Conditions: Stasis Dermatitis
Keywords: Stasis Dermatitis venous hypertension venous insufficiency
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 66
Healthy volunteers: no

Brief summary:
This is a Phase 2a, randomized, double blind, vehicle controlled, parallel group, proof of concept study that will include participants with stasis dermatitis without active skin ulceration, who will receive crisaborole ointment 2% or vehicle twice daily for 6 weeks.

Detailed description:
Study C3291038 is a Phase 2a, randomized, double-blind, vehicle-controlled, parallel-group, proof of concept study to evaluate the efficacy, safety, and local tolerability of 6 weeks of treatment with crisaborole in adult participants with SD without active skin ulceration. Approximately 70 eligible participants will be randomized into the double blind treatment period in a 1:1 ratio to receive crisaborole ointment, 2% or vehicle twice daily for 6 weeks.

The study will recruit male and female participants aged ≥ 45 years with a clinical diagnosis of SD.

The total duration of participation in the study will be up to 14 weeks, including up to 4 weeks for screening, a 6 week double blind treatment period, and a follow-up period of 4 weeks after treatment completion.

Study enrollment and management will be de centralized, where participants do not visit an investigator or a clinic for clinical assessment. The participants will participate in the study at home. The sponsor (or designee) will provide home visits by qualified home visit practitioners (HVP), remote contact by telemedicine (or telephone), and clinical database electronic case report forms (eCRFs), eDiary, and other electronic data entries from 3rd party vendors for study data collection.

Arms:
arm 1: crisaborole ointment arm 2: vehicle ointment

Interventions: intervention 1: crisaborole ointment intervention 2: vehicle ointment
Intervention descriptions: intervention 1: crisaborole ointment intervention 2: vehicle ointment

Protocol document:
Prot_000.pdf: 
Crisaborole (PF-06930164)
C3291038
Final Protocol Amendment 2, 19 July 2021
PFIZER CONFIDENTIAL
Page 1
TITLE PAGE
Protocol Title: A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, 
Proof-of-Concept Study to Evaluate the Efficacy, Safety, and Local Tolerability of 
Crisaborole Ointment, 2%, in Adult Participants with Stasis Dermatitis without Active Skin 
Ulceration
Protocol Number: C3291038
Amendment Number: 2
Compound Number: PF-06930164/AN2728
Study Phase: Phase 2a
Short Title: STUDY EVALUATING THE EFFICACY AND SAFETY OF 
CRISABOROLE OINTMENT, 2% IN ADULT PARTICIPANTS WITH STASIS 
DERMATITIS WITHOUT ACTIVE SKIN ULCERATION
Acronym: N/A
Sponsor Name: Pfizer, Inc
Legal Registered Address: 235 East 42nd Street, New York, NY 10017-5755, USA
Regulatory Agency Identifier Number(s)
Registry
ID
IND
Approval Date: 19 July 2021
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.
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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
26 Sep 2019
Amendment 1
10 Jan 2020
Amendment 2
19 July 2021
Amendment 1 (10 January 2020)
Overall Rationale for the Amendment:
Section # and 
Name
Description of Change
Brief Rationale
Protocol 
Summary; 
Section 3 
Objectives, 
Estimands and 
Endpoints
Updated the following secondary 
 
 endpoints:
•
Achievement of an 
Investigator’s Static Global 
Assessment (ISGA) score of 
Clear (0) or Almost Clear (1) 
with at least a 2-grade 
improvement from baseline at 
all time points;
•
Achievement of an ISGA 
score of Clear (0) or Almost 
Clear (1) at all time points;
 
 
 
 
 
 
 
For binary and categorical endpoints, 
“proportion” is not an endpoint, it is summary 
for binary and categorical endpoints.
Protocol 
Summary, 1.2 
Schema, 4.1 
Overall Design; 
9.2 Sample 
Size 
Determination
Updated sample size to 92 participants.
The in-person assessment will be used for the 
primary analysis.  Because there is only one 
postbaseline assessment, completers will be 
used for the primary analysis (ie, observed cases 
data).  If a 10% dropout is assumed, 
92 participants are required (total, 46 per arm).
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Section # and 
Name
Description of Change
Brief Rationale
Protocol , 
Section 3 
Objectives, 
Estimands and 
Endpoints 
Summary
Updated objectives and endpoints to 
clarify that the primary endpoint is 
based on the in-person assessment.
 
Agreement will be 
evaluated between the efficacy assessments 
made in person by the HVP at home visits and 
the corresponding assessments completed by a 
Central Reader using standardized static digital 
images.  These supportive analyses will 
contribute to validation of the imaging device 
technology.
1.3.1 Screening 
and 
Randomization 
SOA
Added Fitzpatrick Skin Type 
Assessment as a baseline assessment 
(performed only at screening).  
Added a skin check to the training 
visit.
Updated some notes for clarity.
Subgroup analysis based upon Fitzpatrick skin 
Types will be feasible with addition of this 
assessment.  
1.3.2 
Intervention 
Period, Follow 
up and 
Unplanned 
Safety 
Assessment 
SOA
Edited to reflect that the Week 6 or ET 
visit will be a home visit.
Added a skin check to the Week 6/ET 
Visit and the Unplanned Safety 
Assessment.
Updated some notes for clarity.
Added review of eDiary.
 
Agreement will be 
evaluated between the efficacy assessments 
made in person by the HVP at home visits and 
the corresponding assessments completed by a 
Central Reader using standardized static digital 
images.  These supportive analyses will 
contribute to validation of the imaging device 
technology.  
Section 5.1 
Inclusion 
Criteria, 
Section 5.2 
Exclusion 
Criteria
Updated Inclusion Criteria #2 to more 
clearly define known and newly 
diagnosed SD.
Updated Exclusion Criteria #1 
regarding laboratory testing.
Added Exclusion Criteria #16 to 
identify laboratory values which are 
considered exclusionary.
Due to lack of clarity in terminology, 
“inadequate response” has been replaced by 
TSS- and ISGA-based in-person assessment.
Subject safety is further supported by 
exclusionary laboratory values confirmed at 
screening.
Section 6.1.1 
Administration
Updated administration information to 
include definition of FTU dosing.
Crisaborole prescribing information for the 
approved indication of atopic dermatitis 
regarding fingertip unit has been added to 
optimize dosing instructions.
Section 6.3
Updated to reflect that study 
intervention will be dispensed per the 
schedule of activities and not at the 
study visits.
For clarification as study intervention will be 
shipped directly to the participants and not 
dispensed at visits.
Section 6.5.1 
Medication 
Prohibited 
Prior to 
Randomization
Removed “Use of crisaborole ointment, 
2% anywhere on the body”.
Use of crisaborole is exclusionary (Exclusion 
Criteria #10).
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Section # and 
Name
Description of Change
Brief Rationale
Section 8, 
Section 8.1 
Efficacy 
Assessments 
Updated to reflect The Week 6/ET visit 
is a home visit.
Week 6 visit / ET visit in-person efficacy 
assessments are the basis for the primary 
analyses.
Section 8.2.5 
Clinical 
Laboratory 
Safety 
Assessment 
Removed the following bullet:
•
If laboratory values from non-
protocol specified laboratory 
assessments performed at the 
institution’s local laboratory 
require a change in participant 
management or are considered 
clinically significant by the 
investigator (eg, SAE or AE or 
dose modification), then the results 
must be recorded in the eCRF
Removed text as there is no way to record local 
laboratory results in the CRF.
Section 8.1.1 
Rater 
Qualifications
Updated Section 8.1.1 Rater 
Qualifications to include the HVP.
HVP in-person assessments are the basis for the 
primary efficacy analyses.
Section 8.1.2 
Assessments of 
Lower 
Extremities
Added Section 8.1.2 Assessments of 
Lower Extremities, to clarify between 
in person assessment of lower 
extremities and static digital imaging of 
lower extremities for the Central 
Reader. 
Changed Section 8.1.2 Static Digital 
Imaging of the Lower Extremities for 
Investigator Assessments to Section 
8.1.2.2 Static Digital Imaging of the 
Lower Extremities for Central Reader 
Assessments.
Updated text to state that the static 
digital images will be used for the 
Central Reader Assessments only.
Updated Management of Incidental 
Findings to clarify that the Investigator 
is responsible for the management of 
incidental findings.
 
Agreement will be 
evaluated between the efficacy assessments 
made in person by the HVP at home visits and 
the corresponding assessments completed by a 
Central Reader using standardized static digital 
images.  These supportive analyses will 
contribute to validation of the imaging device 
technology.  
Section 8.1.3 
Standardized 
SD Lesion 
Images: 
Acquisition, 
Save and 
Transfer
Updated section to reflect static digital 
images are to be used to complete 
efficacy assessments by the Central 
Reader only.
Remote digital image-based central read 
assessments will be performed by expert 
dermatologists only.  
Section 8.1.4 
Clinician 
Updated to reflect Week 6/ET is a 
home visit.
Week 6 visit/ET visit in-person efficacy 
assessments are the basis for the primary 
analyses.
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Section # and 
Name
Description of Change
Brief Rationale
Reported 
Outcomes
Updated to reflect static digital images 
are to be used to complete efficacy 
assessments by the Central Reader 
only.
Remote digital image-based central read 
assessments will be performed by expert 
dermatologists only.  
Section 8.2.2 
Physical 
Examination
Added application site examination
Stasis Dermatitis targeted skin assessment or 
check has been added to emphasize safety 
assessments at the application sites.
Section 8.25 
Clinical 
Laboratory 
Assessments, 
Appendix 2
Clarified that laboratory tests will be 
performed locally for any unplanned 
safety assessments. 
Since post baseline laboratory tests may extend 
beyond those required for eligibility, we can 
expedite through local laboratory testing.
Section 8.2.7 
Fitzpatrick 
Skin Type 
Assessment
Added a description of this assessment.
Stasis Dermatitis targeted skin assessment or 
check has been added to emphasize safety 
assessments at the application sites.
Section 8.3.6 
Cardiovascular 
and Death 
Events
Removed this section.
This is not required template language and is 
not relevant to this protocol.
Section 9.2 
Sample Size 
Determination, 
Section 9.4.1 
Efficacy 
Analyses
Clarified that the primary endpoint will 
be based on the HVP Week 6 home 
visit assessment.
Clarified that the supporting analyses 
will be based on the Central Reader 
assessments of the static digital images.
 
 
he Central Reader 
assessments will be used for supportive 
analyses.  Agreement will be evaluated between 
the efficacy assessments made in person by the 
HVP at home visits and the corresponding 
assessments completed by a Central Reader 
using standardized static digital images. These 
supportive analyses will contribute to validation 
of the imaging device technology.  
Section 9.3 
Populations for 
Analyses
Populations for analyses table has been 
updated for clarity.
Updated to align with new templates/SAP.
Appendix 6: 
Virtual 
Randomized 
Clinical Trial 
Information
Updated %BSA to lesional % BSA.
Clarified information regarding static 
digital imaging.
For consistency throughout the protocol.
To accurately reflect current procedures.
Appendix 8: 
Abbreviations
Added abbreviation for ANOVA, 
ANCOVA, fingertip unit, and quality 
control.
Added abbreviations relevant to this 
amendment.
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Amendment 2 (19 July 2021)
Overall Rationale for the Amendment:
Section # 
and 
Name
Description of Change
Brief Rationale
Section 1.3
Clarification on investigator’s  review of efficacy 
assessment scoring (Protocol Administrative 
Change Letter [PACL], 26 January 2021)
The investigator reviews HVP scoring, but 
does not review scores from the central 
readers  
Section 1.3 
and 8 
Clarification that the telemedicine interaction 
occurs first at randomization.
There is no telemedicine requirement at 
pre-randomization or on Day 1. 
Section 
1.3, 8.2.4, 
and 10.6
Clarification of the ECG   procedure (PACL 26 
January 2021)
The ECG may be completed by a single 
lead or multiple lead device.  
Section 3, 
4.1,  
9.1.1.1, 
9.1.1.2, 
9.4.2 and 
9.4.3
Estimand 1 was changed as a while-on-treatment 
for the primary endpoint and other non-
longitudinal endpoints analysis.
Estimand 3 was changed as a hypothetical 
estimand for longitudinal continuous endpoints 
analysis.
The primary estimand is not based on 
completion of visits in the treatment phase 
other than the early termination visit when 
participant terminates early. 
Section 5.3
Clarification of allowance of COVID-19 
vaccination (PACL 26 January 2021)
COVID-19 vaccination should be allowed 
for participants on study. 
8.1.1, and 
10.6
Clarification of the rater approval process 
(PACL 24 August 2020).  Removal of sentence 
that references the Rater Assessment Manual. 
Clarification that ratings are performed by HVP.
There is no Rater Assessment Manual.  
Approval of raters is from the sponsor or 
designee rather than from the CIG.  
Section 
8.1.2.3
Clarification of investigator role in review of 
photographic images of SD lesions
Photographic Images of each participant 
will be reviewed during study treatment 
for incidental findings as a safety 
assessment. 
Sections 
1.1, 4.1, 
and 9.2
Significance level was changed to one-side 5%. 
Sample size change to approximately 70 in total 
and approximately 35 per treatment arm.
To reduce sample size, this is a Phase 2 
proof of concept study, 5% one-sided 
significance level is acceptable for 
decision making.
Sections 
9.3, 9.5
An IA may be performed during study conduct. 
An IA may be conducted.
Section 
9.4.2
Detail of supportive/sensitive analyses was 
removed
Detail will be given in the SAP


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Section # 
and 
Name
Description of Change
Brief Rationale
Section 7.1
Clarification of stopping rules around QTcF and 
clarification that study medication 
discontinuation is at the investigator’s discretion 
if skin ulcer (s) occur outside the treatment area. 
QTcF stopping rules were updated to 
clarify when discontinuation should be 
considered by the investigator.  There is 
no requirement to discontinue study 
medication if skin ulcer (s) occur outside 
the treatment area. 
Section 
9.5,  and 
10.1.5.1
Description of  role of IRC for IA data review 
was added
Per SOP, an IRC is necessary for review 
of IA data and to provide 
recommendations per instructions in the 
IRC Charter. 
Section 4.3
Updated the age group for which crisaborole is  
approved for use. 
Crisaborole has been approved for use in 
ages 3 months and older.  
Section 
10.6
Removed references to participant data entry in a 
web-based portal. 
There is no web-based portal for 
participant entry of demographic 
information, date of birth, medical history, 
or concurrent medications.  
Section 1.1 
and 3
Removed HVP from HVP in-person assessment.
Including HVP with in-person assessment 
is redundant since all in-person 
assessments are completed by the HVP 
Section 8.1 
Removed description of the agreement between 
the in-person and centrally read assessments of 
SD. 
This assessment is not relevant to this
section of the protocol. 
Section 6.3
Clarification added to specify that participants 
and study sites will not be unblinded in case a 
futility threshold is met during an IA. 
A futility threshold would be a result of IA 
efficacy results and therefore, there is no
rationale for unblinding. 
Section 7
Clarification added to specify that participants 
may be discontinued from the screening phase 
and participants in the treatment or follow-up 
phase may continue in the study in case a futility 
threshold is met during an IA. 
Participants are not required to terminate 
treatment if they are on treatment at the 
time a futility threshold is met. 
Section 
6.5.1 and 
6.5.2
Clarification that oral antibiotic use for SD 
requires washout and is prohibited during the 
treatment phase. 
Clarification that 
immunosuppressant/immunomodulatory
biologics are prohibited prior to and during study 
treatment. 
Concomitant treatment with oral antibiotic 
is prohibited for use to treat SD, but it is 
not prohibited for other indications.   
Biologics other than those that are 
immunosuppressant/immunomodulatory 
are not prohibited. 


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Section # 
and 
Name
Description of Change
Brief Rationale
Section 8 
Removal of sentence that defines the site as the 
CIG (PACL 24 August 2020)
The site is not defined as the CIG. 
Sections 
8.3.1.2, 
8.3.6, 
8.3.6.1, 
8.3.7, 
8.3.8, 8.4, 
9.1.2, 
9.4.1, 
10.3.2, and 
10.3.3
Changes made to align with updated protocol 
template.
New template language required.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative 
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities (SoA)...................................................................................17
1.3.1. Screening, Pre-randomization and Randomization ....................................17
1.3.2. Intervention Period, Follow-Up and Unplanned Safety Assessment .........21
2. INTRODUCTION ...............................................................................................................28
2.1. Study Rationale .......................................................................................................28
2.2. Background .............................................................................................................28
2.3. Benefit/Risk Assessment.........................................................................................29
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................29
4. STUDY DESIGN.................................................................................................................31
4.1. Overall Design.........................................................................................................31
4.2. Scientific Rationale for Study Design.....................................................................32
4.3. Justification for Dose ..............................................................................................32
4.4. End of Study Definition ..........................................................................................32
5. STUDY POPULATION......................................................................................................33
5.1. Inclusion Criteria.....................................................................................................33
5.2. Exclusion Criteria....................................................................................................34
5.3. Lifestyle Considerations..........................................................................................36
5.3.1. Meals and Dietary Restrictions...................................................................37
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................37
5.4. Screen Failures ........................................................................................................37
6. STUDY INTERVENTION..................................................................................................37
6.1. Study Intervention(s) Administered........................................................................37
6.1.1. Administration............................................................................................38
6.2. Preparation/Handling/Storage/Accountability ........................................................39
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................39
6.4. Study Intervention Compliance...............................................................................40
6.5. Concomitant Therapy..............................................................................................40


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6.5.1. Medications Prohibited Prior to Randomization ........................................40
6.5.2. Medications/Therapies Prohibited During the Study .................................42
6.5.3. Medications/Therapies Allowed During the Study ....................................42
6.5.4. Rescue Medicine.........................................................................................43
6.6. Dose Modification...................................................................................................44
6.7. Intervention after the End of the Study...................................................................44
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................44
7.1. Discontinuation of Study Intervention ....................................................................44
7.1.1. Temporary Discontinuation........................................................................45
7.2. Participant Discontinuation/Withdrawal from the Study........................................45
7.3. Lost to Follow up ....................................................................................................45
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................46
8.1. Efficacy Assessments..............................................................................................47
8.1.1. Rater Qualifications....................................................................................48
8.1.2. Assessments of Stasis Dermatitis Lesions on the Lower Extremities........48
8.1.2.1. In-person Assessments by HVP ................................................48
8.1.2.2. Static Digital Imaging Assessments by Central Reader............48
8.1.2.3. Management of Incidental Findings by the Investigator...........49
8.1.3. Standardized Static SD Lesion Images: Acquisition, Save and 
Transfer............................................................................................................49
8.1.4. Clinician Reported Outcomes.....................................................................50
8.1.4.1. Total Sign Score........................................................................50
8.1.4.2. Investigator’s Static Global Assessment (ISGA)......................50
8.1.4.3. Stasis Dermatitis Lesional % BSA............................................50
 
