Clinical trial NCT04042103
Conditions: Plaque Psoriasis
Sponsor: Organon and Co
Start date: 2019-07-23; Completion date: 2020-01-09
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, multicenter study to evaluate the systemic exposure and safety of topical tapinarof cream, 1% under conditions of maximal use in adults with plaque psoriasis.

Detailed description:

Arms: arm 1: Tapinarof (DMVT-505) cream, 1% applied topically once daily
Interventions: intervention 1: Tapinarof cream, 1%
Intervention descriptions: intervention 1: Tapinarof cream, 1% applied topically once daily

Protocol documents:
Prot_000.pdf: 






Tapinarof 
DMVT-505-2002 
Dermavant Sciences GmbH 
Clinical Study Protocol 
 
Confidential 
Page | 4 
INVESTIGATOR STATEMENT 
Study Title: Open-Label Maximal Use Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Tapinarof Cream, 1% in Adults with Extensive Plaque 
Psoriasis 
• I confirm agreement to conduct the study in compliance with the protocol. 
• I acknowledge that I am responsible for overall study conduct.  I agree to personally 
conduct or supervise the described study. 
• I agree to ensure that all associates, colleagues, and employees assisting in the 
conduct of the study are informed about their obligations and comply with the study 
protocol.  Mechanisms are in place to ensure that site staff receives the appropriate 
information throughout the study. 
 
 
 
 
Principal Investigator Name (Printed) 
 
Signature 
 
 
 
Date 
 
Site 
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Clinical Study Protocol 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
SYNOPSIS .....................................................................................................................................12 
SCHEDULE OF ASSESSMENTS ................................................................................................17 
1. 
INTRODUCTION ......................................................................................................19 
1.1. 
Background Information and Study Rationale ...........................................................19 
1.1.1. 
Background Information .............................................................................................19 
1.1.2. 
Study Rationale ...........................................................................................................21 
1.2. 
Rationale for Study Design and Dose .........................................................................21 
1.3. 
Potential Risks and Benefits .......................................................................................22 
1.3.1. 
Risk Assessment .........................................................................................................22 
1.3.1.1. 
Dermatological Adverse Events, Including Skin Irritation, or Allergic 
Reaction: .....................................................................................................................22 
1.3.1.2. 
Systemic Adverse Events: ..........................................................................................22 
1.3.1.3. 
Reproductive and Developmental Toxicity ................................................................23 
1.3.2. 
Benefit Assessment .....................................................................................................23 
1.3.3. 
Overall Benefit Risk ...................................................................................................23 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
3. 
STUDY DESIGN .......................................................................................................25 
3.1. 
Overall Design ............................................................................................................25 
3.2. 
Treatment Groups and Duration .................................................................................25 
4. 
STUDY POPULATION .............................................................................................26 
4.1. 
Type and Number of Subjects ....................................................................................26 
4.2. 
Inclusion Criteria ........................................................................................................26 
4.3. 
Exclusion Criteria .......................................................................................................27 
4.4. 
Lifestyle Restrictions ..................................................................................................29 
4.5. 
Screening/Baseline Failures ........................................................................................29 
4.6. 
Withdrawal Criteria ....................................................................................................29 
4.6.1. 
Reasons for Withdrawal from the Study ....................................................................29 
4.6.2. 
Withdrawal Procedures ...............................................................................................30 
4.7. 
Lost to Follow-Up .......................................................................................................30 
5. 
STUDY TREATMENT ..............................................................................................31 
5.1. 
Study Drug ..................................................................................................................31 
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Clinical Study Protocol 
 
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5.1.1. 
Description, Packaging, and Labeling ........................................................................31 
5.1.2. 
Storage ........................................................................................................................31 
5.1.3. 
Handling and Disposal ................................................................................................31 
5.1.4. 
Preparation ..................................................................................................................32 
5.1.5. 
Administration of Study Drug ....................................................................................32 
5.2. 
Randomization/Treatment Assignment ......................................................................33 
5.3. 
Blinding ......................................................................................................................33 
5.4. 
Compliance with Study Drug Administration ............................................................33 
5.5. 
Treatment after the End of the Study ..........................................................................33 
5.6. 
Prior and Concomitant Therapy ..................................................................................34 
5.6.1. 
Permitted Medications and Nondrug Therapies .........................................................34 
5.6.2. 
Prohibited Medications and Nondrug Therapies ........................................................34 
6. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................36 
6.1. 
Medical History, Demography, and Baseline Characteristics ....................................36 
6.1.1. 
Medical History ..........................................................................................................36 
6.1.2. 
Demographics .............................................................................................................36 
6.1.3. 
Baseline Characteristics ..............................................................................................36 
6.2. 
Psoriasis Disease Assessments ...................................................................................36 
6.2.1. 
Physician Global Assessment .....................................................................................36 
6.2.2. 
Body Surface Area Affected .......................................................................................37 
6.2.3. 
Psoriasis Area and Severity Index ..............................................................................37 
6.3. 
Safety Assessments .....................................................................................................37 
6.3.1. 
Adverse Events ...........................................................................................................37 
6.3.2. 
Brief Physical Exam ...................................................................................................37 
6.3.3. 
Vital Signs ..................................................................................................................37 
6.3.4. 
Clinical Safety Laboratory Assessments ....................................................................38 
6.3.5. 
...............................................................................40 
6.3.6. 
Local Tolerability Scale ..............................................................................................40 
6.3.7. 
Continuous Holter Monitoring ...................................................................................41 
6.4. 
Treatment of Study Drug Overdose ............................................................................42 
6.5. 
Pharmacokinetics ........................................................................................................43 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................44 
7.1. 
Visit 1; Screening Period (Up to 34 Days Prior to Day 1) .........................................44 
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7.2. 
Visit 2; Day -1 ............................................................................................................45 
7.3. 
Visit 3; Day 1 (Baseline) ............................................................................................45 
7.4. 
Visit 4; Day 2 ..............................................................................................................46 
7.5. 
Day 8 (Phone Call) .....................................................................................................46 
7.6. 
Visit 5; Day 15 ............................................................................................................46 
7.7. 
Day 22 (Phone Call) ...................................................................................................46 
7.8. 
Visit 6; Day 29 ............................................................................................................47 
7.9. 
Visit 7; Day 30 ............................................................................................................47 
7.10. 
Visit 8; Follow-Up (7-10 days After Day 29)/Early Termination ..............................47 
8. 
SAFETY MONITORING AND REPORTING .........................................................48 
8.1. 
Adverse Events, Treatment-Emergent Adverse Events, Serious Adverse 
Events, and Adverse Events of Special Interest .........................................................48 
8.1.1. 
Definition of Adverse Events .....................................................................................48 
8.1.2. 
Definition of Treatment-Emergent Adverse Event .....................................................49 
8.1.3. 
Definition of Serious Adverse Event ..........................................................................49 
8.1.4. 
Adverse Events of Special Interest .............................................................................50 
8.2. 
Classification of Adverse Events ................................................................................50 
8.2.1. 
Assigning Severity Rating for Adverse Events ..........................................................50 
8.2.1.1. 
Criteria for Determining Adverse Event Severity ......................................................50 
8.2.1.2. 
Toxicity Management Criteria ....................................................................................51 
8.2.2. 
Assigning Causal Relationship to Study Drug ...........................................................52 
8.3. 
Time Period and Frequency for Event Assessment and Follow-Up ...........................52 
8.3.1. 
Adverse Event and Serious Adverse Event Reporting ...............................................52 
8.3.2. 
Follow-Up of Adverse Events ....................................................................................53 
8.4. 
Reporting Procedures ..................................................................................................53 
8.4.1. 
Serious Adverse Event Reporting ...............................................................................53 
8.4.2. 
Regulatory Reporting Requirements for Serious Adverse Events .............................53 
8.5. 
Pregnancy Management and Reporting ......................................................................54 
8.6. 
Safety Oversight .........................................................................................................54 
9. 
DATA MANAGEMENT ...........................................................................................55 
10. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................56 
10.1. 
General Considerations ...............................................................................................56 
10.2. 
Determination of Sample Size ....................................................................................56 
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10.3. 
Analysis Sets ...............................................................................................................56 
10.3.1. 
Safety Analysis Set .....................................................................................................56 
10.3.2. 
PK Analysis Set ..........................................................................................................56 
10.3.3. 
QT/QTc Analysis Set ..................................................................................................56 
10.3.4. 
PK/QTc Analysis Set ..................................................................................................56 
10.4. 
Planned Analyses ........................................................................................................56 
10.4.1. 
Disposition and Demographics ...................................................................................57 
10.4.2. 
Safety Analyses ..........................................................................................................57 
10.4.3. 
Cardiodynamic Assessments ......................................................................................57 
10.4.3.1. 
Baseline .......................................................................................................................57 
10.4.3.2. 
By-Time Point Analysis .............................................................................................57 
10.4.3.3. 
Categorical Analysis ...................................................................................................58 
10.4.3.4. 
Concentration-QTc Analysis (Potential Exploratory Analysis) .................................58 
10.4.4. 
Pharmacokinetic Analysis ..........................................................................................59 
10.4.5. 
Efficacy Analyses .......................................................................................................59 
11. 
RESPONSIBILITIES .................................................................................................61 
11.1. 
Investigator Responsibilities .......................................................................................61 
11.1.1. 
Good Clinical Practice ................................................................................................61 
11.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................61 
11.1.3. 
Informed Consent/Assent ...........................................................................................61 
11.1.4. 
Confidentiality ............................................................................................................62 
11.1.5. 
Study Files and Retention of Records ........................................................................62 
11.1.6. 
Electronic Case Report Forms ....................................................................................63 
11.1.7. 
Drug Accountability ...................................................................................................63 
11.1.8. 
Inspections ..................................................................................................................64 
11.1.9. 
Protocol Compliance ..................................................................................................64 
11.2. 
Sponsor Responsibilities .............................................................................................64 
11.2.1. 
Protocol Modifications ...............................................................................................64 
11.2.2. 
Study Report and Publications ....................................................................................64 
11.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ......................65 
11.3. 
Joint Investigator/Sponsor Responsibilities ................................................................65 
11.3.1. 
Access to Information for Monitoring ........................................................................65 
11.3.2. 
Access to Information for Auditing or Inspections ....................................................65 
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11.3.3. 
Study Discontinuation ................................................................................................65 
12. 
REFERENCES ...........................................................................................................66 
APPENDICES ...............................................................................................................................67 
 Physician Global Assessment ................................................................................67 
 Calculation of Percent Body Surface Area Affected and Psoriasis Area 
and Severity Index .................................................................................................68 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................17 
Table 2: 
Tapinarof Cream .........................................................................................................31 
Table 3: 
Laboratory Tests .........................................................................................................39 
Table 4: 
Grading Scale for Local Tolerability ..........................................................................40 
Table 5: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................51 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Description 
%BSA 
percent body surface area 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
AhR 
aryl hydrocarbon receptor 
ALT 
alanine aminotransferase 
Anti-HBc 
anti-hepatitis B core antigen 
AST 
aspartate aminotransferase 
AUC0-τ 
area under the plasma concentration vs time curve in one dosing interval 
BMI 
body mass index 
BP 
blood pressure 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum plasma concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
Dermavant 
Dermavant Sciences GmbH 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FSH 
follicle-stimulating hormone 
 
 
HBC 
hepatitis C virus 
HBsAg 
hepatitis B surface antigen 
Hep 
hepatitis 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
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Term 
Description 
IV 
intravenous 
LS 
least squares 
LTS 
Local Tolerability Scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
PASI 
Psoriasis Area and Severity Index 
PGA 
Physician Global Assessment 
PK 
pharmacokinetic(s) 
PND 
postnatal day 
QTcF 
QT interval corrected with Fridericia’s formula 
RBC 
red blood cell(s) 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum plasma concentration 
t1/2  
elimination half life 
ULN 
upper limit of normal 
US; USA 
United States (of America) 
UV 
ultraviolet 
WBC 
white blood cell(s) 
WOCBP 
women of childbearing potential 
 
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Dermavant Sciences GmbH 
Clinical Study Protocol 
 
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SYNOPSIS 
Name of Sponsor/Company: 
Dermavant Sciences GmbH 
Name of Study Drug: 
DMVT-505 (tapinarof cream, 1%) 
Name of Active Ingredient:   
Tapinarof 
Protocol Number:  DMVT-505-2002 
Phase: 
2a 
Country: United States (US)  
Title of Study: 
Open-Label Maximal Use Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Tapinarof 
Cream, 1% in Adults with Extensive Plaque Psoriasis 
Study Center(s): 
Approximately 6 centers in the US  
Objectives: 
Primary: 
• 
To evaluate the safety and tolerability of tapinarof cream, 1% in adult subjects with extensive plaque 
psoriasis 
• 
To evaluate the pharmacokinetics (PK) of tapinarof cream, 1% in adult subjects with extensive plaque 
psoriasis 
Secondary: 
• 
To exclude clinically relevant effects of tapinarof cream, 1% on QT interval corrected by Fridericia’s 
formula (QTcF) 
• 
To assess the efficacy of tapinarof cream, 1% in adult subjects with extensive plaque psoriasis 
 
 
 
