Clinical trial NCT03703310
Conditions: Basal Cell Nevus Syndrome
Keywords: Gorlin syndrome Basal cell nevus syndrome BCNS Nevoid basal cell carcinoma syndrome Basal cell carcinoma Hedgehog Surgically eligible basal cell carcinomas Patidegib
Sponsor: Sol-Gel Technologies, Ltd.
Start date: 2019-02-19; Completion date: 2020-12-28
Enrollment: 174 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a global, multicenter, randomized, double-blind, stratified, vehicle-controlled study of the efficacy and safety of Patidegib Topical Gel, 2%, applied topically twice daily to the face of adult participants with Gorlin syndrome. Participants will be required to apply the investigational product for 12 months. The primary endpoint is a comparison between the two treatment arms of the number of new BCCs that develop over the 12 month period.

Detailed description:
An open-label, extension safety and tolerability study is planned for at least 12 months duration following the end of this study. All participants who complete the Month 12 Exit Visit having demonstrated adequate compliance with application of the Investigational Product (IP) without major Protocol Deviations (PDs) during the study will be eligible for participation in the extension study.

All participants will be contacted by phone approximately 30 days following the Exit or Discontinuation Visit to determine if the participant has experienced any new adverse events (AEs)/serious AEs (SAEs) since discontinuation/completion of study treatment.

Arms: arm 1: Participants will be randomized to receive Patidegib Topical Gel, 2%. The Patidegib Topical Gel, 2% will be dispensed to participants at each study visit and applied topically twice daily to the face. arm 2: Participants will be randomized to receive Vehicle. The Patidegib Topical Gel, Vehicle will be dispensed to participants at each study visit and applied topically twice daily to the face.
Interventions: intervention 1: Patidegib Topical Gel, 2% intervention 2: Patidegib Topical Gel, Vehicle
Intervention descriptions: intervention 1: Patidegib Topical Gel, 2% intervention 2: Patidegib Topical Gel, Vehicle

Protocol documents:
Prot_000.pdf: 
PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
Page 1 of 73 
Clinical Study Protocol 
Protocol Pelle-926-301  
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Phase 3 Efficacy and Safety 
Study of Patidegib Topical Gel, 2%, for the Reduction of Disease Burden of Persistently 
Developing Basal Cell Carcinomas (BCCs) in Subjects with Basal Cell Nevus Syndrome 
Development Phase of Study: 
3 
Study design: 
Multicenter, Double-Blind, Vehicle-Controlled Clinical Study 
IND #: 
125,461 
Eudra CT number: 
2018-001462-42 
Sponsor Representative: 
Sponsor: 
Version: 
Original: 11 May 2018 
Amendment 1: 06 Sep 2018 
Amendment 2: 18 Jul 2019 
Amendment 3: 04 Jan 2021 
CONFIDENTIAL 
Nothing herein is to be disclosed without prior approval of the sponsor. 
This protocol will be conducted in compliance with procedures outlined in this document, Good 
Clinical Practice (GCP) guidelines and applicable regulatory requirements.  This study will not be 
initiated without the approval of the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC).  Any changes to the protocol will be approved in writing by the IRB/IEC before 
implementation except where necessary to eliminate an immediate harm to the subject. 
NCT03703310




PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 3 of 73 
 
Principal Investigator Protocol Agreement Page 
I have carefully read the protocol entitled: “A Multicenter, Randomized, Double-blind, Vehicle-
controlled, Phase 3 Efficacy and Safety Study of Patidegib Topical Gel, 2%, for the Reduction of 
Disease Burden of Persistently Developing Basal Cell Carcinomas (BCCs) in Subjects with Basal 
Cell Nevus Syndrome” and, I declare that, as a Principal Investigator, the clinical protocol was 
subject to critical review and is approved by PellePharm, Inc. (PellePharm).  
I agree to conduct this study in compliance with procedures outlined in this document according 
to International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, the 
Declaration of Helsinki, and applicable regulatory requirements. This study will not be initiated 
without the approval of the Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) and the competent authority, if applicable. 
I understand that any substantial changes to the protocol must be approved in writing by the 
IRB/IEC and the competent authority, if applicable, before it can be implemented except where 
necessary to eliminate immediate harm to the subject. I will provide copies of the protocol and 
access to all information furnished by PellePharm to study personnel under my supervision and 
will discuss this material with them to ensure they are fully informed about the study. I understand 
that the study may be terminated or enrollment suspended at any time by PellePharm with or 
without cause, or by me if it becomes necessary to protect the best interests of the subjects. 
 
 
Investigator Signature 
 
Date 
 
 
 
Printed Name 
 
 
Institution Name 
 
 
Address 
 
 
City, State/Country Zip or Postal Code 
 
 
 
 
 
 
Phone Number 




PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 5 of 73 
Number of 
Subjects: 
Approximately 
 subjects enrolled  
Study 
Population: 
Subjects of at least 18 years of age at the time of Screening with Gorlin 
Syndrome 
Study 
Duration: 
Study duration is approximately 14 months: up to 45-day Screening period, 
12 months active treatment, and 30-day safety follow up. 
 
All subjects who complete the Month 12/Exit Visit having demonstrated 
adequate compliance with application of IP without major PDs during the study 
will be eligible for participation in the open-label extension study. 
Criteria for 
Evaluation: 
Key Inclusion criteria:  
1. The subject must be at least 18 years old at the Screening visit. 
2. The subject must meet diagnostic criteria for Gorlin Syndrome 
(Inclusion Criteria 3). 
3. The subject must have had at least 10 (with at least 3 on the face) 
clinically typical BCCs present within 24 months prior to Randomization 
(Baseline/Day 1). Additionally, the subject must have at least 2 BCCs 
with longest diameter <
 present on the face prior to randomization. 
4. The subject must be willing to abstain from application of a non-study 
topical medication (prescription or over the counter) to facial skin for the 
duration of the trial. 
 
Key Exclusion criteria:  
1. The subject has used topical treatment to the face or systemic therapies 
that might interfere with the evaluation of the study IP. 
2. The subject is known to have a hypersensitivity to any of the ingredients 
in the IP. 
3. The subject has uncontrolled systemic disease. 
4. The subject has been treated for invasive cancer within the past 5 years 
excluding non-melanoma skin cancer, Stage I cervical cancer, ductal 
carcinoma in situ of the breast, or chronic lymphocytic leukemia (CLL) 
Stage 0. 
 
Full inclusion and exclusion criteria are presented in Section 7.1.  
Investigational 
Product: 
Patidegib Topical Gel, 2% (w/w), or Vehicle 
Assessments: 
Background and demographic assessments: 
Inclusion/exclusion criteria 
Demography 
Medical history 
Prior and concomitant medications 
 
Efficacy: 
BCC imaging (unmarked) 
BCC imaging marked (annotated) 
BCC identification and measurement 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 6 of 73 
Biopsy 
Quality of life assessments 
 
Safety: 
Dermal Safety and Tolerability  
Adverse Events (AEs) 
Safety Laboratory Tests 
Physical Examinations (PEs) 
Pregnancy tests 
PK 
Assessment: 
A single plasma sample will be collected prior to topical application of IP at the 
Baseline Visit and Months 3, 6, and 12 and assessed for circulating drug 
concentration of patidegib.  
Genomic 
Testing 
(Optional): 
A separate blood specimen will be collected at the Baseline Visit for genomic 
testing. This specimen may be used to study genetic and genomic mechanisms 
involved in Gorlin Syndrome pathogenesis, disease progression, and outcome. 
This sample should be collected at the Baseline Visit prior to dosing, but may be 
collected at any time during the study, if necessary. Genomic testing will not be 
available to study participants in Denmark due to country-specific regulations. 
Statistical 
Methods: 
Determination of Sample Size  
The sample size in this study was determined based on number of nSEBs as the 
original primary endpoint. In the UK Phase 2 study, the mean number of new 
BCC lesions at 6 months was 0.42 in the Patidegib Topical Gel, 2%, group with 
a standard deviation (SD) of 
, and a mean of 
 in the Vehicle group with a 
SD of 
. The effect size was 0.81. It is assumed that at 6 months, the mean 
number of nSEBs in the Patidegib Topical Gel, 2%, group will be 
, with a SD 
of 0.94, while at 6 months the mean and SD in the Vehicle group will be the 
same as in the Phase 2 study at 6 months (see Table 4) for an effect size of 
. 
At 12 months, it is assumed that the means and SDs will be twice those 
observed at 6 months. With these assumptions, 63 subjects in the Patidegib 
Topical Gel, 2%, group and 63 in the Vehicle group (for a total of 126 subjects) 
will give >90% power for a two-sided 0.05 level statistical significance. To 
account for a 16% drop-out rate, approximately 
 subjects will be 
randomized. Sample size was calculated based on a Wilcoxon-Mann-Whitney 
test, which is conservative if the underlying distribution is Negative Binomial.  
Given the change in primary endpoint requested by the FDA, it is acknowledged 
that the power for statistical significance in new BCCs may be different than 
what was projected before the initiation of the study, and based on nSEBs. We 
can however state that if the drug effect on new BCCs is the same proportion to 
its vehicle mean as is the drug effect on nSEBs to its vehicle mean, and if the 
coefficient of variations of new BCCs and nSEBs are similar, then the new BCC 
primary endpoint will have the same power as does nSEBs. 
 
Statistical Analysis 
The primary population for efficacy analyses will be the Intent-to-Treat (ITT) 
population, with the per-protocol (PP) population for supportive analyses. The 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 7 of 73 
primary endpoint is the number of new BCCs per subject that develop over 
12 months. This endpoint will be analyzed using a negative binomial regression 
to compare treatment groups with number of BCCs at Baseline, Age 
 
years), gender, prior HHI therapy, and geographic region as covariates. 
Secondary endpoints that are based on number of new BCCs or nSEBs will be 
analyzed similar to the primary endpoint. This includes the proportion of 
subjects with at least two new facial BCCs and the proportion of subjects with at 
least one new facial BCC.  
The primary method of dealing with missing data will be the multiple 
imputation method. Last Observation Carried Forward (LOCF) and observed 
case analyses will be done as sensitivity analyses.  
 
Safety endpoints will be summarized with means and standard errors, or 
proportions.  
 
 
 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 8 of 73 
2 
TABLE OF CONTENTS 
1 
SYNOPSIS ...............................................................................................................4 
2 
TABLE OF CONTENTS .........................................................................................8 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................13 
4 
INTRODUCTION .................................................................................................15 
5 
STUDY OBJECTIVES ..........................................................................................18 
5.1 
Primary Objective ......................................................................................18 
5.2 
Secondary Objective ..................................................................................18 
6 
OVERALL STUDY DESIGN AND PLAN ..........................................................19 
6.1 
Rationale for Study Design ........................................................................19 
 Choice of Primary Endpoint ..........................................................19 
 Stratification Parameters ................................................................19 
 Treatment Duration ........................................................................20 
 BCC Tracking ................................................................................20 
 BCC Measurement .........................................................................21 
 Eligibility Criteria and Disease Severity ........................................21 
6.2 
Dose Rationale ...........................................................................................21 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS .........................................23 
7.1 
Inclusion/Exclusion Criteria ......................................................................23 
 Subject Inclusion Criteria ..............................................................23 
 Subject Exclusion Criteria .............................................................24 
7.2 
Concomitant Medications and Treatments ................................................25 
7.3 
Study Drug Discontinuation ......................................................................25 
7.4 
Subject Withdrawal Criteria ......................................................................25 
7.5 
Study Discontinuation or Termination .......................................................26 
8 
STUDY PROCEDURES AND ASSESSMENTS .................................................27 
8.1 
Study Procedures .......................................................................................27 
 Informed Consent...........................................................................28 
 Inclusion and Exclusion .................................................................28 
 Randomization ...............................................................................28 
 Demographics ................................................................................28 
 Medical History .............................................................................28 
 Prior and Concomitant Medications ..............................................28 
 IP Application ................................................................................29 
 Compliance ....................................................................................29 
 Unscheduled Visit ..........................................................................29 
8.2 
Efficacy Assessments .................................................................................29 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 9 of 73 
 BCC Imaging .................................................................................29 
8.2.1.1 BCC Imaging (Unmarked) .............................................................29 
8.2.1.2 BCC Imaging Marked (Annotated) ...............................................29 
 Biopsy ............................................................................................30 
 Quality of Life Assessments ..........................................................30 
8.3 
Safety Assessments ....................................................................................33 
 Dermal Safety and Tolerability Events ..........................................33 
 Physical Examination and Vital Signs ...........................................35 
 Laboratory Assessments ................................................................35 
 Pregnancy Tests .............................................................................35 
8.4 
Other Assessments .....................................................................................35 
 PK Assessments .............................................................................35 
 Genomic Sample ............................................................................35 
9 
TREATMENT PLAN ............................................................................................37 
9.1 
Methods of Assigning Subjects to Treatment Groups ...............................37 
9.2 
Randomization and Blinding .....................................................................37 
9.3 
Unblinding .................................................................................................37 
9.4 
Treatment Compliance ...............................................................................37 
9.5 
Protocol Deviations ....................................................................................38 
10 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT ........39 
10.1 
Identity of the Investigational Product .......................................................39 
10.2 
Packaging and Dispensation of Investigational Product ............................39 
10.3 
Storage and Handling of Investigational Product ......................................40 
10.4 
Application .................................................................................................40 
10.5 
Investigational Product Accountability and Disposal ................................41 
11 
SAFETY INSTRUCTIONS AND GUIDANCE ...................................................43 
11.1 
Adverse Events ..........................................................................................43 
 Definition of Adverse Event ..........................................................43 
 Documenting Adverse Events........................................................43 
 Serious Adverse Events .................................................................44 
 Assessment of Severity ..................................................................45 
 Assessment of Causality ................................................................45 
 Reporting of Serious Adverse Events ............................................46 
 Emergency Contact ........................................................................46 
 Expedited Serious Adverse Event Reports ....................................47 
12 
STATISTICS .........................................................................................................48 
12.1 
Analysis Population ...................................................................................48 
12.2 
Subject Disposition ....................................................................................48 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 10 of 73 
12.3 
Demographics and Baseline Characteristics ..............................................48 
12.4 
Protocol Deviations ....................................................................................48 
12.5 
Compliance ................................................................................................48 
12.6 
Assessment of Efficacy ..............................................................................49 
12.6.1 Efficacy Summaries .......................................................................49 
12.6.1.1 Primary Endpoint ..........................................................49 
12.6.1.2 Secondary Endpoints .....................................................49 
12.6.1.3 Exploratory Endpoints ..................................................49 
12.6.2 Efficacy Analyses ..........................................................................50 
12.7 
Assessment of Safety .................................................................................51 
12.7.1 Dermal Safety and Tolerability ......................................................51 
12.7.2 Adverse Events ..............................................................................51 
12.7.3 Physical Examination Including Vital Sign Results ......................51 
12.7.4 Safety Laboratory Values ..............................................................51 
12.7.5 Pregnancy Tests .............................................................................52 
12.7.6 Handling of Missing Data ..............................................................52 
12.7.7 Multicenter Issues ..........................................................................52 
12.7.8 Multiplicity Issues ..........................................................................52 
12.8 
Sample Size Determination ........................................................................52 
13 
QUALITY CONTROL AND QUALITY ASSURANCE .....................................54 
13.1 
Study Monitoring .......................................................................................54 
13.2 
Audits and Inspections ...............................................................................54 
13.3 
Data Quality Assurance .............................................................................55 
14 
ETHICS AND ADMINISTRATIVE ISSUES ......................................................56 
14.1 
Ethical Conduct of the Study .....................................................................56 
14.2 
Independent Review Board Review ...........................................................56 
14.3 
Informed Consent.......................................................................................56 
14.4 
Subject Data Protection..............................................................................56 
14.5 
Financial Disclosure ...................................................................................57 
14.6 
Investigator Obligations .............................................................................57 
14.7 
Changes to the Protocol .............................................................................57 
14.8 
Confidentiality ...........................................................................................57 
15 
DATA HANDLING AND RECORD KEEPING .................................................58 
15.1 
Inspection of Records ................................................................................58 
15.2 
Retention of Records ..................................................................................58 
15.3 
Electronic Case Report Form Completion .................................................59 
16 
REFERENCES ......................................................................................................60 
17 
APPENDICES .......................................................................................................61 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 11 of 73 
17.1 
Safety Laboratory Tests .............................................................................61 
17.2 Patient Reported Outcomes (PRO) Questionnaires .......................................62 
 