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8.2. Safety Assessments .................................................................................................52
8.2.1. Medical History ..........................................................................................52
8.2.2. Physical Examinations................................................................................52
8.2.3. Vital Signs ..................................................................................................53
8.2.4. Electrocardiograms.....................................................................................53
8.2.5. Clinical Safety Laboratory Assessments ....................................................53
8.2.6. Mini-Mental State Examination 2nd Edition (MMSE-2, Brief 
Version)............................................................................................................54
8.2.7. Fitzpatrick Skin Type Assessment..............................................................54
8.3. Adverse Events and Serious Adverse Events..........................................................54
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......54
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................55
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF .................55
8.3.2. Method of Detecting AEs and SAEs ..........................................................55
8.3.3. Follow-up of AEs and SAEs.......................................................................56
8.3.4. Regulatory Reporting Requirements for SAEs...........................................56
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................56
8.3.5.1. Exposure During Pregnancy......................................................56
8.3.5.2. Exposure During Breastfeeding ................................................57
8.3.5.3. Occupational Exposure .............................................................57
8.3.6. Adverse Events of Special Interest.............................................................57
8.3.6.1. Lack of Efficacy........................................................................57
8.3.7. Medical Device Deficiencies......................................................................57
8.3.8. Medication Errors .......................................................................................57
8.4. Treatment of Overdose............................................................................................58
8.5. Pharmacokinetics ....................................................................................................59
8.6. Pharmacodynamics..................................................................................................59
8.7. Genetics...................................................................................................................59
8.7.1. Specified Genetics ......................................................................................59
8.7.2. Banked Biospecimens for Genetics............................................................59
8.8. Biomarkers ..............................................................................................................59
8.9. Medical Resource Utilization and Health Economics.............................................59


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9. STATISTICAL CONSIDERATIONS ................................................................................59
9.1. Estimands and Statistical Hypotheses.....................................................................59
9.1.1. Estimands....................................................................................................59
9.1.1.1. Primary Estimand/Co-Primary Estimands ................................59
9.1.1.2. Secondary Estimands ................................................................60
9.1.2. Multiplicity Adjustment..............................................................................61
9.2. Sample Size Determination.....................................................................................61
9.3. Populations for Analyses.........................................................................................61
9.4. Statistical Analyses .................................................................................................61
9.4.1. General Considerations...............................................................................62
9.4.1.1. Analyses for Binary Endpoints .................................................62
9.4.1.2. Analyses for Continuous Endpoints..........................................62
9.4.1.3. Analyses for Categorical Endpoints..........................................62
9.4.2. Primary Endpoint/Estimand Analyses........................................................62
9.4.3. Secondary Endpoints/Estimands Analysis .................................................63
9.4.5. Safety Analyses ..........................................................................................63
9.5. Interim Analyses .....................................................................................................63
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................64
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............64
10.1.1. Regulatory and Ethical Considerations ....................................................64
10.1.2. Financial Disclosure .................................................................................65
10.1.3. Informed Consent Process ........................................................................65
10.1.4. Data Protection .........................................................................................66
10.1.5. Committees Structure ...............................................................................66
10.1.5.1. Data Monitoring Committee (DMC).......................................66
10.1.6. Dissemination of Clinical Study Data ......................................................67
10.1.7. Data Quality Assurance ............................................................................68
10.1.8. Source Documents....................................................................................69
10.1.9. Study and Site Closure..............................................................................70
10.1.10. Publication Policy...................................................................................70
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10.1.11. Sponsor’s Qualified Medical Personnel .................................................71
10.2. Appendix 2: Clinical Laboratory Tests .................................................................72
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................73
10.3.1. Definition of AE .......................................................................................73
10.3.2. Definition of SAE.....................................................................................74
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE.........................75
10.3.4. Reporting of SAEs....................................................................................78
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................80
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........83
10.6. Appendix 6: Virtual Randomized Clinical Trial Information...............................85
10.7. Appendix 7: NYHA Classification, CKD Guidelines, Child - Pugh 
Classification and GOLD Guidelines........................................................................87
10.8. Appendix 8: Abbreviations ...................................................................................90
11. REFERENCES ..................................................................................................................94
LIST OF TABLES
Table 1.
Protocol-Required Safety Laboratory Assessments .................................72


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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A Phase 2, Randomized, Double-Blind, Vehicle-Controlled, 
Proof-of-Concept Study to Evaluate the Efficacy, Safety, and Local Tolerability of 
Crisaborole Ointment, 2%, in Adult Participants with Stasis Dermatitis without Active Skin 
Ulceration
Short Title: Study Evaluating the Efficacy and Safety of Crisaborole Ointment, 2% in Adult 
Participants with Stasis Dermatitis without Active Skin Ulceration
Rationale: Crisaborole is a phosphodiesterase-4 (PDE-4) inhibitor approved for treatment of 
mild to moderate atopic dermatitis (AD) and is being developed as a topical treatment for 
patients with stasis dermatitis (SD) without active skin ulceration.
This is a proof-of-concept study that will evaluate crisaborole therapy twice daily (BID) for 
the treatment of SD without active skin ulceration.
Objectives, Estimands and Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy of crisaborole
ointment, 2%, BID versus vehicle at 
Week 6 in participants with stasis 
dermatitis without active skin 
ulceration.

Percent change from baseline in Total 
Sign Score (TSS) at Week 6/EOT 
(in-person assessment).
Secondary Efficacy

To evaluate the efficacy of crisaborole 
ointment, 2%, BID versus vehicle over 
time in participants with SD without 
active skin ulceration.

Achievement of an Investigator’s Static 
Global Assessment (ISGA) score of 
Clear (0) or Almost Clear (1) with at 
least a 2grade improvement from 
baseline at all time points (analyze both 
in-person assessment and Central 
Readers digital images assessment);

Achievement of an ISGA score of Clear 
(0) or Almost Clear (1) at all time points 
(analyze both in-person assessment and 
Central Readers digital images 
assessment);


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Objectives
Endpoints

Percent change from baseline in TSS at 
all time points except (Central Readers 
digital images assessment);

Percent change from baseline in lesional 
% Body Surface Area (%BSA) at all 
time points (analyze both in-person 
assessment and Central Readers digital 
images assessment).
Secondary Safety

To evaluate the safety and local 
tolerability of crisaborole ointment, 2%, 
BID versus vehicle in participants with 
SD without active skin ulceration.

Incidence and severity of treatment 
emergent adverse events, including local 
tolerability events.
Estimands
Only discontinuation of study intervention will be considered as an intercurrent event.
The primary estimand of this study is a while-on-treatment estimand, which estimates the 
treatment effect of crisaborole compared with vehicle at Week 6 or EOT.  It includes the 
following 5 attributes: 

Population: Participants ≥45 years of age with SD without active skin ulceration;

Variable: non-longitudinal endpoints at Week 6/EOT;

Treatment condition: crisaborole 2% BID or vehicle;

Intercurrent event: all data after an intercurrent event of discontinuation of study 
intervention will be excluded, data at Week 6/EOT will be included;

Population-level summary: difference in LSM for continuous endpoints and 
difference in proportion of participants with response for binary endpoints at 
Week 6/EOT between crisaborole ointment, 2%, BID versus vehicle.
See Section 9.1.1 for additional information on estimands.
Overall Design:
This is a Phase 2a, randomized, double-blind, vehicle-controlled, parallel-group, 
proof-of-concept study enrolling approximately 70 eligible participants randomized into the 
double-blind treatment period in a 1:1 ratio to receive BID crisaborole ointment 2% or 
vehicle for 43 days. 


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The total duration of participation in the study is up to 14 weeks, including up to 4 weeks for 
screening, a 6-week double-blind treatment period, and follow-up period of 4 weeks after 
treatment completion. 
Disclosure Statement: 
This is a Parallel Treatment study with 2 Arms that is Sponsor, Investigator and Participant 
blinded.
Number of Participants:
Approximately 70 participants will be randomized.
Intervention Groups and Duration:
Group 1 (N=35): Crisaborole ointment, 2% (w/w) BID for 43 days
Group 2 (N=35): Vehicle BID for 43 days
Data Monitoring Committee:
An IRC will be utilized if an IA is performed
1.2. Schema


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1.3. Schedule of Activities (SoA)
1.3.1. Screening, Pre-randomization and Randomization
Procedure
Screening Period
Notes
Telemedicine visits are defined as health care 
professional evaluations using synchronous audio and 
video telecommunications technology.  Telephone 
interview only is permitted in the event of technical 
difficulties which preclude video component.
Screening
Visit
(Home Visit)
Pre-
Randomization
Period
Randomization
(telemedicine)
Training 
Visit
(Home Visit)
Day(s)
-28 to -15
-14 to -8
-7 to -2
-2 to +1
Window (days)
±2
±2
±2
±2
Enrollment
Informed consent
X
Section 10.1.3
Demographics, medical 
history, SD history, SD 
prior treatments
X
At screening, the participant’s primary care physician and 
subspecialist physician contact information may be 
collected.  Disease history regarding specific comorbid 
conditions to be recorded on the eCRF.  Section 8.2.1.
Inclusion and exclusion 
criteria
X
X
X
Investigator reviews all screening period information (eg 
HVP face to face assessments, HVP scoring, and eDiary) 
to confirm participant meets all study entry criteria.
Section 8
Mini-Mental State 
Examination-2 
(MMSE-2, Brief 
Version)
X
To be performed by HVP at screening visit.  See 
Section 8.2.6.
Fitzpatrick Skin Type 
Assessment
X
To be performed by HVP at screening visit.  See 
Section 8.2.7.
Randomization by IRT
X
Randomization will result in an order for direct shipment 
of the study intervention to the participant.  See 
Section 6.3


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Procedure
Screening Period
Notes
Telemedicine visits are defined as health care 
professional evaluations using synchronous audio and 
video telecommunications technology.  Telephone 
interview only is permitted in the event of technical 
difficulties which preclude video component.
Screening
Visit
(Home Visit)
Pre-
Randomization
Period
Randomization
(telemedicine)
Training 
Visit
(Home Visit)
Day(s)
-28 to -15
-14 to -8
-7 to -2
-2 to +1
Window (days)
±2
±2
±2
±2
Clinical Examination
Vital Signs
X
To be performed by HVP at home visit.  Section 8.2.3
ECG 
X
To be performed by HVP at the screening visit.  
Section 8.2.4
Height and Weight
X
To be performed by HVP at the screening visit.  
Section 8.2.2
Complete physical 
examination
X
To be performed by HVP at the screening visit.  The 
participant’s family member, friend, or advocate may be 
present if requested by the participant.  Section 8.2.2
Application site (skin) 
examination
X
X
To be performed by HVP at the screening visit (as part of 
the complete physical examination) and Training Visit.  
Section 8.2.2
Laboratory Procedures
Clinical chemistry, 
Hemoglobin A1c, 
PT/INR, and hematology 
(central lab)
X
To be performed by HVP at the screening visit. 
Section 8.2.5, Section 10.2
FSH
X
To confirm postmenopausal status for female participants 
only.  Section 10.4
Efficacy Evaluation


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Procedure
Screening Period
Notes
Telemedicine visits are defined as health care 
professional evaluations using synchronous audio and 
video telecommunications technology.  Telephone 
interview only is permitted in the event of technical 
difficulties which preclude video component.
Screening
Visit
(Home Visit)
Pre-
Randomization
Period
Randomization
(telemedicine)
Training 
Visit
(Home Visit)
Day(s)
-28 to -15
-14 to -8
-7 to -2
-2 to +1
Window (days)
±2
±2
±2
±2
Lower extremity digital 
imaging 
X
X
The HVP will instruct the participant how to obtain static 
SD lesion images at the training visit. Section 8.1.2 and 
Section 8.1.3
Total Sign Score (TSS)
X
X
To be completed by the HVP prior to dose administration 
at the training visit.
Section 8.1.4.1
Investigator’s Static 
Global Assessment 
(ISGA)
X
X
To be completed by the HVP prior to dose administration 
at the training visit.
Section 8.1.4.2
Lesional % of Body 
Surface Area (BSA)
X
X
To be completed by HVP prior to dose administration at 
the training visit.  
Section 8.1.4.3
Patient Reported Outcomes
 
  
 
 
  
CCI


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Procedure
Screening Period
Notes
Telemedicine visits are defined as health care 
professional evaluations using synchronous audio and 
video telecommunications technology.  Telephone 
interview only is permitted in the event of technical 
difficulties which preclude video component.
Screening
Visit
(Home Visit)
Pre-
Randomization
Period
Randomization
(telemedicine)
Training 
Visit
(Home Visit)
Day(s)
-28 to -15
-14 to -8
-7 to -2
-2 to +1
Window (days)
±2
±2
±2
±2
 
Safety Assessment
Serious and non-serious 
AE reporting
X
X
X
X
Including AEs reported during referral clinic visits. 
Section 8.3
Study Intervention
Prior and Concomitant 
medications / therapies 
recording on eCRFs
X
X
X
X
Section 6.5
eDiary
• Device and 
compatibility 
assessment
• eDiary 
completion 
training
X
Training and assessment provided by the HVP at the 
screening visit.  Section 8.1.5
Home visit practitioner 
(HVP) demonstration
• Study 
intervention 
handling and 
dosing 
instruction 
X
Training visit by the HVP will occur following participant 
randomization and study intervention assignment.  In the 
event that study intervention cannot be applied, HVP may 
use ointment without a pharmacologically active 
ingredient for demonstration.
Section 6.1.1 and Section 6.2
CCI


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Procedure
Screening Period
Notes
Telemedicine visits are defined as health care 
professional evaluations using synchronous audio and 
video telecommunications technology.  Telephone 
interview only is permitted in the event of technical 
difficulties which preclude video component.
Screening
Visit
(Home Visit)
Pre-
Randomization
Period
Randomization
(telemedicine)
Training 
Visit
(Home Visit)
Day(s)
-28 to -15
-14 to -8
-7 to -2
-2 to +1
Window (days)
±2
±2
±2
±2
Study intervention 
dispensing
X
Section 6.2
1.3.2. Intervention Period, Follow-Up and Unplanned Safety Assessment
Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
2
2
2
2
2
2
+7
Clinical Examination
Vital Signs
X
X
To be performed by HVP at any unplanned 
safety assessment visits.  Section 8.2.3


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Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
2
2
2
2
2
2
+7
ECG 
(X)
May be performed by HVP at any unplanned 
safety assessment visits.  Section 8.2.4
Complete physical 
examination
(X)
(X)
May be performed by HVP at any unplanned 
safety assessment visits.  The participant’s 
family member, friend, or advocate may be 
present if requested by the participant.  
Section 8.2.2
Application Site Skin 
Examination
X
X
To be performed by HVP at Week 6 (or early 
termination) visit and at unplanned safety 
assessments (s).  Section 8.2.2.
Laboratory Procedures
Clinical chemistry, 
Hemoglobin A1c, 
PT/INR, and hematology 
(central lab)
(X)
(X)
Local labs may be requested at any 
unplanned safety assessment visits. 
Section 8.2.5
Section 10.2
Efficacy Evaluation


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Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
2
2
2
2
2
2
+7
Lower extremity digital 
imaging 
X
X
X
X
X
X
X
(X)
Section 8.1.2 and Section 8.1.3
Total Sign Score (TSS)
X
X
X
X
X
X
X
X
Completed by HVP at all home visits.  
Completed by Central Reader for all weekly 
static digital images.  
Section 8.1.4.1
Investigator’s Static 
Global Assessment 
(ISGA)
X
X
X
X
X
X
X
X
Completed by HVP at all home visits.  
Completed by Central Reader for all weekly 
static digital images.  
Section 8.1.4.2
Lesional % of Body 
Surface Area (BSA)
X
X
X
X
X
X
X
X
Completed by HVP at all home visits.  
Completed by Central Reader for all weekly 
static digital images.  
Section 8.1.4.3
Patient Reported Outcomes


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Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
±2
±2
±2
±2
±2
±2
+7
 
 
 
 
 
 
 
 
 
Safety Assessment
CCI


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Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
2
2
2
2
2
2
+7
Serious and non-serious 
AE reporting
X
X
X
X
X
X
X
X
X
Including AEs reported during referral clinic 
visits
Section 8.3
Study Intervention
Prior and Concomitant 
medications / therapies 
recording on eCRFs
X
X
X
X
X
X
X
X
X
Section 6.5
Study intervention 
dispensing
X
At Day 15, participants confirmed to be 
continuing in the study will have a second 
study intervention supply processed in the 
IRT system and shipped for use beginning 
Day 22.
Section 6.3
Self-administration of 
ointment







Participants will begin applying study 
intervention the morning after it is received.


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Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
2
2
2
2
2
2
+7
eDiary completion for:

study intervention 
compliance

compression 
therapies







Section 6.5
Review eDiary data
X
X
X
X
X
X
X
X
RTC to document weekly review of eDiary 
data entries during the Intervention Period
Study intervention return
X
X
Study intervention should be returned by the 
participant within 7 days of the visit.  
Section 6.3
Study intervention 
accountability
X
X
X
X
X
X
X
X
At each scheduled assessment, tubes (used 
and unused) can be reviewed by the RTC or 
CIG. Section 6.2


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Procedure
Intervention Period (telemedicine) Visits 
and 
Week 6/EOT or Early Termination (home) 
Visit
End of Study 
(follow-up)
(telemedicine)
Unplanned 
Safety 
Assessment 
(home visit or 
telemedicine 
visit)
Notes
Day(s)
1
8
15
22
29
36
43
71
Day 1 is the first day of intervention applied.
Randomization, Day 8, 15, 22, 29, 36, and 
Follow-up (Day 71) are scheduled 
telemedicine contacts.  The contact may be 
conducted solely by phone in the event of 
technical problems.  Interviews may be 
extended over 2 days to accommodate 
unforeseen circumstances.  Section 8.
End of treatment (home) visit to be 
performed by HVP at Week 6 (Day 43) or at 
early termination.
Week(s)
0
1
2
3
4
5
6
At least 
28 days after 
the last dose
Window (days)
±2
±2
±2
±2
±2
±2
+7
AE = adverse event; BSA = body surface area; CIG = central investigator group; 
ECG = electrocardiogram; 
 
FSH = follicle stimulating hormone; HVP = home visit practitioner; ISGA = Investigator’s Static Global 
Assessment; eCRF = electronic case report form; INR = international normalized ratio; IRT = interactive response technology; MMSE-2, Brief Version = Mini 
Mental State Examination; 
 
 PT = prothrombin time; RTC = remote trial coordinator; SD = stasis dermatitis; TSS = Total Sign Score; (X) = performed at the 
Investigator’s or HVP’s discretion.
CCI
CCI
CCI


