Application of a Novel Allergen-Specific Immune Signature Directed Approach to Dietary Elimination Therapy in Patients With Eosinophilic Esophagitis (IDiET)
Phase: NA
Conditions: Eosinophilic Esophagitis
Sponsor: University of North Carolina, Chapel Hill

 
 
Application of a Novel Allergen-Specific Immune Signature Directed 
Approach to Dietary Elimination Therapy in Patients With Eosinophilic 
Esophagitis (IDiET) 
 
 
NCT number 02722148 
Document Date 20Jun2017 
 

 
CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
Application of a Novel Allergen-Specific Immune Signature 
Directed Approach to Dietary Elimination Therapy in Patients 
with Eosinophilic Esophagitis (IDiET) 
 
 
Principal Investigator: 
Evan S Dellon, MD, MPH 
Associate Professor of Medicine 
University of North Carolina School of Medicine 
Chapel Hill, NC  
Co-Investigators: 
Nicholas J Shaheen, MD, MPH 
Professor of Medicine and Epidemiology 
Director, Center of Esophageal Diseases and Swallowing 
University of North Carolina School of Medicine 
Chapel Hill, NC 
 
Funding Sponsor: 
Translational Team Science Award (TTSA) via The North 
Carolina Translational and Clinical Sciences (TraCS) 
Institute 
IRB approval: 
UNC IRB # 15-2719 
 
 
Initial version: March 8, 2016 
Version 2.0: 
October 3, 2016 
Version 3.0:  
June 20, 2017 
 
 

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CONFIDENTIAL 
 
 
Changes from Previous Version 
 
This version includes the following major changes to the previous version of the 
protocol, Version 2.0 (03Oct2016). 
 
Section 1.2, Rationale 
Added additional possible allergens 
tested on research samples for data 
collection. 
Section 6.1, Sample Size Determination 
The number of consented and enrolled 
subjects has been increased to 30, with 
an increased goal of 20 subjects 
completing the study. 
Administrative Changes 
Updated protocol version on first page 
and header of all subsequent pages. 
Minor typographical errors corrected 
throughout. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CONFIDENTIAL 
 
 
Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 2 
1   INTRODUCTION ...................................................................................................................................... 3 
1.1 
BACKGROUND ................................................................................................................................ 3 
1.2 
RATIONALE .................................................................................................................................... 3 
2 
STUDY OBJECTIVES ......................................................................................................................... 6 
3 
STUDY DESIGN ................................................................................................................................... 6 
3.1 
GENERAL DESIGN .......................................................................................................................... 6 
3.2 
NON-SIGNIFICANT RISK .................................................................................................................. 7 
3.3 
PROTOCOL MAP ........................................................................................................................... 11 
3.4 
STUDY OUTCOMES ....................................................................................................................... 12 
4 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 12 
4.1 
INCLUSION CRITERIA .................................................................................................................... 12 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 12 
4.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 12 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 12 
4.4.1 
When and How to Withdraw Subjects ................................................................................... 12 
4.4.2 
Lost to Follow-Up................................................................................................................... 12 
4.4.3 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 13 
5 
STUDY PROCEDURES ..................................................................................................................... 13 
5.1 
SCREENING VISIT ......................................................................................................................... 13 
5.1.1 
Consenting Procedure ........................................................................................................... 14 
5.1.2 
Biopsy Collection and Processing ......................................................................................... 14 
5.1.3 
Blood Sample Collection and Processing ............................................................................. 16 
5.2 
DAY 1 VISIT ................................................................................................................................. 16 
5.3 
6 WEEK FOLLOW-UP VISIT (+/- 7 DAYS) ........................................................................................ 17 
6 
STATISTICAL PLAN ......................................................................................................................... 17 
6.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 17 
6.2 
STATISTICAL METHODS ................................................................................................................ 17 
6.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 18 
7 
SAFETY AND ADVERSE EVENTS ................................................................................................... 18 
7.1 
DEFINITIONS ................................................................................................................................ 18 
7.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 20 
7.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 20 
7.3.1 
Notifying the UNC IRB ........................................................................................................... 20 
7.3.2 
Notifying the FDA – Unanticipated Adverse Device Effects .................................................. 22 
7.4 
STOPPING RULES ......................................................................................................................... 22 
7.5 
MEDICAL MONITORING ................................................................................................................. 22 
8 
DATA HANDLING AND RECORD KEEPING ................................................................................... 22 
8.1 
CONFIDENTIALITY ......................................................................................................................... 22 
8.2 
SOURCE DOCUMENTS .................................................................................................................. 23 
8.3 
CASE REPORT FORMS.................................................................................................................. 23 
8.4 
RECORDS RETENTION .................................................................................................................. 23 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 23 

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9.1 
STUDY MONITORING PLAN ............................................................................................................ 23 
9.2 
AUDITING AND INSPECTING ........................................................................................................... 24 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 24 
11 
STUDY FINANCES ............................................................................................................................ 25 
11.1 
FUNDING SOURCE ........................................................................................................................ 25 
11.2 
CONFLICT OF INTEREST ................................................................................................................ 25 
11.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................... 25 
12 
PUBLICATION PLAN ........................................................................................................................ 25 
13 
REFERENCES ................................................................................................................................... 26 
 
 
 

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Protocol Signature Page 
 
I have read and agree to the protocol entitled ‘Application of a Novel Allergen-Specific Immune Signature-
Directed Approach to Dietary Elimination Therapy in Patients with Eosinophilic Esophagitis (IDiET)’ dated 
20Jun2017. I am aware of my responsibilities as an Investigator under the guidelines of GCP, local 
regulations (as applicable) and the trial protocol. I agree to conduct the trial according to these 
responsibilities and to appropriately direct and assist the staff under my control, who will be involved in 
the trial. 
 
 
Principal Investigator: 
 
 
 
 
 
_________________________________ 
 
 
______________________________ 
Print Name  
 
 
 
 
 
 
Title 
 
 
 
 
 
_________________________________ 
 
 
______________________________ 
Signature  
 
 
 
 
 
 
Date 
 
 
 
 

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List of Abbreviations  
 
 
 
 
Item 
Definition 
CEDAS 
Center for Esophageal Diseases and Swallowing 
CRF 
Electronic Case Report Form 
DSQ 
Dysphagia symptom questionnaire 
EC 
Ethics Committee 
EGD 
Esophagogastroduodenoscopy 
EoE 
Eosinophilic Esophagitis 
EoG 
Eosinophilic Gastroenteritis 
Eos 
Eosinophils 
EREFS Score 
EoE Endoscopic Reference Score 
FDA 
Food and Drug Administration 
HPF 
High Power Field 
IDE 
Investigational device exemption 
IRB 
Institutional Review Board 
IVD 
In-vitro diagnostic 
NSR 
Non-significant risk 
PID 
Participant ID 
 
 
 
 
 
 
 

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Study Summary 
Title 
Application of a Novel Allergen-Specific Immune Signature Directed Approach to 
Dietary Elimination Therapy in Patients with Eosinophilic Esophagitis (IDiET) 
Short Title 
IDiET 
Methodology 
Prospective single center clinical trial  
Study Duration 
2 years 
Study Center(s) 
University of North Carolina, Chapel Hill, NC 
Objectives 
To evaluate prospectively the effectiveness of individualized allergen-specific 
immune signature-based dietary elimination therapy for EoE 
Number of 
Subjects 
30 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion Criteria: 
1) Age 16-80 years old 
2) Meet one of the following: 
a. Active EoE as per consensus guidelines OR 
b. Undergoing upper endoscopy for a clinical suspicion of EoE  
3) No prior history of dietary elimination therapy 
 
Exclusion Criteria: 
1) Concomitant eosinophilic gastroenteritis 
2) Any corticosteroid exposure in the 4 weeks prior to their baseline 
endoscopic exam 
3) Previous esophageal surgery 
4) Medical instability that precludes safely performing upper endoscopy 
5) Inability to read or understand English 
6) Pregnant women 
Statistical 
Methodology 
To determine the response rate for the primary outcome, the number of subjects 
with <15 eos/hpf on follow-up endoscopy will be calculated.  
 