 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 12 of 73 
List of Tables 
Table 1: 
Schedule of Assessments ................................................................................31 
Table 2: 
Dermal Safety and Tolerability Scales ...........................................................34 
Table 3: 
Excipients of Patidegib Topical Gel, 2% (w/w) .............................................39 
Table 4: 
Power and Sample Size (1:1 randomization) ..................................................53 
 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 13 of 73 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or 
Specialist Term 
Definition or Explanation 
aBCCdex 
Advanced Basal Cell Carcinoma Index 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCC 
Basal Cell Carcinoma 
BCNS 
Basal Cell Nevus Syndrome 
BID 
Twice daily 
CAPA 
Corrective and Preventative Action Plan 
cGMP 
Current Good Manufacturing Practices 
CI 
Confidence interval 
CLL 
Chronic Lymphocytic Lymphoma 
CMH 
Cochran-Mantel-Haenszel 
MP 
Monitoring Plan 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
DLQI 
Dermatology Life Quality Index 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form  
EQ-5D-5L 
EuroQol (Quality of Life) using 5 levels 
EU 
European Union 
FCS 
Fully Conditional Specification 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized as Safe 
HH 
Hedgehog 
HHI 
Hedgehog inhibitor 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  
IUD 
Intra-uterine device 
IxRS 
Interactive Web/Phone Randomization System 
LOCF 
Last Observation Carried Forward 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MI 
multiple imputation 
nSEB 
New Surgically Eligible BCC 
OMIM 
Online Mendelian Inheritance in Man 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 14 of 73 
Abbreviation or 
Specialist Term 
Definition or Explanation 
PD 
Protocol deviation 
PDT 
Photodynamic Therapy 
PE 
Physical examination 
PI 
Principal Investigator 
PP 
Per protocol 
PRO/ePRO 
Patient Reported Outcome/electronic Patient Reported Outcome 
PSCP 
Primary Skin Care Physician 
PTCH1 
Patched Protein 1 
QC 
Quality Control/Quality Check 
QD 
Once daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SEB 
Surgically Eligible Basal Cell Carcinoma 
TIV 
Trial Initiation Visit 
SMO 
Smoothened 
SoA 
Schedule of Assessments 
SPF 
Sunscreen Protection Factor 
PTV 
Pre-Trial Visit 
TEAE 
Treatment-Emergent Adverse Event  
US 
United States 
WOCBP 
Woman of Child Bearing Potential 
 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 15 of 73 
4 
INTRODUCTION 
Basal cell carcinomas (BCC) are slow growing tumors of the skin. They can be sporadic or 
inherited. Basal cell nevus (Gorlin) syndrome (
]1) (BCNS) is a rare autosomal 
dominant heritable disease characterized by numerous phenotypic abnormalities, most prominent 
among which is the development of numerous BCCs over a lifetime. Reports of its prevalence 
vary; the highest estimate is 
. The burden of BCCs varies among Gorlin Syndrome 
patients. In general, Gorlin Syndrome patients have their BCCs treated as they become 
problematic (i.e., at risk of invasion of vital structures such as eyes, nose, or ears), large enough 
that scarring will be particularly noticeable if treatment is delayed, or large enough off the face 
such that they are uncomfortable, bleed).  
Several topically-applied drugs (e.g., imiquimod and 5-fluoruracil) are used in the treatment of 
sporadic BCCs. Both of these can cure approximately 
 of the superficial subtype of BCCs, 
which generally occur off the face. However, they generally are not useful for nodular BCCs, 
which are the more prevalent subtype, especially on the face. Surgery is the definitive treatment 
of choice for BCC which are refractory to other interventions.  
Prevention of BCCs so far has been limited to admonitions to avoid sunlight, advice which is 
followed infrequently by patients at risk of developing sporadic skin tumors, and which has not 
been shown to produce a statistically significant reduction in BCC incidence. 
In 1996, two groups identified the PTCH1 gene as the locus of the mutations that cause Gorlin 
Syndrome.2-4 Patients with Gorlin Syndrome have one defective heritable copy of this gene, and 
sporadic loss of the second allele is crucial to the development of all of their BCCs. The PTCH1 
gene encodes the primary inhibitor of the hedgehog (HH) signaling pathway, and its function is 
to inhibit signaling by the next “downstream” member of the HH pathway – 
 
(SMO). All Gorlin Syndrome BCCs, unlike sporadic BCCs, thus far analyzed have loss of 
PTCH1 without activating mutations of SMO.5 This signaling pathway is crucial to development 
of many organs during embryogenesis but in adult life functions in only a limited number of 
sites, among which is the hair follicle. The importance of aberrant HH signaling as the driver of 
BCCs was proved indisputably by the strong anti-tumor effect of small molecules that down-
regulate this pathway. 
Following identification of uncontrolled HH signaling as the driving molecular abnormality in all 
BCCs, several anti-HH drugs have been developed for oral treatment of BCCs. Two of these – 
vismodegib and sonidegib – have been approved for systemic treatment of advanced BCCs. The 
latter are defined as BCCs whose surgical excision likely would produce unsatisfactory results 
(i.e., “locally advanced”) or those which have become metastatic6. Approximately 50% of such 
BCCs fail to respond initially, frequently due to mutations in the SMOOTHENED gene, which 
encodes the protein to which these drugs bind. Of those that do respond, a significant proportion 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 16 of 73 
develop secondary resistance, often due to mutations in the drug binding pocket of the SMO 
protein.7  
Vismodegib also has been studied for efficacy vs. BCCs in patients with Gorlin Syndrome.8 
Unlike results in advanced BCCs, essentially all Gorlin Syndrome non-advanced tumors respond 
by shrinking and eventually most disappear completely, both clinically and histologically. The 
BCCs in Gorlin Syndrome patients fail to develop resistance and, so long as Gorlin Syndrome 
patients continue to take the drug, no nSEBs develop. The combined result of shrinkage of 
existing BCCs and blockage of the development of nSEBs is that these patients have no need for 
surgical treatment of BCCs so long as they continue to ingest vismodegib. But because of 
detrimental class-specific side effects, most patients discontinue vismodegib, and most/all of the 
clinically and histologically cleared BCCs recur to the same size as before treatment.8 Adverse 
events (AEs) seen with systemic hedgehog inhibitor (HHI) include muscle spasms, alopecia, 
dysgeusia, nausea, fatigue, weight loss, diarrhoea and decreased appetite [Vismodegib and 
Sonidegib USPI].  
Patidegib is a semi-synthetic small molecule which when given orally has good therapeutic 
efficacy for advanced BCCs but produces the same types of AEs as do other systemic HH 
inhibitors.  
PellePharm is developing Patidegib Topical Gel, 2%, for the reduction of BCC burden in 
subjects with Gorlin Syndrome. Patidegib Topical Gel, 2%, is manufactured with excipients 
generally accepted as safe, is stable in the developed gel formulation, and can be applied to mini-
pig skin without irritation. Application of Patidegib Topical Gel, 2%, significantly reduces 
murine BCC tumor size in vivo and reduces GLI1 biomarker expression in vitro in human BCC 
tumor explants. 
Patidegib gel has been evaluated in 1 phase 1 and 2 phase 2 studies (UK proof-of-concept study 
in patients with Gorlin syndrome; and US dose escalating study for sporadic BCCs). 
 
) in the clinical 
development program, including 
 
 
The proof-of-concept trial in the UK (Pelle-926-201) evaluated the safety, tolerability and 
efficacy of Patidegib Topical Gel, 2% and 4%, compared to vehicle in Gorlin Syndrome patients. 
Two of 12 topical patidegib gel-treated subjects developed new tumors compared with 
 
).  
The goal of the US dose-escalating trial (Pelle-926-202) was to evaluate patidegib topical gel’s 
safety, tolerability, and effects on the size of preexisting, sporadic, previously untreated, nodular 
BCCs in sporadic BCC patients. Subjects were enrolled into 1 of 4 sequential cohorts to receive 
 
 group experienced the largest median percent decrease in greatest 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 17 of 73 
diameter of treatment targeted BCCs at Week 12 (
 (Patidegib 
Topical Gel Investigator Brochure [IB]).  
Overall patidegib has been found to be safe and well tolerated in previous studies. This trial will 
evaluate the safety and the ability of Patidegib Topical Gel, 2%, to reduce the development of 
BCCs in subjects with Gorlin Syndrome. 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
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Page 18 of 73 
5 
STUDY OBJECTIVES  
5.1 
Primary Objective 
The primary objective of the study is to assess the number of new BCCs in the 2 arms (Patidegib 
Topical Gel, 2%, and Vehicle) when applied twice daily to the face of subjects with Gorlin 
Syndrome. 
5.2 
Secondary Objective 
The secondary objective of the study is to assess the safety and tolerability of Patidegib Topical 
Gel, 2%, in subjects treated twice daily for 12 months. 


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6 
OVERALL STUDY DESIGN AND PLAN 
This is a global, multicenter, randomized, double-blind, stratified, vehicle-controlled study of the 
efficacy and safety of Patidegib Topical Gel, 2%, applied topically twice daily to the face of 
adult subjects with Gorlin Syndrome. Subjects will be required to apply the IP for 12 months. 
The primary endpoint is a comparison between the two treatment arms of the number of new 
BCCs that develop over the 12 month period. BCCs will be imaged and tracked consistently 
throughout the study in order to identify new BCCs and nSEBs. 
An open-label extension safety and tolerability study is planned for at least 12 months duration 
following the end of this study. All subjects who complete the Month 12/Exit Visit having 
demonstrated adequate compliance with application of the IP without major Protocol Deviations 
(PDs) during the study will be eligible for participation in the extension study.  
The principal investigator (PI) or designee will be responsible for the oversight of the study at 
their clinical trial site.  
6.1 
Rationale for Study Design 
The key elements of the study design are choice of the primary endpoint, stratification, eligibility 
criteria, disease severity, a relatively longer treatment duration (12 months) than that in the 
Phase 2 Gorlin Syndrome study (treatment duration 6 months), the methodology for 
measurement of BCCs, and the use of imaging to track BCCs.  
 Choice of Primary Endpoint 
The primary endpoint of the study is a comparison between treatment arms of the number of new 
BCCs per subject that develop over the 12 month period. BCC surgery has significant morbidity 
(e.g., scarring, functional loss of eyelid, nose, ear) and most BCCs in patients with Gorlin 
syndrome are ultimately removed by surgery.  Reduction in the number of facial BCCs and in 
the number of resulting BCC surgeries are serious unmet medical needs and the number of BCCs 
and number of nSEBs are therefore considered appropriate correlating study endpoints.  
Generally, a facial BCC of longest diameter 
 is considered a SEB.8 In this study, a BCC is 
considered a nSEB if the diagnosis was verified histologically, it was not a SEB at Baseline, and 
post Baseline the BCC was either surgically removed because of the development of possible 
functional facial/health impairment, as determined by the Investigator or met objective size 
criteria (irrespective of whether or not it was surgically removed). These objective criteria are 
that post Baseline, the BCC has a longest diameter 
 mm in longest 
diameter from Baseline.  
 Stratification Parameters 
The study design incorporates stratification to ensure that potential Baseline confounders of 
efficacy are distributed evenly across treatment arms. The assignment of subjects into the study 
is being stratified based on Gender, Age and previous HHI therapy.  


