Clinical trial NCT03956355
Conditions: Plaque Psoriasis
Keywords: Tapinarof plaque psoriasis adult phase 3 topical double-blind efficacy safety psoriasis
Sponsor: Organon and Co
Start date: 2019-05-21; Completion date: 2020-05-26
Enrollment: 510 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, vehicle-controlled Phase 3 study to evaluate the efficacy and safety of topical tapinarof cream, 1% once daily for the treatment of plaque psoriasis in adults. Approximately 500 adult subjects with plaque psoriasis will be randomized 2:1 to receive either tapinarof cream, 1% or matching vehicle cream once daily for 12 weeks.

Detailed description:
This study is a 12-week double-blind, vehicle-controlled treatment study in which subjects will be randomized to receive tapinarof cream, 1% or vehicle cream once daily for 12 weeks. At the end of the 12-week study treatment, qualified subjects completing the study will have the option to enter a separate open-label, long-term safety and efficacy study for an additional 40 weeks of treatment with tapinarof cream, 1%. Subjects who do not enroll in the open-label long-term study will complete a follow-up visit approximately 4 weeks after end of treatment in this study (at Week 16).

Arms: arm 1: Tapinarof (DMVT-505) Cream Group arm 2: Vehicle Cream Group
Interventions: intervention 1: Tapinarof intervention 2: Vehicle Cream
Intervention descriptions: intervention 1: Tapinarof cream, 1%, applied once daily intervention 2: Vehicle cream applied once daily

Protocol documents:
Prot_000.pdf: 
1 
CLINICAL STUDY PROTOCOL 
Title 
A Phase 3 Efficacy and Safety Study of Tapinarof for the Treatment 
of Plaque Psoriasis in Adults 
Sponsor 
Dermavant Sciences GmbH 
Viaduktstrasse 8 
4051 Basel, Switzerland 
Compound Name 
Tapinarof (DMVT-505) 
Protocol Number 
DMVT-505-3001 
Indication 
Plaque Psoriasis 
Development Phase 
3 
IND # 
104601 
Version/ 
Effective Date: 
Original Protocol
25-JANUARY-2019 
Amendment 1 (Version 1.1)
08-MAY-2019 
Amendment 2 (Version 2.0)
08-AUGUST-2019 
Confidentiality Statement 
The information contained in this document, particularly unpublished data, is the property or under 
control of Dermavant Sciences GmbH, and is provided to you in confidence as an investigator, potential 
investigator or consultant, for review by you, your staff, and an applicable Institutional Review Board or 
Independent Ethics Committee.  The information is only to be used by you in connection with authorized 
clinical studies of the investigational drug described in the protocol.  You will not disclose any of the 
information to others without written authorization from Dermavant Sciences GmbH, except to the extent 
necessary to obtain informed consent from those persons to whom the drug may be administered. 






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INVESTIGATOR STATEMENT 
Study Title:  A Phase 3 Efficacy and Safety Study of Tapinarof for the Treatment of Plaque 
Psoriasis in Adults 
 
• 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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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
SYNOPSIS ....................................................................................................................................12 
SCHEDULE OF ASSESSMENTS ................................................................................................18 
1. 
INTRODUCTION ......................................................................................................21 
1.1. 
Background Information and Study Rationale ...........................................................21 
1.1.1. 
Background Information .............................................................................................21 
1.1.2. 
Study Rationale ...........................................................................................................22 
1.2. 
Rationale for Study Design, Dose, and Control Groups .............................................23 
1.3. 
Potential Risks and Benefits .......................................................................................23 
1.3.1. 
Risk Assessment .........................................................................................................23 
1.3.1.1. 
Dermatological Adverse Events, Including Skin Irritation or Allergic 
Reaction ......................................................................................................................23 
1.3.1.2. 
Systemic Adverse Events ...........................................................................................24 
1.3.1.3. 
Reproductive and Developmental Toxicity ................................................................24 
1.3.2. 
Benefit Assessment .....................................................................................................25 
1.3.3. 
Overall Benefit Risk ...................................................................................................25 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................26 
3. 
STUDY DESIGN .......................................................................................................28 
3.1. 
Overall Design ............................................................................................................28 
3.2. 
Treatment Groups and Duration .................................................................................29 
4. 
STUDY POPULATION .............................................................................................30 
4.1. 
Type and Number of Subjects ....................................................................................30 
4.2. 
Inclusion Criteria ........................................................................................................30 
4.3. 
Exclusion Criteria .......................................................................................................31 
4.4. 
Lifestyle Restrictions ..................................................................................................33 
4.5. 
Screening/Baseline Failures........................................................................................33 
4.6. 
Withdrawal Criteria ....................................................................................................33 
4.6.1. 
Reasons for Withdrawal from the Study ....................................................................33 
4.6.2. 
Withdrawal Procedures ...............................................................................................34 
4.7. 
Lost to Follow-Up.......................................................................................................34 
5. 
STUDY TREATMENT ..............................................................................................35 
5.1. 
Study Drug ..................................................................................................................35 


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5.1.1. 
Description, Packaging, and Labeling ........................................................................35 
5.1.2. 
Storage ........................................................................................................................35 
5.1.3. 
Handling and Disposal ................................................................................................35 
5.1.4. 
Preparation ..................................................................................................................35 
5.1.5. 
Administration of Study Drug ....................................................................................36 
5.2. 
Randomization/Treatment Assignment ......................................................................37 
5.3. 
Blinding ......................................................................................................................37 
5.4. 
Compliance with Study Drug Administration ............................................................38 
5.5. 
Treatment after the End of the Study ..........................................................................38 
5.6. 
Prior and Concomitant Therapy ..................................................................................38 
5.6.1. 
Permitted Medications and Nondrug Therapies .........................................................39 
5.6.2. 
Prohibited Medications and Nondrug Therapies ........................................................39 
6. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
6.1. 
Demography, Medical History, and Baseline Characteristics ....................................40 
6.1.1. 
Demographics .............................................................................................................40 
6.1.2. 
Medical History ..........................................................................................................40 
6.1.3. 
Baseline Characteristics ..............................................................................................40 
6.2. 
Efficacy Assessments .................................................................................................40 
6.2.1. 
Assessments Completed by Investigator ....................................................................40 
6.2.1.1. 
Physician Global Assessment .....................................................................................40 
6.2.1.2. 
Body Surface Area Affected .......................................................................................41 
6.2.1.3. 
Psoriasis Area and Severity Index ..............................................................................41 
6.2.2. 
Assessments Completed by Subject ...........................................................................41 
6.2.2.1. 
Dermatology Life Quality Index ................................................................................41 
6.2.2.2. 
36−Item Short Form Survey .......................................................................................41 
6.2.2.3. 
Psoriasis Symptom Diary ...........................................................................................42 
6.2.2.4. 
Peak Pruritus-Numeric Rating Scale ..........................................................................42 
6.2.3. 
Optional Clinical Photography ...................................................................................42 
6.3. 
Safety Assessments .....................................................................................................42 
6.3.1. 
Adverse Events ...........................................................................................................42 
6.3.2. 
Brief Physical Examination ........................................................................................42 
6.3.3. 
Vital Signs ..................................................................................................................43 
6.3.4. 
Clinical Safety Laboratory Assessments ....................................................................43 


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6.3.5. 
Local Tolerability Scale ..............................................................................................44 
6.4. 
Treatment of Study Drug Overdose ............................................................................45 
6.5. 
Pharmacokinetics ........................................................................................................45 
7. 
TIMING OF PROCEDURES AND ASSESSMENTS ..............................................46 
7.1. 
Visit 1; Screening Period (Day -34 to Day -1) ...........................................................46 
7.2. 
Visit 2; Baseline (Day 1) ............................................................................................47 
7.3. 
Double-Blind, Vehicle-Controlled Phase ...................................................................47 
7.3.1. 
Visit 3; Week 2 (Day 15 ±2 Days) .............................................................................47 
7.3.2. 
Visit 4; Week 4 (Day 29 ±2 Days) .............................................................................48 
7.3.3. 
Visit 5; Week 8 (Day 57 ±2 Days) .............................................................................48 
7.3.4. 
Visit 6; Week 12 (Day 85 ±2 Days) ...........................................................................49 
7.3.5. 
Phone Contact at Weeks 6 (Day 43 ±2 Days) and 10 (Day 71 ±2 Days) ...................50 
7.4. 
Follow-Up Visit 7; Week 16 (Day 113 ±4 Days) .......................................................50 
7.5. 
Early Termination Visit ..............................................................................................50 
7.6. 
End of Study ...............................................................................................................51 
8. 
SAFETY MONITORING AND REPORTING .........................................................52 
8.1. 
Adverse Events, Serious Adverse Events, and Adverse Events of Special 
Interest ........................................................................................................................52 
8.1.1. 
Definition of Adverse Events .....................................................................................52 
8.1.2. 
Definition of Serious Adverse Event ..........................................................................53 
8.1.3. 
Adverse Events of Special Interest .............................................................................54 
8.2. 
Classification of Adverse Events ................................................................................54 
8.2.1. 
Assigning Severity Rating for Adverse Events ..........................................................54 
8.2.1.1. 
Criteria for Determining Averse Event Severity ........................................................54 
8.2.1.2. 
Toxicity Management Criteria ....................................................................................55 
8.2.2. 
Assigning Causal Relationship to Study Drug ...........................................................56 
8.3. 
Time Period and Frequency for Event Assessment and Follow-Up ...........................56 
8.3.1. 
Adverse Event Reporting ............................................................................................56 
8.3.2. 
Follow-Up of Adverse Events ....................................................................................57 
8.4. 
Reporting Procedures ..................................................................................................57 
8.4.1. 
Serious Adverse Event Reporting ...............................................................................57 
8.4.2. 
Regulatory Reporting Requirements for Serious Adverse Events .............................57 
8.5. 
Pregnancy Management and Reporting ......................................................................58 


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8.6. 
Safety Oversight .........................................................................................................58 
9. 
DATA MANAGEMENT ...........................................................................................59 
10. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ............................60 
10.1. 
General Considerations ...............................................................................................60 
10.2. 
Determination of Sample Size ....................................................................................60 
10.3. 
Analysis Populations ..................................................................................................60 
10.3.1. 
Safety ..........................................................................................................................60 
10.3.2. 
Intent-To-Treat ...........................................................................................................60 
10.3.3. 
Per-Protocol ................................................................................................................60 
10.3.4. 
Pharmacokinetic .........................................................................................................60 
10.4. 
Planned Analyses ........................................................................................................61 
10.4.1. 
Disposition and Demographics ...................................................................................61 
10.4.2. 
Efficacy Analyses .......................................................................................................61 
10.4.2.1. 
Primary Endpoint Analyses ........................................................................................61 
10.4.2.2. 
Secondary and Exploratory Efficacy Endpoint Analyses ...........................................61 
10.4.3. 
Safety Analyses ..........................................................................................................62 
10.4.4. 
Analysis of Functional Outcomes and Quality of Life Endpoints ..............................62 
10.4.5. 
Pharmacokinetic Analyses ..........................................................................................63 
10.5. 
Interim Analyses .........................................................................................................63 
10.6. 
Handling of Missing Data ...........................................................................................63 
11. 
RESPONSIBILITIES .................................................................................................64 
11.1. 
Investigator Responsibilities .......................................................................................64 
11.1.1. 
Good Clinical Practice ................................................................................................64 
11.1.2. 
Institutional Review Board/Independent Ethics Committee Approval ......................64 
11.1.3. 
Informed Consent/Assent ...........................................................................................64 
11.1.4. 
Confidentiality ............................................................................................................65 
11.1.5. 
Study Files and Retention of Records ........................................................................65 
11.1.6. 
Electronic Case Report Forms ....................................................................................66 
11.1.7. 
Drug Accountability ...................................................................................................66 
11.1.8. 
Inspections ..................................................................................................................67 
11.1.9. 
Protocol Compliance ..................................................................................................67 
11.2. 
Sponsor Responsibilities .............................................................................................67 
11.2.1. 
Protocol Modifications ...............................................................................................67 


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11.2.2. 
Study Report and Publications....................................................................................67 
11.2.3. 
Posting of Information on Publicly Available Clinical Trial Registers ......................67 
11.3. 
Joint Investigator/Sponsor Responsibilities ................................................................68 
11.3.1. 
Access to Information for Monitoring ........................................................................68 
11.3.2. 
Access to Information for Auditing or Inspections ....................................................68 
11.3.3. 
Study Discontinuation ................................................................................................68 
12. 
REFERENCES ...........................................................................................................69 
13. 
APPENDICES ............................................................................................................70 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................18 
Table 2: 
Tapinarof and Vehicle Cream .....................................................................................35 
Table 3: 
Laboratory Tests .........................................................................................................44 
Table 4: 
Criteria for Determining the Grade/Severity of Adverse Event Terms Not 
Specified by the National Cancer Institute CTCAE ...................................................55 
 
LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................29 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term 
Description 
AD 
atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
AhR 
aryl hydrocarbon receptor 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
Anti-HBc 
anti-hepatitis B core antigen 
AST 
aspartate aminotransferase 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BSA 
body surface area 
%BSA 
percent of total body surface area 
BUN 
blood urea nitrogen 
BWTP 
Beijing Wenfeng Tianji Pharmaceuticals 
CBP 
child-bearing potential 
CFR 
Code of Federal Regulations 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular 
D/d 
day(s) 
Dermavant 
Dermavant Sciences GmbH 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
FCS 
Fully Conditional Specification 
F-U 
follow-up 
GSK 
GlaxoSmithKline 
HADS 
Hospital Anxiety and Depression Scale 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


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Term 
Description 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LTS 
Local Tolerability Scale 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV  
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputations 
MSDS 
Material Safety Data Sheet 
NA 
not applicable 
Nrf2 
nuclear factor erythroid 2-related factor 2 
NRS 
Numeric Rating Scale 
PASI 
Psoriasis Area Severity Index 
PC 
phone contact 
PK 
Pharmacokinetic(s) 
PND 
postnatal day 
RBC 
red blood cell(s) 
PP 
Per-Protocol 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SF-36 
Short Form-36 
TAMA 
therapeutic AhR-modulating agent 
TF 
Treatment Failure 
ULN 
upper limit of normal 
US; USA 
United States (of America) 
UV 
ultraviolet 
V 
visit 
WBC 
white blood cell(s) 
WOCBP 
women of child-bearing potential 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


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SYNOPSIS 
Name of Sponsor/Company: 
Dermavant Sciences GmbH 
Name of Investigational Product: 
DMVT-505 (tapinarof cream, 1%) 
Name of Active Ingredient:   
Tapinarof 
Protocol Number: DMVT-505-3001 
Phase: 
3 
Country: United States (US) and Canada 
Title of Study: 
A Phase 3 Efficacy and Safety Study of Tapinarof for the Treatment of Plaque Psoriasis in Adults  
Study Center(s): 
Approximately 50 to 60 sites in the United States (US) and Canada 
Objectives: 
Primary: 
• 
To evaluate the efficacy of tapinarof cream, 1% compared with vehicle control in adults with plaque 
psoriasis 
Secondary: 
• 
To further characterize the efficacy of tapinarof cream, 1% compared with vehicle control over time 
• 
To describe the effect of tapinarof cream, 1% on psoriasis symptom severity and the associated impact on 
daily activities and attitudes in adults with plaque psoriasis 
• 
To evaluate the safety and tolerability of tapinarof cream, 1% in adults with plaque psoriasis 
• 
To characterize the pharmacokinetics (PK) of tapinarof in adults with plaque psoriasis  
Methodology: 
This is a double-blind, randomized, vehicle-controlled, Phase 3, multicenter study to evaluate the efficacy and 
safety of topical tapinarof cream, 1% compared with vehicle-control cream in adults with plaque psoriasis.   
Following a 34-day screening period, eligible subjects will be randomized at a 2:1 ratio to receive once daily 
treatment with tapinarof cream, 1% or vehicle cream.  Subjects will return to the clinic at Weeks 2, 4, 8, and 12 for 
efficacy and safety assessments.  Additionally, subjects will be contacted by phone at Weeks 6 and 10 to assess 
adverse events (AEs) and concomitant medications, to review study drug administration instructions, and to 
confirm subject’s continued participation in this study. 
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 lesions and lesions/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 fingernails, toenails, palms, soles, and scalp lesions with study drug; however, efficacy analyses 
will not include assessment of improvement of psoriasis in these areas.) Subjects will be instructed to maintain the 
approximate dosing time chosen at the beginning of the study for their full study participation.  At the phone 
contacts at Weeks 6, and 10, 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 and during any planned 
study phone calls.  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 efficacy and safety assessments have been 
completed.  The time of the dose application and assessments will depend on the time of the clinic visit.  
Therefore, the timing of the clinic visit may lead to a change in the subject’s chosen dosing time, 


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At the end of the 12 weeks of treatment in this study, subjects will have the option to enroll in a separate 
open-label long-term safety and efficacy study for an additional 40 weeks of treatment.  Subjects who choose not 
to participate in the open-label long-term study, who fail to qualify for participation in the open-label long-term 
study, or who qualify to participate in the open-label long-term study but ultimately elect not to enroll in that 
study, will complete a Follow-up Visit approximately 4 weeks (Week 16 visit) after the end of treatment in this 
study.  Subjects who withdraw from the study before Week 12 will complete an Early Termination Visit.   
Number of Subjects: 
Approximately 500 subjects ages 18 to 75 years will be enrolled in the study as follows:   
• 
Approximately 500 subjects will be randomized at a 2:1 ratio to receive tapinarof cream, 1% 
(approximately 333 subjects) or vehicle cream (approximately 167 subjects) 
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 clinical diagnosis of chronic plaque psoriasis and 
stable disease for at least 6 months prior to the study. 
2. Body surface area (BSA) involvement ≥ 3% and ≤ 20% (the subject’s scalp, palms, fingernails, toenails, 
and soles should be excluded from the percent of total BSA (%BSA) calculations). 
3. A Physician’s Global Assessment (PGA) score of 2 (mild), 3 (moderate) or 4 (severe) at screening and 
baseline (pre-randomization).  Subjects with mild and severe psoriasis will be limited to approximately 
10% each of the total randomized population; the majority of the enrolled subjects (approximately 80%) 
will have a PGA of 3, signifying moderate disease. 
4. Females of child-bearing potential 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 partner with vasectomy, OR 
• 
Male condom AND partner use of 1 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-child-bearing 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 IU/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.  Female subjects of 
childbearing potential must have a negative serum pregnancy test at Screening and negative urine 
pregnancy test at Baseline (Day 1). 


