Intervention to Reduce Early (Peanut) Allergy in Children
Phase: NA
Conditions: Food Allergy Peanut, Food Allergy in Infants
Sponsor: Ann & Robert H Lurie Children's Hospital of Chicago

 
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iREACH  
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 [AAABB-U01-LCH-002] 
U01 AI138907 
Intervention to Reduce Early (Peanut) Allergy in Children SHORT TITLE: iREACH 
IND# Not applicable 
 [VERSION NUMBER 2.0/VERSION DATE 27-MAY-2021] 
STUDY SPONSORS: The National Institute of Allergy and Infectious Diseases (NIAID)  
NIAID Funding Mechanism: TBD 
 
 
 
PROTOCOL CHAIR-  
 
Ruchi Gupta, MD, MPH 
Professor of Pediatrics and  
Medicine, Northwestern University 
Feinberg School of Medicine; 
Clinical Attending, Ann & Robert H. 
Lurie Children’s Hospital of 
Chicago; 
Director, Center for Food Allergy & 
Asthma Research (CFAAR) 
750 N. Lake Shore Drive 
Suite 680 
Chicago, IL 60611 
Phone: 312-503-5581 
Fax: 312-573-7825 
E-mail: r-gupta@northwestern.edu 
MEDICAL MONITOR –  
 
Alkis Togias, MD 
Branch Chief  
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone:  240-627-3587 
Fax:   
E-mail: togiasa@niaid.nih.gov 
 BIOSTATISTICIAN-  
 
Lucy Bilaver, PhD 
Assistant Professor of 
Pediatrics, Northwestern University 
Feinberg School of Medicine 
750 N. Lake Shore Drive 
Suite 680 
Chicago, IL 60611 
Phone: 312-503-5618 
E-mail: l-bilaver@northwestern.edu 
 
PROJECT MANAGER- 
 
Joy Laurienzo Panza  
Division of Allergy, Immunology, and 
Transplantation 
National Institute of Allergy and Infectious 
Diseases 
5601 Fishers Lane 
Bethesda, MD 20892-9828, USA 
Phone:   
Fax:   
E-mail:  jlaurienzo@niaid.nih.gov 
 
REGULATORY OFFICER 
 
Julia Goldstein, MD 
Office of Regulatory Affairs 
Division of Allergy, Immunology, 
and Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane, Room 7B29 
Bethesda, MD 20892-9828, USA 
Phone:  240.627.3509 
Fax:  301.480.1537 
E-mail: goldsteinj@niaid.nih.gov 
 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of 
the Division of Allergy, Immunology, and Transplantation, National Insitututes of Allergy and Infectious Diseases, 
National Institutes of Health. 
 
 

 
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SITE INVESTIGATOR SIGNATURE PAGE 
Protocol Number: 
  AAABB-U01-LCH-002 
Version Number/Date:  
2.0/27-MAY-2021 
  
Protocol Title:  Intervention to Reduce Early (Peanut) Allergy in Children (iREACH) 
  
IND/IDE Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID)      
 
Return Signed Form to: 
[A copy of this signature page must be kept for your records. Return the original signed 
signature 
page (as described below*) by USPS mail or Courier to:] 
DAIT Regulatory Management Center 
Pharmaceutical Product Development 
3900 Paramount Parkway 
Morrisville, NC 27560 
[If PPD is not the Regulatory Management Center for this protocol, e.g., for an Investigator 
Initiated clinical trial, contact the DAIT Regulatory Officer for appropriate mailing address.] 
I confirm that I have read the above protocol in the latest version. I understand it, and I will 
work 
according to the principles of Good Clinical Practice (GCP) as described in the United States 
Code of 
Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, 812 and in the 
International Conference for Harmonisation (ICH) document entitled Integrated Addendum to 
ICH 
E6(R1): Guideline for Good Clinical Practice E6(R2). Further, I will conduct the study in 
keeping with 
local legal and regulatory requirements. 
As the site Principal Investigator, I agree to carry out the study by the criteria written in the 
protocol 
and understand that no changes can be made to this protocol without the written permission of 
the IRB and NIAID. 
[*The site Principal Investigator should print, sign, and date at the indicated location below. A 
written 
signature is acceptable, and an electronic signature is acceptable in a pdf version of the form.] 
 
____________________________________     
Site Principal Investigator  (Print) 
 
____________________________________                                      _________________ 
Site Principal Investigator (Signature)                                                          Date 

 
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Protocol Synopsis 
Title 
Intervention to Reduce Early (Peanut) Allergy in Children 
Short Title 
iREACH 
Clinical Phase 
Not applicable 
Number of Sites 
N=30-37; United States 
IND Sponsor/Number   
Not applicable 
Study Objectives 
To determine the effectiveness of iREACH in increasing adherence 
to the Addendum Guidelines for the Prevention of Peanut Allergy 
(PPA Guidelines) among pediatric clinicians. 
Study Design 
Practice-based, two-arm, cluster randomized controlled trial 
Primary Endpoint(s) 
• 
Percent of infants at low risk for peanut allergy whose pediatric 
clinicians adhered to the guidelines. 
• 
Percent of infants at high risk for peanut allergy whose 
pediatric clinicians adhered to the guidelines. 
Secondary Endpoint(s)  
• 
Percent of infants at low risk for peanut allergy who developed 
peanut allergy by age 2.5. 
• 
Percent of infants at high risk for peanut allergy who developed 
peanut allergy by age 2.5. 
(Exploratory Objectives) 
1. Allergist adherence to the PPA Guidelines 
2. Barriers/facilitators for PPA Guideline adherence among 
pediatric clinicians and caregivers. 
3. Caregiver adherence to PPA Guidelines (peanut product 
introduction and feeding frequency). 
Accrual Objective 
Pediatric clinicians: 200; High-risk infants: 500; Low-risk infants: 
10,000; Caregivers: 10,500 
Study Duration 
51 months for practices, maximum 23 months for pediatric 
clinicians, maximum 26 months for infants and caregivers 
Treatment Description  
The iREACH intervention consists of A) an education module on 
the PPA Guidelines and the research on which the guidelines were 
based; B) an EHR-integrated CDS tool in the 4- and 6-month WCC 
templates to support pediatric clinician decision-making around 1) 
proper triage of infants into peanut allergy risk categories, 2) 
allergy testing and interpretation and/or allergist referral for high-
risk infants, and 3) caregiver counseling on peanut introduction 
including educational materials for families; and C) follow-up 
prompts in the 9-and 12-month WCC templates guiding pediatric 

 
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clinicians to ask caregivers about inclusion of peanut products in 
their child’s diet. 
Inclusion Criteria 
Practice sites 
• 
The practice utilizes a centrally-integrated EHR. 
• 
The practice has signed a legally-binding engagement 
agreement with Lurie Children’s Pediatric Practice Research 
Group. 
• 
The practice employs at least one physician who has 
completed a residency in general pediatrics and is practicing 
as a general pediatrician. 
 
Pediatric Clinicians: 
• 
Clinician is a physician, physician assistant, resident, 
advanced practice nurse, family practitioner, or pediatric nurse 
practitioner working in a pediatric practice. 
• 
Clinician is employed by a practice that is a member of one of 
the participating practices in the study. 
• 
Clinician provides well child care to infants ages 4 or 6 
months. 
 
Infants 
• 
Infant has been seen by a pediatric clinician in the 
intervention or control arm for a 4- and/or 6-month WCC. 
 
Caregivers 
• 
Is the caregiver of an infant seen for a 4- and/or 6-month 
WCC by a pediatric clinician in a practice belonging to the 
study’s intervention or control arms. 
• 
Is ≥18 years of age or has parent or guardian permission to 
participate. 
• 
Is able to understand the study and provide informed consent 
for the 12- and 24-month (child’s age) survey. 
 
Exclusion Criteria 
Practice Sites 
• 
Sees <50 newborn patients/year. 
• 
Has only temporary pediatricians on staff. 
• 
The practice prediatric clinicians do not use an EHR system. 
 
Pediatric clinicians 
• 
The clinician is a temporary employee. 
• 
The clinician begins employment at participating practice less 
than three months prior to end of the 18-month study 
enrollment period. 
 
Infants 
• 
The infant has a medical condition that chronically 
inhibits the ability to take food orally (i.e., dysphagia, 

 
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muscular dystrophy, gastrostomy). 
• 
The infant has past or current medical problems that 
prohibit implementation of PPA Guidelines or may have 
impacted the quality or interpretation of the data obtained 
from the study. 
Caregivers 
• 
Caregiver’s primary language is not English or Spanish. 
Study Stopping Rules 
• 
Breach of Confidentiality with Infant Personal Health-Related 
Information: The source of the breach will be investigated, 
identified, and resolved. If the source of the breach of 
confidentiality cannot be resolved, study will be placed on 
hold.    
• 
Change in PPA Guidelines that May Affect Study Procedures 
and Outcomes: The study will pause, and the study team will 
review implications and revise procedures as necessary. 
 
 
 

 
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Study Contacts: Participating Centers  
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR 
Ruchi Gupta, MD, MPH 
Professor of Pediatrics and  
Medicine, Northwestern 
University Feinberg School of 
Medicine; 
Clinical Attending, Ann & 
Robert H. Lurie Children’s 
Hospital of Chicago; 
Director, Center for Food 
Allergy & Asthma Research 
(CFAAR) 
750 N. Lake Shore Drive 
Suite 680 
Chicago, IL 60611 
Phone: 312-503-5581 
Fax: 312-573-7825 
E-mail: r-gupta@northwestern.edu 
 
SITE PRINCIPAL 
INVESTIGATOR 
 
Lucy A Bilaver, PhD 
Assistant Professor 
Northwestern 
University 633 N St. 
Clair, 20th Floor 
Chicago, IL 60611 
Phone: 312-503-5618 
Fax: 312-503-4401 
Email: l-bilaver@northwestern.edu 
SITE PRINCIPAL 
INVESTIGATOR 
Lurie Children’s Hospital 
Community Connect 
 
Adolfo J Ariza, MD 
Research Associate Professor of 
Pediatrics 
Feinberg School of Medicine, 
Northwestern University 
Director, Pediatric Practice Research 
Group (PPRG) 
Stanley Manne Children's Research 
Institute 
Ann & Robert H. Lurie Children’s 
Hospital of Chicago 
225 E. Chicago Avenue,  #157 
Chicago, IL,  60611 
Phone: 312-227-7023 
  E-mail: aariza@luriechildrens.org 
 
SITE PRINCIPAL 
INVESTIGATOR 
Erie Family Health Centers & 
Near North Health Service 
Corporation 
 
Nivedita Mohanty, MD 
Chief Research Officer and 
Director of Evidence Based 
Practice 
AllianceChicago 
215 W. Ohio Street, 4th Floor, 
Chicago, Illinois 60654 
 
Phone: 312.274.0068 
Cell: 312.504.6569 
E-mail: 
nmohanty@alliancechicago.org 
 
SITE PRINCIPAL 
INVESTIGATOR 
OSF Medical Group & 
UnityPoint Health 
 
Amy Christison MD 
Assistant Professor of Pediatrics   
Medical Director, Healthy Kids 
U 
University of Illinois College of 
Medicine Peoria  
Assistant Program Director 
Pediatrics Residency at the  
Childrens Hospital of Illinois  
530 NE Glen Oak Ave 
Peoria IL 61637 
E-mail: alc@uic.edu 
 
 

 
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Table of Contents 
Glossary of Abbreviations .................................................................................................................................... 11 
1. 
Background and Rationale............................................................................................................................. 13 
1.1. 
Background and Scientific Rationale ..................................................................................................... 13 
1.2. 
Rationale for Selection of Investigational Product or Intervention ........................................................ 14 
1.3. 
Preclinical Experience ............................................................................................................................ 15 
1.4. 
Clinical Studies ...................................................................................................................................... 15 
2. 
Study Hypotheses/Objectives ........................................................................................................................ 16 
2.1. 
Hypotheses ............................................................................................................................................. 16 
2.2. 
Primary Objective .................................................................................................................................. 16 
2.3. 
Secondary Objective .............................................................................................................................. 16 
3. 
Study Design.................................................................................................................................................. 17 
3.1. 
Description of Study Design .................................................................................................................. 17 
3.2. 
Primary Endpoint(s) ............................................................................................................................... 18 
3.3. 
Secondary Endpoint(s) ........................................................................................................................... 19 
3.4. 
Exploratory Endpoint(s) ......................................................................................................................... 20 
3.5. 
Stratification, Randomization, and Blinding/Masking ........................................................................... 22 
3.5.1. 
Procedure for Unblinding/Unmasking................................................................................................ 22 
4. 
Selection of Participants and Clinical Sites/Laboratories .............................................................................. 22 
4.1. 
Rationale for Study Population .............................................................................................................. 22 
4.2. 
Inclusion Criteria .................................................................................................................................... 23 
4.3. 
Exclusion Criteria ................................................................................................................................... 23 
4.4. 
Selection of Clinical Sites/Labs ............................................................................................................. 24 
5. 
Known and Potential Risks and Benefits to Participants .............................................................................. 25 
5.1. 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert .. 25 
5.2. 
Risks of Investigational Product or Intervention cited in Medical Literature ........................................ 25 
5.3. 
Risks of Other Protocol Specified Medications ..................................................................................... 25 
5.4. 
Risks of Study Procedures...................................................................................................................... 25 
5.5. 
Potential Benefits ................................................................................................................................... 25 
6. 
Investigational Agent /Device/Intervention ................................................................................................... 25 
6.1. 
Investigational Agents/Devices/Interventions ........................................................................................ 25 
6.1.1. 
Investigational Intervention: Intervention to Reduce Early (Peanut) Allergy in Children (iREACH)
 
