A Community-based Assessment of Skin Care, Allergies, and Eczema
Phase: NA
Conditions: Atopic Dermatitis, Atopic Disorders, Eczema, Atopic Eczema
Sponsor: Oregon Health and Science University

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
 
 
 
 
A Community-based Assessment of Skin Care, Allergies, and Eczema 
(CASCADE) 
University of Utah IRB Protocol Number: 00106351 
NIAMS Grant Number: R01 AR071057 
Principal Investigator: Eric Simpson 
NIAMS Program Official: Ricardo Cibotti 
Version Number:  13.0 
04 June 2021 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
 
STATEMENT OF COMPLIANCE 
 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIAMS 
Clinical Terms of Award. All personnel involved in the conduct of this study have 
completed human subjects protection training. 

________________________________________________________________________________________________________  
____________________________________________________________________________________________ 
SIGNATURE PAGE
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 6/4/2021 
 
Name: Eric Simpson, MD, MCR 
 
Title: Associate Professor 
 
 
 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
Version  
Number 
Version Date 
Summary of Revisions Made: 
1.0 
24Feb2016 
Original version 
2.0 
24Feb2017 
Resubmission version 
3.0 
01Dec2017 
Consent revision 
4.0 
16Jan2018 
Consent revision 
5.0 
16Apr2018 
Revisions in response to Data Safety Monitoring Board 
6.0 
25May2018 
Budget adjustments and Data Safety Monitoring Board 
revision request 
7.0 
25Jul2018 
Adjust shipping timeline in response to deviation 
8.0 
21Dec2018 
Continuing review and new recruitment strategies 
9.0 
18Feb2019 
Duke recruitment strategies and Data and Safety 
Monitoring Board revision recommendations 
10.0 
03May2019 
Revised inclusion criteria to allow participation via e-
mail or text message 
11.0 
05Aug2019 
Select CeraVe cream at baseline for participants who 
do not select the preferred moisturizer 
12.0 
14Nov2020 
Patient portal messages for site recruitment 
13.0 
04Jun2021 
Analysis plan adjusted with removal of interim analysis 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
TABLE OF CONTENTS 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................ 1 
SIGNATURE PAGE .................................................................................................................... 2 
TABLE OF CONTENTS .............................................................................................................. 4 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
PROTOCOL SYNOPSIS ............................................................................................................ 8 
1 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .................................... 17 
1.1 
Background Information ........................................................................................ 17 
1.2 
Rationale for a Barrier Approach to Prevention ..................................................... 17 
1.3 
Previous Trials Using Emollients for AD Prevention .............................................. 18 
1.4 
Development of Protocol ....................................................................................... 19 
1.5 
Potential Risks and Benefits ................................................................................. 19 
1.5.1 
Potential Risks .......................................................................................... 19 
1.5.2 
Potential Benefits ...................................................................................... 20 
2 
STUDY OBJECTIVES ...................................................................................................... 21 
2.1 
Study Objectives ................................................................................................... 21 
2.1.1 
Primary Objective ...................................................................................... 21 
2.1.2 
Secondary Objectives ............................................................................... 21 
2.2 
Study Outcome Measures .................................................................................... 21 
2.2.1 
Primary Outcome ...................................................................................... 21 
2.2.2 
Secondary Outcomes ................................................................................ 21 
3 
STUDY DESIGN .............................................................................................................. 23 
3.1 
Study Design Overview ......................................................................................... 23 
3.2 
Setting .................................................................................................................. 23 
3.3 
Treatment Arms .................................................................................................... 23 
3.3.1 
Intervention Arm ........................................................................................ 24 
3.3.2 
Control Arm ............................................................................................... 24 
3.4 
Rationale for Study Design Elements .................................................................... 24 
3.4.1 
Pragmatic Trial Design .............................................................................. 24 
3.4.2 
Community-based Setting ......................................................................... 24 
3.4.3 
Clinician Training in AD Diagnosis ............................................................. 25 
3.4.4 
Electronic-based Data Gathering ............................................................... 25 
4 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 26 
4.1 
Participant Inclusion Criteria ................................................................................. 26 
4.2 
Inclusion of Vulnerable Populations ...................................................................... 26 
4.2.1 
Inclusion of Women ................................................................................... 26 
4.2.2 
Inclusion of Minorities ................................................................................ 26 
4.2.3 
Inclusion of Children .................................................................................. 26 
4.2.4 
Inclusion of Neonates ................................................................................ 26 
4.3 
Participant Exclusion Criteria ................................................................................ 27 
4.4 
Enrollment Procedures ......................................................................................... 27 
4.4.1 
Screening .................................................................................................. 27 
4.4.2 
Additional Screening Procedures – Duke University .................................. 27 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
4.4.3 
Additional Screening Procedures – Oregon Health & Science University .. 28 
4.4.4 
Consent and Enrollment ............................................................................ 28 
4.4.5 
Randomization .......................................................................................... 28 
4.5 
Blinding Procedures .............................................................................................. 28 
4.6 
Strategies for Recruitment and Retention ............................................................. 29 
4.7 
Participant Withdrawal .......................................................................................... 30 
4.7.1 
Reasons for Withdrawal ............................................................................ 30 
4.7.2 
Handling of Participant Withdrawals or Participant Discontinuation of 
Study Intervention ..................................................................................... 31 
4.7.3 
Lost to Follow Up ...................................................................................... 31 
5 
STUDY INTERVENTION .................................................................................................. 32 
5.1 
Rationale for Promotion of Specific Emollients ...................................................... 32 
5.2 
Emollient Choices ................................................................................................. 32 
5.3 
Formulation, Packaging, and Labeling .................................................................. 33 
5.4 
Emollient Storage and Stability ............................................................................. 33 
5.5 
Dosage, Preparation and Administration of Study Product .................................... 33 
5.6 
Accountability Procedures for the Study Product .................................................. 33 
5.7 
Assessment of Participant Adherence with Study Product Administration ............. 34 
5.8 
Concomitant Medications/Treatments ................................................................... 34 
5.9 
Administration of Intervention ................................................................................ 34 
6 
STUDY SCHEDULE ......................................................................................................... 35 
6.1 
Baseline ................................................................................................................ 35 
6.2 
Intermediate Contacts ........................................................................................... 36 
6.3 
Final Study Contact .............................................................................................. 39 
6.4 
Post-Participation Study Contact .......................................................................... 40 
6.5 
Withdrawal Contact ............................................................................................... 40 
7 
STUDY PROCEDURES /EVALUATIONS ........................................................................ 41 
7.1 
Study Procedures/Evaluations .............................................................................. 41 
8 
ADVERSE EVENTS REPORTING ................................................................................... 42 
8.1 
Definitions ............................................................................................................. 42 
8.1.1 
Adverse Event (AE) ................................................................................... 42 
8.1.2 
Serious Adverse Event (SAE) ................................................................... 42 
8.1.3 
Unanticipated Problem (UP) ...................................................................... 43 
8.1.4 
Deviation ................................................................................................... 43 
8.2 
Reporting Adverse Events .................................................................................... 43 
9 
STUDY OVERSIGHT ....................................................................................................... 44 
10 
STATISTICAL CONSIDERATIONS .................................................................................. 45 
10.1 
Study Hypotheses ................................................................................................. 45 
10.2 
Study Outcomes ................................................................................................... 45 
10.2.1 Primary outcome ....................................................................................... 45 
10.2.2 Key Secondary Endpoints ......................................................................... 45 
10.3 
Power and sample size calculations ..................................................................... 45 
10.3.1 Power and sample size ............................................................................. 45 
10.3.2 Primary Outcome ...................................................................................... 45 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
10.3.3 Power and sample size for detecting effect modifications .......................... 46 
10.4 
Statistical analyses ............................................................................................... 46 
10.4.1 Analysis of Primary Endpoint ..................................................................... 46 
10.4.2 Effect modification of primary endpoint ...................................................... 46 
10.4.3 Secondary analyses of primary endpoint ................................................... 47 
10.4.4 Analysis of Key Secondary Endpoints ....................................................... 47 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 48 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 49 
12.1 
Ethical Standard ................................................................................................... 49 
12.2 
Institutional Review Board .................................................................................... 49 
12.3 
Informed Consent Process ................................................................................... 49 
13 
DATA HANDLING AND RECORD KEEPING ................................................................... 50 
13.1 
Data Management Responsibilities ....................................................................... 50 
13.2 
Data Capture Methods .......................................................................................... 50 
13.3 
Types of Data ....................................................................................................... 50 
13.4 
Performance Monitoring ........................................................................................ 51 
13.5 
Study Records Retention ...................................................................................... 51 
14 
LITERATURE REFERENCES .......................................................................................... 52 
APPENDICES ........................................................................................................................... 58 
APPENDIX A: CHILDREN’S ECZEMA QUESTIONNAIRE ....................................................... 59 
APPENDIX B: MODIFIED ASTHMA PREDICTIVE INDEX (MAPI) ............................................ 60 
APPENDIX C: PEDIATRIC GLOBAL HEALTH (PGH-7) INSTRUMENT, PARENT-PROXY 
REPORT FORM ............................................................................................................... 61 
APPENDIX D: PATIENT-ORIENTED ECZEMA MEASURE (POEM) INSTRUMENT ................ 62 
APPENDIX E: INFANTS’ DERMATITIS QUALITY OF LIFE INDEX (IDQOL) ............................ 63 
APPENDIX F: PRIMARY AND SECONDARY MEASURES ...................................................... 65 
APPENDIX G: FDA E-MAIL COMMUNICATION AND IND EXEMPTION LETTER ................... 66 
APPENDIX H: SCHEDULE OF EVENTS .................................................................................. 70 
APPENDIX I: SCHEMATIC OF STUDY DESIGN ...................................................................... 71 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
LIST OF ABBREVIATIONS 
AAD 
American Academy of Dermatology 
AD 
Atopic Dermatitis 
AE 
Adverse Event/Adverse Experience 
BEEP 
Barrier Enhancement for Eczema Prevention 
CCC 
Clinical Coordinating Center 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOOP 
Manual of Operating Procedures 
N 
Number (typically refers to participants) 
NIAMS 
National Institute of Arthritis, Musculoskeletal and Skin Diseases 
NIH 
National Institutes of Health 
OHRP 
Office for Human Research Protections 
PBRN 
Practice-based Research Network 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
TEWL 
Transepidermal Water Loss 
UP 
Unanticipated Problem 
 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
PROTOCOL SYNOPSIS 
Title 
 
A Community-based Assessment of Skin Care, Allergies, and Eczema 
(CASCADE) 
 
Eric Simpson, MD, MCR, Principal Investigator 
Study Design 
Intervention to 
be tested, brief 
description of 
protocol 
This is a pragmatic, multi-site, randomized community-based trial in which 
dyads of a parent or legal guardian (“parent”) and an infant age 0 to 2 
months are enrolled.  
 
Participating dyads are randomly assigned to receive lipid-rich emollient 
with instructions for daily use to infants plus routine skin care instructions 
(intervention group) or routine skin care instructions alone (control group). 
Both groups will receive mail, e-mail and text message reminders to follow 
protocol instructions based on their group allocation until the infant reaches 
24 months old. Dyads complete brief surveys quarterly with more complete 
survey instruments at 12 months and 24 months. Primary care clinicians 
trained in using standard atopic dermatitis (AD) diagnostic criteria will 
document presence of AD at all visits, including scheduled well child visits 
or at any other unscheduled visits, which will be abstracted from the health 
record. 
Intervention 
dosage and 
frequency 
 
Previous studies found petrolatum-based emollients applied to the skin 
improve barrier function (transepidermal water loss [TEWL] and hydration), 
decrease the effects of skin irritants, and improve clinical outcomes. Five 
emollients shown to improve barrier function or have simple formulations 
with petrolatum are used in the study: 
CeraVe Healing Ointment 
Petrolatum (e.g., Vaseline) 
Cetaphil cream 
CeraVe cream 
Vanicream 
Parents assigned to the intervention arm will receive a lipid-rich emollient 
and educational materials promoting once daily full-body emollient use until 
their infant is 24 months old. Parents will select an emollient to be mailed to 
the dyad’s home at enrollment and approximately every six months for the 
duration of the study; parents may change emollients during the course of 
the study. 
Parents assigned to the control arm will receive educational materials 
promoting general infant skin care guidelines only and will be asked to 
refrain from emollient use unless dry skin develops (current standard of 
care guidelines).  
Parents will receive text messages and e-mails directing them to 
educational materials and materials will be mailed to the parent’s home. 
Both study arms will have access to educational materials, and will receive 
text messages or e-mails two weeks after enrollment and during quarterly 
and annual surveys reinforcing infant skin care messages related to the 
study arm to which they are assigned. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
Primary and 
Secondary 
Endpoints 
Primary Outcome: 
The cumulative incidence of AD at 24 months of age as recorded in health 
records. Clinicians will be trained to use the American Academy of 
Dermatology (AAD) Consensus Criteria for diagnosing pediatric AD. 
Clinicians will assess for AD at each clinic visit and record in the health 
record. 
 
Secondary Outcomes: 
x 
Parental report of provider-diagnosed AD  
x 
AD as diagnosed by the Children’s Eczema Questionnaire (CEQ)  
x 
Parental report of sleep loss of the infant reported as average number 
of days per week (1 week recall) of disrupted sleep in their infant 
measured at 12 and 24 months 
x 
Any prescription topical medication use of over-the-counter 
hydrocortisone usage recorded by parent or recorded from records 
review by research coordinator at 24 months 
x 
Asthma risk using a modification of the Asthma Predictive Index and 
International Study of Asthma and Allergies in Children questionnaire 
x 
Parental report of immediate food allergy symptoms  
x 
Parental report of a provider diagnosis of food allergy that was 
confirmed by prick testing or IgE blood test. 
x 
Global Health Status using one question from the PROMIS Pediatric 
Global Health (PGH-7) instrument 
x 
In infants who develop AD: 
o Time to onset of AD as measured by parental report of eczema 
age of onset 
o Time to onset of AD as measured by provider-recorded date of 
first diagnosis retrieved from record review of health record 
o AD symptom severity (e.g. itch) as reported by the patient-
oriented eczema measure (POEM) instrument 
o Parent-reported global severity of eczema assessment 
o Infant Dermatology Quality of Life Instrument (IDQOL)  
Study 
Population  
 
From our planning period and recent population-based 2-year prevalence 
in the U.K., we expect the cumulative incidence of AD in the control to be 
~24% at two years of age. To estimate at least 30% relative reduction in 
AD, we require 1,044 dyads (522 per group) to achieve 80% power for a 
two-tailed test at the 0.05 level of significance. Allowing for an 
approximately 20% loss to follow-up, we plan to enroll 1,250 babies (625 
per arm). 
 
