Transepidermal Water Loss as a Predictor for Severe Allergic Reactions in Oral Food Challenges
Phase: NA
Conditions: Anaphylaxis Food
Sponsor: University of Michigan

Predicting Peanut Anaphylaxis and Reducing 
Epinephrine (PrePARE) 
 
NCT05696236 
 
Date of IRB Approval: September 11, 2023 

PrePARE Trial v2.2, 30 November 2022 
 
1
Title: Transepidermal Water Loss as a Predictor for Severe Allergic Reactions in Oral 
Food Challenges 
 
Short Title: Predicting peanut anaphylaxis and reducing epinephrine 
 
Acronym: PrePARE 
 
Protocol Number: HUM00205852 
 
National Clinical Trial (NCT) Identified Number: Pending 
 
Principal Investigator:  
Charles F. Schuler, MD; Allergy and Immunology and Food Allergy Center 
 
Co-Investigators:  
Kelly M. O’Shea, MD; Allergy and Immunology and Food Allergy Center 
George Freigeh, MD: Allergy and Immunology 
 
Sponsor: The University of Michigan 
 
Funded By: Gerber Foundation 
 
Version Number: 2.2 
 
30 August 2023 
 
 

PrePARE Trial v2.2, 30 November 2022 
 
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Statement of Compliance 
 
The trial will be carried out in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, 
and/or 21 CFR Part 812)  
 
Investigators and clinical trial site staff who are responsible for the conduct, management, 
or oversight of clinical trials have completed Human Subjects Protection and ICH GCP 
Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials 
will be submitted to the Institutional Review Board (IRB) for review and approval.  Approval 
of both the protocol and the consent form must be obtained before any participant is 
enrolled. Any amendment to the protocol will require review and approval by the IRB 
before the changes are implemented to the study. In addition, all changes to the consent 
form will be IRB-approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved 
consent form. 
 
 

PrePARE Trial v2.2, 30 November 2022 
 
3
Protocol Summary 
Synopsis 
Title: 
Transepidermal Water Loss as a Predictor for Severe Allergic 
Reactions in Oral Food Challenges 
Study Description: 
This is a pilot clinical trial, which will test the hypothesis that 
transepidermal water loss (TEWL) measured continuously 
during an oral food challenge (OFC) for peanut food allergy 
predicts the development of anaphylaxis such that stopping the 
food challenge early based on this change will reduce the rate 
of anaphylaxis during such food challenges. 
Objectives: 
 
Primary Objective:  Define anaphylaxis rates in OFCs for 
peanut allergy halted by TEWL stopping rules plus standard of 
care clinical assessment versus control OFCs, where 
challenges are halted based only on clinical assessment of 
reaction status per standard of care. 
 
Secondary Objectives:  
1. Define overall allergic reaction rates in peanut OFCs 
halted by TEWL stopping rules versus usual care. 
2. Define anaphylaxis likelihood and severity via Brighton 
and CoFAR criteria among anaphylaxis reactions in 
peanut OFCs halted by TEWL stopping rules versus 
usual care. 
   
Endpoints: 
Primary Endpoint: Anaphylaxis occurrence rate  
Secondary Endpoints: Secondary endpoints will include 
anaphylaxis severity and overall allergic reaction rates.  
Anaphylaxis likelihood will be defined by the Brighton criteria. 
Anaphylaxis severity will be defined via the modified CoFAR 
criteria (these are defined in the protocol). 
Study Population: 
The total study population will be 40 individuals aged 6 months 
to 5 years, any gender, any demographic group, with a high 
likelihood of peanut allergy (defined in protocol). The study will 
take place in Michigan. 
Phase: 
N/A 
Description 
of 
Sites/Facilities 
Enrolling 
Participants: 
This will be a single center study at the University of Michigan 
in Ann Arbor, MI.   

PrePARE Trial v2.2, 30 November 2022 
 
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Description of Study 
Intervention: 
This study will evaluate the use of transepidermal water loss 
(TEWL) continuous measurement during oral food challenge 
for food allergy (peanut). A stopping rule based on TEWL will 
be tested against usual oral food challenge care. In both cases, 
the standard of care will be used, where even a single symptom 
of an allergic reaction is used to stop oral food challenges. 
TEWL measures the rate of water loss from the skin in g/m2/h 
as a flux of water mass through an area over time. 
Study Duration: 
24 months 
Participant 
Duration: 
Up to 9 days 
 
 
 
 
 

PrePARE Trial v2.2, 30 November 2022 
 
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Schema 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Arm 2 
No TEWL 
stopping 
rules 
Arm 1 
TEWL 
stopping 
rules 
Single Study Visit: Oral food challenge performed; outcomes assessed. 
End of study for participant; data analysis. 
Pre-visit - Total N=40:  Obtain informed consent. Screen potential 
participants by inclusion and exclusion criteria; obtain history, document. 
Randomize 

PrePARE Trial v2.2, 30 November 2022 
 
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Schedule of Activities 
Procedures 
Screening 
Day -7 to -1 
OFC visit 
Visit 1, Day 1 
Check-in 
call, 
Day 2 
Pre-screening 
questions 
X 
 
 
Informed consent 
X 
 
 
Confirm eligibility 
X 
X 
 
Demographics 
X 
 
 
Medical history 
X 
 
 
Randomization 
X 
 
 
Administer 
study 
OFC 
 
X 
 
Concomitant 
medication review 
X 
 
 
Physical 
exam 
(including 
height 
and weight) 
 
X 
 
Vital signs 
 
X 
 
Weight 
 
X 
 
Adverse 
event 
review 
and 
evaluation 
X 
X 
X 
Complete 
Case 
Report 
Forms 
(CRFs) 
X 
X 
X 
 
 
 

PrePARE Trial v2.2, 30 November 2022 
 
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1. Objective 
 
Primary Objective: Define anaphylaxis rates in OFCs for peanut allergy halted by 
TEWL stopping rules plus standard of care clinical assessment versus control 
OFCs, where challenges are halted based only on clinical assessment of reaction 
status per standard of care. 
 