Methodology: 
This is a Phase 2a, multicenter, open-label, safety, tolerability and PK study.  The study will consist of three 
phases:  Screening (up to 34 days), Treatment (29 days), and Follow-up (7-10 days). 
At Day 1 (Baseline), eligible subjects will be instructed on how to apply tapinarof cream, 1% while under the 
supervision of site personnel in the clinic.  During the treatment period, subjects will apply tapinarof cream, 1% 
to affected areas once a day for 29 days.  Subjects will return to the clinic on Days 2, 15, 29, and 30 for study 
assessments and will receive a phone call on Days 8 and 22.  Subjects will return to the clinic for a follow-up visit 
7-10 days after the Day 29 visit.  On clinic visit days, subjects will apply study drug under the supervision of site 
personnel, after assessments have been completed.  Full PK profiles and Holter monitoring will be collected on 
Days 1 and 29 (with corresponding 24-hour time points collected on Days 2 and 30, respectively).  Limited PK 
sampling will be performed on Day 15.  Pre-treatment, time-matched Holter monitoring will be conducted on 
Day -1 and the morning of Day 1.   
Number of Subjects: 
Approximately 20 subjects ages 18 to 75 years will be enrolled in the study. 
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Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria: 
Each subject must meet all of the following criteria to be eligible to participate in the study: 
1. Male and female subjects ages 18 to 75 years with confirmed clinical diagnosis of chronic psoriasis and 
stable disease for at least 6 months prior to the study; 
2. Body surface area (BSA) involvement ≥ 20% (the subject’s scalp, palms, and soles should be excluded 
from the percent BSA [%BSA] calculations to determine eligibility at Screening); 
3. A Physician Global Assessment (PGA) score of ≥ 3 at Screening; 
4. Women of childbearing potential (WOCBP) and male subjects who are engaging in sexual activity that 
could lead to pregnancy must use at least 1 of the following adequate birth control methods while on 
study and for 4 weeks after the last exposure to study drug.  Acceptable contraception methods are: 
• 
Male or male partner with vasectomy, OR 
• 
Male condom AND partner use of one of the contraceptive options below: 
­ 
Spermicide; 
­ 
Contraceptive subdermal implant that meets effectiveness criteria including a < 1% rate of 
failure per year, as stated in the product label; 
­ 
Intrauterine device or intrauterine system that meets effectiveness criteria including a < 1% rate 
of failure per year, as stated in the product label; 
­ 
Oral contraceptive, either combined or progestogen alone; 
­ 
Injectable progestogen; 
­ 
Contraceptive vaginal ring; 
­ 
Percutaneous contraceptive patches. 
Note:  Subjects using hormonal contraceptives must have been on a stable dose for at least 4 weeks 
before Baseline. 
These allowed methods of contraception are only effective when used consistently, correctly, and in 
accordance with the product label.  The Investigator is responsible for ensuring that subjects understand 
how to properly use these methods of contraception. 
Non-childbearing potential is defined as premenarchal; or pre-menopausal females with a documented 
bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries) or hysterectomy; or hysteroscopic 
sterilization; or postmenopausal females defined as a cessation of menses for at least 12 months without 
an alternative medical cause.  In questionable cases a blood sample with simultaneous follicle-stimulating 
hormone (FSH) > 40 mIU/mL is confirmatory.  Documented verbal history from the subject is 
acceptable. 
Subjects who are abstinent are eligible, but they must agree to use one of the birth control methods listed 
above if they start engaging in sexual activity that could lead to pregnancy during the study. 
WOCBP must have a negative serum pregnancy test at Screening and negative urine pregnancy test at 
Baseline (Day 1). 
5. Presence of venous access for multiple blood draws on an area that is devoid of psoriasis. 
6. Capable of giving written informed consent, as applicable, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF); written informed consent must be 
obtained prior to performing any study-related procedures. 
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Exclusion Criteria: 
A subject who meets any of the following criteria will be excluded and considered ineligible for participation in 
the study: 
1. Psoriasis other than plaque variant; 
2. Any sign of infection of any of the psoriatic plaques; 
3. Concurrent conditions or history of other diseases: 
a. 
Immunocompromised (e.g., lymphoma, acquired immunodeficiency syndrome) or medical history of 
positive human immunodeficiency virus (HIV) antibody at Screening; 
b. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, 
antiprotozoals, or antifungals within 4 weeks prior to the Baseline visit; 
c. 
Acute active bacterial, fungal, or viral (herpes simplex, herpes zoster, or chicken pox) skin infection 
within 1 week prior to the Baseline visit; 
d. Significant dermatologic or inflammatory condition other than plaque psoriasis that, in the 
Investigator’s opinion, would make it difficult to interpret data or assessments during the study. 
4. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2 x the upper limit of 
normal (ULN); 
5. Screening total bilirubin > ULN; total bilirubin > ULN and ≤ 1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin < 35%; 
6. A QTcF > 470 msec; 
7. Current or chronic history of liver disease, known hepatic or biliary abnormalities (with the exception of 
Gilbert's syndrome or asymptomatic gallstones), presence of hepatitis B surface antigen (HBsAg), or 
positive hepatitis C antibody test result, or a positive anti -hepatitis B core antigen (anti-HBc) result; 
8. Ultraviolet (UV) light therapy or prolonged exposure to natural or artificial sources of UV radiation 
(e.g., phototherapy, tanning beds/booths, or therapeutic sunbathing) within 4 weeks prior to the Baseline 
visit and/or plans to have such exposures during the study which could potentially impact the subject’s 
psoriasis (as determined by the Investigator); 
9. Use of any prohibited medication within the indicated period before the Baseline visit; 
NOTE:  Prohibited concomitant medications, therapy, etc., during the defined period are as listed in the 
bullets below.  If a subject requires any of these medications throughout the study period, he/she may be 
excluded from or discontinued from the study, at the discretion of the Investigator and Medical Monitor. 
• 
Minimum of 5 half-lives for biologic agents:  e.g., 12 months for rituximab; 8 months for 
ustekinumab; 5 months for secukinumab; 12 weeks for golimumab; 10 weeks for ixekizumab; 
8 weeks for infliximab, adalimumab, or alefacept; and 4 weeks for etanercept; 
• 
4 weeks for systemic treatments:  cyclosporin, interferon, methotrexate, apremilast, tofacitinib, 
mycophenolate, thioguanine, hydroxyurea, sirolimus, azathioprine, other systemic 
immunosuppressive or immunomodulating agents, fumaric acid derivatives, Vitamin D and 
analogs, retinoids (e.g., acitretin, isotretinoin), psolarens, corticosteroids, or adrenocorticotropic 
hormone analogs; 
• 
2 weeks for immunizations with a live viral component; 
• 
2 weeks for drugs known to possibly worsen psoriasis, such as beta-blockers (e.g., propranolol), 
lithium, iodides, angiotensin-converting enzyme inhibitors, and indomethacin, unless on a stable 
dose for > 12 weeks; 
• 
With the exception of emollients, 2 weeks for topical treatments including corticosteroids, 
immunomodulators, anthralin (dithranol), Vitamin D derivatives (e.g., calcipotriene, calcipotriol), 
retinoids (e.g., tazarotene), or coal tar. 
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10. A history of or ongoing serious illness or medical, physical, or psychiatric condition(s) that, in the 
Investigator’s opinion, may interfere with the subject’s participation in the study and ability to understand 
and give informed consent; 
11. Pregnant females as determined by positive serum (Screening) or urine (Baseline) human chorionic 
gonadotropin test at Screening or prior to dosing; 
12. Lactating females; 
13. History of sensitivity to the study drug, or components thereof or a history of drug or other allergy that, in 
the opinion of the Investigator or Medical Monitor, contraindicates the subject’s participation in the 
study; 
14. The subject has received an investigational drug within the following time period prior to the first dosing 
day in the current study:  30 days, 5 half-lives, or twice the duration of the biological effect of the 
investigational drug (whichever is known to be longer); 
15. Current or a history of cancer within 5 years except for fully excised skin basal cell carcinoma, squamous 
cell carcinoma or carcinoma in situ of the cervix;  
16. Subjects with active infection that required oral, intramuscular, or intravenous (IV) administration of 
antibiotics, antifungal, or antiviral agents within 7 days of the Baseline visit; 
17. Concurrent skin lesions in the treatment area that, in the opinion of the Investigator, would either interfere 
with study evaluations or affect the safety of the subject; 
18. Subjects with advanced disease or abnormal laboratory test values that could affect the safety of the 
subject or the implementation of this study; 
19. Previous known participation in a clinical study with tapinarof; Evidence of significant hepatic, renal, 
respiratory, endocrine, hematologic, neurologic, psychiatric, or cardiovascular (CV) system abnormalities 
or laboratory abnormality that will affect the health of the subject or interfere with interpretation of the 
results. 
Study Drug, Dosage and Mode of Administration: 
Tapinarof cream, 1% is a white to off-white cream containing 10 mg/gram tapinarof, supplied in 30 gram tubes, 
and is to be self-administered once daily via topical application of a thin layer to affected areas.   
Duration of Treatment:  Study duration for subjects who complete this Phase 2a study is approximately 
10 weeks in total (including approximately 34 days for Screening, 29 days of treatment, and a 7-10 day follow-up 
period). 
Study Endpoints: 
Primary: Frequency and severity of adverse events (AEs; local and systemic) 
• 
Laboratory and 
values 
• 
Vital signs 
• 
ECGs 
• 
Mean Local Tolerability Scale scores by visit 
• 
Tapinarof and tapinarof sulfate (metabolite) plasma PK parameters on Day 1 and Day 29, if data permit, 
including: 
­ 
area under the plasma concentration versus time curve in one dosing interval (AUC0-τ) 
­ 
maximum plasma concentration (Cmax) 
­ 
time to maximum plasma concentration (tmax) 
­ 
elimination half-life (t1/2) 
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Secondary: 
• 
Analysis of change from Baseline in QTcF (∆QTcF) at each post-treatment time point on the sampling 
day with the higher Cmax (Day 1 or Day 29) 
• 
Concentration-QTc analysis investigating the relationship between tapinarof plasma concentration and 
∆QTcF, if data permit 
• 
Mean change from Baseline to Day 29 in PGA, PASI, and %BSA 
Statistical Methods: 
Safety and PK data will be presented in tabular and/or graphical format and summarized descriptively.  
For cardiodynamic ECG assessments, the primary analysis will be based on by-time point analysis to evaluate the 
effect of tapinarof cream, 1% on the ΔQTcF at each post-dosing time point using the Intersection Union Test.  The 
effect of tapinarof on ∆HR, ∆PR, and ∆QRS will also be evaluated using the Intersection Union Test.  An analysis 
of categorical outliers will also be performed for changes in HR, PR, QRS, QTcF, T-wave morphology and 
U-wave presence.  In addition, a potential concentration-QTc analysis will be performed if a sufficient number of 
PK samples are measurable, i.e., above the lower limit of quantification, to provide a PK profile in most subjects.  
In this concentration-QTc analysis, the relationship between tapinarof plasma concentrations and ΔQTcF will be 
evaluated using a linear mixed-effects modeling approach. 
PGA, PASI, and %BSA will be compared to Baseline values using a one sample t-test. 
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SCHEDULE OF ASSESSMENTS 
Table 1: 
Schedule of Assessments 
Procedure 
Screening (up 
to 34 days 
prior to Day 1) Day -1 
Treatment Period (Tapinarof Cream, 1% Once Daily) 
Follow-up 
(7-10 days 
after Day 29) 
or ET 
Baseline 
Day 1 
Day 2 
Day 8 
Day 15 
Day 22 
Day 29 
Day 30 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Phone Call Visit 5 Phone Call 
Visit 6 
Visit 7 
Visit 8 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Brief physical exam (including height, 
weight and BMI at Screening) 
X 
 
 
 
 
 
 
 
 
X 
Medical history (including year of 
psoriasis diagnosis) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP)  
X 
 
X 
 
 
 
 
 
 
X 
PGA, PASI, and % BSA evaluationa 
X 
 
X 
 
 
 
 
X 
 
 
HIV, Hep B and Hep C Screen 
X 
 
 
 
 
 
 
 
 
 
Laboratory assessments  
(chemistry including liver chemistries, 
hematology, urinalysis)  
X 
 
X 
 
 
 
 
X 
 
X 
LTS assessment by Investigator 
 
 
X 
 
 
X 
 
X 
 
 
Single 12-lead ECG 
X 
 
 
 
 
 
 
 
 
X 
Continuous Holter Monitoring 
 
Xb 
Xc 
Xd 
 
 
 
Xc 
Xd 
 
Vital signs 
(pre-dose; HR, BP, and temperature) 
X 
 
X 
 
 
 
 
 
 
X 
Randomization  
 
 
X 
 
 
 
 
 
 
 
Study drug Dispensation / Collection 
 
 
X 
 
 
X 
 
X 
 
 
Training on drug application 
 
 
X 
X 
X 
X 
X 
 
 
 
