Quantification of Improvement In Scratch Behavior And Sleep In Patients With Atopic Dermatitis on Crisaborole Ointment, 2%
Phase: PHASE4
Conditions: Atopic Dermatitis
Sponsor: Boston University

 
 
 
1 
Quantification Of Improvement In Scratch Behavior And Sleep In 
Patients With Atopic Dermatitis On Crisaborole Ointment, 2% 
 
 
 
NCT05200403 
 
PI: Kevin Thomas, Ph.D. 
 
kipthoma@bu.edu     
 
650 Albany St. X- 140 
               Boston, MA 02118 
            Study Phone Number: 617-358-9787 
 
 
 Dated: 13 July 2023 
 
 
Statistical Analysis Plan     pages 22-24 
 
 
 

 
 
 
2 
 
LIST OF ABBREVIATIONS 
 
Abbreviation 
Abbreviation definition 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
BID 
Bis in die (twice daily) 
BISQ 
Brief Infant Sleep Questionnaire 
BSA 
Body Surface Area 
BU/BUMC 
Boston University/Boston University Medical Center 
CDISC 
Clinical Data Interchange Standards Consortium 
CDLQI 
Children’s Dermatology Life Quality Index 
CI 
Confidence Interval 
CSHQ 
Children’s Sleep Health Questionnaire 
CSV 
Comma Separated Values 
DCQ 
Device Comfort Questionnaire 
DFIQ 
Dermatitis Family Impact Questionnaire 
DHT 
Digital Health Technologies 
EASI 
Eczema Area and Severity Index 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
FLACC 
Faces, Legs, Activity, Cry, Consolability Scale 
GCP 
Good Clinical Practice 
HRQoL 
Health Related Quality of Life 
ICH 
International Conference on Harmonization 
IDQOL 
Infants Dermatitis Quality of Life Index 
ISGA 
Investigator’s Static Global Assessment 
LS 
Least-squares 
MDPQ 
Mobile Device Proficiency Questionnaire 
MOS 
Medical Outcomes Study 
ObsRO 
Observer Reported Outcome 
ODCQ 
Observer Device Comfort Questionnaire 
OGIC 
Observer Global Impression of Change 
OGIS 
Observer Global Impression of Severity 
ORIA 
Observer Reported Itch Assessment 
PDE-4 
Phosphodiesterase-4 
POEM 
Observer-reported Patient Oriented Eczema Measure 
PPNRS 
Peak Pruritis Numerical Rating Scale 
PRO(s) 
Patient Reported Outcome(s) 
QoL 
Quality of Life 
R, L 
Right, Left 
RRI 
Research Related Injury 
TCI 
Target Controlled Infusion 
V01, V02, V03, V04, V05 
Visit 1, Visit 2, Visit 3, Visit 4, Visit 5 
WASO 
Wake After Sleep Onset 
WRAT-4 
Wide Range Achievement Test 4 
 
 
 
Background 

 
 
 
3 
Atopic Dermatitis (AD) is one of the most common, chronic, relapsing childhood dermatoses, 
impacting up to 36% of children worldwide and many have disease that persists into adulthood (Abuabara 
et al., 2018).  It is a condition that not only leads to red inflamed skin, but also is characterized by 
extensive pruritus/itch, scratching and sleep disturbances. It is stated by patients that the most problematic 
symptom of AD is pruritus.1  
 
While approximately 10-41% of children 3,4 and 7-48% of adults 5,6 experience sleep disturbances, these 
numbers climb substantially in people with AD (47-80% in children and 33-87.1% in adults).7 The 
physical action of scratching can disrupt sleep itself, but also triggers cognitive and behavioral changes 
that trigger and reinforce insomnia and sleep disruptions.8  These sleep disturbances impact the QoL of 
not only the person with the condition but also caregivers and family members. Sleep disturbances can 
also result in impaired performances on neurobehavioral tasks, hyperactivity/inattention, stunted growth 
(children), missed workdays, poorer overall health and behavioral and emotional disturbances (including 
increasing scratching).8 Measurements of itch, though of significant value, are currently accomplished 
through subjective methods such as questionnaires and intensity scales (Erickson & Kim, 2019; 
Hjermstad et al., 2011). This poses several limitations in infants and children where the parents answer 
the questionnaires on behalf of their children, and recall of itch and scratch during the night can be limited 
(Erickson & Kim, 2019). Thus, there is a great need to objectively understand and characterize itch and 
scratch. Objective measurements of sleep disturbances and nocturnal scratch have been employed using 
wearable sensors such as accelerometers (Mahadevan et al., 2021). Previous studies have used actigraphy 
and accelerometry to assess sleep and scratch in infants (Pitchford et al., 2017; Wootton et al., 2012). 
Crisaborole is a phosphodiesterase-4 (PDE-4) inhibitor and was developed as a topical treatment for 
patients with mild-to-moderate AD. It is currently approved for treatment of mild to moderate AD in 
patients 3 months of age and older in US,  Canada, Argentina, Lebanon, Taiwan, Oman and UAE (and 
above 2 years in other countries.) While crisaborole is a topical treatment specifically designed to address 
mild to moderate AD symptoms, it is hypothesized that the reduction in symptomatology in this condition 
may afford lessening of sleep disturbances as a result of symptom reduction. In clinical trials comparing 
crisaborole and the vehicle, a strong “vehicle effect” has been observed. For instance, in a phase III AD 
study (AD-301: NCT02118766), 40.6% of the patients in the vehicle group achieved an ISGA score of 
clear (0) or almost clear (1) in comparison to the 51.7% of those with crisaborole (Paller et al., 2016). It 
has been noted, that emollients (such as the vehicle) have protective benefits by improving the skin 
barrier (Arkwright et al., 2013). In addition, children and adolescent in two-arm clinical trials have 
reported improvement in their QoL; Of the Vehicle-treated patients, 64.9% reported that their AD had 
“small effect” to “no effect” on their QoL in comparison to 75.5% of crisaborole-treated patients 
(Simpson et al., 2018). 
Rationale 
This study will specifically evaluate the rapid onset of itch and night-time scratch relief, improvement in 
sleep (both in the participant and their primary caregiver) and improvement in AD-inflammatory markers 
following crisaborole therapy twice daily (2% BID). To evaluate this experimental paradigm, we propose 
using wearable Digital Health Technologies (DHT), traditional patient-reported outcome (PRO)/observer-
reported outcome (ObsRO) measures, tape stripping biomarker assessment, and physician assessments of 
AD in a well-controlled study in-laboratory and home measures within the study. 
 
 

 
 
 
4 
Primary Objective:  
1. Evaluate the effects of Crisaborole on itch and night-time scratch (as measured by 
accelerometry/actigraphy and Observer Reported Itch Assessment (3 months - ≤ 11 years old) in 
children with mild to moderate AD between the ages of 3 months to ≤ 11 years old. 
 
Secondary Objectives: 
1. Evaluate the effects of Crisaborole on sleep in children ages 3 months to ≤ 11 years with mild to 
moderate AD. 
2. Evaluate sleep in primary caregivers. 
3. Evaluate the QoL measures in response to Crisaborole treatment (children 3 months to ≤ 11 
years). 
4. Evaluate QoL measures in response to the child’s treatment, to the parents/caregivers/families. 
5. Evaluate the effect of crisaborole treatment on AD signs, symptoms and severity in children ages 
3 months to ≤ 11 years with mild to moderate AD.  
 
Exploratory Objectives: 
1. Evaluate changes in skin biomarkers in response to Crisaborole treatment in children ages 3 
months to ≤ 11 years with mild to moderate AD. 
2. Evaluate changes in Digital Health Technologies to assess movement and agitation in children 
(aged 3 months to ≤ 11 years) in response to crisaborole treatment. 
3. Evaluate the participant burden and compliance of use of the devices. 
4. Evaluate the agreement between ORIA and Patient Reported Itch Severity Scale in children 
between the ages of 6 to ≤ 11 years old 
 
Endpoints: 
Final experimental report and a copy of all data, including these endpoints will be provided at the 
completion of the study: 
Primary Endpoint: 
• 
Daily night-time scratch (Number of scratching episodes, Duration of scratching) as measured by 
the accelerometry/actigraphy (devices will be optional for child participants who have active AD 
on location of device placement, with a minimum of at least one wrist device needed for 
enrollment) and the Observer Reported Itch Assessment (ORIA; 3 months - ≤ 11 years old) for 
the AD infant and child population.  
 
Secondary Endpoints: 
• 
Sleep:  
o Nighttime Sleep Quantity (as measured by accelerometry/actigraphy; Children ages 3 months 
to ≤ 11 years and Caregivers ages 18-75 years; devices will be optional for children 
participants who have active AD on location of device placement, with a minimum of at least 
one wrist device needed for enrollment) 
• 
Total Sleep Opportunity 
• 
Total sleep time 
• 
Percent time asleep 
• 
Wake after sleep onset (WASO)  
• 
Sleep onset latency 
• 
Arousals from sleep 
o Modified Medical Outcomes Study Sleep Scale (MOS-Sleep; Caregivers- ages 18-75)  
o Children’s Sleep Health Questionnaire (CSHQ); ages ≥4-≤ 11 years) OR Brief Infant Sleep 
Questionnaire (BISQ; ages 3 months-<4 years) 

 
 
 
5 
 
• 
 PRO/ ObsRO  
o Disease Severity:  
• 
Observer Global Impression of Severity (OGIS) 
• 
Observer Global Impression of Change (OGIC) 
• 
Observer-reported Patient Oriented Eczema Measure (POEM) 
 
• 
HRQoL  
o Dermatitis Family Impact Questionnaire (DFI; Caregivers of participants ages 3 months -≤ 11 
years) 
o Children’s Dermatology Life Quality Index (CDLQI; participants ages ≥4-≤ 11 years) OR 
Infants Dermatitis Quality Of Life Index (IDQOL; caregivers of participants ages 3 months-
<4 years) 
 
Exploratory Endpoints: 
• 
Device Comfort  
o Device Comfort Questionnaire (Caregivers ages 18-75)  
o Observer Device Comfort Questionnaire (ages 3 months - ≤ 11 years) 
• 
Mobile Device Proficiency Questionnaire (MDPQ; Caregivers ages 18-75) 
• 
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) (ages 3 months - 5 years) 
• 
Peak Pruritis NRS (Caregivers) 
• 
Patient Reported Itch Severity Scale (6 years – ≤ 11 years old) 
• 
Skin biomarkers (as measured by Tape Stripping) 
• 
Digital Health Technologies -assessed movement and agitation in children as measured by 
Accelerometry/Actigraphy (ages 3 months- ≤ 11 years) 
o Movement (Accelerometry/actigraphy) 
o Temperature 
 
Study Design 
The main objective of this single blind study is to evaluate wearable devices and Observer Reported Itch 
Assessment in children to assess reduction of itch and night-time scratch in response to Crisaborole 
treatment vs. vehicle treatment (active control comparator without crisaborole*) in children with AD. 
Participants, age 3 months to ≤ 11 years with symptomatic mild to moderate AD, along with their primary 
caregivers will be recruited and assessed by observed scratch behavior captured from 
accelerometry/actigraphy.  
 
Approximately 270 children, age 3 months to ≤ 11 years, and their primary caregiver as participants, for a 
total of 540 participants (270 pairs), will be randomized in 1:1 ratio to either Crisaborole (2% BID) or 
vehicle treatment and will be followed for 2 weeks, with an objective of approximately 50% of recruited 
child participants being ages 5 years old or younger. For this study, we will employ a simple 
randomization procedure. Participants will be randomly assigned (1:1) using computerized random 
numbers to receive either crisaborole or the vehicle. The participants will be asked to apply a thin even-
 
*An active control comparator in clinical trials “refers to the group of participants in a clinical trial who receive a treatment that is 
considered effective and most often currently used in clinical care” (U.S. Department of Health and Human Services, (n.d.)). This 
is further supported by, “the significant efficacy of crisaborole versus vehicle was noted, despite a strong “vehicle effect” 
observed in these studies, which is a common phenomenon in AD clinical studies that compare active therapeutics with their 
emollient bases” (Paller et al., 2016). 
 