For secondary outcomes, median eosinophil counts, endoscopy scores, and 
symptoms scores will be compared before and after treatment with Wilcoxon 
signed-rank. These will be contextualized by calculating odds ratios and 95% 
confidence intervals where appropriate, so as not to over-rely on p values alone. 
Patients who drop out or who have incomplete data for the outcomes will be 
excluded from analysis. Because this study’s outcomes are determined after the 
treatment period and follow-up endoscopy, a subject must complete this end of 
treatment evaluation for us to be able to include their data in the analysis. We do 
not feel that selection bias would impact the analysis if there are incomplete data 
due to drop out. We are not performing a comparative analysis between groups, so 
drop out would not be dependent on different treatments administered in different 
study arms. In addition, in our experience with previous clinical studies of EoE, 
dropout rates have been quite low. 

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1   Introduction 
This document is a protocol for a human research study. This study is to be conducted according to US 
and international standards of Good Clinical Practice, applicable government regulations and Institutional 
research policies and procedures.  
1.1 Background 
Over the past decade, eosinophilic esophagitis (EoE) has rapidly increased in incidence and prevalence, 
becoming a major cause of chronic gastrointestinal morbidity. EoE is defined by pathologic infiltration of 
eosinophils into the esophageal mucosa, leading to dysphagia and progressive esophageal stenosis, and 
is now the most common cause of food impaction in the U.S. EoE is a chronic, allergic/immune-mediated 
condition that appears to be driven primarily by IL-5+ and IL-13+ T cell responses to food antigens, based 
on studies observing disease remission in individuals empirically avoiding all potentially allergenic foods. 
However, such radical elimination diets are not feasible and there is no currently available test to accurately 
identify specific food triggers in EoE. Because of this, successful dietary therapy requires empiric 
elimination of a large number of foods, subsequent reintroduction of single foods, and invasive monitoring 
(endoscopy with biopsy) to assess response. There is a critical need to develop methods to reliably identify 
allergen triggers. 
 
In Phase I of the Team Translational Science Award, we began to address these key knowledge gaps. 
Using prospectively collected biospecimens, we successfully developed a novel T cell directed approach 
whereby allergen-specific T cells were correlated with known dietary triggers of EoE. We examined 
esophageal tissue, duodenal tissue, and blood, and found that the blood compartment was the most reliable 
for extracting, culturing, and stimulating T cells. This demonstration was the first time in humans with EoE 
that potential food triggers could be detected with a T cell signature in the blood, and it provided proof-of-
principle of a clinical application of individualized food elimination regimens. We also performed preliminary 
studies detecting allergen-specific IgG4 in esophageal biopsies, a recently described pathogenic 
mechanism of EoE. We feel that the combination of these techniques will allow determination of allergen-
specific immune signatures in EoE patients. These hold great promise to impact clinical practice by 
accurately identifying foods to eliminate in dietary therapy, thus increasing compliance and ultimately 
response rates. However, additional steps are required before clinical adoption of this approach. 
 
The goal of this study is to conduct a pilot prospective study of allergen-specific immune signature-guided 
dietary elimination therapy to assess the clinical effectiveness of this technique. The overall hypothesis is 
that T cells obtained from the blood of a subject with active EoE, when cultured and stimulated with food 
allergens, and when coupled with allergen-specific IgG4 detected in an esophageal biopsy, will result in a 
food trigger-specific immunological signature that can be used to design highly effective dietary treatment 
specific to that individual. 
1.2 Rationale 
Eosinophilic esophagitis is a rapidly increasing chronic allergic condition 
Over the past decade, eosinophilic esophagitis (EoE) has rapidly increased in incidence and prevalence to 
become a major cause of chronic gastrointestinal morbidity, with annual health care costs estimated at $1 
billion.1-3 EoE is defined by pathologic infiltration of eosinophils into the esophageal mucosa, leading to 
dysphagia and progressive esophageal stenosis,4, 5 and is now the most common cause of food impaction 
in the U.S.6, 7 EoE is a chronic, allergic/immune-mediated condition that is driven primarily by IL-5+ and IL-
13+ T cell responses to food antigens,8-11 rather than a typical immediate IgE response.12 This pathogenesis 
suggests that dietary elimination would be effective, and disease remission has been demonstrated in 
individuals empirically avoiding all allergenic foods or consuming only a hypoallergenic elemental formula.13-
18  
 
 
 

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Dietary elimination, as currently conceived, is a sub-optimal and cumbersome therapy option 
There are multiple problems, however, with the dietary elimination approach to treatment of EoE. Radical 
elimination diets, although effective, are not feasible given their very restrictive nature. For example, more 
than 50% of adults are unable to tolerate an elemental formula diet for more than a few days,15 and children 
often require placement of feeding tubes to obtain adequate nutrition.14, 19 Further, poor ability to adhere to 
the so-called “six food elimination diet”, which empirically removes dairy, wheat, egg, soy, nuts, and 
seafood, has led to variable and unpredictable response rates.20, 21 
 
A major reason for this is that no currently available allergy test can accurately identify specific food triggers 
leading to EoE. For example, two studies have shown that an elimination diet based on skin-prick testing 
correctly identifies food triggers in only 13%, a rate that is far worse than expected by chance alone.17, 22 
Because of this, successful dietary therapy requires empiric elimination of a large number of foods, 
subsequent reintroduction of single foods, then endoscopy and biopsy to assess for recurrent tissue 
eosinophilia.5 This leads to dietary changes that are frequently unnecessary, and the serial endoscopies, 
which can number up to 10 in a single year,22 are costly and risky.3 Finally, while alternative treatment with 
topical corticosteroids is possible in patients who cannot comply with dietary therapy, not all patients 
respond, and long-term use of this medication class is unsafe.23, 24 Therefore, there is a critical need to 
develop methods to reliably identify allergen triggers. This will advance understanding of the biology of EoE, 
lead to substantially improved therapy, and reduce costs. 
 
This study uses novel and highly innovative techniques to identify dietary triggers and individualize 
dietary treatment regimens, making dietary elimination practical and more palatable 
A novel allergen-specific immune signature-directed approach to food trigger identification has great 
promise for EoE. The current model of EoE pathogenesis holds that when food antigens are presented to 
the GI tract, either in the esophagus or in the small intestine, previously sensitized T cells are triggered to 
produce a cascade of Th2 cytokines, including IL-4, IL-5, and IL-13.8 In addition, a recent study has 
identified foodspecific IgG4 as important to the pathogenesis.12 Because this model is neither simply an 
immediate IgE- nor a classic delayed IgG-mediated response, it is not surprising that skin prick or patch 
tests are not accurate. 
 
An alternative approach would be to create a food trigger-specific immunological signature using both 
sensitized T cells and food-specific IgG4 as the basis for elimination diet therapy. The complexity of the 
immune response in EoE suggests that IgG4-secreting B-cells may receive signals from allergen-
responsive T cells after exposure.25 Our previous work has shown that T cells sensitized to specific foods 
can be readily expanded and characterized in response to antigen in non-EoE patients with IgE-mediated 
peanut or egg allergies.26-28 In our work supported by Phase I of the UNC Team Translational Science 
Award (TTSA), we showed for the first time in patients with EoE that this could also be done. Specifically, 
using prospectively collected specimens, we successfully developed a novel T cell directed approach 
whereby allergen-specific T cells were correlated with known dietary triggers of EoE. We examined 
esophageal tissue, duodenal tissue, and blood, and found that the blood compartment was the most reliable 
for extracting, culturing, and stimulating T cells (see below). Moreover, we performed preliminary studies 
detecting food allergen-specific IgG4 in esophageal biopsies in EoE patients (see below). 
 