Dispense/collect subject diary 
 
 
X 
 
 
X 
 
X 
 
 
Tapinarof cream administration in-
clinic under site supervision  
 
 
X 
X 
 
X 
 
X 
 
 
Serial PK profile samplese 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
X 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Note:  Phone calls to subjects are on Day 8 and Day 22 
Abbreviations:  %BSA = percent body surface area; AE = adverse event; BMI = body mass index; BP = blood pressure; ECG = electrocardiogram; ET = early 
termination; Hep = hepatitis; HIV = human immunodeficiency virus; LTS = local tolerability scale; PGA = Physician Global Assessment; PASI = Psoriasis Area 
and Severity Index; PK = pharmacokinetic; SAE = serious adverse event; WOCBP = women of childbearing potential 
a The subject's scalp, palms, and soles should be excluded from the %BSA calculations. 
b On Day -1, a Holter monitor will be attached for approximately 13 hours to collect pre-treatment, time-matched ECG data.  12-lead ECGs will be extracted 
from the continuous recording at time points corresponding to time points on Day 1 and Day 29.  Subjects will rest in a supine or semi-recumbent position for 
at least 10 minutes before and 5 minutes after each time point for ECG extraction. 
c On Day 1 and Day 29, a Holter monitor will be attached one hour prior to dosing and for 12 hours post-dose.  12-lead ECGs will be extracted at the same time 
points as PK samples, i.e., pre-dose and at 1, 2, 3, 4, 5, 8, and 12 hours post-dose.  Subjects will rest in a supine or semi-recumbent position for at least 
10 minutes before and 5 minutes after each time point for ECG extraction.  All ECG extractions will be performed immediately before the PK sample is drawn. 
d On Day 2 and Day 30, a Holter monitor will be attached for one hour prior to the 24-hour post-dose PK time point to allow for extraction of 12-lead ECGs 
corresponding to the 24-hour post-dose PK time point.  Subjects will rest in a supine or semi-recumbent position for at least 10 minutes before and 5 minutes 
after the time point for ECG extraction.  The ECG extraction will be performed immediately before the PK sample is drawn. 
e On Day 1 and Day 2 (Visits 3 and 4) as well as Day 29 and Day 30 (Visits 6 and 7), serial PK profile samples will be collected at pre-dose and at 1, 2, 3, 4, 5, 
8, 12, and 24 hours after dosing.  On Day 15 (Visit 5), serial PK profile samples will be collected pre-dose and at 2 and 4 hours after dosing. 
f 
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1.3. 
Potential Risks and Benefits 
To assess any potential impact on subject eligibility with regard to safety, the Investigator must 
refer to the current version of the tapinarof investigator’s brochure for detailed information 
regarding warnings, precautions, contraindications, AEs, and other significant data pertaining to 
the study drug being used in this study. 
1.3.1. 
Risk Assessment 
1.3.1.1. 
Dermatological Adverse Events, Including Skin Irritation, or Allergic Reaction: 
Tapinarof or its excipients may induce skin irritation.  Allergic or irritant reactions in the 
exposed areas may present as erythema, edema, papules, or vesicles.  In the event of pronounced 
skin reaction, spreading of the eczematous reaction beyond the original application site(s) and/or 
more generalized (remote) skin reactions may be observed. 
In the dose-ranging study (Study 203120) in subjects with psoriasis, the most frequently reported 
dermatologic AEs were folliculitis and contact dermatitis.  In the dose-ranging study 
(Study 203121) in subjects with atopic dermatitis, the most frequently reported dermatologic 
AEs were folliculitis and atopic dermatitis.  Nonclinical dermal toxicity studies of up to 
8% tapinarof for up to 13 weeks indicated local effects are primarily mild-to-moderate skin 
irritation that is reversible; tapinarof did not show evidence of sensitization.  In initial clinical 
studies using a different formulation of tapinarof 
, AEs of skin 
hyperpigmentation, application site dermatitis, papular rash, pruritus, contact dermatitis, 
folliculitis, erythema, and skin burning sensation were reported. 
1.3.1.2. 
Systemic Adverse Events: 
Nasopharyngitis and headache were the most frequently reported nondermatological AEs in the 
dose-ranging study (Study 203120) in subjects with psoriasis.  In the dose-ranging study 
(Study 203121) in subjects with atopic dermatitis, the most frequently reported 
nondermatological AEs were nasopharyngitis, upper respiratory tract infection, and headache.  In 
the initial clinical studies (in psoriasis and atopic dermatitis) using a different tapinarof 
formulation 
, nasopharyngitis, and headache were the most frequently-reported 
nondermatological AEs.  In Study 201851 with 
of tapinarof cream, 1% and 2%, 
headache was most frequently reported during the study (reported for 100% and 60% of subjects 
at the 1% and 2% doses, respectively). 
In a nonclinical study in minipigs using IV administration, reversible decreases in arterial blood 
pressure and PR interval were observed; however, in this study and repeat dermal toxicity 
studies, there were no effects on QT interval or HR.  Repeat-dose dermal toxicity studies also 
showed findings related to the liver (increased weights and hepatocellular 
hypertrophy/regeneration) and thymus (thymic cortex depletion in adult rabbits and rats; changes 
in thymus weight, microscopic decreased cellularity, and changes in thymic T cell maturation in 
juvenile rats) with associated secondary hematological findings.  Thymic findings were also 
noted in repeat adult and juvenile rat studies; however, there were no clinically relevant 
AEs/serious adverse events (SAEs) reported. 
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To mitigate potential systemic risks, subjects will be monitored for AEs and any abnormal vital 
signs, physical examination, and laboratory test results. 
1.3.1.3. 
Reproductive and Developmental Toxicity 
Results of embryo-fetal development studies in rats and rabbits indicated an increased risk for 
embryo-fetal developmental effects, as evidenced by an increase in post-implantation loss and 
incidence of fetal skeletal variations.  Results of a juvenile rat study indicated adverse 
microscopic changes in the form of renal pelvic dilatation in both sexes, along with reversible 
increases in total urinary glucose and protein excretion in males at ≥ 10/15 mg/kg/day tapinarof 
(administered subcutaneously). 
An investigative study in rats suggested an increased risk for hydronephrosis during a narrow 
window of postnatal sensitivity prior to postnatal day (PND) 32 (specifically PND 15 to 21).  Rat 
renal tubule anatomic maturation and nephrogenesis occurs during this period [Cappon, 2010; 
Frazier, 2013; Zoetis, 2003], however tubule morphogenesis/nephrogenesis occurs entirely 
prenatally in humans [Cappon, 2010; Zoetis, 2003]. 
To mitigate these potential risks, women of childbearing potential (WOCBP) must utilize 
abstinence or a highly effective method of contraception consistently and correctly during the 
study and for 4 weeks after the end of treatment (Section 4.2).  Pregnant women and subjects 
under 18 years of age will be excluded from the study.  If a woman becomes pregnant during the 
study, she will immediately discontinue the study drug.  Additionally, AEs will be monitored and 
clinical laboratory testing will be performed. 
1.3.2. 
Benefit Assessment 
Subjects may experience improvements in their psoriasis during the course of the study and may 
benefit from the additional safety assessments conducted as part of the study (e.g., physical 
examination, laboratory tests).  Subjects in the study will also contribute to the process of 
developing a novel anti-inflammatory agent for the topical treatment of psoriasis. 
1.3.3. 
Overall Benefit Risk 
Taking into account the measures taken to minimize risk to subjects in this study, the potential 
risks identified in association with tapinarof are justified by the anticipated benefits that may be 
afforded to subjects with psoriasis. 
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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a Phase 2a, multicenter, open-label study to evaluate the safety and PK of topical 
tapinarof cream in adults with extensive plaque psoriasis.  The study will consist of three phases:  
Screening (up to 34 days), Treatment (29 days), and Follow-up (7-10 days). 
At Day -1, eligible subjects will be enrolled into the study.  During the treatment period 
beginning on Day 1 (Baseline), subjects will apply tapinarof cream, 1% to affected areas once a 
day for 29 days.  Subjects will return to the clinic on Days 2, 15, 29, and 30 for study 
assessments and will receive a phone call on Days 8 and 22.  Subjects will return to the clinic for 
a follow-up visit 7-10 days after the Day 29 visit.  On clinic visit days, subjects will apply the 
study drug under the supervision of site personnel, after assessments have been completed.  Full 
PK profiles and Holter monitoring will be collected on Day 1 and Day 29 (with corresponding 
24-hour time points collected on Day 2 and Day 30, respectively).  Limited PK sampling will be 
performed on Day 15.  Pre-treatment, time-matched Holter monitoring will be conducted on 
Day -1 and the morning of Day 1. 
Study drug will be dispensed to subjects during the clinic visits and will be administered at home 
between clinic visits as instructed by site personnel.  Subjects will be instructed to apply study 
drug once daily to all affected areas, including newly appearing plaques and plaques/areas that 
improve during the study.  Subjects will apply sufficient study drug to cover completely each 
lesion with a thin layer of study drug and will record the time of study drug application in a daily 
diary provided by the study site.  Note that subjects are allowed, but not required, to treat palms, 
fingernails, soles, toenails, and scalp plaques with study drug.  If a subject chooses to treat 
plaques on palms, fingernails, soles, toenails, and/or scalp, they should do so for the entirety of 
the treatment period from Day 1 to Day 29.  Subjects will be instructed to apply study drug in the 
morning throughout the entirety of their participation in the study.  At the phone contacts at 
Days 8 and 22, subjects should be reminded to complete their daily diary and bring it with them 
to the next clinic visit. 
Study drug application instructions will be reviewed at all post-randomization clinic visits.  On 
clinic visit days, subjects will be instructed/reminded on how to apply study drug (except during 
the final treatment/end-of-study visits).  During the clinic visits, subjects will apply the daily 
dose of study drug while on-site under the supervision of site personnel, after other assessments 
have been completed. 
Subjects who withdraw from the study before Day 30 will complete an Early Termination Visit.  
Study duration for subjects who complete this study is approximately 10 weeks in total.  Refer to 
Section 6 for descriptions of study procedures and assessments and Section 7 and the Schedule 
of Assessments (Table 1) for timing of procedures and assessments. 
3.2. 
Treatment Groups and Duration 
All subjects will receive tapinarof cream, 1% for 29 days with once daily application. 
A subject will be considered to have completed the study when he/she completes all required 
procedures/visits for the 29-day treatment phase. 
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4. 
STUDY POPULATION 
4.1. 
Type and Number of Subjects 
Approximately 20 adult subjects with extensive plaque psoriasis will be enrolled in the study at 
approximately 6 sites in the US. 
Protocol violations from inclusion and exclusion criteria are prohibited because ineligible study 
subjects can potentially jeopardize the scientific integrity of the study, regulatory acceptability, 
or subject safety.  Therefore, adherence to the criteria as specified in the protocol is essential. 
4.2. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be eligible to participate in the study: 
1. Male and female subjects ages 18 to 75 years with confirmed clinical diagnosis of 
chronic psoriasis and stable disease for at least 6 months prior to the study; 
2. BSA involvement ≥ 20% (the subject’s scalp, palms, and soles should be excluded from 
the %BSA calculations to determine eligibility at Screening); 
3. A PGA score of ≥ 3 at Screening; 
4. WOCBP and male subjects who are engaging in sexual activity that could lead to 
pregnancy must use at least 1 of the following adequate birth control methods while on 
study and for 4 weeks after the last exposure to study drug.  Acceptable contraception 
methods are: 
• Male or male partner with vasectomy, OR 
• Male condom AND partner use of one of the contraceptive options below: 
­ 
Spermicide; 
­ 
Contraceptive subdermal implant that meets effectiveness criteria including a 
< 1% rate of failure per year, as stated in the product label; 
­ 
Intrauterine device or intrauterine system that meets effectiveness criteria 
including a < 1% rate of failure per year, as stated in the product label; 
­ 
Oral contraceptive, either combined or progestogen alone; 
­ 
Injectable progestogen; 
­ 
Contraceptive vaginal ring; 
­ 
Percutaneous contraceptive patches. 
Note:  Subjects using hormonal contraceptives must have been on a stable dose for at 
least 4 weeks before Baseline. 
These allowed methods of contraception are only effective when used consistently, 
correctly, and in accordance with the product label.  The Investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception. 
Non-childbearing potential is defined as premenarchal; pre-menopausal females with a 
documented bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries) or 
hysterectomy; or hysteroscopic sterilization; or postmenopausal females defined as a 
cessation of menses for at least 12 months without an alternative medical cause.  In 
questionable cases a blood sample with simultaneous follicle-stimulating hormone 
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(FSH) > 40 mIU/mL is confirmatory.  Documented verbal history from the subject is 
acceptable. 
Subjects who are abstinent are eligible, but they must agree to use one of the birth control 
methods listed above if they start engaging in sexual activity that could lead to pregnancy 
during the study. 
WOCBP must have a negative serum pregnancy test at Screening and negative urine 
pregnancy test at Baseline (Day 1). 
5. Presence of venous access for multiple blood draws on an area that is devoid of psoriasis. 
6. Capable of giving written informed consent, as applicable, which includes compliance 
with the requirements and restrictions listed in the informed consent form (ICF); written 
informed consent must be obtained prior to performing any study related procedures. 
4.3. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded and considered ineligible for 
participation in the study: 
1. Psoriasis other than plaque variant; 
2. Any sign of infection of any of the psoriatic plaques; 
3. Concurrent conditions or history of other diseases: 
a. Immunocompromised (e.g., lymphoma, acquired immunodeficiency syndrome) or 
have a history of malignant disease within 5 years prior to the Baseline visit; 
b. Chronic or acute infection requiring treatment with systemic antibiotics, 
antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to the 
Baseline visit; 
c. Acute active bacterial, fungal, or viral (herpes simplex, herpes zoster, or chicken 
pox) skin infection within 1 week prior to the Baseline visit; 
d. Significant dermatologic or inflammatory condition other than plaque psoriasis 
that, in the Investigator’s opinion, would make it difficult to interpret data or 
assessments during the study. 
4. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 
2x upper limit of normal (ULN); 
5. Screening total bilirubin > ULN; total bilirubin > ULN and ≤ 1.5x ULN is acceptable if 
bilirubin is fractionated and direct bilirubin < 35%; 
6. QTcF interval > 470 msec; 
7. Current or chronic history of liver disease, known hepatic or biliary abnormalities (with 
the exception of Gilbert's syndrome or asymptomatic gallstones), presence of hepatitis B 
surface antigen (HBsAg), or positive hepatitis C antibody test result, or a positive anti-
hepatitis B core antigen (anti-HBc) result; 
8. Ultraviolet (UV) light therapy or prolonged exposure to natural or artificial sources of 
UV radiation (e.g., phototherapy, tanning beds/booths, or therapeutic sunbathing) within 
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4 weeks prior to the Baseline visit and/or plans to have such exposures during the study 
which could potentially impact the subject’s psoriasis (as determined by the Investigator); 
9. Use of any prohibited medication within the indicated period before the Baseline visit: 
NOTE:  Prohibited concomitant medications, therapy, etc., during the defined period 
areas listed in the bullets below.  If a subject requires any of these medications 
throughout the study period, he/she may be excluded from or discontinued from the 
study, at the discretion of the Investigator and Medical Monitor. 
• Minimum of 5 half-lives for biologic agents:  e.g., 12 months for rituximab; 
8 months for ustekinumab; 5 months for secukinumab; 12 weeks for golimumab; 
10 weeks for ixekizumab; 8 weeks for infliximab, adalimumab, or alefacept; and 
4 weeks for etanercept; 
• 4 weeks for systemic treatments:  cyclosporin, interferon, methotrexate, 
apremilast, tofacitinib, mycophenolate, thioguanine, hydroxyurea, sirolimus, 
azathioprine, other systemic immunosuppressive or immunomodulating agents, 
fumaric acid derivatives, Vitamin D and analogs, retinoids (e.g., acitretin, 
isotretinoin), psolarens, corticosteroids, or adrenocorticotropic hormone analogs; 
• 2 weeks for immunizations with a live viral component; 
• 2 weeks for drugs known to possibly worsen psoriasis, such as beta-blockers 
(e.g., propranolol), lithium, iodides, angiotensin-converting enzyme inhibitors, 
and indomethacin, unless on a stable dose for > 12 weeks; 
• With the exception of emollients, 2 weeks for topical treatments including 
corticosteroids, immunomodulators, anthralin (dithranol), Vitamin D derivatives 
(e.g., calcipotriene, calcipotriol), retinoids (e.g., tazarotene), or coal tar. 
10. A history of or ongoing serious illness or medical, physical, or psychiatric condition(s) 
that, in the Investigator’s opinion, may interfere with the subject’s participation in the 
study and ability to understand and give informed consent. 
11. Pregnant females as determined by positive serum (Screening) or urine (Baseline) human 
chorionic gonadotropin test at Screening or prior to dosing; 
12. Lactating females; 
13. History of sensitivity to the study drug, or components thereof, or a history of drug or 
other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates 
the subject’s participation in the study; 
14. The subject has received an investigational drug within the following time period prior to 
the first dosing day in the current study:  30 days, 5 half-lives, or twice the duration of the 
biological effect of the investigational drug (whichever is known to be longer); 
15. Current or a history of cancer within 5 years except for fully excised skin basal cell 
carcinoma, squamous cell carcinoma or carcinoma in situ of the cervix; 
16. Subjects with active infection that required oral, intramuscular, or intravenous (IV) 
administration of antibiotics, antifungal, or antiviral agents within 7 days of the Baseline 
visit; 
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17. Concurrent skin lesions in the treatment area that, in the opinion of the Investigator, 
would either interfere with study evaluations or affect the safety of the subject; 
18. Subjects with advanced disease or abnormal laboratory test values that could affect the 
safety of the subject or the implementation of this study; 
19. Previous known participation in a clinical study with tapinarof; 
20. Evidence of significant hepatic, renal, respiratory, endocrine, hematologic, neurologic, 
psychiatric, or CV system abnormalities or laboratory abnormality that will affect the 
health of the subject or interfere with interpretation of the results. 
4.4. 
Lifestyle Restrictions 
Subjects must avoid UV light, phototherapy, and excessive sun exposure throughout the study.  
When prolonged exposure cannot be avoided, use of sunscreen products (except on psoriasis 
plaques) and protective apparel are recommended. 
4.5. 
Screening/Baseline Failures 
To determine subject eligibility at Screening and Baseline, a single repeat of tests or procedures 
may be allowed at the discretion of the Investigator in consultation with the Medical Monitor. 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently enrolled.  A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure subjects to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities.  Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAEs. 
4.6. 
Withdrawal Criteria 
A subject may voluntarily discontinue treatment and/or withdraw from participation in this study 
at any time at his/her own request or may be discontinued from study drug at any time at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons.  
Subjects who discontinue from the study prematurely may be replaced at the discretion of the 
Sponsor. 
4.6.1. 
Reasons for Withdrawal from the Study 
Study drug will be discontinued for any of the following reasons: 
• Subject has an AE that is considered to be related to study drug or procedures AND is 
severe enough to warrant treatment discontinuation, as determined by the Investigator 
• Subject requires concurrent prohibited medication during the study.  If, in the opinion of 
the Investigator and the study Medical Monitor, such medication will not interfere with 
the conduct or interpretation of the study or compromise the safety of the subject, then 
the subject may continue to receive study drug. 
• Pregnancy 
• Any Grade 3 or 4 AE considered causally related to study drug 
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Study drug may be discontinued for any of the following reasons: 
• Subject noncompliance 
• Investigator noncompliance 
• Discontinuation of the study at the request of the Sponsor, regulatory agency, or an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
If a subject meets a withdrawal criterion during treatment, an Early Termination Visit will be 
required (Section 7.10). 
4.6.2. 
Withdrawal Procedures 
The primary reason for the discontinuation of study drug and/or withdrawal from study must be 
recorded in the source document and on the electronic case report form (eCRF).  If a subject is 
prematurely discontinued from study drug, the Investigator must make every effort to perform an 
Early Termination Visit (Section 7.10) and document the primary reason for withdrawal. 
Should a subject fail to attend a required study visit, the site should attempt to contact the subject 
and reschedule the missed visit as soon as possible.  The site should also counsel the subject on 
the importance of maintaining the assigned visit schedule and ascertain whether the subject 
wishes to and/or should continue in the study based on previous noncompliance.  In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule the 
missed visit, the site should make every effort to regain contact with the subject so that they can 
appropriately be withdrawn from the study with a primary reason of “Lost to Follow-up.” 
4.7. 
Lost to Follow-Up 
A subject is considered lost to follow-up if he/she repeatedly fails to return to the study site for 
scheduled visits and is unable to be contacted by the study site.  The following actions must be 
taken if a subject fails to return to the clinic for a required study visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in the 
study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, if 
necessary, a certified letter to the subject’s last known mailing address or local equivalent 
methods).  These contact attempts should be documented in the subject’s medical record. 
• Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
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5.1.4. 
Preparation 
No special preparation of study drug is required. 
5.1.5. 
Administration of Study Drug 
Study drug will be dispensed to subjects at the clinical site in appropriately labeled tubes. 
Subjects will take the tubes home and self-administer study drug (or have caregiver apply if 
necessary), except on clinic visit days (when study drug is applied under supervision at the site), 
to affected areas once daily. 
Subjects will be instructed to apply study drug as follows: 
• Once daily application to affected areas each morning. 
• Study drug should be applied to dry, clean skin. 
• Wash hands after application, unless treating plaques on the hands or fingernails. 
• Study drug should be applied to all plaques, including newly appearing plaques and 
plaques that have improved during the study. 
• Subjects are allowed, but not required, to treat palms, fingernails, toenails, and scalp 
plaques with study drug.  If using study drug on scalp, no other treatment for scalp 
psoriasis is permitted during the study.  If a subject chooses to treat plaques on palms, 
fingernails, soles, toenails, and/or scalp, they should do so for the entirety of the 
treatment period from Day 1 to Day 29. 
• If there is residual cream visible on the disease-affected skin, then the subject should be 
instructed to continue to lightly rub the cream into the skin until it is no longer visible. 
• If study drug is applied to the subject by another person, that person should thoroughly 
wash his/her hands after application.  When possible, use of disposable gloves is 
recommended. 
• Subject should record the time of study drug application in the daily diary. 
• Subjects should avoid swimming, bathing, showering, or strenuous activities for at least 
2 hours after application of study drug. 
• On clinic visit days, study drug should be applied in the clinic under the supervision of 
site personnel and after assessments have been completed. 
NOTE:  The time of the dose and assessments on clinic visit days will depend on the time 
of the clinic visit (clinic visits should be scheduled for the morning to allow time to 
complete all study procedures).  While the subjects should be instructed to apply study 
drug in the morning throughout the entirety of their participation in the study, the timing 
of the clinic visit may lead to a slight deviation from the subject’s normal dosing time; if 
this occurs, it will NOT be considered a protocol deviation; the subject should resume 
their morning dosing time following any such clinic visit application. 
• Subjects will be instructed/reminded on how to apply study drug at each clinic visit and 
phone call (except during the final treatment visit). 
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5.2. 
Randomization/Treatment Assignment 
All subjects will receive tapinarof cream, 1% once daily for 29 days. 
5.3. 
Blinding 
This will be an open-label study. 
5.4. 
Compliance with Study Drug Administration 
At Baseline, study staff will provide the subject with detailed instructions concerning protocol 
requirements and use of study drug.  Additionally, subjects will be asked to complete a daily 
diary with the time of each application of study drug.  At each post-Baseline study visit, study 
staff will review use of study drug, as applicable, with the subject. 
When subjects are dosed at the site, they will apply the study drug under supervision of the study 
staff.  The date and time of each dose administered in the clinic will be recorded in the source 
documents.  The study drug and study subject identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person dispensing the study drug. 
At the time of dispensing study drug to each subject, site personnel will weigh the tubes to be 
dispensed and will record the weight of all tubes dispensed at each visit in the drug 
accountability log.  Subjects will be instructed to bring all used and unused tubes of study drug 
with them to each study visit.  Site personnel will weigh returned tubes (used and unused) and 
record the combined tube weight in drug accountability log.  If a tube has been lost, discarded, or 
forgotten by the subject, then the site personnel will make a notation of this on the drug 
accountability log.  The site personnel will remind the subject to keep all tubes of study drug 
dispensed and to bring all used and unused tubes to each clinic visit.  These data will be used to 
estimate subject compliance with use of study drug.  Tubes of study drug dispensed at the most 
recent prior visit which remain unopened (the foil cap on the tube remains fully 
intact/undisturbed) may be re-dispensed to study subjects at the current visit.  Opened, partially 
used tubes or tubes with foil overlay removed are not to be re-dispensed to study subjects.  If 
there is any question as to re-dispensation, sites should issue new tubes of study drug to the 
subject(s). 
5.5. 
Treatment after the End of the Study 
Subjects will not receive any additional treatment with the study drug from the Sponsor after 
completion of the study because the indication being studied is not life-threatening or seriously 
debilitating and other treatment options are available. 
The Investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition. 
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5.6. 
Prior and Concomitant Therapy 
Any medication (including over the counter or prescription medication, vitamins and/or herbal 
supplements) administered to the subject up to 30 days before the Screening visit, at the time of 
enrollment, and during the study must be recorded in the eCRF along with the reason for use.  
The information to be recorded must also include name of the medication (generic name, as a 
general rule), dose, frequency, administration routes, and dates of the first and last dose, as 
applicable. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
5.6.1. 
Permitted Medications and Nondrug Therapies 
Concomitant medications for medical treatment of other conditions are allowed under the 
condition that the dosage and administration of these treatments are not planned to change during 
the course of the study and that the medication is not a prohibited medication as described in the 
Exclusion Criteria (Section 4.3). 
In the event of skin infection, topical antibacterial agents can be applied to the infected area; 
however, study drug must not be applied to the area until the skin infection is healed. 
Subjects may use nonmedicated shampoos (must not contain corticosteroids, Vitamin D analogs, 
salicylic acid, or coal tar). 
Nonmedicated emollients may be used on nonlesional skin; emollients should not be applied to 
lesional skin during treatment and should not be applied on the morning of clinic visits.  The 
same emollient should be used throughout the subject’s participation in the study. 
Note:  Any emollient used during the study must be recorded as a concomitant medication. 
5.6.2. 
Prohibited Medications and Nondrug Therapies 
Medications and nondrug therapies that are prohibited throughout the study duration are as 
follows: 
• Biologic agents:  rituximab, ustekinumab, secukinumab, golimumab, ixekizumab, 
infliximab, adalimumab, alefacept, etanercept (list is not exclusive, contact Medical 
Monitor for questions) 
• Systemic treatments:  cyclosporin, interferon, methotrexate, apremilast, tofacitinib, 
mycophenolate, thioguanine, hydroxyurea, sirolimus, azathioprine, other systemic 
immunosuppressive or immunomodulating agents, fumaric acid derivatives, Vitamin D3 
and analogs, retinoids (e.g., acitretin, isotretinoin), psoralens, corticosteroids, or 
adrenocorticotropic hormone analogs 
• UV light:  UV light therapy or prolonged exposure to natural or artificial sources of UV 
radiation (e.g., phototherapy, tanning beds/booths, or therapeutic sunbathing); When 
prolonged exposure cannot be avoided, use of sunscreen products (except on psoriasis 
plaques) and protective apparel are recommended. 
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• Topical treatments:  corticosteroids, immunomodulators, anthralin (dithranol), 
Vitamin D derivatives (e.g., calcipotriene, calcipotriol), retinoids (e.g., tazarotene), or 
coal tar 
• Drugs known to possibly worsen psoriasis (unless on a stable dose for >12 weeks):  
beta blockers (e.g., propranolol), lithium, iodides, angiotensin-converting enzyme 
inhibitors, and indomethacin 
• Immunizations:  live, attenuated vaccines (inactivated or subunit vaccines are acceptable 
when required) 
• Other:  Any study drugs or investigational procedures 
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6. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and assessments are summarized in the Schedule of Assessments and in 
Section 7.  Adherence to the study design requirements, including those specified in the Schedule 
of Assessments (Table 1) are essential and required for study conduct.  Protocol waivers or 
exemptions are not allowed, except for immediate safety concerns. 
6.1. 
Medical History, Demography, and Baseline Characteristics 
6.1.1. 
Medical History 
Medical history will be collected to ensure subjects are eligible for participation in the study (per 
inclusion [Section 4.2] and exclusion [Section 4.3] criteria). 
Data collected will include year of plaque psoriasis diagnosis, CV medical history and risk 
factors (including height, weight, blood pressure (BP), smoking history, medical conditions, and 
family history of premature CV disease) and family history of liver disease. 
6.1.2. 
Demographics 
Demographic information collected will include age, sex, race, and ethnicity. 
6.1.3. 
Baseline Characteristics 
During Screening, single 12-lead electrocardiograms (ECGs) will be obtained using an 
ECG machine that automatically calculates the heart rate (HR) and measures PR, QRS, QT, and 
QTcF intervals.  Subjects should be in a supine or semi-recumbent position for at least 5 minutes 
before ECG is measured. 
Holter monitoring will be conducted for approximately 13 hours on Days -1, 1 and 29, and 
approximately 1 hour on Days 2 and 30 to collect pre-treatment and time-matched ECG data. 
6.2. 
Psoriasis Disease Assessments 
6.2.1. 
Physician Global Assessment 
The PGA is a clinical tool for assessing the current state/severity of a subject’s psoriasis at a 
given time point.  It is a static 5-point morphological assessment of overall disease severity, as 
determined by the Investigator, using the clinical characteristics of erythema, scaling, and plaque 
thickness/elevation as guidelines; higher PGA scores represent more severe disease.  The BSA 
affected is not considered in scoring of the PGA (see Section 6.2.2 for details on BSA scoring).  
Variations of the PGA are frequently used in clinical studies because it is a simple assessment 
that is more similar to the assessments actually used in clinical practice (see Appendix 1 for 
details).  The PGA should be performed first, prior to %BSA, PASI, and Local Tolerability 
Scale (LTS) assessments. 
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6.2.2. 
Body Surface Area Affected 
The assessment of the %BSA affected is an estimate of the percentage of total involved skin with 
psoriasis.  For the purpose of clinical estimation, the total palmar surface of the subject’s palm 
(including fingers) may be assumed to be approximately equivalent to 1% BSA.  The %BSA 
affected by psoriasis will be evaluated (from 0 to 100%).  Details on calculation of approximate 
%BSA involvement in each subject (total and individual areas) are provided in Appendix 2.  
%BSA is a static assessment made without reference to previous scores.  Note that plaques on 
the scalp, palms, and soles should be excluded from the %BSA calculations used to determine 
eligibility. 
6.2.3. 
Psoriasis Area and Severity Index 
The PASI scoring system is a widely used standard clinical tool for assessing the severity of 
psoriasis that takes into account the overall severity of erythema (redness), induration (plaque 
thickness), and scale, and the extent of %BSA affected with psoriasis.  The 3 clinical signs are 
each graded on a 5-point scale (0 to 4) and the %BSA affected is scored on a 7-point scale 
(0 to 6) for each of the 4 specified body regions (head, upper extremities, trunk, and lower 
extremities).  The individual scores are multiplied by a weighted factor for each body region; the 
sum of these scores gives the overall PASI score.  Higher scores indicate more severe disease.  
PASI is a static assessment made without reference to previous scores.  Details on PASI 
calculation are provided in Appendix 2. 
6.3. 
Safety Assessments 
6.3.1. 
Adverse Events 
All AEs will be collected from the time the subject signs the ICF until the final visit/contact with 
the subject.  Additional safety information, including the definition of an AE and the methods for 
recording, evaluating, and assessing causality of AEs and the procedures for completing and 
transmitting SAE reports are provided in Section 8. 
6.3.2. 
Brief Physical Exam 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, CV 
system, and abdomen (liver and spleen).  Height and weight will be measured at Screening only.  
Investigators should pay special attention to clinical signs related to previous serious illness. 
6.3.3. 
Vital Signs 
Vital signs will be measured before blood collection for clinical laboratory assessments and PK 
analysis (where applicable) and will include measurement of systolic and diastolic BP, HR, and 
body temperature.  Subjects should be in a supine or semi-recumbent position for at least 
5 minutes before vital signs measurement. 
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6.3.4. 
Clinical Safety Laboratory Assessments 
All protocol-required laboratory assessments must be conducted in accordance with the Study 
Reference Manual or Laboratory Manual and the protocol Schedule of Assessments (Table 1).  
Laboratory requisition forms must be completed, and samples must be clearly labeled with the 
subject number, protocol number, site/center number, and visit date.  Details for the preparation 
and shipment of samples will be provided by the laboratory and are detailed in the Study 
Reference Manual or the Laboratory Manual.  Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments. 
A list of clinical laboratory tests and parameters is provided in Table 3. 
All laboratory tests with values that are considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or Baseline.  If 
such values do not return to normal within a period judged reasonable by the Investigator, the 
etiology should be identified, if possible, and the Sponsor notified. 
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6.3.7. 
Continuous Holter Monitoring 
The 12-lead Holter and ECG equipment will be supplied and supported by ERT.  All ECG data 
will be collected using a Global Instrumentation (Manlius, NY, USA) M12R ECG continuous 
12-lead digital recorder.  The continuous 12-lead digital ECG data will be stored onto secure 
digital memory cards.  ECGs to be used in the analyses will be selected by pre-determined time 
points as defined in the Schedule of Assessments (Table 1) and will be read centrally by ERT. 
The following principles will be followed in ERT’s core laboratory: 
• ECG analysts are blinded to the subject number and visit; 
• Baseline and on-treatment ECGs for a particular subject will be over-read on the same 
lead and will be analyzed by the same reader; 
• The primary analysis lead is lead II.  If lead II is not analyzable, then primary lead of 
analysis will be changed to another lead for the entire subject data set. 
The following is a brief description of ECG analysis methods utilized by ERT’s core laboratory: 
TQT Plus ECG Extraction Technique 
• Ten 14-second digital 12-lead ECG tracings will be extracted from the continuous Holter 
recordings using the ‘Thorough QT Plus method,’ a computer-assisted and statistical 
process utilized by ERT.  The method enables extraction of ECGs with the lowest HR 
variability and noise within the protocol-specified extraction time window (e.g., the HR 
and QT changes from beat-to-beat in the range of < 10%).  At each protocol-specified 
time point, 10 ECG replicates will be extracted from a 5-minute “ECG window” 
(typically, the last 5 minutes of the 15-minute period when the subject is maintained in a 
supine or semi-recumbent quiet position). 
Expert-Precision QT Analysis 
• Expert-precision QT analysis will be performed on all analyzable (non-artifact) beats in 
the 10 ECG replicates.  Statistical quality control procedures are used to review and 
assess all beats and identify “high” and “low” confidence beats using several criteria, 
including: 
o QT or QTc values exceeding or below certain thresholds (biologically unlikely); 
o RR values exceeding or below certain thresholds (biologically unlikely); 
o Rapid changes in QT, QTc or RR from beat to beat. 
• Measurements of all primary ECG parameters (QT, QTc, RR) in all recorded beats of all 
replicates that are deemed “high confidence” are performed using COMPAS software.  
All low confidence beats are reviewed manually and adjudicated using pass-fail criteria.  
The final QC assessment is performed by a cardiologist.  The beats found acceptable by 
manual review are included in the analysis.  The median QT, QTc, and RR values from 
each extracted replicate are calculated, and then the mean of all available medians from a 
nominal time point is used as the subject’s reportable value at that time point. 
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• Categorical T-wave morphology analysis and the measurement of PR and QRS intervals 
will be performed manually in 3 of the 10 ECG replicates at each time point.  Each 
fiducial point (onset of P-wave, onset of Q-wave, offset of S-wave, and offset of T-wave) 
is electronically marked. 
• For T-wave morphology and U-wave presence, treatment-emergent changes will be 
assessed, i.e., changes not present at Baseline.  For each category of T-wave morphology 
and U-waves, the category will be deemed as present if observed in all replicates at the 
time point.  For Baseline, the category will be deemed as present if observed in all 
replicates from all time points that constitute Baseline.  The T-wave morphology 
categories are described as follows: 
Category 
Description 
Normal T-wave 
Any positive T-wave not meeting any criterion below 
Flat T-wave 
T amplitude < 1 mm (either positive or negative) including flat isoelectric line 
Notched T-wave (+) 
Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending 
arm of the positive T-wave 
Biphasic 
T-wave that contains a second component with an opposite phase that is at least 
0.1 mV deep (both positive/negative and negative/positive and polyphasic 
T-waves included) 
Normal T-wave (-) 
T amplitude that is negative, without biphasic T wave or notches 
Notched T-wave (-) 
Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending 
arm of the negative T-wave 
U-waves 
Presence of abnormal U-waves 
6.4. 
Treatment of Study Drug Overdose 
For this study, accidental or intentional oral ingestion of study drug or excessive application onto 
the skin (e.g., using a greater quantity, or applying more frequently than instructed) will be 
considered an overdose.  Ingestion of a 30 gram tube of tapinarof cream, 1% would result in an 
oral dose of 300 mg. 
The Sponsor does not recommend specific treatment for an overdose; however, in the event of an 
overdose, the Investigator (or treating physician) should do the following: 
• Contact Medical Monitor to discuss the event; 
• In the event of excessive topical application, instruct the subject to wash study drug off of 
the skin and monitor for application-site AEs; 
• Closely monitor the subject for AEs/SAEs and laboratory abnormalities; 
• Provide general symptomatic treatment as necessary; 
• Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF; 
• If the Medical Monitor requests a plasma sample for PK analysis, then a blood sample for 
PK should be obtained within 2 days from the date of the last dose of study drug. 
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Decisions regarding dose interruptions or modifications following an overdose will be made by 
the Investigator in consultation with the Medical Monitor based on the clinical evaluation of the 
subject. 
6.5. 
Pharmacokinetics 
Blood samples for PK analysis of tapinarof cream, 1% will be collected at time points indicated 
in the Schedule of Assessments (Table 1) and Section 7.  The actual date and time of each blood 
sample collection will be recorded as well as the date and time of the last dose of study drug 
prior to sample collection.  Collection, processing, storage, and shipping procedures are provided 
in the Laboratory Manual. 
Concentrations of tapinarof and tapinarof sulfate (metabolite) will be determined in plasma 
samples using a validated bioanalytical method.  Raw data will be archived at the bioanalytical 
site.  From the plasma concentration-time data on Days 1 and 29, the following primary PK 
parameters will be determined, if data permit:  AUC0-τ, Cmax, tmax, and t½. 
Limited PK sampling will be performed on Day 15. 
Once the plasma has been analyzed for tapinarof and tapinarof sulfate (metabolite), 
any remaining plasma may be analyzed for other metabolites. 
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7. 
TIMING OF PROCEDURES AND ASSESSMENTS 
This section lists the procedures and assessments to be performed at scheduled time points 
during the study as outlined in the Schedule of Assessments (Table 1).  Information on study 
procedures and assessments is provided in Section 6. 
• Any change in timing or any addition of a time point(s) for any planned study assessment 
must be documented in a “Note to File,” which is approved by the relevant Sponsor study 
team member and then archived in the study Sponsor and site study files; this will NOT 
constitute a protocol amendment. 
• The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF. 
NOTE:  Assessments and procedures should be performed pre-dose on clinic visit days. 
7.1. 
Visit 1; Screening Period (Up to 34 Days Prior to Day 1) 
After the subject has signed the ICF, potential study subjects will undergo Screening procedures 
and assessments to confirm eligibility to participate in the study.  Screening assessments will 
include the following: 
• Serum pregnancy test (WOCBP only) 
• ECG recording 
• Medical history recording 
• Demography recording 
• Brief physical exam (including weight, height, and body mass index [BMI]) 
• Vital signs measurements 
• PGA score 
• %BSA affected calculation (performed before PASI); subject’s scalp, palms, and soles 
should be excluded from the %BSA calculations used to determine eligibility 
• PASI 
• Blood and urine sample collection for clinical laboratory tests (serum chemistry, 
hematology, diagnostic tests) 
• AE recording (from the time the ICF is signed) 
• Concomitant medication recording (from the time ICF is signed) 
To determine subject eligibility at Screening, a single repeat of tests or procedures may be 
allowed at the discretion of the Investigator in consultation with the Medical Monitor. 
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7.2. 
Visit 2; Day -1 
On Day -1, subjects will be reassessed to confirm continued eligibility to participate in the study. 
The following additional procedures and assessments will be performed at Visit 2: 
• AE recording 
• Concomitant medication recording 
• Continuous Holter Monitoring for 13 hours 
7.3. 
Visit 3; Day 1 (Baseline) 
On Day 1, subjects will be reassessed to confirm eligibility to participate in the study.  All 
subjects who continue to meet study eligibility criteria will receive study drug. 
The following additional procedures and assessments will be performed at Visit 3: 
• Urine pregnancy test (WOCBP only) 
• Vital signs measurements 
• PGA score 
• %BSA affected calculation (performed before PASI); subject’s scalp, palms, and soles 
should be excluded from the %BSA calculations 
• PASI 
• Continuous Holter Monitoring for 13 hours (1 hour prior to dosing and 12 hours 
post-dose) 
• Blood and urine sample collection for clinical laboratory tests 
• Blood sample collection for PK analysis and 
 