 
 
 
6 
layer of Crisaborole (2% BID) or vehicle twice daily (excluding mouth, eyes, and vagina, per label), to all 
locations with active lesions and record location and time of application on the daily dosing form (as 
identified on the Dosing Record Sheet, breastfeeding women will be instructed to use the provided gloves 
when applying crisabrole/vehicle). The study will be comprised of an initial screening/baseline visit for 
children participants who have an existing diagnosis of symptomatic AD, screened and enrolled in the 
study along with their primary caregivers after signing an informed consent (or parents/guardians and 
assent when appropriate). Upon enrollment child participants and caregiver participants will complete a 
one week acclimation and training phase, where the children will not be on medication, for wearing 
accelerometry/actigraphy and performing observer-reported outcome assessments (caregivers for 
participants) and self-reported outcome assessments (caregivers). After the one week acclimation and 
training phase, the child participants will be on a Crisaborole or vehicle treatment for two consecutive 
weeks. During those 2 weeks, the children, 3 months up to <2 years will wear one actigraphy or one 
accelerometry device on each wrist and one actigraphy or one accelerometry device on each ankle 
(optional for those who have active AD on location of device placement, with a minimum of at least one 
wrist device needed for enrollment).  Children 2 years to ≤ 11 years will wear one actigraphy or one 
accelerometry on each wrist (optional for those who have active AD on location of device placement, 
with a minimum of at least one wrist device needed for enrollment).  The primary caregiver 
(parents/guardians) will also wear one accelerometer device on each wrist and complete daily assessments 
related to scratching, sleeping habits, pain, AD severity, quality of life, and device comfort questionnaires 
(parent/guardian will complete as appropriate). The participants will be asked to return to the laboratory 
on days 1, 2, 8, and 15 for assessments and biomarker assessment. At the completion of the study, Day 15 
(+3 day) participants (and primary caregiver) will return the devices, and will complete additional 
questionnaires. Participants may come in for an unscheduled visit as needed (i.e., to replace compound, 
etc.). During the performance of the study, participants will be monitored by the study dermatologist, and 
assess participant continuation throughout the study.  
 
The goal of this study is to more fully evaluate the rapid onset of night-time itch and scratch relief 
following treatment with Crisaborole in comparison to vehicle treatment in children with AD. Moreover, 
this study will assess the QoL and sleep within the associated caregivers. 
 
Significance 
Itch, night-time scratch and sleep are key symptoms experienced by patients with AD and impact not only 
the patient but the families of the patients with AD, particularly for young age children.  Therefore, more 
fully understanding the cessation of the feeling of itch, action of scratch and improvements in sleep 
following treatment of Crisaborole (2% BID) would provide additional insight to the treatment profile. 
This study will specifically evaluate the rapid onset of itch and night-time scratch relief, improvement in 
sleep (both in the participant and their primary caregiver) and improvement in AD-inflammatory markers 
following crisaborole therapy twice daily (2% BID) in children 3 months to ≤ 11 years old. 
This study will also provide critical understanding of the ability of the accelerometry/actigraphy devices 
to measure drug-induced changes in scratching, movement and sleep quantity in children with 
symptomatic AD and quality of life in caregivers. It will also provide a physiological comparator for 
PRO/ObsRO assessments and ultimately enhance understanding of AD. 
 
 
 
 
 
 

 
 
 
7 
SCHEDULE OF ACTIVITIES 
Period/Visit 
Screening 
V01 
(Baseline) 
V02 
V03 
V04 
V05 
Day 
-28 to -7 
-7 
1 
2 
8 
15 
Window(days) 
NA 
+/- 3 
+/- 3 
+ 0.5 
+/- 3 
+/- 3 
ENROLLMENT PROCEDURES 
Informed consent / assent  
X 
X 
 
 
 
 
Demographics, medical history including AD history/treatment   
X 
X 
 
 
 
 
Inclusion and exclusion criteria Review (both child and caregiver) 
X 
 
 
 
 
 
Inclusion and exclusion criteria ‡ (both child and caregiver) 
 
X 
 
 
 
 
Pregnancy test for female caregivers of child-bearing potential 
 
X 
 
 
 
 
Wide Range Achievement Test 4 (WRAT-4; caregivers only) 
 
X 
 
 
 
 
MEDICAL PROCEDURES 
Vital signs 
 
X 
 
 
 
 
Height and weight 
 
X 
 
 
 
 
ASSESSMENTS 
Investigator’s Static Global Assessment (ISGA) (both child and caregiver at V01, only 
child thereafter) 
 
X 
X 
 
X 
X 
Eczema Area and Severity Index (EASI) 
 
X 
X 
 
X 
X 
% Body Surface Area (BSA) 
 
X 
X 
 
X 
X 
Childhood Asthma Control Test (ages 4 to ≤ 11 years) 
 
X 
 
 
 
 
Tape Stripping (Biomarker Assessment)** 
 
X 
 
X 
 
X 
PATIENT REPORTED/OBSERVER-REPORTED OUTCOMES (PROs/ObsROs) 
Observer Reported Itch Assessment (ORIA; 3 months - ≤ 11 years old)  
 
X 
------DAILY (Day 1-15 AH)---- 
X 
Patient Reported Itch Severity Scale (6 years - ≤ 11 years old) 
 
X 
------DAILY (Day 1-15 AH)---- 
X 
Observer Global Impression of Severity (OGIS)  
 
X 
------DAILY (Day 1-15 AH)---- 
X 
PPNRS Caregivers  
 
X 
------DAILY (Day 1-15 AH)---- 
X 
Sleep:CSHQ (Age ≥4 - ≤ 11 years)/BISQ(Age 3 months - <4 years)/MOS-Sleep 
(Caregivers) 
 
X 
X 
 
X 
X 
Observer Global Impression of Change (OGIC) 
 
 
 
 
X 
X 
Device Comfort Questionnaire (DCQ)/Observer Device Comfort Questionnaire (ODCQ) 
 
 
 
 
 
X 
Mobile Device Proficiency Questionnaire (MDPQ) 
 
X 
 
 
 
 
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) 
 
X 
X 
 
X 
X 
Dermatitis Family Impact Questionnaire (DFI) 
 
X 
X 
 
X 
X 
Children’s Dermatology Life Quality Index (CDLQI) (Age ≥4 to ≤ 11 years) OR Infants 
Dermatitis Quality of Life Index (IDQOL) (Age 3 months to <4 years) 
 
X 
X 
 
X 
X 
Patient-Oriented Eczema Scale (POEM) (observer-reported for participants age 3 
months-11 years) 
 
X 
X 
 
X 
X 
SAFETY 
Serious and non-serious AE monitoring  
X 
X ---------------------------------------------------------- X 
STUDY INTERVENTION 
In-laboratory dose application training 
 
 
X 
 
X 
 
At home dosing and dosing record sheet (twice daily) 
 
 
---------------- DAILY -------------- 
Drug dispensing 
 
 
X 
 
 
 
DIGITAL HEALTH TECHNOLOGIES ° 
 
Issue/Train/Retrieve Accelerometry Device; (Children: Ages 2 years to ≤ 11 years; On R 
& L wrists); (Caregivers: Ages 18 to 75 years; On R & L wrists)**** 
 
X 
Issue 
 
 
X 
Retrieve, 
Re-Issue 
X 
Retrieve 
Accelerometry Wear (Children: Ages 2 years to ≤ 11 years; On R & L wrists); 
Caregivers: Ages 18 to 75 years; On R & L wrists) **** 
 
X ------------------------------------------------------------- X 
Issue/Train/Retrieve actigraphy or accelerometry (Ages 3 months up to <2 years; On R 
& L wrists and R & L ankles); (Ages 2 years to ≤ 11 years; On R & L wrists) **** 
 
X 
Issue 
 
 
 
X 
Retrieve 
Actigraphy or accelerometry Wear/Measures Collected (Ages 3 months up to <2 years; 
On R & L wrists and R & L ankles); (Ages 2 years to ≤ 11 years; On R & L wrists) **** 
 
X ------------------------------------------------------------- X 

 
 
 
8 
Period/Visit 
Screening 
V01 
(Baseline) 
V02 
V03 
V04 
V05 
Day 
-28 to -7 
-7 
1 
2 
8 
15 
Window(days) 
NA 
+/- 3 
+/- 3 
+ 0.5 
+/- 3 
+/- 3 
*per AD = atopic dermatitis; AE= adverse event; BISQ= Brief Infant Sleep Questionnaire; CSHQ= Children’s Sleep Health Questionnaire; L= 
Left; MOS= Medical Outcomes Study; R= Right; V=Visit number; AH = At Home 
‡ Participants are randomly assigned to one of the two arms of the study 
** Nonlesional tape strips will be collected from an area of skin that is unaffected by atopic dermatitis at the baseline visit (V01). Lesional tape 
strips will be collected from skin adjacent to an atopic dermatitis lesion at the baseline visit (V01) and on Day 2 (V03) and Day 15 (V05). 
° See Appendix for figure 
***Participants may come in for an unscheduled visit as needed (i.e., to replace compound or vehicle, etc.) 
****Devices will be optional for children participants who have active AD on location of device placement, with a minimum of at least one wrist 
device needed for enrollment   
 
1. INTRODUCTION OF RATIONALE  
 
Atopic Dermatitis (AD) is one of the most common, chronic, relapsing childhood dermatoses, impacting up 
to 36% of children worldwide and many have disease that persists into adulthood (Abuabara et al., 2018).  
It is a condition that not only leads to red inflamed skin, but also is characterized by extensive pruritus/itch, 
scratching and sleep disturbances. It is stated by patients that the most problematic symptom of AD is 
pruritus.1  
 
While approximately 10-41% of children 3,4 and 7-48% of adults 5,6 experience sleep disturbances, these 
numbers climb substantially in people with AD (47-80% in children and 33-87.1% in adults).7 The 
physical action of scratching can disrupt sleep itself, but also triggers cognitive and behavioral changes 
that trigger and reinforce insomnia and sleep disruptions.8  These sleep disturbances impact the QoL of 
not only the person with the condition but also caregivers and family members. Sleep disturbances can 
also result in impaired performances on neurobehavioral tasks, hyperactivity/inattention, stunted growth 
(children), missed workdays, poorer overall health and behavioral and emotional disturbances (including 
increasing scratching).8 Measurements of itch, though of significant value, are currently accomplished 
through subjective methods such as questionnaires and intensity scales (Erickson & Kim, 2019; 
Hjermstad et al., 2011). This poses several limitations in infants and children where the parents answer 
the questionnaires on behalf of their children, and recall of itch and scratch during the night can be limited 
(Erickson & Kim, 2019). Thus, there is a great need to objectively understand and characterize itch and 
scratch.Objective measurements of sleep disturbances and nocturnal scratch have been employed using 
wearable sensors such as accelerometers (Mahadevan et al., 2021). Previous studies have used actigraphy 
and accelerometry to assess sleep and scratch in infants (Pitchford et al., 2017; Wootton et al., 2012). 
Crisaborole is a phosphodiesterase-4 (PDE-4) inhibitor and was developed as a topical treatment for 
patients with mild-to-moderate AD. It is currently approved for use in patients 3 months of age and older 
in US, Canada, Argentina, Lebanon, Taiwan, Oman and UAE (and above 2 years in other countries). In 
clinical trials comparing crisaborole and the vehicle, a strong “vehicle effect” has been observed. For 
instance, in a phase III AD study (AD-301: NCT02118766), 40.6% of the patients in the vehicle group 
achieved an ISGA score of clear (0) or almost clear (1) in comparison to the 51.7% of those with 
crisaborole (Paller et al., 2016). It has been noted, that emollients (such as the vehicle) have protective 
benefits by improving the skin barrier (Arkwright et al., 2013). In addition, children and adolescent in 
two-arm clinical trials have reported improvement in their QoL; Of the Vehicle-treated patients, 64.9% 
reported that their AD had “small effect” to “no effect” on their QoL in comparison to 75.5% of 
crisaborole-treated patients (Simpson et al., 2018). 
 