Taken together, these findings demonstrate proof-of-principle of a potential clinical application using 
allergenspecific immune signatures to identify food triggers and create elimination diet regimens in patients 
with EoE.  
 
Optimization of newly developed techniques of determining allergen-specific immune signatures in 
patients with well-characterized, food-driven EoE. 
Investigators studied two allergen-specific signatures.  The first was antigen-specific IgG4 in esophageal 
tissue.  Investigators showed that total and food-specific IgG4 was markedly elevated in esophageal 
biopsies from EoE cases compared to controls (Table 1).  Second, investigators showed that food-specific 
IgG4 levels of trigger foods decreased in EoE patients who responded to dietary elimination (Figure 1).  
Third, using the sub-population of EoE patients who successfully responded to dietary elimination and in 
whom the trigger foods were known, investigators were able to develop optimal thresholds for normalized 
food-specific IgG4 levels that identified food triggers with a good to excellent agreement (Table 2). 

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The second allergen-specific signature we assessed was the lymphocyte proliferation assay developed by 
the investigators.  Here, investigators again used the sub-population of EoE patients who successfully 
responded to dietary elimination and in whom the trigger foods were known to develop a threshold for 
identifying food triggers with good to excellent agreement (Table 3).  When both tests were used together, 
the sensitivity for identifying triggers was improved, with an associated decrease in specificity (Table 4).  
However, investigators will accept this trade-off for this protocol so that investigators identify as many 
potential food triggers as possible to optimize the treatment response rate.  Moreover, the agreement 
across all of the tested foods was substantially better than the reported agreement of 13% using traditional 
skin prick allergy tests.  Investigators have confirmed that the lab studies can yield results within 2 weeks, 
which is a clinically acceptable time frame.  In addition, investigators performed cytokine stimulation testing 
for 14 EoE cases with IL-4, IL-5, and IL-13 but these results did not clearly help to increase the yield for 
identifying food triggers, so investigators will not pursue this direction further (data not shown). 
 
 
These thresholds will be used in this prospective study of allergen-specific immune signature-guided dietary 
elimination therapy to assess the clinical effectiveness of this technique. Samples may be tested using 
additional allergens, including but not limited to beef, corn, fish, shellfish, rice, chicken, potato, pork, 
Table 3:  Performance of lymphocyte proliferation testing for identifying food triggers in EoE  
 
Nut 
Egg 
Soy 
Wheat 
Milk 
Testing parameters (%) 
 
 
 
 
 
    Sensitivity 
100 
63 
60 
20 
45 
    Specificity 
82 
75 
78 
50 
75 
    Agreement 
75 
71 
50 
42 
47 
 
Table 4:  Performance of a positive test on either the lymphocyte proliferation or the IgG4 assay for 
identifying foods 
 
Nut 
Egg 
Soy 
Wheat 
Milk 
Testing parameters (%) 
 
 
 
 
 
    Sensitivity 
100 
100 
75 
80 
64 
    Specificity 
50 
50 
45 
43 
25 
    Agreement 
60 
75 
53 
58 
53 
Table 1:  Esophageal IgG4 levels are markedly elevated in EoE 
cases 
 
EoE cases 
(n = 20) 
Controls 
(n = 10) 
p 
Median 
levels 
(ng/mL) 
 
 
 
    Total 
1847 
469 
0.008 
    Peanut 
4.05 
0.01 
0.003 
    Soy 
2.12 
0.01 
< 0.001 
    Egg 
61.4 
2.88 
< 0.001 
    Milk 
55.8 
0.67 
< 0.001 
Wheat
19.9
1.10
< 0.001
Figure 1:  Food specific IgG4 levels decrease after 
dietary elimination of triggers 
Table 2:  
 performance of esophageal IgG4 for identifying food triggers in EoE 
 
Nut 
Egg 
Soy 
Wheat 
Milk 
 
 
 
 
 
 
Testing parameters (%) 
 
 
 
 
 
    Sensitivity 
0 
88 
0 
60 
55 
    Specificity 
80 
75 
100 
100 
100 
    Agreement 
67 
80 
67 
77 
53 

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legumes, green beans, tomatoes, green peppers, and tree nuts. Results from these additional allergens 
are for data collection only and will not be used to drive subject diet elimination or communicated to subjects. 
2 Study Objectives 
Primary Objective: To evaluate prospectively the effectiveness of individualized allergen-specific immune 
signature-based dietary elimination therapy for EoE.  
 
We hypothesize that at least 75% of patients with active EoE will experience a histologic response following 
treatment with an individualized dietary regimen based on their own allergen-specific immune signature. 
3 Study Design 
3.1 General Design 
This is a prospective single center clinical trial of allergen-specific immune signature-guided dietary 
elimination therapy to assess the clinical effectiveness of this technique.  
 
Potential subjects will be approached regarding the study. If eligible and interested, then informed consent 
will be obtained and they will be enrolled in the study.  If the subject has had an 
esophagogastroduodenoscopy (EGD) at UNC within 3 months since enrollment, clinical biopsies from the 
EGD show active EoE and the subject continues to meet consensus guidelines for active EoE, and research 
biopsies were taken during that EGD that can be used for this study, then the subject will complete 
questionnaires and a blood draw only.  The blood draw may be abbreviated if the subject had research 
blood drawn during the same recent EGD that can be used in this study. 
 
If subjects have not had an EGD with biopsies at UNC within 3 months prior to enrollment, then they will 
complete 
questionnaires, 
a 
blood 
draw, 
and 
be 
scheduled 
to 
receive 
a 
routine 
care 
esophagogastroduodenoscopy (EGD) at UNC facilities with clinical and research biopsies.  However, in 
some cases, samples that were obtained prior to this time frame can be used, as long as the samples were 
obtained when the EoE was active and there were no major changes in clinical status. 
 
During the routine care endoscopy, clinical biopsies will be taken for routine care purposes, and additional 
research biopsies will be collected for research purposes for diet elimination testing and to be stored for 
future research studies from the distal, mid, and proximal esophagus.  Blood will also be collected during 
this visit, and questionnaires completed.  If research biopsies are unable to be obtained during this EGD 
the subject will no longer continue in the study and will be considered a screen fail.  If pathology from routine 
care biopsies does not confirm a diagnosis of active EoE, then the subject will no longer continue in the 
study and will be considered a screen fail.  If subjects have had an EGD with clinical and research biopsies 
within 3 months prior to enrollment, then research biopsies taken during that EGD will be used for this study.  
As noted above, in some cases, samples that were obtained prior to this time frame can be used, as long 
as the samples were obtained when the EoE was active and there were no major changes in clinical status. 
 
After completion of the EGD and/or collection of EGD records and previous biopsies if an EGD was 
previously completed), and confirmation of eligibility, subjects will be scheduled for a routine care nutrition 
counseling appointment.  Two weeks prior to the routine care nutrition counseling appointment, subjects 
will begin the dysphagia symptom questionnaire (DSQ).  During the routine care nutrition counseling 
appointment, the subject will receive counseling on which foods to eliminate based on the T-cell and IgG4 
results from the research biopsies.  Subjects will also receive an allergy skin test during this visit.  Results 
from the allergy skin test will not be used to drive food elimination diet. 
 