• AE recording 
• Concomitant medication recording 
• Paper diary dispensed (subjects will be instructed in how and when to complete diary) 
• LTS scoring 
• Dispense study drug 
• Instruction on how to administer study drug 
• Study drug administration under supervision 
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7.4. 
Visit 4; Day 2 
The following procedures and assessments will be performed at Visit 4: 
• Continuous Holter Monitoring for 1 hour (1 hour prior to PK sample collection) 
• Blood sample collection for PK analysis and 
 
• AE recording 
• Concomitant medication recording 
• Instruction on how to administer study drug 
• Study drug administration under supervision 
7.5. 
Day 8 (Phone Call) 
The following procedures and assessments will be performed by phone call on Day 8: 
• AE recording 
• Concomitant medication recording 
• Instruction on how to administer study drug 
7.6. 
Visit 5; Day 15 
The following procedures and assessments will be performed at Visit 5: 
• Collect and dispense study drug 
• Collect and dispense subject diary 
• Blood sample collection for PK analysis 
• AE recording 
• Concomitant medication recording 
• LTS scoring 
• Instruction on how to administer study drug 
• Study drug administration under supervision 
7.7. 
Day 22 (Phone Call) 
The following procedures and assessments will be performed by phone call on Day 22: 
• AE recording 
• Concomitant medication recording 
• Instruction on how to administer study drug 
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7.8. 
Visit 6; Day 29 
The following procedures and assessments will be performed at Visit 6: 
• PGA score 
• %BSA affected calculation (performed before PASI); subject’s scalp, palms, and soles 
should be excluded from the %BSA calculations 
• PASI 
• Continuous Holter Monitoring for 13 hours (1 hour prior to dosing and 12 hours 
post-dose) 
• Collect subject diary 
• Blood and urine sample collection for clinical laboratory tests 
• Blood sample collection for PK analysis and 
 
• AE recording 
• Concomitant medication recording 
• LTS scoring 
• Study drug administration under supervision 
• Collect study drug 
7.9. 
Visit 7; Day 30 
The following procedures and assessments will be performed at Visit 7: 
• Continuous Holter Monitoring for 1 hour (1 hour prior to PK sample collection) 
• Blood sample collection for PK analysis and 
 