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Gender is a potential confounder as female subjects had more tumor response compared with 
male subjects in the prior Pelle-926-202 Phase 2 study. However, both females and male subjects 
treated with active treatment had fewer nSEBs compared with subjects treated with vehicle. 
Female subjects may have higher topical compliance as seen in other topical trials.9 Gender will 
be used as a stratification factor in this Phase 3 trial. 
Previous HHI therapy might also confound the assessment of efficacy. In the trial of oral 
vismodegib for subjects with Gorlin Syndrome, the rate of development of nSEBs was lower 
after vismodegib was discontinued (
) than it had been during placebo 
treatment prior to vismodegib treatment (
).8 It is also likely that it is the 
subjects with more severe disease that are prescribed oral HHIs. For these reasons, previous HHI 
therapy is a stratification parameter. 
Advanced age has been found to correlate with higher numbers of BCCs and new tumors in 
Gorlin Syndrome subjects from a natural history study.10 Age is therefore a stratification factor 
to avoid confounding age-related rates of Baseline tumor progression across treatment groups.  
 Treatment Duration 
The duration of treatment in the phase 2 UK study in Gorlin Syndrome patients (Pelle-926-201) 
was 6 months. A 12-month study increases the likelihood for the occurrence of new BCCs and 
nSEBs when compared to a 6-month study. This is also appropriate given that BCC are innately 
slowly developing tumors. A 12-month safety database will also further inform the overall 
benefit-risk of patidegib topical gel as a chronic therapy in Gorlin Syndrome. 
 BCC Tracking 
The study design ensures that BCCs are tracked consistently throughout the study. The 
12 months treatment duration necessitates the diligent tracking and photography of BCCs to 
assist the PI with tumor identification and measurement recall. This is accomplished by capturing 
standardized unmarked digital images of the face at every visit (unmarked). Marked (annotated) 
images will also be collected in addition to unmarked images at prespecified visits (see Table 1). 
Pelle-926-201 also included imaging to track BCCs.  
At visits prior to IP application (i.e., Screening and Baseline), a second set of digital images 
(annotated images) will be captured, after the BCCs on the face have been identified, labeled, 
and numbered for tracking purposes. It is possible that in some instances at Screening and/or 
Baseline all BCCs cannot be tracked (labeled and numbered) due to limited space for stickering 
on the face. In such situations, the BCCs will be tracked in order of decreasing (longest) BCC 
diameter. It is of critical importance that all SEBs are identified in the images.  
At prespecified post-Baseline visits, the PI will track and measure BCCs for a second set of 
(marked) images. For a given subject, each BCC will be given the same tracking number as 


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assigned prior to IP application, and all new tumors identified will be given new sequential 
numbers.  
 BCC Measurement  
The primary endpoint requires that all Baseline BCCs be eliminated from consideration as new 
BCCs, and that all BCCs are identified and tracked for growth into nSEBs or for possible clinical 
resolution. At Baseline for all BCCs that have been tracked, the longest diameter will then be 
measured by the Investigator using a standardized method. SEBs identified at Baseline will not 
qualify to be called nSEBs.  
At prespecified post-Baseline visits, the Investigator will identify (label and number) all BCCs 
that were tracked prior to IP application start and will identify any new BCCs that have appeared 
since start of IP application. At these pre-specified post-Baseline visits, the Investigator will 
review the BCCs and identify BCCs that may be approximately 
) in 
size. The Investigator will measure the longest diameter for these BCCs, identify them as new or 
previously existing SEBs, and flag them on the label. Throughout the study for any given subject 
each BCC will have the same number.  
Qualified, trained, and blinded Image Data Quality Reviewer (s) will examine each set of subject 
images (1) to determine the accuracy of mapping annotations, and (2) to rule out wild 
transcription or transposition reporting errors in BCC diameter. The Image Data Quality 
Reviewer (s) may query the Investigator, as appropriate. The Investigator may review the query 
and correct, as appropriate. The Investigator’s decision of the BCC diameter and surgical 
eligibility is final.  
 Eligibility Criteria and Disease Severity  
Patidegib topical gel is being evaluated in subjects with Gorlin Syndrome. Gorlin Syndrome is 
typically diagnosed clinically, based on the major and minor diagnostic criteria which are 
reflected in the inclusion criteria6.  
The protocol requires that the subject must have had at least 10 (with at least 3 on the face) 
clinically typical BCCs present within 24 months prior to Randomization (Baseline/Day 1). This 
is to ensure that subjects with moderate to severe Gorlin Syndrome who are most likely to 
benefit from treatment are enrolled.  
Additionally the subject must have at least 2 BCCs with longest diameter <5 mm present on the 
face prior to Randomization (Baseline/Day 1). This increases the possibility for developing a 
nSEB during the study.  
6.2 Dose Rationale 
The PK data from the UK Phase 2 Proof-of-Concept (Pelle-926-201) study showed 1/6 subjects 
on Patidegib Topical Gel, 4% had a detectable patidegib concentration in plasma at Week 14 
(
) and 1/6 subjects had a detectable concentration at Week 26 (
). No 


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subjects on Patidegib Topical Gel, 2% had detectable concentrations (Patidegib Topical Gel IB). 
The tumors treated with Patidegib Topical Gel, 2% had at least as much efficacy as the Patidegib 
Topical Gel, 4%. The Patidegib Topical Gel, 4% group had treatment-related application site 
AEs (e.g., rash, dermatitis, pain, facial alopecia) that were mild-moderate in 4/6 subjects. In 
contrast, no treatment related AEs were seen in the Patidegib Topical Gel, 2% group (data on 
file, clinical study report [CSR]).  


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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Inclusion/Exclusion Criteria 
 Subject Inclusion Criteria 
Subjects meeting all of the following criteria will be eligible for study entry. 
1. 
The subject must be at least 18 years old at the Screening Visit. 
2. 
The subject must provide written informed consent prior to any study procedures.  
3. 
The subject must meet diagnostic criteria for the basal cell nevus (Gorlin) syndrome 
including major criterion #3a plus 1 additional major criterion or plus 2 additional minor 
criteria listed below.  
Major criteria: 
a. 
>2 histologically confirmed BCCs or 1 for subjects under age 20. 
b. 
Odontogenic keratocysts of the jaw confirmed histologically. 
c. 
≥3 palmar and/or plantar pits seen at the Screening Visit. 
d. 
Bilamellar calcification of the falx cerebri present at less than 20 years old. 
e. 
Fused, bifid, or markedly splayed ribs. 
f. 
First degree relative with Gorlin Syndrome. 
g. 
PTCH1 mutation predicted to be of functional significance in normal tissue. 
 
Minor criteria: 
a. 
Macrocephaly. 
b. 
Congenital malformations including frontal bossing, cleft lip or palate, “coarse 
face”, moderate to severe hypertelorism. 
c. 
Skeletal abnormalities detectable clinically: Sprengel deformity, marked pectus 
deformity, or marked finger syndactyly. 
d. 
Skeletal abnormalities detectable radiographically: bridging of the sella turcica; 
vertebral abnormalities such as hemivertebrae, fusion or elongation of the vertebral 
bodies; modeling defects of the hands and feet; flame shaped lucencies of the hands 
or feet. 
e. 
Ovarian fibroma. 
f. 
Medulloblastoma  
(modification of criteria of V Kimonis et al Am J Med Genet 69: 299-308, 199711) 
4. 
The subject must have had at least 10 (with at least 3 on the face) clinically typical BCCs 
present within 24 months prior to Randomization (Baseline/Day 1). Additionally, the 
subject must have at least 2 BCCs with longest diameter <5 mm present on the face prior 
to Randomization (Baseline/Day 1).  
5. 
The subject must be willing to have blood collected to measure circulating drug levels. 
6. 
The subject must be willing to abstain from application of a non-study topical medication 
(prescription or over the counter) to facial skin for the duration of the trial except as 
prescribed by the Investigator. Moisturizers and emollients are allowed. Subjects will be 
encouraged to use their preferred sunscreen with a sunscreen protection factor (SPF) of at 
least 30 daily on all exposed skin sites. 




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10. 
The subject has any condition or situation which, in the Investigator’s opinion, may put 
the subject at significant risk, could confound the study results, or could interfere 
significantly with the subject’s participation in the study. This may include a history of 
other skin conditions (e.g., severe facial eczema) or diseases, metabolic dysfunction, 
physical examination (PE) findings, or clinical laboratory findings giving reasonable 
suspicion of a disease or condition that contraindicates use of an investigational drug or 
that might affect interpretation of the results of the study or render the subject at high risk 
from treatment complications. 
 
7.2 
Concomitant Medications and Treatments 
All medications listed as exclusion criteria cannot be taken concomitantly during the study.  
During the study, subjects will be allowed to use moisturizers and emollients and will be 
encouraged to use sunscreen of at least 30 SPF at least once daily on all exposed skin sites. 
Subjects must wait 30 minutes after IP application before applying any moisturizer, emollient, or 
sunscreen.  
Facial BCCs may be removed at the discretion of the Investigator by the Investigator or a 
competent physician/surgeon at any time after the Baseline Visit if the Investigator believes that 
continued growth of the BCC might have deleterious effects on the health of the subject. Non-
facial BCCs may be removed at the discretion of the Investigator or PSCP.  
7.3 
Study Drug Discontinuation 
The Investigator has the right to permanently discontinue IP application of a subject at any time 
if in their opinion the continuation of the IP is deleterious to the subject’s health or 
discontinuation is in the subject’s best interest. If the subject becomes pregnant, IP will be 
discontinued immediately.  
If, for any reason, a subject is discontinued during the treatment period prior to Month 12/Exit 
Visit, evaluations should be performed at the time of early termination and the reason for 
termination will be recorded in the end of study source documentation. At the 30 day follow up 
additional information may be collected. All data gathered on the subject will be made available 
to PellePharm.  
7.4 
Subject Withdrawal Criteria 
The Investigator may consider discontinuing a subject with a major protocol violation or 
deviation (e.g., failure to meet study enrollment criteria, use of disallowed medications). 
However, an excessive rate of discontinuation can render the study uninterpretable; therefore, 
unnecessary discontinuation of subjects should be avoided. A protocol violation or deviation 
does not in itself necessarily constitute grounds for removal of the subject from the trial if the 
subject’s safety is not compromised.  


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A subject has the right to withdraw from the study at any time for any reason, without prejudice, 
and is under no obligation to disclose the reason. Once a subject has withdrawn from the study, 
no additional information can be collected. All data gathered on the subject prior to withdrawal 
from the study will be made available to PellePharm. 
7.5 
Study Discontinuation or Termination  
The study may be discontinued by PellePharm in any of, but not limited to, the following events: 
• Medical or ethical reasons affecting the continued performance of the study. 
• Difficulties with subject recruitment that make it likely enrollment goals cannot be met. 
 


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8 
STUDY PROCEDURES AND ASSESSMENTS 
The study will be conducted as outlined in the schedule of assessments (SoA) (Table 1). All 
study visits will take place in person at the study site/clinic, except for the 30-day safety follow-
up visit, which will be by phone call. All subject information and data obtained during the study 
visits will be recorded in the source documents, applicable study logs, and electronic case report 
forms (eCRFs), as appropriate. 
Investigators (and any designee) must have appropriate, documented experience and training, or 
obtain approval from PellePharm based on experience (or through additional training organized 
and provided by PellePharm [or designee]). Sites will undergo a feasibility assessment, and a 
formal Pre-Trial Visit (PTV) conducted by the study Clinical Research Organization (CRO) (or 
designee). Sites that meet the requirements to conduct a study according to Good Clinical 
Practice (GCP) and applicable local and country regulatory requirements, as well as Investigator 
and site personnel with demonstrated experience and qualifications will be approved by 
PellePharm or designee to conduct the study. The CRO will continue the site activation process 
to assist sites to receive IRB approval and IP shipment and conduct of a Trial Initiation Visit 
(TIV) prior to the enrollment of subjects into the study for each site. In addition, at least one and 
preferably two site personnel will be trained in the image capture method by the imaging vendor 
as part of the site activation process. A back-up image capture site staff member should be 
available as needed.  
At each study visit, every attempt should be made to ensure that the same Investigator assesses 
the same subject. PellePharm realizes that the conduct of a clinical trial involves a team of study 
staff who perform a variety of functions under the supervision of the PI. Tasks and 
responsibilities are delegated by the PI, and the PI is responsible for the conduct of the study at 
their site as well the training and oversite of all site personnel and other related non-site 
personnel. There are specific tasks that PellePharm requires be done by a licensed physician with 
appropriate experience. As outlined below and in the SoA (Table 1), these tasks include SEB 
biopsy procedure, assessment and reporting, BCC measurement and assessment, and recording 
application site reactions. The surgical excision of the BCC may be done by the Investigator or 
may be referred to a licensed physician with appropriate experience.  
PellePharm also realizes that scheduling visits can be challenging and has allowed for flexibility 
with study visit days. It should be noted that the indicated visit day is in reference to the Baseline 
Visit. For example, the Month 8 visit is intended to be 8 months after the Baseline Visit. A 
month will be considered to have approximately 30 days. 
8.1 
Study Procedures  
The SoA is provided in Table 1. Subjects should be seen for all visits on the designated day or as 
close as practically possible. The Baseline Visit may take place no more than 45 days after the 
Screening visit. If this period exceeds 45 days, subjects will need to be re-screened.  


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The assessments/procedures to be performed at the different visits are elaborated here.  
 Informed Consent 
All subjects must provide written informed consent before any study related procedures are 
performed. Each subject will receive a copy of the signed consent form. Subjects may be pre-
screened (chart review, etc.) for eligibility prior to any study related procedure.  
 Inclusion and Exclusion 
Following provision of informed consent from each subject, the Investigator will determine 
whether subjects meet the inclusion/exclusion criteria.  
A WOCBP is defined as a woman who (a) has not undergone hysterectomy or bilateral 
oophorectomy or (b) has not been naturally post-menopausal for at least 24 consecutive months 
(i.e., has had no menses in the 24 preceding months).  
A WOCBP may be enrolled if she agrees to complete abstinence from sexual intercourse or the 
couple agrees to use at least 2 forms of birth control as defined by the use of a condom with 
spermicide in association with one of the following: bilateral tubal ligation, combined oral 
contraceptives (estrogens and progesterone), or implanted or injectable contraceptives with a 
stable dose for at least 1 month prior to the Baseline Visit, or hormonal intra-uterine device 
(IUD) inserted at least 1 month prior to the Baseline Visit. 
 Randomization  
Details on randomization are available in Sections 9.1 and 9.2. 
 Demographics 
Subject's date/year of birth, gender at birth, race and ethnicity will be recorded in the eCRF, 
where allowed by local regulatory authorities. Race and ethnicity will not be collected in 
countries where prohibited. 
 Medical History 
Subjects’ relevant family history of Gorlin Syndrome and medical history pertinent to eligibility 
criteria will be collected. Information about medical conditions that resolved 2 or more years 
prior to Screening do not need to be recorded unless considered relevant by the Investigator. 
 Prior and Concomitant Medications 
Prior and concomitant medications will be captured separately for BCC (facial) and other 
indications.  
All medications ongoing in the 12 months prior to Baseline or ongoing at any time during the 
study will be recorded in the eCRF. The start date for all medications that were started during the 
study period must be reported. Likewise, the end date for all medications that were discontinued 
during the study period must be captured.  


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 IP Application  
For the first application, the subject will apply the IP at the study site under the direction of the 
Study Coordinator (or designee). The IP should be applied after all clinical assessments. 
Additional information on IP application is available in Section 10.4.  
 Compliance  
The site pharmacist (or designated site personnel) will collect and weigh the previously 
dispensed IP tubes to assess compliance with IP dosing for the preceding month. The weight of 
the IP tubes will be recorded on the appropriate eCRF. See Section 9.4 and the Pharmacy Manual 
for full details on assessing compliance. 
 Unscheduled Visit  
Subjects may return to the site for unscheduled visits in the event of an AE, SAE or as deemed 
necessary by the Investigator. The same procedures as described in the post-Baseline Visits may 
be conducted. For other subject care management, the Investigator may refer the subject to their 
primary care physician and/or their PSCP. Data collected will be reported in the ‘Unscheduled 
Visit’ eCRF page.  
8.2 
Efficacy Assessments 
 BCC Imaging 
Digital imaging of the BCCs will be taken using a 
. Subjects with facial hair 
should be encouraged to remove or at least to clip short any facial hair so that any BCCs present 
within the facial hair region will be easily identifiable on the captured images. Subjects must 
remove make-up prior to the facial exam. Photos will be taken to assess 5 views of the face in the 
same plane of an arc at a fixed distance from the face (
). The 
unmarked and marked digital facial images will uploaded to the imaging vendor portal for 
further review. Full details for image capture can be found in the Image Review Work 
Instruction. 
8.2.1.1 BCC Imaging (Unmarked) 
Take photos of the subject’s unmarked face using the camera as described above for unmarked 
imaging. 
8.2.1.2 BCC Imaging Marked (Annotated) 
Following image capture of the subject’s unmarked face, repeat the process and annotate the 
image by:  
a. Identifying all BCCs, dot around border and place a sticker (1, 2, etc.). Record the 
measurement of the longest diameter of each BCC. BCCs in the region of the 
eyelids or posterior to the tragus are not numbered and tracked. 
b. Marking each SEB (
  
) with a red dot on the sticker 
to indicate the BCC as a SEB or nSEB. 


