Team-Based Connected Health (TCH) to Improve Clinical Outcomes and Access in Atopic Dermatitis
Phase: NA
Conditions: Atopic Dermatitis Eczema, Atopic Dermatitis, Eczema
Sponsor: University of Southern California

 
Version date 23-Sep-2019 
 
1 
 
 
 
 
Team-Based Connected Health to Improve Clinical Outcomes 
and Access in Atopic Dermatitis 
National Clinical Trial (NCT) Identified Number:  NCT03981926 
September 23, 2019 
 
 
 
 

 
Version date 23-Sep-2019 
 
2 
Table of Contents 
STATEMENT OF COMPLIANCE 
5 
1 
PROTOCOL SUMMARY 
5 
1.1 
SYNOPSIS 
5 
1.2 
SCHEMA 
7 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
8 
2 
INTRODUCTION 
8 
2.1 
STUDY RATIONALE 
8 
2.2 
RISK / BENEFIT ASSESSMENT 
9 
2.2.1 
KNOWN POTENTIAL RISKS 
9 
2.2.2 
KNOWN POTENTIAL BENEFITS 
9 
2.2.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
10 
3 
OBJECTIVES AND ENDPOINTS 
10 
4 
STUDY DESIGN 
11 
4.1 
OVERALL DESIGN 
11 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
12 
4.3 
RATIONALE FOR INTERVENTION 
12 
5 
STUDY POPULATION 
12 
5.1 
INCLUSION CRITERIA 
12 
5.2 
EXCLUSION CRITERIA 
13 
5.3 
SCREEN FAILURES 
13 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
13 
5.4.1 
RECRUITMENT PLAN 
13 
5.4.2 
RETENTION PLAN 
13 
5.4.3 
VULNERABLE SUBJECTS 
14 
6 
STUDY INTERVENTION 
14 
6.1 
STUDY INTERVENTION ADMINISTRATION 
14 

 
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3 
6.1.1 
INTERVENTION DESCRIPTION AND ADMINISTRATION 
14 
6.1.1.1 
WHAT DEFINES AN ONLINE VISIT? 
15 
6.1.1.2 
WHAT HAPPENS DURING AN ONLINE VISIT? 
15 
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
15 
6.3 
STUDY INTERVENTION COMPLIANCE 
15 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
16 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
16 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
16 
7.3 
LOST TO FOLLOW-UP 
16 
8 
STUDY ASSESSMENTS AND PROCEDURES 
17 
8.1 
EFFICACY ASSESSMENTS 
17 
8.2 
SAFETY AND OTHER ASSESSMENTS 
17 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
18 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
18 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
18 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
18 
8.3.3.1 
SEVERITY OF EVENT 
18 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
18 
8.3.3.3 
EXPECTEDNESS 
19 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
19 
8.3.5 
ADVERSE EVENT REPORTING 
19 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING 
20 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS 
20 
8.4 
UNANTICIPATED PROBLEMS 
20 
8.4.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UPs) 
20 
8.4.2 
UNANTICIPATED PROBLEM REPORTING 
21 
8.4.3 
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
21 

 
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4 
9 
STATISTICAL CONSIDERATIONS 
21 
9.1 
SAMPLE SIZE DETERMINATION 
21 
9.2 
POPULATIONS FOR ANALYSES 
22 
9.3 
STATISTICAL ANALYSES 
22 
9.3.1 
GENERAL APPROACH 
22 
9.3.2 
ANALYSIS OF THE PRIMARY EFFICAY ENDPOINTS 
22 
9.3.3 
ANALYSIS OF THE SECONDARY ENDPOINTS 
23 
9.3.4 
SAFETY ANALYSES 
24 
9.3.5 
BASELINE DESCRIPTIVE STATISTICS 
25 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
25 
10.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATION 
25 
10.1.1 
INFORMED CONSENT PROCESS 
25 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS25 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
25 
10.1.2 
STUDY DISCONTINUATION AND CLOSURE 
26 
10.1.3 
CONFIDENTIALITY AND PRIVACY 
26 
10.1.4 
SAFETY OVERSIGHT 
27 
10.1.5 
QUALITY ASSURANCE AND QUALITY CONTROL 
27 
10.1.6 
DATA HANDLING AND RECORD KEEPING 
27 
10.1.6.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
27 
10.1.6.2 
STUDY RECORDS RETENTION 
28 
10.1.7 
PROTOCAL DEVIATIONS 
29 
10.1.8 
CONFLICT OF INTEREST POLICY 
29 
10.2 
ABBREVIATIONS 
30 
11 
REFERENCES 
32 
 
 
 

 
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5 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
Team-Based Connected Health to Improve Clinical Outcomes and Access in 
Atopic Dermatitis 
 
Study Description: 
This is a pragmatic, randomized, controlled, equivalency trial. This 12-
month trial will evaluate the impact of an online, team-based connected 
health (TCH) model for management of atopic dermatitis (AD) as 
compared to in-person care. 300 patients will be randomly assigned to the 
online TCH model or the in-person control arm stratified by two factors: 
age (<18 years vs. 18+ years) and study site. This pragmatic, randomized 
trial will compare AD disease severity (Aim 1), quality-of-life and access-to-
care measures (Aim 2), and costs (Aim 3) between the two models. 
 
Objectives: 
 
The primary goal of the protocol is to evaluate whether an online, team-
based connected (TCH) health model results in equivalent improvements 
in disease severity and quality of life, provides better access to specialist 
care, and is cost-saving compared to usual in-person care for AD 
management. We will perform a pragmatic randomized equivalency trial 
to compare the online, TCH model versus in-person care. 
 
The specific aims of the study are as follows: 
 
 
Primary Objective (Aim 1):  Compare differences in AD severity, as 
measured by the Eczema Area and Severity Index (EASI), Patient-Oriented 
Eczema Measure (POEM), and validated Investigator Global Assessment 
(vIGA), between patients randomized to Team-Based Connected Health 
and in-person care in a 12-month pragmatic, randomized equivalency trial.  

 
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6 
 
 
Secondary Objectives (Aim 2): Compare differences in quality of life as 
measured by dermatology-specific instruments (Dermatology Life Quality 
Index / Children’s Dermatology Life Quality Index) and a generic 
instrument (European Quality of Life-5 Dimensions) between patients 
randomized to Team-Based Connected Health and in-person care. 
Furthermore, we will compare differences in access-to-care measures such 
as transportation and time needed for evaluation between patients 
randomized to Team-Based Connected Health and in-person care.  
 
Secondary Objectives (Aim 3): Compare differences in healthcare costs 
from a societal perspective between Team-Based Connected Health and 
in-person care through cost-minimization analysis.  
 
Endpoints: 
The primary and secondary endpoints are as follows: 
 
Primary Endpoint:  
● Change in EASI from baseline averaged across 12 months. 
 