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2. INTRODUCTION
Stasis dermatitis (SD) affects a significant proportion of the older population. A slight female 
preponderance has been reported in SD most likely due to pregnancy-related stress on the 
lower-extremity venous system, with many women experiencing earlier and more severe 
derangement of lower-extremity venous valvular function.  Studies have estimated an 
approximately 6-7% prevalence of the condition in patients older than 50 years, which 
translates into approximately 15-20 million patients older than 50 years with stasis dermatitis 
in the United States.  This finding makes SD twice as prevalent as psoriasis and only slightly 
less prevalent than seborrheic dermatitis.  The risk of developing SD steadily increases with
each passing decade; when considering only adults older than 70 years, the prevalence of SD 
in developed countries may exceed 20%.1,3
2.1. Study Rationale
2.2. Background
SD occurs in the setting of lymphedema and impaired venous drainage affecting the lower 
extremities.11-14  Concurrent medical conditions which may predispose patients to develop 
SD include, but are not limited to, varicose veins, prior lower extremity vein graft harvest, 
morbid obesity, chronic obstructive pulmonary disease (COPD), congestive heart failure 
(CHF), chronic liver disease with ascites, chronic kidney disease (CKD) with or without 
nephrotic syndrome, diabetes mellitus, pulmonary embolism and inferior vena cava (IVC) 
filter placement, IVC thrombosis, iliac vein thrombosis, and proximal deep vein thrombosis 
(DVT) of the lower extremities.  Tissue hypoxia in edematous skin of the lower extremities 
due to one or more of these conditions produces erythematous/ discolored skin, skin scaling 
and dryness, pruritus, and painful extremities.  As lymphedema and venous insufficiency 
(VI) and venous hypertension (VHTN) progress, increasing hydrostatic pressures in vascular 
watershed (hypoxic) areas in the region of the ankle are observed.  Venous reflux (or reversal 
of venous blood flow) promotes peripheral edema and the SD immunohistochemical changes 
become prominent particularly in the region of the medial malleolus.  Generally, edema and 
spongiosis originating from the feet and ankles progress proximally toward the knees.  
Inadequately treated inflammation associated with SD may become secondarily infected 
resulting in additional limitation of activities of daily living and reduced quality of life.
Histologically, SD is characterized by the onset of papillary structure alteration, spongiosis 
and proliferation of small blood vessels in the papillary dermis.  This morphologically altered 
skin is littered with extravasated erythrocytes and serum macromolecules which act as 
chemoattractant for mononuclear leukocytes.  As lymphocytes and other mononuclear cells 
progressively infiltrate the lower extremity interstitial spaces (“leukocyte trapping”), MMPs 
and TIMP-1 and -2 are also found in abundance as tissue remodeling and inflammation 
persist.  Inflammatory cells continually influence the remodeling of the extracellular matrix 
directly by MMPs and both directly and indirectly by released cytokines (eg, TNFα and 
TGFβ1).6-8,15-17  Mast cells (associated with tissue remodeling) and marked TGFβ1 presence 
(associated with up-regulation of MMPs and down-regulation of TIMPs) herald the onset of 
extracellular matrix deposition and intense tissue fibrosis.18,19  


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SD may be seen unilaterally (occurs due to unilateral DVT or unilateral venous valvular 
dysfunction) or bilaterally.  Regardless of SD etiology and laterality, signs and symptoms 
may include edema, aching and heaviness of the legs, erythema, hyperpigmentation, 
papulation, pruritus, scaling, erosions and denudation, scaling and lichenified skin, pitting 
edema, and fluid weeping from the lower extremities.4,18,20-26
2.3. Benefit/Risk Assessment
Crisaborole ointment is approved for the treatment of AD in pediatric and adult patients.  Its 
safety profile is well-characterized and positive benefit/risk assessment has been established 
in the treatment of AD.  The potential benefits of crisaborole ointment, 2%, for treatment of 
SD have not been established.  It is not known if SD may improve, worsen, or remain 
unchanged during the treatment period.  
Because crisaborole impacts inflammatory pathways relevant to SD, it is anticipated that 
study intervention may ameliorate lower extremity SD signs and symptoms.  Considering 
anticipated benefits and potential risks of the investigational product(s), as well as the low 
risk associated with protocol-specified study procedures, the potential benefits to study 
participation outweigh potential risks of short-term exposure to topical crisaborole ointment. 
Participants will likely have one or more ongoing, chronic conditions which had predisposed 
to the development of SD.  Management of these conditions will be provided by health care 
providers (HCP) already caring for the participant.  Principal Investigators and 
Sub-Investigators will be required to record any interactions between the participant and 
non-study HCP throughout the study period in the electronic database and if any adverse 
events (AEs) include assessments of relatedness, causality, and severity (as appropriate) 
within the electronic database.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of crisaborole ointment, 2% may be found in the Investigator’s 
Brochure, which is the single reference safety document (SRSD) for this study.
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the efficacy of 
crisaborole ointment, 2%, BID 
versus vehicle at Week 6 in 
participants with stasis dermatitis 
without active skin ulceration.

Percent change from baseline in 
Total Sign Score (TSS) at 
Week 6/EOT (in-person assessment).
Secondary Efficacy

To evaluate the efficacy of 
crisaborole ointment, 2%, BID 
versus vehicle over time in 

Achievement of an Investigator’s 
Static Global Assessment (ISGA) 
score of Clear (0) or Almost Clear 
(1) with at least a 2-grade 


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Objectives
Endpoints
participants with SD without active 
skin ulceration.
improvement from baseline at all 
time points (analyze both in-person 
assessment and Central Readers 
digital images assessment);
•
Achievement of an ISGA score of 
Clear (0) or Almost Clear (1) at all 
time points (analyze both in-person 
assessment and Central Readers 
digital images assessment);
•
Percent change from baseline in TSS 
at all time points (Central Readers 
digital images assessment);
•
Percent change from baseline in 
lesional % Body Surface Area 
(%BSA) at all time points (analyze
both in-person assessment and 
Central Readers digital images 
assessment).
Secondary Safety
•
To evaluate the safety and local 
tolerability of crisaborole ointment, 
2%, BID versus vehicle in 
participants with SD without active 
skin ulceration.
•
Incidence and severity of treatment 
emergent adverse events, including 
local tolerability events.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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Estimands
Only discontinuation of study intervention will be considered as an intercurrent event.
The primary estimand of this study is a while-on-treatment estimand, which estimates the 
treatment effect of crisaborole compared with vehicle at Week 6/EOT.  It includes the 
following 5 attributes: 
•
Population: Participants ≥45 years of age with SD without active skin ulceration;
•
Variable: non-longitudinal endpoints at Week 6/EOT;
•
Treatment condition: crisaborole 2% BID or vehicle;
•
Intercurrent event: all data after an intercurrent event of discontinuation of study 
intervention will be excluded, data at Week 6/EOT will be included; 
•
Population-level summary: difference in LSM for continuous endpoints and 
difference in proportion of participants with response for binary endpoints at 
Week 6/EOT between crisaborole ointment, 2%, BID versus vehicle.
See Section 9.1.1 for additional information on estimands.
4. STUDY DESIGN
4.1. Overall Design
Study C3291038 is a Phase 2a, randomized, double-blind, vehicle-controlled, parallel-group, 
proof-of-concept study to evaluate the efficacy, safety, and local tolerability of 6 weeks of 
treatment with crisaborole in adult participants with SD without active skin ulceration.  
Approximately 70 eligible participants will be randomized into the double-blind treatment 
period in a 1:1 ratio to receive crisaborole ointment, 2%, or vehicle twice daily for 6 weeks.
The study will recruit male and female participants aged ≥45 years with a clinical diagnosis 
of SD.  Participants who meet all inclusion but none of the exclusion criteria presented in 
Section 5 will be eligible to participate in the study.  If a participant meets any of the 
exclusion criteria, the participant will be excluded.
CCI


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The total duration of participation in the study will be up to 14 weeks, including up to 
4 weeks for screening, a 6-week double-blind treatment period, and a follow-up period of 
4 weeks after treatment completion.  
Study enrollment and management will be de-centralized, where participants do not visit an 
investigator or a clinic for clinical assessment.  The participants will participate in the study 
at home.  The sponsor (or designee) will provide home visits by qualified home visit 
practitioners (HVP), remote contact by telemedicine, and clinical database electronic case 
report forms (eCRFs), eDiary, and other electronic data entries from 3rd party vendors for 
study data collection. 
Participants who withdraw from further study intervention treatment (but do not withdraw 
consent for further data gathering) should continue to complete all scheduled assessments at 
the EOT visit and complete the follow-up phase of the study.
4.2. Scientific Rationale for Study Design
SD prevalence is up to 2% in the 5th decade of life, 6-7% in the 6th decade of life, and more 
than 20% beyond age 70 years.1,2  Eligible participants must be 45 years or older.  Potentially 
eligible study participants will have one or more concurrent medical conditions which 
predispose20,21 to lymphedema or VI and VHTN resulting in SD lesions: morbid obesity, 
COPD, coronary artery disease/CHF, DVT with or without IVC filter placement, diabetes 
mellitus, and varicose veins of the lower extremities.  
Extrapolating from AD clinical trial efficacy data for BID crisaborole applications, efficacy 
by Week 6 in participants with SD may be expected.  It is relevant to note that active skin 
ulceration may be observed in close proximity to SD-affected skin.  Because active skin 
ulcers may require more than 3 months of debridement and wound repair treatments, 
participants with SD and active skin ulcers will be excluded from study participation.12,13,18
4.3. Justification for Dose
The crisaborole dose strength and regimens selected for this study have been demonstrated to 
be safe, well tolerated, and efficacious in participants with mild to moderate AD in previous 
clinical trials (see the Investigator’s Brochure [IB]).  Crisaborole ointment, 2%, BID is 
proposed as an appropriate dose strength and regimen based on the favorable benefit: risk 
profile established in mild to moderate AD for patients age 3 months and older.  The 2% dose 
strength is the maximum feasible for the ointment formulation.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the End of Study (follow-up) visit.
The end of the study is defined as the date of the last visit of the last participant in the study.


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5. STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Participant must be ≥45 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who have SD:
•
A known diagnosis of SD based upon HCP medical records for at least 3 months 
prior to screening with inadequate response to current treatment.  Inadequate 
response is defined by ISGA ≥2 (range 0-4) and TSS ≥3 (range 0-12) at the 
screening visit; 
OR
•
Newly diagnosed by the Investigator based upon the following:
a.
Participant confirmation of symptoms present on lower extremities for 
at least 3 months prior to screening; 
b. HVP complete physical examination findings;
c.
Telemedicine assessment by the Investigator;
d. Inadequate response to current treatment.  Inadequate response is 
defined by ISGA ≥2 (range 0-4) and TSS ≥3 (range 0-12) at the 
screening visit.
•
Active unilateral or bilateral SD lesions on the lower extremities (from knee to 
ankle and dorsum of foot) and the involved areas total ı1% BSA (1 handprint of 
the participant) at the screening visit.
Sex
3. Male or Female


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Informed Consent
4. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
Other
5. Participant’s mental and physical status allows them to be able to mostly perform 
their activities of daily living with minimal assistance including the ability to:
a.
Apply ointment to the lower part of their legs;
b. Comply with compression therapy, if worn prior to screening; 
c.
Comply with study procedures, including home visits, digital imaging and 
image capture; 
d. Comply with use of an internet-enabled device, (eg smartphone, tablet, laptop 
or desktop computer) to complete patient-reported outcome assessments 
(PROs), and the dosing diary.
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has any clinically significant active or potentially recurrent non-SD dermatological 
conditions and known genetic dermatological conditions that overlap SD or clinically 
significant physical examination finding that in the investigator/designee’s opinion 
may interfere with study objectives (eg, expose participant to unacceptable risk by 
study participation, confound evaluation of treatment response or AEs, or interfere 
with participant’s ability to complete the study).
In the clinical judgment of the Investigator, prior medical testing may be needed to 
determine whether a chronic medical condition is medically stable.  
2. Has any unstable concurrent medical condition(s) associated with lymphedema or VI 
and VHTN such as: morbid obesity, COPD, coronary artery disease/CHF, status/post 
lower extremity vein graft harvest(s), DVT of the lower extremities, status/post IVC 
filter placement, diabetes mellitus, or varicose veins of the lower extremities.  For the 
purposes of this study, any of the following are exclusionary:

Unstable concurrent medical condition defined as a change in treatment of the 
concurrent medical condition(s) within 28 days prior to screening 

Unstable concurrent medical condition defined as a hospitalization for 
management of any concurrent medical condition(s) within 2 months prior to 
screening.


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
New York Heart Association (NYHA) Class III or higher (see Appendix 7) or 
hospitalization for CHF exacerbation within 2 months prior to screening. 

COPD Global Initiative for Obstructive Lung Disease (GOLD) Group C or higher 
(see Appendix 7) or hospitalization for COPD exacerbations within 2 months 
prior to screening. 

CKD with an estimated glomerular filtration rate (eGFR) of <15 mL/min/1.73 m² 
(by CKD-EPI formula) at screening or history of dialysis or kidney transplant.  

Chronic liver disease with ascites (Child-Pugh Category >9 [see Appendix 7]) or 
aspartate aminotransferase (AST), or alanine aminotransferase (ALT) >3 x upper 
limit of normal (ULN) (See Appendix 5), or history of paracentesis for 
management of ascites.
3. Active venous stasis ulceration on either lower extremity.
4. Has current infection or suspected infection of any SD lesions or infection of the 
lower extremities in the 2 months prior to screening.
5. Has a history of angioedema or anaphylaxis to topical products or known sensitivity 
to any of the components of the study interventions.
6. History of or active suicidal ideation or behavior, or chronic psychiatric abnormality 
that may increase the risk associated with study participation or study intervention 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study.
7. Has a history of cancer or has undergone treatment for any type of cancer within 
5 years (except squamous cell carcinoma, basal cell carcinoma, or carcinoma in situ 
of the skin, curatively treated with cryosurgery or surgical excision only).
8. Has received a solid organ (eg kidney, liver, heart, or lung) transplant.
Prior/Concomitant Therapy 
9. Has received any of the prohibited medications/therapies that may alter the course of 
SD without the required minimum washout period or anticipated concomitant use of 
any of the prohibited medications/therapy (See Section 6.5.1).
10. Had previous treatment or is currently being treated with crisaborole, or other topical 
or systemic PDE-4 inhibitor.
11. Participants on biological drugs (eg dupilumab, etanercept, ustekinumab, 
secukinumab, adalimumab, infliximab) (See Section 6.5.1). 
12. Has a concurrent medical condition which requires use of systemic 
immunosuppressive agent(s) (See Section 6.5.1 for prohibited medications).


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Other Exclusions
13. Has any planned surgical or medical procedure that would interfere with study 
participation or influence study results.
14. Women of child-bearing potential (WOCBP) are not eligible for this study (See 
Appendix 4). 
15. Mini-Mental State Examination-2 (MMSE-2, Brief Version) score of <13 (range 0 to 
16).
16. Has any of the following laboratory abnormalities confirmed at screening: 
Hemoglobin value <9.0 g/dL; Platelet count <100,000/mm³; INR > 3.5; Hemoglobin 
A1C ≥10.0%.
5.3. Lifestyle Considerations
1. Participants should continue to use medically prescribed compression therapies if in 
use prior to screening.  Participants not using compression therapies prior to 
screening should not initiate use of compression therapies during study participation.  
2. For participants using compression therapies:

The HVP will check that the participant is using the correct technique for 
compression therapy application, and if required the correct technique will be 
demonstrated with the participant and documented.

Compression therapies must be removed at least 1 hour prior to acquiring the 
static digital images of the lower extremities.

Compression therapies can be worn any time AFTER the morning study 
intervention application;

Compression therapies should not be worn following the afternoon/evening 
application of study intervention.  Participants may apply a non-occlusive 
dressing (eg roll gauze) to prevent loss of ointment to clothes and bedclothes;

Participants should NOT wear compression therapies overnight.
3. Participants not using compression therapies may apply a non-occlusive dressing (eg 
roll gauze) to prevent loss of ointment to clothes and bedclothes.
4. Participants should continue frequently elevating the legs if done prior to screening.
5. Participants should avoid applying study intervention within 4 hours prior to static 
image collection.
6. Participants must avoid swimming, showering/bathing, or other prolonged contact 
with water within 4 hours after the study intervention application. 
7. Participants must avoid sunbathing or tanning bed use that may interfere with 
assessment of their SD disease activity.
8. Routine preventative immunizations, including Emergency Use Authorized 
vaccinations for COVID-19 as per guidance from the local health authority are 


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permitted during the study; however, it is preferred that immunizations be 
administered at least 28 days before the start or following the completion of the study.
9. Use of sunscreen is permitted, but only on areas without SD involvement.
10. When applying study intervention, the participant will not be required to wear gloves.  
However, they must be instructed to wash their hands with mild soap and water 
before and after each application.  
11. Caregivers should avoid accidental exposure by either avoiding applying the study 
intervention or wearing gloves during its application. 
5.3.1. Meals and Dietary Restrictions
Participants should refrain from consumption of foods to which they have known allergy or 
intolerance.  Dietary restrictions for concurrent medical conditions prior to screening should 
continue to be followed during the study. 
5.3.2. Caffeine, Alcohol, and Tobacco
Participants should refrain from excessive caffeine, alcohol, and tobacco consumption that 
may exacerbate concurrent medical conditions or impair the participant’s ability to comply 
with study procedures.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Participants should be assigned a new participant number for rescreening.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1. Study Intervention(s) Administered
ARM Name
Crisaborole Ointment, 2% BID
Vehicle (ointment) BID
Intervention 
Name
Crisaborole 
Vehicle of Crisaborole
Type 
Small molecule 
Other
Dosage Form
Ointment
Ointment
Dose Strength
2% wt/wt (20 mg/g)
Not applicable
Dosage
BID
BID


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Route of 
Administration
Topical
Topical
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labeling
Study intervention will be 
provided in 60 gram tubes in 
cartons in a blind label fashion.  
Each tube and carton will be 
labeled as required per country 
requirement.
Study Intervention will be 
provided in 60 gram tubes in 
cartons in a blind label fashion. 
Each tube and carton will be 
labeled as required per country 
requirement.
Aliases
PF-06930164 or AN2728
Crisaborole Vehicle
For crisaborole ointment ingredients see the IB.  Vehicle contains the same excipients as 
crisaborole, 2% ointment. 
6.1.1. Administration

Study intervention (also known as study ointment) will be applied to the lower 
extremities only.

An even layer of ointment, targeting 3 mg / cm2, should be applied to the lower 
extremities (knees to feet) twice a day at approximately the same times each day.  

One fingertip unit (FTU) is defined as the amount of topical product that is 
squeezed out from a standard tube onto a fingertip (end of the finger to the first 
crease in the finger).  One FTU is sufficient to cover an area of skin the size of 2 
handprints (2% BSA) of the participant.  A handprint refers to a flat hand with 
fingers in a closed position.  Approximately 5 FTUs would be required to treat the 
skin from knee to ankle and dorsum of foot of 1 leg.  

Further details are supplied in the investigational product (IP) manual. 

Study intervention should be applied to the lower extremities (knees to feet) for 
the entire duration (6 weeks) of the study, even when SD lesions have resolved or 
nearly resolved.

If bilateral lower extremity SD lesions are present prior to Day 1, then both lower 
extremities should be treated for the entire 6-week treatment period; 

If unilateral lower extremity SD lesions are present prior to Day 1, then only the 
SD-affected lower extremity should be treated for the entire 6-week treatment 
period.  If bilateral lower extremity SD lesions are present after Day 1, then both 
lower extremities should be treated to the end of the study (Week 6) from the time 
of the onset. 


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
The two dosing applications should be at least 8 hours apart within each day.  
Avoid applying study intervention within 4 hours prior to static image collection. 

The study intervention handling and dosing instruction and other relevant 
information for participants will be provided by the HVP, who will provide 
instructions and demonstration of study intervention application to participant.  In 
the event that study intervention cannot be applied, HVP may use ointment 
without a pharmacologically active ingredient for demonstration.
6.2. Preparation/Handling/Storage/Accountability

The study intervention will be packaged and labeled with double blind labels.  
Each label will be printed with a random and unique container identification (ID) 
number that is linked to a serialized randomization list.

An interactive response technology (IRT) system will be used for the 
randomization of participants into treatment groups and for study intervention 
assignment. 

The study intervention assignment/dispensing events will be converted to an order 
for direct shipment of the study intervention to the participant.

Study intervention shipped at randomization will be sufficient to treat SD lesions 
through Day 21.  Participants will receive one further study intervention supply 
shipment sufficient to treat SD lesions from Day 22 through Day 43.

Participants will receive instructions on how to report receipt, store, use and 
return the study intervention.  At each scheduled assessment, tubes can be 
reviewed by the RTC or CIG.