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c. Taking a photo of face again with markings and stickers.  
d. Uploading unmarked and marked digital facial images to the imaging vendor 
portal for further review.  
 Biopsy 
All biopsies are to be done at the clinical trial site. Prior to the biopsy, the image data quality 
reviewer will confirm that the BCC has been tracked consistently throughout the study. 
However, if the surgeon or Investigator feels that continued growth of a nSEB can pose a 
significant problem, then it can be biopsied and removed at any time. The biopsy will be 
reviewed and reported by a licensed physician with appropriate experience. The biopsy diagnosis 
will be captured in the eCRF. The detailed report of the biopsy will be part of the source 
document. Additionally biopsy slides and photomicrographs will be retained at the site. The 
biopsy report, slides and photomicrographs must be made available for the study monitor or an 
audit by the Sponsor and/or Regulator.   
If the Investigator feels that continued growth of a nSEB can pose a significant problem, then a 
biopsy can be done at anytime, followed by surgery as required.  
 Quality of Life Assessments 
Patient reported outcome (PRO) or electronic PRO (ePRO) will be collected as outlined in 
Table 1. 
 
 
  
 
 
 
  
 
  
 
Table 1 provides the SoA for the study. 




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i 
Subjects may return to the site for unscheduled visits in the event of an AE or SAE or as deemed necessary by the Investigator. The same procedures as described in the post-Baseline 
Visits may be conducted. For other subject care management, the Investigator may refer the subject to their primary care physician and/or their PSCP. 
j 
Subjects will be trained on how to appropriately apply IP and comply with study procedures. Additional reminders may be provided at subsequent visits, as appropriate.  
k 
IP is administered after all other assessments are completed and is followed by a 30-minute observation period. 
l 
All IP tubes (used, partially used, and/or unused) will be returned and weighed. The weight will be recorded on the appropriate eCRF. 
m.    At Baseline, PK samples will be collected prior to the first dose and the date and time of the first dose will be recorded. Post-Baseline, the date and time of the last dose prior to collection 
of the PK sample must be recorded. 
n.     Genomic testing will not be available to study participants in Denmark due to country-specific regulations. 
o.   Patients who fail screen may be rescreened. The patient will need to meet all criteria at rescreen and baseline. Baseline should occur within 45 days of the rescreen. 
 
 
 
 
 
 
 


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8.3 
Safety Assessments 
The safety assessments in the study include vital signs, AEs, dermal safety, and laboratory 
assessments (Section 11.1).  
 Dermal Safety and Tolerability Events 
Safety and tolerability will be evaluated through assessment of selected local signs and 
symptoms (pain/burning, pruritus, erythema, edema, and crusting) on the face. Any local skin 
reaction that requires use of a concomitant therapy or causes interruption or discontinuation 
of the IP should be reported as a dermal safety event. These events will be assessed for 
severity, relative to the skin reactions scale (Table 2). 
 




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 Physical Examination and Vital Signs 
Physical examinations (PEs) including vital signs (blood pressure, heart rate, respiration rate, 
and temperature) will be collected and reported. Height will be collected at the Baseline Visit 
only. Clinically significant changes from Baseline will be captured as AEs. Changes in BCC 
measurements and BCC count will be captured separately as efficacy (imaging and tracking) 
assessments and not as a PE assessment. Changes in BCC count or size will not constitute 
AEs. 
PEs are also done at quarterly visits. Additional PEs at other visits may be collected 
according to any signs/symptoms and/or positive findings at previous PE. 
 Laboratory Assessments 
Routine safety laboratory tests (complete blood count/differential, urinalysis, and serum 
chemistry) will be performed as per the SoA (Table 1) and Appendix 17.1. Any out-of-range 
laboratory result that is considered clinically significant by the Investigator will be recorded 
as an AE and should be confirmed by repeat testing at the discretion of the Investigator. 
Clinically significant laboratory abnormalities at any visit will be followed to resolution 
(return to normal or to the Baseline state) or until clinically stable as determined by the 
Investigator until the study database is closed.  
 Pregnancy Tests 
All WOCBP will have a serum pregnancy test as per the SoA (Table 1), and serum or urine 
pregnancy tests at all other study visits. If the WOCBP becomes pregnant during the course 
of the study, she must immediately stop applying the IP and report the finding to the 
Investigator. Potential teratogenicity should be discussed at each visit with WOCBP and with 
male subjects with partners who are WOCBP. 
8.4 
Other Assessments 
 PK Assessments 
A plasma sample will be collected prior to application of IP per the SoA (Table 1). At 
Baseline, PK samples will be collected prior to the first dose and the date and time of the first 
dose will be recorded. Post-Baseline, the date and time of the last dose prior to collection of 
the PK sample must be recorded. 
 Genomic Sample 
A separate, specific signature will be required to document a subject’s agreement to provide 
additional samples for optional genomic research. From subjects who agree to participate and 
provide their additional, specific consent, a blood specimen will be collected at the Baseline 
Visit for genomic testing. This specimen will be used to study genetic and genomic 
mechanisms involved in Gorlin Syndrome pathogenesis, disease progression, and outcome. 
Stored specimens may also be used to evaluate the association of genetic and genomic 


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markers with study drug response, including metabolism and/or AEs and to determine future 
treatment predictions for patidegib topical gel and/or other approved or exploratory 
medications. This sample should be collected at the Baseline Visit prior to dosing, but may 
be collected at any time during the study, if necessary. 
 


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9 
TREATMENT PLAN 
9.1 
Methods of Assigning Subjects to Treatment Groups 
This is a double-blind study. The study site will assign each consented subject a unique 
 subject number consisting of the 
study site number and the 
 
chronological Screening order number, starting with 
 Site 
numbers will be assigned by country and/or region. Subjects who progress to enrollment in 
the study will retain their Screening number upon Randomization.  
The IP accountability log will be completed by the site pharmacist (or qualified designee), 
and the IP tubes will be provided in a single boxed kit containing 3 tubes of IP gel. It is 
recommended that subjects use tubes consecutively, exhausting the first tube before opening 
and beginning use of subsequent tubes.  
Subjects will be stratified for enrollment based on the following criteria:  
1. 
) 
2. 
Gender at birth 
3. 
History of prior HHI therapy 
) 
9.2 
Randomization and Blinding 
The IPs will be packaged and labeled identically, and the IP kits will be numbered and 
dispensed according to the subject’s assigned randomization number for the study. IP 
supplies will be distributed to the study site to maintain the randomization ratio. 
As a double-blinded study, the Investigators, the site staff, PellePharm, and the Clinical 
Monitor(s) will be blinded to the treatment assigned to individual subjects. Delegated staff 
members at the study site will dispense the IP and will collect and weigh all used and unused 
IP tubes, as scheduled. 
9.3 
Unblinding 
In the case of a medical emergency, subject symptoms must be treated empirically. There is 
no known antidote for patidegib. In a medical emergency, unblinding may not necessarily 
improve the care of the subject.  
Unblinding may be considered when there are two or more identical SAEs that are 
unexpected but considered related to study drug. Should the Investigator feel that unblinding 
is essential, the Investigator should endeavor to contact the PellePharm designated Medical 
Monitor to further discuss the situation.  
9.4 
Treatment Compliance 
Subjects will be required to return the IP tubes that are used and/or unused. Each subject will 
be instructed on the importance of both the application of the IP and return of the used and 


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unused IP tubes. Each tube will be weighed when returned and the results will be entered on 
the source document and eCRF.  
Any interruptions in the schedule of IP administration or use of prohibited concomitant 
medication will be recorded in the eCRFs. 
9.5 
Protocol Deviations  
A PD is any change, divergence, or departure from the study design or procedures defined in 
the protocol. Major PDs are a subset of PDs that might significantly affect the completeness, 
accuracy, and/or reliability of the study data or that might significantly affect a subject's 
rights, safety, or well-being.12 If a major (important) PD has been identified, it should be 
communicated to and discussed with the Medical Monitor. A corrective and preventative 
action (CAPA) plan may be required to be instituted in the case of major PDs at the site. In 
the event of recurring major PDs, the site enrollment may be halted by the Medical Monitor, 
in consultation with PellePharm, until a CAPA plan has been instituted and the issue(s) 
resolved. PDs should be reported on at least an annual basis to the Central IRB or the site’s 
local IRB/IEC.  




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that may compromise the IP shipment will require that the IP kits are quarantined until 
review by the Study Monitor.  
For IP received undamaged, IP will be inventoried and the IP inventory/accountability log 
completed. IP will be stored in a
 
in a secure and restricted location. 
Upon enrollment and randomization of a subject, the pharmacist (or designee) will select the 
IP kit based on the randomization number provided by the Interactive Web/Phone 
Randomization System (IxRS). The initial application of the IP will take place in the clinic 
under observation. No other IP applications at subsequent visits will be required to be 
observed in the clinic setting. However, where it is suspected that inappropriate amounts of 
IP are being applied by the subject (based on tube weights) further review of IP application in 
the clinic may be warranted.  
The subject will return all IP gel tubes (used, partially used, and/or unused) at their 
subsequent study visit. If any IP gel tubes are lost or damaged between clinic visits, 
additional IP may be provided to the subject. The goal is to ensure that the subject has an 
adequate supply of IP to be able to administer all scheduled treatments.  
Refer to the Pharmacy Manual for additional details about administration requirements, IP 
supply, and accountability procedures. 
10.3 
Storage and Handling of Investigational Product 
The IP tubes should be stored 
 
 
10.4 
Application 
The Investigator or site personnel will instruct the subject on how to apply the IP at the 
Baseline Visit and the subject will apply the IP at that visit under observation. The IP should 
be applied to the face, which will be defined as the area extending from the anterior hairline 
to the jaw line (except the eyelids) including the ears. If the anterior hairline is receding, 
application of IP to the forehead will extend no more than 9 cm above the eyebrow or 
superior orbital ridge. 
The Investigator or site personnel will instruct the subject on the proper use of laminated 
dosing cards during the Baseline Visit. In addition to the verbal instructions given during the 
visit, written and/or other media IP application instructions may be provided to the subjects. 
Subjects should be encouraged to keep facial hair short enough to allow adequate application 
of IP to the face, and subjects must remove make-up prior to IP application. 
Subjects will be instructed to wash their face and hands within approximately 10 minutes 
prior to IP application. Subjects will apply their first dose at the study site under observation. 


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Subjects will apply to the face an amount squeezed out as a specified amount on a laminated 
dosing card (
), avoiding the eyelids (as described 
above and in the Pharmacy Manual). If no observable AEs are noted within a 
 
observation period after their first application, subjects can leave the site. Subjects will be 
advised to minimize exposure to direct sunlight while in the study and to wash their hands 
before and after application of the IP. 
 
. If an IP application has been missed or delayed such that there would be 
 between applications, the subject should not apply that dose of IP and just wait to 
apply the next dose. The importance of IP compliance should be discussed with the subject 
during each site visit.  
Subjects will be instructed to store their IP in a secure location away from children. WOCBP 
should not come in contact with the gel unless avoiding pregnancy. 
The amount of IP used by the subjects will be monitored by weighing each returned IP tube 
at all applicable study visits. If it is suspected that inappropriate amounts of IP are being 
applied by the subject (based on tube weights) further review of IP application in the clinic 
may be warranted. 
10.5 
Investigational Product Accountability and Disposal 
Upon receipt of the IP, the Investigator (or designee, e.g., study center pharmacist) will 
acknowledge receipt of the IP after reviewing the shipment’s content and condition. The 
Investigator (or designee) is responsible for ensuring that the designated study site staff 
conduct a complete inventory of study materials and assume responsibility for their storage 
and dispensing. The Investigator (or designee) must agree to keep all study materials in a 
secure location with restricted access. The Investigator (or designee) will keep a record of the 
inventory and dispensing of all IPs. This record will be made available to the Study Monitor 
for the purpose of accounting for all clinical supplies. Any significant discrepancy and/or 
deficiency must be recorded with an explanation. 
All supplies sent to the investigators will be accounted for and, in no case, used in any 
unauthorized situation. Each tube of IP administered at the study center will be administered 
by qualified study center staff. At each site visit, IP compliance will be discussed with the 
subject. 
At the end of the study, following final IP inventory reconciliation by the monitor, the study 
site will dispose of and/or destroy all supplies (including used, partially used, and/or unused 
tubes of IP) where possible, in compliance with the site’s SOPs for IP disposal/destruction. In 
the event that the site is unable to dispose of and/or destroy IP supplies, the Sponsor will be 
notified and a third-party vendor may be contracted to manage destruction of IP supplies.  


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Refer to the Pharmacy Manual for additional details about IP accountability procedures, 
including the IP accountability log. 
 