Subjects will follow their assigned food elimination diet for 6 weeks.  At 6 weeks subjects will be scheduled 
for a routine care esophagogastroduodenoscopy (EGD) with biopsies for clinical purposes.  Two weeks 
prior to the 6 week EGD subjects will restart the DSQ. Data will be collected from the 6 week EGD but no 
research specific biopsies will be obtained during that visit.  Research specific blood will be taken at this 
visit. Study participation is complete after completion of the 6 week EGD. 

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3.2 Non-Significant Risk 
The algorithm used in this study to diagnose food allergens has been deemed a non-significant risk (NSR) 
in vitro diagnostic (IVD) device by the UNC IRB as of March 7, 2016.  This means the device qualifies for 
an abbreviated investigational device exemption (IDE).  Per the UNC IRB, as used in this study, the device 
does not pose a serious risk to the health, safety or welfare of a subject and does not otherwise meet the 
definition of a significant risk device according to 21 CFR 812.3(m). This study has been deemed non-
significant 
risk 
(NSR); the 
sponsor 
and 
investigator 
must 
comply 
with 
"abbreviated 
IDE 
requirements" described in 21CFR812(b).  As the sponsor-investigator, this means Dr. Dellon must ensure 
he:  
(i) Labels the device in accordance with 812.5 (below): 
 
(a) Contents. An investigational device or its immediate package shall bear a label with the 
following information: the name and place of business of the manufacturer, packer, or 
distributor (in accordance with §801.1), the quantity of contents, if appropriate, and the 
following statement: “CAUTION—Investigational device. Limited by Federal (or United 
States) law to investigational use.” The label or other labeling shall describe all relevant 
contraindications, hazards, adverse effects, interfering substances or devices, warnings, 
and precautions. 
 
(b) Prohibitions. The labeling of an investigational device shall not bear any statement that 
is false or misleading in any particular and shall not represent that the device is safe or 
effective for the purposes for which it is being investigated. 
 
(c) Animal research. An investigational device shipped solely for research on or with 
laboratory animals shall bear on its label the following statement: “CAUTION—Device for 
investigational use in laboratory animals or other tests that do not involve human subjects.” 
 
(d) The appropriate FDA Center Director, according to the procedures set forth in §801.128 
or §809.11 of this chapter, may grant an exception or alternative to the provisions in 
paragraphs (a) and (c) of this section, to the extent that these provisions are not explicitly 
required by statute, for specified lots, batches, or other units of a device that are or will be 
included in the Strategic National Stockpile. 
 
(ii) Obtains IRB approval of the investigation after presenting the reviewing IRB with a brief 
explanation of why the device is not a significant risk device, and maintains such approval; 
 
(iii) Ensures that each investigator participating in an investigation of the device obtains 
from each subject under the investigator's care, informed consent under part 50 and 
documents it, unless documentation is waived by an IRB under 56.109(c). 
 
(iv) Complies with the requirements of 812.46 with respect to monitoring investigations 
(below); 
(a) Securing compliance. A sponsor who discovers that an investigator is not complying 
with the signed agreement, the investigational plan, the requirements of this part or other 
applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or 
FDA shall promptly either secure compliance, or discontinue shipments of the device to 
the investigator and terminate the investigator's participation in the investigation. A sponsor 
shall also require such an investigator to dispose of or return the device, unless this action 
would jeopardize the rights, safety, or welfare of a subject. 
 
(b) Unanticipated adverse device effects. (1) A sponsor shall immediately conduct an 
evaluation of any unanticipated adverse device effect. 
 
(2) A sponsor who determines that an unanticipated adverse device effect presents an 
unreasonable risk to subjects shall terminate all investigations or parts of investigations 

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CONFIDENTIAL 
presenting that risk as soon as possible. Termination shall occur not later than 5 working 
days after the sponsor makes this determination and not later than 15 working days after 
the sponsor first received notice of the effect. 
 
(c) Resumption of terminated studies. If the device is a significant risk device, a sponsor 
may not resume a terminated investigation without IRB and FDA approval. If the device is 
not a significant risk device, a sponsor may not resume a terminated investigation without 
IRB approval and, if the investigation was terminated under paragraph (b)(2) of this section, 
FDA approval. 
 
(v) Maintains the records required under 812.140(b) (4) and (5) and makes the reports required 
under 812.150(b) (1) through (3) and (5) through (10); 
 
812.140(b) 4 and 5: 
(4) For each investigation subject to §812.2(b)(1) of a device other than a significant risk 
device, the records described in paragraph (b)(5) of this section and the following records, 
consolidated in one location and available for FDA inspection and copying: 
 
(i) The name and intended use of the device and the objectives of the investigation; 
 
(ii) A brief explanation of why the device is not a significant risk device: 
 
(iii) The name and address of each investigator: 
 
(iv) The name and address of each IRB that has reviewed the investigation: 
 
(v) A statement of the extent to which the good manufacturing practice regulation in part 
820 will be followed in manufacturing the device; and 
 
(vi) Any other information required by FDA. 
 
(5) Records concerning adverse device effects (whether anticipated or unanticipated) and 
complaints 
 
812.150(b) (1) through (3) and (5) through (10); 
(b) Sponsor reports. A sponsor shall prepare and submit the following complete, accurate, 
and timely reports: 
 
(1) Unanticipated adverse device effects. A sponsor who conducts an evaluation of an 
unanticipated adverse device effect under §812.46(b) shall report the results of such 
evaluation to FDA and to all reviewing IRB's and participating investigators within 10 
working days after the sponsor first receives notice of the effect. Thereafter the sponsor 
shall submit such additional reports concerning the effect as FDA requests. 
 
(2) Withdrawal of IRB approval. A sponsor shall notify FDA and all reviewing IRB's and 
participating investigators of any withdrawal of approval of an investigation or a part of an 
investigation by a reviewing IRB within 5 working days after receipt of the withdrawal of 
approval. 
 
(3) Withdrawal of FDA approval. A sponsor shall notify all reviewing IRB's and participating 
investigators of any withdrawal of FDA approval of the investigation, and shall do so within 
5 working days after receipt of notice of the withdrawal of approval. 
 
(5) Progress reports. At regular intervals, and at least yearly, a sponsor shall submit 
progress reports to all reviewing IRB's. In the case of a significant risk device, a sponsor 
shall also submit progress reports to FDA. A sponsor of a treatment IDE shall submit semi-

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annual progress reports to all reviewing IRB's and FDA in accordance with §812.36(f) and 
annual reports in accordance with this section. 
 
(6) Recall and device disposition. A sponsor shall notify FDA and all reviewing IRB's of any 
request that an investigator return, repair, or otherwise dispose of any units of a device. 
Such notice shall occur within 30 working days after the request is made and shall state 
why the request was made. 
 
(7) Final report. In the case of a significant risk device, the sponsor shall notify FDA within 
30 working days of the completion or termination of the investigation and shall submit a 
final report to FDA and all reviewing the IRB's and participating investigators within 6 
months after completion or termination. In the case of a device that is not a significant risk 
device, the sponsor shall submit a final report to all reviewing IRB's within 6 months after 
termination or completion. 
 
(8) Informed consent. A sponsor shall submit to FDA a copy of any report by an investigator 
under paragraph (a)(5) of this section of use of a device without obtaining informed 
consent, within 5 working days of receipt of notice of such use. 
 
(9) Significant risk device determinations. If an IRB determines that a device is a significant 
risk device, and the sponsor had proposed that the IRB consider the device not to be a 
significant risk device, the sponsor shall submit to FDA a report of the IRB's determination 
within 5 working days after the sponsor first learns of the IRB's determination. 
 