Secondary Objectives:  
1. Define overall allergic reaction rates in peanut OFCs halted by TEWL stopping 
rules versus usual care. 
2. Define anaphylaxis likelihood and severity via Brighton and CoFAR criteria 
among anaphylaxis reactions in peanut OFCs halted by TEWL stopping rules 
versus usual care. 
   
2. Specific Aims 
 
Aim 1: Determine the ability of TEWL-based stopping rules to impact OFC safety 
features for peanut OFCs.  
Sub-aim 1: Define anaphylaxis occurrence rate in OFCs halted by TEWL 
stopping rules versus usual care OFCs, where challenges are halted based 
soley on clinical assessment of reaction status. 
Sub-aim 2: Define anaphylaxis likelihood and severity via Brighton and 
CoFAR criteria among anaphylaxis reactions in OFCs halted by TEWL 
stopping rules versus usual care. 
Sub-aim 3: Define overall allergic reaction rates in OFCs halted by TEWL 
stopping rules versus usual care.  
 
 
Table 1 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
Define anaphylaxis rates in 
OFCs for peanut allergy halted 
by TEWL stopping rules versus 
usual 
care 
OFCs, 
where 
challenges are halted based 
on 
clinical 
assessment 
of 
reaction status. 
Anaphylaxis occurrence rate  
 
Anaphylaxis is the 
key adverse clinical 
outcome of “positive” 
OFCs and thus a 
major safety issue of 
OFCs. If TEWL can 
reduce anaphylaxis 
rate 
while 
still 
maintaining 
overall 
peanut 
allergy 
diagnosis accuracy, 
this methodology will 
have utility. 
Secondary 
 
 
Define overall allergic reaction 
rates in peanut OFCs halted by 
TEWL stopping rules versus 
usual care. 
Secondary 
endpoints 
will 
include anaphylaxis severity 
and overall reaction rates.  
 
Anaphylaxis severity 
is 
a 
key 
safety 
question in OFCs. If 
anaphylaxis severity 

PrePARE Trial v2.2, 30 November 2022 
 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
 
Define anaphylaxis likelihood 
and severity via Brighton and 
CoFAR 
criteria 
among 
anaphylaxis 
reactions 
in 
peanut OFCs halted by TEWL 
stopping rules versus usual 
care. 
 
 
Anaphylaxis likelihood will be 
defined 
by 
the 
Brighton 
criteria. Anaphylaxis severity 
will be defined via the modified 
CoFAR criteria (these are 
defined later in the protocol). 
is 
impacted 
by 
TEWL 
stopping 
rules, that would be 
valuable information. 
 
Overall 
allergy 
reaction rates are 
important 
to 
understand 
non-
anaphylaxis events 
within OFCs. Many 
OFCs are stopped 
based on a non-
anaphylactic allergic 
reaction 
(i.e., 
isolated 
hives 
without 
other 
symptoms) 
per 
standard 
of 
care. 
Such 
non-
anaphylactic events 
are 
safer 
than 
anaphylaxis 
by 
definition, 
so 
if 
anaphylaxis events 
without 
TEWL 
stopping rules are 
converted to non-
anaphylactic 
reactions, that would 
be a very useful 
data-point because 
we 
would 
be 
preserving 
the 
accuracy of the OFC 
via standard of care 
while reducing the 
risk 
by 
avoiding 
anaphylaxis. 
Tertiary/Exploratory  
 
 
Define 
descriptive 
characteristics 
of 
allergy 
reactions/anaphylaxis among 
peanut OFCs wherein TEWL 
stopping rules are or are not 
used. 
Exploratory 
endpoints 
may 
include but are not limited to 
time to first treatment, time to 
first 
symptom, 
epinephrine 
use, any medication use, and 
time to meeting a TEWL-
based stopping rule. 
 
 
These 
additional 
endpoints 
provide 
useful 
safety 
and 
descriptive features 
that may help define 
larger clinical trials 
with 
this 
TEWL 
modality 
in 
the 
future. 

PrePARE Trial v2.2, 30 November 2022 
 
9
 
 
 
3. 
Background  
 
Food allergy (FA) presents a major societal health burden because it impacts over 
5 million (8%) children in the United States (US) and grows more common every year 1-3. 
FA causes food anaphylaxis, a deadly, systemic allergic reaction causing over 200,000 
US emergency room visits per year 4-6. FA also causes childhood nutritional and growth 
deficiencies 7-10, severe anxiety for patients and caregivers 11-13, and high healthcare and 
family costs due to the need for epinephrine auto-injectors, healthcare visits, and food 
avoidance 14-18. An accurate diagnosis is therefore crucial to avoiding a “disaster of 
misdiagnosis” where the consequences of perceived FA are realized due to false positive 
testing in the absence of true disease 7,19.  
FA diagnosis relies on clinical history. FA testing such as food-specific skin and 
blood immunoglobulin E (IgE) assays has high false positive rates up to 30-50% and fail 
to predict FA reaction severity 20-22. The oral food challenge (OFC), where a patient ingests 
a potential food allergen and real-life results are observed in the allergy office, is the 
diagnostic criterion standard but carries a substantial risk of anaphylaxis 22,23. During an 
OFC, the patient ingests a food allergen in a graduated fashion up to a total dose until a 
full serving is eaten without incident or until an allergic reaction, typically anaphylaxis, 
occurs; to be clear, anaphylaxis currently relies purely on a clinical diagnosis through 
physician observation as there is no monitoring device for anaphylaxis.24 Allergists face 
barriers to performing OFCs, and families may decline OFCs due to anaphylaxis anxiety 
25-31. Thus, FA over-diagnosis via testing without confirmatory OFCs leads to FA anxiety, 
increased costs, and growth/nutrition deficits from food avoidance 7,14-19,32. Performing 
OFCs gives clear benefits, including improved quality of life, an expanded and more 
nutritious diet, and/or clarifying a diagnosis 24,29,33,34. However, the perceived risks and 
benefits of OFCs may still tilt toward OFC avoidance for many physicians and patient 
families; therefore, a novel method of improving OFC safety and tolerability is sorely 
needed.  
Young children have increasing rates of FA 19,35-37; clinical trials and related 
international guidelines support OFC administration even under age 1 38,39. In young 
children, the lack of expressive language delays anaphylaxis symptom detection, thereby 
impacting challenge cessation and reaction severity 24,40-42.  
No objective monitoring device for OFC-induced anaphylaxis exists. Early 
treatment of anaphylaxis reduces the severity of food reactions and minimizes adverse 
outcomes 43-45, providing rationale for developing an OFC anaphylaxis monitoring tool. 
Therefore, a method of safely diagnosing clinical food allergy in this young age group is 
critical. 