A pharmacy service provider will be appointed by the sponsor to support storage 
and shipment of study intervention, documentation of study intervention 
assignment, collection and return of study intervention, and completion of study 
intervention accountability.

See the investigational product manual for more detailed information.
6.3. Measures to Minimize Bias: Randomization and Blinding
Study using IRT
All participants will be centrally assigned to randomized study 
intervention using an Interactive Response (IRT) Technology System.  
Before the study is initiated the log in information & directions for use 
of the IRT will be provided to the Investigator and appropriately 
trained designees.
Study intervention will be dispensed as summarized in Schedule of 
Activities. 


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Returned study intervention should not be re-dispensed to the 
participants.
Blind Break (IRT)
The IRT will be programmed with blind-breaking instructions. In 
case of an emergency, the investigator or sponsor has the sole 
responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always 
be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, the investigator 
should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay 
emergency treatment of the participant.  If a participant’s treatment 
assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind.  The date and reason that the blind 
was broken must be recorded in the source documentation and case 
report form, as applicable.
An IA may be performed during the conduct of the study.  
Participants or study sites will not be unblinded as a result of a 
meeting a futility threshold. 
6.4. Study Intervention Compliance

Participant compliance with study intervention will be assessed by Investigator 
(or designee) review of eDiary responses. 

A participant will be considered compliant with the dosing regimen if they receive 
80% to 120% of the expected number of doses, in accordance with the protocol.
6.5. Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements), vaccine or non-medication therapies that the participant is receiving at 
the time of enrollment or receives during the study must be recorded at all study 
visits/contacts.
All concomitant medications taken during the study must be recorded in study records with 
indication, reference to any associated adverse event, dose, and start and stop dates of 
administration.
The Pfizer Medical Monitor should be consulted if there are any questions regarding 
concomitant or prior therapy for SD prior to determining participant eligibility.
6.5.1. Medications Prohibited Prior to Randomization
Classes of medications and non-medication therapies that may alter the course of SD and for 
which washout is required prior to randomization are listed below.  If a participant requires a 


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washout, the investigator/designee will provide instructions on discontinuing the prohibited 
medication(s) or non-medication therapy at the screening visit.
Medications Prohibited 12 weeks or 5 half-lives (whichever is longer) Prior to 
Randomization

Biological drugs (e.g., dupilumab, etanercept, ustekinumab, secukinumab, 
adalimumab, infliximab) used primarily for immunosuppressant or 
immunomodulation to treat a pre-existing chronic inflammatory disease.
Medications/Therapies Prohibited 28 Days Prior to Randomization

Use of systemic (oral, parenteral) corticosteroids.
Note: Participants on stable use (regular regimen) of intranasal/inhaled/ophthalmic 
corticosteroids for at least 14 days of intranasal/inhaled/ophthalmic corticosteroids 
with ≥14 days of consistent use prior to randomization are permitted to continue use 
of intranasal/inhaled/ophthalmic corticosteroids but must not alter or stop their 
regimen during the study.

Use of systemic immunosuppressive agents, including but not limited to 
methotrexate, cyclosporine, tacrolimus, Janus kinase (JAK) inhibitors (eg 
tofacitinib), azathioprine, 6 mercaptopurine, cyclophosphamide, chlorambucil, 
rituximab, antilymphocyte globulin, hydroxychloroquine, or mycophenolate 
mofetil (MMF).
Medications Prohibited 14 Days Prior to Randomization

Use of oral or parenteral antibiotics for SD.

Use of topical corticosteroids (TCS) or topical calcineurin inhibitor (TCI) 
anywhere on the body.

Use of topical antihistamines anywhere on the body.
Medications Prohibited 7 Days Prior to Randomization

Use of topical antibacterial medications or products, including soaps, bleach 
baths, or topical sodium hypochlorite-based products anywhere on the body

Escalating, decreasing, or as-needed (PRN) use of topical or systemic 
antihistamines.
Note: Participants on stable dose of oral antihistamines (sedating or non-sedating) for at least 
7 days of consistent use prior to randomization are permitted to continue use of oral 
antihistamines with minimum alteration of dose/regimen during the study.


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Medications Prohibited 1 Day Prior to Randomization

Use of non-medicated emollients (NOTE: can be used on other regions of body, 
except on lower extremities).
6.5.2. Medications/Therapies Prohibited During the Study
Classes of medications and non-medication therapies that may alter the SD disease course are 
prohibited during the study from Day 1 through to the end-of-treatment.

Biological drugs (eg, dupilumab, etanercept, ustekinumab, secukinumab, 
adalimumab, infliximab) used primarily for immunosuppressant or 
immunomodulation to treat a pre-existing chronic inflammatory disease.

Use of systemic (oral, parenteral) corticosteroids, unless on stable 
intranasal/inhaled/ophthalmic regimen (see note in Section 6.5.1).

Use of TCS or TCI anywhere on the body.

Use of systemic immunosuppressive agents, including but not limited to 
methotrexate, cyclosporine, tacrolimus, JAK inhibitors (eg tofacitinib), 
azathioprine, 6-mercaptopurine, cyclophosphamide, chlorambucil, rituximab, 
antilymphocyte globulin hydroxychloroquine, or MMF.

Use of systemic (sedating or non-sedating) antihistamines, unless on stable 
regimen (see note in Section 6.5.1).

Use of any other PDE-4 inhibitor (topical, oral, or parenteral).

Use of oral or parenteral antibiotics for treatment of infection of SD lesion(s).
Note: Short courses (≤14 days) of systemic antibiotics may be given during the study 
if clinically necessary for the treatment of new onset infections.

Use of topical antibacterial medications or products, including soaps, bleach 
baths, or topical sodium hypochlorite-based products on the lower extremities.

Use of bland (non-medicated) emollients, moisturizers or sunscreen on SD 
lesions.

Participation in another drug or device research study.
6.5.3. Medications/Therapies Allowed During the Study
Classes of medications/therapies that are allowed during the study are recorded as 
concomitant medications/therapies on eCRF.  Participants on certain stable regimens should 
minimize alteration of the stable regimen during the study.  Any changes in stable dosages 


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and/or regimens should be recorded on eCRF.  The permitted medications/therapies are 
summarized below:

Stable regimen of non-medicated emollient(s) is permitted during the study to 
manage dry skin outside of the SD-treated areas.Stable regimen of 
intranasal/inhaled/ophthalmic corticosteroids;

Stable regimen of oral (sedating or non-sedating) antihistamine;

Short courses (14 days) of oral or parenteral antibiotics if clinically indicated in 
the judgment of the investigator for the treatment of new onset infections (dermal 
or non-dermal) not involving SD treatment sites.

Nonsteroidal anti-inflammatory drugs (NSAIDs), eg, Ibuprofen;

Concomitant medications for other chronic medical conditions are permitted 
during the study unless specifically prohibited by the protocol.

For management of peripheral edema and antecedent co-morbidities, permitted 
concomitant medications and treatments include the following if regimen has 
been stable for at least 2 weeks prior to screening:

Use of compression therapies;

Oral diuretic(s) for management of peripheral edema and/or ascites;

Inotropic or chronotropic medications for congestive heart failure; 

Oral or subcutaneous anticoagulants (eg warfarin, rivaroxaban, dabigatran, 
apixaban, enoxaparin) for prior DVT,

Use of a continuous positive airway pressure (CPAP) device;

Use of appetite suppressants; 

Dietary regimen for weight loss;

Oral corticosteroids (no more than prednisone (or equivalent) 15 mg daily) for 
treatment of chronic non-dermatologic medical condition (eg, COPD, rheumatoid 
arthritis, nephrotic syndrome, vasculitides, cardiomyopathy).
6.5.4. Rescue Medicine
No rescue medications (eg, corticosteroids, calcineurin inhibitors, or other PDE4 inhibitors) 
are permitted for SD during treatment with study intervention.


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In the event of worsening SD, the Investigator may determine that an unplanned safety visit 
(telemedicine assessment or face-to-face assessment (by HVP or a local HCP) is indicated.
6.6. Dose Modification
Dose Modification is not permitted in this study.  Study intervention must be applied BID at 
the targeted application rate (approximately 3 mg/cm2).
6.7. Intervention after the End of the Study
There is no intervention required by the protocol following the end of study.  Participants 
should resume their usual medical care.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
At the discretion of the Investigator, study intervention may be temporarily or permanently 
discontinued.  In the event of a participant being hospitalized for management of a chronic 
medical condition, study intervention must be permanently withdrawn.
If an IA (described in Section 9.4) is performed and the IRC recommends ending the study 
because of futility, participants in the screening phase may be discontinued from the study
based on sponsor decision.  If a futility threshold is crossed based on the IA results, 
participants may be withdrawn from study treatment, complete an early termination visit, and 
complete the study follow-up phase. 
Participants may be discontinued due to study termination (as described in Section 10.1.9).
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a patient to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant should 
continue to complete all scheduled assessments at the EOT visit and complete the follow-up 
phase of the study.  
Note that discontinuation of study intervention does not represent withdrawal from the study.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the 
investigator or qualified designee will determine if the participant can continue in the study 
and if any change in participant management is needed.  This review of the ECG printed at 
the time of collection must be documented. Any new clinically relevant finding should be 
reported as an AE. Discontinuation of study intervention for abnormal liver function should 
be considered by the investigator when a participant meets one of the conditions outlined in 
Appendix 5 or if the investigator believes that it is in best interest of the participant.
If signs and symptoms of hypersensitivity are attributable to the study intervention, including 
contact urticaria, it must be discontinued immediately, and appropriate therapy initiated.


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If skin ulcer(s) develop in any of the SD treatment areas, then study intervention must be 
permanently discontinued.  If skin ulcer (s) develop in any of the untreated areas (including 
an untreated leg in the case of unilateral disease), study medication may continue at the 
discretion of the investigator.  
If an unscheduled ECG is necessary after randomization to evaluate an AE, discontinuation 
of study ointment should be considered if the QTcF interval on the unscheduled ECG is >
481 msec or if there is an increase in the QTcF interval of > 60 msec in comparison to the 
QTcF interval on the ECG completed during screening. This review of the 
electrocardiogram (ECG) at the time of collection must be documented.  Any new clinically 
relevant finding should be reported as an AE.  
See the Schedule of Activities (SoA) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.1. Temporary Discontinuation
Participants who experience medical conditions that require treatment (not prohibited 
concomitant medications) may have their study intervention temporarily discontinued for 
<6 days after consultation with the Pfizer medical monitor.  Temporary discontinuation of 
study intervention should be recorded in the eCRF.
7.2. Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.  This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the Schedule of Activities.  See Schedule of 
Activities for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the study 
records and notify the sponsor accordingly.

When a participant withdraws from the study because of an SAE, the SAE must be 
recorded on the CRF and reported on the CT SAE Report.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to complete a 
scheduled telemedicine visits and is unable to be contacted by the study site.


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The following actions must be taken if a participant fails to complete a required telemedicine 
visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
In addition to the 3 scheduled HVP home visits, assessments will be conducted by the 
Central Investigator Group (CIG) and Remote Trial Coordinator (RTC) through telemedicine 
(videoconferencing for the purposes of this study) interviews with the participant.  The first 
telemedicine interview will occur at randomization (Section 1.3.1). A telephone only 
interview is permitted in the event of technical difficulties which preclude video component.
During the intervention period, telemedicine interviews with the participant will be 
conducted by the RTC; the CIG may attend if requested by the RTC or if the Investigator 
chooses to attend.
End of treatment (EOT) home visit (Week 6 or Early Termination) will be conducted by the 
HVP.  In addition, telemedicine interviews may be conducted by the  CIG with the 
participant (see Schedule of Activities) if adverse event(s) assessment is indicated in the 
judgment of the investigator.  
Further specifications for study assessments and procedures include:

The CIG and RTCs will perform all the rater assessments except for the scoring of 
TSS, ISGA, and lesional %BSA which will be performed by the HVP (in-person 
assessment at screening visit, training visit, Week 6 or early termination visit, and 
unplanned safety assessment) and by a Central Reader (at scheduled weekly digital 
image acquisition timepoints and at unplanned telemedicine visits [if any]).  See 
Appendix 6 for information on VRCT.

Study procedures and their timing are summarized in the Schedule of Activities. 
Protocol waivers or exemptions are not allowed.


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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Unplanned safety assessments may be conducted during the study using telemedicine 
interviewing to assess any ongoing or new onset safety events.  The CIG will be 
present for any unplanned safety telemedicine interview.  If an AE is suspected or 
determined to have occurred, then the CIG can recommend in person clinical 
evaluation by an HVP or referral to the participant’s local HCP or subspecialist if 
warranted in the clinical judgement of the CIG.  If a determination is made that the 
participant’s medical condition warrants urgent evaluation, then the/ participant may 
be directed to urgent care or emergency department evaluation.

Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the Schedule of Activities.

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
25 mL.  Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
8.1. Efficacy Assessments
In-Person Assessments by HVP
Primary efficacy assessments of the TSS, ISGA, and lesional %BSA will be completed in 
person by the HVP at all home visits (Screening visit, Training visit, Week 6 or Early 
Termination visit, and Unplanned Safety assessments [if any]).  
Remote Assessments by Central Reader
Efficacy assessments of the TSS, ISGA, and lesional %BSA will be completed by Central 
Readers remote review of static digital images acquired by participants trained to use the 
device and imaging accessories provided by the sponsor.  Training will be provided to 
participants by the HVP to support standardized static digital image acquisition at protocol-
specified timepoints outlined in the Schedule of Activities.


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A Central Reader is an appropriately qualified and trained expert dermatologist.  
(Section 8.1.3)
8.1.1. Rater Qualifications
For specific rating assessments (TSS, ISGA, %BSA, and MMSE), only qualified raters will 
be allowed to evaluate and/or rate participants in this study.  The minimum qualifications a 
rater must meet for each study rating assessment will be provided to the site.   The rater must 
become certified to perform selected study assessments before he or she can participate in the 
conduct of the study.  For specifically defined assessments, rater training will be conducted, 
and written documentation will be provided by the sponsor or designee for each rater’s 
certification.  In return, each site will be provided written documentation outlining each 
rater’s certification for specific study assessments.    The raters who administer specific study 
assessments will be documented in a centralized location and all site staff who administer 
ratings will be verified in the site study documentation during the conduct of the study.
8.1.2. Assessments of Stasis Dermatitis Lesions on the Lower Extremities
8.1.2.1. In-person Assessments by HVP
At each home visit, in-person physical examination and assessments will be performed only 
by a medically-qualified HVP with clinical experience conducting physical examination, 
including assessment of the skin.  Prior to conducting home visits and completing in-person 
assessments of TSS, ISGA, and lesional %BSA, HVP rater training and standardization 
exercises and written and signed documentation will be provided by the CIG confirming each 
HVP’s certification.  
8.1.2.2. Static Digital Imaging Assessments by Central Reader 
High-resolution, static, digital images of the participant’s lower extremities (anterior, 
posterior, medial, and lateral aspects) will be obtained by the participant at times  defined in 
the Schedule of Activities using only sponsor-provisioned digital imaging equipment and the 
study-specific Photo Studio.  The provisioned digital imaging device and the Photo Studio 
and instructions for use are provided to each participant.  
 
 
 At the training visit, the 
HVP will train the participant in the intended use of the digital imaging equipment and set-up 
of the Photo Studio.  Participants will be instructed how to save and transfer the requisite 
static digital images for quality control (QC).  Digital images will be subsequently provided 
to a blinded Central Reader for remote assessments of the TSS, ISGA, and lesional %BSA 
(see Section 8.1.3)
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In-person and remote assessments of SD severity may be impacted by variation in time of 
study intervention application, frequency and duration of compression therapy use, the time 
and day of assessment, the presence of study ointment, and presence of debris on the skin of 
the lower extremities.  Each participant will be instructed to:

Cleanse the skin of the lower extremities using warm water and soap to remove any 
remaining study ointment and debris prior to digital images acquisition;

Gently dry the skin of the lower extremities after cleansing and prior to digital 
images acquisition;

Consistently apply study intervention at a similar time each morning and each 
evening;

Avoid applying study intervention within 4 hours prior to static image collection.

Acquire weekly static digital images on the same day of the week (±2 days) at 
approximately the same time of day each week. 
8.1.2.3. Management of Incidental Findings by the Investigator
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study 
but is unrelated to the purpose and beyond the aims of the study.
The investigator (dermatologist) must perform medical review of all available lower 
extremity static, digital images  for incidental findings (eg skin ulcer formation, skin cancer, 
cellulitis) via the central imaging repository.  .  If an unexpected observation is identified, 
and this finding could, in the opinion of the investigator, have a significant health 
consequence, this finding may be shared by the investigator with the study participant.  All 
follow-up testing and final diagnosis will be left to the discretion of the medical professionals 
at the site or those with an existing physician-patient relationship.  The investigator will be 
responsible for identifying and reporting any AEs from incidental findings as described in the 
Adverse Event Reporting section.  
8.1.3. Standardized Static SD Lesion Images: Acquisition, Save and Transfer
At protocol-specified time points, the participant will acquire static digital images of the 
lower extremities using sponsor-provisioned digital imaging equipment.  Images will 
automatically be saved and transferred to the central digital imaging repository.  Following 
QC checks, images will be available for review by a Central Reader via a customized read 
portal.  A Central Reader will assess TSS, ISGA, and lesional %BSA according to the 
Central Reader’s Charter.  


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Participant Training by the Home Visit Practitioner 
To promote consistent image acquisition, the participant must:
•
Complete training for how to set up the digital imaging equipment and Photo Studio 
in the home;
•
Successfully acquire, save, and transfer digital images for initial QC checks.  
If it is determined that digital images are not of sufficient quality to remotely assess TSS, 
ISGA, and lesional %BSA, then the HVP can return to the participant’s home to re-instruct 
the participant how to acquire requisite digital images.
8.1.4. Clinician Reported Outcomes
At all home visits, TSS, ISGA, and lesional %BSA assessments will be assessed in-person by 
the HVP.  In addition, the TSS, ISGA, and lesional %BSA will be remotely assessed by an 
expert dermatologist Central Reader reviewing digital imaging of the lower extremities 
acquired by the participant.  At unplanned safety assessments these TSS, ISGA, and lesional 
%BSA are performed only if relevant to the safety event.  
8.1.4.1. Total Sign Score
The TSS is an assessment of the severity of SD skin lesions.  Each of the 4 clinical signs 
(erythema, papulation/elevation [excluding papulation due to lipodermatosclerosis or 
varicose veins], superficial erosion/denudation, and scaling) across all the treatable SD 
lesions will be rated using the 4-point severity scale (ranging from 0 to 3 points).  The four 
sub scores are summed to create the TSS, 13-point scale; ranging from 0 to 12 points, with a 
higher score representing a higher disease severity.
8.1.4.2. Investigator’s Static Global Assessment (ISGA)
The ISGA is a 5-point scale (range 0-4), with a higher score representing a higher disease 
severity.  ISGA is a global assessment of severity of all treatable SD lesions based on 
erythema, papulation/elevation, superficial erosion/denudation, and scaling.  The assessment 
will be a static evaluation without regard to the score at a previous visit.
8.1.4.3. Stasis Dermatitis Lesional % BSA
Assessment of lesional %BSA skin areas of all treatable SD lesions will be performed by the 
handprint method, where the full palmar hand of the participant (ie, the participant’s fully 
extended palm, fingers and thumb together) represents approximately 1% of BSA.  For 
example, if all lesions added up are equivalent to 4 handprints, then the SD lesional %BSA is 
4%.
 
