study week as well as the 
fixed covariates of baseline score and baseline score-by-study week interaction.  An unstructured 
covariance structure will be used to model the within-patient errors.  If this analysis fails to 
converge, the following structures will be tested: first order ante dependence, heterogeneous first 
order autoregressive, heterogeneous compound symmetry and compound symmetry.  The 
covariance structure converging to the best fit, as determined by Akaike’s information criterion, 
will be used in the analysis (Mallinckrodt et al, 2008).  The Kenward-Roger approximation will 
be used to estimate the denominator degrees of freedom.  Significance test will be based on least-
squares means using a two-sided alpha=0.05 test and two-sided 95% confidence intervals will be 
presented.  The comparison of interest is the contrast between the weeks of challenges and 
baseline. 
MMRM analysis will be implemented with a modified baseline observation carried forward 
(BOCF)/last observation carried forward (LOCF) algorithm. Where the study medication was 
discontinued due to lack of efficacy or to an AE or the cause is unknown, the baseline value is 
used for all values after the last date that study medication was taken (as shown in the Daily Diary). 
If the study medication was discontinued for any other reason, then the last observation will be 
carried forward. This is an MNAR analysis that investigates changes in endpoints using logical 
assumptions. Assessment values collected after treatment discontinuation, and true missing values 
(after withdrawal from the study) will be imputed in this manner.  
 
 


 
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11. REFERENCES 
1. Taylor et al. 2009. “Threshold dose for peanut: Risk characterization based upon published 
results from challenges of peanut-allergic individuals” Food and Chemical Toxicology 47 (2009) 
1198–1204. 
2. Taylor et al. 2010. “Threshold dose for peanut: Risk characterization based upon diagnostic 
oral challenge of a series of 286 peanut-allergic individuals” Food and Chemical Toxicology 48 
(2010) 814–819. 
3. Kim et al. 2011. “Sublingual immunotherapy for peanut allergy: Clinical and immunologic 
evidence of desensitization” The Journal of Allergy and Clinical Immunology. doi: 
10.1016/j.jaci.2010.12.1083 
4. Huang, J, 1996. “Efficient Estimation for the Cox Model with Interval Censoring” Annals of 
Statistics, 24:540-568 
5. Huang J, Wellner J.  1997. “Interval Censored Survival Data: A Review of Recent Progress”.   
Lecture notes in Statistics. 
6. Kosorok et al. 1998. “Comprehensive Analysis of Risk Factors for Acquisition of 
Pseudomonas aeruginosain Young Children With Cystic Fibrosis”. Pediatric Pulmonology 
26:81–88 
7. Sun et al. 2004. “Statistical Analysis of Doubly Interval Censored Failure Time Data”. 
Handbook of Statistics, Vol 23. ISSN 01694 -7161


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Statistical Problem Overview