1,250 parent/infant dyads will be enrolled from 35 community-based family 
medicine and pediatric practices from practice-based research networks 
(PBRNs) in Colorado, Oregon, North Carolina, and Wisconsin. These 
PBRNs are part of the Meta-network Research And Learning Center (Meta-
LARC). Each clinic will be asked to enroll two or more dyads per month for 
approximately two years, for a total of 50 dyads per clinic. Enrolled dyads 
will be representative of the gender, race and ethnicity of patients receiving 
care in participating clinics. 
 
Clinical Site Hubs (practice-based research network, PBRN) 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x Oregon Rural Practice-based Research Network – Oregon Health & 
Science University 
x State Networks of Colorado Ambulatory Practices & Partners – 
University of Colorado 
x Wisconsin Research & Education Network – University of Wisconsin 
x Duke Primary Care Research Consortium – Duke University 
Inclusion / 
Exclusion 
Criteria 
All dyads who meet inclusion/exclusion criteria will be eligible for study 
participation. 
 
Inclusion Criteria 
In order to be eligible to participate in this study all of the following criteria 
must be true for the dyad: 
1. Parent can provide electronic signed and dated informed consent form. 
2. Parent is willing and able to comply with all study procedures for the 
duration of the study. 
3. Parent is a primary caretaker of an infant 0 to 2 months of age. 
4. Parent is 18 years of age or older at time of consent. 
5. Parent can speak, read, and write in English or Spanish. 
6. Parent has a valid e-mail address or phone that can receive text 
messages 
7. Parent has reliable access to the internet. 
8. Infant is a patient of a participating Meta-LARC clinic site at the time of 
consent. 
 
Exclusion Criteria 
A dyad who meets any of the following criteria will be excluded from 
participation in this study: 
1. Infant was born at less than 25 weeks gestational age. 
2. Infant has established eczema as diagnosed by the primary healthcare 
provider at clinic site of enrollment per parent report. 
3. Infant has known adverse reaction to petrolatum-based emollients. 
4. Infant has an immunodeficiency genetic syndrome such as Wiskott-
Aldrich Syndrome or Severe Combined Immunodeficiency Syndrome. 
5. Infant has extremely low birth weight (less than 1000g or 2.2 lbs [2 
pounds 3 ounces] at birth). 
6. Infant has a sibling enrolled in the study. 
7. Parent is unwilling or unable to comply with study procedures. 
Recruitment 
Plans 
Sampling Plan: It is anticipated that 2,500 dyads will need to be screened 
in order to reach the target enrollment of 1,250 dyads. The number for 
target enrollment accounts for attrition. 
 
Recruitment Plan: Dyads will be recruited from 35 PBRN member clinics in 
four states. Staff at PBRN clinics will approach parents with an infant age 0 
to 2 months presenting to a scheduled clinic visit in person, via mail, phone 
(Duke University only) or via patient portal. Parents will review study 
information on a clinic-based tablet computer. Rack cards or postcards with 
link to the enrollment website will be provided for those that do not enroll 
via tablet. Study materials will be available in English and Spanish. Any 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
questions about the study will be directed to a toll-free number operated by 
the clinical coordinating center (CCC). Parents will respond to 
inclusion/exclusion criteria questions. 
Screening: Dyads will review an electronic information sheet and agree to 
be screened. Dyads will be directed to respond to screening questions. 
Eligible dyads will provide contact information. 
 
Informed Consent Process: Eligible parents will be directed to the 
electronic consent form. After reading the consent form, participants who 
have no questions will continue on to sign the consent form. Participants 
who do have questions about the project will be directed to call research 
staff via a toll-free number to discuss the project and review questions; if a 
participant does not call research staff, research staff will initiate a call to 
the participant to complete consent procedures. Once participants’ 
questions are answered, participants will continue to sign the consent form. 
Consented will be provided via electronic signature online, either at the 
clinic via computer tablet or at home via internet-enabled phone or home 
computer. The electronic consenting process follows all IRB requirements 
for electronic consent. Informed consent will be obtained by one parent or 
legal guardian. Consented parents will receive a copy of their signed 
consent form by e-mail. Child assent will not be obtained, as infants are 
unable to provide assent. 
 
Enrollment Plan: Consented dyads will be directed to complete screening 
and enrollment questionnaire. Those unable to complete the survey at that 
time will be sent a link via e-mail and may receive phone or text message 
reminders to complete questionnaires via internet-enabled phone or home 
computer.  
 
Research coordinators from each of the four PBRNs will meet weekly to 
monthly (face-to-face or by phone) with each clinic to resolve recruitment 
challenges with clinic staff, to observe clinical workflows, to identify 
recruitment opportunities.  
Study 
Organizational 
Structure 
The study is organized into two main bodies with oversight from the PI. 
Those bodies include the clinical coordinating center (CCC), the data 
coordinating center (DCC).  
 
The CCC administers the daily activities of the project, including protocol 
maintenance, selection criteria, clinician training, participant 
communication, data collection, statistical analyses, and study oversight. 
The DCC maintains the study database and conducts data management, is 
responsible for enrollment and randomization, intervention delivery, 
maintains data quality assurance, initiates participant reminders, and 
initiates surveys with participants. The DCC and CCC oversee and work in 
partnership with PBRN leadership to promote recruitment and retention, 
ensure training of participating clinicians, update participant contact 
information, complete data quality activities and collect primary outcome 
data from the infant’s health record through 27 months.  
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
The study protocol was developed utilizing input from multiple stakeholders 
organized into a Community Advisory Committee and a Scientific Advisory 
Committee. These committees will guide various aspects of study 
implementation as needs arise. 
Retention 
Plans 
Each PBRN research coordinator will meet regularly with clinic staff to keep 
clinic staff engaged in the study and monitor routine documentation of AD.  
 
The DCC will track survey completion and utilize effective evidence-based 
methods to maximize cohort retention. Methods to use include financial 
incentives, pre-notification of surveys, and web surveys containing images. 
Outreach to participants will include telephone support from the CCC.  
 
Participants will be eligible to receive $135 for completing three surveys 
during approximately 24 months of study participation. The compensation 
schedule will incentivize the completion of questionnaires to enhance 
participant retention. Dyads randomized to the intervention group will also 
receive 24 months’ worth of emollient.  
 
The enrollment questionnaire gathers contact information of alternate 
contacts who may help locate the participant if they become unresponsive 
during the study. During quarterly and annual contacts, participants will be 
asked to confirm or update their current contact information. If participants 
become unresponsive, research coordinators may also update contact 
information from clinic records. 
Group 
Assignment 
Dyads will be automatically randomized after the parent has completed 
enrollment. Randomization will be performed by the central DCC using a 
computer-generated randomization schedule. Randomization will be 
stratified by clinic and parent-reported history of atopic disease in the 
infant's first-degree relatives at the time of randomization to ensure balance 
within sites and groups. Randomized participants will then be directed to 
web-based instructions available for downloading. Materials will be mailed 
to the participant’s home along with study payment. 
 
Participants who withdraw or are terminated from the study will not be 
replaced with a new participant. The proposed dyad recruitment numbers 
account for attrition. Withdrawal and termination outcomes will be recorded 
in the study database. 
Subject 
Participant 
Duration 
 
Dyads participate in the project until the infant is 24 months of age, or for 
about two years. Visits are outlined in the schedule of events. 
 
Schedule of events 
 
 
Procedures 
Screening  
0RQWKV 
Contact 1  
  0RQWKV
Contact 2 
(3 Months)
Contact 3 
(6 Months)
Contact 4 
(9 Months)
Contact 5 
(12 Months) 
Contact 6 
(15 Months) 
Contact 7 
(18 Months) 
Contact 8 
(21 Months) 
Contact 9 
(24 Months) 
Consent 
• 
• 
 
 
 
 
 
 
 
 
Assessment of Eligibility 
(Inclusion/Exclusion criteria) 
• 
 
 
 
 
 
 
 
 
 
Bas
elin
Demographics 
 
• 
 
 
 
 
 
 
 
 
AD Risk 
 
• 
 
 
 
 
 
 
 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
 
Visit Schedule: Participating dyads will not have in-person visits with the 
study team. Annual questionnaires will be administered by e-mail or text 
message at enrollment and when the infant is 12 and 24 months old. Every 
three months, participants will receive a quarterly survey sent via e-mail or 
text message and a reminder of the randomization arm. A reminder of 
randomization arm will be sent two weeks after enrollment. Text and phone 
reminders will occur at baseline and for annual surveys. 
 
Data Collection: A brief anonymous screening survey will be given to 
potential participants. Eligible participants will be then be prompted to 
provide contact information that will be linked to the screening survey. All 
surveys will be collected through internet-based online survey with 
reminders sent via e-mail or text message. Toll-free phone numbers will be 
available to dyads to assist with data collection. 
  
Health record abstraction: PBRN research coordinators who are blinded to 
study arm assignment will abstract data from participating infants’ health 
Living Environment 
 
• 
 
 
 
 
 
 
 
 
Pet Ownership 
 
• 
 
 
 
 
 
 
 
 
Alternate Contact 
 
• 
 
 
 
 
 
 
 
 
Provide/Update Contact Info 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
Quarterly 
Contact 
Confirm PCP 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
AD diagnosis 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Study arm adherence 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Choose and ship emollient 
(Intervention Group Only) 
 
(•) 
 
(•) 
 
(•) 
 
(•) 
 
 
Assessment of AE/SAE 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Annual Questionnaire 
mAPI and ISAAC 
 
 
 
 
 
• 
 
 
 
• 
CEQ 
 
 
 
 
 
• 
 
 
 
• 
Sleep loss 
 
 
 
 
 
• 
 
 
 
• 
Allergies 
 
 
 
 
 
• 
 
 
 
• 
Study arm adherence 
 
 
 
 
 
• 
 
 
 
• 
Medication history 
 
 
 
 
 
• 
 
 
 
• 
PGH-7 Global Health 
 
 
 
 
 
• 
 
 
 
• 
Infant diet 
 
 
 
 
 
• 
 
 
 
• 
Emollient acceptability 
(Intervention Group 
Only) 
 
 
 
 
 
(•) 
 
 
 
(•) 
If infant develops AD: 
-AD age of onset 
-Global severity of AD 
-IDQOL 
-POEM 
 
 
 
 
 
(•) 
 
 
 
(•) 
Chart Abstraction 
AD or eczema diagnosis 
by HCP 
 
 
 
 
 
• 
 
 
 
• 
Intensity of AD 
 
 
 
 
 
(•) 
 
 
 
(•) 
Medication history 
 
 
 
 
 
(•) 
 
 
 
(•) 
Other allergy diagnoses 
 
 
 
 
 
(•) 
 
 
 
(•) 
Assessment of AE/SAE 
 
 
 
 
 
• 
 
 
 
• 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
records through 27 months to review for adverse events, diagnosis of AD, 
treatment of AD, and clinician diagnosis of allergies. The cumulative 
incidence of AD at 24 months of age will be compared between the 
intervention and control arms. 
 
Outcome Assessments: AD assessment performed by a trained clinician at 
well child through 24 months of age. Other outcomes will be assessed via 
parental electronic questionnaires at 12 and 24 months.  
Study Duration  Total study duration will last for five years, with enrollment projected to be 
completed during the second year of the study. An interim analysis will 
occur in quarter 1 of year 4 when 50% of participants have completed 2-
year follow-up. All participants will complete year 2 follow-up by the end of 
study year 4. Final data analyses will occur during quarters 1-3 of year 5 
with final reporting, manuscript development and study clinic site reports to 
follow.  
Availability of 
Investigational 
Product and 
IND/IDE Status 
The Food and Drug Administration has determined investigational new 
drug (IND) exemption and investigational drug exemption (IDE) as 
appropriate for the proposed trial (See Protocol Appendix G for IND 
exemption). Emollients used in the trial registered as over-the-counter 
drugs (i.e. with an active ingredient listed) qualify for an IND exemption, 
which is CeraVe Healing Ointment and petrolatum.  
 
Emollients registered as cosmetics will require an IDE. Emollients used for 
the study include Cetaphil cream, CeraVe cream and Vanicream.  
 
The manufacturing companies for the higher cost emollients will supply 
1,000 jars containing 400-454g of emollient over the 4-year course of the 
study. 
 