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5. 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 any study related procedures. 
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 lesions. 
3. Concurrent conditions or history of other diseases: 
a. 
Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome)  or medical history of 
positive human immunodeficiency virus (HIV) antibody at Screening. 
b. Chronic or acute systemic 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, 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) ≥ 1.5x the upper limit of 
normal (ULN). 
5. Screening total bilirubin > 1.5 x ULN; total bilirubin >  ULN and ≤ 1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin < 35%. 
6. Corrected QT (QTcF) interval > 475 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. 
Subjects with a history of HCV infection who were medically cured and have an undetectable viral load 
are eligible to enroll.  Subjects with a history of stable non-alcoholic fatty liver disease without evidence 
of active inflammation (elevated ALT/AST ≥ 1.5x ULN) or cirrhosis are eligible to enroll.  
8. Ultraviolet (UV) light therapy or prolonged exposure to natural or artificial sources of UV radiation 
(eg, 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 (double-blind and open-label phases) 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. 
• 
Minimum of 5 half-lives for biologic agents:  eg, 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 D3 and analogs 
(> 5000 IU/day), retinoids (eg, acitretin, isotretinoin), psolarens, corticosteroids, or 
adrenocorticotropic hormone analogs 
• 
2 weeks for immunizations with a live viral component; drugs known to possibly worsen psoriasis, 
such as beta-blockers (eg, propranolol), lithium, iodides, angiotensin-converting enzyme inhibitors, 
and indomethacin, unless on a stable dose for > 12 weeks 


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• 
With the exception of non-medicated emollients, 2 weeks for topical treatments including 
corticosteroids, antihistamines, immunomodulators, anthralin (dithranol), Vitamin D derivatives (eg, 
calcipotriene, calcipotriol), retinoids (Note:  4 weeks for 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 drugs, 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 product 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 
study drug (whichever is longer). 
15. Current or a history of cancer within 5 years except for aqequately treated skin basal cell carcinoma, 
squamous cell carcinoma or carcinoma in situ of the cervix (surgical excision or electrodessication and 
curettage). 
16. Subjects with active systemic infection that required oral, intramuscular, or intravenous administration of 
antibiotics, antifungal or antiviral agents within 4 weeks of Baseline/Day 1. 
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 
cardiovascular (CV) system abnormalities or laboratory abnormality that will affect the health of the 
subject or interfere with interpretation of the results. 
Investigational Product, Dosage and Mode of Administration: 
Tapinarof cream, 1% is a white to off-white cream containing 1% (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.   
Reference Therapy, Dosage and Mode of Administration: 
Vehicle cream is a white to off-white cream, 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 3 study and who fail to qualify for 
participation in the open-label long-term study, or who qualify to participate in the open-label long-term study but 
ultimately elect not to enroll in that study is approximately 20 weeks in total (including approximately 34 days 
screening, 12 weeks of treatment, and a 4-week follow-up period). 
• 
Subjects randomized to tapinarof cream, 1% will receive tapinarof for 12 weeks. 
• 
Subjects randomized to vehicle cream will receive treatment with vehicle cream for 12 weeks. 
Criteria for Evaluation: 
Efficacy Assessments:  Investigator assessment of PGA, %BSA affected, and Psoriasis Area Severity Index 
(PASI). 
Functional Outcomes and Quality of Life Assessments:  Dermatology Life Quality Index (DLQI), Psoriasis 
Symptom Diary (PSD), Short Form-36 (SF-36), and Peak Pruritus-Numeric Rating Scale (NRS). 
Safety Assessments:  AEs, vital signs, physical examinations, clinical laboratory tests, and Local Tolerability 
Scale (LTS). 
Pharmacokinetic Assessments:  Plasma concentration of tapinarof. 
Study Endpoints: 


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Primary: 
• 
Proportion of subjects who achieve a PGA score of clear (0) or almost clear (1) with a minimum 2-grade 
improvement from Baseline at Week 12 
Secondary: 
• 
Proportion of subjects with ≥ 75% improvement in PASI from Baseline at Week 12 
• 
Proportion of subjects with a PGA score of 0 or 1 at Week 12 
• 
Mean change in percent of total body surface area (%BSA) affected from Baseline to Week 12 
• 
Proportion of subjects with ≥ 90% improvement in PASI score from Baseline to Week 12 
Exploratory Endpoints 
• 
Time to achieve a PGA score of 0 or 1 with a minimum 2 grade improvement from Baseline 
• 
Change in Peak Pruritus-Numeric Rating Scale (Peak Pruritus-NRS) from Baseline at Weeks 2, 4, 8, and 
12 
• 
Proportion of subjects with a PGA score of 0 or 1 at Weeks 2, 4, 8, and 12 
• 
Proportion of subjects who achieve a PGA score of 0 or 1 with a minimum 2-grade improvement from 
Baseline at Weeks 2, 4, and 8 
• 
Mean absolute and percent change in PASI score from Baseline to Weeks 2, 4, 8, and 12 
• 
Proportion of subjects with ≥ 50% improvement in PASI score from Baseline to Weeks 2, 4, 8, and 12 
• 
Proportion of subjects with ≥ 75% improvement in PASI score from Baseline to weeks 2, 4, and 8 
• 
Proportion of subjects with ≥ 90% improvement in PASI score from Baseline to weeks 2, 4, and 8 
• 
Mean change in %BSA affected from Baseline to Weeks 2, 4, and 8 
• 
Change over time in psoriasis impact on daily activities, as measured by the DLQI total and individual 
dimension scores 
• 
Change over time in psoriasis symptoms, as measured by the PSD 
• 
Change over time in physical component score and mental component score, as measured by the 
SF-36 questionnaire 
Safety: 
• 
Incidence, frequency, and duration of treatment emergent adverse events (TEAEs) and serious adverse 
events (SAEs) 
• 
Clinically significant change from Baseline in laboratory values 
• 
Clinically significant change from Baseline in vital signs 
• 
Mean LTS scores by visit 
Pharmacokinetic: 
• 
Plasma concentration of tapinarof at Weeks 4 and 12 
Statistical Methods: 
Determination of Sample Size:  It is assumed that the proportion of subjects who achieve PGA score of clear (0) or 
almost clear (1) with a minimum 2-grade improvement from Baseline at Week 12 will be 40% for subjects 
receiving tapinarof cream, 1% compared with 15% for subjects receiving vehicle control cream.  With 
500 subjects randomized in a 2:1 ratio (approximately 333 subjects receiving tapinarof cream, 1% and 
approximately 167 subjects receiving vehicle cream), there will be > 99% power for a statistical significance 
(2-sided p< 0.05).  If the tapinarof response rate is 35%, and the vehicle response rate is 20%, the power will be 
> 94%.  The power is calculated from a Fisher Exact sample size calculation which is conservative.  It is assumed 
that up to 25% of the subjects will be lost to follow-up by 12 weeks.  These subjects will be included in the 
primary analysis using the multiple imputation method. 
Efficacy Analyses:  All efficacy analyses will be based on the Intent-to-Treat (ITT) population and will be 
repeated for the Per Protocol (PP) population only for the primary and secondary efficacy endpoints as supportive 
analysis.  The primary efficacy endpoint will be analyzed using a Cochran–Mantel–Haenszel (CMH) test stratified 
by PGA score at Baseline (PGA scores of 2, 3, or 4).  The same method used for the primary analyses will be used 
to analyze all dichotomized secondary endpoints.  The secondary endpoints will be tested sequentially in order, 
and testing will stop if non-significance (2-sided p≥ 0.05) is observed.  Other efficacy endpoints will be analyzed 


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using CMH test for proportions, and analysis of covariance (ANCOVA) model for continuous variables.  CMH 
tests will be stratified by baseline PGA score, and ANCOVA models will include PGA score as a covariate.  
Open-label data will be summarized using summary statistics without testing. 
Safety Analyses:  The Safety Population will be used in the analysis of safety data.  Data will be listed by subject 
and treatment and summarized by treatment.  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 TEAE summaries will include information for AEs 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 
laboratory data will be analyzed using descriptive summary statistics and will be presented by study visit and 
treatment group, including the number of non-missing observations, mean and standard deviation, 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. 
Functional Outcomes and Quality of Life Analysis:  Change from Baseline in the subject reported DLQI, PSD, 
SF-36, and Peak Pruritus-NRS scores will be analyzed using an ANCOVA model with treatment as a main effect, 
and baseline as a covariate. 
Pharmacokinetic Analyses:  Plasma concentration data will be listed and summarized by study visit. 
 


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SCHEDULE OF ASSESSMENTS 
Table 1: 
Schedule of Assessments 
Procedures and Assessment 
Screening 
Baseline 
Double-Blind Vehicle-Controlled Treatment Phase 
FUa 
ETb 
V 1 
V 2 
V 3 
V 4 
P/Cc 
V 5 
P/Cc
V 6 
V 7 
NA 
Day -34 
to 
Day -1 
Day 1 
Week 
2 
D 15 
(±2 d) 
Week 
4 
D 29 
(±2 d) 
Week 
6 
D 43 
(±2 d) 
Week 
8 
D 57 
(±2 d) 
Week 
10 
D 71 
(±2 d) 
Week 
12 
D 85 
(±2 d) 
Week 
16 
D 113 
(±4 d) 
NA 
Informed consent 
X 
Demographics 
X 
Medical historyd 
X 
Xe 
Assess/confirm eligibility 
X 
X 
Serum/urine pregnancy test (WOCBP)f 
X 
Xg 
X 
X 
X 
X 
X 
Brief physical examination 
Xh 
X 
X 
X 
X 
X 
X 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
Blood sample for clinical laboratory testsj 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
HADS 
X 
Subject randomization 
X 
Photograph representative area of disease areak 
X 
X 
X 
X 
PK blood sample collectionl 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Investigator Assessed:  
PGA scorem 
X 
X 
X 
X 
X 
X 
X 
X 
%BSA affectedn 
X 
Xo 
X 
X 
X 
X 
X 
X 
PASI 
X 
X 
X 
X 
X 
X 
X 
LTSp 
X 
X 
X 
X 
X 
X 


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Procedures and Assessment 
Screening 
Baseline 
Double-Blind Vehicle-Controlled Treatment Phase 
FUa 
ETb 
V 1 
V 2 
V 3 
V 4 
P/Cc 
V 5 
P/Cc 
V 6 
V 7 
NA 
Day -34 
to  
Day -1 
Day 1 
Week 
2 
D 15 
(±2 d) 
Week 
4 
D 29 
(±2 d) 
Week 
6 
D 43 
(±2 d) 
Week 
8 
D 57 
(±2 d) 
Week 
10 
D 71 
(±2 d) 
Week 
12 
D 85 
(±2 d) 
Week 
16 
D 113 
(±4 d) 
NA 
Completed by Subject:   
 
 
 
 
 
 
 
 
 
 
DLQI 
 
X 
 
X 
 
 
 
X 
X 
X 
SF-36 
 
X 
 
X 
 
 
 
X 
X 
X 
PSD 
 
X 
X 
X 
 
X 
 
X 
X 
X 
LTS 
 
 
X 
X 
 
X 
 
X 
X 
X 
Peak Pruritus NRSq 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense/collect diaryr 
 
D 
C/D 
C/D 
 
C/D 
 
C 
 
C 
Review subject diaries for treatment compliance 
 
 
X 
X 
 
X 
 
X 
 
X 
Dispense (D)/Collect (C) study drug  
 
D 
C/D 
C/D 
 
C/D 
 
C 
 
C 
Review instructions for study drug applications 
 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug application under supervisiont 
 
X 
X 
X 
 
X 
 
 
 
 
Enrollment (optional) in long-term study 
 
 
 
 
 
 
 
X 
 
 
AE = adverse event (s); BMI = body mass index; BSA = body surface area; %BSA = percent of total BSA; D/d = day(s); DLQI = Dermatology Life Quality Index; ECG = electrocardiogram; eCRF = 
electronic Case Report Form; ET = early termination; FU = follow-up; HADS = Hospital Anxiety and Depression Scale; LTS = Local Tolerability Scale; NA = not applicable; NRS = Numeric Rating 
Scale; PASI = Psoriasis Area and Severity Index; P/C = phone contact; PGA = Physician Global Assessment; PK = Pharrmacokinetics; PSD = Psoriasis Symptom Diary; SF-36 = 36−Item Short Form 
Survey; V = Visit; WOCBP = women of child-bearing potential. 
 
a The Follow-Up Visit will be performed for any subject who:  (a) prematurely withdraws from the study, (b) fails to qualify for participation in the open-label long-term study, or (c) qualifies to 
participate in the open-label long-term study but elects not to enroll in that study. 
b Subjects who withdraw from the study before 12 weeks (Visit 6) will complete an Early Termination Visit. 
c Phone calls are scheduled between visits to assess AEs and concomitant medications, to review study drug application procedures, and to confirm subject’s continued participation in the study.  
Subjects should be reminded to complete the diary and bring with them to the next clinic visit. 
d Medical history will include year of plaque psoriasis diagnosis, CV medical history and risk factors (including height, weight, smoking history, medical conditions, and family history of premature CV 
disease) and family history of liver disease. 
e Record any changes to medical history. 
f Serum pregnancy test to be performed at the Screening visit only and urine pregnancy test to be performed at subsequent clinic visits. 
g Urine pregnancy test to be performed before randomization. 
h Physical examination will include height, weight, and BMI at the Screening visit; a brief physical examination will be performed at other visits (Section 6.3.2). 


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i Vital signs will include blood pressure, pulse, and body temperature. 
j Including serum chemistry and liver chemistry tests, and hematology. 
k Photography will be performed in a subgroup of subjects at selected (8 to 10) study centers; this is not required of subjects for participation in the study.  Informed consent/assent and photographic 
release will be required. 
l Blood sample collection for PK will be performed at a subset of sites in a subset of subjects.  Sample to be collected prior to study drug application in clinic. 
m The PGA assessment should be performed before the %BSA and PASI assessments.  
n The subject’s scalp, palms, fingernails toenails, and soles should be excluded from the %BSA calculations. 
o %BSA affected calculation should be completed before the PASI assessment.  Note that lesions on scalp, palms, fingernails, toenails, and soles will not be included in the calculation of %BSA 
affected as these areas will be excluded from the efficacy analyses. 
p The LTS assessment also consists of a subject-assessed component (Section 6.3.5). 
q Subjects should perform the Peak Pruritus NRS assessment daily (Section 6.2.2.4) and record the results in their diary. On study visit days, subjects will not complete the diary at home; application 
time and NRS will be recorded in the clinic. 
r Subjects will be instructed on when and how to complete diaries. 
s Subjects will be instructed to apply study drug once daily at the approximate same time each day, based on subject preference (Section 5.1.5). 
t At clinic visits, study drug will be applied after safety and efficacy assessments have been conducted (see Section 5.1.5 for additional details on timing of application of study drug during clinic 
visits). 
 
 
 


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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
1.1.1. 
Background Information 
Psoriasis is a common, chronic relapsing inflammatory skin disease [Parisi, 2012] with recurrent 
episodes of prominently erythematous and scaly patches (plaques).  Approximately 2% to 3% of 
the global population is affected by psoriasis; those affected are predominantly adults, who are 
most often diagnosed between the ages of 18 to 35 years.  Psoriasis disrupts daily activities such 
as work and/or school attendance, interpersonal relationships, recreational activities, and 
intimacy, thereby significantly impacting sufferers’ quality of life.  Furthermore, psoriasis 
sufferers can also have co-morbidities such as arthritis, depression, inflammatory bowel disease, 
and cardiovascular (CV) diseases. 
Up to 80% of patients have mild to moderate plaque-type psoriasis, which is generally managed 
with topical treatments.  The most commonly used treatments for psoriasis include topical 
corticosteroids and vitamin D analogs, alone or in combination.  Vitamin D analogs are 
moderately efficacious as monotherapy, whereas application of topical corticosteroids, 
particularly the very potent ones, is restricted in terms of body areas that can be treated and the 
duration of use due to the well-known application site and systemic adverse drug reactions 
[Mason, 2013].  Although numerous topical treatment options are available, there remains a need 
for a topical treatment that combines a high level of efficacy with an acceptable safety profile 
and permits application to a large body surface area (BSA) without restrictions on duration of 
treatment. 
Tapinarof (DMVT-505), formerly known as GSK2894512, is a fully synthetic hydroxylated 
stilbene that is being developed by Dermavant Sciences GmbH (Dermavant) as a novel 
anti-inflammatory agent for the topical treatment of atopic dermatitis (AD) and plaque psoriasis.  
The compound (number WBI 1001) was initially developed by Welichem Biotech Inc.  
(Welichem; Burnaby, British Columbia, Canada) and then was acquired by GlaxoSmithKline 
(GSK) on 31 July 2012 for further development in the rest of the world except China.  Beijing 
Wenfeng Tianji Pharmaceuticals (BWTP) is developing a compound in China identified as 
Benvitimod (active ingredient corresponds to tapinarof) with a unique topical formulation.  
Dermavant acquired the drug from GSK on 20 August 2018 for continued development. 
Tapinarof cream, 1% is a white to off-white, oil-in-water emulsion intended for topical 
application to AD and psoriatic skin lesions, which has a novel mechanism of action.  The drug 
likely mediates its effects via the aryl hydrocarbon receptor (AhR) agonist and nuclear factor 
erythroid 2-related factor 2 (Nrf2) because the pattern of pro-inflammatory mediators inhibited 
by tapinarof is different from that of corticosteroids, calcineurin inhibitors, vitamin D analogs, 
and other immunosuppressive agents commonly used to treat AD and psoriasis.  Rather, the 
profile of biological responses elicited by tapinarof most closely matches that of the dual 
activation properties of coal tar, a common nonprescription treatment for psoriasis.  Together, 
existing data identify tapinarof as a non-steroid, therapeutic AhR-modulating agent (TAMA), 
which is a unique mechanism of action compared with existing therapies. 
Tapinarof cream has been evaluated in nonclinical studies at concentrations up to 8% and in 
clinical studies at concentrations up to 2%.  Three Phase 1 clinical pharmacology studies in 
healthy volunteers and 7 Phase 1/2 studies in subjects with AD and psoriasis have been 


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completed.  Refer to the current version of the tapinarof Investigator’s Brochure for detailed 
information.  Tapinarof has demonstrated an acceptable safety profile and a clear therapeutic 
effect, as compared with vehicle, in both psoriasis and AD. 
Four randomized, double-blind, vehicle-controlled, clinical studies to evaluate the safety and 
efficacy of topically applied tapinarof cream in subjects with AD or psoriasis were conducted by 
Welichem; one 28-day and one 12-week study was completed for each indication. 
These studies enrolled a total of 282 adult subjects, with 235 subjects exposed to tapinarof 
cream, 0.5%, 1%, or 2% (Formulation C) once or twice daily for a period of 28 to 84 days.  
Efficacy was rapid, and statistically significant differences versus vehicle were observed as early 
as Day 14 for the majority of efficacy parameters in both indications.  The most frequently 
reported (1% to 6% of 235 subjects) dermatological adverse events (AEs), regardless of 
causality, were application site discoloration/hyperpigmentation, application site dermatitis, 
papular rash, pruritus, dermatitis contact, folliculitis, erythema, and skin burning sensation.  
Nasopharyngitis and headache were the most frequently reported (> 10% of subjects) 
nondermatological AEs overall.  Overall, results of the clinical studies indicated tapinarof was 
highly efficacious for both AD and psoriasis, with a favorable safety profile. 
The first clinical study with Formulation F (Study 201851) was a Phase 1 study to evaluate the 
systemic exposure and pharmacokinetic (PK) parameters of tapinarof cream, 1% and 2%.  This 
study was conducted in 11 subjects with AD; 5 subjects were treated with the 2% dose and 
6 subjects were treated with the 1% dose.  Headache was the most frequently reported (100% 
and 60% of subjects at the 1% and 2% doses, respectively) nondermatological AE. 
Two Phase 2b, 12 week, randomized, double-blind, vehicle-controlled, 6-arm, parallel group, 
dose-finding studies with topically applied tapinarof cream were conducted by GSK; 1 study 
each in subjects with AD or psoriasis.  These 2 studies evaluated the safety and efficacy of 
tapinarof cream (Formulation F) at 2 concentrations (0.5% or 1%) and 2 application frequencies 
(once daily or twice daily) in 247 adult and adolescent subjects with AD and in 227 adult 
subjects with plaque psoriasis.  In both studies, tapinarof showed a clear therapeutic effect 
compared with vehicle, with the 1% concentration treatment groups demonstrating a higher 
proportion of subjects with treatment success compared with the 0.5% concentration groups 
(applied once daily and twice daily in the AD study).  In both indications, the tapinarof 1% 
dosing groups showed a faster onset of action than the 0.5% dosing groups, and once daily 
application had similar efficacy to twice daily application.  In both Phase 2b studies, tapinarof 
showed an acceptable safety profile.  Treatment-emergent adverse events (TEAEs) were reported 
with a higher frequency in the tapinarof groups than in the vehicle groups.  The most frequent 
TEAEs (≥  5% in any arm or in total) were nasopharyngitis, folliculitis, dermatitis contact, atopic 
dermatitis, upper respiratory tract infection, headache, vomiting, acne, application site dermatitis, 
miliaria, dermatitis allergic, and impetigo.  The majority of TEAEs were mild or moderate in 
severity.  In each study, the tapinarof 1% once daily treatment group had a lower frequency of 
TEAEs than the tapinarof 1% twice daily treatment group. 
1.1.2. 
Study Rationale 
This pivotal Phase 3 study is being conducted as part of a clinical development program to 
evaluate the efficacy and safety of tapinarof cream, 1% for the topical treatment of plaque 
psoriasis in adults with psoriasis.  The results of this study are intended to support product 
registration in the United States. 