PrePARE Trial v2.2, 30 November 2022 
 
10
We propose to use the transepidermal water loss (TEWL) as a safe and specific 
method to monitor outcomes in OFCs in young children aged 6 months to 5 years. This 
age group was chosen due to the lack of expressive language, the high rate of peanut 
allergy, and the perceived difficulties in performing OFCs in this group. TEWL is a well-
established measure of cross-sectional water loss from the skin and used in evaluating 
topical medications and in diagnosing dermatological conditions 
46-48. TEWL 
measurements have shown validity across skin tones and types, with no consistent 
differences noted between skin tones at rest or with perturbances of the skin 49-53. TEWL 
is measured quantitatively, painlessly, and non-
invasively using skin contact probes to give real 
time results 48,54 (Figure 1). TEWL is well-
reported as a measurement among infants and 
young children.55-57 Newer technologies allow 
for continuous measurements taken over hours 
48,54. TEWL correlates with and could predict the 
long-term development of FA 55-57.  
TEWL in real-time anaphylaxis: 
TEWL 
has 
not 
yet 
been 
implemented 
in 
the 
real-time, 
continuous monitoring of allergic 
reactions 
or 
anaphylaxis. 
Anaphylaxis induces rapid blood 
vessel dilation, causing cutaneous 
heat 
and 
water 
loss.58-62 
We 
evaluated histamine-induced skin 
hives via TEWL, the positive control for skin testing.63,64 When a hive is induced on skin 
via histamine, a red flare arises followed by a wheal, a pale raised area. TEWL rises over 
both the flare (< 1-2 minutes) and wheal (< 10 minutes) of a hive (Figure 2A). Most 
patients present with cutaneous manifestations of anaphylaxis,65-67 lending support to 
evaluating continuous TEWL measurement during anaphylaxis. Furthermore, TEWL likely 
does rise with anaphylaxis; during a peanut-induced anaphylaxis episode with symptoms 
of hives and vomiting in an OFC patient, TEWL rose significantly from a baseline of 7.75 
g/m2/h to 12.2 g/m2/h (Figure 2B), even on skin without visible hives. There was a trend 
toward a decrease after epinephrine. This increased TEWL does not occur in non-
reactors. Since this initial observation, we have developed this technique and begun 
testing continuous TEWL monitoring as an anaphylaxis predictor. We have found that 
TEWL rises substantially in the 20 minutes after food dose 1 among anaphylaxis reactions. 
These data are shortly to be published. 
In summary, we propose that deploying TEWL during OFCs with young children 
will facilitate detection of anaphylaxis prior to dangerous symptom development. We 
Figure 1: Transepidermal water loss is 
measured using a skin-contact probe placed 
gently upon the skin (A). Another model (see 
below) uses an adhesive probe head with 
wireless connectivity to a monitor to give 
continuous measurements. Inside the probe, 
temperature and humidity sensors measure 
egressing water and heat concentrations in a 
fixed area over time to produce the 
measurement (B). 
A 
B 
Figure 2: A) TEWL measured on a hive’s wheal and flare. 
Measured at baseline (normal skin) and within 10 minutes after 
histamine applied (flare, wheal). B) TEWL measured on volar 
forearm during peanut-induced anaphylaxis (defined by hives and 
vomiting). Error bars show standard error of the mean. TEWL 
measured via tewameter with MPA_CTA Plus software. Means 
compared via ANOVA. *p<0.05, **p<0.01. NS = not significant. 
A 
B 

PrePARE Trial v2.2, 30 November 2022 
 
11
expect that this will allow the use of OFCs with TEWL-based outcome measurements to 
be a definitive marker of childhood food allergy and will improve safety of the OFC. This 
pilot study represents a key first step in that direction. 
 
 
4. 
Study Team Expertise  
 
Dr. Schuler is a Clinical Assistant Professor in Allergy/Clinical Immunology, has an 
expertise in respiratory virus immunopathology and clinical allergy/immunology, and has 
served as PI on clinical data and sample collection studies as well as clinical trials involving 
anaphylaxis evaluation (such as for the NIH COVID-19 vaccine allergy study). He has 
piloted the TEWL data described and founded the UM food allergy biorepository that 
supported the data collection driving this work. Dr. O’Shea is a Clinical Assistant Professor 
in Allergy/Clinical Immunology with expertise in clinical and research-based oral food 
challenges. She is the PI or a CoI on multiple industry and investigator-initiated clinical 
trials. Dr. Freigeh holds a Master's Degree in Medical Ethics and is an allergy/immunology 
fellow with an interest in food allergy and ethics. He will follow along in this study (though 
not conduct study activities independently) as a learning exercise. 
 