 
 
 
9 
 
2. STUDY OBJECTIVES AND ENDPOINTS  
 
Primary Objective:  
1. Evaluate the effects of Crisaborole on itch and night-time scratch (as measured by 
accelerometry/actigraphy and Observer Reported Itch Assessment (3 months - ≤ 11 years old) in 
children with mild to moderate AD between the ages of 3 months to ≤ 11 years old. 
 
Secondary Objectives: 
1. Evaluate the effects of Crisaborole on sleep in children ages 3 months to ≤ 11 years with mild to 
moderate AD. 
2. Evaluate sleep in primary caregivers. 
3. Evaluate the QoL measures in response to Crisaborole treatment (children 3 months to ≤ 11 years). 
4. Evaluate QoL measures in response to the child’s treatment, to the parents/caregivers/families. 
5. Evaluate the effect of crisaborole treatment on AD signs, symptoms and severity in children ages 
3 months to ≤ 11 years with mild to moderate AD.  
 
Exploratory Objectives: 
1. Evaluate changes in skin biomarkers in response to Crisaborole treatment in children ages 3 months 
to ≤ 11 years with mild to moderate AD. 
2. Evaluate changes in Digital Health Technologies -assessed movement and agitation in children 
(aged 3 months to ≤ 11 years) in response to crisaborole treatment. 
3. Evaluate the participant burden and compliance of use of the devices. 
4. Evaluate the agreement between ORIA and Patient Reported Itch Severity Scale in children 
between the ages of 6 to ≤ 11 years old 
 
ENDPOINTS 
Endpoints: 
Final experimental report and a copy of all data, including these endpoints: 
Primary Endpoint: 
• 
Daily night-time scratch (Number of scratching episodes, Duration of scratching) as measured by 
the accelerometry/actigraphy (optional for children participants who have active AD on location 
of device placement, with a minimum of at least one wrist device needed for enrollment) and the 
Observer Reported Itch Assessment (ORIA; 3 months - ≤ 11 years old) for the AD infant and 
child population.  
 
Secondary Endpoints: 
• 
Sleep:  
o Nighttime Sleep Quantity (as measured by accelerometry/actigraphy; Children ages 3 months 
to ≤ 11 years and Caregivers ages 18-75 years; devices will be optional for children 
participants who have active AD on location of device placement, with a minimum of at least 
one wrist device needed for enrollment) 
• 
Total Sleep Opportunity 
• 
Total sleep time 
• 
Percent time asleep 
• 
Wake after sleep onset (WASO)  
• 
Sleep onset latency 
• 
Arousals from sleep 

 
 
 
10 
o Modified Medical Outcomes Study Sleep Scale (MOS-Sleep; Caregivers- ages 18-75)  
o Children’s Sleep Health Questionnaire (CSHQ); ages ≥4-≤ 11 years) OR Brief Infant 
Sleep Questionnaire (BISQ; ages 3 months-<4 years) 
 
• 
 PRO/ ObsRO  
o Disease Severity:  
• 
Observer Global Impression of Severity (OGIS) 
• 
Observer Global Impression of Change (OGIC) 
• 
Observer-reported Patient Oriented Eczema Measure (POEM) 
• 
HRQoL  
o Dermatitis Family Impact Questionnaire (DFI; Caregivers of participants ages 3 months -≤ 11 
 years) 
o Children’s Dermatology Life Quality Index (CDLQI; participants ages ≥4-≤ 11 years) OR 
Infants Dermatitis Quality Of Life Index (IDQOL; caregivers of participants ages 3 months-
<4 years) 
 
Exploratory Endpoints: 
• 
Device Comfort  
o Device Comfort Questionnaire (Caregivers ages 18-75)  
o Observer Device Comfort Questionnaire (ages 3 months - ≤  11 years) 
• 
Mobile Device Proficiency Questionnaire (MDPQ; Caregivers ages 18-75) 
• 
Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) (ages 3 months - 5 years) 
• 
Peak Pruritis NRS (Caregivers) 
• 
Patient Reported Itch Severity Scale (6 years – ≤ 11 years old) 
• 
Skin biomarkers (as measured by Tape Stripping) 
• 
Digital Health Technologies -assessed movement and agitation in children as measured by 
Actigraphy/accelerometry (ages 3 months- ≤ 11 years) 
o Movement (Accelerometry/actigraphy) 
o Temperature 
 
DEVICE ENDPOINTS 
GENEActiv Wrist Accelerometry Device (50 Hz sampling rate)  
• 
Accelerometry Raw Data in x, y, and z  
• 
Units of g and collected at 50Hz 
• 
Ambient light level (lux) 
• 
Out of Bed time (hh:mm) 
• 
Wake duration (mins) 
• 
Non wear time (mins) 
• 
Sedentary activity time (mins) 
• 
Light activity time (mins) 
• 
Moderate activity time (mins) 
• 
Vigorous activity time (mins) 
• 
Sedentary activity (%) 
• 
Light activity (%) 
• 
Moderate activity (%) 
• 
Vigorous activity (%) 
• 
Sedentary activity estimated MET.mins 

 
 
 
11 
• 
Light activity estimated MET.mins 
• 
Moderate activity estimated MET.mins 
• 
Vigorous activity estimated MET.mins 
• 
Number of Vigorous periods (> 10 mins)  
• 
Going to bed time (hh:mm) 
• 
Bed duration (mins) 
• 
Total sleep time (mins) 
• 
Sleep efficiency (% total sleep time divided by total time in bed) 
• 
Number of Active periods 
• 
Median activity period (mins) 
• 
Temperature 
• 
Actigraphy Digital Health Technology (ages 3 months - ≤ 11 years) 
o Actigraphy at 25 Hz (X,Y,Z movement) 
 
 
3. STUDY DESIGN  
 
The main objective of this single blind study is to evaluate wearable devices and Observer Reported Itch 
Assessment in children to assess reduction of itch and night-time scratch in response to Crisaborole 
treatment vs. vehicle treatment in children with AD. Participants, age 3 months to ≤ 11 years with 
symptomatic mild to moderate AD, along with their primary caregivers will be recruited and assessed by 
observed scratch behavior captured from accelerometry/actigraphy.  
 
Approximately 270 children, age 3 months to ≤ 11 years, and their primary caregiver as participants, for a 
total of 540 participants (270 pairs), will be randomized in 1:1 ratio to either Crisaborole (2% BID) or 
vehicle treatment and will be followed for 2 weeks, with an objective of approximately 50% of recruited 
child participants being ages 5 years old or younger. For this study, we will employ a simple 
randomization procedure. Participants will be randomly assigned (1:1) using computerized random 
numbers to receive either crisaborole or the vehicle.The participants will be asked to apply a thin even-
layer of Crisaborole 2% or vehicle twice daily (excluding mouth, eyes, and vagina, per label), to all 
locations with active lesions and record location and time of application on the daily dosing form (as 
identified on the Dosing Record Sheet, breastfeeding women will be instructed to use the provided gloves 
when applying crisabrole/vehicle). The study will be comprised of an initial screening/baseline visit for 
children participants who have an existing diagnosis of symptomatic AD, screened and enrolled in the 
study along with their primary caregivers after signing an informed consent (or parents/guardians and 
assent when appropriate). Upon enrollment child participants and caregiver participants will complete a 
one week acclimation and training phase, where the children will not be on medication, for wearing 
accelerometry/actigraphy and performing observer-reported outcome assessments (caregivers for 
participants) and self-reported outcome assessments (caregivers). After the one week acclimation and 
training phase, the child participants will be on a Crisaborole or vehicle treatment for two consecutive 
weeks. During those 2 weeks, the children, 3 months up to <2 years will wear one actigraphy or one 
accelerometry device on each wrist and one actigraphy or one accelerometry device on each ankle 
(optional for those who have active AD on location of device placement, with a minimum of at least one 
wrist device needed for enrollment).  Children 2 years to ≤ 11 years will wear one actigraphy or one 
accelerometry device on each wrist (optional for those who have active AD on location of device 
placement, with a minimum of at least one wrist device needed for enrollment).  The primary caregiver 
(parents/guardians) will also wear one accelerometer device on each wrist and complete daily assessments 
related to scratching, sleeping habits, pain, AD severity, quality of life, and device comfort questionnaires 
(parent/guardian will complete as appropriate). The participants will be asked to return to the laboratory 

 
 
 
12 
on days 1, 2, 8, and 15 for assessments and biomarker assessment. At the completion of the study, Day 15 
(+3 day) participants (and primary caregiver) will return the devices, and will complete additional 
questionnaires.  Participants may come in for an unscheduled visit as needed (i.e., to replace compound, 
etc.) 
 
The goal of this study is to more fully evaluate the rapid onset of night-time itch and scratch relief 
following treatment with Crisaborole in comparison to vehicle treatment in children with AD.  Moreover, 
this study will assess the QoL and sleep within the associated caregivers. 
 
4. PARTICIPANT SELECTION 
This protocol can fulfill its objectives only if appropriate participants are enrolled.  Prior to undergoing any 
study procedures, a participant must meet this protocol’s Inclusion/Exclusion criteria.   
 
4.1. Inclusion Criteria 
Both child and caregiver participants must meet all of the following inclusion criteria to be eligible for 
enrollment into the study: 
 
Children (3 months to ≤ 11 years) 
1. Male or female paticipants aged between ≥3 months of age and <11 years of age at Day -7. 
2. Written informed consent from participant/parent(s)/guardian(s).  
3. Native English or demonstrated fluency in English (as age appropriate). 
4. Participants and parent(s)/guardian(s) are willing and able to comply with study instructions, 
study visits, procedures, and device placement (devices will be optional for those who have active 
AD on location of device placement, with a minimum of at least one wrist device needed for 
enrollment). 
5. Have a clinical diagnosis of AD according to the criteria of Hanifin and Rajka. 
6. Have AD involvement ≥ 5% Treatable % Body Surface Area (BSA) excluding the scalp and less 
than 40% BSA. 
7. Have an ISGA score of Mild (2) or Moderate (3) at the baseline visit. 
8. Have an EASI  total score of  ≥3 at Day -7. 
9. Have a minimum Observer Reported Itch Assessment score of 2 at Day -7 (ages 3 months - ≤ 5 
years only) or a minimum Patient Reported Itch Severity Scale score of 2 (ages 6 years - ≤ 11 
years old) at Day -7. 
10. Participant/parent(s)/guardian(s) agrees to refrain from applying diaper rash creams, lotions, 
ointments, powders, etc. where AD lesions are present, unless AD lesions are present where 
crisaborole cannot be applied (face within 1 or 2 fingers away from the mouth and hands/fingers).  
11. Participants must agree to refrain from applying crisaborole/vehicle to AD lesions on the fingers 
or hands or within 1 or 2 fingers away from the the mouth to prevent inadvertent ingestion of 
ointment. 
 