Emollient 
IND 
IDE 
Manufacturer 
LOS 
CeraVe Healing Ointment 
 
XX 
 
L’Oreal 
Yes 
Petrolatum (e.g., Vaseline) 
 
XX 
 
Unilever 
No 
Cetaphil cream 
 
 
XX 
Galderma 
Yes 
CeraVe cream 
 
 
XX 
L’Oreal 
Yes 
Vanicream 
 
 
XX 
Vanicream 
Yes 
 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
KEY ROLES AND CONTACT INFORMATION 
Principal 
Investigator:   
Eric Simpson, MD, MCR 
Oregon Health & Science University, Department of 
Dermatology 
3181 SW Sam Jackson Park Rd. Mail Code CH16D 
Phone: 503-494-3968 
Fax: 503-494-6968 
E-mail: simpsone@ohsu.edu 
 
NIAMS Program 
Official:   
Ricardo Cibotti 
Clinical Site 
Investigators: 
Nancy Elder, Oregon Health & Science University 
Donald Nease, University of Colorado 
Sarina Schrager, University of Wisconsin 
Rowena Dolor, Duke University 
 
Institutions: 
Oregon Health & Science University, Department of 
Dermatology 
3181 SW Sam Jackson Park Rd. Mail Code CH16D 
Investigator: Eric Simpson, MD, MCR 
Phone: 503-494-3968 
Fax: 503-494-6968 
E-mail: simpsone@ohsu.edu 
 
Oregon Rural Practice-based Research Network 
Oregon Clinical & Translational Research Institute 
Department of Medical Informatics & Clinical Epidemiology 
 
Clinical Site Hubs: 
Meta-Network Learning and Research Center (Meta-LARC) 
Oregon Health & Science University, Oregon Rural Practice-
based Research Network  
3181 SW Sam Jackson Park Rd., Mail Code L222 
Portland, OR  97239 
Investigator: Nancy Elder, MD 
Phone: 503-418-2645 
Fax: 503-494-1513 
E-mail: eldern@ohsu.edu 
 
University of Colorado, State Networks of Colorado Ambulatory 
Practices & Partners 
12631 East 17th Ave. 
Aurora, CO 80045 
Investigator: Donald Nease, MD 
Phone: 303-724-7283 
Fax: 303-724-9747  
E-mail: donald.nease@ucdenver.edu 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
 
University of Wisconsin, Wisconsin Research and Education 
Network  
1100 Delaplaine Court 
Madison, WI 53175 
Investigator: Sarina Schrager, MD 
Phone: 608-265-4477 
Fax: 608- 263-5813 
E-mail: Sarina.Schrager@FAMMED.WISC.EDU 
 
Duke University, Duke Primary Care Research Consortium  
2400 Pratt Street 
Durham, NC 27705  
Investigator: Rowena Dolor, MD 
Phone: 919-668-8627 
E-mail: rowena.dolor@duke.edu 
 
Other Key 
Personnel: 
Cynthia Morris 
Oregon Health & Science University 
Dept. of Medical Informatics & Clinical Epidemiology 
3181 SW Sam Jackson Park Rd. Mail Code BICC 
Phone: 503-494-3262 
E-mail: morrisc@ohsu.edu 
 
Jodi Lapidus 
Oregon Health & Science University 
OHSU-PSU School of Public Health 
Phone: 503-494-1167 
Fax: 503- 494-4981 
E-mail: lapidusj@ohsu.edu 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
1.1 
Background Information 
 
The prevalence, socioeconomic costs, comorbidities and impact on children and 
families make the prevention of atopic dermatitis (AD) an important public health goal.  
Our previous work found AD affects approximately 13% of children under the age of 18 
years old in the United States1- a similar prevalence to many areas of the world.2 In all 
continents, the prevalence of AD continues to rise for unknown reasons, but suggests 
environmental factors are partly responsible.3 The vast majority of cases begin within 
the first two years of life, although onset may occur at any age.  Many children with mild 
disease outgrow their disease; however, the number of children who experience 
persistence into adulthood is likely underappreciated.4  
 
Children with AD suffer from chronically inflamed skin lesions accompanied by 
unrelenting pruritus. Skin lesions often have oozing and crusting predisposing the skin 
to secondary bacterial infection.  Studies reveal the impact of AD on a child’s quality of 
life is profound. Children with AD have more disturbed sleep, difficulty in school, and 
more behavioral problems compared to healthy controls.5 The family impact of the 
disease is similar to having a child with diabetes.6 Our group and others have found an 
increased risk of neurodevelopmental disorders such as attention-deficit-hyperactivity 
disorder in children with AD as well.1,7  Annual health care expenditures for AD are also 
significant, estimated at $3-5 billion annually in the U.S., similar to those of other chronic 
childhood diseases such as asthma.8  An effective AD prevention strategy would 
alleviate a very common health problem impacting children and families to an alarming 
degree. In addition, a low-cost strategy represents a good return on investment as it 
could provide substantial savings to the healthcare system. 
1.2 
Rationale for a Barrier Approach to Prevention 
 
A greater understanding of the pathogenesis of AD creates an opportunity for a novel 
approach to prevention.  It is now appreciated that skin barrier dysfunction plays a 
central role in disease pathogenesis. The etiology of this barrier function may vary 
between individuals.  In some cases, defects in skin barrier genes may be the primary 
driver of skin barrier dysfunction. The seminal work by Irwin McLean’s group in Dundee 
found loss-of-function mutation defects in filaggrin (FLG gene) to be the strongest 
predictor of AD ever found.9 Filaggrin deficiency leads to increased transepidermal 
water loss (TEWL) prior to eczema development, reduced cutaneous hydration, and an 
increase in transcutaneous penetration of environmental irritants and allergens thus 
initiating skin inflammation.10,11 While a groundbreaking discovery, FLG mutations do 
not explain the majority of AD cases in a given population.12 Thus, skin barrier 
dysfunction in many cases of AD may be initiated either by other genetic defects in the 
skin barrier (e.g. corneodesmosin or claudin-113,14) or by sub-clinical skin inflammation 
in children with a predisposition to exaggerated immune responses.15 Some authors 
suggest modern skin care practices dry out the skin and alone can initiate skin 
inflammation.16,17 Importantly, Irvine and colleagues recently found skin barrier 
dysfunction in the first 2 months of life to be the strongest predictor of AD development 

________________________________________________________________________________________________________  
____________________________________________________________________________________________ 
at 2 years independent of filaggrin genotype or family history. 18 These findings were 
confirmed by Ohya and colleagues in a separate cohort of 118 infants in Japan.19  Once 
early skin inflammation is initiated, a cycle of skin barrier dysfunction and inflammation 
ensues.  Inflammatory infiltrates and Th2 cytokines then alter the expression of several 
important components of the skin barrier.20,21 This may explain why skin barrier 
dysfunction can be found in patients with AD regardless of filaggrin status.22 Barrier 
enhancement early in life could not only correct skin barrier defects that are the direct 
results of a mutation in skin barrier genes, but should also correct skin barrier 
dysfunction resulting from harsh bathing practices or other environmental insults.  In 
addition, emollients have anti-inflammatory effects that could suppress early sub-clinical 
inflammatory infiltrates that may also initiate the disease.23 This idea is supported by the 
fact that emollients prevent flares of AD in populations not selected for filaggrin status 
and our pilot data shows a protective effect of emollients independent of FLG status.24,25   
1.3 
Previous Trials Using Emollients for AD Prevention 
 
The positive data from previous small trials using emollient-based therapy from birth 
support the need for larger trials of a barrier approach to prevention.  Daily emollient 
therapy has been utilized and published in three prior clinical trials consisting of 264 
newborns at high-risk for the development of AD and showed a significant protective 
effect with no adverse effects.26-28 In the first study of its kind, we performed a pilot trial 
of daily emollient therapy (Cetaphil cream) involving 22 neonates at high risk for the 
development of AD.  High risk was defined as a first-degree relative with an atopic 
disease and a parent with a history of AD. At least 30% of this high-risk population 
would be expected to develop AD in the first 1 year of life according to previous 
prevention trials with similar inclusion criteria.29-31 Some studies found an AD incidence 
in this population to be as high as 46-62% at one year.32,33  
This initial uncontrolled study found that only 3 of 19 (16%) infants developed AD after a 
Figure 1.  We performed an open-label pilot trial of 
Cetaphil cream in high-risk neonates. This approach 
was found to be safe and feasible and there 
appeared to be a reduced incidence of AD 
compared to historical controls.   
Figure 2.  Results of our randomized controlled trial 
(n=124) of daily emollient therapy from birth.  A
significant reduction in AD cumulative incidence at 6 
months was found in the emollient arm compared to 
the control arm. 
16%
30%
0
20
40
Emollient
Intervention
Expected
(Historical
Controls)
Percent with Atopic Dermatitis
Open Label Pilot Trial 
(n=22)
43%
22%
0
5
10
15
20
25
30
35
40
45
50
No Moisturizer
Moisturizer
Randomized Controlled Trial 
(n=124)
Percent with AD at 6 Months
RR 0.50 [95% CI 0.28, 
0.9]  P=0.017 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
median follow-up time of over 1 year, with 3 babies lost to follow-up (Fig. 1).26  Reported 
adherence was excellent (85%) and no significant adverse events occurred.  These 
preliminary results prompted the development of an international randomized controlled 
feasibility trial involving our group at Oregon Health & Science University (OHSU) and 
four sites in the U.K.27 One hundred twenty-four high-risk neonates were randomly 
allocated to one of three emollient choices in each country or to no emollient. In the 
U.S., emollient choices included Aquaphor, Cetaphil cream, or sunflower oil.  In the U.K. 
emollient choices were Doublebase, Diprobase, or sunflower oil. At 6 months, 85.2% of 
participants reported using the intervention at least 5 times per week. The emollient 
intervention group experienced a 2-fold reduction in the 6-month cumulative incidence 
of AD (Fig. 2). Thirteen percent were lost to follow-up. These results remained 
unchanged when filaggrin gene status was taken into account with regression analyses. 
As a sensitivity analysis, a multiple imputation approach was used to account for 
missing data which confirmed the primary analysis (OR 0.33 [95% CI 0.23-0.42, 
P<0.0001]. Horimukai, et al. performed the only other published clinical trial evaluating 
emollients for AD prevention.28 This study from Japan confirmed the findings of our 
BEEP trial finding emollient use in high-risk infants significantly reduced AD 
development by 32% at week 32.  Similar to the BEEP trial, this was a small study 
(n=118) performed in a high-risk population.  While results of these trials are 
encouraging, trials in larger and unselected populations are needed to determine 
whether this approach can be beneficial to larger populations. 
1.4 
Development of Protocol 
 
Consistent with practice-based research principles, the study protocol was developed 
utilizing input from multiple stakeholders organized into a Community Advisory 
Committee and a Scientific Advisory Committee as well as key feedback from practice-
based research network (PBRN) directors. During the development of the study 
protocol, study procedures including enrollment and measuring of outcomes were 
piloted in a “model recruitment” study designed to mimic the procedures for the main 
trial and informed the procedures and outcomes described in this protocol. 
1.5 
Potential Risks and Benefits 
1.5.1 
Potential Risks 
 
The emollients used in our current proposed study will be used in a similar fashion to 
how they are being used currently by the general public with only slight changes that 
should not change the safety profile of the emollients. Data from two published studies 
and our unpublished data reveal over 70% of parents are already using moisturizers on 
a daily basis on their infants.34,35 These data reveal parents primarily use watery lotions.  
Our hypothesis is that a basic moisturizer with higher lipid content than a typical lotion 
will reduce the risk of developing atopic dermatitis by providing better barrier repair than 
water-based lotions. We also hypothesize that more frequent use of a thicker emollient 
(i.e. daily) will lead to enhanced protection of the skin barrier than current skin care 
practices and thus reduce the probability of developing AD. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
 
The daily use of moisturizers in infants in our proposed study will likely not pose an 
increased risk beyond current standard usage.  The main risk of the emollient would 
either be the development of an irritant contact dermatitis or rarely an allergic contact 
dermatitis to an emollient component.  Theoretically, occlusive moisturizers could 
increase the risk of a skin infection, however this has not been seen in previous clinical 
studies of emollients in neonates. Moisturizer marketing campaigns currently promote 
the daily use of moisturizers in infants. Parents will have a choice of multiple legally 
marketed moisturizers for this study that are all freely available over-the-counter.  
 
Parents in the intervention arm will select an emollient from the approved moisturizers 
list to use on their baby over the course of the study. These emollients do not pose any 
additional known risk to newborns or infants beyond current usage patterns in the 
community. 
 
There is a risk of loss of confidentiality. The study team will take precautions to protect 
the confidentiality of participant information.  
1.5.2 
Potential Benefits 
It is not known if there are benefits to using the preferred emollient for infants not at risk 
of developing AD (i.e. there is no family history of AD or allergies). Some studies show 
infants at high-risk for developing AD may benefit from emollient therapy, but these 
studies were small and need confirmation.  While participation in this study may not 
provide direct benefits to participants, participation may help to understand how to 
prevent AD in infants. 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
2 STUDY OBJECTIVES 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
To assess the effectiveness of daily emollient therapy beginning in the first 2 months of 
life in reducing the cumulative incidence of AD at 24 months of age in a community-
based setting. 
2.1.2 
Secondary Objectives 
To determine whether an atopic family history and key early life exposures modify the 
effect of emollient therapy on atopic dermatitis. 
To assess the effectiveness of emollient therapy on the development of reported allergic 
comorbidity symptoms such as food allergy and wheeze episodes. 
2.2 
Study Outcome Measures 
2.2.1 
Primary Outcome 
The primary outcome will be an AD diagnosis made 
by the infant’s primary healthcare provider by 27 
months of age (cumulative incidence). A diagnosis will 
be recorded in the health record for each infant and 
these data will be extracted by PBRN research 
coordinators. Diagnosis guidelines and documentation 
will be introduced at an initial training session and 
provider compliance with this protocol will be 
monitored and reinforced by PBRN research 
coordinators. Any diagnosis of AD made by the 
trained provider during the first 27 months of life will 
be considered as having developed AD (i.e., 
cumulative incidence). Clinicians will be trained to use 
the American Academy of Dermatology (AAD) 
Consensus Criteria for diagnosing pediatric AD.37 
These criteria are a distillation of the original Hanifin-
Rajka criteria with minor enhancements made by 
pediatric dermatologists to facilitate diagnosis in the 
very young. The recently-published AAD guidelines of 
care for AD recommend these criteria for the 
diagnosis of AD in the clinical setting.38 The statistical 
analysis plan contains the full set of primary and secondary outcomes. 
2.2.2 
Secondary Outcomes 
x Parental report of provider-diagnosed AD - This parental report of AD question has 
been validated previously by our group and was found to have adequate sensitivity 
and specificity during our trial planning activities.39 
Table 1: AAD Consensus Criteria 
for diagnosing pediatric AD. 
ESSENTIAL FEATURES 
Must be present: 
-Pruritus 
-Eczema (acute, subacute, chronic) 
-Typical morphology and age-
specific patterns* 
-Chronic or relapsing history 
 
*Patterns include: 
1. Facial, neck, and extensor 
involvement in infants and children 
2. Current or previous flexural 
lesions in any age group 
3. Sparing of the groin and axillary 
regions 
 