(10) Other. A sponsor shall, upon request by a reviewing IRB or FDA, provide accurate, 
complete, and current information about any aspect of the investigation. 
 
(vi) Ensures that participating investigators maintain the records required by 812.140(a)(3)(i) 
and make the reports required under 812.150(a) (1), (2), (5), and (7) (below); and 
 
812.140(a)(3)(i) 
(a) Investigator records. A participating investigator shall maintain the following accurate, 
complete, and current records relating to the investigator's participation in an investigation: 
 
(3) Records of each subject's case history and exposure to the device. Case histories 
include the case report forms and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes of the physician, 
the individual's hospital chart(s), and the nurses' notes. Such records shall include: 
 
(i) Documents evidencing informed consent and, for any use of a device by the investigator 
without informed consent, any written concurrence of a licensed physician and a brief 
description of the circumstances justifying the failure to obtain informed consent. The case 
history for each individual shall document that informed consent was obtained prior to 
participation in the study. 
 
812.150(a) (1), (2), (5), and (7); 
(a) Investigator reports. An investigator shall prepare and submit the following complete, 
accurate, and timely reports: 
 
(1) Unanticipated adverse device effects. An investigator shall submit to the sponsor and 
to the reviewing IRB a report of any unanticipated adverse device effect occurring during 
an investigation as soon as possible, but in no event later than 10 working days after the 
investigator first learns of the effect. 
 

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(2) Withdrawal of IRB approval. An investigator shall report to the sponsor, within 5 working 
days, a withdrawal of approval by the reviewing IRB of the investigator's part of an 
investigation. 
 
(5) Informed consent. If an investigator uses a device without obtaining informed consent, 
the investigator shall report such use to the sponsor and the reviewing IRB within 5 working 
days after the use occurs. 
 
(7) Other. An investigator shall, upon request by a reviewing IRB or FDA, provide accurate, 
complete, and current information about any aspect of the investigation. 
 
(vii) Complies with the prohibitions in 812.7 against promotion and other practices (below): 
 
A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator 
shall not: 
 
(a) Promote or test market an investigational device, until after FDA has approved the 
device for commercial distribution. 
 
(b) Commercialize an investigational device by charging the subjects or investigators for a 
device a price larger than that necessary to recover costs of manufacture, research, 
development, and handling. 
 
(c) Unduly prolong an investigation. If data developed by the investigation indicate in the 
case of a class III device that premarket approval cannot be justified or in the case of a 
class II device that it will not comply with an applicable performance standard or an 
amendment to that standard, the sponsor shall promptly terminate the investigation. 
 
(d) Represent that an investigational device is safe or effective for the purposes for which 
it is being investigated. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3.3 Protocol Map 
 
 

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3.4 Study Outcomes 
The primary outcome will be histologic response, defined as a post-treatment esophageal eosinophil 
count of <15 eos/hpf.41 The esophageal eosinophil counts will be quantified using our previously 
validated protocol.42  
 
The secondary outcomes will be: 1) change in the absolute esophageal eosinophil count; 2) improvement 
in the endoscopic appearance, as measured by a validated endoscopy score;43 and 3) improvement in 
symptoms, as measured by a validated dysphagia symptom score.44 
4 Subject Selection and Withdrawal 
4.1 Inclusion Criteria 
1) Age 16-80 years old 
2) Meet one of the following: 
a. Active EoE as per consensus guidelines OR 
b. Undergoing upper endoscopy for a clinical suspicion of EoE 
3) No prior history of dietary elimination therapy 
4.2 Exclusion Criteria 
1) Concomitant eosinophilic gastroenteritis 
2) Any corticosteroid exposure in the 4 weeks prior to their baseline endoscopic exam 
3) Previous esophageal surgery 
4) Medical instability that precludes safely performing upper endoscopy 
5) Inability to read or understand English 
6) Pregnant women 
4.3 Subject Recruitment and Screening 
Patients with active or suspected EoE or who are undergoing or recently underwent routine care upper 
endoscopy will be screened by research personnel. These patients will be identified by screening the 
endoscopy and CEDAS clinic schedules or via referrals from other physicians. Once a potential subject is 
identified, study personnel will contact the potential subject to describe the study and gauge interest in 
participating.  Initial contact may be in person or on the phone.  If the patient is interested in participating, 
then the study coordinator or other study staff will obtain written informed consent from the subject.  
4.4 Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
Subjects have the right to withdraw from the study at any time, for any reason, and without repercussion. 
The investigator, Dr. Evan Dellon, has the right to withdraw a patient from the study in the event of an 
intercurrent illness, adverse event (AE), treatment failure, protocol violation, and for administrative or other 
reasons. An excessive rate of withdrawals would reduce the amount of data available for analysis and limit 
the ability to interpret the study results; therefore, unnecessary withdrawal of patients should be avoided.  
 
If subjects become pregnant during the study, then their participation will be stopped. 
4.4.2 Lost to Follow-Up 
A subject will be considered lost to follow-up after documentation has been made of at least three 
documented attempts to contact (via phone or email).  At that point a certified letter should be mailed to the 
subject’s home address.  If there is still no response after the certified letter is delivered, then the subject 
will be withdrawn from the study as lost to follow-up. 

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4.4.3 Data Collection and Follow-up for Withdrawn Subjects 
Patients who withdraw prematurely from the study may be asked to complete an end of study visit per the 
study procedures.  In addition, any ongoing adverse drug reactions or study-related adverse events will be 
followed until resolution or documentation of why there will be no resolution if the event will be ongoing. 
5 Study Procedures 
Procedure 
Screening Visit 
Day 1 Visit 
6 Week Follow-Up 
Visit (+/- 7 days) 
Eligibility Review 
X 
 
 
Informed Consent 
X 
 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Current Medications 
X 
X 
 
Vital Signs 
X 
 
X 
Questionnaires 
X 
 
X 
Research blood collection 
X1 
 
X 
EGD with EREF and biopsies  
X1,2 
 
X2 
Adverse Events 
X 
X 
X 
Dysphagia Symptom 
Questionnaire (DSQ) 
 
X3 
X3 
Nutrition Counseling 
 
X2 
 
Allergy Skin Testing 
 
X4 
 
Diet Elimination 
 
X5 
 
1 Subjects must be scheduled for a routine care EGD with biopsies (clinical and research) at UNC or have had a routine care EGD 
with clinical and research biopsies at UNC within 3 months prior to enrollment.  If subjects have had a recent EGD as defined above, 
then results from clinical biopsies taken during that EGD will be used to assess eligibility for this study, and research biopsies and 
EREFs from that EGD will also be used for this study.  In these cases, an additional EGD does not need to be performed.  In addition, 
if research blood was collected during the recent EGD and can be used in this study, then subjects will have an abbreviated blood 
collection during the screening visit. If subjects have not had an EGD with research and clinical biopsies at UNC within 3 months of 
enrollment, then they must be scheduled to receive a routine care EGD with biopsies at UNC during which clinical and research 
biopsies will be collected for this study. 
2 These procedures are considered routine care and are billed to the subject and/or subject’s insurance. 
3 The DSQ is started 2 weeks prior to the Day 1 and 6 week visits. 
4 Results from the allergy skin testing will not be used to drive the food elimination diet. 
5 Subjects will begin diet elimination on day 1 and continue for 6 weeks. 
5.1 Screening Visit 
During the screening visit, eligibility is assessed (based on inclusion/exclusion criteria) and those eligible 
and interested in participating will provide informed consent.  Potential cases will be identified by 
screening endoscopy and clinic schedules.  This will require approval of a limited HIPAA waiver to access 
the personal health information (PHI) of potential research subjects prior to their formal enrollment.     
 