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1.2. 
Rationale for Study Design, Dose, and Control Groups 
This study is a 12 week double-blind, vehicle-controlled treatment study in which subjects will 
be randomized to receive tapinarof cream, 1% or vehicle cream once daily for 12 weeks.  The 
study will be conducted at multiple study centers in more than 1 country to enhance the 
possibility of inclusion of a wider range of population groups and to increase generalizability of 
the results. 
The randomized, double-blind, vehicle-controlled study design will minimize the potential for 
subjective bias related to possible identification of which subjects are receiving active treatment 
and will minimize selection and allocation bias by balancing potential prognostic factors.  The 
12-week treatment endpoint is expected to be an adequate duration to measure full response to 
treatment.  Clinical studies in skin conditions have historically shown a notable vehicle (as well 
as placebo) response rate, which could be attributable to the effects of skin moisturization or to 
the increased emphasis on proper skin care while participating in a clinical study.  A vehicle 
control group is included to provide a control for comparison and to ensure study sensitivity for 
characterization of the safety and efficacy profile of tapinarof cream, 1%. 
Subjects who complete this Phase 3 study will have the option to enroll in a separate open-label 
long-term safety and efficacy study for an additional 40 weeks of treatment.  Subjects who do 
not enroll in the open-label long-term study will complete a follow-up visit approximately 
4 weeks after end of treatment in this study (at Week 16). 
Tapinarof cream has been investigated in prior studies at concentrations from 0.5% to 8.0% and 
at once daily and twice daily dosing frequencies.  The 1% concentration applied once daily was 
chosen as the dose and dosing frequency to take forward in the clinical development program 
based on the data from GSK Phase 2b clinical Study 203120.  In that study, applications of 
tapinarof at concentrations of 0.5% and 1% applied once or twice daily were evaluated.  Overall, 
both concentrations demonstrated an acceptable safety profile when applied once or twice daily.  
A faster onset of action was observed with 1% dosing groups compared with the 0.5% dosing 
groups in both studies; fast onset of action is an important consideration for topical medications.  
A once daily application regimen may reduce systemic exposure as the skin heals, thereby 
providing a better safety profile for a drug intended for long-term use to treat a chronic 
condition.  In addition, once daily application may improve treatment adherence compared with 
more frequent dosing administrations.  Based on the efficacy and safety data from Study 203120, 
1% once daily was chosen as the tapinarof concentration and dosing frequency to be investigated 
in this study and intended for registration. 
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 


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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 203120 in psoriasis, the most frequently reported dermatologic AEs 
were folliculitis and contact dermatitis.  In the dose-ranging study 203121 in AD, the most 
frequently reported dermatologic AEs were folliculitis and AD.  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 
(Formulation C), AEs of skin hyperpigmentation, application site dermatitis, papular rash, 
pruritus, contact dermatitis, folliculitis, erythema, and skin burning sensation were reported. 
To mitigate these potential risks, subjects with a known or suspected intolerance to tapinarof or 
its excipients will be excluded from enrollment.  Subjects’ skin will be evaluated routinely for 
signs of irritation or allergic reaction, and if needed, study treatment may be interrupted and an 
appropriate treatment provided.   
1.3.1.2. 
Systemic Adverse Events 
Nasopharyngitis and headache were the most frequently-reported nondermatological AEs in 
dose-ranging Study 203120 in psoriasis.  In dose-ranging Study 203121 in AD, the most 
frequently reported nondermatological AEs were nasopharyngitis, upper respiratory tract 
infection, and headache.  In the initial clinical studies (in AD and psoriasis) using a different 
tapinarof formulation (Formulation C), nasopharyngitis, and headache were the most frequently 
reported nondermatological AEs.  In the open-label PK Study 201851 with BID dosing of 
Formulation F of tapinarof cream (n=11), 1% and 2%, headache was the 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 intravenous (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 heart rate.  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. 
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). 


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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 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).  Monthly pregnancy testing will be conducted.  
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 study treatment.  
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 (eg, 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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2. 
OBJECTIVES AND ENDPOINTS 
The objectives and associated endpoints of the study are as follows: 
Objectives 
Associated Endpoint 
Primary 
• To evaluate the 
efficacy of tapinarof 
cream, 1% compared 
with vehicle control 
in adults with plaque 
psoriasis 
• Proportion of subjects who achieve a Physician Global Assessment (PGA) 
score of clear (0) or almost clear (1) with a minimum 2-grade improvement 
from Baseline at Week 12 
Secondary 
• To further 
characterize the 
efficacy of tapinarof 
cream, 1% compared 
with vehicle control 
over time 
Secondary: 
• Proportion of subjects with ≥ 75% improvement in Psoriasis Area and 
Severity Index (PASI) from Baseline at Week 12 
• Proportion of subjects with a PGA score of 0 or 1 at Week 12 
• Mean change in percent of total body surface area (%BSA) affected from 
Baseline to Week 12 
• Proportion of subjects with ≥90% improvement in PASI score from 
Baseline to Week 12 
Exploratory Endpoints: 
• Time to achieve a PGA score of 0 or 1 with a minimum 2-grade 
improvement from Baseline 
• Proportion of subjects with a PGA score of 0 or 1 at Weeks 2, 4, 8, and 12 
• Proportion of subjects who achieve a PGA score of 0 or 1 with a minimum 
2-grade improvement from Baseline at Weeks 2, 4, and 8 
• Mean absolute and percent change in PASI score from Baseline to Weeks 
2, 4, 8, and 12 
• Proportion of subjects with ≥ 50% improvement in PASI score from 
Baseline to Weeks 2, 4, 8, and 12 
• Proportion of subjects with ≥ 75% improvement in PASI score from 
Baseline to weeks 2, 4, and 8 
• Proportion of subjects with ≥ 90% improvement in PASI score from 
Baseline to weeks 2, 4, and 8 
• Mean change in %BSA affected from Baseline to Weeks 2, 4, and 8 
• To describe the effect 
of tapinarof cream, 
1% on psoriasis 
symptom severity and 
the associated impact 
on daily activities and 
attitudes in adults 
with plaque psoriasis 
• Change in Peak Pruritus-Numeric Rating Scale (Peak Pruritus-NRS) from 
Baseline at Weeks 2, 4, 8, and 12 
• Change over time in psoriasis impact on daily activities, as measured by 
the Dermatology Life Quality Index (DLQI) total and individual dimension 
scores 
• Change over time in psoriasis symptoms, as measured by the Psoriasis 
Symptom Diary (PSD) 
• Change over time in physical component score and mental component 
score, as measured by the Short Form-36 (SF-36) questionnaire 
• To evaluate the safety 
and tolerability of 
tapinarof cream, 1% 
Safety: 
• Incidence, frequency, and duration of treatment emergent adverse events 
(TEAEs) and serious adverse events (SAEs) 


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Objectives 
Associated Endpoint 
in adults with plaque 
psoriasis 
• Clinically significant change from Baseline in laboratory values 
• Clinically significant change from Baseline in vital signs 
• Mean Local Tolerability Scale (LTS) scores by visit 
• To characterize the 
PK of tapinarof in 
adults with plaque 
psoriasis  
Pharmacokinetic: 
• Plasma concentration of tapinarof at Weeks 4 and 12 


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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a double-blind, randomized, vehicle-controlled, Phase 3, multicenter study to evaluate the 
efficacy and safety of topical tapinarof cream, 1% compared with vehicle-control cream in adults 
with plaque psoriasis.   
Following a 34-day screening period, eligible subjects will be randomized at a 2:1 ratio to 
receive once daily treatment with tapinarof cream, 1% or vehicle cream for 12 weeks.  Subjects 
will return to the clinic at Weeks 2, 4, 8, and 12 for efficacy and safety assessments.  
Additionally, subjects will be contacted by phone at Weeks 6 and 10 to assess AEs and 
concomitant medications, to review study drug administration instructions, and to confirm 
subject’s continued participation in this study. 
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 lesions and lesions/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 
fingernails, toenails, palms, soles, and scalp lesions with study drug; however, efficacy analyses 
will not include assessment of improvement of psoriasis in these areas.)  Subjects will be 
instructed to maintain the approximate dosing time chosen at the beginning of the study for their 
full study participation.  At the phone contacts at Weeks 6, and 10, 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 and 
during any planned study phone calls.  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 at the clinic under the 
supervision of site personnel, after efficacy and safety assessments have been completed.  The 
time of the dose application and assessments will depend on the time of the clinic visit.  
Therefore, the timing of the clinic visit may lead to a change in the subject’s chosen dosing time.  
At the end of the 12 weeks of treatment in this study, subjects will have the option to enroll in a 
separate open-label long-term safety and efficacy study for an additional 40 weeks. Subjects who 
choose not to participate in the open-label long-term study, who fail to qualify for participation 
in the open-label long-term study, or who qualify to participate in the open-label long-term study 
but ultimately elect not to enroll in that study, will complete a Follow-up Visit approximately 
4 weeks (Week 16 visit) after the end of treatment in this study. Subjects who withdraw from the 
study before Week 12 will complete an Early Termination Visit.  Study duration for subjects 
who complete this Phase 3 study and who fail to qualify for participation in the open-label long-
term study, or who qualify to participate in the open-label long-term study but ultimately elect 
not to enroll in that study is approximately 20 weeks in total. Study duration for subjects who 
complete this Phase 3 study and are eligible and decide to participate in the open-label long-term 
study is approximately 16 weeks in total. 
Efficacy assessments will include Investigator assessment of PGA score, %BSA affected, PASI, 
and subject-reported DLQI, SF-36, Peak Pruritus-NRS, and PSD.  Safety assessments will 


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include AEs, clinical laboratory tests, physical examination, vital signs, and LTS.  
Pharmacokinetics will be assessed at a subset of sites in a subset of subjects at Week 4 and 
Week 12. 
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.  The study schema 
is presented in Figure 1. 
Figure 1:  
Study Schema 
 
 
 
3.2. 
Treatment Groups and Duration 
This 12-week, Phase 3 study is a double-blind, vehicle-controlled treatment study in which 
subjects will be randomized in a 2:1 ratio to receive once daily treatment with either tapinarof 
cream, 1% or matching vehicle cream.   
At the conclusion of the 12 weeks of treatment in this study, subjects will have the option to 
enroll  in a separate Phase 3 open-label long-term safety and efficacy study of 40 weeks in 
duration.  Details of that study are provided in a separate clinical trial protocol. 
A subject will be considered to have completed this study when he/she completes all required 
procedures/visits for the 12-week double-blind treatment phase. 
The end of study is defined as when the last active subject has completed the Week 16 Follow-up 
Visit 4 weeks after the end of treatment (if subject does not enroll in the separate long-term 
study) OR the last active subject has completed the 12 weeks of treatment in this study (if subject 
enrolls in the separate long-term study). 


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4. 
STUDY POPULATION 
4.1. 
Type and Number of Subjects 
Approximately 500 adult subjects with plaque psoriasis will be enrolled in the study at 
approximately 50 to 60 study sites in the US and Canada. 
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 clinical diagnosis of chronic plaque 
psoriasis and stable disease for at least 6 months prior to the study 
2. Body surface area involvement ≥ 3% and ≤ 20% (the subject’s scalp, palms, fingernails, 
toenails, and soles should be excluded from the %BSA calculations). 
3. A PGA score of 2 (mild), 3 (moderate) or 4 (severe) at screening and baseline 
(pre-randomization).  Subjects with mild and severe psoriasis will be limited to 
approximately 10% each of the total randomized population; the majority of the enrolled 
subjects (approximately 80%) will have a PGA of 3, signifying moderate disease. 
4. Females of child-bearing potential 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 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-child-bearing potential is defined as premenarchal or pre-menopausal females with a 
documented bilateral tubal ligation, bilateral oophorectomy (removal of the ovaries) or 


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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 IU/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. 
Female subjects of childbearing potential must have a negative serum pregnancy test at 
Screening and negative urine pregnancy test at Baseline (Day 1). 
5. 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 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 lesions 
3. Concurrent conditions or history of other diseases: 
a. Immunocompromised (eg, lymphoma, acquired immunodeficiency syndrome) or medical 
history of positive human immunodeficiency virus (HIV) antibody at Screening  
b. Chronic or acute systemic 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, 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) ≥ 1.5x the upper limit of normal (ULN) 
5. Screening total bilirubin > 1.5 x ULN; total bilirubin >  ULN and ≤  1.5 x ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%. 
6. Corrected QT (QTcF) interval > 475 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.  Subjects with a history of HCV infection who 
were medically cured and have an undetectable viral load are eligible to enroll. Subjects 
with a history of stable non-alcoholic fatty liver disease without evidence of active 
inflammation (elevated ALT/AST ≥ 1.5x ULN) or cirrhosis are eligible to enroll. 
8. Ultraviolet (UV) light therapy or prolonged exposure to natural or artificial sources of 
UV radiation (eg, 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 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. 
• Minimum of 5 half-lives for biologic agents:  eg, 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 D3 and analogs (> 5000 IU / day), retinoids (eg, acitretin, isotretinoin), 
psolarens, corticosteroids, or adrenocorticotropic hormone analogs. 
• 2 weeks for immunizations with a live viral component; drugs known to possibly 
worsen psoriasis, such as beta-blockers (eg, propranolol), lithium, iodides, 
angiotensin-converting enzyme inhibitors, and indomethacin, unless on a stable dose 
for > 12 weeks. 
• With the exception of non-medicated emollients, 2 weeks for topical treatments 
including corticosteroids, antihistamines, immunomodulators, anthralin (dithranol), 
Vitamin D derivatives (eg, calcipotriene, calcipotriol), retinoids (Note:  4 weeks for 
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 drugs, 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 product 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 study drug (whichever is longer). 
15. Current or a history of cancer within 5 years except for adequately treated skin basal cell 
carcinoma, squamous cell carcinoma or carcinoma in situ of the cervix (surgical excision 
or electrodessication and curettage). 
16. Subjects with active systemic infection that required oral, intramuscular, or intravenous 
administration of antibiotics, antifungal or antiviral agents within 4 weeks of 
Baseline/Day 1. 
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. 


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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;   the Medical Monitor should be consulted if 
needed.   
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomized.  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 treatment at any time at 
the discretion of the Investigator for safety, behavioral, compliance, or administrative reasons.  
Subjects withdrawn from the study will not be replaced. 
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 
(Section 8.1). 
• 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.  If the subject is 
discontinued from study drug, they may remain in the study for safety assessments as 
needed, at the discretion of the Investigator and Medical Monitor. 
• Pregnancy 
• Any Grade 3 or 4 AE considered causally related to study drug (Section 8.2.2) 
Study drug may be discontinued for any of the following reasons: 
• Subject noncompliance 


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• 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 7.5). 
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(s), the Investigator must make every effort to perform 
an Early Termination Visit (Section 7.5) 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. 
STUDY TREATMENT 
5.1. 
Study Drug 
5.1.1. 
Description, Packaging, and Labeling 
The descriptions of the study drugs, tapinarof cream, 1% and the vehicle cream, are presented in 
Table 2. 
Table 2: 
Tapinarof and Vehicle Cream  
Study Drug 
Tapinarof (DMVT-505) 
Vehicle Cream 
Physical description 
White to off-white cream 
White to off-white cream 
Unit dose strength/how supplied 
1% (10 mg/gram)/30-gram tube 
NA/30-gram tube 
Route of administration/duration 
Topical/12 weeks 
Topical/12 weeks 
Dosing instructions 
Once daily topical application of thin 
layer to affected areas (Section 5.1.5) 
Once daily topical application of thin 
layer to affected areas (Section 5.1.5) 
Manufacturer 
GlaxoSmithKline 
GlaxoSmithKline 
NA = not applicable. 
The excipients included in tapinarof cream and vehicle cream are propylene glycol, diethylene 
glycol monoethyl ether, polysorbate 80, medium chain triglycerides, emulsifying wax non-ionic, 
polyoxyl stearyl ether 2, polyoxyl stearyl ether 20, benzoic acid, butylated hydroxytoluene, 
purified water, sodium citrate, citric acid monohydrate, and edetate disodium. 
All labels for tapinarof cream, 1% and vehicle cream to be distributed in the participating 
countries will meet all applicable requirements of those countries. 
5.1.2. 
Storage 
All study drugs must be stored in a secure environmentally controlled and monitored (manual or 
automated) area in accordance with the labeled storage conditions, with access limited to the 
Investigator and authorized site staff. 
5.1.3. 
Handling and Disposal 
Under normal conditions of handling and administration, study drug is not expected to pose 
significant safety risks to site staff.  In the case of unintentional occupational exposure notify the 
monitor, Medical Monitor and/or the Sponsor study contact. 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and 
recommended handling precautions either will be provided to the Investigator, where this is 
required by local laws, or is available upon request from the Sponsor. 
Arrangements will be made for used and unused drug supplies to be returned to the Sponsor or 
Sponsor designee, or for destruction on site following acceptable, documented procedures.  
Further guidance and information for final disposition of unused study drug will be provided. 
5.1.4. 
Preparation 
No special preparation of study drug is required. 