IMPORTANT FEATURES 
Seen in most cases, adding 
support to the diagnosis: 
-Early age of onset 
-Atopy-personal and/or family 
history 
-Immunoglobulin E reactivity 
-Xerosis 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x AD as diagnosed by the Children’s Eczema Questionnaire (CEQ) – The CEQ is a 
newly developed 2-question parental questionnaire based on the U.K. Working Party 
criteria.40 This instrument will be used to capture dyads not evaluated by their 
provider or lost to follow-up (Appendix A). 
x Parental report of sleep loss of the infant reported as average parental report of days 
per week of disrupted sleep in their infant (1 week recall) measured at 12 and 24 
months. 
x Any prescription topical medication use or over-the-counter hydrocortisone usage 
recorded by parent or recorded from records review by research coordinator at 24 
months.  
x Asthma risk questions from the modified Asthma Predictive Index (mAPI) that uses 
family history, atopic dermatitis, sensitization history, and wheezing episodes to 
predict the development of asthma measured by parental report.41 This will be 
recorded as either high risk or low-risk at 12 and 24 months following mAPI criteria 
(Appendix B). Wheezing episodes will be assessed using the International Study of 
Asthma and Allergies in Childhood (ISAAC) questionnaire. 
x Parental report of immediate food allergy symptoms – A general question regarding 
the development of red rash/hives, lip swelling, wheezing, abdominal pain, or 
vomiting that developed in the infant within two hours of eating a food. 
x Parental report of a provider diagnosis of food allergy that was confirmed by prick 
testing or IgE blood test. 
x One question global health status from the PROMIS Pediatric Global Health (PGH-
7) instrument.42 (Appendix C) 
x In infants who develop AD, a logic model in our survey instrument will ask the 
following parental reported outcomes in the 12- and 24-month questionnaires: 
1. 
Time to onset of AD as measured by parental report of eczema age of 
onset. 
2. 
Time to onset of AD as measured by provider-recorded date of first 
diagnosis retrieved from record review of chart by research coordinator. 
3. 
AD symptom severity as reported by the Patient-Oriented Eczema 
Measure (POEM) instrument 43 (Appendix D). 
4. 
Parent-reported global severity of eczema assessment – mild, moderate, 
severe 
5. 
Infant Dermatology Quality of Life Instrument (IDQOL) – a validated 10-
question questionnaire designed for children under 4 years of age 44 
(Appendix E). 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
3 STUDY DESIGN 
3.1 
Study Design Overview 
This is a pragmatic, multi-site, randomized community-based trial that will enroll dyads 
of a parent or guardian (“parent”) and an infant who is up to 2 months old. Both high-risk 
infants (with family history of atopic disease) and average-risk infants (with no family 
history of atopic disease) will be eligible. Each dyad will be randomized to the 
intervention arm (daily emollient therapy) or the control arm (encouraged to adhere to 
current infant skin care guidelines without regular emollient use). Over the course of two 
years, 1,250 dyads will be enrolled in the trial with 625 dyads assigned to each study 
arm. It is anticipated that 2,500 dyads will be screened in order to reach the target 
enrollment.   
Once randomized, dyads will participate in the study until the infant is 24 months of age 
(approximately two year study duration). Parents will complete a questionnaire at 
enrollment (prior to randomization) and follow-up annual questionnaires when the infant 
is 12 and 24 months old. Every three months of child’s age (e.g., age 3 months, 6 
months, 9 months, etc.), parents will be contacted via e-mail or SMS text message and 
asked to complete a quarterly survey, have an opportunity to update their contact 
information, report on adherence to study arm, be given messages about daily emollient 
use or general infant skin care guidelines and report adverse events and serious 
adverse events. Finally, two weeks after enrollment into the study, dyads in both arms 
will receive an e-mail or text message with a brief study message for both arms, with the 
intervention arm getting an additional message encouraging daily emollient use.  
Total study duration will last for five years, with enrollment projected to be completed at 
the end of study year 2 and data collection projected to be completed at the end of 
study year 4.  After completion of the screening and enrollment, participant-specific links 
to subsequent questionnaires will be sent by e-mail or SMS text message.  Follow-up 
for incomplete questionnaires, unresponsive participants, as well as for individuals that 
did not have a valid e-mail address or phone that could not receive text messages may 
receive additional contact from the Clinical Coordinating Center (CCC). 
3.2 
Setting 
This study will take place in 35 community-based primary care clinics located in four 
states in the United States: Colorado, North Carolina, Oregon, and Wisconsin. The 
community-based setting, combined with the multi-regional site selection, will increase 
the potential for racial and ethnic diversity representative of the U.S. population. 
Prior to study implementation, the CCC and PBRN research coordinators will train 
participating clinic staff on methods for proper diagnosis of AD. PBRN research 
coordinators will ensure that staff and clinicians who join the study after initial training 
receive the training materials and complete a test. 
3.3 
Treatment Arms 
There are two arms in the study- intervention and control.  Both study arms will receive 
text messages and e-mail links providing general skin care educational material 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
throughout the study. This general skin care information includes information regarding 
the use of gentle cleansers, bathing safety tips and managing rash.  All dyads will be 
reminded of their treatment arm every three months via electronic survey and e-mail. 
Both arms will be contacted at the same frequency.  There are no evidence-based 
guidelines for frequency of bathing.  Because bathing practices vary between families 
considerably, only general bathing tips will be provided to both groups. 
3.3.1 
Intervention Arm 
Dyads assigned to the intervention arm will receive a study-approved emollient of their 
choice by mail at regular intervals throughout the study and instructed to use the 
emollient once-daily over the entire body. Parents may avoid the scalp, if needed.  
Quarterly reminders will be sent during the course of the study instructing parents on 
the daily use of the study emollient. In addition, the intervention group will receive 
general infant skin care information identical to the control group.  
3.3.2 
Control Arm 
Dyads assigned to the control arm will be instructed to refrain from routine emollient use 
and only use emollients on an “as needed” basis if their baby develops dry skin. Like the 
intervention group, dyads in the control arm will also receive general infant skin care 
guidelines. Information in the control educational materials will include general infant 
skin care recommendations, such as bathing and rashes. The information in educational 
materials will be current standard of care for the topics included. 
3.4 
Rationale for Study Design Elements 
3.4.1 
Pragmatic Trial Design 
 
It is now recognized that the results from traditional randomized controlled trials (RCTs) 
often do not generate the information necessary to properly inform health care 
guidelines or policy.45 Trial participants often are not representative of the population in 
which the therapy will be implemented. This discrepancy can lead to well-tested 
therapies either not working, or to unexpected toxicities, when delivered in a real-world 
setting. Clinical trials, in contrast to traditional RCTs, are designed to address real-world 
clinical situations and provide results that are directly applicable to large populations.  
3.4.2 
Community-based Setting 
 
A pragmatic trial using a community-based setting provides several advantages over a 
traditional RCT in the context of this study. First, by recruiting from primary care and 
pediatric clinics, we anticipate improved efficiency in enrollment and reduced loss-to-
follow-up.  Recently, a trial of emollient intervention for AD prevention from Australia 
could not be performed due to the study only enrolling 5% of their target sample size 
using a standard RCT approach.50 Second, a community-based pragmatic trial design, 
unlike many RCTs performed in academic centers, allows for the results of the trial to 
be immediately generalizable to large populations. Trial design better mirrors how the 
intervention would be implemented in the general primary care community.  By 
generating data regarding the effectiveness of this intervention in a community setting, 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
this trial design provides the best chance that the results of the trial will have the largest 
public health impact.  
3.4.3 
Clinician Training in AD Diagnosis 
During the first two months of the funded project, all 25 community-based primary care 
study sites will undergo whole staff protocol training led by the CCC, PI and PBRN 
research coordinator. Training of all clinicians in performing the primary assessment 
occurs during this time using a competency-based training module with clinical 
assessment of AD. Clinicians will be trained in valid and standardized diagnosis using 
the American Academy of Dermatology (AAD) Consensus Criteria for diagnosing 
pediatric AD.37  
3.4.4 
Electronic-based Data Gathering 
 
Parent-derived electronic data gathering greatly improves the overall efficiency of this 
trial.49 Because of the size of the trial population and number of participating sites, 
traditional study visits with in-person assessments or exclusively over-the-phone 
contacts would be extremely costly.  Electronic data gathering reduces the overall 
parent burden and clinic burden when participating in the study and greatly reduces the 
overall cost of the study data management. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
4 STUDY ENROLLMENT AND WITHDRAWAL 
4.1 
Participant Inclusion Criteria 
 
In order to be eligible to participate in this study all of the following criteria must be true 
for the dyad: 
x 
Parent can provide signed and dated electronic informed consent form 
x 
Parent is willing and able to comply with all study procedures for the duration of 
the study  
x 
Parent is a primary caretaker of an infant 0 to 2 months of age 
x 
Parent is 18 years of age or older at time of consent 
x 
Parent can speak, read, and write in English or Spanish 
x 
Parent has a valid e-mail address or phone that can receive text messages 
x 
Parent has reliable access to the internet 
x 
Infant is a patient of a participating Meta-LARC clinic site at the time of consent 
4.2 
Inclusion of Vulnerable Populations 
4.2.1 
Inclusion of Women 
All adults, including women, who are at least 18 years of age and who meet 
inclusion/exclusion criteria will be eligible for study participation. There are no exclusion 
criteria with regards to gender of the infant. 
4.2.2 
Inclusion of Minorities 
All members of racial and ethnic minority groups will be eligible for study participation 
and no participants will be excluded on the basis of race or ethnicity. All study materials 
will be provided in Spanish to include Spanish-speaking populations. 
4.2.3 
Inclusion of Children 
Via parental consent, infants will be enrolled into this study based on the inclusion and 
exclusion criteria. In order to prevent AD, interventions directed at the earliest stages of 
life are needed since the majority of AD begins with the first two years of life. Child 
assent will not be obtained for this study, as children in the target age group upon 
enrollment are not developmentally able to provide assent. Informed consent will be 
obtained by one parent or legal guardian. 
4.2.4 
Inclusion of Neonates 
The project will enroll dyads of parents and neonates/infants 0 to 2 months of age with 
the intervention targeted at parental skin care habits for the infant. Neonates of 
uncertain viability or nonviable neonates will not be included in this study. Viability will 
be determined by the fact that the infant is being seen at the outpatient clinic site (i.e. if 
the infant is a patient at the clinic, they are considered viable). 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
4.3 
Participant Exclusion Criteria 
A dyad who meets any of the following criteria will be excluded from participation in this 
study: 
x 
Infant born at less than 25 weeks gestational age 
x 
Infant has established eczema as diagnosed by the primary healthcare provider 
at clinic site of enrollment per parent report 
x 
Infant has known adverse reaction to petrolatum-based emollients 
x 
Infant has an immunodeficiency genetic syndrome such as Wiskott-Aldrich 
Syndrome or Severe Combined Immunodeficiency Syndrome 
x 
Infant has extremely low birthweight (less than 1000g or 2.2 lbs [2 pounds 3 
ounces] at birth) 
x 
Infant has a sibling enrolled in the study 
x 
Parent is unwilling or unable to comply with study procedures 
4.4 
Enrollment Procedures 
4.4.1 
Screening 
Parent/infant dyads will be recruited from 35 PBRN-affiliated primary care offices in four 
states.  Potential dyads will be informed of the study by clinic staff during any routine 
well-child visits or written communication up to 2 months of life. Clinics will encourage 
dyads to enroll prior to the child’s first month of life to optimize the time that the skin 
barrier is protected. Eligible dyads may enroll in the study up until infant age 2 months 
(63 days). Clinic staff will provide interested parents with a tablet computer, a 
recruitment rack card or recruitment postcard with enrollment URL and QR code. 
Recruitment materials will be provided in clinic waiting rooms, clinic examination rooms, 
enrollment kiosks, through the mail, or via patient portal depending on clinic workflows 
during child or mother scheduled well visits. All screening and enrollment procedures 
will be performed online either in the office via computer tablet (e.g. iPad) or via 
internet-enabled phone or home computer.  The electronic consenting process follows 
all IRB requirements for electronic consent. 
Parents will be asked to review a study information sheet and consent to screening 
procedures. Those who agree will provide their primary contact information and answer 
a brief screening questionnaire to determine eligibility. Automated data checks will 
confirm eligibility via inclusion and exclusion criteria. Eligible dyads who wish to 
continue will be directed to review the consent form. Participants may complete the 
consenting procedure and enrollment questionnaire in clinic or at home. Potential 
participants lacking an e-mail address will be instructed to contact the research 
coordinator to proceed with screening and enrollment. 
4.4.2 
Additional Screening Procedures – Duke University 
In addition to procedures described in section 4.4.1, Duke PBRN coordinators may 
provide recruitment materials to eligible dyads during routine well-child visits or may 
initiate phone, mail and/or portal outreach to families. All screening and enrollment 
procedures will continue online. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
4.4.3 
Additional Screening Procedures – Oregon Health & Science University 
In addition to procedures described in section 4.4.1, and in response to impacts from 
the COVID-19 pandemic, Oregon PBRN coordinators may be granted access to the 
participating clinic’s patient portal to initiate recruitment messages to potentially eligible 
families. All screening and enrollment procedures will continue online. 
4.4.4 
Consent and Enrollment 
After reviewing the consent, parents will respond to a survey question asking whether 
they have any questions about the study. Those who have questions will be instructed 
to call a toll-free number and speak with a research coordinator to review all aspects of 
the project. The electronic data capture system (REDCap) will generate an e-mail to the 
study inbox notifying the research coordinator, who will contact the participant directly if 
a call is not received. After being informed of the study, parents will use the tablet, 
phone screen or computer mouse to electronically sign their name to the signature-
enabled PDF consent form. After the participant has been determined eligible and given 
consent, eligible dyads will then be directed to complete the enrollment questionnaire 
and to provide additional contact information, including details for alternate contacts.  
Upon completion of the enrollment questionnaire, dyads will be automatically assigned 
to a study arm using the randomization schedule.  
4.4.5 
Randomization 
Upon randomization, REDCap will send notification, a PDF of informational materials, 
and a link to a welcome video via e-mail. Dyads randomized to the intervention arm will 
also complete an electronic survey to select an emollient from the approved list. Key 
information regarding treatment allocation (e.g. basics of emollient use or current infant 
skin care practices) will be submitted in the body of the e-mail, with further information 
available in printed study materials mailed to parents. For dyads that enroll with text 
message, the randomization notification and electronic survey to select an emollient will 
be sent via text message.  
 