Secondary Endpoints:  
● Change in vIGA from baseline averaged across 12 months 
● Change in POEM from baseline averaged across 12 months 
● Change in DLQI and CDLQI from baseline averaged across 12 
months 
● Change in EQ-5D-5L and EQ-5D-Y from baseline averaged across 
12 months 
● Patient reported access-to-care outcomes, including 
transportation and time needed for evaluation 
● Healthcare utilization and costs from a societal perspective 
 
Study Population: 
The study population consists of children and adults (age 1 year and older) 
with atopic dermatitis (AD). We plan to enroll 300 patients representing 
the full spectrum of AD disease severity in southern California. 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Ambulatory clinics associated with Keck Medicine of University of 
Southern California and LAC+USC Medical Centers will participate in 
enrolling participants. 
 
Description of Study 
Intervention: 
The Team-Based Connected Health (TCH) model enables structured online 
interactions among patients, primary care providers (PCPs), and 
dermatologists. The goal of TCH is to provide patients and PCPs with high-
quality online communication with specialists that would otherwise occur 
in person. 
 
Study Duration: 
60 months 
Participant Duration: 
12 months 
 

 
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7 
1.2 
SCHEMA 
 
 
Baseline / 
Week 0 
Week 12
Week 24
Week 36
In-person visit 
frequency is 
determined by 
patient and 
provider.
TCH online 
visit frequency 
is determined 
by patient and 
provider.
Week 48
Month 12 Patient Outcomes Assessments:
EASI, vIGA, POEM, DLQI/CDLQI, EQ-5D-5L/EQ-5D-Y,
Access-to-care measures, Cornell Services Index
300 Participants
Randomization
Team-Based Connected Health (TCH)
150 Participants
Patients or parent/legal guardian trained on using 
teledermatology platform.
In-Person Visits
150 Participants
Confirmation of eligibility and informed consent. 
Month 9 Patient Outcomes Assessments:
EASI, vIGA, POEM, DLQI/CDLQI, EQ-5D-5L/EQ-5D-Y,
Access-to-care measures
Month 6 Patient Outcomes Assessments:
EASI, vIGA, POEM, DLQI/CDLQI, EQ-5D-5L/EQ-5D-Y,
Access-to-care measures
Month 3 Patient Outcomes Assessments:
EASI, vIGA, POEM, DLQI/CDLQI, EQ-5D-5L/EQ-5D-Y,
Access-to-care measures
Month 0 Patient Outcomes Assessments:
Baseline Demographics and Medical History, EASI, vIGA, POEM, 
DLQI/CDLQI, EQ-5D-5L/EQ-5D-Y, 
Access-to-care measures, Cornell Services Index

 
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8 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Procedures/Assessments 
Month 0 / 
Baseline 
Month 3 
Month 6 
Month 9 
Month 12 
+ 28 days 
-7 days, +21 
days 
-7 days, +21 
days 
-7 days, +21 
days 
--7 days, +28 
days 
Informed Consent 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
Patient or parent/legal guardian 
training on utilization of the 
teledermatology platform 
X 
 
 
 
 
Baseline Demographics and Medical 
History 
X 
 
 
 
 
Atopic Dermatitis Severity Assessments 
EASI 
X 
X 
X 
X 
X 
vIGA 
X 
X 
X 
X 
X 
POEM 
X 
X 
X 
X 
X 
Quality of Life Assessments 
DLQI / CDLQI 
X 
X 
X 
X 
X 
EQ-5D-5L / EQ-5D-Y 
X 
X 
X 
X 
X 
Access to Care 
Access to Care (Baseline) 
X 
 
 
 
 
Access to Care (Follow-up) 
X 
X 
X 
X 
X 
Healthcare Costs Assessments 
 
 
 
 
 
Cornell Services Index 
X 
 
 
 
X 
Safety Assessments 
Adverse Event Collection Form 
X 
X 
X 
X 
X 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE 
Chronic skin diseases are associated with markedly decreased quality of life and financial 
consequences.1-2 In the U.S., access to dermatologists remains a significant challenge, especially for 
those in underserved or rural communities.3-7 Even after an initial evaluation by a dermatologist, many 
patients have difficulties maintaining regular access to dermatologists for follow-up care. Consequently, 
many patients experience worse clinical outcomes and reduced quality of life.8  
With the maturation in communication technology to facilitate healthcare, now is the critical time to 
determine how technology-enabled healthcare delivery models impact patient outcomes, access, and 
costs in the real world.  
We will evaluate an online, team-based connected health (TCH) model that enables structured 
asynchronous online interactions among patients, primary care providers (PCPs), and dermatologists. 
The goal of TCH is to provide patients and PCPs with high-quality online communication with specialists 
that would otherwise occur in person. TCH leverages innovative health services model and technology 
to bring expert care to patients and PCPs in a location-independent and asynchronous manner. 

 
Version date 23-Sep-2019 
 
9 
Atopic dermatitis (AD) is the ideal disease model to evaluate TCH because it is common, chronic, and can 
inflict substantial morbidity if not managed effectively.9-11 To address skin inflammation, itch, and 
psychosocial consequences, PCPs and dermatologists need to adopt a team-based approach to 
effectively manage all aspects of the disease.  
 
2.2 
RISK / BENEFIT ASSESSMENT 
 
2.2.1 
KNOWN POTENTIAL RISKS 
 
As with all electronic health information exchange and record platforms, potential risks include loss of 
confidentiality. Our research team has extensive experience protecting privacy and maintaining 
confidentiality of our patients’ personal information on telemedicine platforms. The teledermatology 
platform is secure and HIPPA compliant, and it has been used for online telemedicine visits and for 
telemedicine studies. We deem the probability of experiencing loss of confidentiality of protected health 
information low. Specific mitigation strategies to ensure data security and confidentiality are discussed 
below in the section 10.1.3 “Confidentiality and Privacy”.  
Because we are recruiting patients with AD across the spectrum of disease severity, potential risks 
remain with either arm of the study with regards to adverse events related to AD or its associated 
treatments. Because the study is pragmatic in design, it enables in-person or online visits at frequencies 
that are individualized and deemed medically necessary by the provider. Thus, providers and patients in 
both arms can follow up at frequencies that are necessary to manage AD and any treatment-related 
adverse events. Furthermore, the patients randomized to the online arm could seek in-person care if the 
patient or the provider deem that online care is insufficient to address a problem. Thus, we deem the 
probability of experiencing untoward events by the study participants not higher than what would 
otherwise be expected via routine care.  
 
2.2.2 
KNOWN POTENTIAL BENEFITS 
The TCH model offers several distinctive benefits. The model offers multiple ways for both patients and 
PCPs to access dermatologists online asynchronously that are responsive to real-world needs. The 
patients can also upload clinical images and history online and obtain asynchronous evaluation and 
recommendations from the dermatologists. PCPs can upload patient’s photos and history online and 
access dermatologists asynchronously for consultations or to request a dermatologist to assume care of 
a patient’s atopic dermatitis.  
Overall, the TCH model not only increases patient and provider engagement; it also provides 
comprehensive specialist support to both PCPs and patients. TCH eliminates the need for patients to 
find a local healthcare facility with telemedicine capabilities to engage dermatologists via telemedicine. 
After careful consideration of the benefits and risks associated with the study, we deem the benefit-risk 
assessment to be acceptable to research participants. The accessibility of quality and timely specialist 
care for atopic dermatitis patients outweighs the potential adverse risks associated with the study.  
 