• AE recording 
• Concomitant medication recording 
7.10. 
Visit 8; Follow-Up (7-10 days After Day 29)/Early Termination 
Follow-up/Early Termination assessments are as follows: 
• ECG recording 
• Urine pregnancy test (WOCBP only) 
• Brief physical examination 
• Vital signs measurements 
• Blood and urine sample collection for clinical laboratory tests 
• AE recording 
• Concomitant medication recording 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events, Treatment-Emergent Adverse Events, Serious 
Adverse Events, and Adverse Events of Special Interest 
The Investigator or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an AE, TEAE, SAE, or adverse event of special interest (AESI).  At each 
visit/contact, subjects should be questioned in a general way so as not to introduce bias in 
detecting AEs, TEAEs, and/or SAEs.  Open-ended and non-leading verbal questioning of the 
subject is the preferred method to inquire about AE and TEAE occurrence. 
Investigators are not obligated to actively seek AEs, TEAEs, or SAEs in former study subjects.  
However, if the Investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably related to the study 
drug or study participation, the Investigator should promptly notify the Sponsor. 
8.1.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a subject temporally associated with 
the use of a study drug, whether considered causally related or not related to the study drug. 
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 a study drug. 
Events meeting the definition of an AE include: 
• Any abnormal laboratory test results (e.g., hematology, clinical chemistry) or other safety 
assessments (e.g., vital signs measurements), including those that worsen from Baseline, 
and felt to be clinically significant in the medical and scientific judgment of the 
Investigator; 
• Exacerbation of a chronic or intermittent pre-existing condition (e.g., atopic dermatitis) 
including either an increase in frequency and/or intensity of the condition; 
− For skin-related AEs, it should be noted whether or not the event is in the area of 
active application of study drug, and/or if spreading beyond the application site. 
• New conditions detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study; 
• Signs, symptoms, or the clinical sequelae of a suspected interaction; 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or 
a concomitant medication (overdose per se will not be reported as an AE/SAE); 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as AE or SAE if they fulfill the definition 
of an AE or SAE. 
• Evaluation of local tolerability at the site of topical application (e.g., burning/stinging, 
pruritus, and erythema). 
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Events that do not meet the definition of an AE include: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’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 subject’s 
condition; 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE. 
• Situations where 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. 
8.1.2. 
Definition of Treatment-Emergent Adverse Event 
 A TEAE is an AE that occurs following the first application of study drug. 
8.1.3. 
Definition of Serious Adverse Event 
If an event is not an AE per Section 8.1.1 or  a TEAE per Section 8.1.2, then it cannot be an SAE 
even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under 
study, death due to progression of disease, etc.). 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death; 
• Is life-threatening refers to an event in which the subject was at risk of death at the time 
of the event.  It does not refer to an event, which hypothetically might have caused death, 
if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization; 
− In general, signifies that the subject 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. 
• Results in disability/incapacity:  a substantial disruption of a person’s ability to conduct 
normal life functions; 
− This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
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influenza, and accidental trauma (e.g., sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption. 
• Results in a congenital anomaly/birth defect; 
• Medical or scientific judgment should be exercised in deciding whether 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 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are 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. 
8.1.4. 
Adverse Events of Special Interest 
In prior clinical studies, the following AEs have been identified as AEs of particular clinical 
importance and will be reported as AESIs in this study; in each case study drug may be 
discontinued, based upon Investigator’s judgment, and the subject may be discontinued from the 
study. 
• Contact dermatitis:  the study site should collect location, duration, size, associated 
symptoms (itching, burning, pain), severity (mild, moderate, or severe), and photograph 
the affected site (if possible).  If subject contacts the study site to report significant skin 
irritation at or near the site of study drug application between study visits, the subject 
should be brought for an unscheduled visit, if possible. 
• Folliculitis:  the study site should collect the location, duration, size, associated 
symptoms (itching, burning, pain), severity (mild, moderate, or severe), indicate whether 
pustular, and photograph the affected site (if possible). 
• Headache:  site should collect duration, severity (mild, moderate, or severe), onset, and 
location. 
For each AESI, a narrative may be written and included in the Clinical Study Report. 
8.2. 
Classification of Adverse Events 
8.2.1. 
Assigning Severity Rating for Adverse Events 
8.2.1.1. 
Criteria for Determining Adverse Event Severity 
The Investigator will make an assessment of the severity of each AE and SAE according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), 
v. 5.0, 2017.  For terms not specified with the CTCAE, the criteria in Table 5 should be used to 
determine the grade severity. 
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Table 5: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE 
Grade 
Criteria 
1 
Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; intervention not 
indicated 
2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily livinga 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation 
of hospitalization indicated; disabling; limiting self-care activities of daily livingb 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
Abbreviation:  AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
AE severity should be recorded in the appropriate section of the eCRF and in the subject’s source 
documents. 
8.2.1.2. 
Toxicity Management Criteria 
8.2.1.2.1. Grade 1 or Grade 2 Adverse Event 
Subjects who develop a Grade 1 or Grade 2 AE may continue study drug at the discretion of the 
Investigator.  Subjects who choose to withdraw from study due to a Grade 1 or 2 AE should have 
early termination assessments completed as outlined in Section 7.10. 
8.2.1.2.2. Grade 3 Adverse Event 
Subjects who develop a Grade 3 AE should be managed as follows: 
• If the Investigator has compelling evidence that the Grade 3AE has not been caused 
by study drug, then dosing may continue after discussion with the Medical Monitor. 
• Subjects who develop a Grade 3 AE that the Investigator considers related to study 
drug should have the study drug discontinued.  Subjects experiencing Grade 3 AEs 
requiring permanent discontinuation of study drug should be followed weekly until 
resolution or stability of the AE and encouraged to have early termination 
assessments completed as outlined in Section 7.10. 
8.2.1.2.3. Grade 4 Adverse Event 
Subjects who develop a Grade 4 AE should have study drug permanently discontinued. 
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of study drug should be 
followed weekly until resolution or stability of the AE and encouraged to have early termination 
assessments completed as outlined in Section 7.10. 
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8.2.1.2.4. Other Management Criteria 
The Medical Monitor should be notified if any of the following occur: 
• Severe signs or symptoms, or significant changes in any of the safety assessments, 
that put the safety of the subject at risk (e.g., laboratory tests or vital signs, etc.) as 
judged by the Investigator. 
8.2.2. 
Assigning Causal Relationship to Study Drug 
The Investigator is to make the causality assessment.  Causality assessment is not to be 
delegated; however, if delegation is unavoidable due to Investigator inaccessibility, this must be 
recorded as a protocol deviation.  The reasonable possibility of the relationship of an AE to study 
drug is to be assessed with careful medical consideration at the time of evaluation of an AE.  The 
following definitions are to be used for the relationship of the AE to study drug: 
• Related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration that makes a causal relationship plausible, 
unlikely attributed to concurrent disease or other drugs or chemicals, and that follows a 
clinically reasonable response on re-administration (rechallenge) or withdrawal 
(dechallenge), although information on drug withdrawal may be lacking or unclear. 
• Not related:  A clinical event, including laboratory test abnormality, with a temporal 
relationship to study drug administration that makes a causal relationship improbable 
and/or in which other drugs, chemicals, or underlying disease provide a plausible 
explanation. 
Any AEs /SAEs assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to study drug will be recorded from the 
time a subject consented to participate in the study up to and including any follow-up contact. 
All AEs, whether related to study drug or not, must be fully and completely documented on the 
AE page of the eCRF and in the subject’s clinical record.  In the event a subject is withdrawn 
from the study because of an AE, the primary reason for withdrawal (i.e., due to an AE) must be 
recorded on the eCRF as such. 
8.3. 
Time Period and Frequency for Event Assessment and Follow-Up 
8.3.1. 
Adverse Event and Serious Adverse Event Reporting 
All AEs will be collected from the time of signed ICF until the final visit. 
Any AEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive 
tests, or change in existing therapy) will be recorded from the time a subject consented to 
participate in the study up to and including any follow-up contact. 
All SAEs will be recorded in the eCRF and reported to the Sponsor within 24 hours via email or 
phone (see Section 8.4). 
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8.3.2. 
Follow-Up of Adverse Events 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts.  All SAEs and nonserious AEs will be followed until resolution, until 
the condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up. 
The Investigator will assess the outcome of each AE using the following criteria: 
• Recovered/Resolved:  The event has improved or subject recuperated. 
• Recovered/Resolved with sequelae:  The subject has recuperated but retained 
pathological conditions resulting from the prior disease or injury. 
• Recovering/Resolving:  The event is improving. 
• Not recovered/Not resolved:  The event has not improved or subject recuperated. 
• Unknown:  The outcome of the event is not known, not observed, not recorded, or 
refused. 
• Fatal:  Termination of life as an outcome of the AE. 
8.4. 
Reporting Procedures 
8.4.1. 
Serious Adverse Event Reporting 
When an Investigator determines that an AE meets the protocol definition of an SAE during the 
study, he/she must notify the Sponsor using an SAE Report Form within 24 hours of the study 
site personnel’s knowledge of the event, regardless of the Investigator assessment of the 
relationship of the event to study drug.  Relevant information will be entered on the AE page and 
on all other applicable pages of the eCRF; these pages will be submitted with the SAE Report 
Form. 
Follow-up information received on SAEs should be emailed or faxed to the Sponsor within one 
business day of receipt.  This information should be included on a follow-up SAE form and 
placed with the original SAE information. 
All SAEs will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the subject is lost to follow-up. 
The completed SAE Report form should be submitted via email or fax to the SAE Reporting 
Contact which can be found on the Medical Monitor/Sponsor Information Page of this protocol. 
Do not delay reporting a suspected SAE in order to obtain additional information.  Any 
additional information, if collected, can be reported as a follow-up to the initial report. 
8.4.2. 
Regulatory Reporting Requirements for Serious Adverse Events 
Prompt notification by the Investigator to the Sponsor of SAEs (even for non-interventional 
post-marketing studies) is essential so that legal obligations and ethical responsibilities towards 
the safety of subjects and the safety of a product 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 product under clinical investigation.  The Sponsor will 
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comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and are forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE(s) or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will file it with the -
investigator’s brochure and will notify the IRB/IEC, if appropriate, according to local 
requirements. 
8.5. 
Pregnancy Management and Reporting 
Any female subject who becomes pregnant during the study will be withdrawn.  Details will be 
collected for all pregnancies in female subjects that begin after the start of dosing and through 
the Follow-up visit.  Pregnancy is not automatically considered an AE. 
If a pregnancy is reported, then the Investigator should complete a pregnancy data collection 
form and submit via email or fax to the Pregnancy Reporting Contact for which contact 
information can be found on the Medical Monitor/Sponsor Information Page of this protocol, 
within 2 weeks of learning of the pregnancy.  The subject will also be followed to determine the 
outcome of the pregnancy.  Information on the status of the mother and child will be forwarded 
to the Sponsor.  Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any premature termination of the pregnancy will be reported. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention after 
the subject has completed the study and considered by the Investigator as possibly related to the 
study drug must be promptly reported to the Sponsor or the Sponsor’s representative. 
The Investigator must attempt to collect pregnancy information on any female partners of male 
study subjects who become pregnant while the subject is enrolled in the study.  Pregnancy 
information must be reported to the Sponsor or the Sponsor’s representative as described above.  
The partner will also be followed to determine the outcome of the pregnancy.  Information on the 
status of the mother and child will be forwarded to Sponsor or the Sponsor’s representative.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  
Any premature termination of the pregnancy will be reported on the pregnancy report form. 
8.6. 
Safety Oversight 
No independent Data Monitoring Committee will be used for this study; however, the Sponsor 
(including the Medical Monitor) will monitor safety on a periodic basis throughout the study. 
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9. 
DATA MANAGEMENT 
For this study, subject data will be entered into the Sponsor defined eCRFs, transmitted 
electronically to the Sponsor or designee and combined with data provided from other sources in 
a validated data system. 
Management of clinical data will be performed in accordance with applicable Sponsor standards 
and data cleaning procedures will be used to ensure the integrity of the data, e.g., errors will be 
corrected, and inconsistencies queried in the data. 
AEs and relevant medical history will be coded using the most current version of the Medical 
Dictionary for Regulatory Activities.  Concomitant medications will be coded with the most 
current version of World Health Organization Drug Global Dictionary. 
The Investigator will retain original source documents and the Sponsor will receive 
eCRF-required data as electronic datasets.  Subject initials will not be collected or transmitted to 
the Sponsor. 
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10. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES 
This study will evaluate the safety and PK of tapinarof cream, 1% in adults with plaque psoriasis. 
10.1. 
General Considerations 
All study data will be summarized using descriptive statistics.  Categorical variables will be 
reported using frequency and percentage (e.g., gender, race).  Continuous variables will be 
reported using number of subjects, mean, standard deviation (SD), median, minimum, and 
maximum.  All safety and PK data will be listed by subject. 
10.2. 
Determination of Sample Size 
This study will be conducted to evaluate the safety and PK of tapinarof cream, 1% in adult 
subjects with extensive plaque psoriasis.  There is no formal statistical hypothesis planned and 
the sample size is mainly based on feasibility and an estimated number of subjects needed to 
address the objectives of the study. 
10.3. 
Analysis Sets 
10.3.1. 
Safety Analysis Set 
All randomized subjects who receive at least 1 application of study drug will be included in the 
safety analysis set.  Subjects will be analyzed as treated. 
10.3.2. 
PK Analysis Set 
All subjects who have at least 1 application of study drug and have at least 1 evaluable PK assay 
result will be included in the PK analysis set.  A value that is below the limit of quantification is 
considered evaluable. 
10.3.3. 
QT/QTc Analysis Set 
The QT/QTc analysis set will include all subjects in the safety analysis set with measurements at 
Baseline as well as on-treatment with at least 1 post-dose time point with a valid ΔQTcF value. 
10.3.4. 
PK/QTc Analysis Set 
The PK/QTc analysis set will include all subjects who are in both the QT/QTc and PK analysis 
sets with at least 1 pair of post-dose PK and QTcF data from the same time point. 
10.4. 
Planned Analyses 
All safety and PK measures over the course of the study will be presented.  Details of planned 
analyses will be described in the statistical analysis plan (SAP) which will be finalized prior to 
database lock. 
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10.4.1. 
Disposition and Demographics 
Demographic and Baseline characteristics as well as medical history will be summarized using 
the safety analysis set, including frequency and percentages for categorical variables and mean, 
SD, median, minimum, and maximum for continuous variables. 
10.4.2. 
Safety Analyses 
The safety analysis set will be used in the analysis of safety and 
 data.  Data will 
be listed by subject and summarized.  No formal statistical comparisons will be made for 
safety data. 
The number and proportion of subjects with TEAEs will be summarized by treatment, system 
organ class, and preferred term for all TEAEs, all TEAEs considered by the Investigator to be 
related to study drug, all SAEs, and all TEAEs leading to study drug discontinuation.  All AE 
summaries will include information for TEAEs that occurred after administration of the first 
dose of study drug until completion of the final study visit.  Data listings will be provided for 
subjects who discontinued the study due to an AE and for subjects with an SAE. 
Selected 
 data will be analyzed using descriptive summary statistics and 
will be presented by study visit/time point, including the number of non-missing observations, 
mean and SD, median, upper and lower quartiles, minimum and maximum for values and 
changes from Baseline.  Categorical safety data will be analyzed using frequency tables and, 
if applicable, shift tables. 
Vital signs will be listed by subject and summarized by visit. 
Scores from the LTS will be listed by subject and summarized by visit. 
10.4.3. 
Cardiodynamic Assessments 
10.4.3.1. Baseline 
Time-matched Baseline will be derived from measurements on Day -1 and the morning 
(pre-dose) of Day 1 for all ECG parameters. 
10.4.3.2. By-Time Point Analysis 
The QT/QTc analysis set will be used for the by-time point analysis of cardiodynamic ECG 
parameters.  The analysis for QTcF will be based on a linear mixed-effects model with ΔQTcF 
as the dependent variable, time (i.e., time point:  categorical), treatment (tapinarof), and 
time-by-treatment interaction as fixed effects, and Baseline QTcF as a covariate.  An 
unstructured covariance matrix will be specified for the repeated measures at post-dose time 
points within subjects.  If the model with an unstructured covariance matrix fails to converge, 
other covariance matrices such as compound symmetry and autoregressive will be considered.  
From this analysis, the least squares (LS) mean and 2-sided 90% confidence interval (CI) will be 
calculated at each post-dose time point, separately. 
For HR, PR, and QRS intervals, the analysis will be based on the ΔHR, ΔPR, and ΔQRS, 
respectively.  The same (by-time point analysis) model will be used as described for QTcF.  The 
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Investigation of Hysteresis 
Hysteresis will be assessed by graphical methods based on the LS mean of ΔQTcF for each 
post-dose time point and the mean tapinarof plasma concentrations at the same time points.  
In addition, hysteresis plots will be given for mean ΔQTcF and the mean concentrations.  If a 
QT effect (∆QTcF) > 10 msec cannot be excluded in the by-time point analysis and if a delay 
between peak plasma levels and peak QT effect (ΔQTcF) in the plot (ΔQTcF versus tapinarof 
plasma concentration) of more than 1 hour is present, other concentration-QTc models such as a 
model with an effect compartment may be explored.  With the provision stated above, hysteresis 
will be assumed if the curve of hysteresis plot shows a counterclockwise loop. 
Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal Q-Q plots for the standardized residuals 
and the random effects, and plots of standardized residuals versus concentration and versus fitted 
values will be produced.  The scatter plot of standardized residuals versus concentration by 
LOESS fitting (i.e., locally weighted scatter plot smoothing as described by [Cleveland, 1979]) 
will also be produced with an optimal smoothing parameter selected by the Akaike information 
criterion with a correction [Hurvich, 1998].  In addition, a model with the original term and a 
quadratic term in concentration will be fitted and the quadratic term will be tested on the 2 sided 
5% level.  If there is an indication that a linear model is inappropriate, additional models will be 
fitted, in particular an Emax model.  The concentration-QTc analysis will then be repeated for the 
model found to best accommodate the nonlinearity detected. 
10.4.4. 
Pharmacokinetic Analysis 
The PK analysis set will be used in the analysis of PK data.  Data will be listed and summarized.  
Listings will be sorted by subject, day, and time; summaries will be presented by day and time. 
Unless stated otherwise, descriptive summaries for continuous variables will include n, mean, 
SD, median, minimum, and maximum.  If data permit, PK parameters (AUC0-τ, Cmax, tmax, and 
t½) will be derived using non-compartmental methods based on the actual sampling times 
recorded in the study. 
10.4.5. 
Efficacy Analyses 
All efficacy analyses will be performed based on the safety analysis set. 
PGA Assessments 
The PGA will be summarized for the actual, change from Baseline, and percent change from 
Baseline.  The mean and 95% CI for change and percentage change from Baseline will be 
presented along with p-values based on a one sample t-test. 
%BSA Assessments 
The %BSA will be summarized for the actual, change from Baseline, and percent change from 
Baseline.  The mean and 95% CI for change and percentage change from Baseline will be 
presented along with p-values based on a one sample t-test. 
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PASI Assessments 
The PASI will be summarized for the actual, change from Baseline, and percent change from 
Baseline.  The mean and 95% CI for change and percentage change from Baseline will be 
presented along with p-values based on a one sample t-test. 
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11. 
RESPONSIBILITIES 
11.1. 
Investigator Responsibilities 
11.1.1. 
Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South 
Africa), International Conference on Harmonization (ICH) guidelines, or with the laws and 
regulations of the country in which the research is conducted, whichever affords the greater 
protection to the study subject.  For studies conducted under a US Investigational New Drug 
Application, the Investigator will ensure that the basic principles of “Good Clinical Practice,” as 
outlined in 21 Code of Federal Regulations (CFR) 312, subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998, are adhered to.  These 
standards are consistent with the requirements of the European Community 
Directive 2001/20/EC. 
Since this is a “covered” clinical trial, the Investigator will ensure that 21 CFR, Part 54, 1998, is 
adhered to; a “covered” clinical trial is any “study of a drug or device in humans submitted in a 
marketing application or reclassification petition subject to this part that the applicant or 
US Food and Drug Administration relies on to establish that the product is effective (including 
studies that show equivalence to an effective product) or that make a significant contribution to 
the demonstration of safety.”  This requires that Investigators and all sub-Investigators must 
provide documentation of their financial interest or arrangements with the Sponsor, or 
proprietary interests in the drug being studied.  This documentation must be provided before 
participation of the Investigator and any sub-Investigator.  The Investigator and sub-Investigator 
agree to notify the Sponsor of any change of reportable interests during the study and for one 
year following completion of the study.  Study completion is defined as the date that the last 
subject has completed the protocol-defined activities. 
11.1.2. 
Institutional Review Board/Independent Ethics Committee Approval 
This protocol and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain 
informed consent) will be submitted by the Investigator to an IRB or IEC.  Approval from 
the IRB or IEC must be obtained before starting the study and should be documented in a letter 
to the Investigator specifying the protocol number, protocol version, protocol date, documents 
reviewed, and date on which the committee met and granted the approval. 
Any modifications made to the protocol after receipt of IRB or IEC approval must also be 
submitted to the IRB or IEC for approval before implementation. 
11.1.3. 
Informed Consent/Assent 
The Investigator is responsible for obtaining written informed consent/assent from each 
individual participating in this study after adequate explanation of the aims, methods, objectives, 
and potential hazards of the study and before undertaking any study-related procedures.  The 
Investigator must utilize an IRB- or IEC-approved consent form for documenting written 
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informed consent.  Each informed consent/assent will be appropriately signed and dated by the 
subject or the subject’s legally authorized representative and the person obtaining consent. 
11.1.4. 
Confidentiality 
The Investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties.  Only subject number, date of birth, and an 
identification code (i.e., not names) should be recorded on any form or biological sample 
submitted to the Sponsor, IRB or IEC, or laboratory.  The Investigator must keep a Screening 
log showing codes, names, and addresses for all subjects screened and for all subjects enrolled 
in the trial. 
The Investigator agrees that all information received from the Sponsor, including but not limited 
to the investigator’s brochure, this protocol, eCRFs, the investigational new drug, and any other 
study information, remain the sole and exclusive property of the Sponsor during the conduct of 
the study and thereafter.  This information is not to be disclosed to any third party (except 
employees or agents directly involved in the conduct of the study or as required by law) without 
prior written consent from the Sponsor.  The Investigator further agrees to take all reasonable 
precautions to prevent the disclosure by any employee or agent of the study site to any third 
party or otherwise into the public domain. 
11.1.5. 
Study Files and Retention of Records 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified.  These documents should 
be classified into at least the following two categories:  1) Investigator’s study file, and 2) subject 
clinical source documents. 
The Investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB or IEC and governmental approval with correspondence, informed consent, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
The required source data should include at least the following information for each subject: 
• Subject identification (name, date of birth, gender); 
• Documentation that subject meets eligibility criteria, i.e., history, physical 
examination, and confirmation of diagnosis (to support inclusion and exclusion 
criteria); 
• Participation in trial (including trial number); 
• Trial discussed and date of informed consent; 
• Dates of all visits; 
• Documentation that protocol-specific procedures were performed; 
• Results of efficacy parameters, as required by the protocol; 
• Start and end dates (including dose regimen) of study drug (preferably drug 
dispensing and return should be documented as well); 
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• Record of all AEs and other safety parameters (start and end date, and preferably 
including causality and intensity); 
• Concomitant medication (including start and end dates, dose if relevant; dose changes 
should be motivated); 
• Date of trial completion and reason for early discontinuation, if applicable. 
All clinical study documents must be retained by the Investigator until at least 2 years after the 
last approval of a marketing application in an ICH region (i.e., US, Europe, or Japan) and until 
there are no pending or contemplated marketing applications in an ICH region; or, if no 
application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified.  Investigators may be 
required to retain documents longer if required by applicable regulatory requirements, by local 
regulations, or by an agreement with the Sponsor.  The Investigator must notify the Sponsor 
before destroying any clinical study records. 
Should the Investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the Investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the Investigator and the Sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
Investigator in case of a regulatory audit.  When source documents are required for the continued 
care of the subject, appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained in storage by the Sponsor for 
a period up to 10 years for purposes of this study. 
11.1.6. 
Electronic Case Report Forms 
For each subject enrolled, an eCRF must be completed and signed by the Investigator or sub-
Investigator (as appropriate).  This also applies to records for those subjects who fail to complete 
the study.  If a subject withdraws from the study, the reason must be noted on the eCRF.  If a 
subject is withdrawn from the study because of a treatment-limiting AE, thorough efforts should 
be made to clearly document the outcome. 
11.1.7. 
Drug Accountability 
The Investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug.  This includes acknowledgment of receipt of each shipment of 
study drug (quantity and condition), subject dispensing records, and returned or destroyed study 
drug.  Dispensing records will document quantities received from the Sponsor and quantities 
dispensed to subjects, including lot number, date dispensed, subject identifier number, and the 
initials of the person dispensing the study drug. 
At study initiation, the monitor will evaluate the site’s procedure for study drug 
disposal/destruction in order to ensure that it complies with the Sponsor requirements.  At the 
end of the study, following final drug inventory reconciliation by the monitor, the study site will 
dispose of and/or destroy all unused study drug supplies, including empty containers, according 
to these procedures.  If the site cannot meet the Sponsor’s requirements for disposal, 
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arrangements will be made between the site and the Sponsor or its representative for destruction 
or return of unused study drug supplies. 
All study drug supplies and associated documentation will be periodically reviewed and verified 
by the study monitor over the course of the study. 
11.1.8. 
Inspections 
The Investigator should understand that source documents for this trial should be made available 
to appropriately qualified personnel from the Sponsor or its representatives, to IRBs or IECs, or 
to regulatory authority or health authority inspectors. 
11.1.9. 
Protocol Compliance 
The Investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. 
11.2. 
Sponsor Responsibilities 
11.2.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be 
made only by the Sponsor.  All protocol modifications must be submitted to the IRB or IEC and 
regulatory authorities in accordance with local requirements.  Approval must be obtained before 
changes can be implemented. 
11.2.2. 
Study Report and Publications 
A clinical study report will be prepared and provided to the regulatory agency(ies).  The Sponsor 
will ensure that the report meets the standards set out in the ICH Guideline for Structure and 
Content of Clinical Study Reports (ICH E3).  Note that an abbreviated report may be prepared in 
certain cases. 
After conclusion of the study and without prior written approval from Dermavant Sciences 
GmbH, Investigators in this study may communicate, orally present, or publish in scientific 
journals or other scholarly media only after the following conditions have been met: 
• the results of the study in their entirety have been publicly disclosed by or with the 
consent of Dermavant Sciences GmbH in an abstract, manuscript, or presentation 
form; OR 
• the study has been completed at all study sites for at least 5 years. 
No such communication, presentation, or publication will include Dermavant Sciences GmbH 
confidential information (see Section 11.1.4). 
The Investigator will submit any proposed publication or presentation along with the respective 
scientific journal or presentation forum at least 30 days before submission of the publication or 
presentation.  The Investigator will comply with Dermavant Sciences GmbH request to delete 
references to its confidential information (other than the study results) in any paper or 
presentation and agrees to withhold publication or presentation for an additional 60 days in order 
to obtain patent protection if deemed necessary. 
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11.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers 
Study information from this protocol will be posted on publicly available clinical trial registers 
before enrollment of subjects begins.  Results will be posted as required. 
11.3. 
Joint Investigator/Sponsor Responsibilities 
11.3.1. 
Access to Information for Monitoring 
In accordance with ICH Good Clinical Practice guidelines, the study monitor must have direct 
access to the Investigator’s source documentation in order to verify the data recorded in the 
eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them.  The monitor should have access to any subject records needed to 
verify the entries on the eCRFs.  The Investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
11.3.2. 
Access to Information for Auditing or Inspections 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Dermavant Sciences GmbH may conduct a quality assurance audit. 
Authorized representatives of Dermavant Sciences GmbH, a regulatory authority, an IEC or an 
IRB may visit the site to perform audits or inspections, including source data verification.  The 
purpose of a Dermavant Sciences GmbH audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according 
to the protocol, Good Clinical Practice guidelines of the ICH, and any applicable regulatory 
requirements.  The Investigator should contact Dermavant Sciences GmbH immediately if 
contacted by a regulatory agency about an inspection. 
11.3.3. 
Study Discontinuation 
The Sponsor reserves the right to terminate the study at any time.  Should this be necessary, the 
Sponsor will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies), IRBs, and IECs.  In terminating the study, the Sponsor and the Investigator will 
assure that adequate consideration is given to the protection of the subjects’ interests. 
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12. 
REFERENCES 
Bashaw ED, Tran DC, Shukla CG, Liu X.  Maximal usage trial:  an overview of the design of 
systemic bioavailability trial for topical dermatological products.  Ther Innovation & Reg 
Science.  2014; 1-8. 
Cappon GD and Hurtt ME.  Developmental toxicity of the kidney.  In:  Kapp RW and Yyl L, 
editors.  Reproductive Toxicology, Target Organ Series, 3rd edition.  New York: Informa 
Healthcare, 2010:193-204. 
Cleveland WS.  Robust Locally Weighted Regression and Smoothing Scatter Plots.  J Amer 
Statist Assoc.  1979; 74 (368):  829-36. 
Frazier KS and Seely JC.  Urinary system.  In:  Sahota PS, Popp JA, Hardisty JF and Gopinath 
C, editors.  Toxicologic Pathology:  Nonclinical Safety Assessment.  CRC Press, 2013:421-84. 
Hurvich, CM, Simonoff, JS, and Tsai, CL.  Smoothing parameter selection in nonparametric 
regression using an improved Akaike information criterion.  J.  Roy.  Statist.  Soc.  Ser.  B.  
1998; 60 (2):  271-93. 
Mason AR, Mason J, Cork M, Dooley G, Hancock H.  Topical treatments for chronic plaque 
psoriasis.  Cochrane Database of Systematic Reviews.  2013;(3):CD005028. doi:  
10.1002/14651858.CD005028.pub3. 
Parisi R, Symmons DPM, Griffiths CEM, Ashcroft DM.  Global epidemiology of psoriasis:  a 
systematic review of incidence and prevalence.  J Invest Dermatol.  2012;133:377-385. 
Tapinarof Investigator’s Brochure, Version 12.0, December, 2018 
Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV.  Creation of a knowledge 
management system for QT analyses.  J Clin Pharmacol.  2011; 51 (7):  1035-42. 
Zoetis T and Hurtt ME.  Species comparison of anatomical and functional renal development.  
Birth Defects Research Part B.  2003;68:111-120. 
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APPENDICES 
 PHYSICIAN GLOBAL ASSESSMENT 
Each assessment should be made as a visual ‘average’ of the severity of all treated areas at the 
time of the assessment. 
Scoring should not be influenced by extent of plaques, participant symptoms, or impact on 
participant’s quality of life.   
Score/Grade 
Description 
0 
Clear 
No signs of psoriasis; post-inflammatory hyperpigmentation may be present 
1 
Almost clear No thickening; normal to pink coloration; no to minimal focal scaling 
2 
Mild 
Just detectable to mild thickening; pink to light red coloration; predominantly fine scaling 
3 
Moderate 
Clearly distinguishable to moderate thickening; dull to bright red, clearly distinguishable 
erythema; moderate scaling 
4 
Severe 
Severe thickening with hard edges; bright to deep dark red coloration; severe/coarse 
scaling covering almost all or all plaques 
Langley RGB, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C.  The 5-point Investigator’s Global 
Assessment (IGA) Scale:  A modified tool for evaluating plaque psoriasis severity in clinical trials.  J Dermatolog 
Treat.  2015;26(1):23-31. 
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SAP Revision Log 
 