 


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11 
SAFETY INSTRUCTIONS AND GUIDANCE 
11.1 
Adverse Events 
 Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a medicinal product 
and which does not necessarily have a causal relationship with the medicinal (investigational) 
product. AEs include any unfavorable and unintended illness, sign (e.g., including an 
abnormal laboratory finding), symptom, clinically significant laboratory test abnormality, or 
disease associated with the use of a medicinal (investigational) product that has appeared or 
worsened during the course of the clinical trial, regardless of causal relationship to the 
medicinal (investigational) product under study.  
Subjects will be questioned about any concurrent illness or systemic sign or symptom. Any 
incidence of these systemic signs or symptoms will be reported on the AE eCRF. 
Vital signs and laboratory abnormalities are to be recorded as AEs only if they are clinically 
significant (for example: are symptomatic, requiring corrective treatment, leading to 
discontinuation or fulfilling a seriousness criterion). A laboratory abnormality that is part of 
an efficacy endpoint (e.g., histologic confirmation of BCC on a biopsy) is not to be reported 
as an AE. 
An unexpected AE is one that is not listed in the Investigator’s Brochure (IB) or is not listed 
at the specificity or severity that has been observed. 
 Documenting Adverse Events 
It is the responsibility of the Investigator to document in the eCRF all AEs/SAEs that occur 
during the course of the study. AEs/SAEs should be collected after the informed consent 
form is signed and usually at the Screening visit. The AEs/SAEs should be documented as a 
single medical diagnosis. When this is not possible, the AE/SAEs should be documented in 
terms of signs and/or symptoms observed by the Investigator or reported by the subject at 
each study visit. 
All AEs/SAEs occurring after the subject signs the informed consent through the last study 
visit must be reported, regardless of whether or not the AEs/SAEs are considered drug-
related. All AEs/SAEs, whether in response to a query, observed by the study site personnel, 
or reported spontaneously by the subject, will be recorded. 
At each visit during the study, the subject will be assessed for the occurrence of new and 
ongoing AEs. Dermal safety and tolerability that result in the subject requiring a concomitant 
therapy or discontinuation from the study will be reported as an AE/SAE. The following data 
will be collected on all AEs and recorded on the appropriate eCRF: 
• Event name (diagnosis preferred, if unknown, record the signs/symptoms) 


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• Onset date and end date 
• Maximum severity 
• Seriousness 
• Action taken regarding IP 
• Corrective treatment, if given 
• Outcome 
In addition, the Investigator’s assessment of causality will be recorded  
It is not necessary to capture multiple occurrences of an AE separately if the event recurs at 
short intervals. In such instances the end date of the AE is the date when the event resolved 
last and did not recur. If however the event recurs after long intervals, then the subsequent 
event may be captured as a separate event. The PI may use his discretion to determine what 
constitutes a long or short interval between events and which event is reported once versus 
more than once. Furthermore, protocol defined end points (e.g new BCCs on the face, nSEBs 
on the face and BCC surgeries on the face) will be summarized as efficacy parameters and 
are not to be reported as AEs/SAEs. 
In the clinical database, all AEs including SAEs are to be followed for a minimum up to the 
30 day follow up visit. In the source documents, any and all AEs including SAEs must be 
thoroughly documented to conclusion or in the opinion of the investigator, the event has 
resolved or stabilized. 
 Serious Adverse Events 
All AEs will be assessed as either serious or non-serious. 
An SAE or serious adverse reaction is defined as any untoward medical occurrence that at 
any dose: 
• Results in death 
• Is immediately life threatening, (the term "life threatening" in the definition of 
"serious" refers to an event in which the subject is 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 in-patient hospitalization or prolongation of existing hospitalization 
(hospitalization for elective surgery for a condition present at Screening is not 
considered an AE) 
• Results in persistent or significant disability/incapacity (permanent or substantial 
disruption of a person’s ability to conduct normal life functions) 
• Is a congenital anomaly/birth defect 


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• Is a medically important event that may not be immediately life threatening or 
result in death or hospitalization, but may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the above listed outcomes 
If the BCC surgery requires as per standard of care, that the patient be hospitalized, then this 
hospitalization is not an SAE. 
Note: A spontaneous abortion will be considered an SAE and must be reported per Reporting 
of SAEs under Section 11.1.6. Pregnancy in and of itself is not an SAE, but a subject who 
becomes pregnant must discontinue IP application immediately and the pregnancy will be 
followed to term (and ideally the child will be followed afterward if the subject consents) or 
termination. Any birth defect or other serious issue that may arise during the pregnancy or 
due to fetal exposure will be considered an SAE.  
 Assessment of Severity 
The severity assigned to an AE should be determined by the maximum severity of the AE. 
The categories described below should be used to estimate the severity of AEs: 
• Mild: Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• Moderate: Mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention/therapy required 
• Severe: Marked limitation in activity; some assistance usually required; medical 
intervention/therapy required; hospitalization or prolongation of current 
hospitalization possible; may be incapacitating or life threatening 
 Assessment of Causality 
The Investigator should assess the relationship of the AE, if any, to the IP. The following 
should be taken into account when assessing SAE causality: 
• Positive temporal relationship to IP, such as if the IP was discontinued and the 
SAE resolved or the event recurred after re-introduction. 
• If there is a reasonable possibility that the AE is associated with an underlying or 
concomitant illness. 
• Possible association with previous or concomitant therapy. 
• No temporal relationship to the IP and/or a more likely alternative etiology exists. 
• If the AE is directly related to study procedures or a lack of efficacy. 
The following classifications should be used when evaluating the relationship of AEs and 
SAEs to the investigational drug. 
1. Not Related: No relationship between the experience and the administration of IP; 
related to other etiologies such as concomitant medications or subject’s clinical state. 
2. Unlikely: The current state of knowledge indicates that a relationship is unlikely.  


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3. Possibly: A reaction that follows a plausible temporal sequence from administration of 
the IP and follows a known response pattern to the suspected IP. The reaction might have 
been produced by the subject’s clinical state or other modes of therapy administered to 
the subject. 
4. Probably: A reaction that follows a plausible temporal sequence from administration of 
the IP and follows a known response pattern to the suspected IP. The reaction cannot be 
reasonably explained by the known characteristics of the subject’s clinical state or other 
modes of therapy administered to the subject. 
5. Definitely: A reaction that follows a plausible temporal sequence from administration of 
the IP and follows a known response pattern to the suspected IP and can be confirmed 
with a positive re-challenge test or supporting laboratory data. 
 Reporting of Serious Adverse Events 
SAEs will be captured in both the clinical and safety database.  
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signs the informed consent) and throughout the duration of the 
study and for 30 days following the last IP application will be captured in the clinical 
database via the eCRFs (Section 11.1.2).  
SAEs also will be captured in the safety database. An initial SAE Report must be completed 
for all SAEs (irrespective of relatedness) with an onset date within 30 days from the date of 
last IP application. An initial SAE Report must also be completed for Related SAEs 
(possibly, probably or definitely) regardless of the time elapsed from the last dose (even if 
the study has been closed). 
When new, significant information for an SAE is obtained, as well as when the outcome of 
an SAE is known, the Investigator must submit a Follow-Up Report. If the subject was 
hospitalized, a copy of the discharge summary must be included as part of the subject’s 
medical file. For related events, the Investigator should monitor the subject until the outcome 
of the SAE is known. This may require periodic Follow-Up Reports. 
PellePharm and the study CRO must be notified of all SAEs (regardless of causal 
relationship to IP) within 24 hours of the Investigator’s knowledge of the event by faxing or 
emailing a completed SAE report to the CRO Medical Monitor.  
If there are serious, unexpected AEs associated with the use of the IP, PellePharm (or 
designee) will notify the appropriate regulatory agency(ies) and all appropriate parties as 
appropriate (e.g., IRB) on an expedited basis. It is the responsibility of the Investigator to 
promptly notify the IRB/IEC of all unexpected SAEs involving risk to human subjects. 
 Emergency Contact 
In the event of a medical emergency (i.e., an event that requires immediate attention 
regarding the treatment of a subject, operation of the clinical study, and/or the use of 


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investigational drug), investigational site personnel should endeavor to contact the Medical 
Monitor to discuss the situation. 
 Expedited Serious Adverse Event Reports 
An AE, whether serious or non-serious, is designated unexpected if it is not reported in the 
reference safety section of the IB or if the event is of greater frequency, specificity or 
severity than so reported. 
PellePharm will notify regulatory authorities of unexpected related SAEs and all 
participating study sites in writing for submission by the Investigator to the IRB/IEC. This 
notification will be in the form of a Safety Update to the IB (i.e., “15-day letter”). 
Upon receiving such notices, the Investigator must review and retain the notice with the IB 
and immediately submit a copy of this information to the responsible IRB/IEC, according to 
local regulations. The Investigator and IRB/IEC will determine if the informed consent 
requires revision. The Investigator should also comply with the IRB/IEC procedures for 
reporting any other safety information. 


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12 STATISTICS 
All statistical processing will be performed using SAS® unless otherwise stated. For 
categorical parameters, the number and percentage of subjects in each category will be 
presented. For continuous parameters, descriptive statistics will include n (number of 
subjects), mean, standard deviation (SD), median, minimum, and maximum.  
The multiple imputation (MI) method will be the primary method for dealing with missing 
data. Last Observation Carried Forward (LOCF) and observed case analyses will be done as 
sensitivity analyses.  
A statistical analysis plan (SAP), describing all statistical analyses will be provided as a 
separate document. The SAP will be finalized prior to unblinding of the study treatments. 
12.1 
Analysis Population 
The primary population for efficacy analyses will be the Intent-to-Treat (ITT) population, 
defined as all subjects who were randomized. Subjects will be assigned to treatment groups 
as randomized. The per-protocol (PP) population will be used for supportive efficacy 
analyses. Subjects will be assigned to treatment groups as treated (not as randomized). The 
Safety population will consist of all subject who have applied IP at least once. 
12.2 
Subject Disposition 
A tabulation of subject disposition will be provided. The tabulation will include the numbers 
of subjects who enter the study, complete the study, and discontinue the study. The reasons 
for discontinuation will be included. 
12.3 
Demographics and Baseline Characteristics 
Subject demographic data and Baseline characteristics will be summarized by treatment 
group using descriptive statistics for the ITT population.  
12.4 
Protocol Deviations 
All PDs will be reported to PellePharm and recorded throughout the study. A tabulation of 
PDs will be included in the final study report. 
12.5 
Compliance 
Compliance will be tracked throughout the study. Results of compliance assessments (weight 
of returned drug, etc.) will be tabulated, and descriptive statistics will be used to compare the 
2 groups. For the per protocol population, a sensitivity analysis will be conducted based on 
compliance. 
 


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12.6 
Assessment of Efficacy 
12.6.1 Efficacy Summaries 
The efficacy endpoints are intended to compare twice daily application of Patidegib Topical 
Gel, 2%, and Vehicle. Efficacy assessments will be summarized descriptively by treatment 
group and visit. 
12.6.1.1 
Primary Endpoint  
The primary endpoint is the number of new BCCs per subject by Month 12.  
 
 
12.6.1.2 
Secondary Endpoints 
The secondary efficacy endpoints are:  
1. The number of nSEBs per subject by Month 12. 
2. The proportion of subjects developing ≥2 facial new BCCs by Month 12.  
3. The proportion of subjects developing ≥1 facial new BCCs by Month 12.  
4. The number of new BCCs per subject by Month 9.  
5. The number of new BCCs per subject by Month 6.  
6. aBCCdex change in Lesion Symptoms scale score from Baseline to Month 12. 
 
An nSEB is a histologically verified BCC that was surgically removed because of possible 
functional facial/health impairment as determined by the Investigator. 
Also, nSEBs are facial BCCs with a longest diameter of 
 that:  
a. were not surgically eligible BCCs (SEBs) at Baseline,  
b. have grown by 
 in longest diameter from Baseline, and  
c. have been verified histologically. 
 
 
 
12.6.1.3 
Exploratory Endpoints 
The exploratory endpoints are:  
1. The proportion of SEBs that undergo clinical resolution at Month 12.  
2. The number of BCC surgeries from Baseline to Month 12. 
3. Change in aBCCdex Worry About Future Lesions scale score from Baseline to Month 12.  
4. Change in aBCCdex Mental Health scale score from Baseline to Month 12.  
5. Change in aBCCdex Social/Relationships scale score from Baseline to Month 12.  
6. Change in aBCCdex Life Impact scale score from Baseline to Month 12.  
 


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12.6.2 Efficacy Analyses  
The primary endpoint is the number of new BCCs per subject that develop from baseline to 
Month 12. The number of new BCCs that develop from Baseline to Month 12 will be 
analyzed using a negative binomial regression to compare treatment groups with number of 
BCCs at Baseline, Age 
), gender, prior HHI therapy, and geographic 
region strata (North America, Europe) as covariates. PROC GENMOD of SAS will be used 
with distribution=Negbin. 
In order to assess the impact of parametric assumptions, a non-parametric rank analysis of 
covariance (ANCOVA, Stokes et al) will be provided as a sensitivity analysis with number of 
BCCs at Baseline, prior HHI therapy, gender, age 
), and geographic 
region as covariates.  
The Negative Binomial regression was selected as the primary method of analysis to account 
for the potential for overdispersion. Using the Negative Binomial model, the power will be 
somewhat higher than the one calculated using a non-parametric Wilcoxon-Mann-Whitney 
test. The proposed sensitivity analysis, Rank ANCOVA, was selected to corroborate the 
results from the Negative Binomial model. If the distribution is markedly different from 
Negative Binomial (and unknown to sufficiently allow a different parametric regression 
model), then the non-parametric ANCOVA gives type-1 error closer to the nominal level. 
The number of nSEBs that develop from Baseline to Month 12 will be analyzed using a 
Negative Binomial regression to compare treatment groups with number of BCCs at 
Baseline, Age 
 
), gender, prior HHI therapy, and geographic region as 
covariates. Secondary endpoints that are based on number of new BCCs will be analyzed 
similar to the primary endpoint. The proportion of subjects with at least two new BCCs 
lesions and the proportion of subjects with at least one new BCC lesion will be analyzed 
using a logistic regression to compare treatment groups with number of BCCs at Baseline, 
Age 
), Gender, and prior HHI therapy and geographic region as covariates. 
Change in aBCCdex will be analyzed using an ANCOVA model with treatment group as a 
main effect, Baseline aBCCdex, prior HHI therapy, gender, age strata, and geographic region 
as covariates. Testing of secondary endpoints will be done sequentially at a two-sided 0.05 
level.  
The primary method for dealing with missing data will be the MI method discussed in detail 
in Section 12.7.6. 
LOCF and observed case analyses will be done as sensitivity analyses.  


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12.7 
Assessment of Safety 
Safety results will be summarized with means and standard errors, or proportions. Treatment-
emergent AEs (TEAEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). Previous and Concomitant drugs will be coded using the WHO-Drug dictionary. 
12.7.1 Dermal Safety and Tolerability 
The frequency of dermal safety and tolerability assessments including pain/burning, pruritus, 
erythema, and edema will be summarized descriptively by treatment group and visit. 
12.7.2 Adverse Events 
Subjects will be assessed for the occurrence of new and ongoing AEs. Descriptions of AEs 
will include the dates of onset and resolution (if resolved), maximum severity, seriousness, 
action taken regarding the IP, corrective treatment, outcome, and Investigator’s assessment of 
causality. All AEs will be recorded and classified using terminology from the MedDRA. All 
reported TEAEs, defined as any AE with an onset on or after the date of first IP application, 
or worsening of an AE with an onset prior to first IP application, will be summarized by 
treatment group, the number of subjects reporting TEAEs, system organ class, preferred 
term, severity, and relationship to IP. When summarizing TEAEs by severity or relationship 
to IP, each subject will be counted only once within a system organ class or a preferred term 
using the event with the greatest severity or causality, respectively, within each category. All 
reported SAEs will be summarized by treatment group, the number of subjects reporting 
SAEs, system organ class, preferred term, severity, and relationship to IP. 
All information pertaining to AEs noted during the study will be listed by subject and will 
include a verbatim description of the event as reported by the Investigator, as well as the 
preferred term, system organ class, start date, stop date (if stopped), seriousness, severity, 
action taken regarding the IP, corrective treatment, outcome and relationship to the IP. In 
addition, a listing of subjects who prematurely discontinue from the study due to AEs will be 
provided as well as a listing of subjects who reported an SAE. 
12.7.3 Physical Examination Including Vital Sign Results 
Changes from Baseline in vital sign measurements will be summarized with descriptive 
statistics for each treatment group at all applicable study visits. 
12.7.4 Safety Laboratory Values 
Changes from Baseline in safety laboratory values will be summarized with descriptive 
statistics for each treatment group at all applicable study visits. 
Shift tables will be presented for changes in safety laboratory values to summarize laboratory 
test results collected at Screening to Baseline (Day 1) and at Months 1, 3, 6, 9, and 
Month 12/Exit Visit. Normal ranges established by the local laboratory will be used to 
determine the shifts. A listing of all out-of-range laboratory test results at any assessment 