25 
6.1.1.1. 
Formulation, Packaging, and Labeling ....................................................................................... 26 
6.1.1.2. 
Dosage, Preparation, and Administration ................................................................................... 26 
6.1.2. 
Control Arm ........................................................................................................................................ 27 
6.1.2.1. 
Formulation, Packaging, and Labeling ....................................................................................... 27 

 
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6.1.2.2. 
Dosage, Preparation, and Administration ................................................................................... 27 
6.2. 
Drug Accountability ............................................................................................................................... 27 
6.3. 
Assessment of Participant Compliance with Investigational Agent ...................................................... 27 
6.4. 
Toxicity Prevention and Management ................................................................................................... 27 
6.5. 
Premature Discontinuation of Investigational Agent ............................................................................. 27 
7. 
Other Medications ......................................................................................................................................... 27 
7.1. 
Concomitant Medications ...................................................................................................................... 27 
7.2. 
Prophylactic Medications ....................................................................................................................... 27 
7.3. 
Prohibited Medications .......................................................................................................................... 27 
7.4. 
Rescue Medications ................................................................................................................................ 27 
8. 
Study Procedures ........................................................................................................................................... 27 
8.1. 
Enrollment .............................................................................................................................................. 27 
8.2. 
Screening/Baseline Visit ......................................................................... Error! Bookmark not defined. 
8.3. 
Study Assessments ................................................................................................................................. 29 
8.3.1. 
Questionnaires .................................................................................................................................... 29 
8.3.1.1. 
Practices sites ................................................................................... Error! Bookmark not defined. 
8.3.1.2. 
Pediatric Clinicians ......................................................................................................................... 29 
8.3.1.3. 
Caregivers ........................................................................................ Error! Bookmark not defined. 
8.3.2. 
EHR Data Collection .......................................................................................................................... 30 
8.3.3. 
Education ....................................................................................................................................... 31 
8.4. 
Unscheduled Visits .................................................................................. Error! Bookmark not defined. 
8.5. 
Visit Windows ......................................................................................... Error! Bookmark not defined. 
9. 
Mechanistic Assays ....................................................................................................................................... 33 
10. 
Biospecimen Storage ................................................................................................................................. 33 
11. 
Criteria for Participant and Study Completion and Premature Study Termination ................................... 33 
11.1. 
Participant Completion ....................................................................................................................... 33 
11.2. 
Participant Stopping Rules and Withdrawal Criteria ......................................................................... 33 
11.3. 
Participant Replacement ..................................................................................................................... 34 
11.4. 
Follow-up after Early Study Withdrawal ........................................................................................... 34 
12. 
Safety Monitoring and Reporting .............................................................................................................. 34 
12.1 Overview ................................................................................................................................................... 34 
12.2 Definitions ................................................................................................................................................. 35 
12.2.1 Adverse Event (AE)............................................................................................................................ 35 
12.2.2 Unexpected Adverse Event ................................................................................................................ 35 
12.2.3 Serious Adverse Event (SAE) ............................................................................................................ 35 
12.3 Grading and Attribution of Adverse Events .............................................................................................. 35 

 
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12.3.1 Grading Criteria .................................................................................................................................. 35 
12.3.2 Attribution Definitions ....................................................................................................................... 35 
12.4 Collection and Recording of Adverse Events ........................................................................................... 35 
12.4.1 Collection Period ................................................................................................................................ 35 
12.4.2 Collecting Adverse Events ................................................................................................................. 35 
12.4.3 Recording Adverse Events ................................................................................................................. 35 
12.5 Reporting of Serious Adverse Events and Adverse Events ...................................................................... 36 
12.5.1 Reporting of Serious Adverse Events to Sponsor ([DAIT/NIAID or other Sponsor, if applicable]) . 36 
12.5.2 Reporting to Health Authority ............................................................................................................ 36 
12.5.3 Reporting of Adverse Events to IRBs/IECs ....................................................................................... 36 
12.6  Pregnancy Reporting ................................................................................................................................ 36 
12.7 Reporting of Other Safety Information ..................................................................................................... 36 
12.8 Review of Safety Information ................................................................................................................... 36 
12.8.1 Medical Monitor Review .................................................................................................................... 36 
12.8.2 DSMB Review .................................................................................................................................... 36 
13. 
Statistical Considerations and Analytical Plan .......................................................................................... 37 
13.1 
Overview ............................................................................................................................................ 37 
13.2 
Endpoints ............................................................................................................................................ 37 
13.4 
Analysis Plan ...................................................................................................................................... 38 
13.4.1 
Analysis Populations. ...................................................................................................................... 38 
13.4.2 
Primary Analysis of Primary Endpoint(s)....................................................................................... 38 
13.4.4 
Analyses of Secondary and Other Endpoint(s) ............................................................................... 40 
13.4.5 
Analyses of Exploratory Endpoint(s) .............................................................................................. 41 
13.4.6 
Descriptive Analyses ...................................................................................................................... 42 
13.5.1 
Interim Analysis of Efficacy Data ...................................................................................................... 43 
13.5.2 
Interim Analysis of Safety Data ......................................................................................................... 43 
13.5.3 
Futility Analysis ................................................................................................................................. 43 
13.6 
Statistical Hypotheses ......................................................................................................................... 43 
13.7 
Sample Size Considerations ............................................................................................................... 44 
14. 
Identification and Access to Source Data .................................................................................................. 37 
14.1. 
Source Data......................................................................................................................................... 44 
14.2. 
Access to Source Data ........................................................................................................................ 45 
15. 
Quality Assurance and Quality Control ..................................................................................................... 45 
16. 
Protocol Deviations .................................................................................................................................... 46 
16.1. 
Protocol Deviation Definitions ........................................................................................................... 46 
16.2. 
Reporting and Managing Protocol Deviations ................................................................................... 46 

 
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17. 
Ethical Considerations and Compliance with Good Clinical Practice ....................................................... 46 
17.1. 
Statement of Compliance .................................................................................................................... 46 
17.2. 
Informed Consent Process .................................................................................................................. 46 
17.3. 
Privacy and Confidentiality ................................................................................................................ 47 
18. 
Publication Policy ...................................................................................................................................... 47 
19. 
References .................................................................................................................................................. 48 
20. 
Appendices ................................................................................................................................................. 50 
List of Tables ..................................................................................................................................................... 51 
List of Figures ................................................................................................................................................... 51 
List of Appendices ............................................................................................................................................ 51 
 
 

 
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Glossary of Abbreviations 
AAP 
American Academy of Pediatrics 
BPA 
Best Practice Advisory 
CDS 
 Clinical Decision Support 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DCC 
Data Coordinating Center 
DSMB 
 Data Safety Monitoring Board 
EEDI 
Exploratory EHR Data Infant 
EHR 
Electronic Health Record 
ETL 
Extract Transform Load 
FA 
Food Allergy 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
iREACH 
Intervention to Reduce Early (Peanut) Allergy in Children 
LEAP 
Learning Early About Peanut 
MOP 
Manual of Procedures 
NIAID 
National Institute of Allergy and Infectious Diseases 
NLP 
Natural Language Processing 
PA 
Peanut Allergy 
PHI 
Personal Health Information 
PI 
 
Principal Investigator 
PPA 
Prevention of Peanut Allergy 
PEDI 
 
 Primary EHR Data Infant 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SEDI 
Secondary EHR Data Infant 
SFTP 
Secure File Transfer Protocol 

 
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sIgE 
Specific IgE 
SOP 
Standard Operating Procedure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
WCC 
Well Child Check 
 
 
 
 

 
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1. Background and Rationale  
1.1. Background and Scientific Rationale 
The Peanut Allergy Epidemic:  Food allergy (FA) prevalence has increased sharply in recent decades1 and is a 
major health concern. Previous work by our research group found FA to be common, affecting 8% of US 
children,2 and costly—resulting in $24.8 billion dollars per year in expenditures by the healthcare system and 
US families.3 Emergency department visits and hospitalizations for FA and food-induced anaphylaxis have 
increased steadily in the US over the past decade,4 and in 
2010 were estimated to exceed 200,000 visits annually.5 
Results from our latest prevalence survey confirm that 
peanut allergy (PA) remains the most common food 
allergy, affecting 2.2% of U.S. children6 (Figure 1).2,6-9 
It is also one of the least frequently outgrown.8  
Prospective cohort studies in the US and Australia found 
that <20% of peanut-allergic infants outgrew their 
allergy. 10,11 Peanut is also a leading cause of fatal food-
allergic reactions12,13 and has been associated with 
substantially impaired quality of life among both peanut-
allergic children and their families.14,15 
Changing Recommendations for Timing of Peanut Introduction: Due to rising FA prevalence, the American 
Academy of Pediatrics (AAP) released guidelines in 2000 directing pediatricians to counsel caregivers of all 
infants to delay introduction of certain allergenic foods, including peanut, until age three.16 These guidelines 
were substantially revised by AAP in 2008,17 citing “insufficient evidence to recommend any specific practices 
concerning introduction of these foods after 4-6 months for the prevention of allergic disease.” 17-19  
Growing Evidence for Earlier Peanut Introduction: In 2008 Du Toit et al. found that early peanut 
consumption was associated with a 10-fold reduction in PA prevalence among children aged 4-18 years.20 
Subsequently, the Learning Early About Peanut (LEAP) study (N=640) tested whether introduction of dietary 
peanut in high-PA risk infants 4-11 months of age would reduce PA incidence compared to high-risk infants 
counseled to avoid peanut until age 5 years.21 Specifically, the LEAP protocol instructed caregivers in the early 
introduction arm to feed their infants at least 6g of peanut protein/week. The LEAP study found that early 
peanut introduction was safe and resulted in an 81% reduction in subsequent development of PA in high-risk 
children, as well as corresponding modulation of immune responses to peanuts at age 5. Overall, 92% of 
participants adhered to the intervention, demonstrating its feasibility. Moreover, the follow-up LEAP-ON study 
found that even after avoiding peanuts for a year, the children in the early introduction arm retained peanut 
tolerance.22 These findings, in addition to emerging mechanistic evidence for its tolerogenic effects, 23,24 spurred 
a dramatic reversal of 
national guidelines to 
recommend early peanut 
introduction. The 2017 
NIAID-sponsored 
Addendum Guidelines for 
the Prevention of Peanut 
Allergy in the United 
States (PPA Guidelines), 
stratified infants into three 
classes, each with its own evaluation protocol and recommendation for peanut product introduction (Figure 2). 
Based on these guidelines, pediatricians should assess PA risk for infants aged 4-6 months and advise 
accordingly.25  Because the PPA Guidelines recommend peanut introduction for infants in both class 2 and 3 
Figure 2. Summary of Addendum Guidelines for the Prevention of Peanut Allergy 
Figure 1. Prevalence of US Childhood Peanut Allergy 

 
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(Figure 2), this protocol will refer to these infants as a single class of “low-risk” infants and will examine them 
separately from the “high-risk” infants in class 1.   
 
While the provision of clinical practice guideline-consistent care has the potential to improve patient outcomes, 
uptake of the PPA guidelines by key stakeholders has lagged substantially.26-29 Poor PPA guideline adherence 
was recently demonstrated by preliminary results of a large, NIAID-sponsored survey of pediatricians 
conducted from June-July 2018. Only 27% of pediatricians regularly adhered to all PPA Guideline 
recommendations, despite 92% being aware of the guidelines. Poor understanding of the PPA Guidelines and 
their application (35%) and lack of time in clinical encounters (30%) were commonly reported barriers to 
adherence.    
 
A lack of adherence among pediatricians and residents was highlighted by Hoffman et al. Only 11% achieved 
the highest level of adherence to the PPA Guidelines.30 Similarly, a survey of 53 residents found that while most 
reported familiarity with current guidelines for introduction of peanut-containing foods to infants, only 28% 
correctly identified the recommended age for introduction.31 Nearly 75% chose answers that represented the 
currently-abandoned 2000 AAP guidelines; 83% reported that they often apply these outdated guidelines in 
practice. These data show that the PPA Guidelines are not being followed, even among young physicians who 
are currently under training. 
 
There is also evidence that caregivers may be still unwilling to introduce allergenic foods during infancy. Data 
from a 2017 sample of caregivers revealed low willingness and questionable support for early allergenic solid 
food recommendations. Only 31% expressed willingness to introduce peanut before or around six months of 
age; 40% expressed willingness to introduce peanut after 11 months.32 This reluctance from caregivers suggests 
that most are unlikely to spontaneously introduce peanut during the critical period identified by the PPA 
Guidelines. 
 
To understand key barriers to guideline adherence, an influential review by Cabana et al. (1999) demonstrated 
that non-adherence is rooted in lack of awareness, knowledge, and attitudes towards guideline content.33 A 
review affirming Cabana’s findings highlighted electronic Clinical Decision Support (CDS) tools as an effective 
strategy to improve guideline-consistent care by incorporating them into physicians’ clinical workflow.34 
1.2. Rationale for Selection of Investigational Product or Intervention 
The iREACH intervention is designed to address the following identified barriers in the implementation of the 
PPA Guidelines: Poor understanding of the PPA Guidelines and their application, lack of time in clinical 
encounters, and caregiver concerns about allergic reactions. 
 