The following procedures will be completed during the screening visit: 
• 
Informed consent 
• 
Inclusion/exclusion criteria review to determine eligibility  
• 
Demographics 
• 
Medical history 
• 
Current medications 
• 
Vital signs 

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• 
Questionnaires 
• 
Blood collection 
• 
EGD with EREF score and biopsies for pathology, per routine care, and biopsies for research 
purposes*** 
• 
Adverse events 
• 
CRF completion 
 
***If subjects have had an EGD at UNC within 3 months of enrollment including clinical and research 
biopsies that can be used in this study, then the EGD will not be performed and biopsies and EREF 
scores from the recent EGD will be used in this study. 
5.1.1 Consenting Procedure 
If a subject is screened eligible and interested in the study, the subject will be consented on the study 
prior to any study procedure. Written informed consent will be obtained by qualified study personnel.  
Documentation of the consent process will be maintained in the subject’s research record. 
 
Subjects will be given ample time to review the consent document and ask any questions they may have.  
A copy of the written consent form will be provided to the subject and the original maintained in the 
subject’s research record.   
 
If subjects meet all inclusion and none of the exclusion criteria and consent to the study, they will be 
enrolled in the study. Subjects will be assigned a unique subject code.   
 
5.1.2 Biopsy Collection and Processing 
The research biopsy protocol below is frequently used in CEDAS research projects.  If subjects have had 
an EGD with biopsies at UNC within 3 months prior to enrollment and the biopsies are available for use in 
this study, and the subject consented to their use in future research studies, then the subject does not 
need to return for an EGD with biopsies, unless necessary for routine care. 
 
If subjects have not had an EGD within 3 months of enrollment in which biopsies below are available for 
this study, then they can be scheduled for a routine care EGD with biopsies at UNC to be eligible for this 
study.  However, in some cases, samples that were obtained prior to this time frame can be used, as long 
as the samples were obtained when the EoE was active and there were no major changes in clinical 
status.  During the routine care EGD, clinical biopsies will be obtained for pathology assessment. In 
addition, 4 research-specific biopsies will be obtained from each of the following locations:  Distal 
esophagus (3cm from TGF), middle esophagus (8cm from TGF), and proximal esophagus (13cm from 
TGF). Additionally, 2 research-specific biopsies will be obtained from the duodenum, and 2 research-
specific biopsies will be obtained from the stomach (1 from antrum, 1 from body).  The 4 distal biopsies 
will be separated into 4 cryovials: 2 filled with formalin for histology, 1 filled with RNALater, and 1 empty to 
be frozen immediately in liquid nitrogen.        
 
Research biopsies will be used in this study, and will be stored indefinitely for future research.  Subjects 
will sign a separate stored specimens consent form for this purpose. If a complete set of clinical and 
research biopsies is not collected during the routine care EGD, then he subject will be considered a 
screen fail. 
 
 
 
 
 
 
 
 

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Research Related Biopsy Collection Protocol: 
 
Biopsy Location 
Description 
Processing/Labeling Instructions 
4 distal esophageal 
(d) 
4 single biopsies 
3cm from GEJ 
 
2 formalin (h):  
• 
Label: PID_eh_d1 and PID_eh_d2 + 
collection date 
1 RNALater (r): Refrigerate, store long term in -
80deg.F   
• 
Label: PID_er_d + collection date 
1 frozen (f):  
• 
Label: PID_ef_d + collection date 
4 mid esophageal 
(m) 
4 single biopsies 
8cm from GEJ 
1 formalin (h): 
• 
Label: PID_ eh_m  + date 
1 RNALater (r):  
• 
Label: PID_er_m + date 
2 frozen(f):  
• 
Label: PID_ef_m + date and PID_ef_m2 + 
date 
4 proximal 
esophageal (p) 
4 single biopsies 
13cm from GEJ 
2 formalin (h):  
• 
Label: PID_eh_p+ date and PID_eh_p2 + 
date 
1 RNALater (r):  
• 
Label: PID_er_p + date 
1 frozen (f):  
• 
Label: PID_ef_p + date  
 
 
Participant IDs (PIDs) will be assigned in numerical order and follow the convention of ID-###.  For 
example, the first person enrolled will be assigned a PID of ID-001. 
 
Missed biopsies will not be considered protocol deviations or violations. 
 

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5.1.3 Blood Sample Collection and Processing  
Blood samples will be collected and used in this study, and will be stored indefinitely for future research 
studies.  Subjects will sign a separate stored specimens consent form for this purpose. 
 
Items 
Processing 
6 - 5 mL green top tubes 
Hand to PI or representative upon collection 
Label: PID and collection date 
Example:ID-001 08Feb16 
 
The following blood samples should be collected only if the subject has no research blood samples 
previously collected during a recent EGD (within 3 months of enrollment) that can be used in this study. 
 
Items 
Processing 
The following blood samples should be collected only if the subject does not have these samples previously collected from a recent 
EGD (within 3 months of enrollment) and available for use in this study. 
2 red tops 
Spin, aliquot serum into 9 cryovials 
Label: PID_s# and collection date 
Example:ID-001_s1 08Feb16 
 
1 yellow top 
Spin, aliquot plasma into 9 cryovials  
Label: PID_p# and collection date 
buffy into 1 cryovial 
Label:PID_b# 
1 purple top 
Aliquot whole blood into 1mL aliquots – minimum of 3 cryovials 
Label: PID_w# and collection date 
1 PAXgene RNA blood 
Room temp at least 2 hours, then freeze 
Label: PID and collection date 
 
Participant IDs (PIDs) will be assigned in numerical order and follow the convention of ID-###.  For 
example, the first person enrolled will be assigned a PID of ID-001. 
 
Missed blood samples will not be considered protocol deviations or violations. 
5.2 Day 1 Visit 
Two weeks prior to the day 1 visit, and while the lab performs T-cell and IgG4 signatures testing, subjects 
will be asked to fill out the Dysphagia Symptom Questionnaire (DSQ). The DSQ is a daily 3-question 
symptom diary to be completed nightly over a 2 week time period. This can be done on paper or by email. 
 
During the day 1 visit, subjects will be scheduled for a routine care nutrition counseling appointment. 
During this appointment subjects will be advised how to effectively follow an elimination diet based on the 
specific triggers identified between Screening and Day 1 using samples obtained for the research study 
and will under allergy skin prick testing as a research procedure.  Results from the allergy skin prick 
testing will not be used to drive the food elimination diet. 
 
Subjects will be instructed to eliminate between 1 and 5 foods (dairy, wheat, egg, soy, and/or nuts) based 
on results from the T-cell and IgG4 signatures.  Subjects will adhere to the elimination diet for 6 weeks 
 

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The following procedures will be completed during the day 1 visit 
• 
DSQ (started 2 weeks prior to day 1 visit) 
• 
Current medications 
• 
Adverse events 
• 
Nutrition counseling as per routine care 
• 
Begin 6 week diet elimination therapy 
• 
CRF completion 
 
5.3 6 Week Follow-Up Visit (+/- 7 days) 
Two weeks prior to the 6 week follow-up visit, subjects will be asked to fill out the Dysphagia Symptom 
Questionnaire (DSQ). The DSQ is a daily 3-question symptom diary to be completed nightly over a 2 
week time period. This can be done on paper or by email. 
 
After completion of the 6 week food elimination diet, subjects will return to one of the UNC endoscopy 
centers and undergo repeat EGD for routine care.  During the EGD, clinical biopsies will be obtained.  No 
research biopsies are collected for this study during the 6 week follow-up EGD.  Follow up blood samples 
are collected. Subjects will complete the same questionnaires as the screening visit. 
 