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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; subjects are to choose the application time 
they prefer and to apply the study drug at that approximate time each day of study 
participation.  
• If a subject misses a daily dose, it will be recorded as a protocol deviation. The 
subject should continue dosing the next day and should not apply more than once 
daily to make up for the missed dose on the previous day. 
• If chosen application time is in the evening, the dose should be applied at least 
30 minutes prior to bedtime. 
• Study drug should be applied to dry, clean skin. 
• Wash hands after application, unless treating lesions on the hands or fingernails. 
• Study drug should be applied to all lesions, including newly appearing lesions and 
lesions that have improved during the study. 
• Subjects are allowed, but not required, to treat fingernails, toenails, palms, soles, and 
scalp lesions with study drug; however, efficacy analyses will not include assessment 
of improvement of psoriasis in these areas.  If using study drug on the scalp, no other 
treatment for scalp psoriasis is permitted during the study. 
• If there is residual cream visible on the disease-affected lesional 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. 
• Subjects 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 safety and efficacy 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.  Therefore, the timing of the clinic visit may differ from the 
subject’s chosen dosing time. The intention is to allow flexibility to accommodate 
subjects’ schedules. 
Subjects will be instructed/reminded on how to apply study drug at each clinic visit (except 
during the final treatment visit). 


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5.2. 
Randomization/Treatment Assignment 
For the double-blind, vehicle-controlled phase of the study, subjects will be randomized at a ratio 
of 2:1 to receive tapinarof cream, 1% or vehicle cream as follows: 
Randomization in Double-Blind, Vehicle-Controlled Phase 
Regimen 
Number of Subjects 
Tapinarof cream, 1% once daily for 12 weeks 
Approximately 333 Subjects 
Vehicle cream once daily for 12 weeks 
Approximately 167 Subjects 
 
Randomization will be stratified by baseline PGA score so that subjects with mild and severe 
psoriasis (PGA scores of 2 and 4, respectively) will be limited to approximately 10% each of the 
total randomized population, and the majority of the enrolled subjects (approximately 80%) will 
have a PGA score of 3, signifying moderate disease.   
The randomization lists will be generated using a validated system, which involves a 
pseudo-random number generator so that the resulting treatment will be both reproducible and 
non-predictable.  Access to the codes will be controlled and documented. 
5.3. 
Blinding 
The Investigator, study center staff, subject, and Sponsor will be blinded to treatment 
assignment. 
The study blind should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the study drug the subject received.  The 
following conditions will apply for breaking the blind: 
• The Investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study drug is essential for the appropriate clinical 
management or welfare of the subject as judged by the Investigator. 
• Investigators have direct access to the system for unblinding an individual study 
subject. 
• The Investigator should make every effort to first contact the Medical Monitor or 
appropriate study personnel to discuss options before unblinding the subject’s 
treatment assignment. 
• If the Sponsor personnel are not contacted before the unblinding, the Investigator 
must notify the Sponsor as soon as possible after unblinding, but without revealing 
the treatment assignment of the unblinded subject, unless that information is 
important for the safety of subjects currently in the study. 
• The date and reason for the unblinding must be fully documented in the CRF. 
• A subject will be withdrawn if the subject’s treatment code is unblinded by the 
Investigator or treating physician.  The primary reason for discontinuation (the event 
or condition which led to the unblinding) will be recorded in the source documents 
and eCRF. 
• The Sponsor or their designee may unblind the treatment assignment for any subject 
with an SAE.  If the SAE requires that an expedited regulatory report be sent to one 


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or more regulatory agencies, a copy of the report, identifying the subject’s treatment 
assignment, may be sent to Investigators in accordance with local regulations. 
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 logs.  Subjects will be instructed to bring all used and unused tubes with them to 
each study visit.  Site personnel will weigh the returned tubes (used and unused) and record the 
weight in the drug accountability logs.  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 logs.  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 medication 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 medication 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 (with the exception of eligible subjects who enroll in the separate 
open-label, long-term 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 poststudy 
care of the subject’s medical condition, whether or not the Sponsor is providing specific 
poststudy drug. 
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 34 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. 


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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 is not planned to change from 
the Baseline visit to the completion of the treatment phase (Week 12) 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 (>5,000 IU/day), retinoids (eg, acitretin, isotretinoin), 
psoralens, corticosteroids, or adrenocorticotropic hormone analogs 
• Ultraviolet light:  therapy or prolonged exposure to natural or artificial sources of 
UV radiation (eg, 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. 
• Topical treatments:  corticosteroids, antihistamines, immunomodulators, anthralin 
(dithranol), Vitamin D derivatives (eg, calcipotriene, calcipotriol), retinoids (eg, 
tazarotene), or coal tar 
• Drugs known to possibly worsen psoriasis (unless on a stable dose for 
> 12 weeks):  beta blockers (eg, propranolol), lithium, iodides, 
angiotensin-converting enzyme inhibitors, and indomethacin 
• Immunizations:  live, attenuated vaccines (inactivated or subunit vaccines are 
acceptable when required) 
• Other:  any investigational products or 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. 
Demography, Medical History, and Baseline Characteristics 
6.1.1. 
Demographics 
Demographic information collected will include age, sex, race, and ethnicity. 
6.1.2. 
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, smoking history, medical conditions, and 
family history of premature CV disease) and family history of liver disease. 
6.1.3. 
Baseline Characteristics 
Single 12-lead ECGs will be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and QTc intervals.  Subjects should be in a supine or 
semi-supine position for at least 5 minutes before ECG is measured. 
The Hospital Anxiety and Depression Scale (HADS) will be used to evaluate the subject for 
symptoms of depression and anxiety at Screening.  An example of the HADS questionnaire is 
provided in Appendix 1. 
6.2. 
Efficacy Assessments 
To minimize inter-observer variability, Investigators and evaluators/raters will be trained on each 
of the required assessments during an Investigator meeting, site initiation visit, and/or utilizing 
online assessments before enrolling subjects at their study center.  Only trained evaluators/raters 
are permitted to perform the efficacy assessments.  To the fullest extent possible, the same 
Investigator (or designated evaluator/rater) will perform all efficacy assessments for an 
individual subject throughout the study.  If it is not possible for the same evaluator/rater to 
continue performing assessments, it is recommended that the primary and subsequent 
evaluator/rater both examine and discuss their respective scoring during at least 1 visit. 
6.2.1. 
Assessments Completed by Investigator 
6.2.1.1. 
Physician Global Assessment 
The PGA will be used to assess the primary endpoint in this study.  The PGA is a clinical tool for 
assessing the current state/severity of a subject’s psoriasis at a given timepoint.  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 


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considered in scoring of the PGA (see Section 6.2.1.1 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 2 for details).  The 
PGA should be performed first, prior to %BSA and PASI assessments. 
6.2.1.2. 
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 
and digits  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 are provided in Appendix 3).  Percentage BSA 
is a static assessment made without reference to previous scores.   
Note: at screening, baseline, and for all efficacy assessments, lesions on the subject’s scalp, 
palms, fingernails, toenails, and soles will not be included in the calculation of %BSA affected as 
these areas will be excluded from the efficacy analyses.   
6.2.1.3. 
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 3. 
6.2.2. 
Assessments Completed by Subject 
6.2.2.1. 
Dermatology Life Quality Index 
Subjects will complete the DLQI questionnaire.  The DLQI is simple dermatology-specific 
10-question validated questionnaire to assess the impact of the disease on a subject’s quality of 
life (Cardiff University, Department of Dermatology, Quality of Life Questionnaires).  The 
DLQI has become an important outcome measure in dermatology clinical trials and is the most 
frequently used instrument in studies of randomized controlled trials in dermatology 
[Basra, 2015].  The DLQI can be analyzed as a total score (where a higher score indicates greater 
impairment in quality of life) and can also be scored for the following dimensions:  Symptoms 
and Feelings (items 1 and 2), Daily Activities (items 3 and 4), Leisure (items 5 and 6), Work and 
School (item 7), Personal Relationships (items 8 and 9), and Treatment (item 10).  An example 
of this assessment is provided in Appendix 4. 
6.2.2.2. 
36−Item Short Form Survey 
The SF-36 is a self-administered questionnaire about physical functioning, bodily pain, role 
limitations due to physical health or personal or emotional problems, emotional well-being, 
social functioning, energy/fatigue, general health perceptions, and perceived change in health 
[Maruish, 2011].  Eight domain scores and 2 summary component (physical and mental) scores 


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can be calculated; higher scores represent better health status.  This study will use the RAND 
SF-36 Version 1.0.  An example of this assessment is provided in Appendix 5. 
6.2.2.3. 
Psoriasis Symptom Diary 
The Psoriasis Symptom Diary is a 16-item (24-hour recall) assessment that measures self-reports 
of psoriasis symptoms, and impact on functional health [Lebwohl 2014; Strober, 2013; Strober, 
2016].  The participant will complete the diary at the study site at each in-office visit.  The 
severity and bother of psoriasis- related itching, stinging, burning, pain, and scaling and impact 
items about the embarrassment, avoidance of activities with other people, and movement 
restrictions are assessed.  Each item is rated on a 0 to 10 NRS, with unlabeled numbers in 
between the labeled anchors.  Higher scores indicate more severe symptoms, bother, or impact.  
An example of this assessment is provided in Appendix 6. 
6.2.2.4. 
Peak Pruritus-Numeric Rating Scale 
The Peak Pruritus-NRS is used to quickly assess itch/pruritus severity over a 24-hour period.  
The subject will utilize the scale to assess peak pruritus once daily and record the results in their 
daily diaries. On clinic visit days, the Peak-Pruritis NRS will be assessed in the clinic and not 
recorded in the diary.  An example of the Peak Pruritus-NRS is provided in Appendix 7. 
6.2.3. 
Optional Clinical Photography 
Clinical photography may be performed in a subgroup of subjects at selected study centers that 
possess the capabilities.  This is not required of subjects for participation in the study.  Informed 
consent/assent and photographic release will be required.  The photographs may not be referred 
to by the Investigator at any subsequent study visit for the purposes of grading. 
Photographs will be taken of a representative area of the subject’s disease area at the time points 
specified in the Schedule of Assessments (Table 1; see also Section 7).  Three photographs of the 
selected skin area will be taken in a standardized fashion (ie, same camera, angle, background, 
distance).  Procedures for the clinical photography will be contained in the Study Reference 
Manual or Photography Manual. 
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 Examination 
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. 


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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 measurements of systolic and diastolic blood 
pressure, pulse rate, and body temperature.  Subjects should be in a seated position for at least 
5 minutes before vital signs measurement. 
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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Table 3: 
Laboratory Tests 
Diagnostic Screening Tests 
• HBsAg 
• Hepatitis C antibody 
• Anti-HBc 
• Pregnancy tests:  (serum at Screening and urine at other visits; 
women of CBP only) 
• FSH (as needed in women of non-CBP only) 
• At the Investigator’s discretion, subjects may be screened for 
alcohol and illicit drug use. 
Serum Chemistry 
• BUN 
• Creatinine 
• Glucose (fasting not required) 
• Sodium 
• Potassium 
• Chloride 
• Total carbon dioxide 
• Calcium 
• AST 
• ALT 
• Alkaline phosphatase 
• Uric acid 
• Total bilirubin (+fractionated 
if required) 
• Total protein 
• Albumin 
Hematology 
• Platelet count 
• RBC count 
• WBC count (absolute) 
• Reticulocyte count 
• Hemoglobin 
• Hematocrit 
• RBC Indices: 
• MCV 
• MCH 
• MCHC 
• Reticulocyte percentage 
• WBC Differential: 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Urinalysis 
• Specific gravity 
• Microscopic examination (if blood or protein is abnormal  
• Dipstick:  pH, Glucose, 
Protein, Blood Ketones 
ALT = alanine aminotransferase; Anti-HBc = anti-hepatitis B core antigen; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CBP = child-bearing potential; FSH = follicle-stimulating hormone; HBsAg = hepatitis 
B surface antigen; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; RBC = red blood cell(s); WBC = white blood cell(s). 
 
6.3.5. 
Local Tolerability Scale 
At each specified study visit, the Investigator (or qualified evaluator) will assess the presence 
and overall degree of irritation at the application sites, according to the LTS (an example of the 
LTS is provided in Appendix 8).  The score will ideally represent an “average” across all 
application sites.  To the fullest extent possible, the same Investigator (or designated evaluator) 
will perform all tolerability assessments for an individual subject throughout the study.  If the 
subject is applying study treatment to “sensitive areas” (eg, genitals, face, neck, and skin folds), 
then the degree of irritation for these areas should also be assessed by the investigator. 
Additionally, at each specified study visit, the participant will use a 5-point LTS to assess the 
presence and degree of burning/stinging and itching at the treatment areas.  The score will ideally 
represent an “average” across all application sites. 


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6.4. 
Treatment of Study Drug Overdose 
For this study, accidental or intentional oral ingestion of drug product 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 
• 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. 
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 
A single blood sample for PK analysis of tapinarof cream, 1% will be collected at a subset of 
sites in a subset of subjects at timepoints 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 will be determined in plasma samples using a validated bioanalytical 
method.  Raw data will be archived at the bioanalytical site. 


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7. 
TIMING OF PROCEDURES AND ASSESSMENTS 
This section lists the procedures and assessment to be performed at scheduled timepoints during 
the study as outlined in the Schedule of Assessments (Table 1).  Information on study procedures 
and assessment s is provided in Section 6. 
• Any change in timing or any addition of a timepoint(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 Informed Consent Form (ICF). 
NOTE:  Assessments and procedures should be performed predose on clinic visit days. 
7.1. 
Visit 1; Screening Period (Day -34 to Day -1) 
After the subject has signed the Informed Consent Form (ICF), potential study subjects will 
undergo Screening procedures and assessments to confirm eligibility to participate in the study.  
Screening assessments will include the following: 
• Demography recording 
• Serum pregnancy test (females of child-bearing potential) 
• Medical history recording 
• ECG recording  
• Brief physical examination (including weight, height, and body masss index [BMI]) 
• Vital signs measurements 
• HADS assessment 
• PGA score 
• %BSA affected calculation; subject’s scalp, palms, and soles should be excluded 
from the %BSA calculations used to determine patient’s eligibility 
• Blood sample collection for clinical laboratory tests (serum chemistry, hematology, 
diagnostic tests) 
• Urinalysis 
• 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.  The Medical Monitor should be consulted if 
needed. 
 


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7.2. 
Visit 2; Baseline (Day 1) 
On Day 1, subjects will be reassessed to confirm continued eligibility to participate in the study.  
All subjects who continue to meet study eligibility criteria will be randomized to treatment. 
The following additional procedures and assessments will be performed at the Baseline Visit: 
• Urine pregnancy test (females of child-bearing potential) 
• Changes to medical history will be recorded 
• Brief physical examination 
• Vital signs measurement 
• Photography of a representative area of the subject’s disease area (optional; at a 
subsection of study sites) 
• PGA score 
• %BSA affected calculation (performed before PASI); subject’s scalp, palms, and 
soles should be excluded from the %BSA calculations used to confirm patient’s 
eligibility 
• PASI 
• DLQI 
• SF-36 
• PSD 
• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording (from the time ICF is signed) 
• Diary dispensed (subjects will be instructed in how and when to complete diary) 
• Subject randomized to study treatment and registered in IVRS 
• Study drug dispensed 
• Instruction on how to apply study drug 
• Study drug application under supervision 
7.3. 
Double-Blind, Vehicle-Controlled Phase 
Subjects will return to the study site at Weeks 2, 4, 8, and 12 and will be contacted by phone at 
Weeks 6 and 10 of the double-blind phase of the study. 
7.3.1. 
Visit 3; Week 2 (Day 15 ±2 Days) 
The following procedures and assessments will be performed at Visit 3: 
• Vital signs 
• PGA score 
• %BSA affected calculation (performed before PASI) 
• PASI 
• LTS 
• PSD 


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• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording 
• Collect and dispense subject diaries 
• Review subject diaries for treatment compliance 
• Collect and dispense study drug 
• Review instructions on how to apply study drug 
• Study drug application under supervision 
7.3.2. 
Visit 4; Week 4 (Day 29 ±2 Days) 
The following procedures and assessments will be performed at Visit 4: 
• Urine pregnancy test (females of child-bearing potential) 
• Brief physical examination 
• Vital signs measurement 
• Photography of a representative area of the subject’s disease area (optional; at a 
subset of study sites) 
• Blood sample collection for PK analysis (subset of sites and subjects) 
• Blood sample collection for clinical laboratory tests 
• PGA score 
• %BSA affected calculation (performed before PASI) 
• PASI 
• LTS 
• DLQI 
• SF-36 
• PSD 
• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording 
• Collect and dispense subject diaries 
• Review subject diaries for treatment compliance 
• Collect and dispense study drug 
• Review instructions on how to apply study drug 
• Study drug application under supervision 
7.3.3. 
Visit 5; Week 8 (Day 57 ±2 Days) 
The following procedures and assessments will be performed at Visit 5: 
• Urine pregnancy test (females of child-bearing potential) 
• Brief physical examination 


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• Vital signs measurement 
• Photography of a representative area of the subject’s disease area (optional; at a 
subset of study sites only) 
• PGA score 
• %BSA affected calculation (performed before PASI) 
• PASI 
• LTS 
• PSD 
• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording 
• Collect and dispense subject diaries 
• Review subject diaries for treatment compliance 
• Collect and dispense study drug 
• Review instructions on how to apply study drug 
• Study drug application under supervision 
7.3.4. 
Visit 6; Week 12 (Day 85 ±2 Days) 
The following procedures and assessments will be performed at Visit 6: 
• Urine pregnancy test (females of child-bearing potential) 
• Brief physical examination 
• Vital signs measurement 
• Photography of a representative area of the subject’s disease area (optional, at a 
subsection of study sites) 
• Blood sample collection for PK analysis (subset of sites and subjects) 
• Blood sample collection for clinical laboratory tests 
• PGA score 
• %BSA affected calculation (performed before PASI) 
• PASI 
• LTS 
• DLQI 
• SF-36 
• PSD 
• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording 
• Collect subject diaries  
• Review subject diaries for treatment compliance 


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• Collect study drug  
7.3.5. 
Phone Contact at Weeks 6 (Day 43 ±2 Days) and 10 (Day 71 ±2 Days) 
Subjects will be contacted by phone at Weeks 6 and 10 to review study drug application 
instructions and to record AEs and concomitant medication use.  Subjects should be reminded to 
complete their daily diary and bring it with them to the next clinic visit. 
7.4. 
Follow-Up Visit 7; Week 16 (Day 113 ±4 Days) 
Subjects who do not enroll in the open-label long-term study will return to the study site at 
Week 16 to complete follow-up assessments as follows: 
• Urine pregnancy test (females of child-bearing potential) 
• Brief physical examination 
• Vital signs measurement 
• Blood sample collection for clinical laboratory tests 
• Urinalysis 
• PGA score 
• %BSA affected calculation (performed before PASI) 
• PASI 
• LTS 
• DLQI 
• SF-36 
• PSD 
• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording 
7.5. 
Early Termination Visit 
Subjects who withdraw early from the study will be asked to return to the study site to complete 
Early Termination assessments as follows: 
• Urine pregnancy test (females of child-bearing potential) 
• Brief physical examination 
• Vital signs measurement 
• Blood sample collection for clinical laboratory tests 
• Urinalysis 
• PGA score 
• %BSA affected calculation (performed before PASI) 
• PASI 
• LTS 
• DLQI 


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• SF-36 
• PSD 
• Peak Pruritus-NRS 
• AE recording 
• Concomitant medication recording 
• Collect subject diaries 
• Review subject diaries for treatment compliance 
• Collect study drug 
7.6. 
End of Study 
The end of study is defined as when the last active subject has completed the Week 16 Follow-up 
Visit 4 weeks after the end of treatment (if subject does not enroll in the separate long-term 
study) OR the last active subject has completed the 12 weeks of treatment in this study (if subject 
is eligible and enrolls in the separate long-term study). 