Improving Clinical Guideline Adherence through CDS-based Interventions: Adherence to the PPA 
Guidelines involves new clinical responsibilities for pediatricians in all primary care encounters with 4- and 6- 
month-old infants. While data show that CDS-based interventions can improve guideline adherence across 
diverse settings,37 such interventions are particularly important in the pediatric setting where a growing number 
of recommendations compete for clinicians’ time and attention.38 
As part of national efforts to support efficient and effective use of health information technology to improve 
health care outcomes, the Agency for Healthcare Research and Quality endorses the “CDS Five Rights” 
approach. This approach asserts that CDS-supported health care improvement can be achieved via CDS 
interventions that communicate: 
• The right information: evidence-based, suitable to guide action, pertinent to the circumstance 
• To the right person: considering all stakeholders, including clinicians, patients, and caregivers 

 
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• In the right intervention format: such as a best-practice alert or order set 
• Through the right channel: for example, a clinical information system such as an EHR 
• At the right time in the workflow: for example, at time of clinical decision/action/need 
 
In the context of the AHRQ-endorsed Five Rights approach, iREACH was developed through strategic 
engagement of pediatric clinicians, allergists, caregivers, and information technology experts working to ensure 
that iREACH provides:  
 
The right information: Leveraging data from the landmark LEAP trial21 and other research reviewed by the 
expert panel responsible for the PPA Guidelines, the iREACH CDS will provide pediatric clinicians with a 
decision aid and resources to support PPA Guideline-adherent patient care.  
To the right person: The iREACH CDS will directly engage pediatric clinicians explicitly targeted by the PPA 
Guidelines.  
In the right CDS format: The iREACH CDS will employ best practice alerts, which encourage pediatric 
clinicians to provide guideline-consistent care during the clinical encounter.  
Through the right channel: The iREACH CDS will be delivered through the EHR, integrating its functions into 
charting systems already utilized by physicians.  
At the right time in workflow: The iREACH CDS will prompt clinicians to offer PPA Guideline-consistent care 
at the appropriate moment in the patient encounter in a manner that is minimally disruptive to existing 
workflows. 
To our knowledge, no CDS tools currently exist to support decision-making related to peanut introduction 
recommendations for infants. The iREACH tool that we will apply in this trial has the advantage of being 
integrated into existing EHR workflow templates for the 4-, 6-, and 9-month WCCs that are recommended by 
the American Academy of Pediatrics and almost universally well-utilized by US pediatric clinicians. 
Assessing Adherence Among Caregivers 
The pediatric clinician’s adherence to the PPA guidelines and subsequent recommendation to caregivers will 
influence the caregiver’s decision to introduce peanut products early to their infant. Exploratory analyses will be 
conducted to measure caregivers’ adherence ot the guidelines which will be assessed in the form of a survey. 
1.3. Preclinical Experience 
Not applicable 
1.4. Clinical Studies 
A pilot study of iREACH was conducted in a pediatric network at Ann and Robert H. Lurie Children’s Hospital 
of Chicago to assess the utility and effectiveness of the clinical education module and CDS tool components of 
the intervention. Pediatric clinicians in one practice received both components (clinical education and CDS 
tool), and infants in this iREACH practice were compared with infants in a second Lurie Children’s practice 
that did not have the intervention. The study population included all infants seen for a 4- or 6-month routine 
WCC during the study period. Results were obtained through EHR data extraction and chart review. We 
analyzed the proportion of infants whose pediatric clinicians adhered to the PPA Guidelines—characterized by 
appropriately recommending peanut introduction or completing sIgE testing or allergy referral.   

 
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From 06/2017-03/2018, 463 infants were seen 
for 4- or 6-month WCC visits. We found that far 
more pediatric clinicians in the iREACH clinic 
adhered to PPA Guidelines than did infants in a 
comparison clinic without iREACH, supporting 
the efficacy of the education module and CDS 
tool (p<0.001, low-risk infants). Additionally, 
over 90% of pediatric clinicians in the iREACH 
clinic partially adhered to the PPA Guidelines 
by distributing handouts to caregivers on how to introduce peanut products. 
This pilot also included a survey of pediatric clinicians using the iREACH CDS tool to assess acceptability. 
Electronic surveys were sent to all 37 enrolled pediatric clinicians and 86% responded. Pediatric clinicians who 
saw low-risk children cited multiple positive aspects of the CDS tools. The majority (72%) noted the prompts 
were easy to use, and 86% felt the caregiver handout on solid food and peanut product introduction was easy to 
use. Respondents also noted that the caregiver handout helped them counsel families. Time spent using the tools 
varied, but the most common response (30%) was that iREACH neither saved nor added time. In summary, data 
from pediatric clinicians using a pilot version of the iREACH CDS supported its feasibility and acceptability. 
2. Study Hypotheses/Objectives 
2.1. Hypotheses 
Primary:  
High-risk infants (those with severe eczema and/or egg allergy) and low-risk infants (those with mild to 
moderate eczema and no egg allergy as well as those with no eczema or any food allergy) in the iREACH 
intervention arm will have higher rates of pediatric clinician adherence to PPA Guidelines compared to the 
respective infants in the non-intervention arm. 
Secondary: 
High-risk and low-risk infants in the iREACH intervention arm will have a lower incidence of peanut allergy by 
age 2.5 years compared to the respective infants in the non-intervention arm. 
2.2. Primary Objective 
To determine the effectiveness of iREACH in increasing adherence to the PPA Guidelines among pediatric 
clinicians. 
2.3. Secondary Objective 
To determine the effectiveness of iREACH in decreasing the incidence of peanut allergy by age 2.5. 
2.4. Exploratory Objectives 
a. To determine allergists’ adherence to the PPA Guidelines 
b. To identify common barriers/facilitators for PPA Guideline adherence among pediatric clinicians and 
caregivers 
c. To determine caregiver adherence to the PPA Guidelines 
 
 
 
iREACH Clinic 
Non-iREACH Clinic 
 
#adherent/total (%) 
# adherent/total (%) 
Low-risk Infants 
Adherent to 
guidelines 
75/143 (52.4) 
44/311 (14.1) 
High-risk 
Infants Adherent 
to guidelines 
5/8 (62.5) 
0/1 (0.0) 

 
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3. Study Design 
3.1. Study Populations 
This study involves three study populations: 1) pediatric clinicians, 2) infants seen for a 4- and/or 6-
month WCC by the pediatric clinicians, 3) caregivers of these infants. 
3.2. Description of Study Design  
This study is a two-arm, cluster-randomized, controlled clinical trial. A minimum of 30 pediatric practice sites 
will be randomized to the iREACH intervention arm or to the control arm (Figure 3). All pediatric clinicians 
within each participating practice (n≈200 total) will be assigned to the arm to which their practice is 
randomized. Pediatric clinicians in the intervention arm will 1) receive the iREACH education module, 2) have 
the iREACH CDS tool integrated into the EHR templates for use at the 4-, 6-, 9-, 12-month WCC, and 3) will 
be reminded by EHR-embedded prompts at the 9-month WCC to ask caregivers whether peanuts were 
introduced and tolerated.  
No study procedures will be implemented in the non-intervention, control practices, and their pediatric 
clinicians will not receive extra PPA Guidelines education, nor will any EHR modifications be made in their 
practices to support adherence to PPA guidelines. The trial will be conducted over an 18-month period. During 
this time, approximately 500 high-risk infants and 10,000 low-risk infants are expected to be seen for 4- and 6-
month WCC. The primary outcome, pediatric clinician adherence to the PPA Guidelines, will be assessed using 
EHR data for each infant following the 6-month WCC.  
Data for the secondary outcome will be obtained by a combination of EHR data extracted after the infant’s 6-
month WCC and data collected from caregivers. EHR data extraction will be performed to obtain data from the 
infant’s 9-, 12-, 15-, 18-, 24-month WCC and any sick visits and allergist progress notes entered from 4-30 
months of age. Caregivers’ data will be collected via surveys of caregivers of children seen for 4- or 6-month 
WCC visits during the study period. Caregivers will be recruited and asked to provide informed consent at the 
time of the child’s first birthday and questions will be asked to determine the incidence of peanut allergy. A 
follow-up survey will be sent to caregivers after the child’s second birthday. 
Data for exploratory outcomes will be obtained through EHR data extraction and surveys of pediatric clinicians 
and the caregivers of infants seen for 4- or 6-month WCC. Pediatric clinicians in the intervention arm will be 
asked to provide informed consent and will complete three surveys over approximately 21 months. Pediatric 
clinicians in the control arm will be asked to provide informed consent following completion of data collection 
for the primary outcome and will complete one survey. Finally, caregivers, through the two surveys conducted 
at the time of their child’s first and second birthdays, will provide information for exploratory outcomes.      
Figure 3. iREACH Study Design 
   
 

 
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3.3. Primary Endpoint(s) 
The primary endpoint is the percentage of infants within each trial arm whose pediatric clinician adhered to the 
guidelines regarding peanut introduction assessed after completetion of either a 4- or 6-month WCC. The 
primary endpoint concerns only the peanut introduction recommendation by the treating pediatric clinician and 
not additional behavior by the treating allergist or by caregivers. The primary endpoint will be measured 
separately by risk category as follows: 
• % of infants at low risk for peanut allergy whose pediatric clinician adhered to the guidelines for that 
infant. 
• % of infants at high risk for peanut allergy whose pediatric clinician adhered to the guidelines for 
that infant. 
Adherence will be determined as follows: Infants will be stratified into high- versus low-risk categories based 
on the presence of severe eczema and/or egg allergy. Egg allergy and eczema diagnoses will be obtained from 
the “problem list” and “encounter diagnosis” sections of the EHR. Severe eczema will be further identified by 
the presence of prescriptions for topical corticosteroids, calcineurin inhibitors or other anti-inflammatory 
agents and/or clinician documented eczema classification (i.e., use of word “severe” and lack of words “mild 
or moderate”) found in the encounter notes through natural language processing (NLP). 
For high-risk infants, pediatric clinician adherence will be determined as indicated in Figure 4 by: 
1. Actions taken by the pediatric clinician (peanut sIgE testing, referral to an allergy specialist, or 
neither).  The information on these actions will be obtained from laboratory test and referral orders 
entered into the EHR. 
2. Peanut sIgE testing results, if applicable (negative when IgE <0.35 kUA/L versus positive when IgE 
≥ 0.35 kU/L). The information on these results will be obtained from laboratory test results entered 
into the EHR. 
3. Dietary peanut introduction recommendation (recommendation to introduce or no 
recommendation). This information will be obtained from mentions of peanut introduction extracted 
from the encounter note using NLP (if sIgE ordered). If the information is absent from these 
sources, other sources will be utilized (i.e., parent- caregiver surveys and/or pediatric clinician 
surveys) to complement EHR data. 
For low-risk infants, pediatric clinician adherence will be determined based on whether a recommendation for 
dietary peanut introduction was given. This information will be obtained from pediatric clinician notes made in 
the anticipatory guideance section using NLP.  If the information is absent from these sources, other sources 
will be utilized (i.e., caregiver surveys) to complement EHR data. 
 
 
 

 
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Figure 4. Pediatric Clinician Adherence 
 
3.4. Secondary Endpoint(s) 
The secondary endpoint is the incidence of peanut allergy by age 2.5 years and is assessed through a 
combination of parent survey data and extracted EHR data. Secondary endpoints will be measured separately by 
risk category as follows: 
• % of infants at low risk for peanut allergy who developed peanut allergy by age 2.5. 
• % of infants at high risk for peanut allergy who developed peanut allergy by age 2.5. 
Peanut allergy determination will follow a hierarchy based on the source of information (tiers).  This hierarchy 
will offer the first level of diagnostic confidence.  If the diagnosis was made by an allergist, we will consider 
this as the highest confidence for peanut allergy (Tier 1). If the diagnosis was made by a pediatric clinician, we 
will consider it as Tier 2 and if it was only based on information from a caregiver (through the surveys that we 
will conduct at when the child is age 12 and 24 months), Tier 3. 
 
Within each tier, there are diagnostic categories that reflect a decision algorithm based on tier-specific data.  
The diagnostic categories are as follows:  
• Confirmed Diagnosis 
• Convincing Diagnosis 
• Questionable Diagnosis 
• No Peanut Allergy (PA) 
 
 
 
 

 
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This double system approach (tiers and diagnostic categories) will offer substantial transparency for diagnosis 
and will allow us to evaluate whether the impact of our intervention can be evidenced at a particular level of 
diagnostic certainty.  The details of the algorithm can be found in the Manual of Procedures.   
3.5. Exploratory Endpoint(s) 
Allergist Adherence to the PPA Guidelines (Figure 5). Allergist adherence will be assessed once progress 
notes by the allergist to whom the infant was referred to have been added to the patient EHR and will be 
determined based on the following four data elements:  
1) Skin Prick Test result (0-2 mm, 3-7mm, ≥8 mm), 2) peanut sIgE results, 3) results of in-office supervised 
feeding of peanut products or oral food challenge with peanut products and 4) peanut product 
introduction/feeding recommendation. These data will be extracted from laboratory test results, if available, 
and the allergist progress note entered into the patient EHR. If any data elements are missing, however, the 
allergist adherence will be adjudicated by an expert panel of allergists from the study advisory board. 
Figure 5. Allergist Adherence 
*We assume that allergists will evaluate any child who is referred to them. 
Barriers/facilitators for PPA Guideline adherence among pediatric clinicians and caregivers. Barriers and 
facilitators will be assessed through survey of pediatric clinicians and caregivers. 
Caregiver adherence (peanut product introduction and feeding frequency) (Figure 6). Caregiver adherence is 
conceptualized to be independent of the clinician’s adherence.  All pathways to adherence (whether full 
adherence, meaning the clinican and the caregiver adhere, or caregiver adherence despite conflict with 
clinician recommendation) are described in Figure 6.  Caregiver adherence to the PPA Guidelines will be 
assessed through the caregiver survey completed around the child’s first and second birthdays, as well as 
through the child’s EHR records.   
Caregiver adherence will be determined based on the following five data elements: 1) infant risk category 
(high- vs. low-risk based on the presence of an egg allergy and/or severe eczema), 2) peanut sIgE testing 
results, if applicable (negative vs. positive); 3) peanut skin prick test results (if applicable), 4) peanut product 
introduction (introduced or did not introduce), and 5) peanut product feeding frequency and quantity 
(feedings per week). These data will be obtained from the caregiver survey (which will assess the timing, 
amount, frequency, and modes of peanut product consumption by the infant) and from the infant’s EHR 
records (risk category, testing recommended, and testing results).  