 
SAP Section 
Brief Description of Revision 
Date of Revision 
11 
Number of concentrations required for 
computation of AUC 
06-FEB-2020 
11 
Methods of imputation for BQL data 
06-FEB-2020 
 
 
 




 
 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION .................................................................................................................. 8 
2. 
STUDY DOCUMENTS ......................................................................................................... 8 
3. 
STUDY OBJECTIVES .......................................................................................................... 8 
3.1 
PRIMARY OBJECTIVES ................................................................................................... 8 
3.2 
SECONDARY OBJECTIVES .............................................................................................. 8 
3.3 
EXPLORATORY OBJECTIVE ............................................................................................ 9 
4. 
STUDY DESIGN AND PLAN .............................................................................................. 9 
5. 
DETERMINATION OF SAMPLE SIZE .......................................................................... 10 
6. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 10 
7. 
ANALYSIS SETS ................................................................................................................. 12 
8. 
STUDY POPULATION....................................................................................................... 12 
8.1 
SUBJECT DISPOSITION .................................................................................................. 12 
8.2 
PROTOCOL DEVIATIONS .............................................................................................. 13 
8.3 
ELIGIBILITY.................................................................................................................. 13 
8.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 13 
9. 
EFFICACY ANALYSES ..................................................................................................... 13 
10. SAFETY ANALYSES .......................................................................................................... 14 
10.1 INTERIM ANALYSIS AND DATA MONITORING ............................................................. 14 
10.2 EXTENT OF EXPOSURE AND MEASUREMENT OF TREATMENT COMPLIANCE .............. 14 
10.3 PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 14 
10.4 ADVERSE EVENTS ........................................................................................................ 15 
10.5 CLINICAL LABORATORY EVALUATION ....................................................................... 16 
10.6 VITAL SIGNS ................................................................................................................ 16 
10.7 LOCAL TOLERABILITY SCALE ..................................................................................... 17 
10.8 PHYSICAL EXAMINATION ............................................................................................ 17 
10.9 CARDIODYNAMIC ASSESSMENTS (CONTINUOUS HOLTER MONITORING) ................... 17 
11. PHARMACOKINETIC ANALYSES ................................................................................ 17 
12. CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 20 
13. REFERENCES ..................................................................................................................... 22 
14. APPENDICES ...................................................................................................................... 23 
APPENDIX A: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS .................... 23 
APPENDIX B: SAS PROGRAMMING QC REQUIREMENTS ....................................................... 25 
APPENDIX C:  LIST OF TABLES, FIGURES, AND LISTINGS ...................................................... 26 
APPENDIX D: STATISTICAL ANALYSIS PLAN FOR ECG DATA ............................................... 33 
  




 
 
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Term 
Description 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
LS 
least squares 
LTS 
Local Tolerability Scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
PASI 
Psoriasis Area and Severity Index 
PGA 
Physician Global Assessment 
PK 
pharmacokinetic(s) 
PND 
postnatal day 
QTcF 
QT interval corrected with Fridericia’s formula 
RBC 
red blood cell(s) 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
tmax 
time of maximum plasma concentration 
t1/2  
elimination half life 
ULN 
upper limit of normal 
UV 
ultraviolet 
WBC 
white blood cell(s) 
WOCBP 
women of childbearing potential 
 


 
 
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1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Dermavant Sciences GmbH Protocol DMVT-505-2002 [Open-
Label Maximal Use Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
Tapinarof Cream, 1% in Adults with Extensive Plaque Psoriasis]. The purpose of this plan is to 
provide specific guidelines from which the statistical analyses will proceed. Any deviations from 
this plan will be documented in the clinical study report (CSR).  
2. STUDY DOCUMENTS 
The following study documents were used for the preparation of the SAP: 
x Protocol version 1.0, dated 26-April-2019 
x Annotated electronic case report form (eCRF), version 1.4, dated 22-Jul-2019 
3. STUDY OBJECTIVES 
3.1 
Primary Objectives 
x To evaluate the safety and tolerability of tapinarof cream, 1% in adult subjects with 
extensive plaque psoriasis  
     Associated endpoints including: 
o Frequency and severity of adverse events (AEs) (local and systemic) 
o Laboratory and biomarker values 
o Vital signs 
o Electrocardiograms (ECGs) 
o Mean Local Tolerability Scale (LTS) scores by visit 
 
x To evaluate the pharmacokinetics (PK) of tapinarof cream, 1% in adult subjects with 
extensive plaque psoriasis  
      Associated endpoints including: 
o Tapinarof and tapinarof sulfate (metabolite) plasma PK parameters on Day 1 and 
Day 29, if data permit, including: area under the plasma concentration vs time curve 
in one dosing interval (AUC0-τ), maximum plasma concentration (Cmax), time of 
maximum plasma concentration (tmax) and elimination half-life (t1/2). 
3.2 
Secondary Objectives 
x To exclude clinically relevant effects of tapinarof cream, 1% on QT interval corrected by 
Fridericia’s formula (QTcF)  
     Associated endpoints including: 
o Analysis of change from Baseline in QTcF (ΔQTcF) at each post-treatment time point 
on the sampling day with the higher Cmax (Day 1 or Day 29) 




 
 
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plaques on palms, fingernails, soles, toenails, and/or scalp, they should do so for the entirety of 
the treatment period from Day 1 to Day 29. Subjects will be instructed to apply study drug in the 
morning throughout the entirety of their participation in the study. At the phone contacts at 
Day 8 and Day 22, subjects should be reminded to complete their daily diary and bring it with 
them to the next clinic visit. 
Study drug application instructions will be reviewed at all post-baseline clinic visits. On clinic 
visit days, subjects will be instructed/reminded on how to apply study drug (except during the 
final treatment/end-of-study visits). During the clinic visits, subjects will apply the daily dose of 
study drug while on-site under the supervision of site personnel, after other assessments have 
been completed.  
Subjects who withdraw from the study before Day 30 will complete an Early Termination Visit. 
Study duration for subjects who complete this study is approximately 10 weeks in total. Refer to 
the study protocol for further details (Section 6 for descriptions of study procedures and 
assessments and Section 7 and the Schedule of Assessments [Table 1] for timing of procedures 
and assessments). 
Treatment Groups and Duration 
All subjects will receive tapinarof cream, 1% for 29 days with once daily application.  
A subject will be considered to have completed the study when he/she completes all required 
procedures/visits for the 29-day treatment phase. 
5. DETERMINATION OF SAMPLE SIZE 
This study will be conducted to evaluate the safety and PK of tapinarof cream, 1% in adult 
subjects with extensive plaque psoriasis. There is no formal statistical hypothesis testing planned 
and the sample size is mainly based on feasibility and an estimated number of subjects needed to 
address the objectives of the study.  
6. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs.  
Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums. Categorical variables will be summarized by counts and by percentage of 
subjects in corresponding categories. Percentages are based on the number of non-missing results 
unless otherwise mentioned. Percentages showing a rate relative to the total number of subjects 
in this group are given in special tables (e.g., AE tables). Footnotes will specify the percent basis 
in those cases. 