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8.2. Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities.
8.2.1. Medical History
Medical history includes diagnosis and disease duration, intolerance/allergy to any drug or 
food, and history of any significant alcohol, tobacco, controlled substance use. 
Complete SD disease history includes SD diagnosis, the use of topical treatments, systemic 
treatments and other treatments for SD (eg compression stocking use) used within the last 
3 months, including reason for SD treatment discontinuation. 
Medication history includes all prescription or non-prescription drugs, and dietary and herbal 
supplements taken within 28 days prior to the planned first dose.
8.2.2. Physical Examinations
•
A complete physical examination by the HVP will include, at a minimum, 
assessments of general appearance, skin (includes SD areas and non-SD areas), head, 
ears, eyes, nose, throat, mouth, heart, lung, lymph nodes, extremities, abdomen, and 
neurological function. In addition, an assessment will be made of the condition of all 
SD-involved skin.  Examination will not include anogenital region or female breasts.
•
Height and weight will be measured and recorded by the HVP during the home 
visit.  
•
Complete physical examinations should be performed at any unplanned safety 
assessment.
•
Application site (skin) examination, from knee to ankle and dorsum of foot, should 
be performed at all home visits.
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8.2.3. Vital Signs

Temperature, pulse rate, and blood pressure will be assessed.  In the event of an 
adverse event, temperature, blood pressure and pulse rate will be assessed at any 
additional safety visits.

Blood pressure and pulse measurements will be assessed in the sitting position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones).  Participants should refrain from smoking or ingesting caffeine 30 minutes 
before the measurements.
8.2.4. Electrocardiograms

An ECG will be obtained as outlined in the Schedule of Activities to electronically 
calculate the heart rate and measures PR, QRS, QT, QTcF intervals. Refer to 
Section 7.1 for QTcF withdrawal criteria and any additional QTc readings that may be 
necessary.

If the QTcF interval on the screening ECG is > 481 msec, the clinical significance of 
the ECG results should be considered relative to other physical exam findings and 
medical conditions that may exclude the participant from the study.   

ECG may be repeated at unplanned safety assessment at the discretion of the 
investigator.
8.2.5. Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA
for the timing and frequency.

During the pre-randomization period, the investigator must review the results of 
planned laboratory testing to confirm study eligibility and document this review (see 
Appendix 2).  If any unplanned laboratory testing is performed after randomization, it 
should be completed at a local laboratory, then investigator must review the 
laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF.  The laboratory reports must 
be filed with the source documents.  Clinically significant abnormal laboratory 
findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.


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
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of 
Activities.
8.2.6. Mini-Mental State Examination 2nd Edition (MMSE-2, Brief Version)
Prior to randomization, the Mini Mental-State Examination-2 (MMSE-2, Brief Version) will 
be administered to each participant.  The original MMSE is one of the most widely used brief 
screening instruments for cognitive impairment.  It has been used in a variety of settings, 
including screening individual patients, tracking progress over time, screening for large 
populations, and clinical trials.32  The MMSE-2 Brief Version has been determined to be 
adequate for screening large populations and screening individuals in practice who have not 
been referred because of cognitive complaints.32   Participants with a score of <13 (range 0 to 
16) will be excluded from the study.
8.2.7. Fitzpatrick Skin Type Assessment
At the screening home visit, the Fitzpatrick skin-type is documented for each participant.  
Skin Type I-VI will be determined by the HVP at the screening visit.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE, or that caused the participant to discontinue 
the study intervention/study (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
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For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Follow up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AE or SAE after the participant has concluded
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study, and he/she considers the event to be 
reasonably related to the study intervention, the investigator must promptly report the SAE to 
Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the clinical trials (CT) SAE Report Form immediately and under no circumstance 
should this exceed 24 hours, as indicated in Appendix 3.  The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to study 
intervention must be reported to Pfizer Safety.
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.


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8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until the 
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
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding in female participants and female partners of 
male participants must be reported, irrespective of the presence of an associated SAE, to 
Pfizer Safety within 24 hours of the investigator’s awareness, using the CT SAE Report 
Form.  An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use.  However, if the infant experiences an SAE associated with such a drug’s 
administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on an eCRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Adverse Events of Special Interest
Not Applicable
8.3.6.1. Lack of Efficacy
The term “lack of efficacy” is incongruous in the clinical trial setting with pre-approval 
products or marketed products used in a non-approved indication, because the effectiveness 
of the product has not been demonstrated.  Lack of efficacy for a pre-approval product or for 
a marketed product used in a non-approved indication is reportable only if associated with an 
SAE.
8.3.7. Medical Device Deficiencies
Not Applicable
8.3.8. Medication Errors
Medication errors may result from the administration of the study intervention by the wrong 
participant, or at the wrong time, or at the wrong dosage strength, or to areas that have not 
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Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the eCRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the eCRF and, 
if applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of 
the eCRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
Overdose following topical administration is unlikely.  If too much study intervention has 
been applied, the excess can be wiped off.
In the event of an overdose, the investigator/designee should:
1. Contact the Medical Monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of crisaborole (whichever is 
longer).  
3. Obtain a plasma sample for pharmacokinetic (PK) analysis within 5 days from the date of 
the last dose of study intervention if requested by the Medical Monitor (determined on a 
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4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
5. Overdose is reportable to Safety only when associated with an SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.7. Genetics 
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
Banked Biospecimens for Genetics will not be collected in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Medical Resource Utilization and Health Economics
Medical resource utilization and health economics parameters are not evaluated in this study.
9. STATISTICAL CONSIDERATIONS
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
Only discontinuation of study intervention will be considered as an intercurrent event.
9.1.1.1. Primary Estimand/Co-Primary Estimands
Estimand 1: The primary estimand of this study is a while-on-treatment estimand, which 
estimates the treatment effect of crisaborole compare with vehicle at Week 6 /EOT.  It 
includes the following 5 attributes: 

Population: participants ≥45 years of age with SD without active skin ulceration;

Variable: non-longitudinal endpoints at Week 6/EOT;

Treatment condition: crisaborole 2% BID or vehicle;


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•
Intercurrent event: all data after an intercurrent event of discontinuation of study 
intervention will be excluded, data at Week 6/EOT will be included;
•
Population-level summary: difference in LSM for continuous endpoints and 
difference in proportion of participants with response for binary endpoints at 
Week 6/EOT between crisaborole ointment, 2%, BID and vehicle.
Estimand 1 will be used in analyzing the primary endpoint and it will also be used to analyze 
non-longitudinal continuous secondary endpoints %BSA in-person assessment 
 
 and non-longitudinal binary endpoints ISGA success and 
ISGA clear/almost clear in-person assessment.
9.1.1.2. Secondary Estimands
Estimand 2: The second estimand of this study is a composite estimand, which estimates the 
treatment effect of crisaborole compared with vehicle at each time point.  It includes the 
following 5 attributes: 
•
Population: participants ≥45 years of age with SD without active skin ulceration;
•
Variable: binary response endpoint per photography assessment, eg, response defined 
as a participant with an ISGA score of Clear (0) or Almost Clear (1) with at least a 
2-grade improvement from baseline at each time point; a participant after an 
intercurrent event of discontinuation of study intervention will be considered a 
non-responder for the visit of interest;
•
Treatment condition: crisaborole 2% BID or vehicle;
•
Intercurrent event: there will be no intercurrent event since the discontinuation of 
study intervention is part of the variable definition;
•
Population-level summary: difference in proportion of participants with response at 
each time point between crisaborole ointment, 2%, BID and vehicle.
Estimand 2 will be used in analyzing all applicable longitudinal secondary binary 
endpoints.Estimand 3: The third estimand of this study is  a hypothetical estimand, which 
estimates the treatment effect of crisaborole compared with vehicle at each time point under 
the scenario of no discontinuation of study intervention.  It includes the following 
5 attributes: 
•
Population: participants ≥45 years of age with SD without active skin ulceration;
•
Variable: percent change from baseline in TSS at each time point;
•
Treatment condition: crisaborole 2% BID or vehicle;
•
Intercurrent event: all data after any intercurrent events will be excluded;
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
Population-level summary: difference in mean percent change from baseline in TSS 
at each time point between crisaborole ointment, 2%, BID and vehicle.
Estimand 3 will be used in analyzing the longitudinal continuous endpoints.
9.1.2. Multiplicity Adjustment
There is no multiplicity adjustment.
9.2. Sample Size Determination
The primary efficacy analysis is to compare the mean difference in percent change from 
baseline in TSS at Week 6 of crisaborole ointment, 2%, BID versus vehicle based on HVP 
home visit in person assessment.  A sample size of  35 participants per treatment group will 
yield at least 80% power to detect a difference between crisaborole ointment, 2%, BID and 
vehicle at a one-sided significance level of 5%, assuming a mean difference of at least 22% 
and a common standard deviation of no more than 35% based upon clinical trial data of 
crisaborole in AD participants. 
9.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Participant Analysis Set
Description
Screened 
All participants who sign the ICF.
Enrolled
All participants who sign the ICF and are not screen failure.
Randomly Assigned to Study 
Intervention
All participants who are randomized.
Full Analysis Set (FAS)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention.  Participants will be analyzed 
according to the intervention they are randomized.  
Safety Analysis Set (SAF)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention. Participants will be analyzed 
according to the intervention they actually received.
Full Analysis Set-Interim 
Analysis (FAS-IA)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention and complete 6 weeks treatment or 
early discontinue study intervention at the IA cutoff date.  Participants will 
be analyzed according to the intervention they are randomized.  
Safety Analysis Set-Interim 
Analysis (SAF-IA)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention and complete 6 weeks treatment or 
early discontinue study intervention at the IA cutoff date. Participants will 
be analyzed according to the intervention they actually received.
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the participant populations to be included in the analyses, and procedures for 


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accounting for missing, unused, and spurious data.  This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.
9.4.1. General Considerations
In general, number, percent and 90% CI will be presented for binary endpoints.  Descriptive 
summary statistics (n, Mean, Standard deviation, Median, Min., Max.) will be presented for 
continuous endpoints.  In addition, graphics may be used to present the data.
Day 1 will be the date when a participant applies the first dose of study intervention. Baseline 
value will be the last non-missing assessment on or before Day 1 and prior to first dose of 
study intervention.
 
9.4.1.1. Analyses for Binary Endpoints
For binary endpoint at each time point, large sample approximation to the difference in 
binominal proportions will be used for testing (Normal Z-test) the superiority of crisaborole 
ointment, 2%, BID to vehicle and for forming 90% CI’s and calculating p-values (one-sided).  
9.4.1.2. Analyses for Continuous Endpoints
The non-longitudinal continuous data will be analyzed by ANOVA with treatment as the 
factor. ANCOVA will be used if relevant baseline value and/or other factors are included as 
covariates. Comparison of crisaborole ointment, 2%, BID to vehicle (providing LSM of the 
treatments, LSM of the treatment difference, one-sided p-value and 90% CI) will be 
generated.
The longitudinal continuous data will be analyzed using MMRM with fixed effects of
treatment group, visit, and treatment-group by visit interaction, without imputation for 
missing values. If the endpoint is change from baseline, baseline will be included in the 
model as a covariate. A common unstructured variance-covariance matrix will be used, 
provided it converges. If this is a convergence issue, other type of covariance matrix such as 
first order autoregressive, compound symmetry will be used.  Comparison of crisaborole 
ointment, 2%, BID to vehicle (providing LSM of the treatments, LSM of the treatment 
difference, one-sided p-value and 90% CI) at each time point during the first 6 weeks will be 
generated using this model.  
9.4.1.3. Analyses for Categorical Endpoints
The frequency and percentage for each category will be presented for category endpoints.
9.4.2. Primary Endpoint/Estimand Analyses
Percent change from baseline in TSS at Week 6/EOT based on HVP in person assessments 
(primary analysis)will be analyzed using an ANOVA model that includes treatment group as 
a factor (see Section 9.4.1.2). . The primary analysis of the primary endpoint will be based 
on Estimand 1 using FAS.
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Some supportive/sensitivity analyses and subgroup analyses may be performed for the 
primary endpoint. Detail will be given in the SAP. 
9.4.3. Secondary Endpoints/Estimands Analysis
Percentage change from baseline in %BSA at Week 6/EOT based on in-person assessment 
will be analyzed using an ANOVA model that includes treatment group as a factor (see 
Section 9.4.1.2) based on Estimand 1 using FAS.
Achievement of an ISGA success and ISGA clear/almost clear at Week 6/EOT based on in-
person assessment will be analyzed using the method described in Section 9.4.1.1 using 
Estimand 1 and FAS.
Percent change from baseline in TSS and %BSA based on Central Readers assessments will 
be analyzed using MMRM as described in Section 9.4.1.2. Missing data are assumed MAR. 
Under MAR assumption, MMRM will yield unbiased estimates and valid inferences for 
treatment effects assuming all participants maintain therapy.This analysis will be based on 
Estimand 3 using FAS.
Achievement of an ISGA success and ISGA clear/almost clear by time point based on 
Central Readers assessments will be analyzed using the method described in Section 9.4.1.1
Observations after the discontinuation of study intervention or missing values for any reason 
will be handled by setting the endpoint to nonresponsive. Note that this is a composite 
endpoint in the sense that a response requires the participant completes a visit of interest eg, 
Week 6, and achieves a response per the defined response criteria (otherwise it is considered 
a nonresponse).  This method of handling missing response is known as missing response as 
non-response (MR-NR). The analysis will be based on Estimand 2 using FAS.
9.4.5. Safety Analyses
All the safety data will be summarized descriptively through appropriate data tabulations,
descriptive statistics, and graphical presentations.  All safety analyses will be performed on 
the safety population as previously defined.
Endpoint
Statistical Analysis Methods
Secondary
Safety Population, Descriptive statistics.
9.5. Interim Analyses 
An IA may be performed to assess efficacy and safety after approximately 50 participants 
complete 6 weeks treatment or early discontinue study intervention. If an IA is performed, IA 
results will be used for decisions regarding stopping for futility and planning for future 
studies. There is no efficacy claim and no sample size adjustment based on the IA results. 
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Participants may be discontinued from the study as a result of the IA, as described in 
Section 7.
This is an administrative interim analysis; no adjustment of p-values is planned for the 
analysis of the final study data.
Before the IA is performed, the details of the objectives, decision criteria, dissemination plan, 
and method of maintaining the study blind as per Pfizer’s SOPs will be documented and 
approved in an IRC charter. In addition, the analysis details will be documented and 
approved in a SAP. The results of the IA will not be shared with the study team, sites, or 
participants during the conduct of the study, except in a situation where the IRC recommends 
early termination of the study.
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations, including applicable privacy laws.

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
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
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 code of federal regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations

In the event of any prohibition or restriction imposed (ie, clinical hold) by an 
applicable regulatory authority in any area of the world, or if the investigator is aware 
of any new information that might influence the evaluation of the benefits and risks of 
the study intervention, Pfizer should be informed immediately.

In addition, the investigator will inform Pfizer immediately of any urgent safety 
measures taken by the investigator to protect the study participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center.

The investigator must ensure that each study participant is fully informed about the 
nature and objectives of the study, the sharing of data related to the study and possible 
risks associated with participation, including the risks associated with the processing 
of the participant’s personal data.  The participant must be informed that his/her 
personal study-related data will be used by the sponsor in accordance with local data 
protection law.  The level of disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
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
The investigator further must ensure that each study participant is fully informed 
about his or her right to access and correct his or her personal data and to withdraw 
consent for the processing of his or her personal data.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
10.1.4. Data Protection

All parties will comply with all applicable laws, including laws regarding the 
implementation of organizational and technical measures to ensure protection of 
participant data.

Participants’ personal data will be stored at the study site in encrypted electronic or 
paper form and will be password protected or secured in a locked room to ensure that 
only authorized study staff have access.  The study site will implement appropriate 
technical and organizational measures to ensure that the personal data can be 
recovered in the event of disaster.  In the event of a potential personal data breach, the 
study site shall be responsible for determining whether a personal data breach has in 
fact occurred and, if so, providing breach notifications as required by law.

To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical 
code.  Any participant records or datasets that are transferred to the sponsor will 
contain the numerical code; participant names will not be transferred.  All other 
identifiable data transferred to the sponsor will be identified by this single, 
participant-specific code.  The study site will maintain a confidential list of 
participants who participated in the study, linking each participant’s numerical code 
to his or her actual identity. In case of data transfer, the sponsor will protect the 
confidentiality of participants’ personal data consistent with the Clinical Study 
Agreement and applicable privacy laws.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee (DMC)
If an IA is performed, the IRC will be responsible for review of the IA and recommendation 
on any changes to study conduct based on the results of the IA according to the IRC 


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Charter. Safety data and efficacy results will be reviewed by the IRC during study conduct if 
an IA is performed. The recommendations made by the IRC will be forwarded to the 
appropriate authorized Pfizer personnel for review and final decision. Pfizer will 
communicate such decisions, which may include summaries safety data, to regulatory 
authorities, investigators, as appropriate. 
This study will not use an external DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial United States (US) Basic Results on www.clinicaltrials.gov for 
Pfizer-sponsored interventional studies (conducted in patients) that evaluate the safety and/or 
efficacy of a product, regardless of the geographical location in which the study is conducted.  
US Basic Results are generally submitted for posting within 1 year of the primary completion 
date (PCD) for studies in adult populations or within 6 months of the PCD for studies in 
pediatric populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (Clinical Study Report [CSR] synopses in which any 
data that could be used to identify individual participants have been removed) on 
www.pfizer.com for Pfizer-sponsored interventional studies at the same time the US Basic 
Results document is posted to www.clinicaltrials.gov.


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Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website. Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample eCRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  
Policy 0070 applies to new marketing authorization applications submitted via the 
centralized procedure since 01 January 2015 and applications for line extensions and for new 
indications submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data).  The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.

The investigator must ensure that the CRFs are securely stored at the study site in 
encrypted electronic or paper form and are password protected or secured in a locked 
room to prevent access by unauthorized third parties.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
This verification may also occur after study completion.  It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits 
and possible audits or inspections and that sufficient time is devoted to the process.

Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical 


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Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or on-
site monitoring) are provided in the clinical monitoring plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period.  No records 
may be destroyed during the retention period without the written approval of the 
sponsor.  No records may be transferred to another location or party without written 
notification to the sponsor.  The investigator must ensure that the records continue to 
be stored securely for so long as they are maintained.

When participant data are to be deleted, the investigator will ensure that all copies of 
such data are promptly and irrevocably deleted from all systems.

The investigator(s) will notify sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will 
cooperate with sponsor or its agents to prepare the investigator site for the inspection 
and will allow sponsor or its agent, whenever feasible, to be present during the 
inspection.  The investigator site and investigator will promptly resolve any 
discrepancies that are identified between the study data and the participant's medical 
records.  The investigator will promptly provide copies of the inspection findings to 
sponsor or its agent.  Before response submission to the regulatory authorities, the 
investigator will provide sponsor or its agents with an opportunity to review and 
comment on responses to any such findings.
10.1.8. Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.


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
Definition of what constitutes source data can be found in the clinical monitoring 
plan.
10.1.9. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to contract 
research organization (CRO) if requested to do so by the responsible IRB/IEC or if such 
termination is required to protect the health of Study Participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol the contract will control as to termination rights.
10.1.10. Publication Policy

The results of this study may be published or presented at scientific meetings by the 
Investigator after publication of the overall study results or one year after end of the 
study (or study termination), whichever comes first. 