Adult Caregiver 
1. Primary caregiver of the child participant, between ≥18 years of age and <75 years of age. 
2. Able to understand and cooperate with study procedures and give informed consent.  
3. Native English or demonstrated fluency in English. 
4. Evidence of a personally signed and dated informed consent document indicating that the 
participant has been informed of all pertinent aspects of the study.  
5. ISGA score of 0 or 1 of AD at the baseline visit, and no reported diagnosis of Atopic Dermatitis. 
6. WRAT-4 Word Reading Subtest equivalent to 8th grade reading level or greater. 
 

 
 
 
13 
4.2. Exclusion Criteria 
Participants (either child or caregiver) presenting with any of the following will not be included in the 
study: 
 
Children (3 months to ≤ 11 years) 
1. Has any clinically significant medical disorder, condition, disease (including active or potentially 
recurrent non-AD dermatological conditions and known genetic dermatological conditions that 
overlap with AD, such as Netherton syndrome) or clinically significant finding at baseline that 
precludes participant’s participation in study activities.  
2. Participants who are on systemic corticosteroids or immunosuppressive agents within 28 days of 
Day -7 (V01). 
3. Participants who are on topical AD treatment such as low-to-high-potency corticosteroids, TCIs, 
antihistamines, antibiotics, sodium hypochlorite-based products, antibacterial soaps, bleach baths, 
diaper rash creams, lotions, ointments, powders, light therapy, and use of bland emollients on or 
overlapping with treatable AD-involved areas within 7 days of Day -7 (V01), unless AD lesions 
are present where crisaborole cannot be applied (face within 1 or 2 fingers away from the of 
mouth and hands/fingers).  
4. Participants who are or have been on crisaborole treatment regimen in the past.  
5. Allergy to polyurethane resin (strap/wristband component), skin nickel allergy, silicone, and/or 
adhesives.  
6. Has documented non-AD related insomnia, sleep apnea or other sleep-related disorders (e.g., 
narcolepsy, restless legs syndrome, circadian rhythm disorder). 
7. Participant has a known lack of efficacy to any component of crisaborole. 
8. Participant scores <20 on the Childhood Asthma Control Test (ages 4-≤ 11) indicating poorly 
controlled asthma. 
9. If participant has a history of angioedema or anaphylaxis. 
10. Has a significant active systemic or localized infection, including actively infected AD. 
11. Has any planned surgical or medical procedure that would overlap with study participation. 
12. Participants with cardiac pacemakers, electronic pumps or any other implanted medical devices. 
13. Participants who are unable to wear at least one wrist device (one accelerometry device on at least 
one wrist). 
 
Adult Caregiver 
1. Has any clinically significant medical disorder, condition, disease or clinically significant finding 
at baseline that precludes Caregivers participation in study activities (e.g., sleep apnea, 
narcolepsy, etc.) 
2. History of regular alcohol consumption exceeding 7 drinks/week for females or 14 drinks/week 
for males (1 drink = 5 ounces (150 mL) wine, 12 ounces (360 mL) of beer, or 1.5 ounces (45 mL) 
of hard liquor) within 6 months of baseline as disclosed by participant during evaluation. *   
3. Current shift worker or travel across more than two time zones in the past 2 weeks, and/or during 
the study period.   
4. Has any planned surgical or medical procedure that would overlap with study participation.  
5. Participants who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the investigator, or 
participants who are BU/BMC employees directly involved in the conduct of the study.   
6. Allergy to polyurethane resin (strap/wristband component), skin nickel allergy, silicone, and/or 
adhesives.  
7. A female who is pregnant.†  
8. The primary caregiver or share the same domicile of another child who has previously been or is 
currently enrolled in the study. 

 
 
 
14 
 
* One of our secondary objectives is to evaluate sleep in primary caregivers. It is noted in the literature 
that alcohol use and abuse has significant effect on sleep as it can cause insomnia, excessive daytime 
sleepiness, and changes in sleep homeostasis/architecture (Colrain, Turlington, & Baker, 2009; Hu, et al., 
2020). Thus to ensure that we can effectively capture sleep in primary caregivers of children with AD 
(who experience sleep disturbances), we will be excluding caregivers who have sleep disorders, are 
shiftworkers or have traveled more than two time zones in the past 2 weeks and/or during the study 
period, as well as those who have a history of regular alcohol consumption exceeding 7 drinks/week for 
females or 14 drinks/week for males.  
†There is currently no data available regarding associated risks of pregnant women applying crisaborole to 
their child.  Thus, pregnant women are excluded from the study as a precautionary measure.  Furthermore, 
per the crisaborole FDA label, for the use of crisaborole on pregnant women "There is no available data 
with EUCRISA in pregnant women to inform the drug-associated risk for major birth defects and 
miscarriage.”  Since this data is not available, the risks of including a pregnant woman do not outweigh 
the benefits of the study. Women of child-bearing potential will be pregnancy tested using a standard 
drug-store urine test at the Laboratory for Human Neurobiology.  If the participant suspects that they are 
pregnant, or test results indicate that they may be pregnant, they will be asked to follow up with their 
doctor and they will not be included in the study.  
 
5. STUDY PROCEDURES 
The study will consist of a screening/baseline (in- laboratory) visit on Day -7 (V01), an in- laboratory 
visit Day 1 (V02), an in- laboratory visit on Day 2 (V03) for tape-striping, and Day 8 (V04) for an 
assessment of the severity of the AD and a final in- laboratory visit on Day 15 (V05) for an assessment of 
the AD, tape-stripping, completion of ObsROs and return devices. Throughout the study, the participants 
and caregivers will wear accelerometry/actigraphy devices continuously (optional for those who have 
active AD on location of device placement, with a minimum of at least one wrist device needed for 
enrollment; devices may be removed for short periods of time for such things as the purposes of bathing, 
etc.). Enrolled participants will be randomly assigned to each arm of the study. Participants may come in 
for an unscheduled visit as needed (i.e., to replace compound, etc.). All in-person study activities, 
including informed consent and pregnancy testing, will be completed at the Laboratory for Human 
Neurobiology, 650 Albany St X140, Boston, MA, 02118.  All activities performed in the laboratory are 
accomplished in private rooms. Primary caregivers will be provided with ample time and a 
privacy curtain to change into a gown during assessment for exclusion of Atopic Dermatitis, and primary 
caregivers will accompany children during all activities to ensure participant privacy.  All at-home study 
activities will be completed in the participants' home.  
 
Phone Screening - Day-28 to -7 (~15 minutes): 
• 
Verbal consent (including assent where applicable) 
• 
Assign Participant ID (a sequentially assigned numerical ID used to identify participant on 
all study documents and in the electronic data capture [EDC] system) 
• 
Screening demographics, medical history including AD history/treatment (includes, race, 
ethnicity, and gender) 
• 
Eligibility screening (review of inclusion and exclusion criteria) 
 
Baseline Visit 1 (V01)/Day -7 (+/- 3) – In Laboratory (~2 hours): 
• 
Written Informed consent (including assent when applicable) 
• 
Participants are randomly assigned to one of the two arms of the study 
• 
Screening demographics (includes race, ethnicity, gender, and significant medical 

 
 
 
15 
history/treatment) 
• 
Pregnancy test for female caregivers of child-bearing potential 
• 
Wide Range Achievement Test 4 (WRAT-4) 
• 
Eligibility Screening (Inclusion/Exclusion criteria) 
• 
Vital signs 
• 
Height and weight  
• 
Investigator’s Static Global Assessment (ISGA) (scored by a dermatologist or a medically 
qualified individual who has been trained in the assessment; rater to be consistent 
throughout study) 
• 
EASI assessment (scored by a dermatologist or a medically qualified individual who has 
been trained in the assessment; rater to be consistent throughout study) 
• 
Calculate % body surface area (BSA) affected with AD 
• 
Childhood Asthma Control Test 
• 
Tape Stripping (Biomarker Assessment) 
• 
Observer Reported Itch Assessment (ORIA; ages 3 months - ≤ 11 years)   
• 
Patient Reported Itch Severity Scale (ages 6 years to ≤ 11 years old) 
• 
Observer Global Impression of Severity (OGIS; ages 3 months - ≤ 11 years) 
• 
Peak Pruritis NRS (Caregivers) 
• 
Children’s Sleep Health Questionnaire (CSHQ; ages ≥4-≤ 11) OR Brief Infant Sleep 
Questionnaire(BISQ; ages 3 months-<4 years)  
• 
Medical Outcome Sleep Scale (MOS; caregivers only) 
• 
Mobile Device Proficiency Questionnaire (MDPQ; caregivers only) 
• 
Faces, Legs, Activity, Cry, and Consolability Scale (FLACCS) 
• 
Dermatitis Family Impact Questionnaire (DFI; parent/guardian(s); ages 3 months- ≤ 11 
years) 
• 
Children’s Dermatology Life Quality Index (CDLQI; ages ≥4-≤ 11 years) OR Infants 
Dermatitis Quality Of Life Index (IDQOL; ages 3 months-<4 years) 
• 
Observer-reported Patient-Oriented Eczema Measure (POEM); ages 3 months – ≤ 11 years) 
• 
The participant will be asked to don the accelerometry/actigraphy devices (coordinator will 
log dispensing) as follows: The participant will be provided the accelerometry/actigraphy 
devices immediately after completion of informed consent and will be trained. Devices will 
be optional for child participants who have active AD on location of device placement, 
with a minimum of at least one wrist device needed for enrollment. 
• 
Accelerometry 
o Children: Ages 2 years to ≤ 11 years; On R & L wrists 
o Caregivers: Ages 18 to 75 years; On R & L wrists 
• 
Actigraphy or accelerometry:  
o (Ages 3 months up to ≤ 11 years; On R & L wrists and R & L ankles for 
3 months - <2 years; R & L wrists only for 2 – ≤ 11 years) 
 
Out-of-Laboratory (At-Home) Assessments (Days -7–Day 1; Between Visits 1 & 2):  
The purpose of the out-of-laboratory assessment is to evaluate wearable devices in a 
home/routine setting (defined as the participant’s routine environment/activities). Participants will 
be provided a fully-charged set of accelerometery devices for use at home. Devices will be 
optional for child participants who have active AD on location of device placement, with a 
minimum of at least one wrist device needed for enrollment. 
 
1. Continuously wear Accelerometry devices as much as possible 

 
 
 
16 
2. Continuously wear Actigraphy devices as much as possible 
 
Visit 2 (V02)/ Day 1 (+/- 3 days)- In Laboratory (~1 hour): 
1. ISGA 
2. EASI 
3. % affected BSA calculation 
4. Children’s Sleep Health Questionnaire (CSHQ; ages ≥4 to ≤ 11 years) OR BISQ (Brief Infant 
Sleep Questionnaire; ages 3 months - <4 years)  
5. Medical Outcome Sleep Scale (MOS-Sleep; caregivers only) 
6. Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) 
7. Dermatitis Family Impact Questionnaire (DFI; parent/guardian(s); ages 3 months - ≤ 11 years 
8. Children’s Dermatology Life Quality Index (CDLQI; ages ≥4 - ≤ 11) OR Infants Dermatitis 
Quality Of Life Index (IDQOL; ages 3 months - <4 years) 
9. Observer-Reported Patient-Oriented Eczema Measure (POEM; ages 3 months – ≤ 11 years) 
10. In laboratory dose application training, including weight of the compound or vehicle tube 
11. Drug Dispensing  
12. Continuous accelerometry wear (Devices will be optional for child participants who have active 
AD on location of device placement, with a minimum of at least one wrist device needed for 
enrollment.) 
13. Continuous actigraphy wear (Devices will be optional for child participants who have active 
AD on location of device placement, with a minimum of at least one wrist device needed for 
enrollment.) 
 