5. Methodology  
a. Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
1. Age 0.5 – 5 years as this is the time when food allergies are 
detected and OFCs are typically done. In addition, this timeframe is 
when children are least able to express symptoms they experience 
and are in most need of an objective anaphylaxis monitoring option. 
2. Have a known history of food anaphylaxis to peanut confirmed by 
an allergist.  
3. Have had skin and blood food allergy testing to peanut within the 
past 12 months. Meet the 80% likelihood positive predictive value 
threshold for peanut allergy based on at least 1 of either the skin or 
blood IgE tests per current literature corrected for age 21,68. For 
peanut, this requires at least a 3 mm wheal on skin prick testing, 
total peanut IgE 5.0 kUa/L, and ARA H1 or H2 of > 0.35 kUa/L. 
4. Meet all clinical OFC requirements. This includes no asthma or 
atopic dermatitis exacerbations, no recent viral infections, no recent 
antibiotics, and no food allergy reactions in the past month. (See 
appendix for protocol). 
 
Exclusion Criteria 
1. Any known cardiovascular disease, cancer, pulmonary disease 
except well-controlled asthma, or other condition that would 
preclude an OFC otherwise. 
2. Any medication use that would interfere with an OFC result. 
Medications in this category include antihistamines (first or second 
generation) within 1 week, omalizumab within 3 months, and others 
listed in the appendix. 
3. Any skin condition aside from well-controlled eczema that might 
impact TEWL measurement, including such conditions as 

PrePARE Trial v2.2, 30 November 2022 
 
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autoimmune skin conditions (such as psoriasis), congenital 
ichthyoses, hyper-IgE syndromes. 
 
 
b. Recruitment Plan and Study Design 
i. Number of Subjects 
N=40 individuals 
 
ii. Method of Contact 
We will screen and recruit individuals that meet the above enrollment 
criteria from our food allergy clinic visits for peanut food allergy. Individuals’ 
parents/guardians will be contacted initially by a member of the study team in 
clinic, over the phone, and/or email. A posting on UMHealthResearch.org will 
also be created.   
 
iii. Method of Consent 
Individuals’ parents/guardians will be contacted as above. Individuals’ 
parents/guardians approached for the study will be provided the consent 
document for review and offered background on the study. This process may 
take place in person during a clinical visit, over the phone, or via video (such as 
Zoom) by a member of the study team.  Eligible individuals’ parents/guardians 
will be provided the informed consent document and a thorough review of the 
document will take place. Participant parent/guardians will have as much time as 
needed to ask questions and decide if they would like to participate in the 
study.  In most cases, consent will be provided to the participant electronically 
and they will be asked to sign using the University of Michigan’s FDA 21 CFR 
Part 11 compliant e-signature service (“SignNow”).  This service automatically 
provides a copy of the fully signed document to all parties and a copy will be 
placed in the participant’s medical record.  There may be circumstances where 
a participant is able to complete the consent process in person during a clinical 
visit; sufficient time for review and questions will be provided for in person 
consenting as well.  Rarely, consents may send via postal mail for ink 
signatures.  In any case no study procedures will take place until the consent 
has been signed by all parties and a copy of the fully signed document is 
provided to the participant. The method, location, and individuals involved in the 
consent process will be documented in the study records.  
 
iv. Method of Interaction/Procedure/Intervention 
Pre-OFC Visit/Interaction 
1. Collect demographics from the participant and/or electronic 
medical record. 
2. Review medical history and prior peanut food allergy testing 
with participant and within the electronic medical record by a 
study physician. 
3. Assessment of concomitant medications. 
4. Obtain written informed consent. 
5. Participant will then be scheduled for an OFC visit 
 
Strategies for Recruitment and Retention  
We have allowed for multiple methods of contact as above to 
ensure that individuals with different levels of digital connectedness and 

PrePARE Trial v2.2, 30 November 2022 
 
13
socioeconomic status can be included. In addition, we will compensate 
participants $100 total to participate in this study for time, travel, and 
parking. $50 will be provided based on arrival to the study site (to 
compensate for screening time, travel and parking) and the other $50 will 
be provided based on finishing the challenge protocol (to compensate for 
time spent during the challenge).  
 
Given the pilot nature of this study the population sampled will likely 
represent a convenience sample. Our food allergy patients are evenly split 
by sex, and our population represents Washtenaw County and southeast 
Michigan ethnically and racially. We expect a reasonably diverse sample 
for this pilot study, though the lower enrollment number (n=40 total) means 
there is a possibility of randomly asymmetric enrollment across groups. 
Ultimately, ensuring a diverse sample will be even more feasible once we 
move to broader ages and (hopefully) multi-site studies after this pilot 
study.  
 
Research OFC procedure.  
OFCs will be conducted by a food allergy OFC-trained nurse; 
Bridgette Kaul, RN, is a member of our food allergy research team and has 
conducted numerous clinical OFCs. OFCs will be conducted exactly 
according to the clinical OFC parameters (see appendix) and final allergy 
diagnosis will be made per standard of care. Briefly, individuals will come 
to the clinical research area. They will have vital signs (height, weight, 
temperature, heart rate, respiratory rate, blood pressure, and SpO2 on 
room air) and a review of any additional symptoms or new medications 
since screening. The TEWL monitor will be applied to the volar forearm and 
monitoring initiated. Food doses will be given in a graduated fashion up to 
a defined single serving for the food in question and the age/size of the 
participant (see appendix table for food dosing). The OFC will proceed until 
a full dose is consumed without symptoms or a stopping criterion is reached 
(below). Most OFCs require 2-4 hours. Typically, 1-2 hours is required for 
intake and food ingestion, followed by 1-2 hours of monitoring and/or 
treating reactions that arise. 
This will be an open OFC, meaning participants will know they are 
eating a likely reactive food. To be clear, an alternative approach is to 
perform double-blinded, placebo-controlled (DBPC) OFCs; this means the 
participant does two OFCs in which they receive placebo and the food in 
question in two separate challenges (usually a day to a week apart) and 
are blinded to which is done on each day. Blinding food compounds are 
used to obscure the food, such as applesauce or mint chocolate. While the 
DBPC OFC is considered the most definitive OFC method, the open OFC 
is considered an appropriate criterion standard and is in fact the method 
used clinically across the US 69,70. Thus, given the markedly increased 
costs of DBPC OFCs and the lack of their use in FA clinics, we will to use 
the open OFC in this pilot study.  
 