Dyads will be randomly allocated to the intervention or control arm using permuted 
block randomization stratified by clinic and parent-reported family history of AD. 
Stratifying by site will minimize bias from unmeasured clinic population characteristics 
while stratifying on family history will assure balance between treatment and control 
groups in regards to the underlying risk of AD, which has been shown to be 
approximately two-fold higher in this group.53 In setting up the blocks for randomization 
we will use block sizes of eight and assigned at a 1:1 ratio to either the control or 
intervention arm. A randomization schedule will be created using a computer-based 
random number generator. 
4.5 
Blinding Procedures 
Because of the nature of the intervention, it is not possible to keep dyads blinded to the 
intervention. Administering a placebo emollient would not be possible as there are no 
active ingredients in the emollient itself. Using an emollient that has no barrier 
improvement properties would likely be irritating to the skin and unethical to use on 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
infants. The lack of participant blinding is compensated for by the objective nature of the 
assessment (clinician-assessed AD) and by the final assessment being made by a 
blinded assessor. 
Clinic staff at participating clinics will not be informed by study staff of participant 
enrollment or study arm, primarily to maintain blinding. There is a risk that parents may 
disclose their treatment group to clinic staff.  Clinicians and clinic staff will direct 
participants to follow study skin care recommendations as described in study materials. 
Clinic staff should continue to treat skin-related diseases as they arise. After chart audit 
is completed on participants, clinicians will be asked which randomization arm they 
believe was assigned to individual participants. 
PBRN research coordinators will be blinded and will be responsible for infants’ health 
record review to collect the primary outcome from the participating clinics. If the family 
has disclosed the randomization status to the clinician, this information may appear in 
the health record. At completion of health record review, PBRN research coordinators 
will indicate which randomization arm they believe was assigned in order to measure 
whether the assessor became unblinded while reviewing the health record. 
Maintaining integrity of randomization allocation and blinding is an important asset and 
will be maintained as a primary goal of the DCC. The principal investigator remains 
blinded during AE, SAE and UP assessment. DCC study personnel will be unblinded. 
CCC research assistants may become unblinded during conversations with participants 
during consent and enrollment, quarterly surveys, annual surveys, and in responding to 
incoming communications from participants.  
4.6 
Strategies for Recruitment and Retention 
Regional clinics will utilize clinic workflows to identify eligible dyads as they present for 
scheduled well child visits or when mothers present for scheduled prenatal or 
postpartum visits. The typical structure will place a tablet computer in the waiting room, 
recruitment kiosk or exam room to initiate study procedures. Rack cards or recruitment 
postcards will be offered to families to review after the clinic visit or sent via mail or 
patient portal. Recruitment flyers will be placed in waiting rooms and exam rooms with 
enrollment URL and QR code. Front and back office clinical staff will direct parents to 
the tablet or recruitment materials to initiate screening and enrollment. Patient-focused 
recruitment videos will be made available to clinics for use in introducing the study to 
dyads. 
Each PBRN will assign a research coordinator to support participant recruitment efforts 
at regional clinics. Research coordinators will meet regularly with clinic staff, either in 
person or over the phone, to keep clinic staff engaged in the study and help clinics meet 
their enrollment milestones. Research coordinators will also support clinics who 
encounter challenges with meeting the recruitment goal of two dyads per month through 
conducting small tests of workflow changes and clinical observations to identify 
opportunities for recruitment.  
During approximately 24 months of study participation, parents will receive periodic 
study communications in multiple formats. Dyads will receive compensation (Table 2) to 
incentivize completion of questionnaires and to enhance participant retention. Dyads 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
randomized to the intervention group will receive 24 months’ worth of emollient over the 
course of the study. 
Table 2:  Schedule of compensation 
 
Infant Age 
Compensation for 
Completion of: 
 
Compensation Amount 
0 to 2 months 
Enrollment Questionnaire 
$35 
12 Months 
12 Month Questionnaire 
$50 
24 Months 
24 Month Questionnaire 
$50 
Total Study Compensation 
$135 
 
 
Although the primary study outcome is not dependent on information derived from 
questionnaires, maintaining contact with parents for the entire study duration is critical. 
At baseline, parents will be asked to provide alternate contacts. During quarterly 
contacts, parents will be asked to update contact information in order to minimize loss to 
follow-up. If a participant becomes unresponsive during the study, or a participant 
phone number or e-mail address becomes invalid, CCC research coordinators will 
reach out to alternate contacts and may coordinate with clinics to search for updated 
contact information in the health record. 
Parents will receive study information primarily through electronic methods. Electronic 
communication and data gathering is a more efficient and cost-effective method of 
maintaining a longitudinal cohort than traditional mail/paper methods.54 In addition, after 
enrollment, all dyads will receive a mailed welcome packet with study and 
compensation instructions, contact information and a study magnet.  
 
4.7 
Participant Withdrawal 
Dyads may withdraw voluntarily from the study at any time upon request. To withdraw 
from the study, participants will be asked to contact the CCC by phone or e-mail to 
inform of their intention to withdraw and to state the reason for their withdrawal.  
4.7.1 
Reasons for Withdrawal 
An investigator may terminate a dyad’s participation in the study if any of the following 
occur: 
x Any clinical adverse event (AE), laboratory abnormality, or other medical 
condition or situation occurs such that continued participation in the study would 
be contraindicated. 
x The dyad meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. Participants that develop 
atopic dermatitis will not be withdrawn, as that is the primary outcome. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x Serious complications arise where continuation of treatment is deemed 
inappropriate or impossible. 
x An infant is removed from custody of the participating parent. 
4.7.2 
Handling of Participant Withdrawals or Participant Discontinuation of 
Study Intervention 
Parents who withdraw their dyad from study participation or whose participation is 
terminated by the investigator will be informed (at the time of initial informed consent) 
that the investigator will retain and analyze data already collected prior to the date of 
withdrawal or termination. Participants who withdraw will be asked for: 1) reason for 
withdrawal, and 2) whether the participant wishes to withdraw from the intervention only 
or from all components of the research study, including continued survey data collection 
and chart review. The importance of continued follow-up data collection will be 
explained to all participants who withdraw, including information about maintaining the 
integrity of research data and assessing safety and efficacy outcomes. 
A withdrawal or termination will be reported to the IRB if the withdrawal or termination is 
related to an unanticipated problem involving risk to the dyad or serious adverse event. 
Participants who withdraw or are terminated from the study will not be replaced with a 
new participant. The proposed dyad recruitment numbers account for attrition. 
4.7.3 
Lost to Follow Up 
A participant will be considered lost to follow-up if they have no documentation in the 
electronic medical record of AD and they have no 2-year visit data available given 
appropriate time windows.   

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
5 STUDY INTERVENTION 
5.1 
Rationale for Promotion of Specific Emollients 
Studies in both healthy and diseased skin have shown that most oil-in-water emollients 
improve skin barrier function by providing the skin a protective lipid barrier.55-64 A wealth 
of data show petrolatum-based emollients applied to the skin improve barrier function 
(TEWL and hydration), decreases the effects of skin irritants, and improve clinical 
outcomes.23,65-72 While initial studies found emollient formulations with ceramides and 
specific lipid ratios improve the skin barrier in mice,73 studies in humans have failed to 
demonstrate they are superior to simple petrolatum-based emollients.23,70,74 A recent 
clinical study in children found a ceramide-dominant emollient did not provide superior 
clinical results when compared to Aquaphor (41% petrolatum).23 Similar findings were 
found in a clinical study of hand eczema.75 Given the lack of data supporting their use 
over low-cost alternatives, we have primarily included simple petrolatum-based 
emollients in the study.  
  
Consistent with a pragmatic trial approach, parents will be allowed to select an emollient 
from a list of five emollients. We performed a survey of pediatric dermatologists (n=10) 
with a special interest in AD research, who confirmed that the emollients chosen for this 
trial are ones they found most effective in practice to prevent disease recurrence and 
that no one emollient is clinically superior.  Emollients included in the trial:  
1. 
Are petrolatum-based 
2. 
Are widely available  
3. 
Are of reasonable cost for daily use for 24 months 
4. 
Parents will also be instructed that they can change emollients at any point 
during study participation, as long as they change to an emollient on the 
approved list. 
5.2 
Emollient Choices 
During enrollment procedures, parents assigned to the intervention arm will be 
instructed to choose an emollient from a study-approved list. They will be instructed to 
apply full-body emollient once per day on their infant.  The emollients that will be 
recommended for use are shown in Table 3. 
Table 3. Emollient Acquisition 
Emollient 
Evidence supporting use 
CeraVe ointment 
(replacement for Aquaphor*) 
Refs. 56, 58 
Petrolatum (e.g. Vaseline)  
Refs. 68, 71 
Cetaphil Cream 
Ref. 63  
CeraVe Cream 
Ref. 64 
Vanicream 
none, pediatric derm 
recommended 
* CeraVe Ointment contains similar percent petrolatum as Aquaphor (46.5% versus 41%) and 
does not contain lanolin and bisobolol, two potential sensitizers.  

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
We have received donations from all three sponsor companies to supply emollient 
options that will be provided to participants. Emollients will be provided directly to the 
DCC. Other emollients will be acquired using available research funds from the 
Department of Dermatology, if needed. 
After completing the enrollment questionnaire, participants in the intervention arm will 
receive an e-mail with a survey link to select an emollient from the approved list, 
followed by a reminder SMS text message to check their e-mail if emollient is not 
selected. The dyad will be assigned CeraVe cream, the most popular emollient, if one is 
not selected within three business days of enrollment. Participants in the intervention 
arm will receive a six-month supply of emollient at enrollment, 6 months, 12 months, 
and 18 months. Dyads can request additional emollient supplies between scheduled 
shipments, and those requests will be entered into the study database for use in 
adherence monitoring. 
IRB approval will be accomplished through IND and IDE as outlined from 
communication with the FDA (See Protocol Appendix G). 
5.3 
Formulation, Packaging, and Labeling 
No special formulations, packaging, or labeling requirements will be needed as these 
emollients are currently available over-the-counter to the general population and will be 
used in a manner similar to current use in the general population. 
5.4 
Emollient Storage and Stability 
No special storage or stability issues will be needed beyond manufacturers’ 
recommendations. Emollients will be stored in locked cabinets within climate-controlled 
offices at the DCC prior to distribution. Participants will be asked to follow any 
recommendations on the product in regards to storage requirements. Emollient 
expiration dates will be checked prior to shipping and emollients that expire within six 
months of the shipment date will not be distributed. Emollient will be mailed within three 
business days of enrollment and receiving participant’s mailing address.  
5.5 
Dosage, Preparation and Administration of Study Product 
Parents in the intervention group will be asked to use a once-daily dose of the emollient, 
a frequency used currently in the general population on a regular basis.34,35  
5.6 
Accountability Procedures for the Study Product 
 
Receipt of emollient shipped to dyads will be confirmed using e-mail. Dispensing and 
receipt of emollients will be tracked in the study database. Logs will be maintained of 
emollient brands, lot numbers, expiration dates, shipping dates and participant IDs to 
track distribution of products. The DCC will review inventory logs to monitor need to 
request additional batches of emollients. Adherence will be monitored via survey 
questions and used containers will not be collected by the study team. Parents will be 
instructed to discard unused emollient or continue using after the infant reaches 24 
months of age. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
5.7 
Assessment of Participant Adherence with Study Product Administration 
Participant compliance with daily emollient use (intervention) and general infant skin 
care guidelines (control) will be assessed through quarterly and annual surveys through 
24 months. Pragmatic trial design principles de-emphasize adherence monitoring; 
however, because this is the first trial of its kind in this population, adherence will be 
assessed by parental report on quarterly surveys to gain further information on usage 
patterns. Additional requests for refills will be recorded to indicate adherence to study 
product administration. The methods used to enhance adherence to the emollient use 
fall within the scope of what would be feasible in routine practice.  
5.8 
Concomitant Medications/Treatments 
No restrictions on concomitant medications will be placed.  Participants may treat any 
skin condition or other medical condition with therapy deemed appropriate by their 
infant’s healthcare provider. 
5.9 
Administration of Intervention 
The intervention (promotion of emollient use) will be administered electronically. 
Participants in the intervention arm will receive a welcome packet and a welcome e-
mail, which will have links to text and video educational materials, a list of the preferred 
emollients, and contact information for the study team, including for reporting skin 
product-related adverse events. Intervention arm participants at each quarterly survey 
will also receive reminders encouraging use of emollient. Participants in the control arm 
will receive a welcome packet and a welcome e-mail with current skin care 
recommendations and contact information for the study team to report skin product-
related adverse events. All questionnaires and brief contacts will be delivered by SMS 
text message or e-mail, and compensation for study participation will be administered 
electronically. Table 4 corresponds to the timing of questionnaire administration and 
emollient resupply. 
Table 4:  Questionnaire administration and emollient resupply schedule. 
 
Arm 
Intervention 
Control 
Infant Age 
(in months) 
2 
3 
6 
9 12 15 18 21 24 
2 
3 
6 
9 12 15 18 21 
24 
Questionnaire 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
Quarterly 
Contact  
 
X X X 
X 
X 
X 
X 
X 
 
X X X 
X 
X 
X 
X 
X 
Study 
payment 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
X 
 
 
 
X 
Emollient 
supply 
shipped  
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
6 STUDY SCHEDULE 
Please note, the word “contact” will be used in place of “visit” as all study contacts will 
occur electronically and may occur outside of any patient visit to their provider. 
6.1 
Baseline 
Screening Contact (Infant Age 0 to 2 Months) 
The purpose of the screening contact is to determine eligibility for study participation. 
Clinic staff will direct parents of infants under 2 months old to REDCap to complete 
screening. Screening at participating clinics will occur via a tablet computer through 
interacting with the study screening survey. Parents who are unable to complete the 
screening contact in the office will be given a rack card at the clinic, via mail or via 
patient portal with a URL and QR code to access the screening online from a 
smartphone or home computer. The following activities will occur during the screening 
contact: 
x Obtain and document electronic consent from potential participant with a 
screening consent form. 
x Participant completes a brief screening questionnaire to determine eligibility 
based on inclusion/exclusion criteria. 
x If eligible, participant will provide contact information of name, primary phone 
number and e-mail address, then proceed to consent. 
The total time anticipated to complete the screening contact is 5 minutes. Potential 
participants who have questions about the study or who lack an e-mail address will be 
directed to a toll-free number to call the CCC staff and receive additional information 
and clinic staff will be instructed to direct all potential participant questions to the CCC 
staff. 
Logic programmed into REDCap forms will confirm eligibility criteria, and DCC staff may 
review to confirm. 
Enrollment/Randomization (Contact 1, Infant Age 0 to 2 Months) 
Study participants must complete the screening contact and provide informed consent 
to proceed to the Enrollment Contact. The following will then occur in the order specified 
below: 
a. Parents will be directed to an online consent form for the parent/infant dyad. The 
consent will be reviewed and participants will be asked whether they have 
questions to be discussed with research staff. 
a. Parents who have questions will be provided a toll-free number to call. 
Research staff will receive an automated e-mail from REDCap with an 
alert that a parent has questions. The research coordinator will respond to 
all study questions and interested parents will continue to consent. 
b. The consent form will be signed online with an electronic signature. The 
electronic consent form will be available to download and print as a PDF 
document; and an electronic copy will be sent to the primary e-mail address 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
provided by the participant. Electronic copies will not be provided to those lacking 
an e-mail address. 
c. After consent, parents will then be asked to complete the enrollment 
questionnaire online. Dyads will complete all study screening and enrollment 
procedures before they are considered enrolled into the trial. Enrollment 
questionnaire includes the following: 
x Family history of allergies 
x Home environment 
x Skin care practices 
x Demographics 
x Contact information, including alternate contacts 
 
Once dyads complete enrollment procedures, they will be randomized and will receive 
an e-mail with information about their treatment arm, a PDF of study information and a 
link to a welcome video. Dyads who are randomized to the intervention arm will be sent 
a link to a survey to choose from one of five approved emollients, and the emollient will 
be shipped to their designated address within three business days of receiving the 
participant’s shipping address. Study payment and randomization arm-specific details 
will also be mailed to all enrolled participants within three business days of receiving the 
participant’s shipping address. Dyads enrolling with only text message options will 
receive information about treatment arm via text message. 
All procedures completed through randomization are considered ‘baseline'. Parents who 
decline to provide consent to participate will be counted to determine refusal rates. 
 