Out-of-Laboratory (At-Home) Assessments (Days 1-15) (~15 minutes per day):  
The purpose of the out-of-laboratory assessment is to evaluate wearable devices and 
ORIA/Patient Reported Itch Severity Scale in a home/routine setting (defined as the participant’s 
routine environment/activities) while the child participant is receiving either crisabole or vehicle. 
Participants will be provided a fully-charged set of accelerometery devices for use at home. 
  
1. Caregiver to complete ObsRO/PRO measurements as instructed: 
o Observer Reported Itch Assessment (ORIA; ages 3 months-≤ 11 years)  
o Observer Global Impression of Severity (OGIS; ages 3 months-≤ 11 years) 
o Peak Pruritis NRS (Caregivers) 
o Patient Reported Itch Severity Scale (Children 6-≤ 11 years old) 
2. At-home dosing (crisaborole or vehicle) in all affected areas except mouth, eyes, and vagina, 
per label 
3. Continuous Accelerometry wear (Devices will be optional for child participants who have 
active AD on location of device placement, with a minimum of at least one wrist device needed 
for enrollment.) 
4. Continuous Actigraphy wear (Devices will be optional for child participants who have active 
AD on location of device placement, with a minimum of at least one wrist device needed for 
enrollment.) 
 
Visit 3 (V03)/ Day 2 (+/- 12 hours) – In Laboratory (~30 minutes): 
1. Collect Tape Stripping 
2. Weigh tube of compound or vehicle 
 

 
 
 
17 
Visit 4 (V04) / Day 8 (+/- 3 day) In Laboratory (~1 hour): 
1. ISGA 
2. EASI 
3. % affected BSA calculation 
4. Children’s Sleep Health Questionnaire (CSHQ; ages ≥4 to ≤ 11 years) OR BISQ (Brief Infant 
Sleep Questionnaire; ages 3 months - <4 years)  
5. Medical Outcome Sleep Scale (MOS-Sleep; caregivers only) 
6. Observer Global Impression of Change (OGIC) 
7. Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) 
8. Dermatitis Family Impact Questionnaire (DFI; parent/guardian(s); ages 3 months – ≤ 11 years 
9. Children’s Dermatology Life Quality Index (CDLQI; ages ≥4 – ≤ 11) OR Infants Dermatitis 
Quality Of Life Index (IDQOL; ages 3 months- <4 years) 
10. Observer-Reported Patient-Oriented Eczema Measure (POEM; ages 3 months – ≤ 11 years) 
11. In laboratory dose application training, including weight of the compound or vehicle tube 
12. Retrieve and re-issue Accelerometry devices (Devices will be optional for child participants 
who have active AD on location of device placement, with a minimum of at least one wrist 
device needed for enrollment.) 
 
Visit 5 (V05) / Day 15 (+/- 3 day) or Early Termination (ET)– In laboratory (~2 hours): 
The primary purpose of this visit is to retrieve devices and complete end-of-study assessments.  In 
addition, the following procedures will occur. 
1. ISGA 
2. EASI 
3. % affected BSA calculation 
4. Tape Stripping 
5. Observer Reported Itch assessment (ORIA; ages 3 months - ≤ 11 years)  
6. Patient Reported Itch Severity Scale (ages 6 years to ≤ 11 years old) 
7. Observer Global Impression of Severity (OGIS; ages 3 months - ≤ 11 years) 
8. Peak Pruritis NRS (Caregivers) 
9. Children’s Sleep Health Questionnaire (CSHQ; ages ≥4 to ≤ 11 years) OR BISQ (Brief 
Infant Sleep Questionnaire; ages 3 months - <4 years)  
10. Medical Outcome Sleep Scale (MOS-Sleep; caregivers only) 
11. Observer Global Impression of Change (OGIC) 
12. Device Comfort Questionnaire (DCQ) / Observer Device Comfort Questionnaire 
(ODCQ) 
13. Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) 
14. Dermatitis Family Impact Questionnaire (DFI; parent/guardian(s); ages 3 months-≤ 11 
years 
15. Children’s Dermatology Life Quality Index (CDLQI; ages ≥4- ≤ 11) OR Infants 
Dermatitis Quality Of Life Index (IDQOL; ages 3 months-<4 years) 
16. Observer-Reported Patient-Oriented Eczema Measure (POEM; ages 3 months – ≤ 11 
years) 
17. Coordinator to retrieve and track return of devices. 
18. Weigh and return compound or vehicle tube 
19. Record participant disposition (completed study, left study early and reasons) 
 

 
 
 
18 
Participant Withdrawal/Stopping Rules 
Participant comfort with the proposed procedures will be regularly assessed and no procedure will continue 
if the participant expresses discomfort or a desire to stop for any reason. If one Unanticipated Problem (UP) 
occurs, the study will be suspended until the investigators determine, with the BUMC/BMC IRB's input, 
that sufficient corrective measures can be put into place to allow it to proceed. 
 
7. ASSESSMENTS 
Below are the descriptions of the tasks chosen for this study; these brief summaries provide an overview of 
the range of task’s objectives.   
 
Tape Stripping: 
Tape strips will be collected from participants from nonlesional and lesional skin at the time points 
outlined in the SoA. The area(s) to be used for tape stripping will be selected predose at V01 (Day -7) and 
documented. Index lesion selected as noted at V01, and documented on the Lesion/Non-Lesion Tape 
Stripping Site Identification Form, must be skin that is affected by atopic dermatitis and the lesional tape 
strip at V01 should be taken from skin that is adjacent to an affected skin lesion and must be part of the 
designated treatment area. Tape strips at subsequent visits should be taken from the same site as the initial 
index lesion, even if the lesion severity changes during the course of treatment. 
Details on the processes for selection of lesional and non-lesional skin and collection and shipment of 
these samples can be found in the appendix.  
Samples may be stored at a facility selected by the sponsor for a maximum of 10 years (or according to 
local regulations) following the last participant’s last visit for the study and may be used for possible 
additional exploratory analysis only for this study, with all remaining samples being destroyed. 
Biomarkers may include, but are not limited to target expression, nucleic acid analyses, and protein 
analyses. Samples may be analyzed for assessments related to inflammatory skin disease, the mechanism 
of action of crisaborole and/or responder/non-responder analyses.  
All other assessments are included within the appendix section of this protocol.  
8. SAFETY 
8.1. Adverse Events 
Any Adverse Events or Serious Adverse Events (defined below) encountered in the study will be monitored 
and reported to the BUMC IRB as per established procedures. 
 
Adverse Event: Any untoward or unfavorable physical or psychological occurrence in a human participant, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease temporally associated with the participant’s participation in the research, whether or not considered 
related to the participant’s participation in the research.  
 
Serious Adverse Event: Any adverse event that: 
1) Results in death 
2) Is life-threatening (places the participant at immediate risk of death from the event as it occurred) 
3) Results in inpatient hospitalization or prolongation of existing hospitalization 
4) Results in a persistent or significant disability/incapacity 
5) Based upon appropriate medical judgment, may jeopardize the participant’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition. 
 

 
 
 
19 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of the following 
criteria:  
• 
is unexpected; AND 
• 
is related or possibly related to participation 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.  
 
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 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
• 
the known or foreseeable risk of adverse events associated with the procedures involved in the 
research that are described in (a) the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the current IRB-approved informed 
consent document, and (b) other relevant sources of information, such as product labeling and 
package inserts; or 
• 
the expected natural progression of any underlying disease, disorder, or condition of the 
participant(s) experiencing the adverse event and the participant’s predisposing risk factor profile 
for the adverse event. 
 
 
8.2 Safety Review 
 
Safety review for this study will be accomplished throughout the study and monitor all study activities 
identified in the schedule of activities. Risks to be monitored include: hypersensitivity, application site 
pain, application site discomfort, skin irritation, pyrexia, upper respiratory tract infection, diarrhea, cough, 
and any unknown risks or unanticipated problem identified in the performance of the study. This will be 
accomplished by study staff personnel as part of each visit activity, spontaneously reported by the 
caregivers, and monitored for all participants enrolled throughout the study. Specifically during each 
study visit, study staff will assess the level of skin irritation and participant reported discomfort (or AD 
flare up) from both the wearing of devices and/or subsequent topical application of crisaborole/vehicle.  
The Principal Investigator will be notified of any AEs immediately.  All other reporting plans are outlined 
in section 8.3.  
 
Signs of AD (based on % BSA) will be measured and evaluated throughout the study period on laboratory 
visits 3, 4, and 5 (days 2, 8, 15) by the study dermatologist. Participants whose BSA exceeds 40% at visits 
3 and 4, will be instructed to terminate the use of vehicle/crisaborole and will be withdrawn from the 
study. We will monitor collected BSA percentages at each time point and their change from baseline.  
Participants will also be provided with a 24/7 phone number should they need to contact the laboratory 
after hours.  
Appropriate documentation of any and all identified unanticipated or adverse events will be properly 
reported to the IRB including appropriate mitigation and reports for recommended changes, with 
unanticipated problems within 7 days. A document listing any identified safety related events will be 
maintained and monitoring of this list will be ongoing throughout the study as a means to track and 
review these events (accomplished by comparative analysis of each event in comparison to all other 
events throughout the study) to determine expectedness, relatedness, or suggestion of new risks that may 
have been identified. Other events will be documented, assessed and monitored by staff and investigators 
and reported at the time of continuing review. Monthly reviews of blinded adverse events will be 

 
 
 
20 
conducted to assess frequency of events, severity, seriousness, and relatedness to determine any potential 
trending study related items that may indicated a potential safety concern.  
 
The data for adverse events (observed by study staff or spontaneously reported by caregivers) will be 
aggregated using descriptive statistics. Overlap of adverse events will be recorded.  
Caregiver reported treatment-related adverse events will be recorded using MedDRA Version 24.1. 
Severity of adverse events will be categorized as follows: Mild-Symptom(s) barely noticeable with no 
reported participant discomfort; Moderate- Symptom(s) reported as uncomfortable; Severe- Symptom(s) 
causing severe discomfort resulting in participant withdrawl. Relatedness of reported events will be 
categorized as follows: Unrelated- The event deemed to be clearly not study related; Possibly related- The 
event is temporally aligned with study activies but possibly may be due to another circumstance; Related- 
The event is temporally aligned to study activities with no alternative causes present.  
 
8.3 Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, safety 
monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance with IRB 
policies: 
• 
Unanticipated Problems occurring at BMC/BU Medical Campus will be reported to the IRB within 
7 days of the investigator learning of the event. 
• 
Adverse Events (including Serious Adverse Events) will be reported in summary at the time of 
continuing review, along with a statement that the pattern of adverse events, in total, does not 
suggest that the research places participants or others at a greater risk of harm than was previously 
known. 
• 
Monthly reviews of blinded unanticipated problems and adverse events will be reviewed with 
Pfizer to assess frequency of events, severity, seriousness, and relatedness to determine any 
potential trending study related items that may indicated a potential safety concern. 
 
8.4 Research Related Injury 
Possible social risks: These are extremely low in this study and pertain to the unintentional release of 
personal information.  
Mitigation of social risks: To safeguard confidentiality and the privacy of protected information, each 
study participant will be assigned a unique code number. A separate file linking the participants’ name 
with study number and identifiers will be kept in a password-protected data file, accessible only by the PI 
and the study coordinator. All study forms will be kept in secure locked file cabinets. The study 
investigators will assume full responsibility to maintain the confidentiality of all data. All study results 
will be presented only as statistical aggregates that will neither identify, nor permit identification of, 
individual participants.  
 
Possible risk associated with digital health devices: The risks associated with these devices include 
physical discomfort if the participant is not used to wearing wrist accelerometers and/or ankle devices, 
and possible skin irritation or reaction, such as an AD flare-up in children with the skin 
condition. If the participant experiences skin irritation or notice signs of an AD flare-up in the 
area that the child wears the device(s), they will be instructed to remove the device(s) and notify 
the study team immediately. 
  