 
 
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Individual subject data obtained from the eCRFs and any derived data will generally be 
presented by subject in data listings. 
All analyses and tabulations will be performed using SAS£ software Version 9.4 or higher. 
Tables, listings, and figures will be presented in RTF format.  
The process for SAS program validation and quality control (QC) for programs and outputs is 
documented in the Synteract working instruction “SAS programming quality control.” 
Study-specific QC requirements can be found in Appendix B: SAS Programming QC 
Requirements. 
Unless otherwise specified, the Baseline value for each variable is the last non-missing value 
prior to the initiation of study drug. No imputations will be made for missing values. Summaries 
will be based on observed data only. Unscheduled visits will not be summarized but will be 
included in the listings. 
Conventions for handling partial dates and missing dates for AEs and prior and concomitant 
medications are given below. Listings will present the dates in their original format (without any 
imputation).  
Missing or Incomplete Dates for Adverse Events and Concomitant Medications 
Imputation of Start and End Dates of Adverse Events and Concomitant Medications 
The following rules will be used where applicable to impute partial or completely missing start 
dates or end dates: 
x If only the day is missing for a start date, the 1st of the month will be imputed. If the new 
estimated date falls before the date of first dose, while the known month and year match 
the month and year of the first dose, the date of first dose will be used as the new estimated 
date. For AEs, the AE will be considered as a TEAE. 
x If only the day is missing for an end date, the last day of the month will be imputed. If the 
new estimated date falls after the date of last study visit, the date of last study visit will be 
used as the new estimated date.  
x If both the day and the month are missing for a start date or end date, no imputation will 
be used, and the duration will not be calculated. For an AE, if the year of start is the same 
or greater than the year of the first dose date, the AE will be considered as treatment 
emergent. 
x If the start date or end date is completely missing, duration will not be calculated. However, 
an event with completely missing start date will be considered as treatment emergent. 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 


 
 
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x Days – A duration expressed in days between 1 date (date1) and another later date (date2) 
will be calculated using the following formula: 
Duration in days = date2 – date1 + 1 
x Body mass index (BMI) – BMI will be calculated using height (cm) and weight (kg) using 
the following formula: 
BMI (kg/m2) = weight (kg)/[[height (cm)/100]2]. 
x Change from baseline – Change from baseline will be calculated as: 
Change = post-baseline value – baseline value. 
7. ANALYSIS SETS 
Safety Analysis Set 
All subjects who receive at least 1 application of study drug will be included in the safety 
analysis set. Subjects will be analyzed as treated. 
PK Analysis Set 
All subjects who have at least 1 application of study drug and have at least 1 evaluable PK assay 
result will be included in the PK analysis set. A value that is below the limit of quantification is 
considered evaluable. 
QT/QTc Analysis Set 
The QT/QTc analysis set will include all subjects in the safety analysis set with measurements at 
Baseline as well as on-treatment with at least 1 post-dose time point with a valid ΔQTcF value. 
PK/QTc Analysis Set 
The PK/QTc analysis set will include all subjects who are in both the QT/QTc and PK analysis 
sets with at least 1 pair of post-dose PK and QTcF data from the same time point. 
8. STUDY POPULATION 
8.1 
Subject Disposition 
Subject disposition information will be summarized using the safety analysis set. The summary 
will include: the number of subjects in each analysis set, the number of subjects completing the 
study, and the primary reason for discontinuation. 


 
 
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8.2 
Protocol Deviations 
Major protocol deviations that could potentially affect the efficacy or safety conclusions of the 
study will be identified prior to database lock. 
A listing of all protocol deviations including the deviation designation (major or minor) and 
deviation category will be presented in a data listing.   
8.3 
Eligibility 
A listing of subjects not fulfilling any eligibility criteria will be created. 
8.4 
Demographic and Baseline Characteristics 
Demographic variables include age, sex, ethnicity, race, height, weight, and body mass index 
(BMI). Age will be calculated in years relative to the informed consent date. Baseline 
characteristics include physician global assessment (PGA), percent body surface area affected 
(%BSA), and psoriasis area and severity index (PASI) score.  
Demographic and baseline characteristics as well as medical history will be summarized using 
the safety analysis set. In addition, demographic and baseline characteristics as well as medical 
history will be listed by subject. 
9. EFFICACY ANALYSES 
All efficacy analyses will be performed based on the safety analysis set. The secondary study 
endpoints include mean change from Baseline at Day 29 in PGA, %BSA, and PASI. 
Descriptions of these endpoints can be found in Protocol Appendix 1 and 2. 
The PGA, %BSA, and PASI will be summarized using descriptive statistics at Baseline and 
Day 29. Change and percent change from Baseline to Day 29 will be summarized descriptively 
including 95% confidence intervals and analyzed with a one sample t-test.  
 
The one sample t-test will test the following hypotheses: 
H0: The mean change or percent change from baseline to day 29 in efficacy endpoint is equal 
to 0; 
H1: The mean change or percent change from baseline to day 29 in efficacy endpoint is not 
equal to 0; 
 
SAS code examples: 
proc ttest data=DATAset sides=2 alpha=0.05 h0=0; 
     var CHG;       *PCHG-for Percentage Change*; 
run; 
 


 
 
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CHG = Change from Baseline to Day 29. PCHG = Percentage change from Baseline to Day 29. 
In addition to the above, the percent of subjects with treatment success at Day 29 will be 
summarized. Treatment success is defined as at least a 2-grade improvement from Baseline in 
PGA as well as a PGA score of clear or almost clear (score of 0 or 1) at Day 29. Percent of 
subjects with 1-point improvement and percent of subjects with 2-point improvement from 
Baseline at Day 29 will also be summarized. 
In addition, Physician Global Assessment (PGA), Percent Body Surface Area (%BSA) 
Assessment and Psoriasis Area and Severity Index (PASI) Assessment will be listed by subject. 
10. SAFETY ANALYSES 
The safety analysis set will be used in the analysis of safety and biomarker data. Data will be 
listed by subject and summarized. No formal statistical comparisons will be made for safety data. 
Unless otherwise noted, baseline is defined as the last non-missing value recorded prior to the 
first dose of study drug.  
10.1 Interim Analysis and Data Monitoring 
There are no planned interim analyses for this study.  The Sponsor may review PK data in an 
ongoing basis during the study. 
10.2 Extent of Exposure and Measurement of Treatment Compliance 
The extent of exposure to study drug will be summarized by the number of applications, number 
of missed applications and compliance with study treatment. A subject will be considered 
compliant with the dosing regimen if the subject applied 80% to 120% of the total number of 
expected doses during the treatment period. The expected number of doses during the treatment 
period is 29. 
 
Dosing information will be presented in listings and will include the tube dispense and return 
weights as well as dates and time of study drug administration. 
10.3 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms in the eCRFs will be mapped to 
anatomical/therapeutic/chemical class and preferred names using the WHODrug Global B3 
(version 01MAR2019). 
x Prior medications are defined as medications with a stop date before the date of the first 
dose of study drug. 


 
 
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x Concomitant medication are medications with a start date on or after the date of first dose 
of study drug administration or are medications started before study drug administration 
and ended after study drug administration.  
Prior and concomitant medications will be summarized by WHO ATC class and preferred name. 
These summaries will present the number and percentage of subjects using each medication. 
Subjects may have more than 1 medication per ATC class and preferred name. At each level of 
subject summarization, a subject is counted once if he/she reported 1 or more medications at that 
level. Each summary will be ordered by descending order of incidence of ATC class and 
preferred name within each ATC class. 
10.4 Adverse Events 
Treatment-emergent AEs (TEAEs) are defined as those AEs that occurred on or after the date of 
first dosing and those existing AEs that worsened during the study. Verbatim terms in the eCRFs 
will be mapped to preferred terms and system organ classes using the Medical Dictionary for 
Regulatory Activities (MedDRA) (version 22.0).  
For this study, AEs of particular clinical importance will be reported as AESIs in the eCRFS to 
include: Contact dermatitis, Folliculitis and Headache which could be found from eCRF pages 
AESI Contact Dermatitis, AESI Folliculitis and AESI Headache, respectively. These AEs will 
not be summarized separately but rather will be included in the summaries described below.  
Each AE summary will be summarized by system organ class and preferred term and ordered by 
descending order of incidence of system organ class and preferred term within each system organ 
class. Summaries will include the following: 
x Overall summary of AEs that contain an overview of each item below. 
x Subject incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term.  
x Subject incidence of TEAEs by MedDRA system organ class, preferred term, and highest 
severity. At each level of subject summarization, a subject is classified according to the 
highest severity if the subject reported 1 or more events. Adverse events with missing 
severity will be considered severe for this summary. 
x Subject incidence of TEAEs by MedDRA system organ class, preferred term, and closest 
relationship to study drug (Related/Not Related). At each level of subject summarization, 
a subject is classified according to the closest relationship if the subject reported 1 or 
more events. Adverse events with a missing relationship will be considered related for 
this summary. 
x Subject incidence of serious TEAEs by MedDRA system organ class and preferred term. 
x Subject incidence of TEAEs leading to discontinuation of study drug by MedDRA 
system organ class and preferred term.  




 
 
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x Systolic Blood Pressure >=40 mmHg 
x Diastolic Blood Pressure >=20 mmHg 
x Heart Rate >=30 bpm 
A listing of vital signs will also be presented. 
10.7 Local Tolerability Scale 
Local tolerability scale (LTS) overall score for dryness, erythema, and peeling will be 
summarized using descriptive statistics at Baseline and at Days 15 and 29 as will the number and 
percent of subjects who apply study drug to the following sensitive areas: face, neck, skin folds, 
axilla, inframammary, anal crux, and genitalia. If 5 more subjects treat a sensitive area(s) at any 
time during the treatment period, LTS scores will be summarized at Baseline and Days 15 and 29 
for that specific area(s). 
In addition, LTS scores will be listed by subject overall and by sensitive area as applicable. 
10.8 Physical Examination 
Nicotine usage assessed at Baseline and pregnancy test results at Screening, Baseline, and 
Follow-up will be presented in listings. 
10.9  Cardiodynamic Assessments (Continuous Holter Monitoring) 
ECG data from Baseline and while on study treatment will be collected using a 12-lead Holter 
monitor. ECG data will be summarized in tables, presented graphically in figures and listed in 
data listings by 
 The final 
-signed SAP including mock TFLs can be found in 
Appendix D.  
11. PHARMACOKINETIC ANALYSES 
Unless otherwise specified below, missing sampling or concentration values should not be 
imputed, but left missing in the calculation of derived PK parameters. If the actual sampling time 
is missing, but a valid concentration value has been measured, the scheduled protocol time will be 
used for the calculation of derived PK parameters. A missing pre-dose value will be set to 0 for 
the PK calculations corresponding to an observation at dosing time. 
All pharmacokinetic (PK) analyses and generation of the tables, figures, and listings (TFLs) will 
be performed using a validated installation of Phoenix WinNonlin® version 8.1 (
 
) as part of a 21 CFR Part 11 compliant database system (Pharsight Knowledge Database 
“PKS”).  
Blood samples for the analysis of tapinarof and its metabolite, tapinarof sulfate, will be collected 
pre-dose and post dose on Day 1 and Day 2 (Visits 3 and 4) as well as Day 29 and Day 30 (Visits 


 
 
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6 and 7) at 1, 2, 3, 4, 5, 8, 12, and 24 hours after dosing. On Day 15 (Visit 5), samples will be 
collected pre-dose and at 2- and 4-hours post dose (±10 mins). Samples collected outside the pre-
determined intervals will be flagged and footnoted. 
PK data from the PK population will be presented in listings. Plasma concentrations will be 
summarized using descriptive statistics.  The number of plasma samples that were BQL will be 
summarized by subject and overall. 
PK parameter estimates for tapinarof and its metabolite tapinarof sulfate on Day 1 and Day 29 
will be calculated using non-compartmental analysis (NCA) of the plasma concentration versus 
time data utilizing actual sample collection time. NCA will be conducted using validated PK data 
analysis software (Phoenix WinNonlin version 8.1). AUC values will be estimated using the 
linear up-log down method. A minimum number of 3 data points are required for determination 
of AUC. The apparent first-order terminal elimination rate constant (λz) will be calculated as the 
negative of the slope from linear regression of the semi-log concentration-time curve during the 
terminal phase. The apparent first-order terminal elimination half-life, t1/2, will be calculated as 
0.693/ λz. A minimum of three descending concentration-time points, excluding the Cmax, above 
the lower limit of quantification (LLOQ) will be used in the estimation of the terminal phase rate 
constant (λz), for the determination of the terminal half-life (t1/2). PK parameter estimates are 
listed in Table 1, other parameters can be added, if data permits.  
PK parameters Cmax and AUC0-τ will also be normalized to %BSA treated by dividing each 
parameter by cm2 of body surface area of disease. For this calculation, 1% BSA is equal to 
185 cm2.  
Imputation of BQL data should be addressed as follows: 
x If a BQL value occurs in a profile before the first measurable concentration, it will be 
assigned a value of zero concentration. Therefore, a subject with BQL values for the entire 
dosing interval will have a Cmax of zero. 
x If a BQL value occurs after a measurable concentration in a profile and is followed by a 
value above the lower limit of quantitation (LLOQ), then BQL should be treated as 
‘missing’.   
x If a BQL value occurs at the end of the collection interval (after the last quantifiable 
concentration) it will generally be treated as ‘missing’  
x If two BQL values occur in succession after Cmax, the profile will be deemed to have 
terminated at the first BLQ value and any subsequent concentrations will be omitted from 
pharmacokinetic calculations and individual plots, which are to reflect data that were used in 
the NCA, but will be maintained in concentration-time tables and plots of mean data 
BQL values will be treated as zero for summary statistics tables or mean figures.  
On a case by case basis, it may be necessary to exclude individual PK concentration values for 
the calculation of derived PK parameters because they are erroneous, abnormal or appear 


 
 
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implausible to the pharmacokineticist in charge of the analysis. Any excluded data will be 
flagged in the individual data listings. The reason for exclusion will also be documented. If the 
exclusion has a meaningful impact on the overall interpretation of the results, then it will be 
discussed.  
 
 


 
 
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Table 1: PK Parameters and Definitions 
Parameter 
Description of Parameter 
Cmax 
The maximum observed concentration of tapinarof and its metabolite tapinarof 
sulfate measured after dosing 
Tmax 
Time at which the Cmax is observed. 
AUC0-τ 
The area under the tapinarof and its metabolite tapinarof sulfate concentration 
versus time curve from time zero to the end of the dosing period 
t1/2 
Apparent first-order terminal elimination half-life of tapinarof and its metabolite 
tapinarof sulfate 
 
 
 
Individual PK parameter estimates from non-compartmental analysis, sorted by Day, will be listed 
for all individuals and will include tapinarof and its metabolite tapinarof sulfate. 
PK parameters for tapinarof and its metabolite tapinarof sulfate will be summarized separately and 
will include the count, mean, geometric mean, standard deviation, CV%, median, min, max and 
geometric CV% range. 
Individual Day 1 and Day 29 time-concentration graphs for tapinarof and its metabolite tapinarof 
sulfate will be provided for each subject in both linear and semi-log scales. Actual sampling times 
will be used for individual plots. Overlaid individual concentration-time plots by Day for tapinarof 
and its metabolite tapinarof sulfate will be provided in linear and semi-log scale. Mean 
concentration-time graphs by Day for tapinarof and its metabolite tapinarof sulfate will be 
provided in both linear and semi-log scales.  
12. CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
Note the following modifications and/or clarifications to the methodology specified in the 
protocol: 
 
x The following efficacy summaries were added to Section 10 to include the primary 
endpoint of treatment success used in Phase 3 psoriasis studies as well as a summary of 
the percent of subjects with 1-grade and 2-grade improvement from Baseline at Day 29. 
 
o The percent of subjects with treatment success at Day 29 will be summarized. 
Treatment success is defined as at least a 2-grade improvement from Baseline in 
PGA as well as a PGA score of clear or almost clear (score of 0 or 1) at Day 29. 


 
 
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o Dosing compliance will be determined for each subject and summarized 
descriptively. A subject will be considered compliant with the dosing regimen if 
the subject applied 80% to 120% of the total number of expected doses during the 
treatment period. The expected number of doses during the treatment period is 29. 
 
x Drug-related AEs will be summarized overall and by maximum severity.  
 
 


 
 
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13. REFERENCES 
Not applicable 
 
 


 
 
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14. APPENDICES 
Appendix A: Presentation of Data and Programming Specifications 
General  
x Specialized text styles, such as bold, italics, borders, shading, superscripted, and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing. 
x Only standard keyboard characters are to be used in tables and data listings. 
x Special characters, such as nonprintable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
x Hexadecimal character representations are allowed (e.g., μ, D, ß). 
x All footnotes will be left justified and at the bottom of a page. Footnotes must be used 
sparingly and must add value to the table, figure, or data listing. 
Tables 
x Formal organization of tabulations may be changed during programming, if appropriate, 
e.g., tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
x Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to 2 more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
x Percentages will be presented to the tenths place. 
x For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
x Lower and upper confidence interval values must be presented to 1 decimal place more 
than the raw/derived data (i.e., to the same number of decimal places as the mean). 
x Percentiles (e.g., 25%, 75%) must be presented to 1 decimal place more than the 
raw/derived data. 
x For all inferential analyses, P values will be rounded to 4 decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P values less than 0.0001 will be 
presented as “<0.0001.” 
x The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated 
results like mean or median are plotted) or the source listing(s) (in case individual responses are 
plotted) and/or source dataset(s) (e.g., ADaM).  
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date is the date stamp of the data snapshot used. 


 
 
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Figures 
x Legends will be used for all figures with more than 1 variable or item displayed. 
Treatment group sizes (n=xx) will be included, as appropriate. 
x Figures will be in black and white but can be in color to add value to the clarity and 
readability of a figure. Lines must be wide enough to see the line after being copied. 
x The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source listing number(s) and/or source dataset(s) (e.g., ADaM).  
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date is the date stamp of the data snapshot used. 
Listings 
x Formal organization of the listing may be changed during programming, if appropriate, 
e.g., additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints. 
x If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
subject number, visit, and date/time, as appropriate.  
x All date values will be presented in a SAS date (e.g., 29AUG2001) format.  
x All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part of 
the study. 
x The last footnote will be 
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: 
DDMMYY hh:mm”. 
where extract date is the date stamp of the data snapshot used. 
 
 
 


 
 
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Appendix B: SAS Programming QC Requirements  
Derived datasets are independently reprogrammed by a second programmer. The separate 
datasets produced by the 2 programmers must match 100%. Detailed specifications for the 
derived datasets are documented in the study Analysis Dataset Specifications provided to the 
client at study conclusion. 
Tables are independently reprogrammed by a second programmer for numeric results.  
Listings are checked for consistency against corresponding tables, figures, and derived datasets. 
Figures are checked for consistency against corresponding tables and listings, or independently 
reprogrammed if there are no corresponding tables or listings. 
The entire set of TLFs is checked for completeness and consistency prior to its delivery to the 
client by the lead biostatistician and a senior level, or above, reviewer.  
 