 
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For low-risk infants, the caregiver is adherent if the caregiver introduces peanut by 12 months of age. For 
high-risk infants, the caregiver is adherent if the clinician’stesting indicates  the introduction of peanut and 
the caregiver introduced peanut products by 7 months of age and continued feeding at least 6g over ≥ 3 
feedings per week as reported around the infant’s 1st birthday or the clinician’s testing indicates avoidance of 
peanut and the caregiver does not introduce peanut products as reported around the infant’s 1st birthday. For 
high-risk infants, the caregiver  is partially adherent if the pediatric clinician and/or allergist’s testing 
supports the introduction of peanut, and the caregiver introduces peanut products but does not do so by 6 
months of age or does not continue feedings with at least 6 gm of peanut protein or over ≥ 3 feedings per 
week as reported around the infant’s 1st birthday.  
Figure 6. Caregiver Adherence  
 

 
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3.6. Stratification, Randomization, and Blinding/Masking 
Randomization will be accomplished through a password-protected, web-based, randomized system 
maintained by the Statistical and Data Coordinating Center. Practices will be randomized to intervention 
using a random number generator. Randomization will be stratified by size of the practice site, so that large 
volume practices are randomized to intervention separately from practices with fewer annual patients. 
Neither the control arm practice sites nor intervention sites will be blinded to their trial arm status. 
3.6.1. Procedure for Unblinding/Unmasking 
Not applicable. 
4. Selection of Participants and Clinical Sites/Laboratories 
4.1. Rationale for Study Population 
• Primary care pediatric clinicians are the clinicians to whom the PPA Guidelines are primarily 
directed and who see the majority of infants during the time frame that peanut product introduction 
is recommended for high-risk infants (4-6 months).  
• All infants, regardless of peanut allergy risk, are subject to the NIAID-sponsored PPA Guidelines.  
Infants seen by primary care pediatric clinicians working in study-participanting clinics will have 
their EHR data extracted to determine whether pediatric clinicians in the intervention arm adhered to 
the PPA Guidelines moreso than those in the non-intervention arm and to measure incidence of 

 
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peanut allergy. 
• Caregivers are the final and most important conduits for PPA Guidelines implementation. Therefore, 
caregivers of infants seen at all participating practices at a 4- and/or 6-month WCC during the 
designated study period will be surveyed when their infants are 12 and 24 months in order to 
determine PPA Guidelines adherence regardless what their pediatric clinician’s and/or allergist’s 
recommendation was. In addition, caregivers will be surveyed for the presence of peanut allergy in 
their infant.  
• Particularly for high-risk infants, allergists to whom the pediatric clinicians of the study refer infants 
for early dietary peanut product introduction are important for Guidelines implementation.  
Therefore, in order to assess adherence to the portion of the PPA Guidelines directed towards 
allergists, the study will review the specific management approach these allergists will use. It is 
anticipated that a given allergist will see patients referred by pediatric clinicians from both study 
arms. 
 
4.2. Inclusion Criteria 
For each of the following entities/individuals, all criteria need to be met for participation in the study:  
a) Practice sites: 
a. The practice utilizes a centrally-integrated EHR. 
b. The practice has signed a legally-binding engagement agreement with Lurie Children’s Pediatric 
Practice Research Group. 
c. The practice employs at least one physician who has completed a residency in general pediatrics 
and is practicing as a general pediatrician. 
b) Pediatric Clinicians: 
a. Clinician is a physician, physician assistant, resident, advanced practice nurse, family 
practitioner, or pediatric nurse practitioner working in a pediatric practice. 
b. Clinician is employed by a practice that is a member of one of the participating practices in the 
study. 
c. Clinician provides well child care to infants ages 4 or 6 months.   
c) Infants: 
a. Infant has been seen by a pediatric clinician in the intervention or control arm for a 4- and/or 6-
month WCC. (Note: Because infants will be followed through EHR data extraction, inclusion of 
an infant’s data in the study will not require caregiver consent.) 
d) Caregivers: 
a. Is the caregiver of an infant seen for a 4- and/or 6-month WCC by a pediatric clinician in a practice 
belonging to the study’s intervention or control arms. 
b. Is at least 18 years of age or has parent or guardian permission to participate. 
c. Is able to understand the study and provide informed consent for the 12- and 24-month (child’s age) 
survey. 
 
4.3. Exclusion Criteria 

 
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For each of the following entities/individuals, if any of the following criteria are met, they will be excluded 
from participation in the study:  
a) Practice Site: 
a. 
The site sees <50 newborn patients/year. 
b. The site has only temporary pediatricians on staff (e.g., resident physicians). 
c. 
The practice prediatric clinicians do not use an EHR system. 
b) Pediatric Clinicians: 
a. 
The clinician is a temporary employee. 
b. The clinician begins employment at participating practice less than three months prior to end of the 18-
month study enrollment period. 
c) Infants: 
a. 
The infant has a medical condition that chronically inhibits the ability to take food orally (i.e., 
dysphagia, muscular dystrophy, gastrostomy). 
b. The infant has past or current medical problems or findings that prohibit implementation of 
PPA Guidelines or may have impacted the quality or interpretation of the data obtained from 
the study. This will be identified from the caregiver survey and a post-hoc review of EHR 
data. . 
d) Caregivers:  
a. Caregiver’s primary language is not English or Spanish. 
i) The study is presently limited to participants fluent in English and/or Spanish because 
practice sites have not indicated a significant patient population with additional language 
needs. If a need is identified, the study team will allocate resources to develop appropriate 
materials and obtain any needed staff for translation(s).  
 
4.4. Selection of Clinical Sites/Labs  
Thirty-seven practices that are members of the Pediatric Practice Research Group (PPRG), a pediatric 
practice-based research network at the Ann and Robert H. Lurie Children’s Hospital of Chicago (Lurie 
Children’s Hospital) may participate in the study. In order to account for possible attrition prior to the start of 
the study, the study has been designed (see Section 13.7) for at least 30 randomized practice sites providing 
adequate statistical power to test the primary hypothesis. The PPRG will ensure that all engagement 
agreements with practice networks or practices are completed for the participating sites. The practices are part 
of networks that utilize a centrally-integrated EHR system. Practice networks include but are not limited to: 
1. 
Lurie Children’s Hospital of Chicago's multi-site primary care practice (Town & Country) 
and Community Connect Health Exchange network. These practices share the outpatient 
version of Lurie Children’s Hospital Epic EHR. 
2. 
AllianceChicago, a network of community health centers that share Centricity EHRs. 
3. 
OSF HealthCare in Peoria, IL is a network of practices that share an Epic EHR system.   
4. 
Unity Point Health in Peoria, IL is a network that has a history of participating in practice based 

 
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research with OSF HealthCare. The practices share an Epic EHR system. 
 
5. Known and Potential Risks and Benefits to Participants 
5.1. Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert 
Not Applicable 
5.2. Risks of Investigational Product or Intervention cited in Medical Literature 
Not Applicable 
5.3. Risks of Other Protocol Specified Medications 
Not Applicable 
5.4. Risks of Study Procedures  
1. Pediatric clinicians: There are no risks to pediatric clinicians due to any procedure in this trial. 
2. Infants/caregivers: There is a risk of breach of confidentiality. There are no additional risks to 
infants due to any procedure in this trial compared to not participating in the study (all clinical 
procedures outlined in the PPA Guidelines are considered standard of care and the infants are 
not subject to any of those procedures as a result of study participation). 
5.5. Potential Benefits 
1. The iREACH intervention may improve the clinical decision making process of pediatric 
clinicians around peanut allergy risk assessment and counseling of caregivers and may lead to 
increased implementation of guidelines-based peanut product introduction. 
2. If the intervention improves adherence to the PPA Guidelines, the following benefits may be seen: 
a. Improved identification of infants at risk for peanut allergy by pediatric clinicians. 
b. Prevention of unnecessary referrals to allergy specialists for infants at low-risk for peanut 
allergy. 
c. Reduction in allergic reactions to peanut introduction in the home setting through 
improved identification of infants at risk for allergic reactions. 
d. Improved confidence of caregivers regarding peanut introduction for prevention of peanut 
allergy. 
e. Reduction in the incidence of peanut allergy in children. 
 
6. Investigational Agent /Device/Intervention  
6.1. Investigational Agents/Devices/Interventions 
6.1.1. Investigational Intervention: Intervention to Reduce Early (Peanut) Allergy in Children 
(iREACH) 
The iREACH intervention consists of A) an education module about the PPA Guidelines and the 
research on which the guidelines were based; B) an EHR-integrated CDS tool in the 4- and 6-month 
WCC templates to support pediatric clinician decision-making around 1) proper triage of infants into 
peanut allergy risk categories, 2) allergy testing and interpretation and/or allergist referral for high-risk 
infants, and 3) caregivers counseling on peanut introduction including educational materials for families 

 
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and a minor addition to the anticipatory guidance section of the note template to facilitate documentation 
of PPA Guidelines discussion; and C) follow-up prompts in the 9- and 12-month WCC templates 
guiding pediatric clinicians to ask caregivers about inclusion of peanut products in their child’s diet. The 
components of the intervention are detailed below: 
A. Education Module: Text- and video-based educational materials covering the PPA Guidelines, the 
research on which the guidelines were based, and instructions for using the iREACH CDS tool will be 
delivered as an online module. Pre-and post-test knowledge surveys will be embedded into the module 
and permits monitoring of provider compliance with the assigned training. Key study personnel will be 
available via email, phone, or in-person to answer any questions that arise after completion of the 
educational module posttests. 
B. CDS Tool:  A multi-component tool within the EHR that includes the following: 
a. A Best Practice Advisory (BPA) will be triggered at 4- and 6-month well child visits to remind 
pediatric clinicians to evaluate child for peanut product introduction.  
 
b. A Smart List within note template to remind pediatric clinicians to assess the infant for 
conditions that would classify the infant as high-risk for PA (i.e., egg allergy or severe 
eczema). 
 
c. A Smart Set (order set) to guide the pediatric clinician in choosing peanut sIgE or allergist referral 
based upon PA risk status. The pediatric clinician selects orders based upon their assessment of 
PA risk. This Smart Set includes the option to print out a caregiver educational handout to assist 
with caregiver counseling on peanut product introduction. 
 
d. A BPA triggered when the pediatric clinician views peanut sIgE results (for those patients for 
whom sIgE has been ordered. The BPA will provide the criteria for “positive” results (≥0.35 
kU/L) and a recommendation to refer to an allergy specialist if results are positive. 
 
Caregiver Handout on How to Introduce Peanut Containing Products: Handout adapted from the 
NIAID caregiver materials (English and Spanish versions). The handouts were simplified and tested with 
caregiver groups including low-literacy, underserved families. This handout can be used as part of 
pediatric clinician counseling and can go home with caregivers as a reminder.  
 
C. Follow-up Prompts at 9- and 12-month WCC: Smart Texts and Data Elements that advise the 
pediatric clinician to ask caregivers and chart whether peanut products have been introduced into their 
infant’s diet. If the caregiver reports that peanut products were introduced, the clinician will be directed to 
document whether introduction was tolerated. If caregiver reports that peanut products were not 
introduced, the clinician will be directed to ask the caregiver for reasons why they did not.  
Note: For those practices that do not use an Epic-based EHR, Lurie Children’s study team will facilitate 
and work with their informatics teams to implement an iteration of the CDS tool that is compatible with 
the practice EHR. 
 
6.1.1.1. Formulation, Packaging, and Labeling 
Not Applicable 
6.1.1.2. Dosage, Preparation, and Administration 

 
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Not Applicable 
6.1.2. Control Arm 
Pediatric clinicians in practices that will be randomized to the control arm will provide standard care. 
 
Following the completion of data collection for the primary outcome, practice sites in the control arm 
will be offered the iREACH intervention. This will not affect the outcome of any of the primary, 
secondary, or exploratory analyses. 
6.1.2.1.Formulation, Packaging, and Labeling 
Not Applicable 
6.1.2.2.Dosage, Preparation, and Administration 
Not Applicable 
6.2. Drug Accountability 
Not Applicable 
6.3. Assessment of Participant Compliance with Investigational Agent 
Not Applicable 
6.4. Toxicity Prevention and Management 
Not Applicable 
6.5. Premature Discontinuation of Investigational Agent 
Not Applicable 
7. Other Medications 
7.1. Concomitant Medications 
7.1.1. Protocol-mandated 
Not Applicable 
7.1.2.  Other permitted concomitant medications 
Not Applicable 
7.2. Prophylactic Medications 
Not Applicable 
7.3. Prohibited Medications 
Not Applicable 
7.4. Rescue Medications  
Not Applicable 
8. Study Procedures 
8.1. Enrollment/Screening 
Screening and enrollment of practice sites, pediatric clinicians, infants, and caregivers will largely take place by 
collecting data from practice managers or via the EHR pull. Pediatric clinicians and caregivers will provide 
consent prior to completing any surveys. We have received a waiver of informed consent and written signed 