Blinding procedures.  
Participants and families, the food allergy nurse administering the 
OFC, and the allergist physician assessing and treating the patient will be 
blinded to the study arm status (i.e., TEWL stopping rule intervention group 

PrePARE Trial v2.2, 30 November 2022 
 
14
or control group). The study coordinator monitoring TEWL during the OFC 
will need to know the intervention arm vs control arm status to declare the 
OFC ceased when stopping rules are reached; this person will have no say 
in assessment or treatment of reactions. The study coordinator monitoring 
TEWL will be in the same room as the participant but will be behind a 
screen so that the screen displaying the TEWL results and the study 
coordinator’s face will not be immediately visible to the other team 
members. All subjects will have TEWL monitored throughout to control for 
confounding factors associated with having a monitoring device on the skin. 
At the end of the OFC, after the determination of OFC outcomes, the 
participants and families will be made aware of the overall OFC 
determination of allergy status.  
Regardless of group assignment (TEWL stopping rule or usual care 
with TEWL simply measured but not reported during the OFC), we expect 
that participants will be able to use the results of the OFC to reliably define 
true clinical food allergy status. Diagnosis will rely on standard of care in 
both cases. 
 
Randomization.  
Participants will be randomized 1:1 to the intervention and control 
groups. We will use permuted block randomization. We will vary the block 
size from 2 to 4 in order to enhance blinding. We will upload a 40-person 
participant list to randomization software that will produce the 
randomization, which will be performed at visit 1 (initial screening visit) or 
no later than the day of the research food challenge. The TEWL study 
coordinator will learn the group designation for each participant at the start 
of that participant’s challenge by the software.   
 
TEWL measurement methods.  
All subjects will undergo continuous TEWL measurement 48,54. We 
will use a Tewameter VT310 device (Khazaka, Germany); these probes 
and supporting software were supplied at no cost and with no obligation 
except mention of material support in publications by the manufacturer. 
Measurements are taken using a small adhesive to attach the probe to the 
skin. Measurements are taken on the volar forearm. Data are collected in 
MPA CT Plus software (Khazaka, Germany) which provides note-taking 
functions and exports data into Microsoft Excel (Seattle, WA) for analysis.  
 
Adjudication of OFC results.  
A FA physician will adjudicate reactions and diagnose anaphylaxis 
identically to usual care in the FA clinic. The Brighton anaphylaxis likelihood 
scale will be used to assess anaphylaxis likelihood. The decision tree is 
copied here (next page, Figure 3). The CoFAR anaphylaxis severity scale 
will be used for anaphylaxis severity71 and is below in the adverse event 
grading section of the protocol. The Brighton score gives a 0-3 score of 
anaphylaxis likelihood (0 = no anaphylaxis, 3 = highly likely). The CoFAR 
severity scare gives a grade of 1-5 of anaphylaxis severity (where 1 = mild, 
5 = death). 
 
Any symptom typical of food allergy (see Brighton and CoFAR 
scales) will count as a reaction, consistent with standard of care diagnosis 
for peanut allergy. Note that this is distinct from anaphylaxis. 

PrePARE Trial v2.2, 30 November 2022 
 
15
 
TEWL-based stopping rules will be applied to the intervention 
group. We plan to use a 1 g/m2/h increase in TEWL value averaged over 
the 2 minute period after a fully-consumed food dose versus the 2 minute 
period averaged over the period just prior to that food dose. If the individual 
meets this threshold, at the first sign of a clinical symptom, the food 
challenge will be stopped.  

PrePARE Trial v2.2, 30 November 2022 
 
16
Figure 3: Brighton Anaphylaxis Likelihood Scale 
 

PrePARE Trial v2.2, 30 November 2022 
 
17
 
Treatment of reactions.  
Reaction treatment will be based on symptoms assessed by the 
allergist per the clinical standard of care. If the participant meets 
anaphylaxis criteria 71, then weight-based anaphylaxis epinephrine dosing 
will be given, with a follow-up dose 5 minutes later if symptoms do not 
resolve. Albuterol via nebulizer or inhaler/mask (depending on age) and 
liquid diphenhydramine and cetirizine (both are antihistamines and use 
weight-based dosing) will be available and used after epinephrine in the 
case of anaphylaxis. All doses will be calculated prior to the challenge. If a 
participant has a reaction not meeting anaphylaxis criteria (i.e., they only 
have hives but no additional symptoms), the physician may choose to stop 
the OFC and give an antihistamine. If the TEWL-based stopping rule is 
invoked, the OFC will be stopped (no more food doses given); if the 
participant meets anaphylaxis criteria at that time, epinephrine will be 
given, otherwise an antihistamine dose will be given per standard of care.  
 
 
Outcome measures. The outcome measures collected for each group in 
Table 2 show the hypothesized relationship for each group. If a stopping 
rule is implemented, that will be considered a positive challenge. We 
hypothesize that the intervention group will have lower anaphylaxis rates 
and/or severity via earlier OFC stoppage and earlier time to or more 
frequent 
treatment 
with 
non-epinephrine 
medications 
(such 
as 
antihistamines). We suspect the overall reaction rate will remain the same, 
but that these reactions will not devolve into anaphylaxis in the intervention 
group due to the above factors. Anaphylaxis will be defined according to 
current practice parameters 72, which is broadly considered to be at least 
two 
symptoms 
consistent 
with 
allergic 
reactions 
(cutaneous, 
gastrointestinal, respiratory, elevated heart rate, among others) or a 
decrease in blood pressure.  
 