 


 
 
 
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Appendix C:  List of Tables, Figures, and Listings 
The following proposal for Sections 14 and 16.2 is completed according to ICH E3 guidelines. The ICH heading numbers and descriptions are in 
bold. Minor changes from this planned index do not need to be amended in the SAP.   
 
Formal organization of tabulations may be changed during programming, if appropriate, e.g., tables for the different variables may be combined into 
a single table, or tables with more than 1 variable may be split into several tables. 
 
  
TABLES, FIGURES AND LISTINGS  
ICH Table Number
Table Title
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN THE TEXT 
14.1 
DEMOGRAPHIC DATA 
14.1.1
Subject Disposition (Safety Analysis Set) 
14.1.2
Demographic Characteristics (Safety Analysis Set) 
14.1.3
Baseline Characteristics (Safety Analysis Set) 
14.1.4
Medical History (Safety Analysis Set) 
14.1.5.1
Prior Medications (Safety Analysis Set) 
14.1.5.2
Concomitant Medications (Safety Analysis Set) 
14.2
Efficacy data
14.2.1.1
Physician Global Assessment (PGA) - Summary of PGA by Visit (Safety Analysis Set)
14.2.1.2 
Physician Global Assessment (PGA) – Summary Statistics Including Change and Percent Change from Baseline 
(Safety Analysis Set)
14.2.2 
Percent Body Surface Area (%BSA) - Summary Statistics Including Change and Percent Change from Baseline 
(Safety Analysis Set)
14.2.3 
Psoriasis Area and Severity Index (PASI) - Summary Statistics Including Change and Percent Change from Baseline 
(Safety Analysis Set)
14.3
SAFETY DATA
14.3.1
Extent of Exposure, Dose Information, and Compliance 
14.3.1
Extent of Exposure and Study Drug Compliance (Safety Analysis Set) 






 
 
 
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Section 16.2: List of Data Listings 
ICH Listing 
Number
 
Listing Title
16.2 
SUBJECT DATA LISTINGS 
16.2.1 
Discontinued Subjects 
16.2.1
Subject Disposition
16.2.2 
Protocol Deviations 
16.2.2.1
Protocol Deviations 
16.2.2.2 
Inclusion/Exclusion Criteria 
16.2.3 
Subjects Excluded from the Efficacy Analysis 
Not applicable
16.2.4 
Demographic Data 
16.2.4.1
Demographics
16.2.4.2
Medical History
16.2.4.3
Psoriasis and Family History
16.2.4.4
Nicotine Use
16.2.4.5
Prior and Concomitant Medications
16.2.5 
Compliance and/or Drug Concentration Data  
16.2.5.1
Study Visits
16.2.5.2
IMP Dispensation/Collection 
16.2.5.3
In-Clinic Administration Tapinarof, Subject Diary, and Dosing Compliance 
16.2.6
Efficacy Data
16.2.6.1.1
Physician Global Assessment (PGA) 
16.2.6.1.2
Physician Global Assessment (PGA) - Derived 
16.2.6.2.1 
Body Surface Area (BSA) Evaluation 
 
 








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Appendix D: Statistical Analysis Plan for ECG Data 


Statistical Analysis Plan for Dermavant Sciences GmbH Study DMVT-505-2002 
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Statistical Analysis Plan 
 
 
Open-Label Maximal Use Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Tapinarof Cream, 1% in Adults with Extensive 
Plaque Psoriasis 
 
 
 
 
Protocol: DMVT-505-2002 
 
 
Sponsor: Dermavant Sciences GmbH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version:  
Final 1.0 
Authors:  
 
  
Date:   
06 November 2019 




 
 
 
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Table of Contents 
1 Abbreviations .........................................................................................................................................4 
2 Introduction ............................................................................................................................................5 
3 Study Design ..........................................................................................................................................5 
4 Cardiodynamic ECG Assessment ..........................................................................................................5 
4.1 
Cardiodynamic ECG Objectives.....................................................................................................6 
4.1.1 Primary Objective ....................................................................................................................6 
4.1.2 Secondary Objective ................................................................................................................6 
4.2 
Cardiodynamic ECG Endpoints .....................................................................................................6 
4.2.1 Primary Endpoint .....................................................................................................................6 
4.2.2 Secondary Endpoints ................................................................................................................6 
5 Statistical Methods .................................................................................................................................7 
5.1 
General Methodology .....................................................................................................................7 
5.2 
Analysis Sets ...................................................................................................................................7 
5.3 
Baseline ...........................................................................................................................................8 
5.4 
QT Correction Methods ..................................................................................................................8 
6 Analysis..................................................................................................................................................8 
6.1 
By-Time Point Analysis (Primary Analysis) ..................................................................................8 
6.2 
Categorical Analysis .......................................................................................................................9 
6.3 
Concentration-QTc Analysis (Potential Exploratory Analysis) ...................................................11 
6.3.1 Investigation of Hysteresis .....................................................................................................12 
6.3.2 Appropriateness of a Linear Model ........................................................................................12 
6.4 
Method Bias Sensitivity Analysis .................................................................................................12 
6.5 
Determination of Sample Size ......................................................................................................13 
7 References ............................................................................................................................................13 
8 Tables, Figures, and Listings ...............................................................................................................13 
8.1 
Tables ............................................................................................................................................14 
8.2 
Figures ..........................................................................................................................................14 
8.3 
Listings .........................................................................................................................................16 
9 Approvals .............................................................................................................................................17 
Appendix A: Expert Precision QT Analysis ..............................................................................................18 
 
 




 
 
 
 
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2 Introduction 
This statistical analysis plan (SAP) was developed after review of the protocol DMVT-505-2002 
(Version 1.0 dated 26 April 2019) for the study “Open-Label Maximal Use Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Tapinarof Cream, 1% in Adults with Extensive Plaque Psoriasis” 
and the
 contract/proposal. This document defines the populations to be analyzed and provides full 
details of the statistical analyses, data displays, and algorithms to be used for data derivations to aid in 
the production of the statistical output and the statistical section of the cardiac safety report in regard to 
electrocardiogram (ECG) and concentration-QTc analyses. Relevant subject characteristics as well as 
the electrocardiographic parameters that will be evaluated are described along with the specific 
statistical methods.  
3 Study Design 
This is a Phase 2a, multicenter, open-label study to evaluate the safety and pharmacokinetics (PK) of 
topical tapinarof cream in adults with extensive plaque psoriasis. The study will consist of 3 phases: 
screening (up to 34 days), treatment (29 days), and follow-up (7-10 days). 
At Day −1, eligible subjects will be enrolled into the study. During the treatment period beginning on 
Day 1 (baseline), subjects will apply tapinarof cream, 1% to affected areas once a day for 29 days. 
Subjects will return to the clinic on Days 2, 15, 29, and 30 for study assessments and will receive a 
phone call on Days 8 and 22. Subjects will return to the clinic for a follow-up visit 7-10 days after the 
Day 29 visit. On clinic visit days, subjects will apply the study drug under the supervision of site 
personnel, after assessments have been completed. Full PK profiles and Holter monitoring will be 
collected on Day 1 and Day 29 (with corresponding 24-hour time points collected on Day 2 and Day 30, 
respectively). Limited PK sampling will be performed on Day 15. Pre-treatment, time-matched Holter 
monitoring will be conducted on Day −1 and the morning of Day 1. 
Subjects who withdraw from the study before Day 30 will complete an early termination visit. Study 
duration for subjects who complete this study is approximately 10 weeks in total. 
4 Cardiodynamic ECG Assessment 
Continuous Holter recordings will be performed on Days −1, 1, 2, 29, and 30.  
On Day −1, a Holter monitor will be attached for approximately 13 hours to collect pre-treatment, time-
matched ECG data. Digital 12-lead ECGs will be extracted from the continuous recording at time points 
corresponding to time points on Day 1 and Day 29.  
On Day 1 and Day 29, a Holter monitor will be attached 1 hour prior to dosing and for 12 hours post-
dose. Digital 12-lead ECGs will be extracted at the same time points as PK samples, i.e., pre-dose and at 
1, 2, 3, 4, 5, 8, and 12 hours post-dose.  














 
 
 
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6.3.1 Investigation of Hysteresis 
Hysteresis will be assessed by graphical methods based on the LS mean of ΔQTcF for each post-
baseline time point and the mean tapinarof plasma concentrations at the same time points. In addition, 
hysteresis plots will be given for LS mean ΔQTcF and the mean concentrations. If a QT effect (∆QTcF) 
> 10 ms cannot be excluded in the by-time point analysis and if a delay between peak plasma levels and 
peak QT effect (ΔQTcF) in the plot (ΔQTcF versus tapinarof plasma concentration) of more than 1 hour 
is present, other concentration-QTc models such as a model with an effect compartment may be 
explored. With the provision stated above, hysteresis will be assumed if the curve of hysteresis plot 
shows a counterclockwise loop. 
6.3.2 Appropriateness of a Linear Model 
To assess the appropriateness of a linear model, normal Q-Q plots for the standardized residuals and the 
random effects, and plots of standardized residuals versus concentration and versus fitted values will be 
produced. The scatter plot of standardized residuals versus concentration by LOESS fitting (i.e., locally 
weighted scatter plot smoothing as described by Cleveland3) will also be produced with an optimal 
smoothing parameter selected by the Akaike information criterion with a correction.4 In addition, a 
scatter plot of observed concentration and ΔQTcF with a LOESS smooth line with 90% CI and linear 
regression line will be provided to check the assumption of linear concentration-QTc relationship. If 
there is an indication that a linear model is inappropriate, additional models will be fitted, specifically an 
Emax model. The concentration-QTc analysis will then be repeated for the model found to best 
accommodate the nonlinearity detected. 
6.4 Method Bias Sensitivity Analysis 
The purpose of the Method Bias Sensitivity analysis is to ensure that the ECG measurement technique 
used by the central ECG laboratory, Expert Precision QT (EPQT), did not introduce bias at a level that 
would significantly affect the results.  
The QT/QTc analysis set on the Study Day will be used for the Method Bias Sensitivity analysis. In this 
analysis the fully automated measurements from the iCOMPAS software will be compared to the results 
of the EPQT measurement technique, as described by Ferber et al.5 In Bland-Altman (BA) plots, QTcF 
values from fully automated iCOMPAS measurements from the 5-minute time window will be 
subtracted from the QTcF values using EPQT at the same time point for each subject; obtained 
differences were displayed as a function of the mean of the two.6 The relationship between the means 
and differences of the 2 methods will be investigated by robust regression using an M estimator, which 
reduces the impact of individual outlier values.7 From the model, the fitted slope (hereafter called the 
BA slope) and associated 2-sided 95% CIs will be given to show the linear trends between the 2 
variables. The BA slope indicates whether the observed difference between methods varies with the 
magnitude of the absolute QTcF value. A negative BA slope would indicate that the central ECG 
laboratory method (in this case, EPQT) measures relatively shorter QTcF intervals at prolonged levels 
than does the fully automated reference method (iCOMPAS), i.e., EPQT introduces a negative bias and 
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The unit of BA slope is given as ms per QTcF range of 100 ms; a value of, for example, -10 ms per 
QTcF range of 100 ms is hereafter given as -0.10 ms. A bias exceeding -0.10 would indicate that EPQT 
has introduced a bias severe enough to negatively impact the result, potentially leading to false negative 
predictions using concentration-QTc analysis.5 
6.5 Determination of Sample Size 
This study will be conducted to evaluate the safety and PK of tapinarof cream, 1% in adult subjects with 
extensive plaque psoriasis. Approximately 20 subjects aged 18 to 75 years will be enrolled in the study. 
There is no formal statistical hypothesis planned and the sample size is mainly based on feasibility and 
an estimated number of subjects needed to address the objectives of the study.  
7 References 
1. Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. [Published correction appears in J Pharmacokinet Pharmacodyn. 
2018;45(3):399]. J Pharmacokinet Pharmacodyn. 2018;45(3):383-397. 
2. Tornøe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV. Creation of a knowledge 
management system for QT analyses. J Clin Pharmacol. 2011;51(7):1035-1042. 
3. Cleveland WS. Robust locally weighted regression and smoothing scatterplots. J Am Stat Assoc. 
1979;74(368):829-836. 
4. Hurvich CM, Simonoff JS, and Tsai CL. Smoothing parameter selection in nonparametric regression 
using an improved Akaike Information Criterion. J R Stat Soc Series B Stat Methodol. 
1998;60(2):271-293. 
5. Ferber G, Zhou M, Dota C, Garnett C, Keirns J, Malik M, Stockbridge N., and Darpo B. Can Bias 
Evaluation Provide Protection Against False-Negative Results in QT Studies Without a Positive 
Control Using Exposure-Response Analysis? J Clin Pharmacol. 2017;57(1):85-95. 
6. Bland, JM, Altman, DG. Comparing methods of measurement: why plotting difference against 
standard method is misleading. Lancet. 1995;346(1982):1085-7. 
7. Gervivi, D, Yohai, VJ. A class of robust and fully efficient regression estimators. Ann Stat. 
2002;30(2):583-616. 
8 Tables, Figures, and Listings 
All tables 14.1.8-14.1.9, figures 14.2.4-14.2.13, and listings 16.2.3 will be provided separately for 
concentration-QTc analysis (1), and sensitivity analysis (2), when applicable, by using serial number 1-2 
(such as Table 14.1.8.1 for concentration-QTc analysis, and Table 14.1.8.2 for sensitivity analysis, and 
so on).  




 
 
 
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14.2.1 
Absolute QTcF across time points  
Mean and 90% CI from descriptive analysis will be 
given by treatment.  
14.2.2.1-
14.2.2.4 
Change-from-baseline QTcF, HR, 
PR, and QRS (ΔQTcF, ΔHR, ΔPR, 
and ΔQRS) across time point 
LS mean and 90% CI from the statistical modeling 
will be shown by treatment (Section 6.1). 
14.2.3.1 
Scatter plot of QTcF versus RR by 
treatment  
Scatter plots of QTcF and RR intervals by treatment 
with regression lines will be given (Section 6.3).  
14.2.3.2 
QTcF-RR quantile plot by treatment  
QTcF-RR quantile plots (with quantiles) with linear 
mixed-effects line and 90% CI will be given 
(Section 6.3).  
14.2.4 
Mean tapinarof plasma 
concentrations over time  
Section 6.3. 
14.2.5 
Joint plot of tapinarof plasma 
concentrations and ΔQTcF over time 
Section 6.3.1.  
14.2.6 
Hysteresis plot of tapinarof plasma 
concentration and ΔQTcF connected 
in temporal order by dose  
Section 6.3.1.  
14.2.7.1 
Scatter plot of observed tapinarof 
plasma concentrations and ΔQTcF 
(with LOESS and simple regression) 
Scatter plot of ∆QTcF versus concentration with 
LOESS line and 90% CI and simple regression line 
(Section 6.3.2). 
14.2.7.2 
Scatter plot of observed tapinarof 
plasma concentrations and ΔQTcF 
(with linear mixed-effects regression)  
Scatter plot of ∆QTcF versus concentration with 
linear mixed-effects regression line and 90% CI 
(Section 6.3). 
14.2.8 
Model-predicted ΔQTcF (mean and 
90% CI) and observed ΔQTcF (mean 
and 90% CI) across deciles of 
tapinarof plasma concentrations  
Section 6.3.  
14.2.9 
Predicted ΔQTcF interval at 
geometric mean peak tapinarof 
concentrations  
Section 6.3.  
14.2.10 
Scatter plot of standardized residuals 
versus fitted values  
Section 6.3.2.  
14.2.11 
Scatter plot of standardized residuals 
versus concentrations with LOESS  
Section 6.3.2.  
14.2.12 
Normal Q-Q plot of standardized 
residuals  
Section 6.3.2.  
14.2.13 
Normal Q-Q plots of the estimated 
random effects  
Section 6.3.2.  
14.2.14 
Bland-Altman plot by treatment  
Method Bias Sensitivity analysis (Section 6.4).  
14.2.15 
Bland-Altman plot: all treatments 
Method Bias Sensitivity analysis (Section 6.4).  
 






 
 
 
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Appendix A: Expert Precision QT Analysis 
Expert Precision QT analysis (formerly High Precision QT analysis) will be performed on all analyzable 
(non-artifact) beats in the 10 ECG replicates (1 replicate consists of one 14 second ECG). Statistical 
quality control procedures will be used to review and assess all beats and identify “high” and “low” 
confidence beats using several criteria including: 
• QT or QTc values exceeding or below certain thresholds (biologically unlikely) 
• RR values exceeding or below certain thresholds (biologically unlikely) 
• Rapid changes in QT, QTc, or RR from beat to beat 
Placement of fiducials and measurements of all primary ECG parameters (QT, QTc, RR) in all recorded 
beats of all replicates will be performed using the iCOMPAS software. All beats that are deemed “high 
confidence” will not be reviewed by an 
ECG analyst. All low confidence beats will be reviewed 
manually by an 
 ECG analyst and adjudicated using pass-fail criteria. The beats found acceptable by 
manual review will be included in the analysis. The beats confirmed to meet fail criteria will not be 
included in the analysis. 
For the purpose of measuring PR and QRS intervals and to assess T-wave morphology and presence of 
U-waves, the TQT Plus algorithm will select the 3 ECG replicates with the highest quality score from 
the ECG extraction window. These 3 ECGs will be analyzed using a semi-automated process to 
determine these parameters. If 3 consecutive usable beats cannot be identified in at least 2 of the 3 
replicates, then all beats in all replicates will be reviewed for that time point using a manual analysis. 
If manual analysis is required, then all beats in a minimum of 3 replicates will be reviewed using the 
iCOMPAS software. The 
 ECG analyst will review all usable beats in Lead II (or an alternate lead) 
for each replicate and will review and/or adjust the fiducial placements (onset of P, onset of Q, offset of 
S, and offset of T-wave that were electronically marked) of each waveform and also document the 
T-wave morphology and the presence of U-waves for each beat. A replicate will only be reported if it 
has 3 approved, usable beats.