 
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consent for the pediatric clinicians to complete surveys. We have also receieved a waiver of informed consent 
and signed consent for caregivers to complete surveys. However, for those caregivers that give permission to 
link their survey responses with their child’s medical records, written signed consent will be obtained.  
1. Practice sites will have completed legally-binding engagement agreements with Lurie Children’s 
PPRG prior to study activation. These agreements will describe how EHR data will be accessed, 
copied, used, and transmitted for research. Once agreements are signed, practices will sign a study-
specific Memorandum of Agreement (MOA), which summarizes study procedures and 
expectations. In addition to the MOA, practices will complete a practice characteristic questionnaire 
that will document that practice inclusion and exclusion criteria are met.   
2. Pediatric clinicians within participating practices will be engaged in the study via practice managers 
and/or study practice champions once engagement agreements are executed and the Memorandum 
of Agreements are signed by practice representatives. Practice champions will complete a CRF 
form ensuring each clinician within participating practice fulfills inclusion/exclusion criteria. The 
study will be activated and practices are assigned to the respective randomization arms. Prior to 
survey administration, pediatric clinicians will provide informed consent.  
3. Caregivers will have signed a Notice of Privacy agreement (a HIPAA directed agreement) in the 
practice for which their child is a patient. This document describes how that practice will access, 
copy, use, and transmit PHI for research purposes. Aroundthe infant’s first birthday, the study team 
will recruit caregivers of all children seen for 4- and/or 6- month WCC (caregivers and infants need 
to fulfill study inclusion/exclusion criteria) to take the caregiver survey. Caregiver survey will 
include consent for both 12- and 24-month questionnaires. Procedures for caregiver recruitment will 
vary across practices and fall into two broad categories: in-person recruitment or remote 
recruitment, based on practice preferences and policy.   
Around the child’s first birthday,,  an opt-out letter on practice letterhead will be sent to each 
caregiver whose child was seen at the 4- and/or 6-month WCC. This letter will provide the 
caregiver an opportunity to opt-out of being contacted for participation in the iREACH study. For 
those caregivers who do not opt-out, the method for follow-up contact will vary and be based on 
preference of the practice.  
In-person recruitment:  This method will use study staff members to recruit caregivers on-site in 
the pediatric clinics. In coordination with clinic staff, the study staff will approach caregivers 
arriving for 12-month WCC appointments, collect informed consent, and provide access to the 
electronic survey instrument. 
Remote recruitment:   
• If the practices agree to sharing eligible caregiver contact information with the study team, 
the study team will email, text, and/or call to recruit caregivers. Caregivers have the option 
to complete the consent, screening questionnaire, and survey online or over the phone. 
Consent will be obtained and recorded in REDCap prior to administration of surveys.  
• For those practices who do not wish to share caregiver contact details, the practices will 
have a practice representative email and/or call caregivers. Consent will be obtained and 
recorded in REDCap prior to administration of surveys. 
4. Infants seen for a 4- and/or 6-month WCC and who fulfill inclusion/exclusion criteria will be 
assigned a unique participant number. The caregiver’s informed consent will include text allowing 
for the infant’s EHR data to be linked to the caregiver’s survey. Once caregivers provide informed 
consent to link their child’s EHR data to the survey, both the survey data and EHR data will be 
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link their chid’s EHR data to the survey, they can indicate this on the consent form and their survey 
responses will not be linked to their child’s EHR record.  
8.2. Study Assessments  
The assessments for this study are the collection of information through questionnaires (surveys) (Table 8.2.1) 
and the EHR (Table 8.2.2).  
8.2.1. Questionnaires/Surveys 
8.2.1.1. 
Pediatric Clinicians 
• 
Pediatric Clinician Characteristics Questionnaire 
• 
Pediatric Clinician Knowledge, Attitudes, Barriers and Facilitators to Guideline 
Implementation Questionnaire (KABF) 
8.2.1.2. 
Caregivers 
• 
Caregivers Characteristics Questionnaire (English and Spanish versions) 
• 
Caregivers Feeding, Outcomes, Attitudes, Barriers and Facilitators to Guideline 
Implementation Questionnaire (FOABF) (English and Spanish versions) 
 
Table 8.1 Data To Be Collected 
Topic 
Data  
When Collected 
Pediatric Clinician 
Characteristics 
Age, sex, years in practice, type of 
medical professional, patient 
volume 
After informed consent 
Pediatric Clinician 
Knowledge, Attitudes, 
Barriers, Facilitators to 
Guideline Implementation 
(KABF) 
Knowledge of PPA Guidelines, 
attitudes towards guidelines, barriers 
and facilitators of guideline 
implementation 
Intervention arm: 
After informed 
consent, mid-point of 
observation period  & 
after 1˚ outcome data 
collection 
Control arm: after 
1˚ outcome data 
collection 
Caregiver 
Characteristics  
Age, sex, ethnicity, education, 
income level, geographic location 
After informed 
consent 

 
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Caregiver Feeding, 
Outcomes, Attitudes, 
Barriers, Facilitators to 
Guideline 
Implementation 
(FOABF) 
Peanut introduction practices, 
attitudes towards PPA Guidelines 
and barriers/facilitators of 
guideline implementation 
After informed 
consent 
Caregiver Report of 
Child’s Adverse 
Reactions 
Any reactions to peanut, and 
infant’s allergy status 
After informed 
consent and when 
infant is around 24 
months old 
Caregiver Account of 
Clinician Peanut 
Recommendations, 
Testing and 
Introduction 
Information shared with caregiver 
by pediatric clinician regarding 
peanut introduction, allergy 
testing, and/or allergist referrals 
After informed 
consent 
Caregiver Stress, 
Quality of Life 
Perceived stress and  psychosocial 
outcomes 
After informed 
consent and/or when 
infant is around 24 
months old 
Child Food Frequency 
Questionnaire 
Detailed peanut and total diet food 
frequency questionnaire 
After informed 
consent and/or when 
infant is around 24 
months 
 
8.2.2. EHR Data Extraction 
Data collection will take place at both the practice network (e.g., Lurie Community Connect, 
Peoria area-OSF and Unity Point, Alliance Chicago) or practice level for inclusion in the EHR 
study database.  
 
Each practice will have an information technology analyst responsible for facilitating data 
extraction at the practice level. Data from participating practices’ EHRs will be extracted on a 
weekly basis through an automated process established by Lurie Children’s Data Coordinating 
Center team (DCC) and sent to DCC via a secure file transfer protocol (SFTP). Practices will be 
provided a data dictionary and natural language processing code to identify the appropriate 
elements and visits/services to extract. DCC will develop Extract Transform Load (ETL) scripts 
on behalf of the practice network (with the appropriate approvals from the practices). The ETL 

 
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scripts will be run weekly so that each week the Lurie Children’s DCC data manager will have a 
complete EHR-based data file for reporting compliance and participation metrics. The weekly file 
will also be used to identify new providers hired by the practices who may need training in the 
intervention.  
 
The EHR study database will include data from each of the following types of health care 
encounters documented in the EHR: 
1. 4-month WCC 
2. 6-month WCC 
3. 9-month WCC 
4. 12-month WCC 
5. 15-month WCC 
6. 18-month WCC 
7. 24-month WCC 
8. Additional sick visits until 30 months of age 
9. Allergy visits until 30 months of age 
10. Emergency department visits until 30 months of age 
 
Table 8.2 presents the data elements that will be collected in the EHR study database.  Partial PHI including the 
full date of birth, patient zip code, and date of service will be included. 
 
Table 8.2  EHR Data Elements  
EHR Activities 
Data Collected 
Infant 
characteristics 
Gender, race, ethnicity, date of birth, height and weight over time, patient zip code at 
4- month WCC, patient zip code at 6-month WCC, health insurance type at 4-month 
WCC, health insurance type at 6-month WCC 
Problem list 
Type of problem, date problem entered, date problem resolved 
Medications list 
Medications ordered, order date 
Primary care 
visits (well or 
sick) 
Date of service, peanut product introduction recommendation (NLP based), severe 
eczema (NLP based), eczema ICD-10 code, food allergy ICD-10 codes, date of 
allergy referral, CDS-specific fields (intervention arm only) 
Allergy visits 
Date of service, peanut product introduction recommendation (NLP based), severe 
eczema (NLP based), food allergy ICD-10 codes. 
Peanut testing 
Date of test, type of test (peanut sIgE or peanut skin prick test), test result 
Emergency 
Department visits 
Date of ED visit, food allergy or anaphylaxis ICD-10 codes 
 
8.2.3. Education 
iREACH training (intervention arm) occurs shortly after enrollment. Pediatric clinicians in the intervention 
arm will be sent a link to complete a web-based video training module covering the PPA Guidelines and use 
of the iREACH CDS tool. In-person training will be conducted by the study team as requested by the 

 
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practice. 
8.3. Timeline for Study Activities  
Study activities will begin with practice randomization and continue for 18 months of observation. 
 
During the 18-month observation period, all infants that will be seen by pediatric clinicians in participant 
practices for at least one 4- or 6-month WCC will be considered eligible for EHR data extraction, as long as 
they (and their caregivers) fulfill inclusion/exclusion criteria. During this period, EHR data will be extracted as 
described above (Table 8.2). Additional study activities related to the pediatric clinicians that will take place 
during the same period are described in Table 8.5.1. 
 
For each study infant, information will be obtained through EHR until age 30 months. In addition, activities 
related to the infant caregivers will take place at 11, 12 and 24 months of the infant’s age, as described in Table 
8.5.2.      
 
Table  8.5.1. Schedule of Activities-Practice Sites, Pediatric Clinicians 
18-Month Study 
Observation Period 
Beginning Middle 
End 
PRACTICES 
Randomization of Practice Sites  
X 
INTERVENTION ARM PEDIATRIC CLINICIANS 
Pediatric Clinician Informed Consent 
X 
 
Pediatric Clinician Characteristics Questionnaire 
X 
 
Pediatric Clinician Knowledge Attitudes Barriers Facilitators Survey #1 
X 
 
Pediatric Clinician Knowledge Attitudes Barriers Facilitators Survey #2 
X 
 
Pediatric Clinician Knowledge Attitudes Barriers Facilitators Survey #3 
X 
CONTROL ARM PEDIATRIC CLINICIANS 
Obtain Pediatric Clinician Informed Consent 
X 
Pediatric Clinician Characteristics Questionnaire 
X 
Pediatric Clinician Knowledge Attitudes Barriers Facilitators Survey 
X 
 
Table 8.5.2. Schedule of Activities-Caregivers 
Age of Infant 
Around12-
months 
Around 
24-months 
CAREGIVERS 
Caregiver Opt-out Letter (if needed based on recruitment method) 
 
X 
 
Caregiver Informed Consent and Consent to Link Survey with 
 
X 
X 
Caregiver Characteristics Questionnaire 
 
X 
X 
Caregiver Feeding, Outcomes Attitudes, Barriers, Facilitators 
 
X 
X 
Caregiver Account of Clinician Peanut Recommendations, Testing 
and Introduction Survey 
 
X 
 
Caregiver Stress, Quality of Life 
 
X 
X 

 
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Infant Food Frequency Questionnaire 
 
X 
X 
9. Mechanistic Assays 
Not Applicable 
10. Biospecimen Storage 
Not Applicable 
11. Criteria for Participant and Study Completion and Premature Study Termination 
11.1. Participant Completion 
Practice Sites: A practice site will be considered as having completed the study after the caregiver of the 
last infant that was observed though EHR during the 18-month practice observation period has been 
contacted before that infant reaches 12 months of age.  
Pediatric Clinicians: A pediatric clinician will be considered as having completed the study after having 
finished the last pediatric clinician survey, at the end of the study’s 18-month practice observation period.   
Infants: An infant will be considered as having completed the study after the last observations from her/his 
EHR record at 30 months of age are extracted.  
Caregivers: A caregiver will be considered as having completed the study after participating in the study 
questionnaire and survey, when the child is 24 months of age.  
11.2. Participant Stopping Rules and Withdrawal Criteria 
Practice Sites:  
1. A practice site may elect to withdraw from current or future study activities. 
2. The investigator, with the NIAID medical monitor’s approval, can terminate a practice site if it fails to 
fulfill its obligations in accordance to the iREACH protocol. 
Pediatric Clinicians: 
1. A pediatric clinician may withdraw consent from participating in surveys. 
2. When pediatric clinician leaves the practice for any reason they will be withdrawn from the study. 
3. The investigator, with the NIAID medical monitor’s approval, can terminate a pediatric clinician from 
participating in study activities if the investigator believes that further participation compromises the 
integrity of the study.  
Infants: 
1. Because infant data are obtained through the EHR and are only observational, no stopping rules nor 
withdrawal criteria apply. 
Caregivers: 
1. A caregiver may elect to withdraw consent from all future study activities; in such case, the caregiver 
will not be contacted by study staff for any future surveys or questionnaires. 