Post-OFC 
1. Participants without evidence of an allergic reaction during the 
OFC will receive a follow-up phone call 1 day after the OFC to 
follow up on any additional symptoms or concerns.   
Table 2: Outcome measures 
Definition 
Primary 
outcome 
Anaphylaxis rate 
Any Brighton Level 1, 2, or 3 anaphylaxis 
(see table above) 
Secondary 
outcomes 
Reaction rate 
Any objective symptom of allergic reaction 
occurs (e.g., hives, angioedema, vomiting, 
wheeze, etc) not rising to the definition of 
anaphylaxis. 
Anaphylaxis severity 
CoFAR score, defined below 
Anaphylaxis likelihood 
Brighton score, defined above 
Exploratory 
endpoints 
(Partial list) 
Time to first symptom 
Time from first food dose to any symptom 
Reaction symptoms 
All reaction symptoms listed 
Epinephrine use 
Any epinephrine administration 
Any medication use 
Any medication administration 
Time to stopping rule 
Time in minutes to stopping rule trigger 

PrePARE Trial v2.2, 30 November 2022 
 
18
2. Participants that had a reaction will be scheduled for a follow-
up call within 1 day of the OFC to assess for additional 
symptoms or resolution of symptoms per the standard of care.  
 
 
 
c. Subject Withdrawal 
i. Under what conditions will a subject be withdrawn prior to completion  
ii. If a subject withdraws prior to completion, what is the plan for the use of their 
data 
 
Any subject may withdraw at any time for any reason. These reasons 
may include but are not limited to: 
• 
Subject’s request, no reason needed 
• 
Adverse event – at Investigator’s request. Potential examples 
include concern that proceeding further would impose 
unanticipated risk not otherwise delineated here or for any 
reason that continued participation could impact study integrity. 
 
The data for any subject who withdraws prior to completion will be 
flagged as incomplete data in our data set. We will delete data if the 
subject requests this. 
 
d. Data Retention and/or Data Destruction Plan 
i. How long will you keep subject data? 
ii. If you plan to destroy the data, how will you destroy it? 
 
Data collected will be retained for study record keeping purposes 
and for future research use for up to 5 years or in accordance with 
our sponsor’s policies. Thereafter, data will be fully de-identified 
fully and retained indefinitely. No data will be destroyed.  
 
Risks & Benefits 
a. What are the risks and what will be done to monitor the risks? 
b. What is the likelihood of each risk (common, likely, infrequent, or rare)? 
 
Potential Risks 
• 
Allergic reactions, including anaphylaxis, other hypersensitivity reactions (e.g., 
rash, flushing, pruritus, urticaria, angioedema), diarrhea, vomiting do occur 
during positive OFCs. Given the goal of this study is to enroll participants who 
are likely to have a reaction, this is deemed LIKELY 
• 
If a participant experiences a systemic allergic reaction, the site will provide the 
participant with an epinephrine auto-injector 2-pack if they do not have one. In 
addition, participants who experience a systemic allergic reaction will receive 
a Food Allergy Action Plan at the OFC visit if one does not exist. The PI or 
designee will review the plan including symptoms of an allergic reaction and 
steps to take in the event of an allergic reaction, including training on how to 
use the epinephrine auto-injector, with the participant prior to discharge. If a 
participant has an allergic reaction, he/she may need oral, IM, or IV 
medications. The investigators for this trial are allergists, trained to recognize, 

PrePARE Trial v2.2, 30 November 2022 
 
19
and familiar with the treatment of anaphylaxis, and will be available within 60 
seconds in the event of a reaction. Emergency medications, oxygen, and 
equipment will be available to treat any allergic reactions.  POSSIBLE 
• 
Treatment of individual acute allergic reactions during the conduct of the study 
should be with epinephrine, IV fluids, β-adrenergic agonists (e.g., albuterol), 
oxygen, antihistamines, and steroids, as indicated for the severity of the 
reaction according to the standard of care.  POSSIBLE 
o Risks of these common medications are summarized below:  
 
Antihistamines: 
drowsiness, 
dizziness, 
constipation, 
stomach upset, blurred vision, or dry mouth/nose/throat 
 
Epinephrine: 
tachycardia, 
palpitations, 
nervousness, 
sweating, nausea, vomiting, trouble breathing, headache, 
dizziness, anxiety, tremors, or pale skin 
 
β-adrenergic agonists: nervousness, shaking (tremor), 
headache, or dizziness 
 
Steroids: nausea, vomiting, loss of appetite, heartburn, 
trouble sleeping, increased sweating, or acne 
• 
Risks associated with TEWL measurement could conceivably include skin 
irritation. RARE 
• 
Participation in this study could cause distress due to the experience of 
anaphylaxis. LIKELY. 
• 
Participation in this study poses a risk for breach of confidentiality.  RARE 
• 
Taking part in more than one research study may be harmful to the subject.  If 
subjects are already taking part in another study, we ask that they let us know. 
Subjects should not take part in more than one study at the same time, unless 
the subject and the investigators agree that the subject is not likely to be 
harmed, and the outcome of the study will not be disturbed.  RARE 
• 
As with any research study, though, there may be additional risks of 
participating that are unforeseeable or hard to predict. RARE 
 
What will be done to reduce or monitor these risks? 
• 
Any information sharing would only be done in the context of a new IRB review 
and in concert with UM’s Data Management Office. To minimize the breach of 
confidentiality risk, information shared outside of the University of Michigan will 
not use the subject’s name or hospital number, but rather a unique study 
number, and would only occur under a data use agreement supported by the 
University. Any publications that result from this work will only report de-
identified data. 
• 
The site investigators for this trial are allergists. They are trained to recognize 
symptoms and are expert in the treatment of anaphylaxis. They will be 
available within 60 seconds in the event of a reaction. Emergency medications, 
oxygen, and equipment will be available to treat any allergic reactions.   
• 
The clinical team will provide prescriptions for epinephrine auto-injectors for 
participants that experience systemic allergic reactions who do not have them. 
In addition, participants will receive Food Allergy Action Plan at the OFC visit if 
they do not have one already. The PI or designee will review the plan including 
symptoms of an allergic reaction and steps to take in the event of an allergic 
reaction, including training on how to use the epinephrine auto-injector, with 
the participant prior to discharge. 
 