2 Week Followup, 14 days after enrollment 
Two weeks after enrollment, a survey sent via e-mail or text message to the participant 
with instructions related to study arm. Dyads are asked whether they would like to talk 
with someone about randomization instructions and are directed to contact research 
staff via a toll-free number or e-mail. Research staff will initiate a phone call to the 
participant if the participant does not contact the researcher. 
 
6.2 
Intermediate Contacts 
Contact 2, Infant Age 3 Months ± 14 days 
Quarterly contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x Parental report of AD or eczema diagnosis by a clinician. 
x Average daily usage of emollient 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Intervention group only: record emollient supply and ship resupply if requested 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
Contact 3, Infant Age 6 Months ± 14 days 
Quarterly contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x Parental report of AD or eczema diagnosis by a clinician. 
x Average daily usage of emollient 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Intervention group only: confirm preferred emollient and ship resupply 
Contact 4, Infant Age 9 Months ± 14 days 
Quarterly contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x Parental report of AD or eczema diagnosis by a clinician. 
x Average daily usage of emollient 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Intervention group only: record emollient supply and ship resupply if requested 
Contact 5, Infant Age 12 Months - 4 weeks + 12 weeks 
12 month questionnaire contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x AD or eczema diagnosis by a clinician. 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Skin care practices, adherence to intervention/control instructions 
x Parental report of sleep loss 
x Medication history 
x Modified Asthma Predictive Index (mAPI) and International Study of Asthma and 
Allergies in Childhood (ISAAC) questionnaire 
x Infant diet 
x Food allergy questions, including parental report of clinician-diagnosed food 
allergies 
x In infants who develop AD: 
o Parental report of AD age of onset 
o AD symptom severity using POEM 
o Parent-reported global severity of eczema 
o Infant Dermatology Quality of Life Instrument (IDQOL) 
x Intervention group only: confirm preferred emollient and ship resupply 
 
After the infant is 12 months of age, the health record will be reviewed by a blinded 
research coordinator to collect the following: 
x Provider diagnosis of AD or eczema 
x Medication history 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x Provider diagnosis of hay fever/allergies, asthma, and/or food allergies 
x Skin product-related adverse events 
x Serious adverse events 
x In infants who were diagnosed with AD/eczema: 
o Date of diagnosis 
o Severity 
o Prescribed medications for treatment of AD, eczema, or rash 
Contact 6, Infant Age 15 Months ± 14 days 
Quarterly contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x Parental report of AD or eczema diagnosis by a clinician. 
x Average daily usage of emollient 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Intervention group only: record emollient supply and ship resupply if requested 
Contact 7, Infant Age 18 Months ± 14 days 
Quarterly contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x Parental report of AD or eczema diagnosis by a clinician.  
x Average daily usage of emollient 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Intervention group only: confirm preferred emollient and ship resupply 
Contact 8, Infant Age 21 Months ± 14 days 
Quarterly contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x Parental report of AD or eczema diagnosis by a clinician. 
x Average daily usage of emollient 
x Parental report of skin product-related adverse events and any serious adverse 
events 
x Intervention group only: record emollient supply and ship resupply if requested 
Contact 9, Infant Age 24 Months - 4 weeks + 12 weeks 
24 month questionnaire contact sent to parents by text message and/or e-mail. 
x Confirm or update contact information. 
x Confirm or update primary care clinic where infant receives care. 
x AD or eczema diagnosis by a clinician. 
x Skin product-related adverse events 
x Serious adverse events 
x Skin care practices, adherence to intervention/control instructions 
x Parental report of sleep loss 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x Prescription or over-the-counter topical medication use 
x Modified Asthma Predictive Index (mAPI) and International Study of Asthma and 
Allergies in Childhood (ISAAC) questionnaire 
x Food allergy questions, including parental report of clinician-diagnosed food 
allergies 
x In infants who develop AD: 
o Parental report of AD age of onset 
o AD symptom severity using POEM 
o Parent-reported global severity of eczema 
o Infant Dermatology Quality of Life Instrument (IDQOL) 
6.3 
Final Study Contact 
Contact 10, Infant Age 24 Months + 90 days 
Infant health record review by blinded research coordinator to record clinical 
assessments through 2-year well-child check (up to 27 months of age). Coordinator 
to collect the following: 
x Primary Endpoint: Provider diagnosis of AD or eczema 
o Any diagnosis of eczema, atopic dermatitis, or atopic eczema at any visit 
o Any qualifiers like “probable” or “probable.” These will be coded as having 
atopic dermatitis for the primary analyses. 
o Date of first diagnosis 
o Treatment(s) used for AD- dose, frequency 
x Secondary Endpoints from chart review 
o Date of first diagnosis of AD by clinician in chart 
o Approximate date of onset of symptoms if recorded (age of child in 
months) 
o Presence of wheeze and date of onset 
o Diagnosis of atopic comorbidities: asthma, allergic rhinitis, food allergy 
o Any allergy testing- skin prick tests or blood 
x Medication history: Any skin-directed prescription therapies: 
o Antibacterial (e.g. mupirocin, bacitracin) 
o Anti-inflammatory (topical corticosteroids, topical calcineurin inhibitors, 
crisaborole) 
o Antifungals (e.g. ketoconazole, econazole, terbinafine) 
o Antivirals (e.g. acyclovir ointment) 
o Any oral antibiotics prescribed for any indication- name of antibiotic, 
duration indicated on prescription, and indication if stated 
x Provider diagnosis of hay fever/allergies, asthma, and/or food allergies 
x Gestational age 
x Birth weight 
x Adverse events 
o Only skin product-related adverse events mentioned in the clinical chart 
will be captured. Event start and stop dates (if known) will be recorded, 
outcome and treatments needed. 
o Any serious adverse events (SAEs), not only skin-related, will be captured  

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x In infants who were diagnosed with AD/eczema: 
o Date of diagnosis 
o Severity 
o Prescribed medications for treatment of AD, eczema, or rash 
 
6.4 
Post-Participation Study Contact 
After participation in the study surveys has concluded, parents will be asked about 
willingness to participate in additional research: 
x Willingness to continue in the cohort or other research 
o Preferred contact method 
6.5 
Withdrawal Contact 
If a dyad withdraws early parents will be asked to provide the following information: 
x Reason for withdrawal 
x Components of the study from which they will withdraw participation (e.g. 
intervention only, intervention plus continued data collection) 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
7 STUDY PROCEDURES /EVALUATIONS 
Questionnaires and data abstracted from the infant’s health record comprise the 
majority of study procedures. No in-person study procedures will take place, though 
infant/parent dyads will complete well-child visits with their provider during the first 2 
years of life as part of standard clinical care. Appendix I and Appendix J provide a 
schedule of events with an overview of the study schedule and procedures. 
7.1 
Study Procedures/Evaluations 
x Questionnaires: quantitative, parent-reported data will be collected from 
questionnaires. Parents will complete questionnaires about their infant’s health, 
AD symptoms or diagnosis, allergy symptoms or diagnosis, AD risk or family 
history, and other measures listed in Appendix F.  
x Validated AD instruments: validated instruments which measure AD symptoms, 
severity, risk-factors, and impact of AD on quality of life (Appendix A-E) will be 
used in the questionnaires. 
x Medication history: only information about skin-related medications and antibiotic 
use will be collected from parents and from the infant medical record. These 
medications may include topical over-the-counter and/or prescribed medications, 
as well as oral medications that are used to treat skin conditions (i.e. antibiotics 
or steroids). 
x Health record abstraction: a health record abstraction conducted at 12 months 
and the final study contact will collect data about provider-diagnosis of AD and 
allergies, treatment of AD and skin-related diseases, and severity of AD.  

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
8 ADVERSE EVENTS REPORTING 
Adverse events (AEs) in this study will be identified (1) by parent report through 
responses the parent provides in electronic contacts (refer to section 5.4), selecting the 
link for reporting skin product-related AEs provided on the websites, (2) by parent report 
via phone or email contact to the CCC, and (3) by review of the infants’ medical record 
through ages 27 months. AEs will be graded as to their expectedness and attribution by 
the principal investigator (unrelated, possibly, probably or definitely related to the 
protocol). Due to the nature and low risk of the intervention, only skin product- related 
adverse events in randomized infants will be actively captured by patient report at least 
quarterly. These skin product-related AEs may qualify as serious adverse events 
(SAEs) or Unanticipated Problems (UPs) and will be actively monitored and reported by 
the PI and study team on a daily basis. All SAEs, not just skin product-related, will also 
be captured by patient report quarterly. 
Clinic chart audits through 27 months will record all skin product-related AEs and UPs 
and all SAEs (whether or not they are skin product-related) and will be reported 
according to the timelines specified in the MOOP and the DSMP. 
8.1 
Definitions 
8.1.1 
Adverse Event (AE) 
Any untoward or undesirable, although not necessarily unexpected, event experienced 
by a human participant that may be a result of: 
x The interventions and interactions in the research 
x The collection of identifiable private information in the research 
x An underlying disease, disorder, or condition of the participant that could be 
reasonably attributed to emollient use 
x Other circumstances unrelated to the research or any underlying disease, 
disorder, or condition of the participant 
8.1.2 
Serious Adverse Event (SAE) 
Any AE that: 
x Is fatal 
x Is life-threatening 
x Is persistent or significantly disabling or incapacitating 
x Results in inpatient hospitalization or prolongation of hospitalization 
x Results in psychological or emotional harm requiring treatment (not applicable in 
our population) 
x Creates a persistent or significant disability 
x Causes a congenital anomaly or birth defect (not applicable in our population) 
x Results in a significant medical incident (considered to be a serious study related 
event because, based upon appropriate medical judgment, it may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition) 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
8.1.3 
Unanticipated Problem (UP) 
Events that are not expected given the nature of the research procedures and the 
participant population being studied and suggest that the research places participants or 
others at a greater risk of harm or discomfort related to the research than was 
previously known or recognized.  Harm to a participant need not occur for an event to 
be an unanticipated problem. 
8.1.4 
Deviation 
A deviation is any noncompliance with the clinical study protocol, Good Clinical 
Practice, or Manual of Operating Procedures requirements.  The noncompliance may 
be on the part of the participant, the investigator, or study staff.  As a result of 
deviations, corrective actions are to be developed by the study staff and implemented 
promptly. 
All deviations will be reported according to the timelines specified in the MOOP and the 
DSMP. 
8.2 
Reporting Adverse Events 
All AEs, SAEs, and UPs will be documented on the appropriate adverse event 
questionnaire, entered into the REDCap database, and reported to the DCC as outlined 
below. 
x All skin product-related AEs and all SAEs will be reported by participants in their 
surveys (at defined contacts) or by direct notification of study staff (through 
website links or by directly calling study phone number). 
x All skin product-related AEs and all SAEs identified during chart audit will be 
entered into REDCap by PBRN research coordinators. 
 
The DCC will evaluate each event and will determine reporting requirements.  The DCC 
will report events to the Data and Safety Monitoring Board (DSMB) according to the 
following timeframes: 
x All SAEs and UPs that require expedited reporting (SAEs that are deemed 
related and unexpected, all UPs) will be reported to the IRB within 48 hours of 
the time the PI learns of the event. 
x Only SAEs provided to the study team will be reported. 
x All other AEs will be reported to the DSMB semi-annually. 
x Summary AE and SAE reports will also be submitted to the IRB at least annually. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
9 STUDY OVERSIGHT 
In addition to the PI, Clinical Coordinating Center, and Data Coordinating Center having 
responsibility for oversight, study oversight will be under the direction of a Data and 
Safety Monitoring Board (DSMB) created with the NIAMS.  The DSMB will review 
reports bi-annually, starting 6 months after the first patient enrolls, to assess safety, 
study progress, and data integrity for the study.  If safety concerns arise, more frequent 
meetings may be held.  The DSMB will operate under the rules of a NIAMS-approved 
Data and Safety Monitoring Plan (DSMP) with oversight by NCR (formerly KAI) 
Research, the NIAMS Collaborator.  The DSMP will outline the charge to the NIAMS-
approved monitoring body and is intended to be a living document to be modified at any 
time if any processes or procedures were to change. 
The PI will routinely report ongoing study activities with emphasis on data integrity and 
participant safety issues, such as SAEs and other events requiring expedited reporting. 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
10 STATISTICAL CONSIDERATIONS 
10.1 
Study Hypotheses 
The primary hypothesis of this study is that an intervention to encourage parents to 
apply daily emollients will reduce the cumulative incidence of AD at two years of age. 
We will test the hypothesis that the relative risk of AD for the treatment versus control 
group is not equal to one. 
10.2 
Study Outcomes 
10.2.1 Primary outcome 
The primary outcome will be any AD diagnosis made by the child’s healthcare provider 
by 27 months of age (cumulative incidence or cumulative proportion) using standard 
crtieria.76 (See Section 2.2) 
10.2.2 Key Secondary Endpoints 
The key secondary endpoints include: AD diagnosis using parental report, need for 
prescription anti-inflammatory cream for the skin, incidence of skin care-related adverse 
events and skin infection, tolerability of the intervention, number and type of yearly 
wheezing episodes that predict asthma risk 41 and immediate type I hypersensitivity 
symptoms related to foods. In children who develop AD, the severity of symptoms 
(POEM) and the impact on infant quality of life (IDQOL) will be measured.43,44 The 
Statistical Analysis Plan contains a full list of secondary outcomes with supporting 
references. 
10.3 
Power and sample size 
calculations 
10.3.1 Power and sample size  
10.3.2 Primary Outcome 
For the purpose of the primary 
analysis, we will include a sufficient 
number of babies in a 1:1 ratio for 
the two study arms to provide an 
overall type I error rate of 0.05 and 
80% power to detect a 30% relative 
reduction in cumulative incidence 
over 2 years (also known as 
incidence proportion) of AD (RR=0.7). From our planning grant, we estimated the 
baseline cumulative incidence of AD in this age group and target clinics at 24% at age 
2, The trials in high-risk populations of daily vs no emollient have shown reductions of 
50%, we assumed a more conservative 30% reduction to 16.8%. Using the O’Brien-
Fleming group sequential spending function approach, a total of 982 infants (491 per 
arm) are required to detect this difference in proportions. Allowing for an approximate 
20% loss to follow-up, we plan to enroll 1,250 dyads (625 per arm). Sample size 
calculations were performed using Stat/IC version 16.1. 
Table 6. Power to detect plausible interactions in exploratory analyses 
(Aim 2). 
Risk factor  
AD 
risk 
Prev-
alence 
Tx 
effect 
if RF+ 
Tx 
effect 
if RF- 
Tx 
effect 
DIFF 
Power 
DWĮ 
0.1 
Family hx of 
atopy 
2.0 
0.50 
0.63 
0.60 
0.57 
0.83 
0.90 
0.97 
-0.20 
-0.30 
-0.40 
0.48 
0.56 
0.64 
High humidity 
0.8 
0.44 
0.82 
0.89 
0.95 
0.62 
0.58 
0.54 
0.20 
0.30 
0.40 
0.40 
0.52 
0.65 
Cat owner 
1.0 
0.30 
0.84 
0.91 
0.98 
0.64 
0.61 
0.58 
0.20 
0.30 
0.40 
0.36 
0.48 
0.60 
Dog owner 
0.7 
0.37 
0.84 
0.91 
0.98 
0.64 
0.61 
0.58 
0.20 
0.30 
0.40 
0.36 
0.46 
0.59 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
10.3.3 Power and sample size for detecting effect modifications  
To determine our power to detect significant effect size differences stratified by various 
baseline variables (interaction) such as sex, race or ethnicity, atopic family history, 
climate, and pet ownership, we generated plausible 2x2 tables of risk factors (RFs) and 
AD for each treatment group that would yield absolute differences in the treatment effect 
of 0.2, 0.3, and 0.4, taking into consideration the study sample size, overall projected 
AD and treatment effect, previously published risk of AD for the RF, and prevalence of 
the RF. We simulated 500 replicates of each scenario using the binomial probabilities 
from the 2x2 tables and tested for significance of the interaction in a log-binomial 
(relative risk) model as described below. The power estimates in Table 6 are the 
proportion of simulated datasets in which the null hypothesis was appropriately rejected.  
 