 

 
Version date 23-Sep-2019 
 
10 
2.2.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
 
Evidence supports accuracy and reliability of diagnosis by asynchronous teledermatology. Furthermore, 
multiple studies have demonstrated concordance in management plans between care delivered through 
asynchronous teledermatology versus in person. However, potential risks remain with either arm of the 
study with regards to adverse events related to AD exacerbation or adverse events arising from AD 
treatment. Because the study is pragmatic in design, it enables in-person or online visits at frequencies 
that are individualized and deemed medically necessary by the provider. Thus, providers and patients in 
both arms can follow up at frequencies that are necessary to manage AD and any treatment-related 
adverse events. Thus, we deem the probability of experiencing untoward events beyond what would 
otherwise be expected via routine care for this population to be low.  
Protection against Adverse Events during Management of Atopic Dermatitis 
To mitigate risks of adverse events related to AD or the treatment, the PI and the study staff will 
continuously monitor patients for adverse events. Patients can report adverse events using two 
methods: (1) using the “Adverse Event Collection Form”, which is captured at quarterly intervals, or (2) 
reporting AEs spontaneously to the study at any time 24/7. The study team or the patient’s provider will 
address adverse events as they occur. 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
Aim 1: Compare differences in atopic 
dermatitis disease severity, as 
measured by Eczema Area and 
Severity Index (EASI), and validated 
Investigator Global Assessment 
(vIGA), and Patient-Oriented Eczema 
Measure (POEM) between patients 
randomized to TCH and in-person 
care in a 12-month pragmatic, 
randomized equivalency trial. 
 
 
 
 
 
 
The primary endpoint of the study is 
the mean improvement from baseline 
in EASI averaged across 12 months.  
The mean improvement in EASI is 
defined as the difference in EASI 
between baseline and the average of 
the follow-up visits (months 3-12). 
 
Secondary endpoints for Aim 1 include: 
● 
Change in vIGA from baseline 
averaged across 12 months 
● 
Change in POEM from baseline 
averaged across 12 months 
 
 
 
 
EASI is a validated, 
granular assessment of 
AD patient disease 
severity. It is commonly 
used in clinical trials, 
including trials for 
therapeutic approvals. 
By using EASI, we will be 
able to compare the 
results of this study with 
other studies in AD 
patients. 
  
The 5-point IGA is a 
valid measure of disease 
severity and meets the 
need for a clinically 
meaningful measure for 
atopic dermatitis. 
 
POEM is a validated 
patient-reported 
outcome used to 

 
Version date 23-Sep-2019 
 
11 
monitor AD severity 
that focuses on the 
illness as experienced by 
the patient. 
Secondary 
 
 
Aim 2: Compare differences in 
quality of life as measured by 
dermatology-specific instruments 
(Dermatology Life Quality Index 
(DLQI)/ Children’s Dermatology Life 
Quality Index (CDQI)) and a generic 
preference-based instrument 
(European Quality of Life-5 
Dimensions), between patients 
randomized to TCH and in-person 
care.  
 
Compare differences in access-to-
care measures such as 
transportation and time needed for 
evaluation between patients 
randomized to TCH and in-person 
care.  
The secondary endpoints for Aim 2 
include: 
● 
Change in DLQI or CDLQI from 
baseline averaged across 12 
months between the in-person 
and online groups 
● 
Change in EQ-5D-5L or EQ-5D-
Y from baseline averaged 
across 12 months between the 
in-person and online groups. 
● 
Transportation and time 
needed for evaluation 
between the in-person and 
online groups. 
 
 
 
 
The DLQI and the CDLQI 
are validated, 10-
question questionnaires 
that can be used to 
assess dermatology-
specific quality of life in 
adults and children with 
atopic dermatitis.  
 
EQ-5D-5L and EQ-5D-Y 
are validated measures 
of health status. The EQ-
5D-5L and EQ-5D-Y 
provide a single index 
value that can be used 
for QoL and economic 
evaluations. 
 
Transportation and time 
needed for evaluation 
are measures of access.  
Secondary 
 
 
Aim 3: Compare differences in 
healthcare costs between TCH and 
in-person care. 
 
The secondary endpoints for Aim 3 are: 
 
• 
Healthcare utilization 
• 
Healthcare costs 
 
 
 
 
The Cornell Services 
Index is a validated 
method to assess health 
service use. The 
measure provides a 
reliable snapshot of 
service use patterns 
across types, providers, 
and sites of service 
among adults who seek 
medical care. 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This study is testing the hypothesis that team-based connected health (TCH) model results in equivalent 
improvements in disease severity and quality of life, provides better access to specialist care, and is cost-
saving as compared to usual in-person care for management of patients with atopic dermatitis (AD).  

 
Version date 23-Sep-2019 
 
12 
This is a 12-month, pragmatic, randomized, controlled, equivalency trial to evaluate the impact of an 
online, team-based connected health (TCH) model for management of atopic dermatitis (AD) as 
compared to in-person care. A total of 300 participants will be randomly assigned to the online TCH 
model or the in-person control arm.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The rationale for proposing this 12-month pragmatic trial is to test whether the TCH model works in the 
real world. This design allows for a large spectrum of everyday clinical settings in order to maximize 
applicability and generalizability. These pragmatic approaches are especially pronounced along the 
Pragmatic Explanatory Continuum Indicator Summaries (PRECIS) domains of experimental intervention 
flexibility, usual in-person care as control, and outcomes being highly relevant to patients. 
4.3 
RATIONALE FOR INTERVENTION 
 
Lack of access to dermatologic care and problems with traditional teledermatology models: In the U.S., 
access to dermatologists remains a significant challenge for many patients. Many patients have 
difficulties maintaining regular access to dermatologists due to factors such as lack of transportation or 
the inability to take time away from work for medical visits. Consequently, these patients with chronic 
skin diseases suffer from poor clinical outcomes and reduced quality of life.  
Teledermatology is a specialty-care delivery model in which skin diseases are diagnosed and treated 
remotely by means of telecommunications technology.12 While ample evidence supports accuracy and 
reliability of asynchronous teledermatology, few studies have examined patient outcomes.  
To develop more effective methods for specialty-care delivery, it is important to first recognize why 
traditional models of teledermatology have not worked well. 13-21 Several key limitations exist with 
traditional consultative teledermatology. First, patients must find a nearby healthcare facility with 
telemedicine capabilities in order to access dermatologists online. Second, there is no direct contact 
between patients and the specialists, and this is the key reason for patient dissatisfaction. Third, the 
PCPs are variably effective in conveying and implementing specialists’ recommendations.  
Team-based connected health (TCH) model to provide expert care online. In this proposal, we will 
evaluate an online TCH model that provides high-quality, asynchronous online care for AD patients. 
Specifically, TCH will bring quality specialist care to patients and PCPs in a location-independent and 
asynchronous manner. Importantly, because dermatologists are central to the sustainability of this 
online model, the intervention is designed to maximally support the dermatologists.  
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Age 1 year or older 
• 
Physician-diagnosed atopic dermatitis (AD) 
• 
Access to a digital-photo capturing device (mobile phone or camera) capable of capturing 
images with a minimum resolution of 1024x768 pixels 
• 
Access to internet 
• 
Able to establish care or have established care with providers 
• 
Provision of signed and dated informed consent and youth assent form  