PrePARE Trial v2.2, 30 November 2022 
 
20
c. What are the benefits?   
iii. To the individual 
Individuals and their families who undergo OFCs experience greater 
peace of mind and improved quality of life, even when the OFC leads 
to a reaction, due to improved certainty and a clarified diagnosis. 
Individuals and their families who pass the OFC (estimated to be 20% 
of both groups) will learn that they do not have a clinical food allergy, 
which has profound psychological, nutritional, cost, and overall health 
benefits, allowing the family to incorporate that food back into the diet. 
Overall, we expect that individuals and their families who 
participate will have an accurate determination of food allergy 
status for the food challenged (peanut), which can be used 
clinically to define allergy, or the lack of allergy, for that food, per 
the standard of care. 
 
In addition, our co-investigator Kelly O’Shea, MD, who will conduct 
many of these research challenges, is the peanut oral immunotherapy 
clinic expert here at U-M. She can provide a brief discussion of the risks 
and benefits of OIT (which is the only FDA-approved peanut allergy 
preventative therapy available) for individuals who do have a peanut 
reaction during this clinical trial. If that therapy option is of interest, they 
can be streamlined into the OIT clinical practice based on the results of 
this OFC. 
iv. To society  
This data is valuable for evaluating a novel detection/prediction method 
for anaphylaxis. We expect results from this project to show that TEWL 
can detect evolving anaphylaxis and that stopping rules based on 
TEWL will allow OFCs to be stopped and reactions treated prior that 
endpoint. This would reduce the risk and potentially the cost of an OFC, 
thereby allowing more allergists and patients to access this critical 
procedure, the OFC. Furthermore, TEWL measurement may ultimately 
have a role in anaphylaxis measurement in additional contexts such as 
the ambulance, emergency room, or hospital. This is an unmet need, 
as anaphylaxis frequently goes unrecognized, leading to absent or 
delayed lifesaving epinephrine administration, even in the emergency 
room. 
 
Data & Safety Monitoring 
a. Will there be a board your study will report adverse events and other problems 
to? 
 
Yes, the study will have a Data Safety and Monitoring Board (DSMB). The 
DSMB has a charter, which defines the membership, responsibilities, meeting 
schedule, and meeting substance/materials in detail. This charter is attached.  
 
Briefly, the DSMB will meet at study initiation, every 6 months while the study 
is enrolling, and at least once after the final subject is enrolled and finishes 
study activities. All adverse events will be compiled and reported to the DSMB 
in written format. Any serious adverse events deemed possibly, probably, or 
definitely related to study procedures will be communicated to the chair of the 
DSMB who will decide whether the Board needs to have an interim meeting to 

PrePARE Trial v2.2, 30 November 2022 
 
21
discuss the event. We anticipate 4-5 scheduled DSMB meetings during the 
12–24-month study period. 
 
b. Adverse Events 
Adverse Events (AEs): Any untoward medical occurrence associated with the 
use of an intervention in humans, whether or not considered intervention 
related. AEs include expected and unexpected harmful effects, and 
unexpected risks of an interaction or an intervention. 
 
Serious Adverse Event (SAE): An adverse event or suspected adverse 
reaction is considered “serious” if, in the view of the investigator:  
1. Death. 
2. A life-threatening event: An AE is considered “life-threatening” if, in the 
view of the investigator, its occurrence places the subject at immediate risk 
of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. For the purposes of this study, which 
is expected to include anaphylaxis during the majority of these food 
challenges, if the anaphylaxis event is treated during the study visit 
and does not require escalation to Emergency Room care, this would 
NOT be considered an SAE. 
3. Inpatient hospitalization.  
4. Persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions.  
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
The investigator must report adverse events regardless of relationship to study 
therapy regimen or study mandated procedures.  
 
 
i. Method of Identifying, Recording, Monitoring and Reporting Adverse 
Events 
 
Identifying:  
For this study, an adverse event will include the following associated 
with the oral food challenge: 
All AEs occurring within 1 day of the OFC visit. 
 
Collecting Adverse Events: Adverse events may be discovered through 
any of these methods:  
Observing the participant 
Receiving an unsolicited complaint from the participant/family. 
Participants/families will have study contact information including a 
monitored phone number to report AEs. We will also provide advice 
on whether urgent medical attention is required, even though this 
would be expected to be a rare event. 
Follow up phone call above. 

PrePARE Trial v2.2, 30 November 2022 
 
22
 
 
Grading of Adverse Events Other than Systemic Allergic Reactions: 
The study sites will grade the severity of non-allergic adverse events 
experienced by the study participants according to the criteria set forth 
in the FDA Guidance for Industry Toxicity Grading Scale for Healthy 
Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Clinical Trials (September 2007); hereafter, referred to as the FDA 
Toxicity Grading Scale. Adverse events will be graded on a scale from 
1 to 5 according to the following standards in the FDA Toxicity Grading 
Scale: 
Grade 1 = Mild  
Grade 2 = Moderate  
Grade 3 = Severe  
Grade 4 = Life-threatening  
Grade 5 = Death 
 
Grading of Systemic Allergic Reactions:  
 
The investigator will grade severity of systemic allergic reactions on a 
scale of 1 to 5 according to criteria set forth in the CoFAR Grading 
Scale.  
 