Mitigation of risks associated with digital health devices:  If the participant is unable to wear the device 
due to discomfort (or AD flare up) the participant will notify study staff and the Principal Investigator 
may allow the participant to continue the study without wearing the discomforting device or withdraw the 

 
 
 
21 
participant from the study. Devices will be optional for child participants who have active AD on location 
of device placement, with a minimum of at least one wrist device needed for enrollment. 
 
Possible risk associated with tape stripping: Tape stripping is routinely performed and is considered a 
minimally invasive approach for identifying biomarkers for Atopic Dermatitis and is an acceptable 
alternative to traditional biopsies.  The only minimal risk associated with tape stripping is mild discomfort 
and potentially superficial surface reddening of the skin at the location of the tape.  This is typically 
reported after 50-60 tape strippings.  In this study we will only be doing ~20 tape strippings per 
sample.  Tape stripping sensation is similar to removal of a band-aid. 
Mitigation of risk associated with tape stripping: Tape strippings will only be conducted three times with 
a minimum of 3 days between each tape stripping. If the participant experiences discomfort, adjacent sites 
to previous stripping area will be used.  
 
Possible risk associated with crisaborole: Possible risks associated with crisaborole include application 
site pain or burning/stinging sensation (lasting one to two days) and/or hypersensitivity reaction and/or 
development of a skin allergy and/or severe pruritis and/or swelling and/or erythema. Less common risks 
(<1%) include contact urticaria  (hives - a skin reaction that results in red, itchy welts).  AD by nature is a 
disease that has recurrent flares on active treatment or without active treatment.  Therefore, participants 
on crisaborole or vehicle could experience worsening of their natural course of disease.  
Mitigation of risk associated with crisaborole: If the participant develops a hypersensitivity reaction, 
severe pruritis, swelling, or erythema, (and/or development of skin allergy (e.g. hives)), dosing will be 
discontinued and the site will be contacted, and the participant should seek medical attention as needed. If 
minor application site pain or burning/stinging sensation is reported, and participant is uncomfortable 
with continuation, the principal investigator may allow the participant to continue in the study with 
dosing discontinued, or participant will be withdrawn. If signs and symptoms of hypersensitivity occur, 
discontinue EUCRISA immediately and initiate appropriate therapy. Hypersensitivity Reactions Advise 
patients to discontinue EUCRISA and seek medical attention immediately if signs or symptoms of 
hypersensitivity occur [see Warnings and Precautions (5.1) from label]. Administration Instructions 
Advise patients or caregivers that EUCRISA is for external use only and is not for ophthalmic, oral, or 
intravaginal use.  All participants may withdraw from the study at any time, including if they experience 
worsening of symptoms.   
 
Possible Risk Associated with vehicle treatment: Possible risks associated with vehicle include 
application site pain or burning/stinging sensation, severe pruritis (itching), swelling, redness and/or 
hypersensitivity reaction (an exaggerated immune response which may cause skin discomfort) and/or 
development of a skin allergy. Possible risks associated with vehicle treatment where vehicle contains the 
excipients of crisaborole ointment, and the base of crisaborole ointment has no difference in appearance, 
texture, color, or odor to crisaborole ointment, 2% and as such no specific risks identified other than 
hypersensitivity reaction and/or development of skin allergy. No additional risks are known with respect 
to vehicle treatment as it provides white petrolatum as the main excipient and base of crisaborole 
ointment, 2%, which was selected for its emollient properties and favorable tolerability profile, where 
the importance of an emollient effect is highlighted by the use of emollients in basic skin care for patients 
with AD, to aid in restoration of barrier function 
Mitigation of Risk Associated with vehicle treatment: If the participant develops a hypersensitivity 
reaction, severe pruritis (itching), swelling, redness (and/or development of skin allergy (e.g. hives)), 
dosing will be discontinued and the site will be contacted, and the participant should seek medical 
attention as needed. If minor application site pain or burning/stinging sensation is reported, and 
participant is uncomfortable with continuation, the principal investigator may allow the participant to 
continue in the study with dosing discontinued, or participant will be withdrawn. AD by nature is a 

 
 
 
22 
disease that has recurrent flares on active treatment or without active treatment.  Therefore, participants 
on vehicle could experience worsening of their natural course of disease. 
 
Participants may become bored/fatigued over the course of a testing session. The same considerations 
apply to the study visits.   
 
9. DATA ANALYSIS 
 
Study Hypotheses: The primary objective of this study is to evaluate the reduction of itch and nighttime 
scratch (as measured by accelerometry/actigraphy and Observer Reported Itch Assessment (ages 3 
months to ≤ 11 years old) with application of crisaborole.  A clinically significant change in scratching as 
measured by accelerometry/actigraphy has not yet been determined.  The relationship between 
accelerometry/actigraphy scratching parameters and PRO scratching assessments is being studied 
currently.  This study adds to the knowledge base by studying the association between changes in PRO 
scratching assessments and changes in accelerometry/actigraphy scratching parameters when treatment is 
initiated or changed.  Estimates of their variability from this study can also fill the literature gap and be 
used to help design future studies.  
 
As this study is a research collaborative agreement, both the Laboratory for Human Neurobiology and the 
collaborator/sponsor will perform statistical analyses. Only deidentified data is shared with the 
collaborator.  
 
Sample Size: The sample size calculation of this study is therefore based on the primary endpoint for itch 
assessment. An open-label internal Pfizer study with a similar scale to the Observer Reported Itch 
Assessment in 3-months to 5-year olds, the reduction of itch/scratch was evaluated from baseline to 14 
days. Based on the results of that study, a 2.6 points common standard deviation in the observer reported 
pruritus score change from baseline for 2 weeks in children ages 3 months to 5 years with mild to 
moderate AD was assumed. There is no data available for 6-≤ 11 year olds. Therefore, the assumption is 
made that children ages 6 to ≤ 11 will have the same standard deviation. We will employ a simple 
randomized procedure using a computerized random numbers to assign participants to the two groups. A 
total of 244 randomized participants (in 1:1 ratio) will provide approximately 85% power to detect a 1.0 
points of the observer reported pruritus score reduction difference in crisaborole treatment group 
compared to vehicle group, with a two-sided 5% significance. 
 
With an expected dropout rate of ~10%, approximately 540 (270 children and 270 primary adult 
caregivers) are expected to be recruited for this study. 
 
Statistical Methods and Analysis:  
 
The primary and secondary endpoints will be tested at the significance level of 0.05 (2-sided). There is no 
multiplicity adjustment. Number, percent and 95% confidence interval (CI) will be presented for binary 
endpoints.  Descriptive summary statistics (n, Mean, Std. Dev, Median, Min., Max.) will be presented for 
continuous endpoints.  In addition, graphics may be used to present the data.   
 
The primary objective is to evaluate the effects of Crisaborole on itch and night-time scratch. The primary 
endpoints include number of scratching episodes (children aged 2 – ≤ 11 years), duration of scratching 
(children aged 2 – ≤ 11 years), and ORIA (ages 3 months to ≤ 11 years). For these endpoints, change 
from baseline will be analyzed using a mixed-effects model with repeated measures (MMRM) including 
data from Day 1 (for acceleometry measured scratch episodes and duration)/Day 2 (for ORIA) to Day 15 
with baseline score as a covariate and an unstructed covariance matrix. The least-squares (LS) means and 

 
 
 
23 
the corresponding 95% CIs, the LS mean difference between treatment groups, and the corresponding 
95% CI will be presented for change from baseline for all postbaseline timepoints. As a sensitivity 
analysis, instead of daily data, average of every 3 days data will be used to account for day-to-day 
variation. 
The binary endpoints will be descriptively summarized using sample size, number, percentage and 95% 
confidence interval (CI) of percentage at each time point. Binary data will be analyzed by comparing 
response rates between treatment groups. Normal approximation to the difference in response rates will 
be used to obtain p-values and 95% CI. For binary endpoints analyzed at each scheduled visit separately, 
participants who drop out for any reason or require a prohibited medication for the treatment of their 
atopic dermatitis will be defined as “non‑responsive” at all subsequent visits. This method of handling 
missing response is known as missing response as non-response (MR-NR). 
 
Mixed model repeated measures (MMRM) will be used to analyze longitudinal continuous data. 
Treatment, visit, treatment‑by‑visit interaction are fixed effects in the model, baseline value as a 
covariate. Within‑participant variability will be accounted for using a random effect with the unstructured 
covariance matrix. If this is a convergence issue, other type of covariance matrix will be used. The 
following structures will be executed in the order specified (essentially in decreasing order of complexity) 
until convergence is achieved: heterogeneous Toeplitz, heterogeneous first order autoregressive, 
autoregressive, heterogeneous compound symmetry, compound symmetry, and variance components.  
The first structure yielding convergence will be used as the primary analysis.  The Kenward and Roger 
method for calculating the denominator degrees of freedom for tests of fixed effects will be used. Least 
square (LS) estimates of mean values and the LS mean differences between crisaborole 2% BID and 
vehicle groups at each visit will be derived from the model.  The corresponding p‑value, standard error 
(SE) and 95% CI will also be derived from the model. 
ANCOVA model will be used to analyze nonlongitudinal continuous endpoints with treatment as a factor 
baseline value as a covariate.  Least square (LS) estimates of mean values and the LS mean differences 
between crisaborole 2% BID and vehicle groups at each visit will be derived from the model.  The 
corresponding p‑value, standard error (SE) and 95% CI will also be derived from the model. 
 
For any accelerometry/actigraphy continuous variables that exhibit right skewed distribution (i.e. skewed 
to positive values), log transformation may be used as appropriate. Specifically, for number of scratching, 
length of time scratching, arousals from sleep, WASO, and sleep onset latency, log(x+1) transformation 
will be employed (to include possible zero values). For time duration between scratching, log(x) will be 
employed. 
 
For efficacy continuous endpoint not measured longitudinally, the post-baseline missing values will not 
be imputed, ie, the values are assumed to be missing completely at random. For efficacy continuous 
endpoints measured longitudinally, missing values post‑baseline will be handled in a linear mixed-effect 
model with repeated measures for this continuous variable, where the values are assumed to be missing at 
random. For the continuous ObsROs variables, rules suggested by the developers of these instruments 
will be followed in calculating the missing values.  If these rules are not enough for imputing a value, 
then the missing values will be handled in the same way as efficacy variables. 
 
Specific analyses to be conducted:  
• 
Evaluate drug-induced changes of itch ORIA, scratching and sleep quantity, and additional 
PRO/ObsRO and biomakers; comparing start of the study to measures obtained while on treatment  
• 
Summary of AEs and RRIs 

 
 
 
24 
• 
Comparison of PRO/ObsRO assessments to scratching and sleep values obtained from device 
measurements. 
• 
Comparison of digital measures of scratching and sleep with QoL PRO assessments. 
10. DATA HANDLING, RECORD KEEPING, QUALITY CONTROL AND QUALITY 
ASSURANCE  
Data handling, record keeping, quality control and quality assurance is discussed in the approved Boston 
University Institutional Review Board (IRB) application. 
 
10.1 Confidentiality 
 
In order to minimize the accidental release of sensitive test information, study data will be labeled 
with only the participant's randomly generated study ID. To protect the confidentiality of each participant, 
the only place where the participant ID and their identifiable information will exist together will be on a 
separate master spreadsheet, which will be password protected and to which the PI and the study 
coordinator will have access to. In order to further ensure the confidentiality of the participants, the 
password for this master spreadsheet will be different than the password for documents containing the de-
identified data. We will use a coded ID number on all results and data acquired and stored. 
 