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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
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, SAE, or adverse events of special interest (AESIs).  At each 
visit/contact, subjects should be questioned in a general way so as not to introduce bias in 
detecting AEs and/or SAEs.  Open-ended and non-leading verbal questioning of the subject is 
the preferred method to inquire about AE occurrence. 
Investigators are not obligated to actively seek AEs 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 
medicinal product, whether considered causally related or not related to the medicinal product. 
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 
medicinal product. 
Events meeting the definition of an AE include: 
• Any abnormal laboratory test results (hematology, clinical chemistry) or other safety 
assessments (eg, 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 (eg, 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.  Such instances will be captured in the efficacy 
assessments.  However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
• Symptomatic complaints at the site of local application (eg, burning/stinging, 
pruritus, and erythema) 
Events that do not meet the definition of an AE include: 


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• 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 (eg, 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 Serious Adverse Event 
If an event is not an AE per Section 8.1.1, then it cannot be an SAE even if serious conditions are 
met (eg, hospitalization for signs/symptoms of the disease under study, death due to progression 
of disease, etc.). 
An SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
− The term “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, 
influenza, and accidental trauma (eg, 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 


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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. 
8.1.3. 
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 on Investigator judgment, and may be restarted when the event resolves: 
• Contact dermatitis:  the study site should collect location, duration, size, associated 
symptoms (itching, burning, pain), severity (mild, moderate, severe), and photograph 
the affected site (if possible).  If the 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 in for an unscheduled visit, if possible. 
• Folliculitis:  the study site should collect the location, duration, size, associated 
symptoms (itching, burning, pain), severity (mild, moderate, severe), indicate whether 
pustular, and photograph the affected site (if possible). 
• Headache:  the study site should collect duration, severity (mild, moderate, severe), 
onset, and location (e.g., frontal, temporal, occipital, diffuse). 
Additional AESIs may be identified by the Drug Safety Physician and if applicable by the 
Clinical Study Team Physician during the evaluation of safety data for the Clinical Study Report.  
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 Averse 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 4 should be used to 
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Table 4: 
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 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. 
 
Adverse event severity should be recorded in the appropriate section of the adverse event case 
report form 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 investigational product at the 
discretion of the Investigator.  Subjects who choose to withdraw from study due to a Grade 1 or 
2 AE should have study withdrawal/follow-up evaluations completed. 
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 3 AE has not been caused 
by investigational product, then dosing may continue after discussion with the 
Medical Monitor. 
• Subjects who develop a Grade 3 AE that the Investigator considers related or possibly 
related to investigational product should have the investigational product 
discontinued.  Subjects experiencing Grade 3 AEs requiring permanent 
discontinuation of investigational product should be followed weekly until resolution 
or stability of the AE and encouraged to have withdrawal study evaluations 
completed. 
8.2.1.2.3. Grade 4 Adverse Event 
Subjects who develop a Grade 4 AE should have investigational product permanently 
discontinued. 
Subjects experiencing Grade 4 AEs requiring permanent discontinuation of investigational 
product should be followed weekly until resolution or stability of the AE and encouraged to have 
withdrawal study evaluations completed. 


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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 (eg, laboratory tests or vital signs, etc.) as 
judged by the Investigator. 
8.2.2. 
Assigning Causal Relationship to Study Drug 
The Principal 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 adverse 
event to study drug is to be assessed with careful medical consideration at the time of evaluation 
of an adverse event.  The following definitions are to be used for the relationship of the adverse 
event 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 (eg, 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 (ie, 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 Reporting 
All AEs will be collected from the time of signed informed consent until the final visit. 
Any AEs assessed as related to study participation (eg, protocol-mandated procedures, invasive 
tests, or change in existing therapy) will be collected 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 (refer to Medical Monitor/Sponsor Information page for contact information) (see 
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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; source documentation should not be sent with the 
SAE Report Form unless requested. 
Follow-up information received on SAEs should be faxed to the Sponsor within 1 business day 
of receipt (refer to Medical Monitor/Sponsor Information page for contact information).  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 a SAE(s) or other specific 
safety information (eg, 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 and female partners of male 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 Report 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, eg, errors will be 
corrected, and inconsistencies queried in the data. 
Adverse events and relevant medical history will be coded using the most current version of the 
Medical Dictionary for Regulatory Activities (MedDRA).  Concomitant medications will be 
coded with the most current version of World Health Organization Drug Global Dictionary 
(WHODrug Global). 
The Investigator will retain original source documents and the Sponsor will receive 
CRF-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 efficacy and safety of tapinarof cream, 1% compared with vehicle 
control cream in adults with plaque psoriasis. 
10.1. 
General Considerations 
All study data will be summarized by treatment group using descriptive statistics.  Categorical 
variables will be reported using frequency and percentage (eg, gender, race).  Continuous 
variables will be reported using number of patients, mean, standard deviation (SD), median, 
minimum, and maximum.  All efficacy and safety data will be listed by subject. 
10.2. 
Determination of Sample Size 
It is assumed that the proportion of subjects who achieve PGA score of clear (0) or almost 
clear (1) with a minimum 2-grade improvement from Baseline at Week 12 will be 40% for 
subjects receiving tapinarof compared with 15% for subjects receiving vehicle control.  With 
500 subjects randomized in a 2:1 ratio (approximately 333 subjects receiving tapinarof cream, 
1% and approximately 167 subjects receiving vehicle cream) there will be > 99% power for a 
statistical significance (2-sided p< 0.05).  If tapinarof response rate is 35%, and vehicle response 
rate is 20%, the power will be > 94%.  The power is calculated from a Fisher Exact sample size 
calculation which is conservative.  It is assumed that up to 25% of the subjects will be lost to 
follow-up by 12 weeks.  These subjects will be included in the primary analysis using the 
multiple imputation method. 
10.3. 
Analysis Populations 
10.3.1. 
Safety 
All randomized subjects who receive at least 1 application of study drug will be included in the 
Safety population.  Subjects will be analyzed as treated. 
10.3.2. 
Intent-To-Treat 
All randomized subjects will be included in the Intent-to-treat (ITT) population.  Subjects will be 
analyzed as randomized. 
10.3.3. 
Per-Protocol 
All subjects in the ITT population who did not have any major protocol deviations will be 
included in the Per Protocol (PP) population.  Subjects will be analyzed as treated. 
10.3.4. 
Pharmacokinetic 
All subjects who undergo plasma PK sampling and have evaluable concentration-time data for 
analysis will be included in the PK population.  A sample that is below the limit of quantification 
(BLQ) of the assay is considered evaluable. 


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10.4. 
Planned Analyses 
All efficacy and safety 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. 
10.4.1. 
Disposition and Demographics 
Demographic and baseline characteristics as well as medical history will be summarized using 
the ITT population, including frequency and percentages for categorical variables and mean, 
standard deviation, median, minimum, and maximum for continuous variables. 
The numbers of subjects in the different analysis populations will be summarized by treatment 
group, including overall categories. 
10.4.2. 
Efficacy Analyses 
All efficacy analyses will be based on the ITT population and will be repeated for the 
PP population only for the primary and secondary efficacy endpoints as supportive analysis. 
 
10.4.2.1.  Primary Endpoint Analyses 
The primary efficacy endpoint is proportion of subjects who achieve PGA score of clear (0) or 
almost clear (1) with a minimum 2-grade improvement from Baseline at Week 12.  The primary 
efficacy endpoint will be analyzed using a Cochran–Mantel–Haenszel (CMH) test stratified by 
PGA score at Baseline (PGA scores of 2, 3 or 4). 
10.4.2.2. Secondary and Exploratory Efficacy Endpoint Analyses 
The secondary efficacy endpoints are as follows: 
• Proportion of subjects with ≥ 75% improvement in PASI from Baseline at Week 12 
• Mean change in %BSA affected from Baseline to Week 12 
• Proportion of subjects with a PGA score of 0 or 1 at Week 12 
• Proportion of subjects with ≥90% improvement in PASI score from Baseline to Week 
12 
Exploratory efficacy endpoints are as follows: 
• Time to achieve a PGA score of 0 or 1 with a minimum 2-grade improvement from 
Baseline 
• Proportion of subjects with a PGA score of 0 or 1 at Weeks 2, 4, and 8 
• Proportion of subjects who achieve a PGA score of 0 or 1 with a minimum 2-grade 
improvement from Baseline at Weeks 2, 4, and 8 
• Mean absolute and percent change in PASI score from Baseline to Weeks 2, 4, 8, 
and 12 
• Proportion of subjects with ≥ 50% improvement in PASI score from Baseline to 
Weeks 2, 4, 8, and 12 
• Proportion of subjects with ≥ 75% improvement in PASI score from Baseline to 
Weeks 2, 4, and 8 


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• Proportion of subjects with ≥ 90% improvement in PASI score from Baseline to 
Weeks 2, 4, and 8 
• Mean change in %BSA affected from Baseline to Weeks 2, 4, and 8 
The same methods as discussed for the primary analyses will be used to analyze all dichotomized 
secondary endpoints.  The secondary efficacy endpoints will be tested sequentially in the order 
listed.  Testing will stop if non-significance (2-sided p≥ 0.05) is observed. 
Other efficacy endpoints will be analyzed using CMH test for proportions, and analysis of 
covariance (ANCOVA) model for continuous variables.  CMH tests will be stratified by baseline 
PGA score, and ANCOVA models will include PGA score as a covariate. 
All endpoints will be summarized descriptively as follows:  continuous data will include the 
mean, SD, minimum, maximum, median, and number of observations; descriptive summary 
statistics for categorical data will include frequency counts and percentages. 
10.4.3. 
Safety Analyses 
The Safety Population will be used in the analysis of safety data.  Data will be listed by subject 
and treatment and summarized by treatment.  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.  
Summaries of AEs will be presented separately for double-blind and open-label treatment 
phases.  All AE summaries will include information for AEs 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 laboratory data will be analyzed using descriptive summary statistics and will be 
presented by study visit and treatment group, 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. 
Mean scores from the LTS will be summarized by visit. 
10.4.4. 
Analysis of Functional Outcomes and Quality of Life Endpoints 
The subject-reported endpoints to examine the effect of study drug on psoriasis symptom 
severity and the associated impact on daily activities and attitudes are as follows: 
• Change in Peak Pruritus-NRS from Baseline at Weeks 2, 4, 8, and 12 
• Change over time in psoriasis impact on daily activities, as measured by the DLQI 
total and individual dimension scores 
• Change over time in psoriasis symptoms, as measured by the PSD 
• Change over time in physical component score and mental component score, as 
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Change from baseline in DLQI , PSD, SF-36, and Peak Pruritus-NRS scores will be analyzed 
using an ANCOVA model with treatment as a main effect, and baseline as a covariate. 
10.4.5. 
Pharmacokinetic Analyses 
Data will be listed and summarized.  Listings will be sorted by subject, day, and time; summaries 
will be presented by study visit and time from last dose. 
Unless stated otherwise, descriptive summaries for continuous variables will include n, mean, 
SD, median, minimum, and maximum.  If data permit, time to steady state will be assessed using 
the sampled trough values.  Exploratory analyses may include relationships of plasma 
concentrations with patient demographics or AEs. 
10.5. 
Interim Analyses 
No interim analyses will be performed from a statistical standpoint. 
10.6. 
Handling of Missing Data 
Every effort will be made to collect complete data at all visits. 
The primary method of handling of missing data will utilize Multiple Imputations (MI).  For 
sensitivity analysis, Treatment Failure (TF) will be imputed for missing data. 
For the MI model, 100 imputations will be generated using PROC MI of SAS.  Fully Conditional 
Specification (FCS) model using the regression method will be used with the response (eg, PGA 
score) at prior post-baseline visits, baseline strata, and treatment group as covariates, The 
ROUND and MINIMUM options will be utilized to ensure imputed values are non-negative 
integers.  The seed to be used is 20180330.  The results of the 100 analyses will be transformed 
into a normal statistic and combined into a single analysis using PROC MIANALYZE. 


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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 United States Investigational New 
Drug Application (IND), 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 Food 
and Drug Administration (FDA) 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 reportable interests during the study and for 1 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 
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. 


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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 (ie, 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 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 2 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, ie, 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 trial medication (preferably drug 
dispensing and return should be documented as well) 
• Record of all adverse events 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 


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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 (ie, United States, 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 electronic case report form (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 
adverse event, thorough efforts should be made to clearly document the outcome. 
11.1.7. 
Drug Accountability 
The Investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability 
of all used and unused investigational medicinal product.  This includes acknowledgment of 
receipt of each shipment of study product (quantity and condition), subject dispensing records, 
and returned or destroyed study product.  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 medication. 
At study initiation, the monitor will evaluate the site’s procedure for investigational medicinal 
product 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 investigational medicinal product supplies, 
including empty containers, according to these procedures.  If the site cannot meet the Sponsor’s 
requirements for disposal, arrangements will be made between the site and the Sponsor or its 
representative for destruction or return of unused investigational medicinal product supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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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. 
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. 


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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 
Independent Ethics Committee or an Institutional Review Board 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 International Conference on Harmonization, and any applicable regulatory 
requirements.  The investigator should contact Dermavant Sciences GmbH immediately if 
contacted by a regulatory agency about an inspection. 
Representatives of regulatory authorities or of the Sponsor may conduct inspections or audits of 
the clinical study.  If the Investigator is notified of an inspection by a regulatory authority the 
Investigator agrees to notify the Sponsor Medical Monitor immediately.  The Investigator agrees 
to provide to representatives of a regulatory agency or the Sponsor access to records, facilities, 
and personnel for the effective conduct of any inspection or audit. 
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 
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY Dermatology.  Determining the 
minimal clinically important difference and responsiveness of the Dermatology Life Quality 
Index (DLQI):  further data.2015;230(1):27-33. 
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. 
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. 
Lebwohl M, Swensen AR, Nyirady J, Kim E, Gwaltney CJ, Strober BE.  The Psoriasis Symptom 
Diary:  development and content validity of a novel patient-reported outcome instrument.  Int J 
Dermatol.  2014;53:714-722. 
Maruish, ME, editor.  User’s manual for the SF-36v2 health survey.  Edition 3.  Quality Metric 
Inc.  2011. 
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. 
Strober BE, Yirady J, Mallya UG, Guettner A, Papavassilis C, Gottlieb AB, et al. Item-level 
psychometric properties for a new patient-reported Psoriasis Symptom Diary.  Value Health 
2013;16(6):1014-1022. 
Strober B, Zhao Y, Tran MH, Gnanasakthy A, Nyirady J, Papavassilis C, et al. Psychometric 
validation of the Psoriasis Symptom Diary using Phase III study data from patients with chronic 
plaque psoriasis.  Int J Dermatol.  2016:55(3):e147-155. 
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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13. 
APPENDICES 
APPENDIX 1. HOSPITAL ANXIETY AND DEPRESSION SCALE 
(HADS) 
 


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    FOLD HERE 
Hospital Anxiety and 
Depression Scale (HADS) 
Name: _______________________________________________________  Date: _______________ 
Clinicians are aware that emotions play an important part in most illnesses. If your clinician knows about 
these feelings he or she will be able to help you more. 
This questionnaire is designed to help your clinician to know how you feel. Read each item below and 
underline the reply which comes closest to how you have been feeling in the past week. Ignore the 
numbers printed at the edge of the questionnaire. 
Don’t take too long over your replies, your immediate reaction to each item will probably be more 
accurate than a long, thought-out response. 
FOLD HERE 
Please make sure you have answered all the questions. 
A 
D 
TOTAL
HADS copyright © R P  Snaith and A S  Zigmond, 1983, 1992, 1994   
Record form items originally published in Acta Psychiatrica Scandinavica, 67, 361–70,  
copyright © Munksgaard International Publishers Ltd, Copenhagen, 1983  
This edition first published in 1994 by nferNelson Publishing Company Ltd, now GL Assessment Limited,  
1st Floor Vantage London, Great West Road, Brentford TW8 9A, United Kingdom  
GL Assessment is part of GL Education  www gl-assessment co uk 
This form may not be reproduced by any means without first obtaining permission from the publisher   
E-mail: permissions@gl-assessment co uk 
All rights reserved including translations  
A 
D 
I feel tense or "wound up" 
3 
Most of the time 
2 
A lot of the time 
1 
From time to time, occasionally 
0 
Never 
I enjoy the things I used to enjoy 
0 
Definitely  
1 
Not quite so much 
2 
Only a little 
3 
Hardly at all  
I get a sort of frightened feeling as if 
something awful is about to happen 
3 
Very definitely and fairly badly 
2 
Yes, but not too badly 
1 
Sometimes, but it doesn’t worry me 
0 
Never 
I can laugh and see the funny side of things 
0 
As much as I always could 
1 
Not quite so much now 
2 
Definitely not so much now 
3 
Never 
Worrying thoughts go through my mind 
3 
A great deal of the time 
2 
A lot of the time 
1 
Not too often 
0 
Almost never 
I feel cheerful 
3 
Never 
2 
Not often 
1 
Sometimes 
0 
Most of the time 
I can sit at ease and feel relaxed 
0 
Always 
1 
Usually 
2 
Not often 
3 
Never 
A 
D 
I feel as if I am slowed down 
Nearly all the time 
3 
Very often 
2 
Sometimes 
1 
Never 
0 
I get a sort of anxious feeling like 
"butterflies" in the stomach 
Never 
0 
Occasionally 
1 
Often 
2 
Very often 
3 
I have lost interest in my appearance 
Definitely 
3 
Often I don't take as much care as I should 
2 
Sometimes I don't take as much care as I should 
1 
I take just as much care as ever 
0 
I feel restless as if I have to be on the move 
Definitely 
3 
Quite a lot 
2 
Not very much 
1 
Never 
0 
I look forward with enjoyment to things 
As much as I ever have 
0 
Somewhat less than I used to 
1 
Much less than I used to 
2 
Rarely 
3 
I get sudden feelings of panic 
Very often 
3 
Often 
2 
Not very often 
1 
Never 
0 
I can enjoy a good book, radio or  
television program 
Often 
0 
Sometimes 
1 
Not often 
2 
Very seldom 
3 


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APPENDIX 2. PHYSICIAN GLOBAL ASSESSMENT (PGA) 
Each assessment should be made as a visual “average” of the severity of all treated areas at the 
time of the assessment.  Following the Baseline visit, assessments will be made without 
reference to Baseline state or any other previous scores. 
Scoring should not be influenced by extent of lesions, participant symptoms, or impact on 
participant’s quality of life.   
Score/Grade 
Description 
0 
Clear 
No signs of psoriasis; postinflammatory 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 lesions 
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. 