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time point will also be provided. Determination of clinical significance for all out-of-range 
laboratory values will be made by each Investigator and reported as an AE accordingly. In 
addition, a listing of all clinically significant laboratory test results will be provided. 
12.7.5 Pregnancy Tests 
Pregnancy test results will be presented in a data listing. 
12.7.6 Handling of Missing Data 
The primary method for dealing with missing data will be the MI method. The MI model will 
be detailed in the SAP. One hundred imputations will be generated using PROC MI of SAS. 
Fully Conditional Specification (FCS) model will be used with either new BCCs or nSEBs at 
prior post-Baseline visits, treatment group, number of BCCs at Baseline, prior HHI therapy, 
gender, age strata, and geographic region as covariates to impute the data. 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. 
LOCF and observed case analyses will be done as sensitivity analyses.  
12.7.7 Multicenter Issues 
For the purpose of the summaries and analyses, the term ‘Center’ will be used to define each 
study site. All data collected from participating Centers will be monitored and reviewed as 
specified in this protocol. 
Approximately 50 Centers are planned in this study to enable a sufficient number of subjects 
to be enrolled. In the event that a Center has low numbers of subjects enrolled, pooling of 
results for Centers may be performed. The algorithm for pooling of Centers will be described 
in the SAP. Descriptive summary statistics will be generated including Center and pooled-
Center (when appropriate) by primary and secondary efficacy endpoints.  
12.7.8 Multiplicity Issues 
Testing of secondary endpoints will be done sequentially at a two-sided 0.05 level. 
12.8 
Sample Size Determination 
 
 
 
 
 
 
 
 




PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 54 of 73 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Study Monitoring 
An Investigator Meeting and/or a TIV will be conducted with the PI, Sub-Investigator(s), 
Study Coordinator(s) and other site personnel present. During the TIV the following items 
will be reviewed/discussed: IB review; key elements of the protocol including but not limited 
to the eligibility criteria, safety monitoring, endpoints, and image capture (with additional 
training and review by the imaging vendor); site personnel roles and responsibilities; all 
study procedures; source documents; IP application; compliance monitoring; and eCRFs 
completion. 
Use of the image capture system will require training and qualification by the Imaging 
Vendor prior to site personnel being allowed to capture subject facial images.  
The CRAs will be trained to the protocol and undergo CRO-specific training. Specific 
monitoring guidelines (Monitoring Plan [MP]) and procedures to be followed during 
monitoring visits will also be utilized. During the course of the study, source documents will 
be verified by the CRAs and the percentage of Source Data Verification detailed in the MP. 
All subject source records must be made available to the CRAs. 
The conduct of the study will be closely monitored by PellePharm following GCP guidelines. 
A risk assessment and mitigation plan will be prepared in collaboration with PellePharm and 
the study CRO prior to enrollment of the first subject at the Baseline Visit. PellePharm will 
also provide Vendor and CRO oversight as part of PellePharm’s responsibilities.  
In addition, inspections or on-site audits may be carried out by local authorities or by 
PellePharm. The PI will allow members of PellePharm, the study CRO, and any regulatory 
agency access to examine all study records, corresponding subject medical records, clinical 
dispensing records and storage area, and any other documents considered source 
documentation. The PIs agree to assist the representative(s) as required. 
13.2 
Audits and Inspections 
The study will be conducted under the sponsorship of PellePharm in conformation with all 
appropriate legal regulations, as well as ICH guidelines. Interim and end of study audits of 
raw data, study files, and final report may be conducted by the study CRO and/or 
PellePharm’s QA Department or designee. 
PellePharm is responsible for implementing and maintaining quality assurance and quality 
control systems to ensure that studies are conducted and data are generated, documented, and 
reported in compliance with the protocol, GCP, and applicable regulatory requirements. In 
addition, PellePharm will be responsible for securing agreement from all involved parties to 
ensure direct access to all study sites, source data/documents, eCRFs, and reports for the 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 55 of 73 
purpose of monitoring and auditing by PellePharm, and inspection by domestic and foreign 
regulatory authorities. 
13.3 
Data Quality Assurance 
All assessments performed will be accurately documented in the subject’s source documents 
and eCRFs. The Investigator or designee will enter the information required by the protocol 
into the source documents and eCRFs provided by PellePharm or designee. Subjects will be 
identified in the eCRFs by their assigned subject number only. 
The Investigators must read the protocol thoroughly and must follow the instructions. Any 
deviations should be agreed to by prior discussion between PellePharm and the Investigator, 
with appropriate written protocol amendments made prior to implementing the agreed 
changes. Any amendment containing major modifications (particularly if it may involve an 
increased risk to the subjects) will be approved by the IRB before it may be implemented. No 
change in the conduct of the study can be instituted without written approval from 
PellePharm. 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 56 of 73 
14 ETHICS AND ADMINISTRATIVE ISSUES 
14.1 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles originating from the 
Declaration of Helsinki, ICH guidelines, GCP, and in compliance with local regulatory 
requirements. The Investigator agrees, when signing the protocol, to adhere to the 
instructions and procedures described in it and thereby to adhere to the principles of GCP. 
14.2 
Independent Review Board Review 
This protocol, proposed informed consent form and other information provided to subjects, 
and all appropriate amendments will be properly reviewed and approved by the IRB/IEC. A 
signed and dated notification of the IRB/IEC approval will be provided to PellePharm and 
Investigator prior to study initiation. The name and occupation of the chairman and members 
of the IRB/IEC will be supplied to PellePharm. The Investigator will provide required 
progress reports and report all SAEs to the IRB/IEC as required by the IRB/IEC. 
14.3 
Informed Consent 
An IRB-approved Informed Consent Form (ICF) that displays the version and date of 
approval is required for completion by signature from each subject prior to conduct of any 
study procedures under this protocol, including Screening tests and evaluations. The ICF, as 
specified by the investigational site’s IRB/IEC, must follow the Protection of Human 
Subjects regulations listed in 21 Code of Federal Regulations Part 50.  
The background of the proposed study and the benefits and risks of the procedures and study 
must be clearly and understandably explained to the subjects. It is the responsibility of the 
Investigator to obtain consent and to provide the subject with a copy of the signed and dated 
ICF. Confirmation of a subject’s informed consent must also be documented in the source 
documentation prior to any testing under this protocol, including Screening tests and 
evaluations. 
All ICFs used in this study must be approved by the appropriate IRB/IEC and by the study 
CRO and/or PellePharm or designee. The ICF must not be altered without the prior 
agreement of the relevant IRB/IEC and study CRO and/or PellePharm. 
14.4 
Subject Data Protection 
Subject data will be protected by ensuring that no captured data contain subject names, 
addresses, telephone numbers, email addresses, or other direct personally identifying 
information. It is acknowledged that subject initials, demographics (including birthdate), 
medical histories, and prior concomitant medication uses, along with the name and address of 
the enrolling investigator may allow for personal identification of study participants. Other 
than where necessary to meet regulatory requirements, all data collected in this study will be 
presented in tabulated (i.e., aggregate) form, and listings containing information that could be 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 57 of 73 
used to identify an individual subject will not be included in any public disclosures of the 
study data or the study results. Any individual data listings required to be presented to 
comply with regulatory requirements will be de-identified prior to disclosure. 
14.5 
Financial Disclosure 
Financial disclosures will be obtained from all investigators in order to document any 
potential conflicts of interest. 
14.6 
Investigator Obligations 
The Investigator agrees, when signing the protocol, to adhere to the instructions and 
procedures described in it and thereby to adhere to the principles of GCP. 
14.7 
Changes to the Protocol 
The Investigators must read the protocol thoroughly and must follow the instructions. 
Waivers for enrollment should be avoided, and PellePharm does not plan to provide any 
waivers. Any amendment to the protocol containing major modifications will be approved by 
the IRB before it may be implemented. No change in the conduct of the study can be 
instituted without written approval from PellePharm. 
14.8 
Confidentiality 
All the data furnished to the Investigator and his/her staff and all data obtained through this 
protocol will be regarded as confidential and proprietary in nature and will not be disclosed 
to any third party, except for the study CRO, FDA or other regulatory body, without written 
consent from PellePharm. 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 58 of 73 
15 DATA HANDLING AND RECORD KEEPING 
15.1 
Inspection of Records 
Investigators must maintain detailed records on all subjects who are enrolled in the study or 
undergo Screening. Data will be recorded in the subject’s source documents and in applicable 
study logs provided by the study CRO and/or PellePharm. Source documents include subject 
medical records, hospital charts, site charts, investigator subject study files, as well as the 
results of diagnostic tests (e.g., laboratory tests). All required data should be recorded in the 
study documentation completely for prompt data review. Upon study completion or at any 
other time specified by the study CRO and/or PellePharm, the appropriate study documents 
must be submitted. 
The Investigator must keep accurate separate records (source documentation) of all subject 
visits, being sure to include all pertinent study related information. At a minimum, this 
includes the following information: 
• A statement indicating that the subject has been enrolled in the study and the 
subject number 
• Date that the ICF was obtained 
• Evidence that the subject meets study eligibility requirements (e.g., medical 
history, Screening evaluations) 
• Dates of all study related visits and results of any evaluations/procedures 
performed, including who performed each assessment at each visit 
• Use of any concurrent medications during the study 
• Documentation of IP accountability 
• Any and all side effects and AEs must be thoroughly documented to conclusion or 
until the event has stabilized in the opinion of the Investigator 
• Results of any diagnostic tests conducted during the study 
• The date the subject exited the study and a statement indicating that the subject 
completed the study or was discontinued early, including the reason for 
discontinuation 
Notes describing telephone conversations and all electronic mail with the subject, 
PellePharm, or PellePharm’s designee concerning the study must be recorded or kept on file. 
All source documents must be made available to PellePharm and PellePharm’s designated 
monitor upon request. 
15.2 
Retention of Records 
The Investigator should properly store and maintain all study records in accordance with 
PellePharm directives. All records relating to the conduct of this study are to be retained by 
the Investigator until notified by PellePharm in writing that the records may be destroyed. 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 59 of 73 
The Investigator will allow representatives of PellePharm’s monitoring team, the governing 
IRB/IEC, the FDA or other applicable local authorities to inspect all study records, eCRFs, 
and corresponding portions of the subject’s study site and/or hospital medical records at 
regular intervals throughout the study. These inspections are for the purpose of verifying 
adherence to the protocol, completeness and accuracy of the data being entered onto the 
eCRF, and compliance with FDA or other local authority regulations. 
15.3 
Electronic Case Report Form Completion 
eCRFs will be completed for each enrolled subject. It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the subject’s eCRF. 
Source documentation supporting the eCRF data should indicate the subject’s participation in 
the study and should document the dates and details of study procedures, AEs, and subject 
status. The eCRFs should be completed within 48 hours of the subject visit.  
Investigators will maintain copies of the eCRFs at the investigational site. For subjects who 
discontinue or terminate from the study, the eCRFs will be completed as much as possible, 
and the reason for the discontinuance or termination clearly and concisely specified on the 
appropriate eCRF. 
 


PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
 
Page 60 of 73 
16 REFERENCES 
1. 
Gorlin RJ, Goltz RW. Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib: 
a syndrome. New England Journal of Medicine 1960;262:908-12. 
2. 
Hahn H, Wicking C, Zaphiropoulos PG, et al. Mutations of the human homolog of 
Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85:841-
51. 
3. 
Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene 
for the basal cell nevus syndrome. Science 1996;272:1668-71. 
4. 
Epstein EH. Basal cell carcinomas: attack of the hedgehog. Nature Reviews Cancer 
2008;8:743-54. 
5. 
Sarin A, Migden M, et al. Lack of resistant SMO mutations and decreased mutational 
load of Gorlin-associated basal cell cancers explain marked response to smoothened 
inhibitors. SID 2015, Atlanta Poster #135. 
6. 
Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced 
basal-cell carcinoma. New England Journal of Medicine 2012;366:2171-9. 
7. 
Sharpe HJ, Pau G, Dijkgraaf GJ, et al. Genomic analysis of smoothened inhibitor 
resistance in basal cell carcinoma. Cancer Cell 2015;27:327-41. 
8. 
Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog 
pathway in patients with the basal-cell nevus syndrome. New England Journal of 
Medicine 2012;366:2180-8. 
9.  
Harper J, et al. The efficacy and tolerability of dapsone 5% gel in female versus male 
patients with facial acne vulgaris: Gender as a clinically relevant outcome variable. 
Poster Presented at the Fall Clinical Dermatology Conference. Las Vegas, NV. 
October, 2010. 
10. 
Solis DC, Kwon GP, Ransohoff KJ, et al. Risk factors for basal cell carcinoma among 
patients with basal cell nevus syndrome: development of a basal cell nevus syndrome 
patient registry. JAMA Dermatology 2016;153(2):189-192. 
11. 
Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons 
with nevoid basal cell carcinoma syndrome. American Journal of Medical Genetics 
1997;69:299-308. 
12. 
https://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/ 
guidancesinformationsheetsandnotices/ucm219488.htm 
13. 
Stokes ME, Davis CS, Koch GG, Categorical Data Analysis Using the SAS System, 
SAS Institute, Inc., Cary, NC, 1996 
 




PellePharm, Inc. 
Phase 3 Efficacy and Safety for Reduction of Disease Burden of Basal Cell Carcinomas 
Pelle-926-301, Protocol Amendment 3, 04JAN2021 
PROPRIETARY AND CONFIDENTIAL 
Page 62 of 73 
17.2 Patient Reported Outcomes (PRO) Questionnaires 
• Appendix 17.2.1 Advanced Basal Cell Carcinoma index (aBCCdex) (4 pages)
• Appendix 17.2.2 Skindex-16 administration (2 pages)
• Appendix 17.2.3 Dermatology Life Quality Index (DLQI) (2 pages)
• Appendix 17.2.4 EuroQol Group 5-level EQ-5D (EQ-5D-5L) (3 pages) 


General Instructions: 
Please answer each question to the best of your ability. 
There are no right or wrong answers.  
These questions ask you about your symptoms and your functioning 
and well-being.  For each question, please choose the response that 
best describes your experience during the past week.   
Your responses will be confidential and will be summarized with 
other study participant’s responses.   
© Genentech Inc 2013 


 
 
 
 
2.  People sometimes experience different emotions because of their condition. Please indicate how 
much of the time you had these emotions during the past week as a result of your advanced BCC 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Inc 2013 
 


 
 
 
 
3. Please circle the one number that comes closest to indicating how worried you were about the 
following issues in the past week as a result of your advanced BCC or BCCNS.                                          
 
4.  Many people make changes to their lifestyle as a result of their condition.  Please indicate how 
often you AVOIDED each of the following activities in the past week as a result of your advanced 
BCC or BCCNS. 
 