 
Version date 23-Sep-2019 
 
13 
5.2 
EXCLUSION CRITERIA 
• 
Unable to fulfill study-related tasks by adult AD patients or parent/legal guardian of pediatric AD 
patients 
5.3 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. To ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements, we will include demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE).  
 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
5.4.1 
RECRUITMENT PLAN 
In this pragmatic, randomized equivalency trial, we will recruit pediatric and adult patients with AD from 
both genders, diverse racial and ethnic groups, and across the full spectrum of AD severity. Patients will 
be randomized 1:1 stratified by age and study site to either the online TCH model or in-person visits for 
management of AD.22  
Medical records of patients with AD or eczema who had presented to the study sites since 2013 will be 
reviewed by the study staff to prescreen for eligibility.  For patients who are potentially eligible, the 
study team will send these patients or their parents a letter that introduces the study. Following the 
letter, the study team will call these patients to inquire about their interest in the study.  
In addition, the study team will also examine the clinic schedule and identify patients with visits for 
“eczema”, “atopic dermatitis”, “dermatitis”, or other related terms. The study staff will contact these 
patients prior to their appointment to alert them that a study member may speak to them about the 
study on the day of their visit.   
Other recruitment methods include flyers placed at the study sites, online and social media 
advertisements, ResearchMatch, local newspapers, and referral from colleagues. Selection is based 
solely on the participant's ability to meet the criteria stated in the protocol and his/her willingness to 
participate in the study.  
5.4.2 
RETENTION PLAN 
Prior to study initiation, we will conduct pre-trial retention training for the study staff. Prior to 
enrollment, the study staff will communicate with eligible patients regarding the importance of 
completing all outcome assessments. We will emphasize the importance of full participation during 
screening, enrollment, and throughout the trial.  
It is important to note that, for online and in-person visits between the provider and patients, these 
visits occur at an individualized frequency based on medical necessity. However, the collection of 
outcome assessments (disease-severity, quality-of-life endpoints, and selected access-to-care measures) 
occurs at a quarterly basis for all participants.  

 
Version date 23-Sep-2019 
 
14 
All subjects will be reminded via email, text, or telephone to submit their quarterly outcome 
assessments beginning 7 days prior to the due date. If a subject fails to submit the quarterly outcome 
assessments within 2 days of the due date, the subject will be contacted using telephone and/or 
electronic methods to remind them to submit the assessments. The study staff will also discuss with the 
participant strategies to improve adherence with the study requirements. If the participant cannot be 
contacted after at least five attempts, a certified return receipt letter will be sent to encourage 
continuation in the trial.  
If a participant fails to complete a quarterly assessment within 21 days of the due date, the study staff 
will make at least five attempts to contact (at least three telephone calls, two emails, and, if necessary, a 
certified return receipt letter to the participant’s last known mailing address or local equivalent 
method). These contact attempts will be documented in the participant’s study file. 
If a participant wishes to withdraw from the study, the study coordinators will attempt to collect the 
Month 12 visit data as well as detailed data on the reasons for the discontinuation from the study. The 
study coordinators are encouraged to share their ideas and experiences to promote participant 
retention via regular communication during staff meetings.  
5.4.3 
VULNERABLE SUBJECTS 
 
While the study does not specifically target pregnant women, we will not exclude pregnant women from 
participation. Pregnant women who meet eligibility criteria and are willing to participate will be enrolled 
in the study, and their AD will be managed by their providers on an individualized basis. 
Children that meet the eligibility requirements will be able to enroll. Assent from the child and written 
consent from the parent or authorized legal guardian will be obtained in accordance with the provisions 
of Subpart D, 45 CRF 46.  
Prisoners, fetuses, or neonates will not be included in the study.  
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION ADMINISTRATION 
6.1.1 
INTERVENTION DESCRIPTION AND ADMINISTRATION  
We will evaluate an online team-based connected health (TCH) model that facilitates high-quality, 
efficient, and accessible care for patients with AD in a location-independent and asynchronous manner.  
Specifically, TCH enables dermatologists, PCPs, and patients to conduct structured and efficient online 
visits that would otherwise occur in person. TCH offers several ways of online communication: (1) PCP-
dermatologist, (2) Patient-dermatologist, and (3) Patient-PCP interactions. For example, either PCPs or 
patients can upload clinical images and history online to obtain dermatologist expertise for evaluation 
and management of AD. TCH is responsive to real-world workflow needs, and it focuses on team-based 
care by fostering multidirectional, informed communication among patients, PCPs, and dermatologists. 
 
 

 
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6.1.1.1 
WHAT DEFINES AN ONLINE VISIT? 
In the TCH model, online communication is classified as either “online visits” or “follow-up questions.” 
An online visit contains photos of appropriate quality, history of present illness, medications, allergies, 
review of systems, and a provider’s assessment and plan.  
In contrast, a follow-up question refers to an ad hoc question from a patient that is submitted within 30 
days following a prior online visit.  
6.1.1.2 
WHAT HAPPENS DURING AN ONLINE VISIT? 
When the patient initiates an online visit, the platform begins a process with “required fields” to ensure 
completion of all required elements of an online visit before transmission to the dermatologist. 
Specifically, the patient uploads images of skin lesions and submits clinical history.  
Within three business days, the dermatologist reviews the patient’s history and images. The 
dermatologist then communicates the recommendations to the patient, prescribes the medications, and 
where appropriate, provides standard-care educational materials to patients online asynchronously.  
The frequency of the follow-up online visits will be determined by the dermatologists and patients based 
on medical necessity.  
6.2 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
A total of 300 participants will be randomly assigned to the online, TCH arm or the in-person control 
arm. To ensure balance of demographic and clinical characteristics between the two arms across the 
recruitment sites, we will perform randomization stratified by two factors: age and study site. Age will 
be dichotomized into two categories indicative of adulthood: < 18 years vs. 18+ years.  
A randomization schema for each site, with blocks ranging from 6 to 12 will be created by the study 
statistician and uploaded to REDCap in accordance with the REDCap Randomization Model.22 Then, the 
randomization will be predicated on the participant age and study site and provided to research staff. In 
this study, blinding of patients and providers is not possible due to the nature of the intervention. 
However, the randomization schema will not be known to the staff until revealed at time of 
randomization. Only the statistician, who has no interactions with the patients, will have access to the 
full randomization schema to check for balance between groups.  
6.3 
STUDY INTERVENTION COMPLIANCE 
We will ensure compliance in delivering the telemedicine intervention via continuous monitoring of 
interventional fidelity throughout the study. If patients or providers face difficulties with online visits or 
completion of assessments, they are able to access the study staff 24/7 to obtain assistance. 
Additionally, throughout the study, the study staff will also ensure providers’ compliance in using TCH 
intervention by monitoring online communications “in the background” and provide feedback and/or 
assistance when necessary.  
 