The investigator agrees to refer to the primary publication in any subsequent 
publications such as secondary manuscripts and submit all manuscripts or abstracts to 
the sponsor 30 days before submission.  This allows the sponsor to protect proprietary 
information and to provide comments and the Investigator will, on request, remove 
any previously undisclosed confidential information before disclosure, except for any 
study- or Pfizer intervention-related information necessary to the appropriate 
scientific presentation or understanding of the study results.

For all publications relating to the study, the Investigator will comply with recognized 
ethical standards concerning publications and authorship, including those established 
by the International Committee of Medical Journal Editors.

The sponsor will comply with the requirements for publication of the overall study 
results covering all Investigator sites.  In accordance with standard editorial and 
ethical practice, the sponsor will support publication of multicenter studies only in 


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their entirety and not as individual site data.  In this case, a coordinating investigator 
will be designated by mutual agreement.

Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors 
authorship requirements.

If publication is addressed in the clinical study agreement, the publication policy set 
out in this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study portal. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and study intervention identifiers, participant study 
numbers, contact information for the investigator site, and contact details for a contact center 
in the event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  For sites other than 
a Pfizer Clinical Research Unit (CRU), the contact number is not intended for use by the 
participant directly, and if a participant calls that number, he or she will be directed back to 
the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 1 will be performed by the central laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study at a local lab as 
determined necessary by the investigator or required by local regulations.
Table 1.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
White blood cell (WBC) count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Albumin
Bicarbonate or
total carbon 
dioxide (CO2)
Creatinine
Total Protein
Alanine 
Aminotransferase 
(ALT)
Blood urea 
nitrogen (BUN)
Glucose 
(nonfasting)
Sodium
Alkaline 
phosphatase
Calcium
Potassium
Hemoglobin A1c
Aspartate 
Aminotransferase 
(AST)
Chloride
Total bilirubin
Other
Prothrombin time (PT)/ international normalized ratio (INR), follicle stimulating 
hormone (FSH)2
NOTES:
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Appendix 5.  All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR measured which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis).
2 For confirmation of postmenopausal status only.
Investigators must document their review of each laboratory safety report.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE.  Such instances will be captured in the efficacy 
assessments.  However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, that
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.


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A SAE is defined as any untoward medical occurrence that, at any dose:

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF
and for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) non-serious adverse events (AEs); and (3) exposure to the study 
intervention under study during pregnancy or breastfeeding, and occupational exposure.  
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (And exposure during 
pregnancy [EDP] 
supplemental form for 
EDP)  
Note:  Include all SAEs
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the Pfizer Safety/AE/SAE 
CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.


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
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Pfizer Safety. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Pfizer Safety.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor" and "In addition, if the investigator determines 
that an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 


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assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Pfizer 
Safety to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide Pfizer Safety with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.

Contacts for SAE reporting can be found in the investigator site file.


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SAE Reporting to Pfizer Safety via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to Pfizer Safety.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the investigator site file.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female

A postmenopausal state is defined as age 60 or older or no menses for 12 months 
without an alternative medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT).
Contraception Guidance:
Contraception is not required for participants in this study.


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Collection of Pregnancy Information:
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the study 
intervention; or the female becomes or is found to be pregnant after discontinuing 
and/or being exposed to the study intervention;

An example of environmental exposure would be a case involving direct 
contact with a Pfizer product in a pregnant woman (eg, a nurse reports that she 
is pregnant and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to 
the study intervention prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the study intervention, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.
Additional information regarding the EDP may be requested by the sponsor.  Further follow-
up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner.


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a 
participant presents with clinical signs/symptoms, such LFT results should be managed and 
followed as described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).


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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.The participant 
should return to the investigator site and be evaluated as soon as possible, preferably within 
48 hours from awareness of the abnormal results.  This evaluation should include laboratory 
tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s Law, additional laboratory tests should include albumin, creatine kinase (CK), direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time 
(PT)/international normalized ratio (INR), total bile acids, and alkaline phosphatase. 
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) and collection of serum sample for acetaminophen drug and/or protein 
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.6. Appendix 6: Virtual Randomized Clinical Trial Information
The CIG and RTCs will perform all the rater assessments except for the scoring of TSS, 
ISGA, and lesional %BSA which are completed by the HVP.
All VRCT processes would follow GCP standards, CFR compliance, and relevant local laws 
(there may be differences in process from state to state).  Study operational processes and 
documentation will comply with all applicable privacy requirements.  All new technologies 
proposed will be validated to be in compliance with CFR Part 11. 
Completion of the IRB-approved electronic Informed Consent Document, participant 
eligibility, participant randomization using the Sponsor’s IRT system, study drug 
compliance, efficacy assessment completion, and monitoring of participant safety will be 
documented within the remote data capture electronic platform to facilitate ongoing Sponsor 
oversight and Regulatory Agency auditing of trial conduct.  
C3291038 VRCT study data will be entered electronically or uploaded electronically by 
investigators, remote trial coordinators, HVPs, and other 3rd-party vendors (eg, central 
laboratory, central pharmacy).  Once participants have completed training for the use of an 
electronic diary, the participant will complete ePROs using smart-devices during study 
participation.
Sponsor representatives will monitor adverse event data (including but not limited to 
severity, causality, onset and outcome), review clinical trial data to identify potential AEs 
and SAEs, and oversee input of electronic source documents for Pfizer’s ARGUS database 
for every study participant.  
Sponsor representatives (RTCs, HVPs, and CIG-based Investigators) will elicit and enter 
adverse event information monitor adverse event data (including but not limited to severity, 
causality, onset and outcome) at each encounter with participants.  The principal investigator 
(PI) and sub-investigators (SubI) and Sponsor will review clinical trial data to identify 
potential SAEs and oversee input of electronic source documents for Pfizer’s ARGUS 
database for every study participant.  
Prior to database lock, all external data will be transferred to the electronic data capture 
(EDC)-based clinical trial database.  
This study will utilize various methods of electronic data capture to provide source 
documentation.  All electronic data will be integrated into an EDC-based clinical trial 
database.  Electronic data from the trial will be obtained from the following sources:
1. Third-Party Vendor online portal.  The vendor will manage the online portal, which is 
accessible through an application on the participant’s smart device or through a 
web-based portal.  The following study participants will use the portal to enter study 
data: PI, Sub-Is, HVPs, RTCs, and other designees. 
2. Central Lab Laboratory vendor: participant blood samples will be sent to a central 
laboratory for analysis.  Laboratory data will be transferred electronically to an 


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external vendor and the data are loaded in the EDC system.  Data generated by 
laboratories will be stored in their diagnostic databases and serve as the source data.
3. Static Dermatologic Images of SD areas for % lesional BSA, TSS and ISGA 
assessment:  after training by HVP, static digital images will be obtained by the 
trained participant using only provisioned digital imaging equipment.  Participants 
will be trained on how to obtain the images by the HVP.  Images will be sent from the 
mobile digital imaging equipment electronically to a central digital imaging 
repository and transferred to a central imaging vendor for central reading of digital 
images.
4. Third party vendors, such as a central imaging vendor, will manage a digital imaging 
repository, and provide blinded access to imaging for each Central Reader and the 
CIG.
5. ECG: An ECG will be obtained as outlined in the Schedule of Activities to 
electronically calculate the heart rate and measure PR, QRS, QT, QTcF intervals.
Interactive Response Technology Updates to any data will originate from the source data 
system and be resent to the other system(s), as per the initial transfer process.4-8


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10.7. Appendix 7: NYHA Classification, CKD Guidelines, Child - Pugh Classification 
and GOLD Guidelines
NYHA Classification - Stages of Heart Failure
Class I - No symptoms and no limitation in ordinary physical activity, eg, shortness of breath 
when walking, climbing stairs etc. 
Class II - Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
Class III - Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, eg, walking short distances (20 - 100 m).  Comfortable only at rest. 
Class IV - Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients. 
National Kidney Foundation CKD Guidelines 
The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative has 
published clinical practice guidelines for staging CKD.  These guidelines stage CKD using a 
classification system (G1 to G5) based upon glomerular filtration rate (GFR):
GFR Category
GFR (ml/min/1.73 m2)
Terms
G1
>90
Normal or high
G2
60-89
Mildly decreased
G3a
45-59
Mildly to moderately decreased
G3b
30-44
Moderately to severely decreased
G4
15-29
Severely decreased
G5
<15
Kidney failure


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Child-Pugh Classification
The Child-Pugh Classification was developed to assess the prognosis of chronic liver disease 
and cirrhosis.  There are 5 components of the Child-Pugh score: 
The 5 components are summed to yield a Child-Pugh Classification-Class A (5-6 points), 
Class B (7-9 points), or Class C (10-15 points).
GOLD Guidelines
The GOLD guideline uses a combined COPD assessment approach to group patients 
according to symptoms and previous history of exacerbations. Symptoms are assessed using 
the Modified British Medical Research Council (mMRC) dyspnea scale or COPD assessment 
test (CAT) scale.
Modified British Medical Research Council (mMRC) Dyspnea Scale
mMRC Grade
Symptomatology
0
I only get breathless with strenuous exercise
1
I get short of breath when hurrying (on level ground)
2
I walk slower than people of the same age on level ground because of 
breathless, or I have to stop for breath when walking at my own pace on 
level ground. 
3
I stop for breath after walking about 100 meters or after a few minutes on 
level ground.
4
I am too breathless to leave the house OR I am breathless when dressing 
or undressing.


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COPD Assessment Test (CAT)
The CAT contains 8 unidimensional sub-scores assessing health status impairment in 
COPD.33  The summation of each sub-score (range, 0-5) provides a total score (range, 0-40):
  
Individual participant risk group assignment (Group A to D) is determined using the mMRC 
and CAT:

Group A: low risk (0-1 exacerbation per year, not requiring hospitalization) and 
fewer symptoms (mMRC 0-1 or CAT <10). 

Group B: low risk (0-1 exacerbation per year, not requiring hospitalization) and 
more symptoms (mMRC≥ 2 or CAT≥10). 

Group C: high risk (≥2 exacerbations per year, or one or more requiring 
hospitalization) and fewer symptoms (mMRC 0-1 or CAT <10). 

Group D: high risk (≥2 exacerbations per year, or one or more requiring 
hospitalization) and more symptoms (mMRC≥2 or CAT≥10).


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10.8. Appendix 8: Abbreviations
Abbreviation
Term
AD
atopic dermatitis
AE
adverse event
ALT
alanine aminotransferase
ANOVA
analysis of variance
ANCOVA
analysis of covariate
AST
aspartate aminotransferase
BID
twice daily
BSA
body surface area
BUN
blood urea nitrogen
CAT
COPD assessment test
CFR
code of federal regulations
CHF
chronic heart failure
CI
confidence interval
CIG
Central Investigator Group
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD
chronic kidney disease
CO2
carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus Disease (2019)
CPAP
continuous positive airway pressure
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
clinical study report
CT
clinical trials
CTTI
clinical trials transformation initiative
DILI
drug-induced liver injury
DMC
Data monitoring committee
DVT
deep vein thrombosis
ECG
electrocardiogram
EDC
electronic data capture
eCRF
electronic case report form
EC50
half maximal effective concentration
EDP
exposure during pregnancy
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EOT
End of Treatment
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Abbreviation
Term
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set 
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
FTU
fingertip unit
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
Gamma-glutamyl transferase
GOLD
Global Initiative for Obstructive Lung Disease
HCP
Health Care Provider
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormone replacement therapy
HVP
Home Visit Practitioner
IA
Interim Analysis
IB
Investigator’s Brochure 
ICF 
Informed consent form
ICH
International Conference on Harmonisation
IC50
half maximal inhibitory concentration
ID
identification
IEC
Independent Ethics Committee
IL
interleukin
IMP
Investigational medicinal product
IND
investigational new drug application
INF-
Interferon gamma
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
Internal Review Committee
IRT
interactive response technology
ISGA
Investigator’s Static Global Assessment
IVC
Inferior vena cava
JAK
Janus kinase
LFT
liver function test
LSM
least squares mean
MAR
Missing Data Are Assumed
mMRC
British Medical Research Council
MMF
mycophenolate mofetil
MMP
matrix metalloproteinases
MMRM
mixed model for repeated measures
MMSE-2
Mini Mental State Examination
N/A
Not applicable
NIMP
Non-investigational medicinal product


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Abbreviation
Term
NSAIDS
nonsteroidal anti-inflammatory drugs
NYHA
New York Heart Association
MR-NR
missing response as non-response
PCD
primary completion date
PDE-4
phosphodiesterase 4
PI
principal investigator
PK
Pharmacokinetic(s)
PRN
as needed
PRO
patient reported outcome
PACL
Protocol Administrative Change Letter
PT
prothrombin time
QC
quality control
QTcF
Fridericia's Correction Formula
RBC
red blood cell
RTC
Remote Trial Coordinator
SAE
serious adverse event
SAF
Safety Analysis Set 
SD
stasis dermatitis
SoA
schedule of activities
SAP
Statistical Analysis Plan 
SOP
standard operating procedure
SRSD
single reference safety document
SubI
sub investigator
SUSAR
suspected unexpected serious adverse reactions
TBili
total bilirubin
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
TGFβ1
transforming growth factor β1
TIMP
tissue inhibitors of metalloproteinases
TNFα
tumor necrosis factor alpha
TSS
total sign score
% BSA
percent body surface area
ULN
upper limit of normal
US
United States
USA
United States of America
VHTN
venous hypertension
VI
venous insufficiency
VRCT
virtual randomized clinical trials
WBC
White blood cells
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Abbreviation
Term
WOCBP
women of child-bearing potential


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11. REFERENCES
1.
Brown KR, Rossi PJ. Superficial venous disease. Surg Clin North Am. 2013;93(4):963-
82, ix-x.
2.
Hahnel E, Lichterfeld A, Blume-Peytavi U, et al. The epidemiology of skin conditions 
in the aged: A systematic review. J Tissue Viability. 2017;26(1):20-8.
3.
Cheatle TR, Scott HJ, Scurr JH, et al. White cells, skin blood flow and venous ulcers. 
Br J Dermatol. 1991;125(3):288-90.
4.
Herouy Y, Mellios P, Bandemir E, et al. Inflammation in stasis dermatitis upregulates 
MMP-1, MMP-2 and MMP-13 expression. J Dermatol Sci. 2001;25(3):198-205.
5.
Cheng J, Diaz Encarnacion MM, Warner GM, et al. TGF-beta1 stimulates monocyte 
chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase 
isoenzyme 4-dependent process. Am J Physiol Cell Physiol. 2005;289(4):C959-70.
6.
Zhang J, Yang X, Wang H, et al. PKCζ as a promising therapeutic target for TNFα-
induced inflammatory disorders in chronic cutaneous wounds. International journal of 
molecular medicine. 2017;40(5):1335-46.
7.
Pappas PJ, You R, Rameshwar P, et al. Dermal tissue fibrosis in patients with chronic 
venous insufficiency is associated with increased transforming growth factor-beta1 gene 
expression and protein production. J Vasc Surg. 1999;30(6):1129-45.
8.
Corbel M, Germain N, Lanchou J, et al. The selective phosphodiesterase 4 inhibitor RP 
73-401 reduced matrix metalloproteinase 9 activity and transforming growth factor-beta 
release during acute lung injury in mice: the role of the balance between Tumor necrosis 
factor-alpha and interleukin-10. J Pharmacol Exp Ther. 2002;301(1):258-65.
9.
Caffery LJ, Clunie D, Curiel-Lewandrowski C, et al. Transforming Dermatologic 
Imaging for the Digital Era: Metadata and Standards. J Digit Imaging. 2018;31(4):568-
77.
10.
Clinical Trials Transformation Initiative. https://www.ctti-clinicaltrials.org/.  Accessed 
08 March 2019.
11.
Serra R, Gallelli L, Butrico L, et al. From varices to venous ulceration: the story of 
chronic venous disease described by metalloproteinases. Int Wound J. 2017;14(1):233-
40.
12.
Vasquez MA, Rabe E, McLafferty RB, et al. Revision of the venous clinical severity 
score: venous outcomes consensus statement: special communication of the American 
Venous Forum Ad Hoc Outcomes Working Group. J Vasc Surg. 2010;52(5):1387-96.
13.
Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for 
chronic venous disorders: consensus statement. J Vasc Surg. 2004;40(6):1248-52.


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Page 95
14.
Ardigo M, Longo C, Gonzalez S, et al. Multicentre study on inflammatory skin diseases 
from The International Confocal Working Group: specific confocal microscopy features 
and an algorithmic method of diagnosis. Br J Dermatol. 2016;175(2):364-74.
15.
Peschen M, Lahaye T, Hennig B, et al. Expression of the adhesion molecules ICAM-1, 
VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic 
venous insufficiency. Acta Derm Venereol. 1999;79(1):27-32.
16.
Cheng J, Encarnacion MMD, Warner GM, et al. TGF-β1 stimulates monocyte 
chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase 
isoenzyme 4-dependent process. American Journal of Physiology-Cell Physiology. 
2005;289(4):C959-C70.
17.
Moore CS, Crocker SJ. An alternate perspective on the roles of TIMPs and MMPs in 
pathology. Am J Pathol. 2012;180(1):12-6.
18.
Word R. Medical and surgical therapy for advanced chronic venous insufficiency. Surg 
Clin North Am. 2010;90(6):1195-214.
19.
Tominaga M, Tengara S, Kamo A, et al. Matrix metalloproteinase-8 is involved in 
dermal nerve growth: implications for possible application to pruritus from in vitro 
models. Journal of Investigative Dermatology. 2011;131(10):2105-12.
20.
Sippel K, Mayer D, Ballmer B, et al. Evidence that venous hypertension causes stasis 
dermatitis. Phlebology. 2011;26(8):361-5.
21.
Brinster NK. Dermatopathology for the surgical pathologist: a pattern-based approach 
to the diagnosis of inflammatory skin disorders (part II). Adv Anat Pathol. 
2008;15(6):350-69.
22.
National Center for Complementary and Integrative Health. 
https://nccih.nih.gov/health/providers/digest/herb-drug.  Accessed 28 Jun 2019.
23.
Weaver J, Billings SD. Initial presentation of stasis dermatitis mimicking solitary 
lesions: a previously unrecognized clinical scenario. J Am Acad Dermatol. 
2009;61(6):1028-32.
24.
Cheatle TR, Scurr JH, Smith PD. Drug treatment of chronic venous insufficiency and 
venous ulceration: a review. J R Soc Med. 1991;84(6):354-8.
25.
Sundaresan S, Migden MR, Silapunt S. Stasis Dermatitis: Pathophysiology, Evaluation, 
and Management. Am J Clin Dermatol. 2017;18(3):383-90.
26.
Shevchenko A, Valdes-Rodriguez R, Yosipovitch G. Causes, pathophysiology, and 
treatment of pruritus in the mature patient. Clin Dermatol. 2018;36(2):140-51.