 
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2. A caregiver is “lost to follow-up” and assumed withdrawn after five attempts to reestablish contact by 
study representatives have failed.  
3. A caregiver is withdrawn if they die. 
4. The investigator may opt to withdraw a caregiver if they believe further participation compromises the 
integrity of the study. 
5. A caregiver may elect to withdraw their “notice of privacy agreement” with the practice of which their 
child is a patient. If this occurs and the study team is notified, the child’s EHR data will be deleted from 
the EHR database.   
11.3. Participant Replacement 
Practice Sites: In the event the number of participating randomized study sites falls below the target of 30, 
additional practices will be approached and, if agree to study participation, will complete a practice 
characteristic questionnaire that will document that practice inclusion and exclusion criteria are met.  
Infants or Caregivers: Not applicable. There is no target number of infants that are to be observed via EHR 
data extraction in this study.    
11.4. Follow-up after Early Study Withdrawal 
Caregivers will have no follow-up if they choose to withdraw from participating in any remaining 
study surveys and questionnaires. The data that have already been obtained from these individuals will 
remain in the iREACH study database.  
11.5.  Study Stopping Rules 
The study may be prematurely terminated for the following reasons: 
If a breach of confidentiality as it pertains to infant personal health-related information occurs, the source 
of the breach will be investigated, identified, and resolved. If the source of the breach of confidentiality 
cannot be resolved, study will be placed on hold. If this stopping rule is met, the DSMB will be asked to 
review the circumstances under which breaches occurred and provide an opinion whether the study should 
be terminated or whether specific changes will need to be made in order for the study to resume.    
If there is a change in PPA Guidelines that may affect study procedures and outcomes, the study will 
pause, and the study team will review implications and revise procedures as necessary.  
12. Safety Monitoring and Reporting 
12.1 Overview 
 
This is an educational intervention trial with the subjects of the intervention being pediatric clinicians. The 
objective of the intervention is to improve the implementation of the PPA Guidelines, which are now 
considered standard of care in the USA.  As such, no adverse events (AEs) in the pediatric clinicians are 
expected or will be recorded. 
It is possible that, as a result of implementing the standard of care PPA Guidelines, some infants under the care 
of the study’s pediatric clinicians may experience reactions to the introduction and/or later use of peanut-
containing food. These reactions will not be recorded as AEs because a) such reactions may or may not be 
captured by the clinician in the EHR and the study has no control over this factor, b) since the study team is 
blinded as to the identity of the child that may experience such a reaction, study staff has no means of 

 
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contacting the child’s caregiver and obtaining any information about the reaction to allow appropriate grading, 
attribution and follow-up.  
When the child reaches 12 months of age, and if the caregiver consents to participation in the survey, 
information on whether peanut-containing food was tolerated after early introduction and whether any allergic 
reactions occurred will be obtained by the study staff through a) the caregiver survey and b) linking the child’s 
information extracted from the EHR to the caregiver’survey. At that stage of the study, immediate reactions to 
early introduction of peanut-containing foods or later reactions, after peanut-containing foods have been 
introduced into the child’s diet, will be captured as a study outcome, but not as AEs, and reported as such to 
NIAID and to the Institutional Review Board (IRB) and the Data Monitoring Safety Board (DSMB) with 
routine reporting, in accordance with applicable regulations. 
12.2 Definitions 
12.2.1 Adverse Event (AE) 
Not applicable to this study. 
12.2.1.1 Suspected Adverse Reaction (SAR)  
Not applicable. 
12.2.2 Unexpected Adverse Event  
Not applicable.   
12.2.3 Serious Adverse Event (SAE) 
Not applicable. 
12.3 Grading and Attribution of Adverse Events 
12.3.1 Grading Criteria 
Not applicable. 
Table 12.3.1. Grading of Adverse Events Related to Exposure to Peanut-Containing Foods 
Not applicable. 
12.3.2 Attribution Definitions 
Not applicable. 
Table 12.3.2 Attribution of Adverse Events 
Not applicable. 
12.4 Collection and Recording of Adverse Events 
12.4.1 Collection Period 
Not applicable. 
12.4.2 Collecting Adverse Events 
Not applicable 
12.4.3 Recording Adverse Events 
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12.5 Reporting of Serious Adverse Events and Adverse Events 
12.5.1 Reporting of Serious Adverse Events to Sponsor ([DAIT/NIAID or other Sponsor, if 
applicable]) 
Not applicable. 
12.5.2 Reporting to Health Authority 
Not applicable: This study, which does not involve an investigational product or device, is not regulated 
by a Health Authority. 
12.5.2.1 Annual Reporting 
Not applicable. 
12.5.2.2 Expedited Safety Reporting  
Not applicable. 
12.5.3 Reporting of Adverse Events to IRBs/IECs 
Not applicable. 
12.6  Pregnancy Reporting 
Not applicable. 
12.7 Reporting of Other Safety Information 
The study Principal Investigator shall promptly notify the SACCC, DAIT/NIAID, and the IRBs when an 
“unanticipated problem involving risks to subjects or others” is identified, which is not otherwise reportable as 
an adverse event. The Office for Human Research Protections considers unanticipated problems, in general, to 
include any incident, experience, or outcome that meets all of the following criteria: 
 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in 
the protocol-related documents, such as the IRB-approved research protocol and informed consent document; 
and (b) the characteristics of the subject population being studied; 
 
Related or possibly related to participation in the research (in this guidance document, 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); and 
 
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. 
12.8 Review of Safety Information 
12.8.1 Medical Monitor Review 
The DAIT/NIAID Medical Monitor shall receive periodic reports, at a frequency determined by 
DAIT/NIAID, from the study’s Data Center compiling new and accumulating information on 
unanticipated problems. In addition, the Medical Monitor shall review and make decisions on the 
disposition of such problems. 
12.8.2 DSMB Review 
12.8.2.1 Planned DSMB Reviews  

 
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The Data and Safety Monitoring Board (DSMB) shall review the progress of the study and any 
available safety information at least yearly during planned DSMB Data Review Meetings. Data 
for the planned safety reviews will include, at a minimum, a listing of all reported unanticipated 
problems. 
 
12.8.2.2 Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews, the DSMB may be called upon for ad hoc 
reviews. The DSMB will review any event that potentially impacts safety at the request of the 
Principal Investigator or DAIT/NIAID.  After review of the data, the DSMB will make 
recommendations regarding study conduct and/or continuation. 
 
12.8.2.2.1 Temporary Study Suspension of <enrollment/drug dosing or both> for ad hoc 
DSMB Safety Review  
If an ad hoc safety review is triggered, the DAIT/NIAID will decide whether any aspects of the 
study should be temporarily suspended before an ad hoc DSMB review. 
13. Statistical Considerations and Analytical Plan 
13.1 
Overview  
Analysis of study data will be conducted to address all study objectives and to understand other 
interrelationships among all data elements of interest to the investigators and of relevance to the 
objectives of the study. Although the study has recruited 37 practice sites prior to protocol initiation, the 
analytical plan is based on 30 practice sites as a conservative estimate due to potential attrition. 
13.2 
Endpoints  
 
Primary Endpoints:  
• % of infants at low risk for peanut allergy whose pediatric clinician adhered to the guidelines for that 
infant. 
• % of infants at high risk for peanut allergy whose pediatric clinician adhered to the guidelines for 
that infant. 
 
Secondary Endpoint:  
• % of infants at low risk for peanut allergy who developed peanut allergy by age 2.5. 
• % of infants at high risk for peanut allergy who developed peanut allergy by age 2.5. 
 
Exploratory Endpoint 1:  
• % of infants at high risk for peanut allergy whose allergist adhered to the guidelines.   
Exploratory Endpoint 2: Pediatric clinician and caregiver reported knowledge, attitudes, and barriers and 
facilitators to PPA Guideline adherence. 
 
Exploratory Endpoint 3: Each of the following endpoints include infants that are fully adherent and 
those that are adherent despite conflict with the clinician recommendation as defined in Figure 6. The 
endpoints for high risk infants can only be determined for infants where clinician testing (e.g. IgE and/or 
skin prick tests) is available in order to determine guideline consistent caregiver behavior.    
• % of infants at low risk for peanut allergy whose caregiver introduced peanut by 12 months of age.    

 
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• 
% of infants at high risk for peanut allergy whose caregiver introduces peanut products by 7  months of 
age and continues feedings with at least 6 g of peanut protein over ≥ 3 feedings per week as reported 
around the infant’s 1st birthday in accordance with the peanut allergy prevention guidelines.% of infants 
at high risk for peanut allergy whose caregiver introduces peanut products but does not do so by 7 
months of age or does not continue feedings with at least 6 g of peanut protein or over  ≥3 feedings per 
week as reported around the infant’s 1st birthday. 13.3 
Measures to Minimize Bias  
A minimum of 30 participating clinic sites will be randomized in a 1:1 ratio to the intervention arm (i.e., 
offering iREACH intervention) or standard care (i.e. without iREACH). Using a computerized random 
number generator, the randomization will be stratified by practice site size to achieve balanced 
allocation of participants into the intervention and standard care arms. This process will be performed by 
the Lurie DCC biostatistician, who is blinded to the intervention delivery and will not be aware of the 
identity of participating sites. 
13.4 
Analysis Plan 
13.4.1 Analysis Populations. 
Primary EHR data infant (PEDI) sample: All infants meeting inclusion/exclusion criteria for 
whom EHR data has been obtained at a 4-month or 6-month WCC in order to assess the primary 
endpoint of pediatric clinician adherence. Data regarding characteristics of the treating pediatric 
clinician are not required for an infant to be included in this population. 
 
Secondary EHR data infant (SEDI) samples with pediatric clinician characteristics obtained: All 
infants meeting inclusion/exclusion criteria for whom EHR data has been obtained at a 4-month 
or 6-month WCC in order to assess the primary endpoint of pediatric clinician adherence and 
whose pediatric clinician has consented and completed the characteristics questionnaire 
information. In addition to characteristics obtained through the characteristics questionnaire 
information, data on completion of pre-study training for pediatric clinicians in the intervention 
arm will also be captured.   
 
 
Exploratory EHR data infant (EEDI) samples 
• With allergist adherence obtained (EEDI1): All high-risk infants meeting eligibility 
criteria who are referred to an allergist for testing and for whom data are obtained 
regarding the testing that was conducted, the outcome of the allergist testing and the 
recommendation provided by the allergist as to early introduction of peanut-containing 
food. 
 
• With caregiver adherence obtained (EEDI2): All infants whose caregivers complete the 
FOABF and Caregiver Account of Clinician Peanut Recommendations, Testing and 
Introduction surveys at 12 and/or 24 months. 
 
Pediatric clinician sample: All pediatric clinicians within the intervention group meeting consent 
and eligibility criteria who complete baseline and at least one follow-up knowledge, attitudes, or 
barriers and facilitators survey. Those clinicians in the control group will complete one follow-up 
knowledge, attitudes, or barriers and facilitators survey.  
13.4.2 Primary Analysis of Primary Endpoint(s)   
The primary endpoint is the percentage of infants in the PEDI sample within each trial arm 
whose pediatric clinician adhered to the guidelines regarding peanut introduction. The primary 

 
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endpoint concerns peanut introduction recommendation by the treating pediatric clinician only 
and not additional behavior by the treating allergist or by caregivers. 
 
The primary endpoint will be computed using EHR data from the 4-month and 6-month WCCs 
as follows:  
For low-risk infants:  
• 
Adherence is achieved if the pediatric clinician recommends introduction of peanut 
products. 
• 
Non-adherence is achieved if the pediatric clinician fails to recommend introduction. 
 
For high-risk infants, adherence is assessed through three routes. A pediatric clinician is 
adherent if: 
• 
The pediatric clinician does not order an sIgE test and refers the infant to an allergist. 
• 
The pediatric clinician does order an sIgE test, the result is ≤0.35, and the pediatric 
clinician recommends introduction. 
• 
The pediatric clinician does order an sIgE test, the result is >0.35, and the pediatric 
clinician refers the infant to an allergist. 
 
A pediatric clinician is non-adherent if: 
• 
The pediatric clinician does not order an sIgE test and does not refer the infant to an 
allergist. 
• 
The pediatric clinician does order an sIgE test, the result is ≤0.35, and the pediatric clinician 
fails to recommend introduction. 
• 
The pediatric clinician does order an sIgE test, the result is >0.35, and the pediatric clinician 
does not refer the infant to an allergist. 
 
Analysis of the primary endpoint will be performed separately for high- and low-risk infants. 
The primary pediatric clinician (yes/no) adherence outcome will be compared between trial arms 
with generalized linear mixed models using infants as the unit of analysis using Kenward-Roger 
degrees of freedom. Fixed effect predictors will include the intervention arm and  the categorical 
measure of practice volume used as a stratification variable for randomization. To account for 
correlation of treatment procedures within practices, a random effect for practices will also be 
included resulting in a compound symmetry covariance structure for infants within a practice. 
Compound symmetry is the only appropriate choice, since repeated measures of infants within a 
practice are exchangeable and have no natural ordering. Odds ratios will be computed to describe 
the odds of adherence for the iREACH intervention compared to the control intervention.  In 
order to satisfy the ITT principle, pediatric clinician adherence will be imputed as non-adherent 
when the criteria for adherence defined earlier are not met. 
 
13.4.3 Supportive Analyses of the Primary Endpoint(s)  
Consistent with the intent-to-treat principle, infants seen by all clinicians in each participating 
practice are included in the primary analysis (PEDI sample). Recognizing that some clinicians in 
treatment arm practices might decline to participate in the pre-study training and/or decline to 
utilize the CDS tool, we will also perform sensitivity analyses to investigate any change in these 
results that would be associated with excluding infants seen by each of these categories of non-
participating clinicians: (1) declines training/uses CDS, (2) has training/declines CDS, (3) 
declines training and declines CDS. 
 

 
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The primary analysis will be repeated in the PEDI sample to evaluate the impact of missing 
data,clinician-level clustering, and type of pediatric clinician. Sensitivity analyses will be 
performed where 1) missing adherence data are not imputed and are left missing and 2) where 
missing data are imputed as being adherent. It is not possible to have missing data in the context 
of low-risk infants but is possible for high-risk infants. For high risk infants, adherence can be 
incomplete  and data  missing, if peanut-specific IgE is ordered for an infant but never 
conducted.  Sensitivity analysis with a clinician-level random effect will also be performed to 
evaluate the impact of clinician-level clustering. Finally, sensitivity analysis will be conducted to 
assess any potential differences between types of pediatric clinicians (pediatricians and advanced 
practice nurses).  
 
 
The primary analysis will be repeated in the PEDI sample combining all infants from both the 
high- and low-risk groups. Risk group and the interaction of risk group and intervention group 
will be included as fixed effects predictors. 
 
The primary analysis will be performed again using the SEDI infant sample and adjusting for 
relevant covariates from the pediatric clinician questionnaire and practice site enrollment data. 
All questions in these forms and questionnaires will be explored one at a time for possible 
inclusion as covariates. Infants will be excluded from these analyses if information was not 
collected for each particular question. 
 
Exploratory analyses will be conducted using data collected from the practice characteristics and 
clinician surveys.  Specifically, we will examine whether the primary analysis differs according 
to practice-level interest in peanut allergy or affiliation with an allergy practice.  We will also 
examine the potential influence of additional clinician education received outside of the study 
(i.e. professional conferences, research results, other teaching conduits).  
 