 
 
 
© Genentech Inc 2013 


 
 
 
 
5. Advanced BCC and BCCNS can affect many aspects of a person’s life.  In this next section, please 
indicate how much you agree or disagree with each statement.  
 
 


Skindex16 
MMChren,1997 
Skindex16 - United States/English - Mapi. 
ID6862 / Skindex16_AU2.0_eng-USori.doc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Skindex16 
MMChren,1997 
Skindex16 - United States/English - Mapi. 
ID6862 / Skindex16_AU2.0_eng-USori.doc 
 
 
 
 
 
 
 
 
Have you answered every item? Yes  No  


 
 


AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. 
DERMATOLOGY LIFE QUALITY INDEX (DLQI) - INSTRUCTIONS FOR USE 
of 0. The higher the score, the more quality of life is impaired.  
 
 
HOW TO INTERPRET MEANING OF DLQI SCORES 
 
REFERENCES 
 
Finlay AY and Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine 
clinical use. Clin Exp Dermatol 1994; 19:210-216. 
 
Basra MK, Fenech R, Gatt RM, Salek MS and Finlay AY. The Dermatology Life Quality Index 1994-2007: a 
comprehensive review of validation data and clinical results. Br J Dermatol 2008; 159:997-1035. 
 
Hongbo Y, Thomas CL, Harrison MA, Salek MS and Finlay AY. Translating the science of quality of life into 
practice: What do dermatology life quality index scores mean? J Invest Dermatol 2005; 125:659-64. 
 
 
 
There is more information about the DLQI, including over 85 translations, at www.dermatology.org.uk. The 
DLQI is copyright but may be used without seeking permission by clinicians for routine clinical purposes. For 
other purposes, please contact the copyright owners. 
 


 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
 
English version for the USA 
 
 
 


2 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
ODAY. 


3 
 
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 
 
 
 
 
  

SAP_001.pdf: 
Statistical Analysis Plan 
Sponsor: 
PellePharm, Inc. 
Protocol No: 
Pelle-926-301 
Protocol Title: 
A Multicenter, Randomized, Double-blind, Vehicle-controlled, Phase 
3 Efficacy and Safety Study of Patidegib Topical Gel, 2%, for the 
Reduction of Disease Burden of Persistently Developing Basal Cell 
Carcinomas (BCCs) in Subjects with Basal Cell Nevus Syndrome 
Document Date: 
17-Jun-2020
Document Version: 
6.0 
NCT03703310






Pelle-926-301 Statistical Analysis Plan 
17 June 2020 
Version 6.0 
CONFIDENTIAL 
Page 4 of 27 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ................................................................................................................. 7 
1.1 
Study Background ............................................................................................................ 7 
1.2 
Study Design .................................................................................................................... 7 
1.3 
Study Objectives .............................................................................................................. 8 
1.3.1 
Primary Objectives.................................................................................................... 8 
1.3.2 
Secondary Objectives................................................................................................ 8 
2. 
STATISTICAL METHODOLOGY .................................................................................... 8 
2.1 
General Principles ............................................................................................................ 8 
2.2 
Sample Size Determination .............................................................................................. 9 
2.3 
Study Populations ............................................................................................................. 9 
2.4 
Subject Accounting and Baseline Characteristics ............................................................ 9 
2.5 
Efficacy Analyses ........................................................................................................... 10 
2.5.1 
Primary Efficacy Analysis ...................................................................................... 10 
2.5.2 
Secondary Efficacy Analysis .................................................................................. 12 
2.5.3 
Exploratory Endpoints ............................................................................................ 13 
2.5.4 
Interim Analysis ...................................................................................................... 13 
2.6 
Safety Analyses .............................................................................................................. 14 
3. 
DATA HANDLING ............................................................................................................. 16 
3.1 
Baseline and Study Visits ............................................................................................... 16 
3.2 
Missing Data .................................................................................................................. 16 
3.3 
Pooling of Sites .............................................................................................................. 17 
3.4 
Protocol Deviations ........................................................................................................ 17 
3.5 
Compliance with Study Drug Application ..................................................................... 18 
4. 
CHANGES FROM THE PROTOCOL ............................................................................. 18 
5. 
REFERENCES .................................................................................................................... 19 
APPENDIX A: ABCCDEX SCORING .................................................................................... 20 
APPENDIX B: SKINDEX-16 SCORING ................................................................................. 21 


Pelle-926-301 Statistical Analysis Plan 
17 June 2020 
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CONFIDENTIAL 
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APPENDIX C: DLQI SCORING .............................................................................................. 22 
APPENDIX D: PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS  
 
 ............................................................................................................................................... 23 
APPENDIX E: SAS PROGRAMMING QC REQUIREMENTS .......................................... 27 
 


Pelle-926-301 Statistical Analysis Plan 
17 June 2020 
Version 6.0 
CONFIDENTIAL 
Page 6 of 27 
LIST OF ABBREVIATIONS 
aBCCdex 
Advanced Basal Cell Carcinoma Index 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BCC 
Basal Cell Carcinoma 
BCNS 
Basal Cell Nevus Syndrome 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CMH 
Cochran–Mantel–Haenszel 
CSR 
Clinical Study Report 
DLQI 
Dermatology Life Quality Index 
DMC 
Data Monitoring Committee 
EQ-5D-5L 
EuroQol (Quality of Life) using 5 levels 
FCS 
Fully Conditional Specification 
HHI 
Hedgehog Signaling Pathway Inhibitor 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
nSEB 
New Surgically Eligible Basal Cell Carcinomas 
PellePharm PellePharm, Inc. 
PP 
Per-Protocol 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SEB 
Surgically Eligible Basal Cell Carcinomas 
TEAE 
Treatment-emergent Adverse Event 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 


Pelle-926-301 Statistical Analysis Plan 
17 June 2020 
Version 6.0 
CONFIDENTIAL 
Page 7 of 27 
 
1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data collected 
within the scope of PellePharm, Inc. (PellePharm) Phase 3 Protocol Pelle-926-301 
 
 and associated country specific amendments. The purpose of this plan is to provide specific 
guidelines from which the statistical analyses will proceed. Any deviations from this plan will be 
documented in the clinical study report (CSR). 
. 
1.1 Study Background 
PellePharm is developing Patidegib Topical Gel to help reduce the disease burden of basal cell 
carcinomas (BCCs) in patients with basal cell nevus syndrome (BCNS or Gorlin Syndrome). Patidegib 
is a semi-synthetic small molecule which when given orally has good therapeutic efficacy in the 
treatment of locally advanced and metastatic BCCs but produces the same types of adverse events (AEs) 
as do other systemic hedgehog inhibitors (HHIs). Patidegib Topical Gel is manufactured with excipients 
generally accepted as safe, is stable in the developed gel formulation. Topical application of patidegib 
significantly reduces murine BCC tumor size in vivo and reduces GLI1 biomarker expression in vitro in 
human BCC tumor explants. The clinical results from the Phase 2 study in patients with Gorlin 
syndrome are discussed in the Sample Size Determination section. 
1.2 Study Design 
This is a global, multicenter, randomized, double-blind, stratified, vehicle-controlled study of the 
efficacy and safety of Patidegib Topical Gel, 2%, compared with Vehicle Gel, applied topically twice 
daily to the face of adult subjects with Gorlin Syndrome. Subjects are required to apply the study 
treatment for 12 months. The primary endpoint is a comparison between the 2 treatment arms of the 
number of new surgically eligible BCCs (nSEBs) that develop over the 12-month period. A nSEB is 
defined as a BCC that meets protocol-defined criteria for surgical eligibility and that was not eligible for 
surgery at baseline. These criteria are that a nSEB is a histologically verified BCC that (1) was 
surgically removed because of possible functional facial/health impairment as determined by the 
Investigator or (2) met objective size criteria (irrespective of whether or not it was surgically removed). 
These objective size criteria are that post Baseline, the BCC has a 
 
. 
BCCs will be imaged and tracked consistently throughout the study in order to identify nSEBs. 
 
 


Pelle-926-301 Statistical Analysis Plan 
17 June 2020 
Version 6.0 
CONFIDENTIAL 
Page 8 of 27 
 
Subjects will be stratified for enrollment based on the following criteria: 
1. Age 
  
2. Gender 
3. History of prior HHI therapy 
 
Digital imaging of the BCCs will be taken using Canfield 2-D camera. Photos will be taken to assess 5 
views of the face in the same plane of an arc at a fixed distance from the face 
 
 
 The unmarked and marked digital facial images will be uploaded to the imaging vendor portal for 
further review. Full details for image capture can be found in the Imaging Review Work Instruction 
(
). Lesions suspicious for a BCC will 
be measured by the PI for their longest diameter. 
 
 
 
 
. 
1.3 Study Objectives 
1.3.1 Primary Objectives 
The primary objective of the study is to assess the number of nSEBs in the 2 arms (Patidegib Topical 
Gel, 2%, and Vehicle Gel) when applied twice daily to the face of subjects with Gorlin Syndrome. 
1.3.2 Secondary Objectives 
The secondary objective of the study is to assess the safety and tolerability of Patidegib Topical Gel, 
2%, in subjects treated twice daily for 12 months. 
2. 
STATISTICAL METHODOLOGY 
2.1 General Principles 
Continuous parameters will be summarized by number of non-missing observations (n), mean, standard 
deviation (SD), median, minimum, and maximum (with the exception of laboratory and vital sign 
parameters which will be summarized by mean, SD, and median). Categorical parameters will be 
summarized by count and percentage of the non-missing responses. All statistical analyses will be 
performed using SAS® Version 9.4 or later. AEs and medical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 21.1 or later. Prior and concomitant medications 
and procedures/therapies will be coded using the World Health Organization (WHO) Drug Dictionary 
version Global B3 01SEP2018 or later. 


Pelle-926-301 Statistical Analysis Plan 
17 June 2020 
Version 6.0 
CONFIDENTIAL 
Page 9 of 27 
 
2.2 Sample Size Determination 
In the UK Phase 2 study of patients with Gorlin syndrome (Pelle-926-201), the mean number of nSEBs 
(erroneously stated in the protocol as mean number of new BCCs in the Section on Sample size 
determinations) at 6 months was 
in the Patidegib Topical Gel, 2%, group with an SD of 
, and a 
mean of 1.4 in the Vehicle Gel group with a SD of 1.52. The effect size was 0.81. Because the current 
trial is longer, more conservative assumptions are made. It is assumed that at 6 months, the mean 
number of nSEBs in the Patidegib Topical Gel, 2%, group will be 0.6, with an SD of 
, while at 6 
months the mean and SD in the Vehicle Gel group will be the same as in the Phase 2 study at 6 months 
for an effect size of 0.63. At 12 months, it is assumed that the means and SDs will be twice those of 6 
months. With these assumptions,
 subjects in the Patidegib Topical Gel, 2%, group and 63 in the 
Vehicle Gel group (for a total of 
 subjects) will give >90% power for a 2-sided 0.05 level statistical 
significance. To account for a 16% drop-out rate, approximately 150 subjects will be randomized.  
The primary endpoint of number of qualifying nSEBs per subject by Month 12 may be affected by 
follow-up time. Based on the UK Phase 2 study (Pelle-926-201), it is projected that the power calculated 
above will be substantially similar unless marked differences are seen between the treatment arms in 
follow-up time. Sample size was calculated based on a Wilcoxon-Mann-Whitney test which is 
conservative if the underlying distribution is Negative Binomial.   
2.3 Study Populations 
The enrolled population, defined as all subjects who signed informed consent, will be used for study 
disposition summaries. The primary population for efficacy analyses will be the Intent-to-Treat (ITT) 
population, defined as all subjects who were randomized. Subjects will be assigned to treatment groups 
as randomized. The per-protocol (PP) population will be used for supportive efficacy analyses and is 
defined as all randomized subjects who completed 12 months of treatment with between 
 
treatment compliance and without any major protocol deviations in regard to inclusion/exclusion criteria 
or prohibited concomitant medications. In the PP population, subjects will be assigned to treatment 
groups as treated (not as randomized). The Safety population will consist of all subjects who have 
applied treatment at least once and will be assigned to treatment groups as treated. Subjects who receive 
both Patidegib and Vehicle will be summarized in the Patidegib group. 
Listings of all subjects who signed informed consent but did not fulfill all eligibility criteria, 
randomization assignments, and subject disposition will be created. 
2.4 Subject Accounting and Baseline Characteristics 
Subject disposition including population counts, treatment discontinuation reason, duration on study, 
completion of study (defined as being contacted for the 30 day follow-up), and reason for study 
discontinuation will be summarized for all subjects who signed an informed consent (enrolled 
population). A Kaplan-Meier plot of the time to treatment discontinuation will be presented in the Safety 


Pelle-926-301 Statistical Analysis Plan 
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Population. Demographic and baseline characteristics will be summarized for all subjects in the ITT 
Population. Demographics will be presented in a listing. A summary of baseline efficacy parameters 
including time since diagnosis of BCNS, number of SEBs at baseline, number of BCCs including and 
excluding SEBs, and history of prior HHI therapy use will be provided in the ITT Population. Medical 
history, prior and concomitant medications/products, prior and concomitant procedures/therapies, study 
completion status and reasons for discontinuation will also be summarized and listed for this population. 
Prior medications/products and procedures/therapies are those that started and ended prior to the date of 
initial dose of study drug and are not ongoing at baseline. Concomitant medications are defined as any 
medication ongoing at baseline (date of first dose) or which are taken at/after date of first study 
medication. 
A summary and a listing of subjects with any blood relatives with BCNS will be provided. A table of 
Gorlin diagnostic criteria will be presented.  
2.5 Efficacy Analyses 
2.5.1 Primary Efficacy Analysis 
The primary endpoint is the number of nSEBs per subject by Month 12. A nSEB is a histologically 
verified BCC that was surgically removed because of possible functional facial/health impairment as 
determined by the Investigator. Also, nSEBs are facial BCCs with a longest diameter of ≥5 mm that:  
a. were not SEBs at Baseline,  
b. have grown by 
 mm in longest diameter from Baseline, and  
c. have been verified histologically. 
If two or more lesions merge together and become a nSEB, then this will count as only 1 nSEB. If an 
investigator indicates that the lesion grew at least  mm from Baseline and the lesion is subsequently 
histologically confirmed, then it will count as a nSEB for the purposes of analysis. 
Primary Estimand 
The primary estimand – “Treatment policy” is defined as follows:  
The difference in rates of nSEBs if subjects were to continue to be treated for the entire study unless forced 
to discontinue treatment due to an AE or lack of efficacy. The imputation of missing data in accordance 
with this estimand is discussed in detail in Section 3.2. 
The treatment policy estimand assesses the expected effect on nSEBs in a patient population offered 
treatment with Patidegib Topical Gel, 2%,  as compared to vehicle.  
This endpoint will be analyzed using a Negative Binomial regression to compare treatment groups, with 
number of BCCs that are not SEBs at Baseline, prior HHI therapy, gender, age 
), 


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and geographic region strata (North America, Europe), as covariates.  PROC GENMOD of SAS will be 
used with distribution=NEGBIN. 
A non-parametric rank analysis of covariance (ANCOVA, Stokes et al) will be provided as a sensitivity 
analysis with number of BCCs that are not SEBs at Baseline, prior HHI therapy, gender, age (
 
years old), and geographic region as covariates. 
The Negative Binomial regression was selected as the primary method of analysis to account for the 
potential for overdispersion. Using the Negative Binomial model, the power will be somewhat higher 
than the one calculated using a non-parametric Wilcoxon-Mann-Whitney test. The proposed sensitivity 
analysis, Rank ANCOVA, was selected to corroborate the results from the Negative Binomial model. If 
the distribution is markedly different from Negative Binomial (and unknown to sufficiently allow a 
different parametric regression model), then the non-parametric ANCOVA gives type-1 error closer to 
the nominal level. 
 