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32.
Psychological Assessment Resources Inc [US]. 
https://www.parinc.com/Products/Pkey/238.  Accessed 15 Jul 2019.
33.
Jones PW, Harding G, Berry P, et al. Development and first validation of the COPD 
Assessment Test. Eur Respir J. 2009;34(3):648-54.
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SAP_001.pdf: 
Protocol C3291038 (Crisaborole; PF-06930164) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol C3291038
A PHASE 2, RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED, 
PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFICACY, SAFETY, AND
LOCAL TOLERABILITY OF CRISABOROLE OINTMENT, 2%, IN ADULT 
PARTICIPANTS WITH STASIS DERMATITIS WITHOUT ACTIVE SKIN 
ULCERATION
Statistical Analysis Plan 
(SAP)
Version:
4
Date:
16Sep2021


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives, Endpoints, and Estimands............................................................7
2.1.1. Study Objectives and Endpoints...................................................................7
2.1.2. Estimands......................................................................................................8
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................11
3.1. Primary Endpoint ....................................................................................................11
3.2. Secondary Endpoints...............................................................................................11
3.4. Baseline Variables...................................................................................................12
3.5. Safety Endpoints .....................................................................................................12
3.5.1. Adverse Events...........................................................................................12
3.5.2. Laboratory Data..........................................................................................13
3.5.3. Vital Signs ..................................................................................................13
3.5.4. Physical Examinations, Including Height and Weight...............................13
3.5.5. Electrocardiograms.....................................................................................14
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................14
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................14
5.1. Hypotheses and Decision Rules ..............................................................................14
5.2. General Methods .....................................................................................................15
5.2.1. Analyses for Continuous Data....................................................................15
5.2.2. Analyses for Binary Data............................................................................15
5.2.3. Analyses for Categorical Data....................................................................16
5.3. Methods to Manage Missing Data ..........................................................................16
5.3.1. Binary Endpoints ........................................................................................16
5.3.2. Continuous Endpoints.................................................................................16
6. ANALYSES AND SUMMARIES ......................................................................................16
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6.1. Primary Endpoint ....................................................................................................16
6.1.1. Primary Analysis ........................................................................................16
6.1.2. Sensitivity Analyses....................................................................................17
6.2. Secondary Endpoints...............................................................................................18
6.2.1. ISGA Success based on Central Readers Assessment................................18
6.2.2. ISGA Success at Week 6/EOT based on In-person Assessment................18
6.2.3. ISGA Score of Clear or Almost Clear based on Central Readers 
Assessment.......................................................................................................18
6.2.4. ISGA Score of Clear or Almost Clear based on In-person 
Assessment.......................................................................................................19
6.2.5. Percentage Change from Baseline in TSS at Weeks 1-6 based on 
Central Readers Assessments ..........................................................................19
6.2.6. Percent Change from Baseline in Lesional %BSA based on In-person 
Assessment.......................................................................................................20
6.2.7. Percent Change from Baseline in Lesional %BSA based on Central 
Readers Assessment.........................................................................................20
6.4. Subset Analyses.......................................................................................................21
6.5. Baseline and Other Summaries and Analyses.........................................................21
6.5.1. Baseline Summaries....................................................................................21
6.5.2. Study Conduct and Participant Disposition................................................21
6.5.3. Study Intervention Compliance..................................................................21
6.5.4. Concomitant Medications and Non-drug Treatments.................................21
6.6. Safety Summaries and Analyses .............................................................................22
6.6.1. Adverse Events...........................................................................................22
6.6.2. Laboratory Data..........................................................................................22
6.6.3. Physical Examination .................................................................................22
7. INTERIM ANALYSES.......................................................................................................22
7.1.1. Data Monitoring Committee.......................................................................23
8. REFERENCES ....................................................................................................................23
9. APPENDICES .....................................................................................................................23
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
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Table 2.
Study Objectives and Endpoints.................................................................7
Table 3. 
Visit windows for longitudinal efficacy variables....................................26
Table 4. 
Visit windows for non-longitudinal efficacy variables ............................26
Table 5.
ISGA Score...............................................................................................27
LIST OF FIGURES
Figure 1.
Schema......................................................................................................10
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1. VERSION HISTORY
This statistical analysis plan (SAP) for Study C3291038 is based on Protocol Amendment 2 
dated 19July2021.
Table 1.
Summary of Changes
Version/Date
Associated Protocol 
Amendment
Rationale
Specific Changes
1
10Mar2020
Amendment 1 
10January2020 
N/A
N/A
2
11Mar2021
Amendment 1 
10January2020
No efficacy data are 
collected after 
intercurrent event (ie, 
discontinuation of study 
intervention)
Estimand 3 and related analyses 
were removed
Only one post-baseline 
assessment will be 
performed for these 
endpoints. All 
participant with post-
baseline assessments can 
be included in analysis
based on new visit 
windows. 
New visit windows are defined for 
TSS, ISGA, %BSA in-person 
assessment, 
Subset analyses will be 
performed just for in-
person assessment 
endpoints. 
“based on HVP in-person 
assessment” was added to  Section 
6.4 Subset Analyses
Validation analysis will 
be described in a 
separate analysis plan
Validation Section was removed.
Don’t need summary and 
listing for vital signs, 
height, weight and ECG 
Vital signs and ECG were removed 
from Section 6
3
28Jul2021
Amendment 2 
19Jul2021
For non-longitudinal 
endpoints, the 
assessments at EOT for 
early terminated 
participants are included 
in the analysis. 
Estimand 1 was changed as a while-
on-treatment estimand.
Estimand 3 was added as a 
hypothetical estimand for 
longitudinal continuous endpoints
Interim analysis may be 
performed
Details for interim analysis was 
added.
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To reduce sample size 
Sample size was reduced to 70, 
significance level was changed to 
5% one-sided. CI was changed to 
90%
For consistency with 
protocol
Screened population was added.
Enrolled population was changed.
Subgroup analysis will 
be performed by type of 
standard of care/skin 
type. This supportive 
analysis is not necessary.
Removed supportive analysis for 
TSS change from baseline at Week 
6/EOT based on in-person 
assessment (ANCOVA model 
including type of standard of 
care/skin type)
4
16Sep2021
Amendment 2 
19Jul2021
Sensitivity analyses
Added analyses for % change from 
baseline in TSS at Week 6 based on 
in-person assessment for observed 
cases and multiple imputation for 
missing data. 
Exclude the assessments 
far away from last dose  
For Week 6 or EOT, the visit 
window cut at the last dose + 10 
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C3291038. The summaries and analyses described in this SAP will be 
reported in the clinical study report (CSR). Validation analysis for comparison between in-
person assessment and Central Readers assessments based on images will be described in a 
separate analysis plan and reported separately from the CSR.
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition or its analysis will also be reflected in a 
protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
2.1.1. Study Objectives and Endpoints
Study objectives and corresponding endpoints are provided in the Table 2 below.
Table 2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy of crisaborole 
ointment, 2%, twice daily (BID) versus vehicle 
at Week 6 in participants with stasis dermatitis 
(SD) without active skin ulceration.

Percent change from baseline in Total Sign 
Score (TSS) at Week 6/EOT (Home Visit 
Practitioner [HVP] in-person assessment).
Secondary Efficacy

To evaluate the efficacy of crisaborole 
ointment, 2%, BID versus vehicle over time in 
participants with SD without active skin 
ulceration.

Achievement of an Investigator’s Static Global 
Assessment (ISGA) score of Clear (0) or 
Almost Clear (1) with at least a 2-grade 
improvement from baseline at all time points
(analyze both HVP in-person assessment and 
Central Readers digital images assessment);

Achievement of an ISGA score of Clear (0) or 
Almost Clear (1) at all time points (analyze 
both HVP in-person assessment and Central 
Readers digital images assessment);

Percent change from baseline in TSS at all time 
points (Central Readers digital images 
assessment);

Percent change from baseline in lesional % 
Body Surface Area (%BSA) at all time points
(analyze both HVP in-person assessment and 
Central Readers digital images assessment).
Secondary Safety


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•
To evaluate the safety and local tolerability of 
crisaborole ointment, 2%, BID versus vehicle
in participants with SD without active skin 
ulceration.
•
Incidence and severity of treatment emergent 
adverse events (AEs), including local 
tolerability events.
 
 
 
 
 
 
 
 
 
 
 
2.1.2. Estimands
Only discontinuation of study intervention will be considered as an intercurrent event.
Estimand 1: The primary estimand of this study is a while-on-treatment estimand, which 
estimates the treatment effect of crisaborole compared with vehicle at Week 6/EOT.  It 
includes the following 5 attributes:
•
Population: participants ≥45 years of age with SD without active skin ulceration;
•
Variable: non-longitudinal endpoints at Week 6/EOT;
•
Treatment condition: crisaborole 2% BID or vehicle;
•
Intercurrent event: all data after an intercurrent event of discontinuation of study 
intervention will be excluded, data at Week 6 or EOT (within date of last dose + 10
days) will be included;
•
Population-level summary: difference in LSM for continuous endpoint and difference 
in proportion of participants with response for binary endpoints at Week 6/EOT
between crisaborole ointment, 2%, BID and vehicle.
Estimand 1 will be used in analyzing the primary endpoint and it will also be used to analyze 
non-longitudinal continuous secondary endpoints %BSA in-person assessment 
 
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and non-longitudinal binary endpoints ISGA success (ISGA 
score of clear/almost clear with at least a 2-grade improvement from baseline) and ISGA 
clear/almost clear based on in-person assessment.
Estimand 2: The second estimand of this study is a composite estimand, which estimates the 
treatment effect of crisaborole compared with vehicle at each timepoint.  It includes the 
following 4 attributes:
•
Population: participants ≥45 years of age with SD without active skin ulceration;
•
Variable: binary response endpoint per photography assessment, eg, response defined 
as a participant with an ISGA score of clear  or almost clear with at least a 2-grade 
improvement from baseline at each time point; a participant after an intercurrent 
event of discontinuation of study intervention will be considered a non-responder for 
the visit of interest;
•
Treatment condition: crisaborole 2% BID or vehicle;
•
Intercurrent event: there will be no intercurrent event since the discontinuation of 
study intervention is part of the variable definition;
•
Population-level summary: difference in proportion of participants with response at 
each time point between crisaborole ointment, 2%, BID and vehicle.
Estimand 2 will be used in analyzing all applicable longitudinal secondary binary endpoints.
Estimand 3: The third estimand of this study is a hypothetical estimand, which estimates the 
treatment effect of crisaborole compared with vehicle at each time point under the scenario of 
no discontinuation of study intervention.  It includes the following 5 attributes: 
•
Population: participants ≥45 years of age with SD without active skin ulceration;
•
Variable: percent change from baseline in TSS at each time point;
•
Treatment condition: crisaborole 2% BID or vehicle;
•
Intercurrent event: all data collected after any intercurrent events will be excluded;
•
Population-level summary: difference in mean percent change from baseline in TSS 
at each time point between crisaborole ointment, 2%, BID and vehicle.
Estimand 3 will be used in analyzing the longitudinal continuous endpoints.
2.2. Study Design
Study C3291038 is a Phase 2a, randomized, double-blind, vehicle-controlled, parallel-group, 
proof-of-concept study to evaluate the efficacy, safety, and local tolerability of 6 weeks of 
treatment with crisaborole in adult participants with SD without active skin ulceration.  
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Approximately 70 eligible participants will be randomized into the double-blind treatment 
period in a 1:1 ratio to receive crisaborole ointment, 2% or vehicle twice daily for 6 weeks.
The study will recruit male and female participants aged ≥45 years with a clinical diagnosis 
of SD.  Participants who meet all inclusion but none of the exclusion criteria presented in 
Section 5 of the protocol will be eligible to participate in the study.  If a participant meets any 
of the exclusion criteria, the participant will be excluded.
The total duration of participation in the study will be up to 14 weeks, including up to 
4 weeks for screening, a 6-week double-blind treatment period, and a follow-up period of 
4 weeks after treatment completion.
Study enrollment and management will be de-centralized, where participants do not visit an 
investigator or a clinic for clinical assessment.  The participants will participate in the study 
at home.  The sponsor (or designee) will provide home visits by qualified HVP, remote 
contact by telemedicine (or telephone), and clinical database electronic case report forms 
(eCRFs), eDiary, and other electronic data entries from 3rd party vendors for study data 
collection.
Participants who withdraw from further study intervention treatment (but do not withdraw 
consent for further data gathering) should continue to complete all scheduled assessments at 
the EOT visit and complete the follow-up phase of the study.
Figure 1.
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS
TSS, ISGA and lesional %BSA will be assessed in-person by HVP at the home visits at 
screening, baseline, and Week 6 (or early termination) and will be used for the primary 
analyses. Theses efficacy parameters will also be remotely assessed at all scheduled 
timepoints by an expert dermatologist central reader reviewing digital imaging of the lower 
extremities acquired by the participant. The data based on Central Readers assessments will 
be used for supportive analyses. Only initial Central Readers assessments will be used for 
supportive analyses. Central Readers re-assessments will be used for validation and 
reliability analyses.
3.1. Primary Endpoint
The primary efficacy endpoint is a percent change from baseline in TSS at Week 6/EOT
(HVP in-person assessment).
3.2. Secondary Endpoints
The secondary endpoints are:
•
Achievement of an ISGA score of Clear (0) or Almost Clear (1) with at least a 2-
grade improvement from baseline at all time points (analyze both HVP in-person 
assessment and Central Readers digital images assessment).
•
Achievement of an ISGA score of Clear (0) or Almost Clear (1) at all time points
(analyze both HVP in-person assessment and Central Readers digital images 
assessment).
•
Percent change from baseline in TSS at all time points (Central Readers digital 
images assessment).
•
Percent change from baseline in lesional %BSA at all time points (analyze both HVP 
in-person assessment and Central Readers digital images assessment).
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3.4. Baseline Variables
Demographic and baseline characteristics include:

Age

Sex

Race

Ethnicity

Height (cm)

Weight (kg)

Body mass index (kg/m2)

Duration of disease (years)

Prior TCS/TCI

Fitzpatrick Skin Type

Type of standard of care

TSS

ISGA

%BSA
The baseline value is defined as the last observation up to and including Day 1 of 
intervention period. For daily assessed endpoints, the average of 7-day scores immediately 
prior to Day 1 (Day -6 to Day 1) will be used as the baseline.
3.5. Safety Endpoints
Safety will be assessed by medical history, physical examinations, vital signs,
electrocardiograms (ECG), clinical laboratory tests, and the spontaneous reporting of AEs, in 
all participants who received at least one dose of study intervention.  Unscheduled safety 
assessments may be performed at any time during the study to assess any perceived safety 
concerns.  Investigators and Pfizer Clinicians will review individual participant data 
throughout the conduct of the study to ensure participants’ well-being.  
3.5.1. Adverse Events
An AE is considered treatment-emergent adverse event (TEAE) to a given treatment if the 
event start date is on or after the treatment period start date and before end of study.
Safety endpoints will be assessed by the spontaneous reporting of:

Incidence of TEAEs

Incidence of serious adverse events (SAEs)

Incidence of AEs leading to discontinuation


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3.5.2. Laboratory Data
Laboratory testing will be performed at screening and may be performed at unplanned safety 
assessment or early termination visit.  The tests detailed in the table below will be performed 
by the central laboratory.
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
White blood cell (WBC) count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Albumin
Bicarbonate or
total carbon 
dioxide (CO2)
Creatinine
Total Protein
Alanine 
Aminotransferase 
(ALT)
Blood urea 
nitrogen (BUN)
Glucose 
(nonfasting)
Sodium
Alkaline 
phosphatase
Calcium
Potassium
Hemoglobin A1c
Aspartate 
Aminotransferase 
(AST)
Chloride
Total bilirubin
Other
Prothrombin time (PT)/ international normalized ratio (INR), follicle stimulating 
hormone (FSH)2
NOTES:
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Appendix 5.  All events of ALT 3 × upper limit of normal (ULN) 
and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, if INR measured which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis).
2 For confirmation of postmenopausal status only.
3.5.3. Vital Signs
Vital signs will be assessed at screening and unplanned safety assessment or early 
termination visit.
3.5.4. Physical Examinations, Including Height and Weight
A complete physical examination will be assessed at screening and may be performed at 
unplanned safety assessment or early termination visit.


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3.5.5. Electrocardiograms
A single lead ECG will be performed at screening and may be performed at unplanned safety 
assessment or early termination visit.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
For purposes of analysis, the following analysis sets are defined:
Population
Description
Screened
All participants who sign the informed consent form (ICF).
Enrolled
All participants who sign the ICF and are not screen failure.
Randomly Assigned to Study 
Intervention
All participants who are randomized.
Full Analysis Set (FAS)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention.  Participants will be analyzed 
according to the intervention they are randomized.  
For change from baseline or percent change from baseline endpoints it 
would require that a participant have a baseline value and at least one 
post-baseline value to be included in the analysis for that endpoint.  
For the endpoint with a threshold requirement for change from baseline, 
only participants with a baseline value ≥ the threshold will be included in 
the analysis.
Safety Analysis Set (SAF)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention.  Participants will be analyzed 
according to the intervention they actually received.
Full Analysis Set-Interim 
Analysis (FAS-IA)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention and complete 6 weeks treatment or 
early discontinue study intervention at the IA cutoff date.  Participants will 
be analyzed according to the intervention they are randomized.  
Safety Analysis Set-Interim 
Analysis (SAF-IA)
All participants who are randomly assigned to study intervention and apply 
at least 1 dose of study intervention and complete 6 weeks treatment or 
early discontinue study intervention at the IA cutoff date. Participants will 
be analyzed according to the intervention they actually received.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database lock after Last Participant Last Visit (LPLV).
5.1. Hypotheses and Decision Rules
This protocol is designed to establish the superiority of crisaborole 2% BID to vehicle for the
primary endpoint percent change from baseline in the TSS at Week 6/EOT (based on in
person assessment by HVP at the home visit). The null hypothesis is that there is no
difference between crisaborole arm and vehicle arm, and the alternative hypothesis is that
there is a significant difference between crisaborole arm and vehicle arm. Specifically, the 
alternative hypothesis is that the mean percentage improvement from baseline for crisaborole
group is 22% greater than vehicle group. The significance level is 5% one-sided. The interim 
analysis (if conducted) is an administrative interim analysis; no adjustment of p-values is 
planned for the analysis of the final study data.


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5.2. General Methods
In general, number, percent and 90% confidence interval (CI) will be presented for binary 
endpoints.  Descriptive summary statistics (n, Mean, Standard deviation (Std), Median, Min., 
Max.) will be presented for continuous endpoints.  In addition, graphics may be used to 
present the data.
Day 1 will be the date when a participant applies the first dose of study intervention.  
Baseline value will be the last non-missing assessment on or before Day 1 and prior to first 
dose of study intervention.
 