Ta pi nar of  
D M V T -5 0 5 -3 0 0 1  
Der ma va nt Scie nces G m b H.  
Cli nical St u d y Pr ot oc ol – Versi o n 2. 0  
C o nfi de ntial  
Pa ge | 7 5  
A P P E N DI X  4.  D E R M A T O L O G Y LI F E Q U A LI T Y I N D E X ( D L QI) A G E S 
1 6 A N D U P  
T he ai m of t his q uesti o n naire is t o meas ure h o w m uc h y o ur s ki n pr o ble m has affecte d y o ur life 
O V E R T H E L A S T W E E K .  Please c hec k o ne b o x f or eac h q uesti o n. 
1.  
 
O ver t he last wee k, h o w itc h y, s ore, p ai nf ul  or sti n gi n g h as y o ur s ki n b ee n ?  
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
2.  
 
O ver t he last wee k, h o w e m b a rr asse d  or self c o nsci o us h a v e y o u b ee n b eca use 
of y o ur s ki n ?  
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
3.  
 
O ver t he last wee k, h o w m u c h h as y o ur s ki n i nterfere d wit h y o u g oi n g 
s h o p pi n g or l o o ki n g after y o ur h o m e  or y a r d ?  
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
4.  
 
O ver t he last wee k, h o w m u c h h as y o ur s ki n i nfl u e n ce d t h e cl ot hes y o u 
wear?  
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
5.  
 
O ver t he last wee k, h o w m u c h h as y o ur s ki n affecte d a n y s o ci al or leis ure 
acti vities?  
  
  
 
Ver y m u c h  
A l ot  
A little 
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
6.  
 
O ver t he last wee k, h o w m u c h h as y o ur s ki n ma d e it diffic ult f or y o u t o d o 
a n y s p ort? 
 
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
7.  
 
O ver t he last wee k, h as y o ur s ki n pre v e nte d y o u fr o m w o r ki n g  or st u d yi n g? 
Yes  
N o  
 
 
 
   N ot rele v a nt   
If " N o", o v er t h e last wee k h o w m u c h h as y o ur s ki n b ee n a pr o ble m at w o r k  or 
st u d yi n g? 
A l ot  
A little  
N ot at all  
 
 
 
 
 
8.  
 
O ver t he last wee k, h o w m u c h h as y o ur s ki n create d pr o ble ms wit h y o ur 
p art ner  or a n y of y o ur cl ose frie n ds or rel ati v es?    
 
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
9.  
 
O ver t he last wee k, h o w m u c h h as y o ur s ki n ca use d a n y se x u al diffic ulties? 
 
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
1 0.  
 
O ver t he last wee k, h o w m u c h of a pr o ble m h as t h e tre at m e nt f or y o ur s ki n 
bee n, f or e x a m ple b y ma ki n g y o ur h o me mess y, or b y ta ki n g u p ti me?  
Ver y m u c h  
A l ot  
A little  
N ot at all  
 
 
 
 
 
 
 
   N ot rele v a nt   
© A Y Fi nla y, G K K ha n, A pril 1 9 9 2  w w w. der mat ol o g y. or g. u k , this m ust n ot be c o pie d wit h o ut t he per missi o n of 
t he a ut h ors. 
 


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APPENDIX 5. 36−ITEM SHORT FORM SURVEY; VERSION 1.0 (SF-36) 
36-Item Short Form Survey Instrument (SF-36)  
 
RAND 36-Item Health Survey 1.0 Questionnaire Items 
 
Choose one option for each questionnaire item. 
 
1. In general, would you say your health is: 
o 1 – Excellent 
o 2 – Very good 
o 3 – Good 
o 4 – Fair 
o 5 – Poor 
 
2. Compared to one year ago, how would you rate your health in general now? 
o 1 – Much better now than one year ago 
o 2 – Somewhat better now than one year ago 
o 3 – About the same 
o 4 – Somewhat worse now than one year ago 
o 5 – Much worse now than one year ago 
 
 


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The following items are about activities you might do during a typical day. Does your health now 
limit you in these activities? If so, how much? 
 
Yes, 
limited a 
lot 
Yes, 
limited a 
little 
No, not 
limited at 
all 
3. Vigorous activities, such as running, lifting heavy objects, 
participating in strenuous sports 
o 1 
o 2 
o 3 
4. Moderate activities, such as moving a table, pushing a vacuum 
cleaner, bowling, or playing golf 
o 1 
o 2 
o 3 
5. Lifting or carrying groceries 
o 1 
o 2 
o 3 
6. Climbing several flights of stairs 
o 1 
o 2 
o 3 
7. Climbing one flight of stairs 
o 1 
o 2 
o 3 
8. Bending, kneeling, or stooping 
o 1 
o 2 
o 3 
9. Walking more than a mile 
o 1 
o 2 
o 3 
10. Walking several blocks 
o 1 
o 2 
o 3 
11. Walking one block 
o 1 
o 2 
o 3 
12. Bathing or dressing yourself 
o 1 
o 2 
o 3 
During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of your physical health? 
 
 
Yes 
No 
13. Cut down the amount of time you spent on work or other activities 
o 1 
o 2 
14. Accomplished less than you would like 
 
o 1 
o 2 
15. Were limited in the kind of work or other activities 
 
o 1 
o 2 
16. Had difficulty performing the work or other activities (for example, it took 
extra effort) 
o 1 
o 2 
 
 


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During the past 4 weeks, have you had any of the following problems with your work or other regular 
daily activities as a result of any emotional problems (such as feeling depressed or anxious)? 
 
 
 
Yes 
 
No 
17. Cut down the amount of time you spent on work or other activities 
o 1 
o 2 
18. Accomplished less than you would like 
o 1 
o 2 
19. Didn’t do work or other activities as carefully as usual 
o 1 
o 2 
20. During the past 4 weeks, to what extent has your physical health or emotional problems interfered 
with your normal social activities with family, friends, neighbors, or groups? 
 
o 1 – Not at all 
o 2 – Slightly 
o 3 – Moderately 
o 4 – Quite a bit 
o 5 - Extremely 
21. How much bodily pain have you had during the past 4 weeks? 
o 1 – None 
o 2 – Very mild 
o 3 – Mild 
o 4 – Moderate 
o 5 – Severe 
o 6 – Very severe 
 


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22. During the past 4 weeks, how much did pain interfere with your normal work (including both 
work outside the home and housework)? 
 
o 1 – Not at all 
o 2 – A little bit 
o 3 – Moderately 
o 4 – Quite a bit 
o 5 - Extremely 
These questions are about how you feel and how things have been with you during the past 4 weeks. 
For each question, please give the one answer that comes closest to the way you have been feeling. 
 
How much of the time during the past 4 weeks… 
 
All of 
the 
time 
Most of 
the time 
A good 
bit of the 
time 
Some 
of the 
time 
A little 
of the 
time 
None of 
the time 
23. Did you feel full of pep? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
24. Have you been a very nervous 
person? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
25. Have you felt so down in the 
dumps that nothing could cheer 
you up? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
26. Have you felt calm and peaceful? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
27. Did you have a lot of energy? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
28. Have you felt downhearted and 
blue? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
29. Did you feel worn out? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
30. Have you been a happy person? 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 
31. Did you feel tired? 
 
o 1 
o 2 
o 3 
o 4 
o 5 
o 6 


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32. During the past 4 weeks, how much of the time has your physical health or emotional problems 
interfered with your social activities (like visiting with friends, relatives, etc.)? 
 
o 1 – All of the time 
o 2 – Most of the time 
o 3 – Some of the time 
o 4 – A little of the time 
o 5 – None of the time 
 
 
How TRUE or FALSE is each of the following statements for you. 
 
Definitely 
true 
Mostly 
true 
Don’t 
know 
Mostly 
false 
Definitely 
false 
33. I seem to get sick a little easier than other 
people 
o 1 
o 2 
o 3 
o 4 
o 5 
34. I am as healthy as anybody I know 
o 1 
o 2 
o 3 
o 4 
o 5 
35. I expect my health to get worse 
o 1 
o 2 
o 3 
o 4 
o 5 
36. My health is excellent 
o 1 
o 2 
o 3 
o 4 
o 5 
 
RAND® is a registered trademark. Copyright © 1994-2018 RAND Corporation.  
 
 
 
 
 


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Clinical Study Protocol – Version 2.0 
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APPENDIX 6. PSORIASIS SYMPTOM DIARY (PSD) 
 


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APPENDIX 7. PEAK PRURITUS-NUMERIC RATING SCALE 
(PRURITUS-NRS) 
Peak Pruritus-NRS is a scale used to quickly assess itch/pruritus severity over a 24-hour period.  
The subject will utilize the scale shown daily to assess peak pruritus. 
 


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APPENDIX 8. LOCAL TOLERABILITY SCALE ASSESSMENT 
At each specified study visit, the Investigator (or qualified evaluator) will assess the presence 
and overall degree of irritation at the application sites, according to the 5-point scale below.  The 
score will ideally represent an “average” across all application sites.  To the fullest extent 
possible, the same investigator (or designated evaluator) will perform all tolerability assessments 
for an individual participant throughout the study.   
If the participant is applying study treatment to “sensitive areas” (eg, genitals, face, neck, and 
skin folds), then also assess the degree of irritation for these areas. 
Local Tolerability – Dryness, Erythema, and Peeling 
Score 
Severity 
Description 
0 
No irritation 
No evidence of local irritation/intolerance 
1 
Mild 
Minimal erythema and/or edema, slight glazed appearance 
2 
Moderate 
Definite erythema and/or edema with peeling and/or cracking but does not 
require treatment modification 
3 
Severe 
Erythema, edema glazing with fissures, few vesicles or papules 
4 
Very Severe 
Strong reaction spreading beyond the treated area, bullous reaction, 
erosions 
At each specified study visit, the participant will use 5-point tolerability scale presented in the 
table below to assess the presence and degree of burning/stinging and itching at the treatment 
areas.  The score will ideally represent an “average” across all application sites. 
Local Tolerability – Burning/Stinging and Itching 
Score 
Severity 
Description 
0 
None 
Normal, no discomfort 
1 
Slight 
An awareness, but no discomfort and no intervention required 
2 
Mild 
A noticeable discomfort that causes intermittent awareness 
3 
Moderate 
A noticeable discomfort that causes intermittent awareness and interferes 
occasionally with normal daily activities 
4 
Strong/Severe 
A definite continuous discomfort that interferes with normal daily activities 
 
 
 


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APPENDIX 9: PROTOCOL AMENDMENT SUMMARY OF CHANGES 
The protocol has been updated with the following changes.  Edits to the protocol are shown in 
bold. 
Table 1. Schedule of Assessment 
Urinalysis and clinical laboratory tests added to the Early Termination visit. 
Section 1.1, page 23. Background Information 
Correction made to reflect language in study report; “contact dermatitis” changed to “dermatitis 
contact.” 
The most frequently reported (1% to 6% of 235 subjects) dermatological adverse events (AEs), 
regardless of causality, were application site discoloration/hyperpigmentation, application site 
dermatitis, papular rash, pruritus, contact dermatitis contact, folliculitis, erythema, and skin 
burning sensation.   
Section 1.3.1.2.  Clarification on study design added; 
In the open-label PK Study 201851 with BID dosing of Formulation F of tapinarof cream 
(n=11), 1% and 2%, headache was the most frequently reported during the study (reported for 
100% and 60% of subjects at the 1% and 2% doses, respectively). 
Section 3.1 Overall Design 
Clarified wording around time of dosing each day and protocol violations which is further 
addressed in Section 5.1.5 (Administration of Study Drug) 
Section 4.3. Exclusion criteria #3b and #16 
Corrected inconsistencies between 2 criteria in systemic infections requiring treatment prior to 
enrollment as 4 weeks before the baseline visit. 
Section 4.3. Exclusion criterion #7 
Clarified that a subject with previous HCV infection who had been treated and who has an 
undetectable viral load is eligible to enroll. Clarified that a subject with stable non-alcoholic fatty 
liver disease without evidence of active inflammation or cirrhosis is eligible to enroll. 
Section 4.3. Exclusion criterion #9 and Section 5.6.2 Prohibited Medications and Nondrug 
Therapies 
Added a daily dose for the oral Vitamin D3 and analogs exclusion and added topical 
antihistamines as prohibited medications 
Section 4.3. Exclusion criterion #15 
Clarified exemptions for current or history of cancer to “adequately treated skin basal cell 
carcinoma, squamous cell carcinoma or carcinoma in situ of the cervix (surgical excision or 
electrodessication and curettage).” 
Section 4.5 Screening / Baseline Failures and Section 7.1. Visit 1; Screening Period 
Revised wording regarding repeat lab and procedures based on the Investigator’s discretion with 
consultation of the Medical Monitor on an “as needed” basis. 
Section 5.1.5.  Administration of Study Drug 


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Added clarification wording around missed doses and protocol deviations: “If a subject misses a 
daily dose, it will be recorded as a protocol deviation. The subject should continue dosing 
the next day and should not apply more than once daily to make up for the missed dose on 
the previous day.” 
Section 6.2.2.4.  Peak Pruritus-Numeric rating Scale 
Added clarification wording: “On clinic visit days, the Peak-Pruritis NRS will be assessed in 
the clinic and not recorded in the diary.”   
Section 7.2, page 48. 7.2. Visit 2; Baseline (Day 1) 
Removed the collection of a PK sample to be consistent with Table 1, Schedule of Assessments 
Section 7.5 Assessments  
Addition of additional safety assessments.  Urinalysis  and clinical laboratory tests added at 
Early Termination visit. 
Section 8.1.1. Definition of Adverse Events 
To avoid confusion, the wording that defines local adverse events has been edited since 
“evaluation of local tolerability” is being assessed with a specific scale (Appendix 8). 
Appendix 1. HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) 
Revised HADS example added. 
Appendix 3, page 75. CALCULATION of BSA and PASI 
Clarification of body surface area calculation and correction in table for calculation of PASI; 
score of 0 changed from 1% to 0% skin covered with psoriasis and score of 1 changed from 1 - 
<10% to <10% consistent with published paper (Feldman Feldman SR, Krueger GG. Psoriasis 
assessment tools in clinical trials. Ann Rheum Dis.2005;64 (suppl II):ii65-ii68.) 
 
Percentage of skin covered with psoriasis for each of the 4 areas 
Affected  
0% 
< 10% 
10 - < 30% 
30 - < 50% 
50 - < 70% 
70 - < 90% 
≥ 90% 
Score 
0 
1 
2 
3 
4 
5 
6 
Appendix 8, page 85. LOCAL TOLERABILITY SCALE ASSESSMENT 
Removed unnecessary footnote under the Local Tolerability – Dryness, Erythema, and Peeling 
table. 
 

SAP_001.pdf: 
                                                                               
Protocol No. DMVT-505-3001
IQVIA Biotech Study No. FZA90364
A PHASE 3 EFFICACY AND SAFETY STUDY OF TAPINAROF FOR THE 
TREATMENT OF PLAQUE PSORIASIS IN ADULTS
Statistical Analysis Plan Amendment 2, version 3.0
Document last saved: 4-May-2020 11:49 AM


Dermavant Sciences, Inc./ Protocol No. DMVT-505-3001
                       Page 2 of 28
IQVIA Biotech (Confidential) Project FZA90364
Revision History
Date
Reason for update
Section Updated
05AUG2019
Original Version 1.0
NA
04OCT2019
Amendment 1 
Version 2.0
Section 9 Handling of Missing Data: 
o
Added LOCF and TF imputation method to 
handle missing efficacy data.
Section 12.1 Subject Disposition: 
o
Added summary for screen failures along with 
screen failure reasons.
Section 12.6 Medical History and Concurrent 
Procedures: 
o
Added a summary for psoriasis history, 
cardiovascular risk factors and liver disease
family history;
o
Updated duration of disease categories from 
“<1, 1-5 years and 5 years” to “<5, 5-10 years,
and 10 years”
Section 12.7.3 Exploratory Efficacy Endpoints: 
o
Added endpoint mean % change in % BSA 
affected from baseline to weeks 2, 4, and 8
Section 12.7.4 Functional Outcomes and Health-
related Quality of Life Endpoints:
o
Added description for PSD total score 
calculation.
o
Clarified the RAND SF-36 version was used in 
the study.
Section 12.8 Efficacy Analyses:
o
Added LOCF on ITT population as sensitivity 
analysis for primary and secondary endpoints.
o
Added additional subgroup analysis for 
primary and all secondary endpoints: age 
group, sex, race, duration of disease, total 
%BSA affected, %BSA affected by body 
region.
Section 12.9.1 Adverse Events:
o
Added treatment-related serious TEAE and 
serious TEAE leading to study drug 
discontinuation to overall AE summary.
o
Added additional summaries for treatment-


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IQVIA Biotech (Confidential) Project FZA90364
Date
Reason for update
Section Updated
related TEAEs; TEAEs leading to study
discontinuation; serious TEAEs
o
Added subgroup analysis for TEAEs and 
serious TEAEs: age group, sex and race
o
Clarified duration summary for AESIs.
04MAY2020
Amendment 2
Version 3.0
Added additional summary and analysis due to the
impact of the novel Coronavirus Disease 2019 
(COVID-19):
o
Section 12.11 Additional Analyses – COVID-
19
Section 8 Analysis Populations:
o
Added a sentence that additional criteria that 
are not documented as protocol deviations may 
be added to determine PP population prior to
unblinding the study database.
o
Updated exclusion criteria to specify use of 
oral corticosteroids
Section 9 Handling of Missing Data:
o
Clarified baseline PGA score and baseline
value of the corresponding endpoint are
included in multiple imputation model
o
Updated the example SAS code for multiple 
imputation
Section 11.4 Analysis Visit Window:
o
Updated analysis visit window for Week 12
and Week 16
Section 12.4 Study Exposure and Compliance:
o
Renamed the parameter “number of days 
actually dosed” to “number of doses 
administered”
Section 12.7.4 Functional Outcomes and Health-
related Quality of Life Endpoints:
o
DLQI: Added texts for handling of missing 
data in domain scores
o
SF-36: Removed physical component score 
and mental component score; Added 8 domain 
scores.
Section 12.8 Efficacy Analyses:
o
Added percent change from baseline for peak 