Only the consent form, screening forms, BuildClinical recruitment database, and the master identifier 
spreadsheet will contain identifiable information. Consent and screening forms will be locked in a cabinet 
at the Spivack Center. All electronic data will be stored in password-protected computers located in a 
secure lab space in the Spivack Center. Data being stored electronically will be stored according to BU 
policy for the secure storage of such data.  
 
No identifiable data will go anywhere outside of BU. All data transferred will be coded with no direct 
identifiers with a unique study ID. 
 
The master identifier spreadsheet will be kept past the end of the study for a minimum of 7 years after 
which point it will be securely deleted (electronic) or shredded (paper forms). Only the Principal 
Investigator and study coordinator will have access to this data. Publications will not contain the 
participants' names or any identifying characteristics 
 
The study monitor or other authorized representatives of the sponsor may inspect all deidentified 
documents and records required to be maintained by the investigator, including but not limited to 
pharmacy records, for the participants in this study. The clinical study site will permit access to such 
records. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify participants. The website may be updated 
to include a summary of the results.  
 
10.2 Data handling, data collection and extract transform and load (etl) processes 
Electronic Data Capture: Both a web-based electronic data capture (EDC) system and computing 
applications (apps) on a mobile device will be utilized for this study, in addition to sensor data. 
 
Source Documents: Study visit data (e.g., screening, demographics, medical history, ISGA, EASI, BSA, 
vitals, concomitant medications, and inclusion exclusion criteria) will be collected for all screened and 
enrolled participants and entered into Excel CSV files for transfer via CONFORM to Pfizer.  

 
 
 
25 
Sensor-acquired data (Actigraphy/accelerometry devices) will include no identifiable information and will 
be exported from each sensor device via each device’s proprietary companion software application. Data 
obtained from the watches will be transferred to Pfizer for processing via a cloud-based data repository, 
CONFORM, and the results will then be subsequently shared back with BU via CONFORM.  
Data dictionary will be aligned to CDISC and Pfizer Standards.  Device type, manufacturer, serial 
number, firmware and software versioning will also be collected as well as all the pertinent metadata 
associated with the generated files.   
Data generated by the methods described in the protocol will be recorded in the participants' study records 
and/or study progress notes. Data may be transcribed legibly on study records for each participant or 
directly inputted into an electronic system or any combination thereof. 
 
BuildClinical Recruitment Database:  The BuildClinical online database for participant recruitment will 
be maintained until the end of the study.  
 
10.3 Participant Study Records and Report Forms  
The participant study records and report forms will be the primary data collection instrument for the 
study. All data requested on the participant records will be recorded. All missing data will be explained. If 
a space on the participant records is left blank because the procedure was not done or the question was not 
asked, “NaN” will be written. If the item is not applicable to the individual case, “N/A” will be written. 
All entries will be printed legibly in black ink. If any entry error has been made, to correct such an error, a 
single straight line will be drawn through the incorrect entry and the correct data will be entered above it. 
All such changes will be initialed and dated.  There will be no erasures or white-out on participant 
records.  For clarification of illegible or uncertain entries, the clarification will be printed above the item, 
then initialed and dated. 
 
10.4 Study Records Retention 
Data from the intake of eligible participants will be retained in a locked file cabinet. The investigators will 
maintain a password-protected list containing the names and contact information of those individuals who 
are ineligible. All files will be destroyed 7 years after study completion. Only approved researchers will 
have access to these files. Answers to screening questions will be destroyed for both persons who are 
eligible and persons who are not eligible. The only information that will be retained from persons who 
were screened will be contact information and general reason for screening out (for those who are not 
eligible).  The BuildClinical database for participant recruitment will be maintained until the end of the 
study. All potential participants who respond to BuildClinical recruitment materials will be contacted by 
study staff to verify eligibility via the Phone Screening Questionnaire. The only information that will be 
retained from persons who were screened will be contact information and general reason for screening out 
(for those who are not eligible).  
 
The BMC/BU Medical Campus IRB requires that documentation of informed consent of participants be 
retained for at least seven years after the study is closed. Such records will be preserved in hardcopy 
and/or electronic or other media form and must be accessible for inspection and copying by authorized 
individuals.  
 
11. COMPLIANCE WITH GOOD CLINICAL PRACTICE  
11.1. Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles for 
Medical Research Involving Human Participants, adopted by the General Assembly of the World Medical 
Association (2008). 

 
 
 
26 
 
In addition, the study will be conducted in accordance with the protocol, the principles of the International 
Conference on Harmonization (ICH) guideline on Good Clinical Practice (GCP) and applicable local 
regulatory requirements and laws. 
 
11.2. Institutional Review Board (IRB)/Ethics Committee (EC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, protocol 
amendments, informed consent documents, and other relevant documents, e.g. advertisements, if 
applicable, from the IRB/EC.  All correspondence with the IRB/EC should be retained in the investigator 
file.  
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston University 
Medical Campus IRB, for formal approval of the study conduct. The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator. A copy of the initial IRB approval letter 
will be provided to the sponsor before commencement of this study.  
 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is where the 
change is necessary to eliminate apparent immediate hazards to the participants.  In that event, the 
investigator must notify the IRB/EC in writing within 5 working days after the implementation. 
 
11.3. Participant Information and Consent 
 
All participants for this study will be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their participation in this study. 
The consent form will be submitted with the protocol for review and approval by the IRB. The consent of 
a participant, using the IRB-approved consent form, must be obtained before that participant is submitted 
to any study procedure. Consent will be documented as required by the IRB.   
 
All parties will ensure protection of participant personal data and will not include participant names or 
other identifiable data in any reports, publications, or other disclosures, except where required by law. 
 
When study data is compiled for transfer to other authorized parties, participant names, addresses, and 
other identifiable data will be replaced by a numerical code in order to anonymize study participants. The 
study site will maintain a confidential list of participants who participated in the study linking their 
numerical code to the participant’s actual identity. In case of data transfer, all parties will maintain high 
standards of confidentiality and protection of participant personal data consistent with applicable privacy 
laws. 
 
The informed consent and assent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. The investigator will ensure that 
each study participant and his or her parent(s)/legal guardian are fully informed about the nature and 
objectives of the study and possible risks associated with participation. The informed consent and assent 
documents used during the informed consent process must be reviewed by the sponsor, approved by the 
IRB/EC before use, and available for inspection. The investigator must ensure that each study participant 
is fully informed about the nature and objectives of the study and possible risks associated with 
participation.  
 
The investigator, or a person designated by the investigator, will obtain written informed consent from 
each participant’s legal guardian before any study-specific activity is performed, unless a waiver of 

 
 
 
27 
informed consent has been granted by an IRB/EC. The investigator will retain the original of each 
participant’s guardian(s) signed consent document.  
 
The informed consent document used during the informed consent process will convey that only 
anonymized information (including protected health information related to age, and sex) from each 
participant may be conveyed to Pfizer and its third parties/affiliates. 
 
11.4 Participant Recruitment and Participation 
Recruitment:  Advertisements, including via patient advocacy groups and pediatric dermatology clinics, 
approved by ethics committees and investigator databases may be used as recruitment procedures. 
Participants will be recruited via electronic announcements, the BUMC Corporate Communications 
weekly email, and posted flyers.  Moreover, participants will be recruited through physician referral at the 
dermatology clinics.  BuildClinical, a recruitment platform, will also be used to identify potential study 
participants, in accordance with BUMC policy. Individuals who respond to recruitment materials will be 
provided with a brief description of the study, including the methodologies used, and asked a series of 
questions to determine eligibility and informed that snacks and liquids will be available during onsite 
study visits.  The investigators will maintain a list containing the names and contact information (but 
absolutely no protected health information) of those individuals who are ineligible. 
 
Location where study will be performed: Boston University  
 
Participant payment:  
Participants who partially complete study activities will be compensated based on activities completed, outlined 
below. Participants whose total amount of compensation for activities completed is less than $400 will be paid 
through Cash Cards. Participants whose total amount of compensation for activities completed is greater than $400 
will be paid via checks after study withdrawal or completion.  Participant Compensation (inclusive of child and 
caregiver; all study activities): $1,350  
• 
V01 [Day -7] (Intake): $25 
• 
V01 [Day -7] (Baseline: completion of PROs, training, tape stripping, assessments): $150 
• 
V02 [Day 1] (Completion of PROs / assessments): $100 
• 
V03 [Day 2]: (Tape stripping): $200 
• 
V04 [Day 8]: Completion of PROs / assessments): $100 
• 
In-Home Activities [Day -7 to Day 15]: $525 
• 
V05 [Day 15]: (In-lab assessments, turn-in wearable devices): $250 
 
12. REFERENCES 
Abuabara, K., Yu, A. M., Okhovat, J.-P., Allen, I. E., & Langan, S. M. (2018). The prevalence of atopic 
dermatitis beyond childhood: A systematic review and meta-analysis of longitudinal studies. Allergy, 
73(3), 696–704. https://doi.org/10.1111/all.13320  
 
Arkwright, P. D., Motala, C., Subramanian, H., Spergel, J., Schneider, L. C., & Wollenberg, A. (2013). 
Management of Difficult-to-Treat Atopic Dermatitis. The Journal of Allergy and Clinical Immunology: In 
Practice, 1(2), 142–151. https://doi.org/10.1016/j.jaip.2012.09.002 
 
Drugs@FDA glossary of terms. (2017, November 14). U.S. Food and Drug Administration. Retrieved 
March 21, 2022, from https://www.fda.gov/drugs/drug-approvals-and-databases/drugsfda-glossary-terms  
Hanifin JM and Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 
1980;92(suppl):44-7. 
 

 
 
 
28 
Lewis-Jones, M. S., & Finlay, A. Y. (1995). The Children’s Dermatology Life Quality Index (CDLQI): 
initial validation and practical use. The British Journal of Dermatology, 132(6), 942–949. 
 
Mahadevan, N., Christakis, Y., Di, J., Bruno, J., Zhang, Y., Dorsey, E. R., Pigeon, W. R., Beck, L. A., 
Thomas, K., Liu, Y., Wicker, M., Brooks, C., Kabiri, N. S., Bhangu, J., Northcott, C., & Patel, S. (2021). 
Development of digital measures for nighttime scratch and sleep using wrist-worn wearable devices. Npj 
Digital Medicine, 4(1), 42. https://doi.org/10.1038/s41746-021-00402-x 
 
Moreau A, Anderer P, Ross M, Cerny A, Almazan T, Peterson B.  Detection of Nocturnal Scratching 
Movements in Patients with Atopic Dermatitis Using Accelerometers and Recurrent Neural Networks.  
IEEE J Biomed Health Inform. 2017. Jun 8. DOI: 10.1109/JBHI.2017.2710798. 
 
OTC Active Ingredients. (2010, April 7). FDA. Retrieved March 21, 2022, 
from https://www.fda.gov/media/75750/download 
 
Paller, A. S., Tom, W. L., Lebwohl, M. G., Blumenthal, R. L., Boguniewicz, M., Call, R. S., Eichenfield, 
L. F., Forsha, D. W., Rees, W. C., Simpson, E. L., Spellman, M. C., Stein Gold, L. F., Zaenglein, A. L., 
Hughes, M. H., Zane, L. T., & Hebert, A. A. (2016). Efficacy and safety of crisaborole ointment, a novel, 
nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in 
children and adults. Journal of the American Academy of Dermatology, 75(3), 494-503.e6. 
https://doi.org/10.1016/j.jaad.2016.05.046 
 
Pitchford, E. A., Ketcheson, L. R., Kwon, H.-J., & Ulrich, D. A. (2017). Minimum Accelerometer Wear 
Time in Infants: A Generalizability Study. Journal of Physical Activity and Health, 14(6), 421–428. 
https://doi.org/10.1123/jpah.2016-0395 
 
Silverberg JI, Simpson EL, Durkin HG, Joks R.  Prevalence of allergic disease is lower in foreign-born 
American children, but increases with prolonged US residence.  JAMA Pediatr, 167 (2013); 554-560.  
 