 

 
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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
The criteria for discontinuing the online intervention include (1) the patient expresses desire to 
discontinue study intervention, (2) the provider expresses desire to discontinue patient from study 
intervention for any reason, which include AD exacerbation or adverse events that cannot be managed 
online for the remainder of the study. We will record the reasons for discontinuing the study 
intervention in detail via structured data capturing.  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
The study team will ensure that participants are fully informed and understand the study commitments 
as presented in the informed consent form to minimize patient withdrawal. Patients are encouraged to 
complete the study regardless of their response. Participants may withdraw from the study at any time 
without impact to their care. In the event a participant discontinues study treatment before study 
completion, the study team will attempt to collect the Month 12 visit data. They may also be 
discontinued from the study at the discretion of the PI if patient’s participation poses a safety concern to 
himself/herself or to the study staff. 
The reason for participant discontinuation or withdrawal from the study will be documented on the 
Enrollment Status eCRF. Subjects who sign the informed consent form and are randomized and receive 
the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the study 
will not be replaced, nor will they be eligible for rescreening. 
7.3 
LOST TO FOLLOW-UP 
 
All attempts will be made to minimize lost to follow-up. A participant will be considered lost to follow-up 
if he or she fails to complete a quarterly assessment according to the Schedule of Activities within 6 
weeks of scheduled date of completion. 
If a participant fails to complete a quarterly assessment within 2 days of the due date, the subject will be 
contacted by phone and electronically to submit the assessments. The study staff will also discuss with 
the participant strategies to improve adherence with the study requirements. 
If a participant fails to complete a quarterly assessment within 7 days of the due date, the following 
steps to will be initiated:  
● The study staff will make at least five attempts to contact (at least three telephone calls, two emails, 
and, if necessary, a certified return receipt letter to the participant’s last known mailing address or 
local equivalent methods.) These contact attempts will be documented in the participant’s study 
file.  
● Should the participant continue to be unreachable within 6 weeks of the scheduled date of 
completion, he or she will be considered to have withdrawn from the study with a primary reason of 
lost to follow-up. 
● The Principal Investigator will have the ultimate discretion on the final determination of whether 
additional attempts should be made to contact the participant or if the participant should be 
declared lost to follow up. 

 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS 
Study investigators and designated study staff will determine patient eligibility during the screening 
period, using a screening checklist form. Screening can occur on the same day the patient is enrolled if 
the participant meets the specified inclusion and exclusion criteria.  
Outcomes data will be collected using patient-reported, validated instruments as described below. 
 
Assessments and Evaluations (Patient-Report Measures) 
• 
Eczema Area and Severity Index (EASI): the EASI is a validated scoring system that grades the 
physical signs of atopic dermatitis/eczema. EASI is a core outcome for measuring the clinical 
signs of eczema in all trials. 
• 
Validated Investigator’s Global assessment (vIGA): This is a three-item measure that 
assesses the thickness, redness, and scale of atopic dermatitis lesions. 
• 
Patient Oriented Eczema Measure (POEM): POEM is a 7-item tool for patient and/or proxy 
self-completion used to monitor atopic dermatitis severity, focusing on the illness as 
experienced by the patient. 
• 
Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index (CDLQI): 
DLQI/CLDQI is a 10-item survey that asks patients questions about their health-related 
quality of life on a 0-3 scale. DLQI and CDLQI are routinely used in clinical trials of 
dermatology treatments and can also be used routinely in clinical practice. 
• 
EQ-5D-5L or EQ-5D-Y: These are generic and utility-based health-related quality of life 
measures that capture outcomes based on 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension is measured based on 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems. 
• 
Patient reported access-to-care outcomes, including transportation and time needed for 
evaluation. 
• 
Cornell Services Index: The Cornell Services Index (CSI) assesses the frequency and duration 
of use of a range of services over the past three months. Services are aggregated into four 
types: outpatient psychiatric or psychological, outpatient medical, professional support, and 
intensive services. Each service use includes information on the discipline of the primary 
provider, the location of the service, and the reason for the service. Finally, the CSI collects 
information on out-of-pocket cost to the individual and the primary method of payment (for 
example, Medicare, Medicaid, or self-pay). 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
  
The patients will contact their healthcare provider for any significant problems related to their atopic 
dermatitis. Patients will also be asked to complete quarterly forms that capture any AEs/SAEs that may 
have occurred over the past three months of the study. Importantly, patients can spontaneously report 
Aes/SAEs at any point during the study.  
Safety Assessments 
• 
AE/SAE occurrence form (patient-reported) 

 
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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  
 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
● Death 
● Life-threatening adverse event 
● Inpatient hospitalization or prolongation of existing hospitalization 
● Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
● Congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  
 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 
SEVERITY OF EVENT 
 
For adverse events (Aes) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (Aes) will have their relationship to study intervention assessed by the principal 
investigator or authorized designee who examines and evaluates the participant based on temporal 
relationship and his/her clinical judgment. The degree of certainty about causality will be graded using 
the categories below.  

 
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19 
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 
EXPECTEDNESS 
 
The principal investigator or designee will be responsible for determining whether an adverse event (AE) 
is expected or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study intervention. 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All Aes including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All Aes 
occurring while on study must be documented appropriately regardless of relationship. All Aes will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. Aes characterized as intermittent require documentation of 
onset and duration of each episode. 
 
The principal investigator or designated study staff member will record all reportable events with start 
dates occurring any time after informed consent is obtained until 7 (for non-serious Aes) or 30 days (for 
SAEs) after the last day of study participation.  During each scheduled assessment, study subjects will be 
asked to complete a form to capture any occurrence of AE/SAEs since the last visit.  Events will be 
followed for outcome information until resolution or stabilization. 
 
8.3.5 
ADVERSE EVENT REPORTING 
 
Patients can report adverse events using two methods: (1) using the “Adverse Event Collection Form”, 
which is collected at quarterly intervals, or (2) reporting Aes spontaneously to the study staff at any time 
24/7. All adverse events reported during the course of the study will be reported to the PI.  