10.4 
Statistical analyses 
10.4.1 Analysis of Primary Endpoint  
For our primary analysis, we will contrast the risk of diagnosed AD by two years of age 
for the intervention versus control groups under an intention-to-treat (ITT) assumption, 
where all subjects will be analyzed according to the group to which they were allocated 
regardless of adherence or group cross-over, and missing outcome values will be 
multiply imputed using the expectation-maximization (EM) algorithm.78 Model: We will 
use logistic regression with a treatment variable (intervention=1, control=0) and perform 
a two-tailed likelihood ratio test of the treatment effect at the overall 0.05 level of 
significance using an O’Brien-Fleming critical boundary to accommodate one planned 
interim analysis. Because randomization will have been stratified by clinic and family 
history of AD in a first-degree relative (yes/no), we will include these variables to avoid 
overestimation of the p-value.79,80 We will estimate the absolute and relative differences 
between groups as the (1) difference and (2) ratio, respectively, of the average 
conditional predicted risk for intervention versus controls from the logistic model, 
calculating standard errors and 95% confidence intervals using the delta method. We 
will use an inclusive strategy to select variables when imputing the missing outcomes 
77,81 using intervention status and clinic along with parent-reported provider diagnosis, 
risk factors, and emollient use from electronic survey and text responses, as well as 
interaction terms found to be significant in Aim 2 (below). 
10.4.2 Effect modification of primary endpoint  
We will examine potential modification of the intervention effect by sex (consistent with 
NIH guidelines), race or ethnicity, atopic family history, climate, and pet ownership by 
creating separate logistic regression models under multiple imputation that include the 
variable of interest with intervention status and an interaction term, adjusting for 
stratification variables. Multiple imputation will be performed as above with the 
interaction term included in the imputation step. We will test for significance of the 
interaction term with a two-sided Wald test at the 0.1 level. A level of 0.1 was used 
because of the exploratory nature of this aim that will be solely used to guide future 
research and due to the impracticality of fully powering this secondary analysis. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
10.4.3 Secondary analyses of primary endpoint 
As a sensitivity analysis, we will perform a complete-case analysis using only subjects 
who have non-missing outcome data in a logistic regression model adjusting for 
stratification variables as well as covariates that we find to be associated with missing 
AD status.78 The effect of emollient use will be evaluated with a model similar to the 
SULPDU\DQDO\VLVEXWVXEVWLWXWLQJDQLQGLFDWRURIUHJXODUUHSRUWHGHPROOLHQWXVHGD\V
per week) for intervention allocation. In a separate model, we will include a variable for 
bathing frequency. In the likely case that bathing and emollient use frequency are 
associated, we will create and test a combined categorical variable. We will return to the 
primary intervention-effect model and consider additional covariates previously found or 
suspected to be associated with AD, such as climate, season of birth, pet ownership, 
bathing frequency, and characteristics of the living environment using a change-in-
estimate approach.83 Finally, we will compare clinic-stratified intervention effects on the 
primary AD outcome and test their equality with a Breslow-Day test; the purpose is to 
identify 'large' differences where further investigation into potential protocol deviations or 
other factors may be warranted, and these results will be interpreted with caution. 
10.4.4 Analysis of Key Secondary Endpoints  
To test the hypothesis that emollient use delays onset of AD, we will compare time to 
onset using child's age in months with discrete time-to-event methods.84 Time to AD 
onset will be defined in two ways, as (1) parental report of age of eczema onset and (2) 
age at first diagnosis recorded in patient chart. Censoring will occur at the date of last 
parental report or last visit recorded in the patient chart. We will also compare the 
intervention and control groups with respect to conditions and symptoms that include 
the need for topical therapy, asthma, food allergy symptoms, and dichotomized disease 
severity measures as binary measures, sleep loss days as counts, and AD severity 
scores (POEM and IDQOL) as continuous measures. We will test for differences using 
logistic, Poisson, or linear regression, adjusting for stratification variables. The incidence 
of adverse events at two years of age will also be compared between the treatment and 
control groups with a two-tailed chi-square test at the 0.05 level of significance.  
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
11 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate research records for this study, in compliance with 
ICH E6, Section 4.9 and regulatory and institutional requirements for the protection of 
confidentiality of participants.  Study staff will permit authorized representatives of 
NIAMS and regulatory agencies to examine (and when required by applicable law, to 
copy) research records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety, progress and data validity. 
 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6.  
12.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the 
changes are implemented in the study.   
12.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation. A description of 
possible risks and benefits of study participation will be provided to families.  An IRB-
approved consent form describing in detail the study procedures and risks will be 
reviewed electronically and made available to the participant. The CCC will be available 
via toll-free phone number to explain the research study to the participant and answer 
any questions that may arise. The participant will electronically sign the informed 
consent document prior to any study-related assessments or procedures. Participants 
will be given the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. Participants may withdraw consent at any time 
throughout the course of the study. An electronic copy of the signed informed consent 
document will be available to download and will be e-mailed to participants for their 
records. Participants will be informed that the quality of their clinical care will not be 
adversely affected if they decline to participate in this study. 
The consent process will be documented in the research record. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
13 DATA HANDLING AND RECORD KEEPING 
13.1 
Data Management Responsibilities 
Data collection and accurate documentation are the responsibility of the study staff 
under the supervision of the investigator.  All source documents and medical chart 
abstractions must be reviewed by the CCC and DCC staff, who will ensure that they are 
accurate and complete.  Unanticipated problems and adverse events will be reviewed 
by the PI. 
13.2 
Data Capture Methods 
Data will be collected on standardized forms on which nearly all responses have been 
pre-coded. Data will be collected directly from parents using web-based surveys. PBRN 
research coordinators will perform health record reviews of enrolled infants at 24 
months and send data to the CCC to enter directly into the REDCap database. In both 
cases, the case report forms will serve as source documentation. The DCC will monitor 
for timely entry of data and maintain a study calendar. 
13.3 
Types of Data 
The following types of data will be collected over the course of the study: 
x Questionnaire responses: electronic surveys will allow parents to enter data 
directly into a REDCap database. If necessary, DCC staff may contact parents to 
answer survey questions over the phone and will enter responses into REDCap. 
x Health record review: research coordinators will perform health record review at 
infant age 27 months to see if an AD diagnosis has been made by the primary 
care provider, as well as other clinical data of interest. 
x Current participant contact information 
x Participant contacts and contact attempts 
x Emollient preference and tracking 
x Participant compensation 
x Safety data: Safety data will be stored in REDCap with other study data. 
x Missing Data 
The study’s approach to missing data follows the recommendations of the National 
Research Council of the prevention and treatment of missing data in clinical trials.83   
Specifically, we will use the following methods to prevent missing data and account for it 
in the analyses: 
x Participants will be informed at the time of consent the importance of remaining 
in the study and providing reasons for withdrawal if needed 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
x Participant retention methods including text messaging and medical record 
review 
x Key covariates will be collected at baseline regardless of intervention arm 
x Missing data are addressed in our statistical analyses using state-of-the-art 
procedures like multiple imputation procedures and use of sensitivity analyses 
13.4 
Performance Monitoring 
The DCC will present regular reports to the CCC and PBRN directors. These include:  
x Monthly recruitment reports: reports of the number of dyads screened, enrolled, 
screen-failed, and randomized by month and by PBRN, as well as average 
randomized per month. 
x Annual committee reports: reports detailing recruitment, baseline patient 
characteristics, data quality, incidence of missing data and adherence to study 
protocol by clinical site, will be provided semi-annually to the Steering 
Committee.    
x Semi-annual Safety Monitor reports: every report includes adverse events, 
patient recruitment, retention, baseline patient characteristics, center 
performance, timeliness of data submission and protocol adherence, withdrawals 
(in addition to safety and efficacy data). Data will be reported by clinic.  
13.5 
Study Records Retention 
Study records will be maintained for at least three years from the date that the grant 
federal financial report (FFR) is submitted to the NIAMS. These documents may be 
retained for a longer period, however, if required by local regulations.  No records will be 
destroyed without the written consent of the sponsor, if applicable.  It is the 
responsibility of the sponsor to inform the investigator when these documents no longer 
need to be retained. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
14 LITERATURE REFERENCES 
1. 
Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients 
with atopic dermatitis. The Journal of allergy and clinical immunology. 
2013;131(2):428-433. 
2. 
Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI, Group IPTS. 
Global variations in prevalence of eczema symptoms in children from ISAAC 
Phase Three. The Journal of allergy and clinical immunology. 2009;124(6):1251-
1258.e1223. 
3. 
Williams H, Stewart A, von Mutius E, et al. Is eczema really on the increase 
worldwide? The Journal of allergy and clinical immunology. 2008;121(4):947-
954.e915. 
4. 
Margolis DJ, Apter AJ, Gupta J, et al. The persistence of atopic dermatitis and 
filaggrin (FLG) mutations in a US longitudinal cohort. Journal of Allergy and 
Clinical Immunology. 2012;130(4):912-917. 
5. 
Chamlin SL. The psychosocial burden of childhood atopic dermatitis. 
Dermatologic therapy. 2006;19(2):104-107. 
6. 
Su JC, Kemp AS, Varigos GA, Nolan TM. Atopic eczema: its impact on the family 
and financial cost. Archives of Disease in Childhood. 1997;76(2):159-162. 
7. 
Schmitt J, Buske-Kirschbaum A, Roessner V. Is atopic disease a risk factor for 
attention-deficit/hyperactivity disorder? A systematic review. Allergy. 
2010;65(12):1506-1524. 
8. 
Mancini AJ, Kaulback K, Chamlin SL. The socioeconomic impact of atopic 
dermatitis in the United States: a systematic review. Pediatric dermatology. 
2008;25(1):1-6. 
9. 
Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function 
variants of the epidermal barrier protein filaggrin are a major predisposing factor 
for atopic dermatitis. Nature genetics. 2006;38(4):441-446. 
10. 
Brown SJ, McLean WH. One remarkable molecule: filaggrin. The Journal of 
investigative dermatology. 2012;132(3 Pt 2):751-762. 
11. 
Flohr C, England K, Radulovic S, et al. Filaggrin loss-of-function mutations are 
associated with early-onset eczema, eczema severity and transepidermal water 
loss at 3 months of age. The British journal of dermatology. 2010;163(6):1333-
1336. 
12. 
Henderson J, Northstone K, Lee SP, et al. The burden of disease associated with 
filaggrin mutations: a population-based, longitudinal birth cohort study. The 
Journal of allergy and clinical immunology. 2008;121(4):872-877.e879. 
13. 
Oji V, Eckl KM, Aufenvenne K, et al. Loss of corneodesmosin leads to severe 
skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease. 
American Journal of Human Genetics. 2010;87(2):274-281. 
14. 
De Benedetto A, Rafaels NM, McGirt LY, et al. Tight junction defects in patients 
with atopic dermatitis. 2011;127(3):773-786.e771-777. 
15. 
Boguniewicz M, Leung DY. Atopic dermatitis: a disease of altered skin barrier 
and immune dysregulation. Immunological reviews. 2011;242(1):233-246. 
16. 
Cork MJ, Robinson D, Vasilopoulos Y, et al. Predisposition to Sensitive Skin and 
Atopic Eczema. Community Practitioner. 2005;78(12). 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
17. 
Proksch E, Elias PM. Epidermal barrier in atopic dermatitis. In: Bieber T, Leung 
DYM, eds. Atopic Dermatitis. Vol 1st. Ney York, NY: Marcel Dekker, Inc; 2002. 
18. 
Kelleher M, Dunn-Galvin A, Hourihane JOB, et al. Skin barrier dysfunction 
measured by transepidermal water loss at 2 days and 2 months predates and 
predicts atopic dermatitis at 1 year. Journal of Allergy and Clinical Immunology. 
2015;135(4):930-935.e931. 
19. 
Horimukai K, Morita K, Narita M, et al. Transepidermal water loss measurement 
during infancy can predict the subsequent development of atopic dermatitis 
regardless of filaggrin mutations. Allergology international : official journal of the 
Japanese Society of Allergology. 2016;65(1):103-108. 
20. 
Sawada E, Yoshida N, Sugiura A, Imokawa G. Th1 cytokines accentuate but Th2 
cytokines attenuate ceramide production in the stratum corneum of human 
epidermal equivalents: an implication for the disrupted barrier mechanism in 
atopic dermatitis. Journal of dermatological science. 2012;68(1):25-35. 
21. 
Howell MD, Kim BE, Gao P, et al. Cytokine modulation of atopic dermatitis 
filaggrin skin expression. The Journal of allergy and clinical immunology. 
2009;124(3 Suppl 2):R7-R12. 
22. 
Kezic S, O'Regan GM, Yau N, et al. Levels of filaggrin degradation products are 
influenced by both filaggrin genotype and atopic dermatitis severity. Allergy. 
2011;66(7):934-940. 
23. 
Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is as 
clinically effective as, and more cost-effective than, prescription barrier creams in 
the treatment of children with mild-to-moderate atopic dermatitis: a randomized, 
controlled trial. Journal of drugs in dermatology : JDD. 2011;10(5):531-537. 
24. 
Cork MJ, Britton J, Butler L, Young S, Murphy R, Keohane SG. Comparison of 
parent knowledge, therapy utilization and severity of atopic eczema before and 
after explanation and demonstration of topical therapies by a specialist 
dermatology nurse. The British journal of dermatology. 2003;149(3):582-589. 
25. 
Szczepanowska J, Reich A, Szepietowski JC. Emollients improve treatment 
results with topical corticosteroids in childhood atopic dermatitis: a randomized 
comparative study. Pediatric allergy and immunology : official publication of the 
European Society of Pediatric Allergy and Immunology. 2008;19(7):614-618. 
26. 
Simpson EL, Berry TM, Brown PA, Hanifin JM. A pilot study of emollient therapy 
for the primary prevention of atopic dermatitis. Journal of the American Academy 
of Dermatology. 2010;63(4):587-593. 
27. 
Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhancement of the skin 
barrier from birth offers effective atopic dermatitis prevention. The Journal of 
allergy and clinical immunology. 2014;134(4):818-823. 
28. 
Horimukai K, Morita K, Narita M, et al. Application of moisturizer to neonates 
prevents development of atopic dermatitis. Journal of Allergy and Clinical 
Immunology. 2014;134(4):824-830.e826. 
29. 
Taylor AL, Dunstan JA, Prescott SL. Probiotic supplementation for the first 6 
months of life fails to reduce the risk of atopic dermatitis and increases the risk of 
allergen sensitization in high-risk children: A randomized controlled trial. Journal 
of Allergy and Clinical Immunology. 2007;119(1):184-191. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
30. 
Abrahamsson TR, Jakobsson T, Böttcher MF, et al. Probiotics in prevention of 
IgE-associated eczema: A double-blind, randomized, placebo-controlled trial. 
Journal of Allergy and Clinical Immunology. 2007;119(5):1174-1180. 
31. 
YDQ*RRO&-$:7KLMV&+HQTXHW&-0HWDOȖ-Linolenic acid supplementation 
for prophylaxis of atopic dermatitis—a randomized controlled trial in infants at 
high familial risk. The American Journal of Clinical Nutrition. 2003;77(4):943-951. 
32. 
Denburg JA, Hatfield HM, Cyr MM, et al. Fish oil supplementation in pregnancy 
modifies neonatal progenitors at birth in infants at risk of atopy. Pediatric 
research. 2005;57(2):276-281. 
33. 
Laitinen K, Laitinen K, Kalliomaki M, Poussa T, Lagstrom H, Isolauri E. 
Evaluation of diet and growth in children with and without atopic eczema: follow-
up study from birth to 4 years. British Journal of Nursing. 2005;94(4):565. 
34. 
Rendell ME, Baig-Lewis SF, Berry TM, et al. Do early skin care practices alter 
the risk of atopic dermatitis? A case-control study. Pediatric dermatology. 
2011;28(5):593-595. 
35. 
Gao X, Simpson EL. Market trends in baby skin care products and implications 
for clinical practice. Pediatr Dermatol. 2014;31(6):734-738. 
36. 
Czarnowicki T, Malajian D, Khattri S, et al. Petrolatum: Barrier repair and 
antimicrobial responses underlying this "inert" moisturizer. The Journal of allergy 
and clinical immunology. 2015. 
37. 
Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB. Consensus 
conference on pediatric atopic dermatitis. Journal of the American Academy of 
Dermatology. 2003;49(6):1088-1095. 
38. 
Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the 
management of atopic dermatitis: section 1. Diagnosis and assessment of atopic 
dermatitis. Journal of the American Academy of Dermatology. 2014;70(2):338-
351. 
39. 
Silverberg JI, Patel N, Immaneni S, et al. Assessment of atopic dermatitis using 
self-report and caregiver report: a multicentre validation study. The British journal 
of dermatology. 2015;173(6):1400-1404. 
40. 
von Kobyletzki LB, Berner A, Carlstedt F, Hasselgren M, Bornehag CG, 
Svensson A. Validation of a parental questionnaire to identify atopic dermatitis in 
a population-based sample of children up to 2 years of age. Dermatology. 
2013;226(3):222-226. 
41. 
Chang TS, Lemanske RF, Jr., Guilbert TW, et al. Evaluation of the modified 
asthma predictive index in high-risk preschool children. The journal of allergy and 
clinical immunologyIn practice. 2013;1(2):152-156. 
42. 
Forrest CB, Bevans KB, Pratiwadi R, et al. Development of the PROMIS (R) 
pediatric global health (PGH-7) measure. Quality of life research : an 
international journal of quality of life aspects of treatment, care and rehabilitation. 
2014;23(4):1221-1231. 
43. 
Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Translating Patient-
Oriented Eczema Measure (POEM) scores into clinical practice by suggesting 
severity strata derived using anchor-based methods. British Journal of 
Dermatology. 2013;169(6):1326-1332. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
44. 
Lewis-Jones MS, Finlay AY, Dykes PJ. The Infant's Dermatitis Quality of Life 
Index. British Journal of Dermatology. 2001;144(1):104-110. 
45. 
Chalkidou K, Tunis S, Whicher D, Fowler R, Zwarenstein M. The role for 
pragmatic randomized controlled trials (pRCTs) in comparative effectiveness 
research. Clinical trials (London, England). 2012;9(4):436-446. 
46. 
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity 
and mortality in patients with severe heart failure. Randomized Aldactone 
Evaluation Study Investigators. The New England journal of medicine. 
1999;341(10):709-717. 
47. 
Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication 
of the Randomized Aldactone Evaluation Study. The New England journal of 
medicine. 2004;351(6):543-551. 
48. 
Zwarenstein M, Treweek S. What kind of randomised trials do patients and 
clinicians need? Evidence Based Medicine. 2009;14(4):101-103. 
49. 
Ware JH, Hamel MB. Pragmatic Trials — Guides to Better Patient Care? The 
New England journal of medicine. 2011;364(18):1685-1687. 
50. 
Lowe AJ, Tang ML, Dharmage SC, et al. A phase I study of daily treatment with a 
ceramide-dominant triple lipid mixture commencing in neonates. BMC 
dermatology. 2012;12:3-5945-5912-5943. 
51. 
McGlynn EA, Asch SM, Adams J, et al. The quality of health care delivered to 
adults in the United States. The New England journal of medicine. 
2003;348(26):2635-2645. 
52. 
Westfall JM, Mold J, Fagnan L. Practice-based research--"Blue Highways" on the 
NIH roadmap. JAMA : the journal of the American Medical Association. 
2007;297(4):403-406. 
53. 
Moore MM, Rifas-Shiman SL, Rich-Edwards JW, et al. Perinatal predictors of 
atopic dermatitis occurring in the first six months of life. Pediatrics. 2004;113(3 Pt 
1):468-474. 
54. 
Toledano MB, Smith RB, Brook JP, Douglass M, Elliott P. How to Establish and 
Follow up a Large Prospective Cohort Study in the 21st Century--Lessons from 
UK COSMOS. PloS one. 2015;10(7):e0131521. 
55. 
Darmstadt GL, Badrawi N, Law PA, et al. Topically applied sunflower seed oil 
prevents invasive bacterial infections in preterm infants in Egypt: a randomized, 
controlled clinical trial. The Pediatric infectious disease journal. 2004;23(8):719-
725. 
56. 
Darmstadt GL, Saha SK, Ahmed AS, et al. Effect of topical emollient treatment of 
preterm neonates in Bangladesh on invasion of pathogens into the bloodstream. 
Pediatric research. 2007;61(5 Pt 1):588-593. 
57. 
Ghali FE. Improved clinical outcomes with moisturization in dermatologic 
disease. Cutis; cutaneous medicine for the practitioner. 2005;76(6 Suppl):13-18. 
58. 
Pabst RC, Starr KP, Qaiyumi S, Schwalbe RS, Gewolb IH. The effect of 
application of aquaphor on skin condition, fluid requirements, and bacterial 
colonization in very low birth weight infants. Journal of perinatology : official 
journal of the California Perinatal Association. 1999;19(4):278-283. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
59. 
Loden M, Andersson AC, Lindberg M. Improvement in skin barrier function in 
patients with atopic dermatitis after treatment with a moisturizing cream 
(Canoderm). The British journal of dermatology. 1999;140(2):264-267. 
60. 
Nopper AJ, Horii KA, Sookdeo-Drost S, Wang TH, Mancini AJ, Lane AT. Topical 
ointment therapy benefits premature infants. The Journal of pediatrics. 
1996;128(5 Pt 1):660-669. 
61. 
lebwohl m, herrmann m. Impaired Skin Barrier Function in Dermatologic Disease 
and Repair with Moisturization. Cutis. 2005;76(Supplement):7. 
62. 
Nebus J, Wallo W, Fowler J. Evaluating the safety and tolerance of a body wash 
and moisturizing regimen in patients with atopic dermatitis. Poster presented at: 
65th Annual Meeting of the American Academy of Dermatology; February 2-6, 
2007;Washington, D.C. P714. 
63. 
Laquieze S, Czernielewski J, Baltas E. Beneficial use of Cetaphil moisturizing 
cream as part of a daily skin care regimen for individuals with rosacea. The 
Journal of dermatological treatment. 2007;18(3):158-162. 
64. 
Draelos ZD. Moisturizing cream ameliorates dryness and desquamation in 
participants not receiving topical psoriasis treatment. Cutis; cutaneous medicine 
for the practitioner. 2008;82(3):211-216. 
65. 
Loden M. The skin barrier and use of moisturizers in atopic dermatitis. Clinics in 
dermatology. 2003;21(2):145-157. 
66. 
Loden M. Role of topical emollients and moisturizers in the treatment of dry skin 
barrier disorders. American journal of clinical dermatology. 2003;4(11):771-788. 
67. 
Hoggarth A, Waring M, Alexander J, Greenwood A, Callaghan T. A controlled, 
three-part trial to investigate the barrier function and skin hydration properties of 
six skin protectants. Ostomy/wound management. 2005;51(12):30-42. 
68. 
Ghadially R, Halkier-Sorensen L, Elias PM. Effects of petrolatum on stratum 
corneum structure and function. Journal of the American Academy of 
Dermatology. 1992;26(3 Pt 2):387-396. 
69. 
Patzelt A, Lademann J, Richter H, et al. In vivo investigations on the penetration 
of various oils and their influence on the skin barrier. Skin research and 
technology : official journal of International Society for Bioengineering and the 
Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] 
International Society for Skin Imaging (ISSI). 2012;18(3):364-369. 
70. 
Nolan K, Marmur E. Moisturizers: reality and the skin benefits. Dermatologic 
therapy. 2012;25(3):229-233. 
71. 
Wigger-Alberti W, Elsner P. Petrolatum prevents irritation in a human cumulative 
exposure model in vivo. Dermatology (Basel, Switzerland). 1997;194(3):247-250. 
72. 
Soll RF, Edwards WH. Emollient ointment for preventing infection in preterm 
infants. Cochrane database of systematic reviews (Online). 
2000;(2)(2):CD001150. 
73. 
Man Mq M, Feingold KR, Thornfeldt CR, Elias PM. Optimization of physiological 
lipid mixtures for barrier repair. The Journal of investigative dermatology. 
1996;106(5):1096-1101. 
74. 
Loden M, Barany E. Skin-identical lipids versus petrolatum in the treatment of 
tape-stripped and detergent-perturbed human skin. Acta Dermato-Venereologica. 
2000;80(6):412-415. 