13.4.4 Analyses of Secondary and Other Endpoint(s) 
Analysis of the secondary endpoint will be performed separately for high- and low-risk 
infants. Incidence of peanut allergy will be analyzed with generalized linear mixed models 
in the PEDI sample in the same manner as the primary pediatric clinician endpoint with 
infants as the unit of analysis.  
Data for diagnosis of peanut allergy (yes/no) from the 4 month - 30 month EHR data 
collection time points will be combined into one binary variable describing whether (yes/no) 
diagnosis occurred at any time up through the 30-month time point. Data from caregivers 
FOABF surveys at 12 and/or 24 months will be used to determine the presence of a 
caregiver reported peanut allergy or physician diagnosed peanut allergy. 
The peanut allergy endpoint will be determined by combining information from EHR and 
caregiver survey information as described in the MOP.  
Exploratory analyses of the secondary peanut allergy endpoint will include the following. 
Analyses will be treated as exploratory and hypothesis- generating, so no formal correction 
for multiple testing will be applied. 
• 
The primary analysis of the secondary endpoint will be repeated to evaluate the impact 
of missing data. Missing data will be classified in three ways as follows: 
o Missing data are not imputed via multiple imputation and are left missing. 

 
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o Missing data are imputed as non-peanut allergic. 
o Missing data are imputed as peanut allergic. 
• 
The primary analysis of the secondary endpoint will be repeated combining all infants 
from both the high- and low-risk groups. Risk group and the interaction of risk group 
and intervention group will be included as fixed effects predictors. 
• 
The primary analysis of the secondary endpoint will be repeated in the PEDI sample 
including pediatric clinician adherence, allergist adherence (high-risk only), their 
interaction, and their interactions with intervention group as fixed effects predictors. 
• 
The primary analysis of the secondary endpoint will be repeated in the EEDI2 sample 
including pediatric clinician adherence, allergist adherence (high-risk only), caregiver 
adherence, and all two- and three-way interactions with each other and intervention 
group, as fixed effects predictors. 
o The primary analysis of the secondary endpoint will be repeated in the EEDI2 sample 
including the presence and extent (e.g., duration and amount) of peanut exposure as 
predictors. 
13.4.5 Analyses of Exploratory Endpoint(s) 
All analyses will be provided separately for high- and low-risk groups as noted. The entire infant 
sample of both risk groups will also be analyzed together where noted. Analyses will be treated 
as exploratory and hypothesis- generating, so no formal correction for multiple testing will be 
applied. 
 
Allergist adherence will be analyzed with generalized linear mixed models for high-risk infants 
in the EEDI1 sample in the same manner as the primary pediatric clinician endpoint with infants 
as the unit of analysis. The allergist adherence endpoint will be determined as follows: 
 
An allergist is adherent if: 
• 
The allergist recommends introduction following a sIgE test ≤0.35, a skin prick test 0-2mm, 
a successful supervised feeding or a successful oral graded food challenge. 
• 
The allergist recommends avoidance and continued monitoring after a skin prick test ≥8 mm 
or a failed supervised feeding or oral graded food challenge.  
 
An allergist is non-adherent if: 
• 
The allergist fails to recommend introduction following a sIgE test ≤0.35, a skin prick test 0-
2mm, a successful supervised feeding or a successful oral graded food challenge.  
• 
The allergist recommends introduction following a skin prick test 3-7mm without 
performing a supervised feeding or oral graded food challenge. 
• 
The allergist recommends introduction following a skin prick test of ≥8mm. 
 
Caregiver adherence (yes/no) will be analyzed with generalized linear mixed models in the 
EEDI2 sample in the same manner as the primary pediatric clinician endpoint with infants as the 
unit of analysis. Only high risk infants with data on clinician and/or allergist testing will be used 
in the analysis of caregiver adherence. For the high risk infants in the primary analysis of the 
exploratory endpoint, partial caregiver adherence (as defined below) will be grouped with non-
adherence. The caregiver adherence endpoint will be determined as follows:  
 
For low-risk infants: 

 
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• 
A caregiver is adherent if the caregiver introduces peanut by 12 months of age, regardless of 
the pediatric clinician’s recommendation. 
• 
A caregiver is non-adherent if the caregiver does not introduce peanut by 12 months of age, 
regardless of the pediatric clinician’s recommendation. 
 
For high-risk infants:  
• 
A caregiver is adherent if the pediatric clinician and/or allergist’s testing supports the 
introduction of peanut,  and the caregiver introduces peanut products by 7 months of age 
and continues feedings with at least 6 g of peanut protein over  ≥ 3 feedings per week as 
reported around the infant’s 1st birthday .. 
• 
A caregiver is adherent if the pediatric clinician and allergist’s testing supports the 
avoidance of peanut and the caregiver does not introduce peanut products as reported around 
the infant’s 1st birthday. 
• 
A caregiver is partially adherent if the pediatric clinician and/or allergist’s testing supports 
the introduction of peanut, and the caregiver introduces peanut products but does not do so 
by 6 months of age or does not continues feedings with at least 6 gm of peanut protein or 
over ≥ 3 feedings per week as reported around the infant’s 1st birthday.  
• 
A caregiver is non-adherent if the pediatric clinician and/or allergist’s testing supports the 
avoidance of peanut, and the caregiver introduces peanut products as reported around the 
infant’s 1st birthday.  
The primary analysis of the exploratory endpoint will be repeated in the EEDI2 sample 
including pediatric clinician adherence, allergist adherence (high-risk only) and two-way 
interactions with each other and intervention group, as fixed effects predictors. 
The primary analysis of the exploratory endpoint will be repeated in the EEDI2 sample by 
combining adherence and partial adherence and comparing partial and non-adherence. 
 
Pediatric clinician knowledge of guidelines, attitudes towards implementation, and barriers and 
facilitators of adherence will be summarized in the pediatric clinician sample with descriptive 
statistics using pediatric clinicians as the unit of analysis. A proportion adherent summary 
statistic will be computed for each pediatric clinician and will be related to KABF with 
generalized linear mixed models as described in the primary endpoint analysis. The final 
pediatric clinician KABF assessed after primary outcome data collection  will be compared 
between trial arms. Pediatric clinician KABF after primary outcome data collection in the control 
group will also be compared to the KABF of pediatric clinicians in the intervention arm at initial 
informed consent. Pediatric clinician KABF in the intervention arm at 6 months after informed 
consent and after primary outcome data collection will be separately analyzed for change over 
time. Any pediatric clinician who did not see infants for 4- or 6-month WCC during the 18-
month observation period will be excluded from the analyses. 
 
Caregiver survey data on feeding practices, reaction history, and barriers and facilitators to 
guideline implementation will be summarized in the EEDI2 sample with descriptive statistics 
using infants as the unit of analysis. 
13.4.6 Descriptive Analyses  
The number and percent of infants in all infant analysis samples will be tabulated by high- and 
low-risk group. Number and percent of infants for whom EHR data is obtained at each visit in 
the 4-month through 30-month data collection period will be summarized. Number and 
percent of infants who are lost to followup from each analysis sample will also be 

 
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summarized. Number and percent of pediatric clinicians and caregivers responding to each 
survey will be summarized. 
The disposition of all pediatric clinicians treating infants in any infant sample will be 
summarized in tables and listed. The numbers and percent of treating pediatric clinicians 
consenting to participate in the study, withdrawing consent from study participation, and who 
treated infants throughout the entire study data collection, will be presented. Any information 
regarding reasons for pediatric clinician withdrawal of consent will be summarized and listed. 
Summary descriptive statistics for demographics and baseline characteristics will be reported 
for all infant analysis samples and will be compared across samples to check for consistency. 
Variables to be summarized include age, race, ethnicity, and sex, as well as all components 
included in the assessment of high- or low-risk status. 
Two types of outcomes will be monitored for all children in the infant analysis sample based on 
EHR data and caregiver surveys.  First, the number of infants who react to first exposure to 
peanut will be reported.  Second, the number of infants who have been fed peanut more than 
once and report a reaction after the first exposure.   
Responses to all questions in the practice site, pediatric clinician characteristics 
questionnaires will be summarized overall and by trial arm. 
Protocol deviations will be listed by practice with information such as type of deviation, 
severity of the deviation (major or non-major), date of occurrence, and the reason for the 
deviation. Protocol deviations will be summarized in tabular format by type of deviation. 
Number and percent of pediatric clinicians utilizing individual iREACH prompts will be 
summarized to describe overall utilization of the iREACH intervention. 
13.5 
Interim Analyses  
Not applicable. 
13.5.1 Interim Analysis of Efficacy Data 
 
 
Not applicable. 
13.5.2 Interim Analysis of Safety Data 
 
 
Not applicable. 
13.5.3 Futility Analysis 
 
 
Not applicable. 
13.6 
Statistical Hypotheses  
Primary hypotheses: In each of the high-risk and low-risk strata, the primary endpoint analysis performs 
a test of superiority to assess whether the proportion of infants whose pediatric clinician is adherent to 
PPA Guidelines is different in the intervention arm compared to the control arm. A multiplicity 
adjustment will not be applied to the primary analysis because high and low-risk children represent 
independent risk strata where pediatric clinicians must take different steps to achieve adherence.   
 
 
Null hypothesis: P(intervention group) = P(control group) where P denotes the proportion 
adherent.  
 
Alternative hypothesis: P(intervention group) ≠ P(control group) 

 
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13.7 
Sample Size Considerations  
Power has been computed for primary and exploratory binary adherence outcomes and secondary 
peanut allergy outcomes. In order to compute power, six quantities have been specified: the type 1 
error rate, the number of practice sites, the number of patients expected per practice site, the within 
cluster correlation, the average proportion adherent (or peanut allergic) over all practice sites and 
intervention arms, and the difference in proportion adherent (or peanut allergic) between the 
intervention and control arms. Calculations assume a type 1 error of 0.05. In this study, investigators 
can control the number of practice sites invited to participate in the study but cannot control the 
number of infants assessed at each practice site. Since deployment of the intervention and data 
collection are through the EHR, inclusion of additional practice sites does not require significant 
additional budget. Therefore, the choice of number of practice sites is based primarily on the number 
expected to participate and not on budgetary or statistical power concerns. We estimate that at 
minimum 30 clinics will participate. Using a preliminary EHR data pull, we estimate being able to 
assess on average 17 high-risk and 333 low-risk per clinic in 18 months for a total sample size of 
approximately 500 high-risk and 10,000 low-risk infants.  
Since investigators cannot control the number of infants assessed, power calculations describe the 
differences between intervention arms in study outcomes that are detectable with 80% power for our 
given study sample sizes, rather than the sample sizes needed to be able to detect given differences 
between intervention arms in study outcomes.  
Statistical power for primary and exploratory adherence outcomes: We assume a within cluster 
correlation of 0.07 for the pediatric clinician adherence outcomes, estimated from a preliminary EHR 
data pull. Similar studies have assumed lower correlations in the range of 0.001-0.01 39,40 however, so 
we expect this estimate to be conservative. To further be conservative, we assume the average 
proportion adherent over all practice sites and intervention to be 0.50. These and the previously 
described assumptions and sample sizes allow us to detect with >80% power an absolute difference in 
proportions of adherence of ≥18% in high-risk infants and ≥14% in low-risk infants. 
Statistical power for secondary peanut allergy outcome: We assume a within cluster correlation of 0.02 
for the peanut allergy outcome, estimated from a preliminary EHR data pull on general food allergy. 
Peanut allergy prevalence data referenced earlier in this document provide estimates of the incidence 
of peanut allergy at age 2 of 13.8% for high-risk infants and 1.5% in low-risk infants. In high-risk 
infants, these and the previously described assumptions and sample sizes allow us to detect with >80% 
power an absolute difference in proportions with peanut allergy of 8.2% in high-risk infants 
(intervention and control arm proportions 5.4% and 13.8%). In low-risk infants, we can detect an 
absolute difference in proportions with peanut allergy of 0.98% (intervention and control arm 
proportions 0.11% and 1.50%). In high-risk infants, the LEAP study showed a 14% absolute 
difference in proportions with peanut allergy contrasting early introduction of peanut to avoidance. 
Compared to this, we are powered to detect smaller reductions in peanut allergy that might be 
expected with a CDS intervention. 
14. Identification and Access to Source Data, Monitoring Plan 
14.1. Source Data 
Source documents and source data are considered to be the original documentation where subject information, 
visits consultations, examinations and other information are recorded. Documentation of source data is 
necessary for the reconstruction, evaluation and validation of clinical findings, observations and other activities 
during a clinical trial. In this trial, the following source documents will be present: 
 

 
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• 
Paper source documents will be created when a study coordinator obtains an informed consent form, 
generates a log that links the child participants to a practice, pediatric clinician and caregivers, and 
links all participants to a unique study identification number. 
• 
Electronic health records data 
 
The completion of each online survey will create source electronic data on the survey vendor’s 
14.2. Access to Source Data 
The site investigators and site staff will make all source data available to the DAIT/NIAID, as well as to 
relevant health authorities.  Authorized representatives as noted above are bound to maintain the strict 
confidentiality of medical and research information that may be linked to identified individuals. 
 
14.3. Monitoring Plan for Consent Process 
A copy of the caregiver survey information sheet will be provided to the participant and stored in the study 
records on a secure system. Every month, study staff will review study records to ensure that consent was 
obtained and documented. In the event of a failed consent documentation we will immediately pause study 
activity for the participant in question and document the protocol deviation and report it to the appropriate 
parties.  
 
No monitoring is necessary for clinician survey consent forms as consent is implicit upon survey completion.  
15. Quality Assurance and Quality Control 
 
Data collection will take place at both the practice network (e.g., Lurie Community Connect, Peoria area, 
Alliance Chicago) and practice level. Each clinical site will perform internal quality management of study 
conduct, data collection, documentation and completion. An individualized quality management plan will be 
developed to describe each site’s quality management processes. Each practice network PI will be responsible 
for organizing data collection at the practice level.  
  
Data from participating practices’ EHRs will be extracted through an automated process established by the 
DCC and sent via a secure file transfer protocol (SFTP). Practices will be provided a data dictionary to identify 
the appropriate elements and visits/services to extract. The DCC will develop Extract Transform Load (ETL) 
scripts on behalf of each practice network (with the appropriate approvals from the practices). The ETL scripts 
will be run on a regular basis so the DCC data manager will have a complete EHR-based data file for reporting 
compliance and participation metrics.   
 