 
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Each week, the study team will review the quarterly AE Collection Forms and Aes that were 
spontaneously reported. In accordance with IRB regulations, reportable adverse effects arising from any 
research procedures will be submitted promptly to University of Southern California’s Office of Human 
Research Protection (OHRP) within 10 working days after the investigator becomes aware of the event.  
All adverse events will be collected and reported in aggregate to the DSMB. 
 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING 
 
Any AE that meets any criterion for a SAE requires the completion of an SAE Report Form in addition to 
being recorded on the AE pages of the CRF.  The principal investigator is required to ensure that the data 
on these forms is accurate and consistent.  This applies to all SAEs, regardless of relationship to study 
intervention, that occur after informed consent has been obtained. 
All SAEs regardless of relatedness of expectedness will be reported immediately (within 48 hours of the 
principal investigators’ knowledge of the event) to the NIAMS and the Data and Safety Monitoring 
Officer through the Executive Secretary (KAI).  
The SAE report must provide a detailed description of the SAE.  If a subject has died and an autopsy has 
been performed, copies of the autopsy report and death certificate will be sent to the NIAMS and Data 
and Safety Monitoring Board (DSMB) as soon as the information becomes available.  Any follow-up data 
will be detailed in a subsequent SAE Report Form and sent to the NIAMS and DSMB accordingly. 
The principal investigator or designee is responsible for informing the Institutional Review Board/Ethics 
Committee (IRB/IEC) of the SAE and providing them with all relevant initial and follow-up information 
about the event. The principal investigator or designee will keep copies of all SAE information, including 
correspondence with the NIAMS, DSMB and the IRB, on file.  All SAEs that have not resolved upon 
discontinuation of the subject’s participation in the study will be followed until either the event resolves 
completely, stabilizes/resolves with sequelae, or returns to baseline (if a baseline value is available). 
 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS 
 
If any adverse or serious adverse event results in a change to the risk/benefit ratio of the study, 
participants will be notified immediately, and asked to re-consent to participating in the study by signing 
an updated informed consent form  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UPS) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 

 
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• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
8.4.2 
 UNANTICIPATED PROBLEM REPORTING  
 
The principal investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the NIAMS Data and Safety Monitoring Board (DSMB). The UP report will include the 
following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the NIAMS and 
DSMB through the Executive Secretary (KAI) within 48 hours of the investigator becoming aware 
of the event.  
• 
Any other UP will be reported to the IRB and to the NIAMS DSMB within 10 working days of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 10 working days of the IRB’s receipt of the report of 
the problem from the investigator. 
 
8.4.3 
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
 
Participants will be notified of any unanticipated problems via emailed letter from the Principal 
Investigator.   
 
9 
STATISTICAL CONSIDERATIONS  
 
 
9.1 
SAMPLE SIZE DETERMINATION 
We consider δU = ±6.5 as the equivalence limit for our primary outcome, SA-EASI, which is half of a 
clinically significant difference and much more conservative than prior studies.11 We computed sample 
size estimates for equivalency comparison of means for the primary endpoint and secondary endpoints 
from Aim 1 and Aim 2 using one-sided a = 0.05 and 80% power (PASS version 14). 272 patients 
randomized are sufficient to determine equivalency with 80% power for the primary endpoint of EASI 
given the range of SD (15-20), with anticipated 15% attrition. This N is larger than that required for any 

 
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22 
of the other outcomes.23-25 Thus, enrolling 300 patients provides adequate power to evaluate primary 
and all secondary outcomes and accounts for attrition.  
 
9.2 
POPULATIONS FOR ANALYSES 
 
We will use an intent-to-treat (ITT) approach to evaluate equivalency of changes between the two arms 
across 12 months for AD-disease-severity and quality-of-life endpoints using longitudinal linear mixed 
modeling.  
 
9.3 
STATISTICAL ANALYSES 
 
9.3.1 
GENERAL APPROACH 
 
For this pragmatic, randomized trial, we will compare patients randomized to the online, team-based 
connected health (TCH) versus patients receiving in-person care across one year. The overall analytical 
strategy is to use linear mixed or generalized estimating equations, depending on the outcome variable, 
to account for repeated measures within patients. Random effects for patients will be included in the 
model so that the estimates of any patient-level variables will be appropriately calculated. Additionally, 
we will adjust a priori for the randomization stratification factors site and age group (<18 years, and 18+ 
years) in all models. While we do not anticipate a site-level main effect, random effects for site will be 
included in the model in case there are factors common to patients within a site that affect the 
outcome.  
For comparison of AD disease severity (Aim 1) and quality of life (Aim 2), we will test an equivalence 
hypothesis between the interventions using longitudinal linear mixed effects modeling; this allows for 
the estimation of intra-individual variance. Using this same technique, we will test the hypothesis of 
improved access to specialist care (Aim 2) and cost-saving (Aim 3) with the TCH model compared to the 
in- person model.  
 
9.3.2 
ANALYSIS OF THE PRIMARY EFFICAY ENDPOINTS  
 
The primary endpoint of the study is the mean improvement from baseline in EASI versus the follow-up 
visits (months 3-12). The comparison of improvement in EASI will incorporate all available post- 
intervention follow-up visits. Our primary goal will be to compare the mean difference in improvement 
between groups to examine if they are equivalent.  
We will use an intent-to-treat (ITT) approach to evaluate equivalency of changes between the two arms 
across 12 months for AD-disease-severity and quality-of-life endpoints using longitudinal linear mixed 
modeling. This modeling allows us to account for intra-individual variability and the possibility of 
different numbers of follow-up measurements inherent in this pragmatic research design. For these 
analyses, the null hypothesis is that there is a differential treatment effect between the groups: H0: μIn-
person ≠ μTCH. The alternate hypothesis is HA: μIn-person = μTCH, where μ represents the average change from 
baseline across the follow-up visits (3 months – 12 months).  
For the primary comparison of baseline versus average of follow-up visits, a dummy-coded time variable 
will be coded with 0 = baseline and 1 for all follow-up visits, so that the estimate of the effect will 
indicate the difference between baseline and the average of follow-up visits. In addition, a group 

 
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variable will be added to the model (coded 0 for in-person and 1 for TCH) along with a group x time 
effect.  
We consider δU = ±6.5 as the equivalence limit for the primary endpoint of EASI. This equivalence limit of 
6.5 was selected for EASI because it represents the minimal clinically important difference in the AD 
literature.28 It is also more conservative than equivalency limits of 12-20 from pilot studies.29  
9.3.3 
ANALYSIS OF THE SECONDARY ENDPOINTS 
 