5.2.1. Analyses for Continuous Data
Analysis of Variance (ANOVA)/Analysis of Covariance (ANCOVA) for Non-longitudinal 
Continuous Data:
The non-longitudinal continuous data will be analyzed by ANOVA with treatment as the
factor. ANCOVA will be used if relevant baseline value and/or other factors are included as 
covariates. Comparison of crisaborole ointment, 2%, BID to vehicle (providing LSM of the 
treatments, LSM of the treatment difference, 1-sided p-value and 90% CI) will be generated.
Mixed Effect Model Repeat Measurement (MMRM) for Longitudinal Continuous Data:
The longitudinal continuous endpoints will be analyzed with MMRM that includes fixed
effects of treatment group, visit, and treatment-group by visit interaction, without imputation 
for missing values. If the endpoint is change from baseline, baseline will be included in the 
model as a covariate. A common unstructured variance-covariance matrix will be used, 
provided it converges. If this is a convergence issue, other type of covariance matrix such as 
first order autoregressive (AR[1]), compound symmetry will be used.  Comparison of 
crisaborole ointment, 2%, BID to vehicle (providing least squares means [LSM] of the 
treatments, LSM of the treatment difference, 1-sided p-value and 90% CI) at each time point 
during the first 6 weeks will be generated using this model.  
5.2.2. Analyses for Binary Data
For binary endpoint at each time point, large sample approximation to the difference in 
binominal proportions will be used for testing (Normal Z-test) the superiority of crisaborole 
ointment, 2%, BID to vehicle and for forming 90% CI’s and calculating 1-sided p-values.  
For non-longitudinal binary endpoints, data at Week 6 or EOT will be included in the 
analysis.
For analysis of longitudinal binary endpoints, observations after the discontinuation of study 
intervention or missing values for any reason will be handled by setting the endpoint to 
nonresponsive.  Note that this is a composite endpoint in the sense that a response requires 
the participant completes a visit of interest eg, Week 6, and achieves a response per the 
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defined response criteria (otherwise it is considered a nonresponse).  This method of handling 
missing response is known as missing response as non-response (MR-NR).  For a single time 
point (eg, ISGA Clear (0) or Almost Clear (1) with at least a 2-grade improvement from 
baseline at Week 6), large sample approximation to the difference in binominal proportions 
will be used for testing (Normal Z-test) the superiority of crisaborole ointment, 2%, BID to 
vehicle and for forming 90% CI’s and calculating p-values.  The analysis will be based on 
Estimand 2 using FAS.
5.2.3. Analyses for Categorical Data
The frequency and percentage for each category will be presented for category endpoints.
5.3. Methods to Manage Missing Data
5.3.1. Binary Endpoints
For non-longitudinal binary endpoints, there is no imputation for missing data, data at Week 
6 or EOT will be included in the analysis.
For longitudinal binary endpoints analyzed at each scheduled visit separately, participants 
with missing data at a time point for any reason will be defined as MR-NR at that time point
in the intervention period.
5.3.2. Continuous Endpoints
For non-longitudinal continuous data, primary analysis will be based on the observed cases, 
there is no imputation for missing data. 
For continuous efficacy endpoints measured longitudinally, missing values post-baseline will 
be handled in a MMRM.  For longitudinal continuous endpoints, assuming that the missing 
data mechanism is missing at random (MAR), the data will be analyzed using a MMRM 
model for these continuous variables (see Section 5.2.1).  Under an assumption that the 
missing data mechanism is MAR, this model will yield unbiased estimates and valid 
inferences for treatment effects assuming all participants maintain therapy.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Primary Analysis
The primary endpoint is percent change from baseline in the TSS at Week 6/EOT based on 
HVP in-person assessment.

Estimand strategy: while-on-treatment, Estimand 1 (Section 2.1.2)

Analysis set: FAS (Section 4)

Variable: Percent change from baseline to Week 6/EOT  in TSS

Analysis method: ANOVA in Section 5.2.1


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
Intercurrent event: All data after an intercurrent event (eg, discontinuation of 
treatment), if collected, will be excluded; data at Week 6 or EOT (within date of last 
dose + 10 days) will be included.

The LSM along with the corresponding standard error (SE) for each treatment group, 
LSM difference along with the corresponding SE, 90% CI, and p-value will be 
presented. LSM ± SE will also be presented graphically by treatment group.
6.1.2. Sensitivity Analyses
Two sensitivity analyses will be performed for the percent change from baseline in the TSS 
at Week 6 based on HVP in-person assessment. 
1. Observed cases: Principal Stratum estimand will be used. The data after an intercurrent 
event discontinuation of study intervention, if collected, will be excluded, only no-missing 
observed cases in-person assessment at Week 6 (based on window definition in Table 3) will 
be included in the analysis. No imputation for missing data. ANOVA (Section 5.2.1) will be 
used. The LSM along with the corresponding SE for each treatment group, LSM difference 
along with the corresponding SE, 90% CI, and 1-sided p-value will be presented. The data 
after an intercurrent event, if collected, will be excluded, observed cases at Week 6 will be 
included.  
2. Multiple imputations: Hypothetical estimand will be used. The data after an intercurrent 
event discontinuation of study intervention, if collected, will be excluded, observed cases in-
person assessment at Week 6 (based on window definition in Table 3) will be included in the 
analysis. Missing TSS at Week 6 will be imputed using the method of MCMC multiple 
imputation under MAR assumption. Multiple imputation and subsequent analysis will involve 
the following four principal tasks:
1) Calculate the total number of missing values to be imputed by MCMC (nmiss) for 
Week 6 value.
2) Create a data set, one for each treatment group, of participants with observed values 
and those needing imputation by MCMC. The missing TSS values in each data set 
will be filled in using the MCMC method “10 × nmiss” times to generate “10 × 
nmiss” data sets. The resulting data sets for each treatment group will be combined 
into one complete data set by imputation. The imputed values will be rounded to the 
nearest integer of 0 - 12.
3) For each complete data set, derive % change from baseline in TSS at Week 6. The 
estimated treatment effect and its standard error for each complete data set will be 
calculated using ANOVA (Section 5.2.1).
4) Combine the estimated treatment effects and standard errors from the above into a 
single inference using Rubin’s formulae as implemented in SAS PROC 
MIANALYZE.


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6.2. Secondary Endpoints
6.2.1. ISGA Success based on Central Readers Assessment

Estimand strategy: composite, Estimand 2 (Section 2.1.2)

Analysis set: FAS (Section 4)

Variable: ISGA success at Weeks 1-6 based on Central Readers digital images 
assessment

Analysis method: Normal approximation to binomial

Intercurrent event: A participant with a missing observation or after an intercurrent 
event of discontinuation of treatment will be considered a non-responder for the visit 
of interest.

P-value from normal approximation test, the estimate of proportion, difference in 
proportion and the corresponding 90% CI of participants with response at each visit
between crisaborole ointment, 2% versus vehicle will be presented. Proportions of 
response (± SE) will also be presented graphically by treatment group.
6.2.2. ISGA Success at Week 6/EOT based on In-person Assessment

Estimand strategy: while-on-treatment, Estimand 1 (Section 2.1.2)

Analysis set: FAS (Section 4)

Variable: ISGA success at Week 6/EOT based on in-person assessment

Analysis method: Normal approximation to binomial

Intercurrent event: all data after an intercurrent event of discontinuation of study 
intervention will be excluded, data at Week 6 or EOT will be included;

P-value from normal approximation test, the estimate of proportion, difference in 
proportion and the corresponding 90% CI of participants with response at Week 
6/EOT between crisaborole ointment, 2% versus vehicle will be presented. 
Proportions of response (± SE) will also be presented graphically by treatment group.
6.2.3. ISGA Score of Clear or Almost Clear based on Central Readers Assessment

Estimand strategy: composite, Estimand 2 (Section 2.1.2)

Analysis set: FAS (Section 4)

Variable: ISGA clear or almost clear at Weeks 1-6 based on Central Readers digital 
images assessment


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
Analysis method: Normal approximation to binomial

Intercurrent event: A participant with a missing observation or after an intercurrent 
event of discontinuation of treatment will be considered a non-responder for the visit 
of interest.

P-value from normal approximation test, the estimate of proportion, difference in 
proportion and the corresponding 90% CI of participants with response at each visit 
between crisaborole ointment, 2% versus vehicle will be presented. 
6.2.4. ISGA Score of Clear or Almost Clear based on In-person Assessment

Estimand strategy: while-on-treatment, Estimand 1 (Section 2.1.2)

Analysis set: FAS (Section 4)

Variable: ISGA clear or almost clear at Week 6/EOT based on in-person assessment

Analysis method: Normal approximation to binomial

Intercurrent event: all data after an intercurrent event of discontinuation of study 
intervention will be excluded, data at Week 6 or EOT will be included

P-value from normal approximation test, the estimate of proportion, difference in 
proportion and the corresponding 90% CI of participants with response at Week 
6/EOT between crisaborole ointment, 2% versus vehicle will be presented. 
6.2.5. Percentage Change from Baseline in TSS at Weeks 1-6 based on Central Readers 
Assessments

Estimand strategy: hypothetical, Estimand 3 (Section 2.1.2)

Analysis set: FAS (Section 4)

Variable: Percent change from baseline to Weeks 1-6 in TSS based on central readers 
assessment

Analysis method: MMRM in Section 5.2.1

Intercurrent event: All data after an intercurrent event (eg, discontinuation of 
treatment), if collected, will be excluded; 

The LSM along with the corresponding SE for each treatment group, LSM difference 
along with the corresponding SE, 90% CI, and p-value will be presented. LSM (± SE)
will also be presented graphically by treatment group.


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6.2.6. Percent Change from Baseline in Lesional %BSA based on In-person Assessment
•
Estimand strategy: while-on-treatment, Estimand 1 (Section 2.1.2)
•
Analysis set: FAS (Section 4)
•
Variable: Percent change from baseline to Week 6/EOT in %BSA based on in-person 
assessment
•
Analysis method: ANOVA in Section 5.2.1
•
Intercurrent event: All data after an intercurrent event (eg, discontinuation of 
treatment), if collected, will be excluded, data at Week 6 or EOT will be included.
•
The LSM along with the corresponding SE for each treatment group, LSM difference 
along with the corresponding SE, 90% CI, and p-value will be presented. 
6.2.7. Percent Change from Baseline in Lesional %BSA based on Central Readers 
Assessment
•
Estimand strategy: hypothetical, Estimand 3 (Section 2.1.2)
•
Analysis set: FAS (Section 4)
•
Variable: Percent change from baseline to Week 1- 6 in %BSA based on Central 
Readers digital images assessment
•
Analysis method: MMRM in Section 5.2.1
•
Intercurrent event: All data after an intercurrent event (eg, discontinuation of 
treatment), if collected, will be excluded.
•
The LSM along with the corresponding SE and 90% CI for each treatment group, 
LSM difference along with the corresponding SE, 90% CI, and p-value will be 
presented. 
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6.4. Subset Analyses
Percentage change from baseline in TSS, ISGA success, ISGA clear/almost based on HVP 
in-person assessment will be analyzed by subgroups of type of standard of care, skin type, 
baseline ISGA, disease duration (by median), age (≤64 vs ≥65), race (White vs Non-white). 
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographics and baseline characteristics listed in Section 3.4 will be summarized 
according to Pfizer standards.
6.5.2. Study Conduct and Participant Disposition
Participants evaluation, disposition, discontinuation will be summarized according to Pfizer 
standards.
6.5.3. Study Intervention Compliance
Participant compliance with study intervention will be assessed by Investigator (or designee) 
review of eDiary responses.
A participant will be considered compliant with the dosing regimen if he/she receive 80% to 
120% of the expected number of doses, in accordance with the protocol.
The number and percentage of participants who are compliant with the dosing regimen, 
number of dosing days and number of applications, and total amount of intervention used
will be summarized according to Pfizer standards.
6.5.4. Concomitant Medications and Non-drug Treatments
Any medication (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements), vaccine or non-medication therapies that the participant is receiving at 
the time of enrollment or receives during the study must be recorded at all study 
visits/contacts.
All concomitant medications taken during the study must be recorded in study records with 
indication, reference to any associated adverse event, dose, and start and stop dates of 
administration.
The Pfizer Medical Monitor should be consulted if there are any questions regarding 
concomitant or prior therapy for SD prior to determining participant eligibility.
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Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.  The summary will be performed by treatment 
group for overall and separated by SD and non-SD treatments.
6.6. Safety Summaries and Analyses
Safety analyses will be summarized in accordance with Pfizer Data Standards.
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, will be reviewed and summarized 
on an ongoing basis during the study to evaluate the safety of participants.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards.  Categorical outcomes (eg, AEs) will be summarized by 
participant counts and percentage.  Continuous outcome (eg, pulse rate, etc) will be 
summarized using n, mean, median, standard deviation, etc.  Participant listings will be 
produced for these safety endpoints accordingly.
6.6.1. Adverse Events
The safety data will be summarized in accordance with Pfizer Data Standards.  All safety 
data will be summarized descriptively through appropriate data tabulations, descriptive 
statistics, categorical summaries, and graphical presentations.  Safety endpoints for the study 
include:
•
Treatment-emergent AEs and SAEs;
•
Withdrawals from treatment/study due to AEs.
6.6.2. Laboratory Data
Laboratory data will be listed.
6.6.3. Physical Examination
Physical examination data will be listed.
7. INTERIM ANALYSES
An IA may be performed to assess efficacy after approximately 50 participants complete 6 
weeks treatment or early discontinue study intervention. Interim analysis results will be used 
for decisions regarding stopping for futility and planning for future studies.
All study personnel and sponsor’s staff involved with this study will remain blinded to 
individual subject data for interim analysis.
A third party Pfizer programmer/biostatistician who is unrelated to the study team will 
conduct the interim analysis. The third party will receive the unblinded treatment codes from 
clinical pharmacy and make the appropriate changes to the analysis programs prepared by the 
clinical programmer and study biostatistician in the 
. After successful execution of 
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all interim analysis programs, the third party will place the results in 
. An 
 
folder containing summary data will be created and protected such that only designated 
persons can gain access.
The decision criterion is based on the primary endpoint. The efficacy will not be claimed 
based on this interim analysis. If the efficacy criterion is met, the study will continue and 
remain blinded to study personnel until the final database unblinding, and phase 3 studies can 
start planning. The final analysis will be performed at the final official database release. If
futility criterion is met, this study will be terminated.
7.1.1. Data Monitoring Committee
This study will not use a data monitoring committee. However, if an IA is performed, an IRC 
will be established to review the interim analysis results and make the decision for this study 
and crisaborole stasis dermatitis project.
8. REFERENCES
None.
9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and 
Rules for Handling 
Intercurrent Events 
and Missing Data 
Analysis Model
Percent Change 
from baseline to 
Week 6/EOT in 
TSS based on 
HVP in-person 
assessment
Summary
FAS
observed data 
  N/A
Main analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded, data 
at Week 6 or EOT
(within date of 
last dose +10
days) will be 
included.
ANOVA with term 
treatment
Sensitivity 
analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded,
observed cases at 
ANOVA with term 
treatment
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Week 6 will be 
included. No 
imputation for 
missing data.
Sensitivity 
analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded,
observed cases at 
Week 6 will be 
included. Missing 
data at Week 6 
will be derived 
for the analysis 
using the method 
of multiple
imputation.
ANOVA with term 
treatment
Percent Change 
from baseline to 
Weeks 1 - 6 in 
TSS based on 
central readers 
assessment
Summary
FAS
observed data 
  N/A
Main analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded.
Missing data will 
not be imputed.
MMRM with terms 
treatment, visit, and 
interaction of 
treatment and visit
ISGA success
and ISGA 
clear/almost 
clear at Week 
6/EOT based on 
HVP in-person 
assessment
Main analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded, data 
at Week 6 or EOT 
will be included.
Normal 
approximation
ISGA success 
and ISGA 
clear/almost 
clear at Weeks 
Main analysis
FAS
A participant with 
a missing 
observation or 
after an 
Normal 
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1- 6 based on 
central readers 
assessment 
intercurrent event 
of discontinuation 
of treatment will 
be considered a 
non-responder for 
the visit of 
interest
Percent change 
from baseline in 
%BSA at Week 
6/EOT based on 
HVP in-person 
assessment
Summary
FAS
observed data 
  N/A
Main analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded, data 
at Week 6 or EOT 
will be included.
ANOVA with term 
treatment
Percent change 
from baseline in 
%BSA at Weeks 
1-6 based on 
central readers 
assessment
Summary
FAS
observed data 
  N/A
Main analysis
FAS
The data after an 
intercurrent event, 
if collected, will 
be excluded.
Missing data will 
not be imputed.
MMRM with terms 
treatment, visit, and 
interaction of 
treatment and visit
Appendix 2. Definition and Use of Visit Windows in Reporting
Visit windows defined in Table 3 will be used for longitudinal efficacy variables. For TSS, 
ISGA, %BSA in-person assessment, these visit windows will be used for sensitivity 
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Table 3.
Visit windows for longitudinal efficacy variables
Visit Label
Target Day
Definition [Day window]
Screening
up to -1
Baseline
Day 1, Baseline
Day 1
Week 1
8
Days 2 to 11
Week 2
15
Days 12 to 18
Week 3
22
Days 19 to 25
Week 4
29
Days 26 to 32
Week 5
36
Days 33 to 39
Week 6
43
Days 40 - last dose + 10 days
Note: Participants will have an end-of-study (follow-up) by phone at least 28 days after the last study 
dose.
Below visit windows in Table 4 will be used for non-longitudinal efficacy variables.
Table 4.
Visit windows for non-longitudinal efficacy variables
Visit Label
Target Day
Definition [Day window]
Screening
up to -1
Baseline
Day 1, Baseline
Day 1
Week 6/EOT
43
Day 2 - last dose + 10 days
Note: Participants will have an end-of-study (follow-up) by phone at least 28 days after the last study 
dose.
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.
Safety analysis will follow Pfizer standards.
Appendix 3. Total Sign Score (TSS)
The TSS is an assessment of the severity of SD skin lesions.  Each of the 4 clinical signs 
(erythema, papulation/elevation [excluding papulation due to lipodermatosclerosis or 
varicose veins], superficial erosion/denudation, and scaling) across all the treatable SD 


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lesions will be rated using the 4-point severity scale (ranging from 0 to 3 points).  The four 
sub scores are summed to create the TSS, 13-point scale; ranging from 0 to 12 points, with a 
higher score representing a higher disease severity. TSS is considered missing if one or more 
item is missing.
Appendix 4. Investigator’s Static Global Assessment (ISGA)
The ISGA, a five-point global assessment of AD severity, will be assessed at times specified 
in the Study Procedure section of study protocol to characterize subjects’ overall disease 
severity across all treatable AD lesions (excluding the scalp).
The ISGA will be a static evaluation without regard to the score at a previous visit.  It must 
be completed by a clinical assessor blinded for treatment arms.  Every effort should be made 
to ensure that all ISGA assessments for a given subject are done by the same qualified 
individual throughout the study.
Table 5.
ISGA Score
Score Grade
Definition
0
Clear
Minor residual hypo/hyperpigmentation; no erythema or induration/papulation; no 
oozing/crusting
1
Almost 
Clear
Trace faint pink erythema, with barely perceptible induration/papulation and no 
oozing/crusting
2
Mild
Faint pink erythema with mild induration/papulation and no oozing/crusting 
3
Moderate Pink-red erythema with moderate induration/papulation with or without oozing/crusting
4
Severe
Deep or bright red erythema with severe induration/papulation and with oozing/crusting
∗The ISGA will exclude scalp from the assessment/scoring
 
 
 
 
 
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CCI
CCI


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CCI
CCI


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Detailed analysis of the DLQI
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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Appendix 11. List of Abbreviations
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AR[1]
first order autoregressive
BID
twice daily
BSA
Body surface area
CI
confidence interval
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
HVP
home visit practitioner
IA
Interim analysis
ICF
informed consent form
ISGA
investigator’s static global assessment
LPLV
last participant last visit
LSM
least-squares mean
MAR
missing at random
MMRM
mixed-effects model with repeated measures
MR-NR
missing response as non-response
N/A
not applicable
SAE
serious adverse event
SAP
statistical analysis plan
Std
Standard deviation
SD
stasis dermatitis
SE
standard error
TCI
Topical Calcineurin Inhibitors
TCS
Topical Corticosteroids
TEAE
treatment emergent adverse event
TSS
total sign score
ULN
upper limit of normal
CCI
CCI
CCI
CCI
CCI