 ________________________________________________________________________________________________________  
 
 ____________________________________________________________________________________________ 
 
75. 
Kucharekova M, Van De Kerkhof PC, Van Der Valk PG. A randomized 
comparison of an emollient containing skin-related lipids with a petrolatum-based 
emollient as adjunct in the treatment of chronic hand dermatitis. Contact 
dermatitis. 2003;48(6):293-299. 
76. 
Eichenfield LF, Hanifin JM, Luger TA, Stevens SR, Pride HB. Consensus 
conference on pediatric atopic dermatitis*. Journal of the American Academy of 
Dermatology. 2003;49(6):1088-1095. 
77. 
Punekar YS, Sheikh A. Establishing the incidence and prevalence of clinician-
diagnosed allergic conditions in children and adolescents using routinely 
collected data from general practices. Clin Exp Allergy. 2009;39(8):1209-1216. 
78. 
Little RJ, Rubin DB. Statistical analysis with missing data. Wiley; 1987. 
79. 
Bisgaard H, Simpson A, Palmer CN, et al. Gene-environment interaction in the 
onset of eczema in infancy: filaggrin loss-of-function mutations enhanced by 
neonatal cat exposure. PLoS medicine. 2008;5(6):e131. 
80. 
Schuttelaar MLA, Kerkhof M, Jonkman MF, et al. Filaggrin mutations in the onset 
of eczema, sensitization, asthma, hay fever and the interaction with cat 
exposure. Allergy. 2009;64(12):1758-1765. 
81. 
Biagini Myers JM, Wang N, LeMasters GK, et al. Genetic and environmental risk 
factors for childhood eczema development and allergic sensitization in the 
CCAAPS cohort. The Journal of investigative dermatology. 2010;130(2):430-437. 
82. 
Proschan MA, Lan KG, Wittes JT. Statistical monitoring of clinical trials: a unified 
approach. Springer Science & Business Media; 2006. 
83. 
Greenland S. Modeling and variable selection in epidemiologic analysis. 
American Journal of Public Health. 1989;79(3):340-349. 
84. 
Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. John 
Wiley & Sons; 2011.