Analysis of Disease Severity (Aim 1) 
In Aim 1, we will assess a secondary endpoint, vIGA, which is an ordinal scale that provides a global 
assessment of the patient’s AD disease severity. vIGA is scored on a 5-point ordinal scale ranging from 0 
(clear) to 4 (severe). We will apply the same general modeling procedure using generalized estimating 
equations with the ordinal outcome of vIGA. The reference category will be 0 = clear. The equivalence 
margin for vIGA is 0.5, which is smaller than the minimal clinically important difference and considered a 
conservative equivalence margin by AD experts. 
We will also assess a secondary endpoint of patient-reported symptoms using the validated instrument 
POEM. For POEM, we will use the same modeling method as the one described for EASI. The scores for 
the POEM instrument range from 0 to 28. The equivalence margin for POEM is 3.4, which is the minimal 
clinically important difference defined in the AD literature.28  
Analysis of Health-Related Quality of Life and Access-to-Care Measures (Aim 2) 
In Aim 2, we will compare health-related quality of life between patients from practices randomized to 
the two interventions. The hypothesis is that the TCH model results in equivalent improvement in 
health-related quality of life as that in the in-person arm, as measured by DLQI and Children’s DLQI 
(CDLQI), and EQ- 5D-5L/EQ-5D-Y. 
DLQI and CDLQI are validated dermatology-specific quality-of-life instruments for adults and children, 
respectively. The scores range from 0 to 30, with higher scores indicating more severe impact on quality 
of life. The equivalence margin for DLQI and CDLQI is ± 4, which corresponds to the established minimal 
clinically important difference.29  
EQ-5D-5L and EQ-5D-Y are valid and reliable, generic preference-based quality of life instruments. In 
dermatology, EQ-5D-5L has been used in numerous AD trials. The equivalence margins for the utility 
index (± 0.15) and VAS (± 10) of the instrument are no larger than half of SD (Cohen’s d = 0.5) and are 
considered the minimal clinically important difference.  
The same repeated-measures, equivalency-evaluation approach described above for Aim 1 “Analysis of 
Atopic Dermatitis Disease Severity” will be used to compare responses to DLQI/CDLQI, and EQ-5D-
5L/EQ-5D-Y between patients from practices randomized to the TCH model and in-person care across 
time.  
The hypothesis for access-to-care measures is that TCH provides superior access to specialist care than 
in- person model. For these analyses, access-to-care measures include transportation and time needed 
for evaluation. 
Linear regression models will be used to test whether there is a difference between the groups.  
 
 

 
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24 
Analysis of Costs (Aim 3) 
Cost analysis in healthcare research is essential for evaluating the financial impact of different treatment 
models on both patients and healthcare systems.26-27 For this aim, out-of-pocket (OOP) costs represent a 
significant factor in determining the feasibility and accessibility of team-based connected health (TCH) 
compared to traditional in-person care for atopic dermatitis (AD). By analyzing OOP expenditures, this 
study will provide insights into whether TCH offers a cost-effective alternative while maintaining 
equivalent clinical outcomes.31-38  
Healthcare utilization will be analyzed using the Cornell Services Index (CSI), which quantifies visit 
frequency, duration, and associated costs for medical, psychological, and professional consultations.30 
CSI data will be collected at baseline and again at 12 months, with ITT analysis requiring baseline values 
to be duplicated for patients missing follow-up data. Visit counts for different service categories will be 
analyzed through linear models, with treatment status as the primary predictor. Mean visit duration per 
patient and visit type will be compared across the two groups using Welch’s two-sample t-tests and 
linear regression models incorporating total visit count as a covariate. The impact of TCH on visit 
duration will be further assessed using analysis of variance (ANOVA) models to determine potential 
treatment group differences. Additionally, sub-analyses will be conducted to explore whether utilization 
patterns differ by age or baseline disease severity. Given the pragmatic design of the study, an emphasis 
will be placed on real-world applicability, ensuring that findings account for the variability seen in 
routine clinical settings. 
Out-of-pocket (OOP) costs will be evaluated using a combination of t-tests, ANOVA, least squares 
regression, and random-effects gamma regression. Initial analyses will compare total OOP costs per visit 
and overall OOP costs between the two treatment groups using simple t-tests. Subsequently, multiple 
linear regression models will be used to assess the impact of TCH on total OOP costs while adjusting for 
relevant covariates such as treatment site, age, sex, baseline EASI score, and history of asthma. A 
sensitivity analysis will be performed using gamma regression models. Given that cost data often exhibit 
a skewed distribution, appropriate transformations or robust estimation methods will be applied where 
necessary to improve model fit and interpretability.32 Statistical significance for all analyses will be set at 
p<0.05, and all statistical computations will be conducted using standard statistical software such as R. 
 
9.3.4 
SAFETY ANALYSES 
 
All safety data will be descriptively summarized by treatment groups and analyzed using the safety 
population. 
 
 
 
 
 
Treatment Emergent Adverse Events (TEAE)s are defined as Aes that first occurred or worsened in 
severity after the initiation of online or in-person visits. The number of TEAEs as well as the number and 
percentage of patients who experienced at least 1 TEAE will be summarized using Medical Dictionary for 
Regulatory Activities for each system organ class (or a body system) and each preferred term by 
intervention group. SAEs and Aes that lead to discontinuation of the study intervention will also be 
summarized by the intervention group. 
 
 

 
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25 
9.3.5 
BASELINE DESCRIPTIVE STATISTICS 
 
 
 
 
 
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
Descriptive statistics including number of patients, mean, standard deviation, median, minimum, and 
maximum will be provided for continuous measures, and frequency counts and percentages will be 
tabulated for categorical measures.  
  
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATION 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Electronic consent forms describing in detail the study intervention, study procedures, and risks are 
given to the participant and electronic documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following electronic consent materials are 
submitted with this protocol: Adult Informed Consent Form and Youth Assent Form. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
The informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. 
Only the trained study staff listed on the protocol will obtain informed consent. Specifically, the study 
staff will explain the study procedures, benefits, and risks in detail to the interested adult patients. A 
verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the electronic consent form through the NORA® platform and 
ask questions prior to providing an electronic signature. The participants should have the opportunity to 
discuss the study with their family or surrogates or think about it prior to agreeing to participate. The 
participant will sign the informed consent document electronically prior to any procedures being done 
specifically for the study.  Participants must be informed that participation is voluntary and that they 
may withdraw from the study at any time, without prejudice. A copy of the electronically-signed 
informed consent document will be available to the participants to print for their records via an emailed 
link. The informed consent process will be conducted and documented in the electronic source 
document (including the date), and the form electronically signed, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to participate in 
this study.  
We take special care with the assent process for minors and will adhere to all applicable institutional, 
state, and federal guidelines. Following the established USC IRB guidelines, we will review the study 
process with all minors below age 18 and his/her parent(s). For minors between 13-17 years of age and 
who agree to participate in the study, we will utilize the University of Southern California (USC) IRB-