The DCC data manager will supervise data collection progress, consent and study enrollment, survey 
completion, identify potential data quality issues, alert study leadership and appropriate staff members to 
resolve any issues and will assure overall integrity of the data used for analysis. The DCC data manager will 
work with each practice network through the network PI and Informatics team to assure adherence to the study 
protocol and to implement quality control (QC) procedures. Data QC checks will be generated from the EHR 
database on a weekly basis.  
  
  
The practice networks will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities. 

 
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16. Protocol Deviations 
16.1. Protocol Deviation Definitions 
Protocol Deviation: The investigators and site staff will conduct the study in accordance to the protocol; no 
deviations from the protocol are permitted.  Any change, divergence, or departure from the study design or 
procedures constitutes a protocol deviation.  As a result of any deviation, corrective actions will be developed 
by the site and implemented promptly. 
Major Protocol Deviation (Protocol Violation): A Protocol Violation is a deviation from the IRB approved 
protocol that may affect the subject's rights, safety, or well-being and/or the completeness, accuracy and 
reliability of the study data.  In addition, protocol violations include willful or knowing breaches of human 
subject protection regulations, or policies, any action that is inconsistent with the NIH Human Research 
Protection Program’s research, medical, and ethical principles, and a serious or continuing noncompliance with 
federal, state, local or institutional human subject protection regulations, policies, or procedures.  
 
Non-Major Protocol Deviation: A non-major protocol deviation is any change, divergence, or departure from 
the study design or procedures of a research protocol that does not have a major impact on the subject's rights, 
safety or well-being, or the completeness, accuracy and reliability of the study data. 
16.2. Reporting and Managing Protocol Deviations 
The study site principal investigator has the responsibility to identify, document and report protocol deviations 
as directed by the study Sponsor.  However, protocol deviations may also be identified during site monitoring 
visits or during other forms of study conduct review.  
Upon determination that a protocol deviation has occurred, the study staff will a) notify the site Principal 
Investigator, b) notify the study data center, and c) will complete a Protocol Deviation form. The Protocol Chair 
will document all protocol deviations in the Trial Master File and promptly report the deviations to the 
DAIT/NIAID Medical Monitor and Project Manager. The DAIT/NIAID Medical Monitor and Project Manager 
will make the decision as to whether the Deviation is major or not and what the impact of the Deviation on the 
study participant or the entire study may be, and will review and approve the action plan that will be 
implemented as a result of the Protocol Deviation. 
17. Ethical Considerations and Compliance with Good Clinical Practice 
17.1. Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for 
Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria specified in this 
study protocol.  Before study initiation, the protocol and the informed consent documents will be reviewed and 
approved by the IRB.  Any amendments to the protocol or to the consent materials will also be approved by the 
IRB before they are implemented. 
17.2. Informed Consent Process 
 
Caregiver Survey Consent 
The informed consent process for caregiver survey participation will occur via phone or in-person to provide 
information about the study to a prospective participant and allow adequate time for review and discussion prior 
to his/her decision. The method of consent will be at the discretion of the prospective participant  During both 
the phone and in-person consent process, research study staff will review the consent with the prospective 

 
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participant in the  preferred language and answer any questions. The prospective participant will be told that 
being in the trial is voluntary and that he or she may withdraw from their part at any time, for any reason. 
Consent materials will be presented to participants in English or Spanish. A copy  of the information sheet will 
be provided  to the participant.  
 
The consent process will be ongoing.  The information sheet will be revised when important new safety 
information is available, the protocol is amended, and/or new information becomes available that may affect 
participation in the study.  
 
Pediatric Clinician Survey Consent 
The pediatric clinician will only receive an online information sheet to complete the consent process. They will 
directly receive an email with the online survey invitation link and a statement of consent. The invitation will 
state:“Your participation in this survey is voluntary. Your individual answers will remain confidential and 
reported only in the aggregate.” Consent of the invited respondent to participate will be implied when the 
participant opens the survey URL in their web browser and/or answers at least one question in the survey. 
While taking the survey, a participant may end the survey at any time by not answering any further questions. 
Once a participant provides any survey data, the data automatically enters the study database. 
17.3. Privacy and Confidentiality 
Participant (including caregivers, their children, and pediatric clinicians) privacy and confidentiality will be 
respected throughout the study.  Each participant will be assigned a unique identification number and these 
numbers rather than names will be used to collect, store, and report participant information.  Site personnel will 
not transmit documents containing personal health identifiers (PHI) to the study sponsor or their representatives. 
Each pediatric clinician and caregiver survey will be coded with a unique identification number and stored on 
password protected computers and servers. Only aggregated data will be shared. Participant-specific data will 
not be shared with care providers or colleagues at the practice and no practice personnel will have access to 
survey responses. To further protect the confidentiality of pediatric clinicians, aggregated data by practice will 
not be shared. 
18. Publication Policy 
This trial will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. 

 
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References 
1. 
Keet CA, Savage JH, Seopaul S, Peng RD, Wood RA, Matsui EC. Temporal trends and racial/ethnic disparity in 
self-reported pediatric food allergy in the United States. Annals of Allergy, Asthma & Immunology. 
2014;112(3):222-229.e223. 
2. 
Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy 
in the United States. Pediatrics. 2011;128(1):e9-17. 
3. 
Gupta R, Holdford D, Bilaver L, Dyer A, Holl JL, Meltzer D. The economic impact of childhood food allergy in 
the United States. JAMA Pediatr. 2013;167(11):1026-1031. 
4. 
Ma L, Danoff TM, Borish L. Case fatality and population mortality associated with anaphylaxis in the United 
States. J Allergy Clin Immunol. 2014;133(4):1075-1083. 
5. 
Clark S, Espinola J, Rudders SA, Banerji A, Camargo CA, Jr. Frequency of US emergency department visits for 
food-related acute allergic reactions. J Allergy Clin Immunol. 2011;127(3):682-683. 
6. 
Gupta R, Warren C, Smith B, et al. The Public Health Impact of Parent-Reported Childhood Food Allergies in the 
United States. Pediatrics. 2019 Mar;143(3).  
7. 
Sicherer SH, Munoz-Furlong A, Burks AW, Sampson HA. Prevalence of peanut and tree nut allergy in the US 
determined by a random digit dial telephone survey. J Allergy Clin Immunol. 1999;103(4):559-562. 
8. 
Sicherer SH, Munoz-Furlong A, Godbold JH, Sampson HA. US prevalence of self-reported peanut, tree nut, and 
sesame allergy: 11-year follow-up. J Allergy Clin Immunol. 2010;125(6):1322-1326. 
9. 
Sicherer SH, Munoz-Furlong A, Sampson HA. Prevalence of peanut and tree nut allergy in the United States 
determined by means of a random digit dial telephone survey: a 5-year follow-up study. J Allergy Clin Immunol. 
2003;112(6):1203-1207. 
10. 
Begin P, Paradis L, Paradis J, Picard M, Des Roches A. Natural resolution of peanut allergy: a 12-year 
longitudinal follow-up study. J Allergy Clin Immunol Pract. 2013;1(5):528-530 e521-524. 
11. 
Ho MH, Wong WH, Heine RG, Hosking CS, Hill DJ, Allen KJ. Early clinical predictors of remission of peanut 
allergy in children. J Allergy Clin Immunol. 2008;121(3):731-736. 
12. 
Bock SA, Munoz-Furlong A, Sampson HA. Fatalities due to anaphylactic reactions to foods. J Allergy Clin 
Immunol. 2001;107(1):191-193. 
13. 
Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001-
2006. J Allergy Clin Immunol. 2007;119(4):1016-1018. 
14. 
Warren CM, Otto AK, Walkner MM, Gupta RS. Quality of Life Among Food Allergic Patients and Their 
Caregivers. Curr Allergy Asthma Rep. 2016;16(5):38. 
15. 
Avery NJ, King RM, Knight S, Hourihane JO. Assessment of quality of life in children with peanut allergy. 
Pediatr Allergy Immunol. 2003;14(5):378-382. 
16. 
American Academy of Pediatrics. Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 
2000;106(2 Pt 1):346-349. 
17. 
Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease 
in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of 
complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183-191. 
18. 
Sicherer SH, Burks AW. Maternal and infant diets for prevention of allergic diseases: understanding menu 
changes in 2008. J Allergy Clin Immunol. 2008;122(1):29-33. 
19. 
Host A, Halken S, Muraro A, et al. Dietary prevention of allergic diseases in infants and small children. Pediatr 
Allergy Immunol. 2008;19(1):1-4. 
20. 
Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence 
of peanut allergy. J Allergy Clin Immunol. 2008;122(5):984-991. 
21. 
Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut 
allergy. N Engl J Med. 2015;372(9):803-813. 
22. 
Du Toit G, Sayre PH, Roberts G, et al. Effect of Avoidance on Peanut Allergy after Early Peanut Consumption. N 
Engl J Med. 2016;374(15):1435-1443. 
23. 
du Toit G, Tsakok T, Lack S, Lack G. Prevention of food allergy. J Allergy Clin Immunol. 2016;137(4):998-1010. 
24. 
Lack G. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012;129(5):1187-1197. 
25. 
Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United 
States: Report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin 

 
Confidential  
Page 49 of 51 
 
iREACH  
Version 2.0 
 
27-MAY-2021 
Immunol. 2017;139(1):29-44. 
26. 
Echlin PS, Upshur RE, Markova TP. Lack of chart reminder effectiveness on family medicine resident JNC-VI 
and NCEP III guideline knowledge and attitudes. BMC Fam Pract. 2004;5:14. 
27. 
Heidrich J, Behrens T, Raspe F, Keil U. Knowledge and perception of guidelines and secondary prevention of 
coronary heart disease among general practitioners and internists. Results from a physician survey in Germany. 
Eur J Cardiovasc Prev Rehabil. 2005;12(6):521-529. 
28. 
Sheldon TA, Cullum N, Dawson D, et al. What's the evidence that NICE guidance has been implemented? Results 
from a national evaluation using time series analysis, audit of patients' notes, and interviews. BMJ. 
2004;329(7473):999. 
29. 
Rycroft-Malone J, Seers K, Crichton N, et al. A pragmatic cluster randomised trial evaluating three 
implementation interventions. Implement Sci. 2012;7:80. 
30. 
Hoffman B, Moreno L, Gerber L, D'Angelo D, Abramson E. OR075 What pediatricians are advising on infant 
peanut introduction. Annals of Allergy, Asthma & Immunology. 2017;119(5):S10. 
31. 
Albustani M, Albustani S, Alsarray S, Alchlabi H. Residents’ Knowledge of and Adherence to Current Guidelines 
Regarding the Introduction of Highly Allergenic Foods to Infants. Pediatrics. 2018;141(1 MeetingAbstract):166. 
32. 
Greenhawt M, Chan ES, Fleischer DM, et al. Caregiver and expecting caregiver support for early peanut 
introduction guidelines. Ann Allergy Asthma Immunol. 2018;120(6):620-625. 
33. 
Cabana MD, Rand CS, Powe NR, et al. Why don't physicians follow clinical practice guidelines? A framework 
for improvement. JAMA. 1999;282(15):1458-1465. 
34. 
Fischer F, Lange K, Klose K, Greiner W, Kraemer A. Barriers and Strategies in Guideline Implementation-A 
Scoping Review. Healthcare (Basel). 2016;4(3). 
35. 
Scarfone RJ, Zorc JJ, Capraro GA. Patient self-management of acute asthma: adherence to national guidelines a 
decade later. Pediatrics. 2001;108(6):1332-1338. 
36. 
Lobach D, Sanders GD, Bright TJ, et al. Enabling health care decisionmaking through clinical decision support 
and knowledge management. Evid Rep Technol Assess (Full Rep). 2012(203):1-784. 
37. 
Otto AK, Dyer AA, Warren CM, Walkner M, Smith BM, Gupta RS. The Development of a Clinical Decision 
Support System for the Management of Pediatric Food Allergy. Clin Pediatr (Phila). 2017;56(6):571-578. 
38. 
Carroll AE, Biondich P, Anand V, Dugan TM, Downs SM. A randomized controlled trial of screening for 
maternal depression with a clinical decision support system. Journal of the American Medical Informatics 
Association : JAMIA. 2013;20(2):311-316. 
39.  
Hannon TS, Dugan TM, Saha CK, McKee SJ, Downs SM, Carroll AE. Effectiveness of Computer Automation 
for the Diagnosis and Management of Childhood Type 2 Diabetes: A Randomized Clinical Trial. JAMA Pediatr. 
February 2017. doi:10.1001/jamapediatrics.2016.4207 
40.  
Carroll AE, Bauer NS, Dugan TM, Anand V, Saha C, Downs SM. Use of a computerized decision aid for 
developmental surveillance and screening: a randomized clinical trial. JAMA Pediatr. 2014;168(9):815-821. 
doi:10.1001/jamapediatrics.2014.464 
 
 
 
 

 
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19. Appendices 
 
Figure 7. Clinician Pathway 
 
 
 
Figure 8. Caregiver Pathway 
  
 

 
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List of Tables 
Table 8.1: Questionnaires 
Table 8.2: EHR Data Element  
Table 8.5.1: Schedule of Activities-Practice Sites, Pediatric Clinicians 
Table 8.5.2. Schedule of Activities-Caregivers 
List of Figures 
Figure 1: Prevalence of US Childhood Peanut Allergy  
Figure 2: Summary of Addendum Guidelines for the Prevention of Peanute Allergy  
Figure 3: iREACH Study Design  
Figure 4: Pediatric Clinician Adherence  
Figure 5: Allergist Adherence  
Figure 6: Caregiver Adherence 
List of Appendices 
Figure 7: Clinician Pathway 
Figure 8: Caregiver Pathway