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IQVIA Biotech (Confidential) Project FZA90364
Date
Reason for update
Section Updated
NRS, DLQI and PSD.
o
Added a new responder analysis for Peak NRS
o
Added new analysis for itch scores (in-clinic
and at-home diary): change from baseline, 
treatment difference and a plot
o
Added country as new subgroup analysis
o
Added a Kaplan-Meier figure for time to PGA 
success
Section 12.9.1 Adverse Events:
o
Clarified all AEs with onset on the Week 12 
visit will be included in the summary
o
Added more extensive summary for each
AESI.
o
Added Kaplan-Meier figure for each AESI of
time to first event
Section 12.9.2 Local Tolerability Scale (LTS):
o
Added a summary for LTS at the sensitive 
areas
Section 12.9.3 Clinical Laboratory Testing:
o
Clarified normal reference range and reference 
range indicators are provided by central lab. 
o
Clarified only urinalysis lab tests with numeric
results reported are included in shift tables.
o
Added mapping table between central lab 
reported reference range indicators and 
indicators in shift tables
Section 12.10 Pharmacokinetic Analyses:
o
Added additional summary for PK 
concentration divided by baseline total %BSA
o
Added subgroup summaries for PK 
concentrations
o
Removed geometric mean from the PK 
concentration summaries.
Section 13 Changes From the Protocol and Planned 
Analyses:
o
Updated to indicate SF-36 analysis changed
from the protocol
o
Clarified additional analyses added due to 
COVID-19


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Table of Contents
Revision History.............................................................................................................................2 
Table of Contents...........................................................................................................................5 
List of Abbreviations and Definitions of Terms..........................................................................7 
1. 
INTRODUCTION..................................................................................................................9 
2. 
STUDY OBJECTIVES..........................................................................................................9 
3. 
STUDY DESIGN....................................................................................................................9 
4. 
HARDWARE AND SOFTWARE......................................................................................10 
5. 
DATABASE LOCK.............................................................................................................10 
6. 
RANDOMIZATION............................................................................................................10 
7. 
SAMPLE SIZE DETERMINATION.................................................................................11 
8. 
ANALYSIS POPULATIONS .............................................................................................11 
9. 
HANDLING OF MISSING DATA ....................................................................................12 
10. INTERIM ANALYSIS ........................................................................................................14 
11. DATA CONVENTIONS FOR ANALYSIS.......................................................................14 
11.1 General Statistical Principles..............................................................................................14 
11.2 Study Day..............................................................................................................................14 
11.3 Baseline and Change from Baseline ...................................................................................14 
11.4 Analysis Visit Window.........................................................................................................14 
11.5 Study Centers .......................................................................................................................15 
11.6 Multiple Comparisons .........................................................................................................15 
12. STATISTICAL EVALUATION.........................................................................................15 
12.1 Subject Disposition...............................................................................................................15 
12.2 Protocol Deviations ..............................................................................................................16 
12.3 Demographic and Baseline Characteristics.......................................................................16 
12.4 Study Medication Exposure and Compliance ...................................................................16 
12.5 Prior and Concomitant Medications..................................................................................17 
12.6 Medical History and Concurrent Procedures ...................................................................17 
12.7 Efficacy Endpoints...............................................................................................................18 
12.7.1 
Primary Efficacy Endpoint.......................................................................................18 
12.7.2 
Secondary Efficacy Endpoints..................................................................................18 
12.7.3 
Exploratory Efficacy Endpoints...............................................................................18 


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12.7.4 
Functional Outcomes and Health-related Quality of Life Endpoints...................19 
12.8 Efficacy Analyses .................................................................................................................20 
12.8.1 
Primary Efficacy Analyses........................................................................................21 
12.8.2 
Secondary and Exploratory Efficacy Analyses.......................................................22 
12.8.3 
Other Efficacy Analyses ............................................................................................23 
12.8.4 
Subgroup Analyses.....................................................................................................23 
12.9 Safety Analysis .....................................................................................................................23 
12.9.1 
Adverse Events...........................................................................................................23 
12.9.2 
Local Tolerability Scale (LTS)..................................................................................25 
12.9.3 
Clinical Laboratory Testing......................................................................................25 
12.9.4 
Vital Signs...................................................................................................................26 
12.9.5 
Physical Examination ................................................................................................26 
12.10 
Pharmacokinetic Analyses ........................................................................................26 
12.11 
Additional Analyses - COVID-19 .............................................................................27 
13. CHANGES FROM THE PROTOCOL AND PLANNED ANALYSES.........................27 
14. FORMATTING....................................................................................................................27 
15. ARCHIVING AND RETENTION OF DOCUMENTS....................................................28 


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List of Abbreviations and Definitions of Terms
Abbreviation
Definition
ADaM
Analysis dataset model
AE
Adverse event
AESI
Adverse event of special interest
ANCOVA
Analysis of covariance
ATC
Anatomical Therapeutic Chemical Classification System
BLQ
Below limit of quantitation
BMI
Body mass index
BSA
Body surface area
CI
Confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease 2019
DLQI
Dermatology Life Quality Index
eCRF
Electronic Case Report Form
EOS
End of study
HADS
Hospital Anxiety and Depression Scale
ITT
Intent-to-Treat
LOCF
Last observation carried forward
LTS
Local Tolerability Scale
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple imputation
NRS
Numeric rating scale
OC
Observed cases
ODS
Output Delivery System
PASI
Psoriasis Area and Severity Index
PGA
Physician’s Global Assessment
PK
Pharmacokinetic
PP
Per protocol
PSD
Psoriasis Symptom Diary
PT
Preferred Term
QoL
Quality of Life
RTF
Rich-text-formatted
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SDTM
Study data tabulation model
SE
Standard error


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Abbreviation
Definition
SF-36
36-item Short Form Survey
SOC
System Organ Class
TEAE
Treatment-emergent adverse event
TF
Treatment failure
WHO-DD
World Health Organization – Drug Dictionary


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1.
INTRODUCTION
This Statistical Analysis Plan (SAP), based on the study protocol amendment 1 dated May 8th,
2019, provides additional details concerning the statistical analyses outlined in the protocol and 
reflects any changes to the protocol from amendments. This plan will not repeat all the 
definitions given in the protocol but will provide further details of the summaries and analyses 
planned therein.
The scope of this plan includes analyses pertaining to all data collected in the Double-Blind, 
Vehicle-Controlled Phase of the study. Analyses pertaining to data collected in the Open-Label 
Long-Term study will be described in a separate plan.
2.
STUDY OBJECTIVES
The primary objective is:
To evaluate the efficacy of tapinarof cream, 1% compared with vehicle control in adults 
with plaque psoriasis.
The secondary objectives are:
To further characterize the efficacy of tapinarof cream, 1% compared with vehicle 
control over time
To describe the effect of tapinarof cream, 1% on psoriasis symptom severity and the
associated impact on daily activities and attitudes in adults with plaque psoriasis
To evaluate the safety and tolerability of tapinarof cream, 1% in adults with plaque 
psoriasis
To characterize the pharmacokinetics (PK) of tapinarof in adults with plaque psoriasis
3.
STUDY DESIGN
This is a double-blind, randomized, vehicle-controlled, Phase 3, multicenter study to evaluate the
efficacy and safety of topical tapinarof cream, 1% compared with vehicle-control cream in adults 
with plaque psoriasis.
Following a 34-day screening period, eligible subjects will be randomized at a 2:1 ratio to 
receive once daily treatment with tapinarof cream, 1% or vehicle cream.  Subjects will return to 
the clinic at Weeks 2, 4, 8, and 12 for efficacy and safety assessments. Additionally, subjects will 
be contacted by phone at Weeks 6 and 10 to assess adverse events (AEs) and concomitant 
medications, to review study drug administration instructions, and to confirm subject’s continued 
participation in this study. 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 


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IQVIA Biotech (Confidential) Project FZA90364
be instructed to apply study drug once daily to all affected areas, including newly appearing 
lesions and lesions/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 fingernails, toenails, palms, soles, and scalp lesions with study drug;
however, efficacy analyses will not include assessment of improvement of psoriasis in these 
areas.) Subjects will be instructed to maintain the dosing time chosen at the beginning of the 
study for their full study participation. At the phone contacts at Weeks 6, 10, and 14, subjects 
should be reminded to complete their daily diary and bring it with them to the next clinic visit.
At the end of 12 weeks of treatment in this study, subjects will have the option to enroll in a 
separate open-label long-term safety and efficacy study for an additional 40 weeks of treatment.
Subjects who choose not to participate in the open-label long-term study, who fail to qualify for 
participation in the open-label long-term study, or who qualify to participate in the open-label 
long-term study but ultimately elect not to enroll in that study, will complete a Follow-up Visit 
approximately 4 weeks (Week 16 visit) after the end of treatment in this study.  Subjects who 
withdraw from the study before Week 12 will complete an Early Termination Visit.   
4.
HARDWARE AND SOFTWARE
Statistical analysis will be performed following IQVIA Biotech standard operating procedures 
and on the IQVIA Biotech computer network. All statistical analysis will be performed using
SAS Version 9.4 or higher with program code prepared specifically for the project by qualified 
IQVIA Biotech statisticians and SAS programmers.
5.
DATABASE LOCK
After completion of all data review procedures, validation of the project database, and approval
of the data review document by the study sponsor, the clinical database will be locked and the 
study will be unblinded. Any change to the clinical database after this time will require written 
authorization, with explanation, by the Sponsor and the project Biostatistician.
6.
RANDOMIZATION
For the double-blind, vehicle-controlled phase of the study, subjects will be randomized at a ratio 
of 2:1 to receive tapinarof cream, 1% or vehicle cream as follows:
Randomization in Double-Blind, Vehicle-Controlled Phase
Regimen
Number of Subjects
Tapinarof cream, 1% once daily for 12 weeks
Approximately 333 Subjects
Vehicle cream once daily for 12 weeks
Approximately 167 Subjects


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Randomization will be stratified by baseline PGA score so that subjects with mild and severe 
psoriasis (PGA scores of 2 and 4, respectively) will be limited to approximately 10% each of the 
total randomized population, and approximately 80% will have a PGA score of 3, signifying 
moderate disease.  
The randomization lists will be generated using a validated system, which involves a 
pseudo-random number generator so that the resulting sequence of treatments will be both 
reproducible and non-predictable.  Access to the codes will be controlled and documented.
7.
SAMPLE SIZE DETERMINATION
It is assumed that the proportion of subjects who achieve PGA score of clear (0) or almost clear
(1) with a minimum 2-grade improvement from Baseline at Week 12 will be 40% for subjects 
receiving tapinarof compared with 15% for subjects receiving vehicle control. With 500 subjects
randomized in a 2:1 ratio (approximately 333 subjects receiving tapinarof cream, 1% and
approximately 167 subjects receiving vehicle cream) there will be > 99% power for statistical 
significance (2-sided p< 0.05).  If tapinarof response rate is 35%, and vehicle response rate is 
20%, the power will be > 94%.  Power comes from a Fisher Exact sample size calculation which 
is conservative.  It is assumed that up to 25% of the subjects will be lost to follow-up by 12 
weeks.  These subjects will be included in the primary analysis in the ITT population using the 
multiple imputation method as detailed below.
8.
ANALYSIS POPULATIONS
The following populations are defined:
Safety population: All randomized subjects who receive at least 1 application of study 
drug will be included in the Safety population. Subjects will be analyzed as treated.
Intent-to-treat (ITT) population: All randomized subjects will be included in the Intent-
to-treat population.  Subjects will be analyzed as randomized.
Per Protocol (PP) population: All subjects in the ITT population who did not have any 
major protocol deviations or other events that may impact the interpretation of the
primary efficacy endpoint will be included in the PP population. Exclusion criteria for the
PP Population may include: 
o
Failure to meet the enrollment inclusion/exclusion criteria
o
On-study use of oral corticosteroids for >3 days and/or at >10mg dose
o
Failure to have a Week 12 assessment that occurs <=3 days post last dose and also 
between study day 78 to 91 (inclusive) for the primary efficacy endpoint.
Alternative days post dose and visit window may be used upon review of the actual 
blinded data before database lock. 


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o
Failure to be compliant with treatment regimen (as defined in Section 12.4, i.e., 
compliance < 80%)
Additional criteria that may or may not be documented as protocol deviations may be
added to determine PP population. The composition of the PP population will be 
determined and documented in blind reviews of the database conducted prior to 
unblinding the study database.
The ITT and PP Populations will be used for the analyses of efficacy endpoints. The ITT
population is considered as the primary population for efficacy analyses and the PP will
be considered as supportive. If a subject receives an incorrect study treatment other than 
the intended study treatment, the analysis of that subject's data will be based on the actual
treatment received for the safety and PP analyses and the randomized assignment for the 
ITT analyses. If a subject receives more than 1 study treatment, the treatment group
assignment for the safety and PP analyses will be determined on a case by case basis.
Pharmacokinetic (PK) population: All subjects who undergo plasma PK sampling and 
have evaluable concentration-time data for analysis will be included in the PK 
population.  A sample that is below the limit of quantification (BLQ) of the assay is 
considered evaluable.
9.
HANDLING OF MISSING DATA
Imputation of Start and End Dates of Adverse Event (AE)
To calculate duration of Adverse Events, the following rules will be used where applicable to
impute partial or completely missing start dates or end dates:
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. The AE will be considered as a treatment-emergent AE (TEAE).
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. Last study visit is defined as the Week 12 visit for those 
who elect to participate in the open-label long-term study, or the Week 16 Follow-up visit 
for those who fail to qualify for participation in the open-label study, or who qualify to 
participate but ultimately elect not to enroll.
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. However, 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.


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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.
Imputation of Missing Efficacy Data
The primary method of handling of missing efficacy data will utilize Multiple Imputations (MI). 
Last observation carried forward (LOCF) method will be used as supportive analysis of the 
primary and secondary endpoints. For sensitivity analysis of the primary and secondary 
endpoints, missing data will be imputed as Treatment Failures (TF). Only missing data up to 
Week 12 will be imputed. Missing data at the Week 16 Follow-up visit will be analyzed as 
Observed Cases (OC) only.
MI: For the MI model, 100 imputations will be generated using PROC MI of SAS.  Fully 
Conditional Specification (FCS) model using the regression method will be used with the
response (e.g., PGA score) at prior post-baseline visits, baseline PGA score, baseline value of the 
corresponding endpoint, and treatment group as covariates, The ROUND and MINIMUM 
options will be utilized to ensure imputed values are non-negative integers.  The seed to be used
in all MI model is 20180330.  
One set of MI datasets will be generated for the PGA scores, PASI scores and %BSA results
separately.
Response status (Yes, No) will be derived from the imputed scores in each MI 
dataset. Analysis of each primary, secondary and exploratory outcome will then be performed for
each of the relevant MI datasets. The results of the 100 analyses will be transformed into a 
normal statistic and combined into a single analysis using PROC MIANALYZE.
Example SAS code for the PGA scores is as follows:
PROC MI DATA = PGA1 OUT = PGA2 SEED = 20180330 NIMPUTE = 100 NOPRINT;
CLASS TRTPN BASEPGA;
FCS LOGISTIC(BASEPGA = TRTPN / DETAILS);
FCS REG(PGA3 = TRTPN BASEPGA / DETAILS);
FCS REG(PGA4 = TRTPN BASEPGA PGA3 / DETAILS);
FCS REG(PGA5 = TRTPN BASEPGA PGA3 PGA4 / DETAILS);
FCS REG(PGA6 = TRTPN BASEPGA PGA3 PGA4 PGA5 / DETAILS);
VAR TRTPN BASEPGA PGA3-PGA6;
RUN; 
The imputation models may be modified based on the actual data if there is an issue in model
convergence.
LOCF: The last observed value will be carried forward for any subsequent missing values. 
Baseline values will not be carried forward.
TF: missing data will be imputed as treatment failures for responder endpoint. 
Missing functional outcomes, quality of life endpoints or safety endpoints will not be imputed. 


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10. INTERIM ANALYSIS
No interim analysis is planned.
11. DATA CONVENTIONS FOR ANALYSIS
11.1
General Statistical Principles
All statistical tests will be performed at the 0.05 (two-sided) level of significance.
All observed and derived variables (e.g., change from baseline, percentage change from baseline, 
and response status) that are analyzed or summarized will be listed by subject. Descriptive
statistics will provide an overview of the efficacy and safety results. For categorical parameters,
the number and percentage of subjects in each category will be presented. The denominator for 
percentage will be appropriate for the purpose of the analysis. For continuous parameters, 
descriptive statistics will include number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum.
11.2
Study Day
Day 1 is the date of first study drug administration. As subjects apply study drug under 
supervision on the day of randomization, this will generally be the day of the Baseline Visit. 
Study day is calculated relative to the date of Baseline (Day 1).
11.3
Baseline and Change from Baseline
Baseline value is defined as the last non-missing value prior to the first dose of study drug. 
Change from baseline is defined as the post-baseline value minus the baseline value unless
otherwise specified. Percent change from baseline is calculated as follows: Percent change =
(Change from baseline / Baseline) * 100.
11.4
Analysis Visit Window
All efficacy and safety endpoints will be analyzed according to the nominal visits (i.e. actual
visit) except for assessments collected on early termination and unscheduled visits. Early 
termination and unscheduled visits will be re-numbered to an analysis visit based on their
windowed visits defined by actual study day. If more than one visit occurs within a single visit 
window, then the analysis will take the one closest to the target day. If the 2 visits are equidistant 
from the target day, the visit with later date and time will be used.
The following analysis visit windows will apply to early termination and unscheduled visits:


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Visit
Week
Target Day
Analysis Window
2
Baseline
1
On or prior to Day 1
3
2
15
Post first dose – Day 21
4
4
29
Day 22 – Day 42
5
8
57
Day 43 – Day 70
6
12
85
Day 71 – Maximum (last day of treatment + 3 days, 
Day 87) 
7
16
113
> Maximum (last day of treatment + 3 days, Day 87) 
11.5
Study Centers
There will be approximately 50-60 study sites in the United States (US) and Canada.
The primary and secondary efficacy endpoints will be summarized by study site using 
descriptive statistics. Exploratory analyses of the primary and secondary endpoints may be 
performed to elucidate any identified sources of heterogeneity in the results.
11.6
Multiple Comparisons
Multiple comparisons of the secondary endpoints will be controlled using the Fixed-Sequence 
method. Hypotheses testing for the secondary efficacy endpoints will only be conducted if the 
primary efficacy endpoint has demonstrated statistical significance at 0.05 two-sided in favor of
tapinarof. Testing of the secondary endpoints will be performed sequentially following the below 
pre-specified order (see details in Section 12.7.2):
Proportion of subjects w
improvement in PASI from Baseline at Week 12 
Proportion of subjects with a PGA score of 0 or 1 at Week 12 
Mean change in %BSA affected from Baseline to Week 12 
Proportion of subjec
ment in PASI score from Baseline to Week 12
Hypothesis testing for secondary endpoints will stop if statistical significance at 0.05 two-sided 
in favor of tapinarof is not observed.
12. STATISTICAL EVALUATION 
12.1
Subject Disposition
The number and percentage of subjects screened, screen failed along with reason for screen 
failures, randomized, included in each analysis population, completing 12-Week Double-Blind 
treatment, completing the study, withdrawing from treatment (together with the reasons for 
withdrawal), withdrawing from the study (together with the reasons for withdrawal), and subjects 


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excluded from PP population (together with the reasons for exclusion) will be summarized using 
frequencies and percentages by treatment group. For subjects who have completed the 12-Week 
treatment, the number and percentage of those who elect to enroll in the open-label study will be 
summarized.
Enrollment and disposition will be listed by subject. Screen failures and subjects not randomized 
will also be listed by subject.
The number of days in the study (date of study completion / discontinuation minus date of Day 1 
plus 1) will be summarized descriptively by treatment group.
12.2
Protocol Deviations
Protocol deviations will be listed by subject. Protocol deviation categories (major vs minor) will 
be summarized by treatment group.
12.3
Demographic and Baseline Characteristics
Demographics and baseline characteristics will be summarized overall and by treatment for the 
ITT, PP and Safety populations. The following demographic and baseline variables will be 
included:
Age
Gender
Race
Ethnicity
Weight
Height
BMI
Baseline PGA
Baseline PASI score
Baseline %BSA Affected
12.4
Study Medication Exposure and Compliance
The following exposure and compliance parameters will be summarized descriptively by 
treatment group:
Total number of days exposed, defined as date of last dose of study drug minus date of
first dose of study drug plus 1.