 
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approved Adult Informed Consent/Youth Assent/Parental Permission Form to be electronically signed by 
both the minor and the parents or legal guardian. If the minor is between the ages of 7 to 12 years of 
age, the study staff will review the IRB- approved “Assent to be in Research” with the minor (to be 
electronically signed by the minor), and his or her parents or legal guardian will electronically sign the 
Adult Informed Consent/Youth Assent/Parental Permission Form. If the minor is between ages 4 to 6, 
the study staff will speak with the minor in age-appropriate language to explain the details of the study. 
This discussion will occur in the presence of the parent(s) and one other staff member serving as a 
witness. The study staff will thoroughly document the details of the discussion. If the minor expresses 
any hesitation to participating in the study, the minor will not be enrolled in the study. If the minor 
expresses willingness to participate in the study, his or her parents or legal guardian(s) will electronically 
sign the Adult Informed Consent/Youth Assent/Parental Permission Form. For minors between ages 1 to 
3, the study staff will obtain parental permission using a USC IRB-approved the Adult Informed 
Consent/Youth Assent/Parental Permission Form. In all cases, both parents must give their permission 
via electronic signature unless one parent is deceased, unknown, incompetent, or not reasonably 
available, or when only one parent has legal responsibility for the care and custody of the child. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigators, funding agency, 
and regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and 
sponsor and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
● Determination of unexpected, significant, or unacceptable risk to participants 
● Demonstration of efficacy that would warrant stopping 
● Determination that the primary endpoint has been met 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor and IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the funding agency. Therefore, the study protocol, documentation, data, and all other 
information generated will be held in strict confidence. No information concerning the study or the data 
will be released to any unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor and representatives of the 
Institutional Review Board (IRB) may inspect all documents and records required to be maintained by 
the investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. The clinical study site will permit access to such records. 

 
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The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the University of Southern California (Data Coordinating Center). This 
will not include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data entry and 
study management systems used by clinical sites and by the University of Southern California research 
staff will be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at the University of Southern California. 
 
10.1.4 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise, including dermatology, teledermatology, and inflammatory 
skin diseases. Members of the DSMB should be independent from the study conduct and free of conflict 
of interest, or measures should be in place to minimize perceived conflict of interest.  The DSMB will 
meet semi-annually to assess safety and efficacy data on each arm of the study. The DMSB will operate 
under the rules of an approved charter that will be written and reviewed at the organizational meeting 
of the DSMB. The DSMB will provide its input to the National Institute of Arthritis and Musculoskeletal 
and Skin Diseases. 
 
10.1.5 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan will be 
developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Structured research data will be captured electronically into NORA®, a secure, HIPAA compliant 
electronic data capture system powered by Science 37, Inc. Similarly. The study-specific database will be 
designed such that only data meeting certain criteria and ranges will be accepted. Additionally, missing 
values and incongruent or potentially erroneous data will be flagged atomically for study site review.  
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
10.1.6 DATA HANDLING AND RECORD KEEPING 
 
10.1.6.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 

 
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Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
Data Collection 
The study staff will enter all structured research data into NORA®, which is a secure, HIPAA compliant 
electronic data capture system powered by Science 37, Inc. Similarly, all subject questionnaires will be 
entered electronically and captured directly in the NORA® database. The study-specific database will be 
used to collect patient-reported outcomes as well as nature and severity of adverse events.  
The database will be designed such that acceptable ranges for input will be included for all subject data 
points. Data not meeting the specified parameters will not be accepted. All database data capture will 
be validated and response parameters will be included to minimize the risk of erroneous entries, missing 
fields, and data discrepancies. Automatically triggered error messages will allow the users to correct the 
entry instantaneously online. The study team will perform data quality checks at monthly intervals. The 
PI and designated study staff will review the data entered in to NORA®  to assess completeness and 
accuracy. Data queries generated from the data quality checks will be addressed by the research study 
staff in a timely manner.  
In the unlikely event of noncompliance, the PI will speak directly with the study staff to identify the 
cause of noncompliance and develop strategies to prevent such noncompliance in the future. Immediate 
and frequent reassessment will be done by the research team to ensure compliance. 
Data Confidentiality and Subject Privacy 
All HIPAA, IRB, State and Federal policies and guidelines will be followed to ensure confidentiality. 
Research data collected in NORA® will be labeled with a code that the research team can link to 
protected health information (PHI). All protected health information (PHI) in electronic format will be 
safeguarded by password-protected files and computers. Any hardcopies of PHI will be stored in secured 
drawers in locked offices. Only the PI and study staff will have access to hard-copy materials in the 
locked locations.  
Only data specified in the protocol will be collected from the study participants. All research data will be 
kept in the password-protected, encrypted database NORA®. Only the PI, trained study staff, IRB, and 
other authorized individuals specified in the protocol will be allowed access to the database. Electronic 
access to the secured drive is automatically logged by Science 37. 
Data Lock 
Data will be verified prior to data lock. Once the data has been locked, the dataset will be considered 
complete and accurate. The dataset will be de-identified prior to analysis. The study findings will be 
reported using common data elements to enable comparison with other studies. Finally, we will follow 
all NIH guidelines regarding data sharing as outlined in: 
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm. 
 
10.1.6.2 STUDY RECORDS RETENTION 
 
Study documents should be retained until at least 3 years have elapsed since the formal discontinuation 
of clinical development of the study intervention. 
 

 
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10.1.7 PROTOCAL DEVIATIONS 
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the PI to use continuous vigilance to identify and report deviations within 30 
days of identification of the protocol deviation, or within 30 working days of the scheduled protocol-
required activity.  All deviations must be addressed in study source documents, reported to the NIAMS 
Program Official, the DSMB, and the University of Southern California.  Protocol deviations must be sent 
to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible 
for knowing and adhering to the reviewing IRB requirements. Further details about the handling of 
protocol deviations will be included in the MOOP. 
 
10.1.8 CONFLICT OF INTEREST POLICY 
Any conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any 
aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict 
of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial.  The study leadership in conjunction with the 
Institutional Review Board and NIAMS has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
 

 
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30 
10.2 ABBREVIATIONS 
 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
CDLQI 
Children’s Dermatology Life Quality Index 
CEA 
Cost Effectiveness Analysis 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CONSORT 
Consolidated Standards of Reporting Trials 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
CSI 
Cornell Services Index 
DCC 
Data Coordinating Center 
DLQI 
Dermatology Life Quality Index 
DSMB 
Data Safety Monitoring Board 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
HRQol 
Health-related Quality of Life 
ICER 
Incremental Cost Effectiveness Rations 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
NIAMS 
National Institute of Arthritis and Musculoskeletal and Skin Diseases 
NIH  
National Institutes of Health 
NIH IC 
NIH Institute or Center 
NMB 
Net Monetary Benefit 
NORA® 
Network Oriented Research Assistant 
OHRP 
Office for Human Research Protections 
PCP 
Primary Care Physician 
PI 
Principal Investigator 
POEM 
Patient Oriented Eczema Measure 
PRISMA 
Preferred Reporting Items for Systematic Reviews and Meta-Analyses 
QA 
Quality Assurance 
QALY 
Quality Adjusted Life Years 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
SC CTSI 
Southern California Clinical Translational Science Institute 
SD 
Standard Deviation 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
TCH 
Team-Based Connected Health 
UP 
Unanticipated Problem 
US 
United States 

 
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USC 
University of Southern California 
VAS 
Visual Analog Scale 
vIGA 
Validated Investigator’s Global Assessment 
WTP 
Willingness to Pay 
 
 
 

 
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