Simpson, E. L., Paller, A. S., Boguniewicz, M., Eichenfield, L. F., Feldman, S. R., Silverberg, J. I., 
Chamlin, S. L., & Zane, L. T. (2018). Crisaborole Ointment Improves Quality of Life of Patients with 
Mild to Moderate Atopic Dermatitis and Their Families. Dermatology and Therapy, 8(4), 605–619. 
https://doi.org/10.1007/s13555-018-0263-0 
 
Tal A, Shinar Z, Shaki D, Codish S, Goldbart A. Validation of Contact-Free Sleep Monitoring Device with 
Comparison to Polysomnography.  Journal of Clinical Sleep Medicine. 13(2017); 137-142. 
 
U.S. Department of Health and Human Services. (n.d.). Active-comparator arm. National Center for 
Advancing Translational Sciences. Retrieved March 22, 2022, 
from https://toolkit.ncats.nih.gov/glossary/active-comparator-arm/  
 
Wootton, C. I., Koller, K., Lawton, S., O’Leary, C., Thomas, K. S., & on behalf of the SWET study team. 
(2012). Are accelerometers a useful tool for measuring disease activity in children with eczema? Validity, 
responsiveness to change, and acceptability of use in a clinical trial setting: Are accelerometers useful for 
measuring disease activity in eczema? British Journal of Dermatology, 167(5), 1131–1137. 
https://doi.org/10.1111/j.1365-2133.2012.11184.x 
 
 
 
 

 
 
 
29 
Appendix A- Instruments attached below are the assessments to be performed. In all cases only participant 
ID will be recorded in locations where name is identified. In no case will identifiable data be recorded.  
 
 
Appendix A: INCLUSION CRITERIA 
 
Per Inclusion Criterion, a participant is to have a clinical diagnosis of atopic dermatitis according to the 
criteria of Hanifin and Rajka (1980).  
Table 1: Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis 
Major Criteria: Must have three or more basic features described below: 
Pruritus 
Typical morphology and distribution: 
Flexural lichenification in adults 
Facial and extensor eruptions in infants and children 
Chronic or chronically-relapsing dermatitis 
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
Minor Criteria: Must have three or more following minor features: 
Xerosis 
Ichthyosis/palmar hyperlinearity, keratosis pilaris 
Immediate (type 1) skin test reaction 
Elevated serum IgE 
Early age of onset 
Tendency toward cutaneous infections (esp. staph. aureus and herpes simplex), impaired cell-mediated 
immunity 
Tendency toward non-specific hand or foot dermatitis 
Nipple eczema 
Cheilitis 
Recurrent conjunctivitis 
Dennie-Morgan infraorbital fold 
Keratoconus 
Anterior subcapsular cataracts 
Orbital darkening 
Facial pallor, facial erythema 
Pityriasis alba 
Anterior neck folds 
Itch when sweating 
Intolerance to wool and lipid solvents 
Periofollicular accentuation 
Food intolerance 
Course influenced by environmental and emotional factors 

 
 
 
30 
White demographism, delayed blanch 
 
Suggested Universal Criteria for Atopic Dermatitis (AD) by American Academy of Dermatology 
A. Essential features; must be present and, if complete, are sufficient for diagnosis: 
1. Pruritus 
2. Eczematous changes that are acute, subacute, or chronic: 
a. Typical and age-specific patterns 
(i) Facial, neck, and extensor involvement in infants and children 
(ii) Current or prior flexural lesions in adults/any age 
(iii) Sparing of groin and axillary regions 
b. Chronic or relapsing course 
B. Important features that are seen in most cases, adding support to the diagnosis: 
1. Early age at onset 
2. Atopy (IgE reactivity) 
3. Xerosis 
C. Associated features: Clinical associations; help in suggesting the diagnosis of AD but are too nonspecific 
to be used for defining or detecting AD for research and epidemiologic studies 
1. Keratosis pilaris/Ichthyosis/Palmar hyperlinearity 
2. Atypical vascular responses 
3. Perifollicular accentuation/Lichenification/Prurigo 
4. Ocular/periorbital changes 
5. Perioral/periauricular lesions 
D. Exclusions: Firm diagnosis of AD depends on excluding conditions such as scabies, allergic contact 
dermatitis, seborrheic dermatitis, cutaneous lymphoma, ichthyoses, psoriasis, and other primary disease 
entities. 
 
 
 

 
 
 
31 
 
 

 
 
 
32 
Eczema Area and Severity Index (EASI) 
 
The EASI quantifies the severity of a participant’s AD based on both severity of lesion clinical signs and 
the percent of BSA affected.  EASI is a composite scoring of the degree of erythema, 
induration/papulation, excoriation, and lichenification (each scored separately) for each of four body 
regions, with adjustment for the percent of BSA involved for each body region and for the proportion of 
the body region to the whole body.  
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing 
greater severity of AD. Since the scalp will be excluded from the EASI assessment in this study, the 
maximum possible score will be less than 72.0. 
 
Table 1.Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity Index (EASI) 
 
Score 
Description 
Erythema (E) 
0 
Absent 
None; may have residual discoloration (post-inflammatory hyperpigmentation 
and/or hypopigmentation). 
1 
Mild 
Light pink to light red 
2 
Moderate 
Red 
3 
Severe 
Deep, dark red 
Induration/Papulation (I) 
0 
Absent 
None 
1 
Mild 
Barely palpable to slight, but definite hard thickened skin and/or papules 
2 
Moderate 
Easily palpable moderate hard thickened skin and/or papules 
3 
Severe 
Severe hard thickened skin and/or papules 
Excoriation (Ex) 
0 
Absent 
None 
1 
Mild 
Slight, but definite linear or picked scratch marks or penetrating surface injury 
2 
Moderate 
Moderate linear or picked scratch marks or penetrating surface injury 
3 
Severe 
Severe linear or picked scratch marks or penetrating surface injury 
Lichenification (L) 
0 
Absent 
None 
1 
Mild 
Barely perceptible to slight, but definite thickened skin, fine skin markings, and 
lichenoid scale 
2 
Moderate 
Moderate thickened skin, ObsROrse skin markings, and ObsROrse lichenoid 
scale 
3 
Severe 
Severe thickened skin with very ObsROrse skin markings and lichenoid scale 
* The EASI will exclude scalp from the assessment/scoring  
 
 
 
 
 
 
 
 
 

 
 
 
33 
 
The extent (%) to which each of the 4 body regions is involved with AD is categorized using a non-linear 
scaling method to a numerical area score according to the following BSA scoring criteria. 
Table 3. 
Eczema Area and Severity Index (EASI) Area Score Criteria 
Percent Body Surface Area (BSA) with Atopic 
Dermatitis in a Body Region 
Area Score 
0% 
0 
>0 - <10% 
1 
10 - <30% 
2 
30 - <50% 
3 
50 - <70% 
4 
70 - <90% 
5 
90 – 100% 
6 
 
Table 4. 
Eczema Area and Severity Index (EASI) Body Region Weighting 
Body Region 
Body Region Weighting for 
≥8 years old participants 
Body Region Weighting for 
≤7 years old participants 
Head and Neck 
0.1 
0.2 
Upper Limbs 
0.2 
0.2 
Trunk (including axillae) 
0.3 
0.3 
Lower Limbs (including buttocks) 
0.4 
0.3 
 
In each body region, the sum of the Clinical Signs Severity Scores for erythema, induration/papulation, 
excoriation, and lichenification is multiplied by the Area Score and by the Body Region Weighting to 
provide a body region value, which is then summed across all four body regions resulting in an EASI 
score as described in Equation 1 and Equation 2: 
 
Equation 1 (participants aged ≥8 years old):  EASI =0.1Ah(Eh+Ih+Exh+Lh) + 0.2Au(Eu+Iu+Exu+Lu) 
+ 0.3At(Et+It+Ext+Lt) + 0.4Al(El+Il+Exl+Ll) 
Equation 2 (participants aged ≤7 years old):  EASI =0.2Ah(Eh+Ih+Exh+Lh) + 0.2Au(Eu+Iu+Exu+Lu) 
+ 0.3At(Et+It+Ext+Lt) + 0.3Al(El+Il+Exl+Ll) 
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and neck; 
u = upper limbs; t = trunk; l = lower limbs 
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores representing 
greater severity of AD.  Since the scalp will be excluded from the EASI assessment in this study, the 
maximum possible score will be less than 72.0. 

 
 
 
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Appendix B: PATIENT REPORTED OUTCOME (PRO) / OBSERVER REPORTED 
OUTCOME(ObsRO) ASSESSMENTS 
 
Observer Reported Itch Assessment 
The Observer Reported Itch Assessment assesses the severity of itch (pruritus) in the child due to AD. 
The participants primary caregiver will be asked to assess their child’s worst itch (I.e., scratching, 
rubbing) due to AD over the past 24 hours in an eDiary every day during the study. Observer Reported 
Itch Assessment for 3 months - ≤ 11 years of age is an 11-point scale and must be completed by an 
observer (caregiver). Instruments to be provided to participants as age appropriate below:  
  

 
 
 
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Appendix C. QUALITY OF LIFE (QoL) QUESTIONNAIRES  
 
Dermatology-related QoL scores will be collected during the study.  
 
• 
The Dermatitis Family Impact Questionnaire will be completed by all parents/guardians of 
participants aged 3 months-≤ 11 years, based on the age at enrollment. 
• 
The CDLQI will be completed by all participants aged  ≥4 - ≤ 11 years 
• 
The IDLQI will be completed by all participants aged 3 months - <4 years 
The following Quality-of-Life (QoL) questionnaires will be administered to the participant and/or 
parent/guardian of the participant on a supplied tablet (the paper form is shown below for review).  
Directions on how to complete the assessments will be provided to the participant and/or parent/guardian. 
The Schedule of Activities identifies the administration timing for the various assessments. 
 
 
 
 
 

 
 
 
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Dosing record sheet 
Subject ID: _____________  
 
Instructions: Everyday, you will be applying the ointment twice a day on all affected areas in thin even 
layers except on the eyes, mouth, and vagina. Do not apply the study ointment to the face within 1 or 2 
fingers away from the of the mouth, or hands/fingers to avoid inadvertent ingestion of the ointment. 
Wash your hands after everytime you apply the ointment; if you are breastfeeding, use the provided 
gloves to apply the ointment. Following diaper change, any study ointment inadvertently wiped off soiled 
skin should not be reapplied until the next scheduled dose.  In the case of rash in the diaper area without 
AD involvement, standard treatments may be applied, and agree to refrain from applying diaper rash 
creams, lotions, ointments, powders, etc. where AD lesions are present, unless the lesions are on locations 
where the study ointment may not be applied (face within 1 or 2 fingers away from the of mouth and 
hands/fingers). 
Every time you apply the ointment, please record the date and time on a separate sheet. On each dosing 
record sheet, please circle on the pictures where you applied the ointment each application time.  
 
Date: _____________ Time: _____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Appendix B- Location of accelerometry and actigraphy devices on the children participants Devices will 
be optional for child participants who have active AD on location of device placement, with a minimum 
of at least one wrist device needed for enrollment. 
 
 
 
 
 
 
 
  
2-11 year olds 
Accelerometry  
Actigraphy or Accelerometry  
2 – ≤ 11 years old  
3 months - < 2 years old  

 
 
 
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