CoFAR Grading Scale for Systemic Allergic Reactions Version 3.0: 
 
Grade 1: Reaction involving one of the following organ systems in which 
the symptoms are mild:  
• 
Cutaneous: 
Generalized 
pruritus, 
generalized 
urticaria, 
flushing, angioedema  
• 
Upper respiratory: Rhinitis, cough unrelated to laryngeal edema 
or bronchospasm  
• 
Conjunctival: Injection/redness, itching, tearing  
• 
GI: Nausea, abdominal pain (no change in activity level), single 
episode of vomiting and/or single episode of diarrhea 
 
Grade 2: Reaction involving two or more of the following organ systems 
in which the symptoms are mild:  
• 
Cutaneous: 
Generalized 
pruritus, 
generalized 
urticaria, 
flushing, angioedema  
• 
Upper respiratory: Rhinitis, cough unrelated to laryngeal edema 
or bronchospasm  
• 
Conjunctival: Injection/redness, itching, tearing GI Nausea, 
abdominal pain (no change in activity level), single episode of 
vomiting, and/or single episode of diarrhea  
OR  
Reaction involving at least one of the following organ systems in 
which the symptoms are moderate:  
• 
Cutaneous: 
Generalized 
pruritus, 
generalized 
urticaria, 
flushing, angioedema  

PrePARE Trial v2.2, 30 November 2022 
 
23
• 
Upper respiratory: Rhinitis, cough unrelated to laryngeal edema 
or bronchospasm  
• 
Conjunctival: Injection/redness, itching, tearing  
• 
GI: Nausea, abdominal pain (with change in activity level), two 
episodes of vomiting and/or diarrhea 
 
Grade 3: Reaction involving one or more of the following organ 
systems:  
• 
Lower respiratory: Throat tightness, wheezing, chest tightness, 
dyspnea, cough that respond to short acting bronchodilator 
treatment 
(including 
IM 
epinephrine) 
with 
or 
without 
supplemental oxygen  
• 
GI: Severe abdominal pain, more than two episodes of vomiting 
and/or diarrhea  
• 
Cardiovascular: 
Reduced 
BP 
with 
lightheadedness, 
presyncope or tachycardia 
 
Grade 4: Life-threatening reaction involving one or more of the following 
organ systems with or without other symptoms listed in Grades 1 to 3:  
• 
Lower respiratory: Throat tightness with stridor, wheezing, chest 
tightness, dyspnea, or cough associated with a requirement for 
supplemental oxygen and refractoriness to short-acting 
bronchodilator treatment (including IM epinephrine)1  
OR  
• 
Respiratory compromise requiring mechanical support  
• 
Cardiovascular: Reduced BP with associated symptoms of end-
organ dysfunction (e.g., hypotonia [collapse], syncope) defined 
as: systolic BP of less than 90 mmHg or >30% decrease from 
baseline 
 
Grade 5: Death  
 
1. Examples of refractoriness could include continuous albuterol 
nebulizer or epinephrine IV infusion or more than three IM epinephrine 
injections 
 
The investigator will also grade likelihood of systemic allergic reactions 
according to criteria set forth by the Brighton Collaboration case 
definition and guidelines for anaphylaxis. Please see attached 
supporting documents in Section 44.   
 
Recording/Monitoring: 
Throughout the study, the investigator will record adverse events and 
serious adverse events on the appropriate AE/SAE electronic Case 
Report Form (eCRF) regardless of the relationship to the OFC or study 
procedure. Once recorded, an AE/SAE will be followed until it resolves 
with or without sequelae, or the AE/SAE stabilizes, or until 1 days after 
the participant’s OFC, whichever occurs first.  
 
Attribution of Adverse Events Code Descriptor Relationship 

PrePARE Trial v2.2, 30 November 2022 
 
24
RELATED CATEGORIES  
1. Definitely Related 
2. Probably Related 
3. Possibly Related  
NOT RELATED CATEGORY  
4. Unlikely to be Related 
5. Definitely not Related 
 
Reporting: 
We will report any adverse events and other reportable incidences and 
occurrences (ORIO) to the IRB.  Any adverse event or ORIO will be 
documented of that event including a description, subject number, date, 
outcome, and follow-up. Reporting of adverse events and ORIOs will 
follow IRBMED’s reporting timetable and will occur at least yearly.    
 
Statistical Design  
Stopping rules. The anaphylaxis prediction threshold used in the study 2 trial will 
be data-driven based on results from our ongoing data collection study. We will 
perform a series of logistic regression models testing the predictive value of 
various levels of absolute increases in TEWL, thresholds of TEWL and their 
combinations. These will be tested against time to first symptom, time to formal 
anaphylaxis diagnosis, time to first medication use, and time to epinephrine use. 
To avoid overfitting, these analyses will use a 2:1 derivation: validation random 
split. Corrections will include baseline TEWL value and variance. A minimum 
sustained timespan meeting the threshold (such as 30-60 seconds) may be 
needed to minimize the effects of noise in the measurement. 
 
Endpoints. The primary endpoint will be anaphylaxis rate among the intervention 
group versus the control group and will be reported with a 95% confidence interval. 
Secondary endpoints will include anaphylaxis severity and overall reaction rates. 
Exploratory endpoints may include but are not limited to time to first treatment, time 
to first symptom, epinephrine use, any medication use, and time to meeting a 
stopping rule (regardless of whether it was implemented); all will be reported with 
95% confidence intervals. Exact p-values will be calculated using Fischer’s test.  
 
Descriptive analyses. Descriptive analyses will be reported. Continuous baseline 
measures will be reported using either mean (or geometric mean) with 95% 
confidence interval or median with first and third quartiles, as appropriate. 
Categorical baseline and demographic characteristics and study disposition will be 
reported as frequencies and proportions.   
 
Population size. To achieve 80% power with two-sided alpha=0.05 to detect a 
minimum 50% absolute difference in anaphylaxis rate reducing in anaphylaxis 
between the intervention group (anticipated anaphylaxis rate 30%) and the control 
group (80%) using a Fischer’s exact test and at a ratio of 1:1 for both groups, 38 
total subjects (19 per group) would be needed for this phase. To account for 5% 
drop-out, we will enroll 40 total subjects (20 per group). This is achievable with the 
enrollment-eligible population available to us. The Food Allergy clinics at the 
University of Michigan see approximately 500-1000 peanut allergy patients 
annually age 5 and under at the Domino Farms clinic site alone. Over 18-24 
months and with a 2.5-5% rate of enrollment, enrollment of 40 participants is 

PrePARE Trial v2.2, 30 November 2022 
 
25
feasible. There are also 3 additional Allergy clinics at U-M that could also provide 
a similar patient population size as well to augment this. 
 
 
 
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