The following procedures will be completed during the 6 week follow-up visit 
• 
DSQ (started 2 weeks prior to 6 week follow-up visit) 
• 
Vital Signs 
• 
Questionnaires 
• 
EGD with EREF score and biopsies for pathology, per routine care (no research biopsies are 
obtained at the 6 week follow-up visit for this study) 
• 
Blood collection 
• 
Adverse events 
 
Study participation is complete after completion of the 6 week follow-up visit. 
6 Statistical Plan 
6.1 Sample Size Determination 
Because this is a proof-of-principle effectiveness study without a comparison group, there is not a formal 
sample size calculation. However, we plan to consent and enroll up to 30 subjects with a goal of 20 subjects 
completing the study to show that 75% (15) have a histologic response to the allergen-specific immune-
signature dietary elimination. We feel that this is a robust number of patients to demonstrate a preliminary 
effect, while also being a realistic number to enroll during this pilot study. In addition, while the 95% CIs 
around this goal are somewhat wide (47-92%), current allergy testing only has the ability to accurately 
predict triggers 13% of the time, so even if we are at the lower end of the range, it’s still a major clinical step 
forward in practice. 
 
In the proposed study, we will be performing the first prospective effectiveness study of an allergen-specific 
immune signature-based individualized dietary elimination regimen in patients with EoE. Because we are 
conducting what will essentially be a pilot or proof-of-principle study, the data we collect, including response 
rates and magnitude of response, will directly inform a planned large scale (ie R01) grant application for a 
randomized study of immune-signature-based elimination versus empiric food elimination. 
6.2 Statistical Methods 
To determine the response rate for the primary outcome, the number of subjects with <15 eos/hpf on follow-
up endoscopy will be calculated. For secondary outcomes, median eosinophil counts, endoscopy scores, 
and symptoms scores will be compared before and after treatment with Wilcoxon signed-rank. These will 
be contextualized by calculating odds ratios and 95% confidence intervals where appropriate, so as not to 

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over-rely on p values alone. Patients who drop out or who have incomplete data for the outcomes will be 
excluded from analysis. Because this study’s outcomes are determined after the treatment period and 
follow-up endoscopy, a subject must complete this end of treatment evaluation for us to be able to include 
their data in the analysis. We do not feel that selection bias would impact the analysis if there are incomplete 
data due to drop out. We are not performing a comparative analysis between groups, so drop out would 
not be dependent on different treatments administered in different study arms. In addition, in our experience 
with previous clinical studies of EoE, dropout rates have been quite low. 
6.3 Subject Population(s) for Analysis 
Patients who drop out or who have incomplete data for the outcomes will be excluded from analysis 
7 Safety and Adverse Events 
7.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRSOs) 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research, 
• Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
 
Adverse Event 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human subject, including 
any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, experience, or 
disease, temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. Adverse events encompass both physical and 
psychological harms. Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal 
results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
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All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
 
Serious vs. Severe 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, 
or severe); the event itself, however, may be of relatively minor medical significance (such as severe 
headache).  This is not the same as “serious,” which is based on patient/event outcome or action criteria 
usually associated with events that pose a threat to a patient’s life or functioning.  Seriousness (not severity) 
serves as a guide for defining regulatory reporting obligations. 
 
Unanticipated Adverse Device Effect  
Any serious adverse effect on health or safety or any life-threatening problem or death caused by, or 
associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, 
or degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects (231CFR812.3(s)). 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse 
event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the subject’s 
personal physician, believes might reasonably be related to participation in this study.  The investigator 
should notify the study sponsor of any death or adverse event occurring at any time after a subject has 
discontinued or terminated study participation that may reasonably be related to this study.  The sponsor 
should also be notified if the investigator should become aware of the development of cancer or of a 
congenital anomaly in a subsequently conceived offspring of a subject that has participated in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for 
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Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical investigator. 
7.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation should be 
recorded and reported immediately. 
7.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum those events that must 
be reported are those that are: 
• related to study participation, 
• unexpected, and  
• serious or involve risks to subjects or others  
(see definitions, section 7.1).   
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment 
 
7.3.1 Notifying the UNC IRB 
Dr. Evan Dellon is responsible for reporting adverse events to the UNC IRB per the UNC IRB SOPs for 
reporting adverse events. Federal regulations require investigators to report unanticipated problems 
involving risks to subjects or others to the IRB. Historically, there has been confusion about what needs to 
be reported. OHRP and FDA have issued guidance that clarifies that investigators need only report 
“unanticipated problems involving risks to subjects or others” (or UPIRSOs). The UNC-Chapel Hill policy is 
based on this guidance. “Adverse events” that are not UPIRSOs are not required to be reported to the IRB. 
Site should refer to the most recent version of UNC IRB SOPs for up to date reporting requirements. 
 

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7.3.1.1 
Differentiating between an UPIRSO and an Adverse Event 
By definition, an UPIRSO is unexpected, whereas an “adverse event” may be anticipated or unanticipated. 
Additionally, an UPIRSO may involve the increased risk of harm—whether or not any actual harm occurred. 
In order to decide which events or circumstances constitute an UPIRSO, it is important to bear in mind the 
following: 
• 
Not all Adverse Events are UPIRSOs. Only a small subset of “adverse events” occurring in FDA-
regulated clinical trials and other types of studies constitute UPIRSOs. Many events that are 
required to be reported to the sponsor or federal agency are not UPIRSOs. 
• 
An UPIRSO may not be an adverse event. It is possible for an event that does not involve actual 
physical, psychological, social, or economic harm to a research subject or another person 
nevertheless to constitute an UPIRSO that must be reported to the IRB. This is the case if the event 
places subjects or others at increased or different risk of harm, regardless of whether actual harm 
has occurred. 
 
There are other types of incidents, experiences and outcomes that occur during the conduct of human 
subjects research that represent UPIRSOs but are not considered adverse events. Some UPIRSOs involve 
social or economic harm instead of the physical or psychological harm associated with adverse events. In 
other cases, UPIRSOs place subjects or others at risk of harm, but no harm occurs. For example, an 
investigator conducting behavioral research collects individually identifiable sensitive information about illicit 
drug use and other illegal behaviors by surveying college students. The data are stored on a laptop 
computer without encryption, and the laptop computer is stolen from the investigator’s car. This is an 
UPIRSO and must be reported because the incident was (a) unexpected (i.e., the investigators did not 
anticipate the theft); (b) related to participation in the research; and (c) placed the subjects at a greater risk 
of psychological and social harm from the breach in confidentiality of the study data than was previously 
known or recognized. 
 
Other examples of UPIRSOs that should be reported to the IRB, even though they are not adverse events, 
include: 
• 
Publication in the literature, safety monitoring report (e.g., DSMB report), interim result, or other 
finding that indicates an unexpected change to the risk/benefit ratio of the research; 
• 
Breach in confidentiality resulting from a disclosure of confidential information or from lost or stolen 
confidential information; 
• 
Unresolved complaint of a participant, family member or other individual; 
• 
Laboratory or medication errors that may involve potential risk to that individual or others; 
• 
Change in FDA labeling because of adverse consequences or withdrawal from marketing of a drug, 
device, or biologic used in a research protocol; 
• 
Disqualification or suspension of investigators; 
• 
Accidental or unintentional change to the IRB-approved protocol that involves risks or has the 
potential to recur; 
• 
Deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard 
to a research participant 
• 
Any deviation from the IRB-approved protocol that increases the risk or affects the participant’s 
rights, safety, or welfare. 
7.3.1.2 
UNC IRB Reporting Timelines 
Reporting is required of all UPIRSOs, including those which may occur after the participant has completed 
or is withdrawn from the study, or following study closure. Reporting is completed via IRBIS, UNC’s online 
IRB information system. 
 