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Number of doses administered, calculated from the subject dose diary. If a subject does 
not return diary or returns the diary with missing dosing record, the number of doses 
taken during that period is assumed to be 0.
Grams (g) of study drug administered, total and average per day. Drug administered is 
calculated as the summation of the difference between dispensed weight and returned 
weight for all returned tubes. Unreturned tubes will be assumed unused and will be 
included as 0 gram in amount drug used calculation.
Percent compliance will be calculated as the number of doses administered over the 
number of days exposed.
Subject compliance, defined as 80% compliance over the entire duration of study. If the 
percentage of study medication compliance is unknown, the subject is assumed to be non-
compliant with study medication.
12.5
Prior and Concomitant Medications
Prior (within the 34 days before Visit 1 and with stop dates prior to first dose of study drug) and 
concomitant (ongoing or with stop dates on or after first dose of study drug) medications will be 
listed by subject for each treatment group. If the medication is ongoing or the stop year is 
missing, the medication will be considered as received for the entire duration of the study. 
Medications will be coded using WHO-DD terminology. 
To distinguish prior vs concomitant medications, the following rules for stop dates will apply:
If only year was recorded, and it is before Baseline, it is a prior medication; if year is 
same or after Baseline, it is assumed to be a concomitant medication. 
If day is missing, but month and year are before Baseline, it is a prior medication; if 
month and year are the same as Baseline, it is assumed to be a concomitant medication; if 
month and year are after Baseline, it is a concomitant medication. 
If start date is after Baseline, it is a concomitant medication regardless. 
Prior and concomitant medications will be summarized separately by treatment, WHO-DD 
Anatomical-Therapeutic-Chemical (ATC) classification and preferred term (PT).
12.6
Medical History and Concurrent Procedures
Medical history (including previous and ongoing medical conditions) will be coded using
MedDRA and listed by subject. Medical history will be summarized by system organ class 
(SOC) and PT for each treatment.
Psoriasis History, Cardiovascular Risk Factors and Liver Disease Family History will be 
summarized and listed by subject separately.


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The following will be summarized by treatment group for psoriasis history:
Duration (year) of disease, defined as year of Screening visit minus year of initial 
psoriasis diagnosis. Duration of disease will be reported as <5, 5-10, and >10 years for 
summary purpose.
Area affected (scalp, pam, fingernails, toenails, soles)
12.7
Efficacy Endpoints
12.7.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of subjects who achieve a Physician Global
Assessment (PGA) treatment response, defined as a PGA score of clear (0) or almost clear (1) 
with a minimum 2-grade improvement from Baseline at Week 12.
The PGA is a static 5-point assessment of overall disease severity, as determined by the 
Investigator, ranging from 0 (clear) to 4 (severe).
12.7.2 Secondary Efficacy Endpoints
The secondary endpoints are:
from Baseline (PASI-75) at Week 12 
Proportion of subjects with a PGA score of 0 or 1 at Week 12 
Mean change in percent of total body surface area (%BSA) affected from Baseline to 
Week 12 
from Baseline (PASI-90)
to Week 12.
The PASI score assesses the severity of psoriasis taking 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.
12.7.3 Exploratory Efficacy Endpoints
The exploratory endpoints to further characterize the efficacy of tapinarof cream, 1% compared 
with vehicle control over time are:


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Time (days) to achieving a PGA treatment response, defined as days from date of first 
dose until achieving a PGA score of 0 or 1 with a minimum 2-grade improvement from 
Baseline. Subjects who have no PGA response will be censored at the date of their last 
PGA assessment. 
Proportion of subjects with a PGA score of 0 or 1 at Weeks 2, 4, and 8
Proportion of subjects who achieve a PGA treatment response at Weeks 2, 4, and 8 
Mean absolute and percent change in PASI score from Baseline to Weeks 2, 4, 8, and 12 
(PASI-50) from Baseline 
to Weeks 2, 4, 8, and 12 
(PASI-75) from Baseline 
to weeks 2, 4, and 8 
(PASI-90) from Baseline 
to weeks 2, 4, and 8 
Mean change in %BSA affected from Baseline to Weeks 2, 4, and 8
Mean % change in %BSA affected from Baseline to Weeks 2, 4, 8, and 12.
12.7.4 Functional Outcomes and Health-related Quality of Life Endpoints
To describe the effect of tapinarof cream, 1% on functional outcomes and the associated impact 
on daily activities and attitudes in adults with plaque psoriasis:
Change in Peak Pruritus-Numeric Rating Scale (Peak Pruritus-NRS) from Baseline at 
Weeks 2, 4, 6, 8, 10, 12 and 16
Change in psoriasis impact on daily activities, as measured by the Dermatology Life 
Quality Index (DLQI) total and individual dimension scores from Baseline at Weeks 4, 
12, and 16
The DLQI is a 10-item PRO measure that assesses the extent to which the skin condition 
has affected the subject’s quality of life over the past week, including 6 domains (daily 
activities, personal relationships, symptoms and feelings, leisure, work/school, and 
treatment). The total score (0-30) will be calculated as the sum of 10 questions with each 
ranging from 0 to 3. The scoring of each question is as follows:
Very much
Scored 3
A lot
Scored 2
A little
Scored 1
Not at all
Scored 0
Not relevant
Scored 0


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Question unanswered
Scored 0
Question 7: “prevented work or studying”
Scored 3
If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. If two or more questions are left unanswered 
the total DLQI score is missing. If question 7a is answered ‘yes’ or ‘not relevant’, then 
the answer of 7b will be ignored.
When summarizing the domain scores, if a domain contains two questions and the answer 
to one of the questions is missing, that domain will be scored as the answer to the non-
missing question. If all the answers to questions in a domain are missing, the domain will 
not be scored.
Change in psoriasis symptoms, as measured by the Psoriasis Symptom Diary (PSD),
including total and 16 individual scores from Baseline at Weeks 2, 4, 8, 12, and 16.
PSD is a 16-item assessment measures self-reports of psoriasis symptoms, and impact on 
functional health. The total score will be calculated as the sum of 16 questions with each 
ranging from 0 to 10. If any of the 16 questions is unanswered, the total score will be 
considered as missing.
Change in the eight domain scores, as measured by the RAND Short Form-36 (SF-36) 
questionnaire from Baseline at Weeks 4, 12, and 16.
The 8 domain scores below will be computed using the scoring rules for the RAND 36-
Item Health Survey (Version 1.0):
o
Physical functioning
o
Role limitations due to physical health
o
Role limitations due to emotional problems
o
Energy/fatigue
o
Emotional well-being
o
Social functioning
o
Pain
o
General health
12.8
Efficacy Analyses
All efficacy outcomes will be analyzed in the ITT population. Only the primary and secondary 
efficacy endpoints will be analyzed in the PP population as supportive analyses, as summarized 
in the Table below.
Efficacy Endpoints 
Primary 
Sensitivity Analysis




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The primary efficacy endpoint will be analyzed using a Cochran–Mantel–Haenszel (CMH) test 
stratified by PGA score at Baseline (PGA scores of 2, 3 or 4) based on the ITT population using 
the multiple imputation approach.
For each multiple imputation dataset, the CMH option in PROC FREQ will calculate the 
adjusted estimate of the common relative risk of success (tapinarof/placebo) over all 
strata with its 95% confidence interval (CI).
The logit-based version of the estimate and its confidence bounds will be log-transformed 
and the SE of the estimate of the log(relative risk) will be back-calculated from the
log(confidence bounds) by assuming an asymptotic normal distribution.
The estimates of the log(relative risk) and their standard errors for all the multiple 
imputation datasets will be input to PROC MIANALYZE to test the null hypothesis that 
tapinarof is not different from placebo. The p-value of the combined results will be
reported for interpretation.
PROC MIANALYZE will output an overall estimate of the log(relative risk) and its 95% 
CI. These will be exponentiated to produce an overall estimate of the relative risk and its 
95% CI.
Sensitivity analyses in the ITT population will be conducted in which missing values are not 
imputed, i.e., Observed Cases (OC), or imputed as treatment failures (TF), and efficacy is tested 
with the CMH statistic as described above. Supporting analyses of the primary endpoint will 
also be performed 
in the PP population based on OC only,
in the ITT population with missing values imputed by LOCF,
12.8.2 Secondary and Exploratory Efficacy Analyses
The same methods as discussed for the primary analyses will be used to analyze all dichotomized 
and continuous secondary endpoints.  The secondary efficacy endpoints will be tested 
sequentially in the order listed.  Testing will stop if non-significance (2-sided p
observed as described in Section 11.6.
Other exploratory efficacy endpoints will be analyzed using CMH test for proportions, and 
analysis of covariance (ANCOVA) model for continuous variables.  CMH tests will be stratified 
by baseline PGA score, and ANCOVA models will include baseline PGA score as a covariate (2, 
3 or 4), and baseline value of the endpoint as a continuous covariate. For proportions, the same 
MI approach describe above will be taken to deal with missing data.  For continuous variables, 
the standard MI procedures for ANCOVA will be followed. Least squared means of treatment
difference (tapinarof – placebo) along with the 95% CI will be reported. 


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Time to achieving a PGA success will be analyzed with the Kaplan Meier method in the ITT
population based on Observed Cases. Treatment groups will be compared using a log-rank test. 
Estimates of median time to response from Kaplan Meier distribution will be computed. A
Kaplan-Meier figure will also be generated.
12.8.3 Other Efficacy Analyses
Change from baseline in DLQI, PSD, SF-36, and Peak Pruritus-NRS will be analyzed using an 
ANCOVA model with treatment as a main effect, baseline PGA score as a categorical covariate,
and baseline value of the endpoint as a covariate. Percent change from baseline in DLQI, PSD 
and Peak Pruritus-NRS will be summarized and analyzed using the same method.
In addition, the proportion of subjects with at least a 4-point reduction from baseline in the Peak 
Pruritus-NRS among subjects with a baseline NRS score
4 will be summarized and analyzed 
following the same method as the dichotomized secondary endpoints. A plot will be used to 
illustrate this information. 
Subject itch diary and in-clinic itch score assessments will be listed and summarized using 
descriptive statistics by day. If a subject completed diary itch score on the date of in-clinic visit, 
the itch score assessed in-clinic will be used in the summary. Change from baseline, treatment 
difference (Tapinarof cream 1% – Vehicle Cream) in mean change from baseline values and its 
associated 95% CI will be summarized by day. In addition, the treatment difference and its 
associated 95% CI will be plotted by day. 
12.8.4 Subgroup Analyses
The primary and all secondary efficacy endpoints will be summarized descriptively in each 
baseline PGA subgroup, study center, age (<65, >=65), sex, race (White, Other), duration of 
disease (<5 Years, 5-10 Years, >10 Years), %BSA affected (<10%, >=10%) and country (USA 
and Canada). The %BSA Affected continuous outcome will be further explored with summaries 
of change and % change in %BSA Affected at Week 12 by body region. The implications of any
significant heterogeneity on the assessment of overall efficacy will be explored.
12.9
Safety Analysis
All safety analyses will be conducted in the Safety Population.  Data will be listed by subject and 
treatment and summarized by treatment.  No formal statistical comparisons will be made for 
safety data. 
Single 12-lead ECGs, Hospital Anxiety and Depression Scale (HADS) collected at Screening 
visit will be presented in a by-subject listing. 
12.9.1 Adverse Events


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AE terms will be coded using the MedDRA dictionary. A treatment-emergent AE (TEAE) is 
defined as an AE that starts after the first dose of study medication. For subjects not rolling over 
to Open-label study, all reported AEs will be included in the Double-Blind phase summaries. For 
subjects rolling over to the Open-label study, all AEs with an onset date on or before the Week 
12 visit date will be included in the Double-Blind phase summaries. 
If relationship to treatment is missing, the event will be conservatively treated as related to study 
drug. Missing severity will be imputed to the highest severity level (most severe). 
All AEs will be listed by treatment and by subject, detailing the verbatim term given by the 
investigator, the preferred term (PT), system organ class (SOC), onset date and time, end date
and time, duration (days), CTCAE grade, outcome, relationship to study drug/treatment, action 
taken with study drug/treatment, other action taken to treat the event, seriousness and criteria for 
seriousness. Serious AEs (SAEs), TEAEs leading to study discontinuation, TEAEs related to 
study drug will also be listed separately. The following adverse event of special interest (AESIs)
will be identified and listed separately: contact dermatitis, folliculitis, and headache.
AEs will be summarized by treatment and overall as incidence rates of: 
Any AE 
Any TEAE 
Any AESIs 
Any treatment-related TEAE, including definitely, probably, and possibly related 
Any TEAE leading to study drug discontinuation 
Any SAE (non-Fatal)
Any serious TEAE 
Death
Treatment-related Serious TEAE
Serious TEAE leading to study drug discontinuation
Individual PTs will be summarized by treatment according to the following: 
All TEAEs by SOC in alphabetical order and PT in descending order of combined 
frequency (also for treatment-related TEAEs, TEAEs leading to study discontinuation 
and serious TEAEs)
All TEAEs by SOC, PT, and maximum CTCAE grade
All TEAEs by SOC, PT, and maximum causality (not related, related) to the study drug 
In addition, TEAEs and serious TEAEs will be summarized by SOC (alphabetical order) and PT 
(descending order) for the following subgroups:


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Age (<65 and >= 65 years old)
Sex 
Race (White, Other)
At each level of summarization, a subject will be counted once if he/she reported one or more 
events. The severity of TEAEs and relationship to study drug will be summarized in a similar 
manner. For summaries of relationship to study drug, a subject will be classified according to the 
closest relationship. For summaries of TEAE CTCAE grade, a subject will be classified
according to the worst grade.
For AESIs, summarization will be more extensive, reflecting the more detailed information 
collected. Information summarized will include number of events per subject, earliest onset day, 
duration (in days), causality, grade and seriousness of AESIs, outcome, actions taken with study 
drug, assorted physical characteristics of the AESIs, and demographic/baseline characteristics 
and PGA status of the subjects experiencing them. Each type of AESI will be summarized 
separately. If a subject has more than one treatment-emergent occurrence of an AESI, the 
subject’s maximum duration, highest levels of causality and seriousness, maximum grade and
generally the most extreme level of each characteristic will be summarized.
If an AESI was 
ongoing at EOS, it will not be included in the duration summary.
A Kaplan-Meier figure will be generated for each AESI of time to first event. Subjects not 
experiencing the AESI will be censored at the date of study completion or discontinuation. 
12.9.2 Local Tolerability Scale (LTS)
LTS scores will be summarized by treatment and visit for subject overall assessment (scores 
from 0=None to 4=Strong/Severe) and Investigator overall assessment (scores from 0=No 
irritation to 4=Very Severe) separately. LTS scores at the sensitive areas will be summarized by 
visit, area and treatment group for Investigator overall assessment, as well as listed by subject 
and anatomical site.
12.9.3 Clinical Laboratory Testing
All clinical laboratory (hematology, clinical chemistry, urinalysis) values will be listed by
subject. The reference normal ranges and reference range indicators (e.g. high, low, normal etc.) 
will be supplied by the central laboratory and displayed in the data listings. For the purpose of 
shift table summaries, the central lab reported reference range indicators will be classified as
low, normal and high accordingly based on the table below. Change from baseline in
abnormality status will be summarized using shift tables. For urinalysis, only lab tests with 
numeric results reported are included in shift tables. Separate listings will identify subjects with 
markedly abnormal values. For quantitative measures, observed values and changes in clinical 
laboratory values will be summarized descriptively by visit and treatment group.




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Exploratory analyses may include relationships of plasma concentrations with patient 
demographics or AEs.
12.11
Additional Analyses - COVID-19
In order to describe the impact of COVID-19 on current study, the following disposition events 
will be summarized in the tables separately:
Subjects discontinued from the treatment/study as a result of a positive COVID-19 
diagnosis.
Subjects discontinued from the treatment/study due to other reasons related to COVID-
19. This is excluding COVID-19 diagnosis but may include reasons such as site closure, 
travel restrictions, fear of infection, etc.
Subjects with study visits altered (including modified in-clinic visit, virtual and phone 
visits) and missed due to COVID-19
COVID-19 related protocol deviations will be summarized separately. The impact of COVID-19
(including protocol deviation, visit alteration, treatment/study discontinuation and diagnosis of 
COVID-19) will also be flagged at subject-level in a data listing. Subject profile will be used to 
compile all COVID-19 related information for affected subjects. 
An additional sensitivity analysis of the primary endpoint will be added in the ITT population 
based on OC only and excluding any virtual PGA assessments at Week 12.
Also, all COVID-19 related symptoms and confirmed cases occur during the study will be 
reported as AEs and included in the summaries.
13. CHANGES FROM THE PROTOCOL AND PLANNED ANALYSES
The protocol specified change over time in physical component score and mental component 
score as measured by the SF-36 questionnaire as an exploratory endpoint. Scoring rules for the 
RAND 36-Item Health Survey (Version 1.0) are provided for the eight domain scores but not for 
the physical component score or the mental component score. Hence, summaries of the eight 
domain scores are planned.
No other changes from the protocol in planned analyses are noted. Any additional statistical
analyses to handle modifications to study conduct and/or missing data due to the COVID-19 
pandemic have been documented in Section 12.11 above in this SAP and will be finalized prior 
to database lock and unblinding of the study.
14. FORMATTING
Each page of the analysis will show the sponsor’s name, and the protocol number. Report tables 
will be embedded in the MS Word report document from SAS program output without change. 


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The footer of each table will show the name of the SAS program module which generated it and 
the date and time the table was generated.
The SAS programs will generate rich-text-formatted (RTF) output with the “RTF” extension 
using the SAS Output Delivery System (ODS). The summary tables and listings will be 
formatted using the Courier New 9-point font. The RTF output is included in report documents 
prepared with Microsoft Word and converted to PDF format without typographical change.
Datasets will be created and taken as input to validated SAS programs to generate the report-
ready tables, listings, and figures. Each output display will show the names of the data sets and 
SAS program used to produce it. 
15. ARCHIVING AND RETENTION OF DOCUMENTS
After finalization of the analysis, the following will be archived at IQVIA Biotech and/or with 
the study sponsor:
SAP and any amendments
All SAS code used in the project for statistical analysis, report tables generation, and
analysis data set creation
Tables, listings and figures as included in the clinical study report
SAS study data tabulation model (SDTM) and analysis dataset model (ADaM) datasets