Events that meet the criteria for an UPIRSO and are also serious adverse events should be reported to the 
IRB within one (1) week of the investigator becoming aware of the event. 
 
Any other events that meet the criteria for a UPIRSO should be reported to the IRB within two (2) weeks 
of the investigator becoming aware of the problem. 

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If the report cannot be completed in its entirety within the required time period, a preliminary report should 
be submitted. The report should be amended once the event is resolved and/or more information becomes 
available.  
 
Site should refer to the most recent version of UNC IRB SOPs for up to date reporting requirements. 
7.3.2 Notifying the FDA – Unanticipated Adverse Device Effects 
Unanticipated adverse device effect means any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was 
not previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects (231CFR812.3(s)). 
 
Per 21CFR812.46(b) the sponsor (Dr. Dellon) shall immediately conduct an evaluation of any unanticipated 
adverse device effect. 
 
A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to 
subjects shall terminate all investigations or parts of investigations presenting that risk as soon as possible. 
Termination shall occur not later than 5 working days after the sponsor makes this determination and not 
later than 15 working days after the sponsor first received notice of the effect 
 
Per 21CFR812.150(b), a sponsor (Dr. Dellon) who conducts an evaluation of an unanticipated adverse 
device effect under §812.46(b) shall report the results of such evaluation to FDA and to all reviewing IRB's 
and participating investigators within 10 working days after the sponsor first receives notice of the effect. 
Thereafter the sponsor shall submit such additional reports concerning the effect as FDA requests. 
7.4 Stopping Rules  
This study does not have stopping rules, and there are no plans for an interim analysis. 
7.5 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see section 
9).  Medical monitoring will include a regular assessment of the number and type of adverse events. 
 
Safety data will be aggregated and reviewed by the principal investigator, Dr. Evan Dellon periodically. 
Individual adverse events will be reviewed weekly, or as necessary, by study investigators. Adverse events 
will be reported to the IRB per local IRB SOPs. 
 
While an overall study stop is not anticipated due to the low risk profile of the study, Dr. Evan Dellon will 
closely monitor adverse events. Any unusual or unanticipated events will be carefully considered and 
reported to the IRB as per IRB SOPs. The site PI, Dr. Evan Dellon, will review all safety data and determine 
severity, and causality on an ongoing basis. Research personnel will communicate safety information to 
the PI in a timely manner. 
8 Data Handling and Record Keeping 
8.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 

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• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect 
at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
8.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as 
being accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, 
subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments 
involved in the clinical trial. 
8.3 Case Report Forms 
The study will utilize paper case report forms (eCRFs). All data requested on the CRF must be recorded.  
All missing data must be explained in the comments section of the CRF.  Data will then be entered into a 
secure Excel workbook. 
8.4 Records Retention 
Per 21CFR812.140(d), an investigator or sponsor shall maintain the records required by this subpart during 
the investigation and for a period of 2 years after the latter of the following two dates: The date on which 
the investigation is terminated or completed, or the date that the records are no longer required for purposes 
of supporting a premarket approval application or a notice of completion of a product development protocol. 
9 Study Monitoring, Auditing, and Inspecting 
9.1 Study Monitoring Plan 
This study will be monitored regularly by a study monitor who is not directly involved in the project to ensure 
accurate data entry and reporting, as well as compliance with all applicable federal regulations.  Refer to 
the most recent study monitoring plan for additional details.   
The monitor is responsible for ensuring:  
(a) the rights and well-being of trial participants are protected, 
(b) reported trial data are accurate, complete, and verifiable from source documents,  
(c) the conduct of the trial is in compliance with the currently approved 
protocol/amendments, with GCP, and with the applicable regulatory requirements, and 
data reported are verifiable to support meeting the study objectives. 
 
Procedures and sources of information: 
A) Protection of the rights and well-being of study subjects by verifying: 
1. Investigator(s) have adequate qualifications, education and training, and resources 
necessary to conduct the study. 
2. Verify the investigator and his staff follow the approved protocol and all approved 
amendments, if any 
3. The investigator personally conducts or adequately supervises his study staff  
4. Study staff are adequately trained and study functions are delegated to authorized individuals 
5. Written informed consent was obtained before each subject’s participation in the study 
6. Enrollment of only eligible subjects 

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7. Subjects are instructed in the proper use, storage and return of the investigational product 
8. Adequate and accurate case histories that record all observations are maintained 
9. Unanticipated adverse events are reported in accordance with the protocol 
B) Trial data are accurate, complete and verifiable from source documents as verified from review 
of subject file, case report forms, and medical procedures reports 
1. Verify that the investigative staff are performing the specific trial functions in accordance 
with the protocol  
2. Checking the accuracy and completeness of case report form entries, source documents 
and other trial related records against each other 
3. Adequate and accurate case histories that record all observations are maintained 
4. All withdrawals and dropouts are properly reported and explained 
5. Investigator is informed of protocol deviations, data entry errors and omissions and 
illegibility  
C) Study is conducted in compliance with the currently approved protocol/amendments, with GCP, 
and applicable regulatory requirements 
1. Verify the investigator follows the approved protocol and all approved amendments, if any 
2. Ensuring that an IRB approval is obtained prior to study initiation and that the IRB is kept 
informed of changes in research activity and unanticipated problems involving risk to 
subjects 
3. Determine if investigator is maintaining essential documents in a regulatory binder 
4. Investigational product is properly procured, stored and destroyed accordingly 
5. Documenting deviations from the protocol, SOPs, GCP and applicable requirements to 
the investigator and taking appropriate action designed to prevent recurrence of the 
detected deviations. 
6. Monitor will provide a written report after each study visit or study visit communication 
D) Data reported are verifiable to support meeting the study objectives of the study 
 
If other agencies choose to monitor the site such as the FDA, or institution (UNC),  then the Investigator 
will ensure the monitor or other compliance or quality assurance reviewer is given access to all the above 
noted study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and 
has adequate space to conduct the monitoring visit. 
9.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
10 Ethical Considerations 
This trial will be conducted in compliance with institutional review board (IRB) and ICH GCP Guidelines 
including Title 21 Part 56 of the United States of America (USA) Code of Federal Regulations (CFR) relating 
to IRBs and GCP as described in the United States Food and Drug Administration (FDA) CFR (21 CFR § 
50, 56, 812) in accordance with applicable ICH regulations regarding clinical safety data management (E2A, 
E2B(R3)), with ICH regulations regarding scientific integrity (E4, E8, E9 and E10) and with FDA regulations 
regarding financial disclosure (21 CFR § 54). In addition this trial will adhere to all local regulatory 
requirements, and requirements for data protection. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the EC/IRB concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 

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commencement of this study.  The investigator should provide a list of EC/IRB members and their affiliate 
to the sponsor. 
 
All subjects for this study will be provided an IRB-approved consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this study.  The 
formal consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject 
undergoes any study procedure.  The consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent.  
11 Study Finances 
11.1 Funding Source 
This study is funded by a Translational Team Science Award (TTSA) through the North Carolina 
Translational & Clinical Sciences Institute. 
11.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that has 
been reviewed and approved by the study sponsor prior to participation in this study.  All University of North 
Carolina investigators will follow the University conflict of interest policy. 
11.3 Subject Stipends or Payments 
Subjects will receive up to $100 for participation in this study.  The subject consent form provides details 
on how payment will be remunerated.  
12 Publication Plan 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study. 
 
 

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13 References 
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E, Zwahlen M, Safroneeva E. Development and validation of a symptom-based activity index for 
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