ITT 
PP 
Analysis 
Negative Binomial 
Rank 
Negative 
Binomial 
Rank 
MI 
x; s 
x; s 
 
 
LOCF 
x 
x 
 
 
OC 
x 
x 
x; s 
x; s 
Derived 
Listing Only 
 
 
 
Note: ‘x’ denotes that the full population will be used, and ‘s’ denotes that subgroup analyses will be provided in the given population and analysis type. 
The primary method for dealing with missing data will be the multiple imputation (MI) method 
discussed in detail in Section 3.2. An analysis in the PP Population using the observed case (OC) 
method with the offset option specified to account for different follow-up times will be provided as a 
sensitivity analysis. A box plot of the mean number of nSEBs per subject over time will be presented. 
Additionally, a stacked histogram showing the proportion of subjects with 0, 1, 2, 3, 4, and 
 nSEBs 
will be presented over time in the ITT Population. 
Last Observation Carried Forward (LOCF) and OC analyses using both the Negative Binomial and Rank 
ANCOVA models will be done as sensitivity analyses. Additional sensitivity analyses (conservative 
multiple imputations and tipping point analysis) are described in Section 3.2. 
The derived number of nSEBs, determined using the actual measurements provided instead of relying on 
the answer to the question “Lesion has a longest diameter 
 mm and has grown by at least  mm in 
longest diameter from Baseline:”, will be presented in the listings. If the post-baseline measurement is 
missing which makes the derivation impossible and the baseline measurement is present, then the 
question will be used instead to determine if the BCC qualifies as a nSEB. However, if there is no 
baseline measurement, then the lesion will not count as a nSEB. 


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Listings of derived efficacy endpoints, BCC measurements, facial BCC procedures, and digital imaging 
of BCCs will be created. 
2.5.2 Secondary Efficacy Analysis 
The secondary efficacy endpoints are:  
1. The number of new BCCs that develop from Baseline to Month 12. 
2. The proportion of subjects developing ≥2 facial nSEB(s) by Month 12.  
3. The proportion of subjects developing ≥1 facial nSEB(s) by Month 12.  
4. The number of qualifying nSEBs per subject at Month 9 (defined as the number of qualifying nSEBs 
per subject by Month 9).  
5. The number of qualifying nSEBs per subject at Month 6 (defined as the number of qualifying nSEBs 
per subject by Month 6).  
6. Advanced BCC Index (aBCCdex) change in lesion score from Baseline to Month 12. 
The number of new BCCs that develop from Baseline to Month 12 will be analyzed using a negative 
binomial regression to compare treatment groups with number of BCCs at Baseline, Age (
 
years), gender, prior HHI therapy, and geographic region strata (North America, Europe) as covariates. 
Secondary endpoints that are based on number of nSEBs will be analyzed similar to the primary 
endpoint. The proportion of subjects with at least 2 nSEB lesions and the proportion of subjects with at 
least 1 nSEB lesion will be analyzed using a logistic regression to compare treatment groups with 
number of BCCs that are not SEBs at Baseline, Age (
 years), gender, prior HHI therapy, and 
geographic region strata (North America, Europe) as covariates. Change in aBCCdex scores will be 
analyzed using an ANCOVA model with treatment group as a main effect, the corresponding baseline 
aBCCdex scale score, prior HHI therapy, gender, age 
 old), and geographic region 
strata as covariates. Please see Appendix A for the scoring instructions for the aBCCdex lesion scale 
score. A box plot of the number of new BCCS per subject over time will be presented. An analysis of 
the number of new BCCs by Month 12 in the PP Population using OC will be provided as a sensitivity 
analysis. 
The secondary endpoints will be tested sequentially in the order above using a gatekeeping strategy with 
type-1 error of 0.05 at 12 months. If and only if the primary endpoint is statistically significant will the 
secondary efficacy endpoints be tested using the gate-keeping procedure.  
All efficacy assessments (secondary and exploratory endpoints) will be summarized descriptively by 
treatment group and visit.  
 
 


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2.5.3 Exploratory Endpoints 
The exploratory endpoints are:  
1. Time to first nSEB. 
2. The proportion of SEBs that undergo clinical resolution at Month 12. 
3. The number of BCC surgeries from Baseline to Month 12. 
4. Change in aBCCdex Worry About Future Lesions scale score from Baseline to Month 12.  
5. Change in aBCCdex Mental Health scale score from Baseline to Month 12.  
6. Change in aBCCdex Social/Relationships scale score from Baseline to Month 12.  
7. Change in aBCCdex Life Impact scale score from Baseline to Month 12.  
8. Change in Skindex-16 subscales (Symptoms, Emotions, and Functioning) from Baseline to Month 
12 
9. Change in Dermatology Life Quality Index (DLQI) total score from Baseline to Month 12 
10.  Shift in EuroQol (Quality of Life) using 5 levels (EQ-5D-5L) from Baseline to Month 12 
11.  Change in EQ-5D-5L Visual Analog Scale (VAS) from Baseline to Month 12 
The time to first nSEB, defined as the date of first new SEB – date of randomization + 1, will be 
summarized using the Kaplan-Meier method. Subjects who do not develop an nSEB will be censored at 
the date of last tumor assessment, regardless of whether or not the subject was still on treatment. A 
Kaplan-Meier plot will also be provided. 
The proportion of SEBs that undergo clinical resolution at Month 12 (or last assessment utilizing LOCF 
imputation) and the number of BCC surgeries will be summarized descriptively. 
Change in Skindex-16 subscale scores and the DLQI total score will be summarized descriptively by 
visit Please see Appendix B for the Skindex-16, and Appendix C for the DLQI. 
A separate analysis plan for the pharmacokinetic data will be provided.  
A shift table will be presented for changes from baseline of the EQ-5D-5L dimension scores. 
Additionally, the VAS Scores will be summarized descriptively by visit. 
2.5.4 Interim Analysis 
An Interim analysis was initially planned per protocol when all subjects have completed 6 months of 
treatment (or terminated the study earlier) and if at least 126 nSEBs have been observed. However, 
based on advice received during 1H 2020 interactions with FDA and EMA, and given both agencies’ 
recommendation to not conduct the interim analysis, the option for an interim analysis was cancelled 
and the DMC disbanded prior to the original IA time point and prior to any unblinding; only a final 
analysis will be performed.  


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2.6 Safety Analyses 
Dermal Safety and Tolerability  
Shift tables of the frequency of dermal safety and tolerability assessments including pain/burning, 
pruritus, erythema, edema, and crusting will be summarized using counts and percentages by treatment 
group and visits of the most severe post baseline assessment and end of treatment from baseline. 
A listing of all dermal safety and tolerability assessments will be provided. 
Adverse Events 
Subjects will be assessed for the occurrence of new and ongoing AEs from the time of informed consent. 
Descriptions of AEs will include the dates of onset and resolution (if resolved) including study days, 
maximum severity, seriousness, action taken regarding the treatment, corrective treatment, outcome, and 
Investigator’s assessment of causality. All AEs will be recorded and classified using terminology from 
the MedDRA. AEs prior to treatment application will be summarized by preferred term. All reported 
treatment-emergent AEs (TEAEs), defined as any AE with an onset on or after the date of first treatment 
application and on or prior to the date of last application plus 30 days, or worsening of a condition with 
an onset prior to first treatment application and on or prior to the date of last application plus 30 days, 
will be summarized by treatment group, the number of subjects reporting TEAEs, system organ class, 
preferred term, severity, and relationship to treatment. Additionally, a summary of TEAEs by preferred 
terms will be provided for all preferred terms with at least 1 TEAE in the Patidegib arm. When 
summarizing TEAEs by severity or relationship to treatment, each subject will be counted only once 
within a system organ class or a preferred term using the event with the greatest severity or causality, 
respectively, within each category. All reported treatment-emergent Serious AEs (SAEs) will be 
summarized by treatment group, the number of subjects reporting SAEs, system organ class and 
preferred term as well as by preferred term. All reported TEAEs leading to treatment discontinuation 
(those TEAEs with action taken with study treatment of Drug Withdrawn) will be summarized by 
treatment group, the number of subjects reporting treatment-related TEAEs/TEAEs leading to treatment 
discontinuation, system organ class and preferred term as well as by preferred term. Additionally, 
paralesional TEAEs and TEAEs on complete area of treatment application will be summarized by 
preferred term.  
AEs with a missing relationship to treatment will be classified as related to treatment. AEs with missing 
severity will be classified as severe.  
All information pertaining to AEs (separately for AEs prior to treatment application and TEAEs) noted 
during the study will be listed by subject and will include a verbatim description of the event as reported 
by the Investigator, as well as the preferred term, system organ class, start date, stop date (if stopped), 
seriousness, severity, action taken regarding the treatment, corrective treatment, outcome and 
relationship to the treatment. In addition, separate listings of subjects who prematurely discontinue from 


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the study due to TEAEs, subjects who reported an AE leading to death, and subjects who experienced 
treatment-emergent SAEs will be provided. 
Safety Laboratory Tests 
Safety laboratory tests were initially intended to be done at one central laboratory (Clinical Reference 
Laboratory; CRL). However, since CRL decided to shut down its operations, midway through the study, 
laboratory testing has been migrated to a second laboratory (Cerba). Since two central labs will be used 
during the trial, the data from CRL will be normalized to the data from Cerba data using the 
methodology outlined in Karvanen (2003). The lab data from CRL will be normalized to the Cerba data 
by applying the following location-scale family transformation for each parameter using the female 
range if the ranges are different for males and females: 
𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑 𝑟𝑒𝑠𝑢𝑙𝑡= 𝐿𝐶𝑒𝑟𝑏𝑎+ (𝑥𝐶𝑅𝐿− 𝐿𝐶𝑅𝐿) ∗(𝑈𝐶𝑒𝑟𝑏𝑎−𝐿𝐶𝑒𝑟𝑏𝑎
𝑈𝐶𝑅𝐿−𝐿𝐶𝑅𝐿
) 
Where LCerba and LCRL are the lower limits of normal of the parameter from Cerba and CRL, 
respectively, xCRL is the result of the parameter for the subject, and  UCerba and UCRL are the upper limits 
of normal of the parameter from Cerba and CRL, respectively.  
Then, if any normalized result for a given parameter is negative, then the scale family transformation 
will be applied instead: 
𝑛𝑜𝑟𝑚𝑎𝑙𝑖𝑧𝑒𝑑 𝑟𝑒𝑠𝑢𝑙𝑡= (𝑥𝐶𝑅𝐿) ∗(𝑈𝐶𝑒𝑟𝑏𝑎
𝑈𝐶𝑅𝐿
) 
Changes from Baseline to last on treatment in safety laboratory values, including chemistry and 
hematology, will be summarized separately with descriptive statistics in SI units for each treatment 
group at all applicable study visits. Separate listings for each panel will be provided.  
Shift tables will be presented for changes in safety laboratory values to summarize laboratory test results 
from baseline to last on treatment. Normal ranges established by each of the central laboratories will be 
used to determine the shifts. A listing of all out-of-range laboratory test results at any assessment time 
point will also be provided. Determination of clinical significance for all out-of-range laboratory values, 
derived as any AE with a system organ class of Investigations, will be made by each Investigator and 
included in the listing. In addition, a listing of all clinically significant laboratory test results will be 
provided. 
Pregnancy and urinalysis results will be provided in listings. A shift table for urinalysis results  (normal 
vs. abnormal) from baseline to last on treatment will be provided. 
Physical Examinations 
Changes from Baseline for last on treatment in vital sign measurements will be summarized with 
descriptive statistics for each treatment group. A listing of vital signs results will be provided. 


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3. 
DATA HANDLING 
3.1 Baseline and Study Visits 
Visits for all analyses will be as recorded on the electronic Case Report Forms. Baseline will be the 
latest of the non-missing values prior to receiving treatment. The following analysis windows will be 
used for all efficacy and safety data: 
Visit 
Target Day 
Beginning of the 
Window 
End of the Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: All days are relative to the date of first treatment application. 
If there is more than 1 assessment of the same data in the same window, then the latest assessment 
within the window will be used for analysis in the tables. 
3.2 Missing Data 
For the primary analysis, the MI method will be the primary method for dealing with missing data. 
LOCF and OC analyses will be done as sensitivity analyses. For the count secondary endpoints, MI will 
be used; for the dichotomous secondary endpoints and the aBCCdex endpoint, LOCF will be used. 
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 change from the last time-
point in the number of SEBs at prior post-baseline visits, number of BCCs that are not SEBs at baseline, 
prior HHI therapy, gender, geographic region, and age 
) as covariates to impute 
any missing  data including missed visits and missing data due to dropouts. Missing data of subjects on 
Patidegib who discontinued due to intercurrent events of AEs, use of a prohibited concomitant 
medication or lack of efficacy (determined during blind data review of the reasons for study treatment 
stopped) will be imputed based on vehicle and imputed based on randomized treatment for remaining 
subjects to estimate the treatment effect if patients would continue to be treated for the entire study 
unless forced to discontinue treatment due to an AE or lack of efficacy or used a prohibited concomitant 
medication. If there is a problem with imputing based on the full model, then region will be dropped. 
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 from the MI will then be used to derive the 
number of nSEBs at each timepoint and then analyzed using the primary analysis model. The results of 
the 100 analyses will be transformed into a normal statistic and combined into a single analysis using 


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PROC MIANALYZE. The Wilson-Hilferty transformation (Wilson and Hilferty, 1931) will be utilized 
to combine the results of the 100 non-parametric Rank ANCOVA analyses. 
For the primary and secondary efficacy endpoints related to number of nSEBs, a nSEB that was first 
reported at or prior to Month 12 will be counted in the endpoint. The lesion will be considered a nSEB at 
the time it was first reported clinically even if it is biopsied and confirmed later. 
The following additional sensitivity analyses utilizing Negative Binomial regression will be provided for 
the primary endpoint to explore the space of plausible missing data assumptions: 
 An MI analysis using the model for the primary imputation but by vehicle for all subjects who 
dropped out, irrespective of the cause, and MI by randomized treatment for the remaining 
subjects. 
 A tipping point analysis which will impute the results at the months prior to the analysis using 
the same model for the primary imputation will be performed if and only if the result of the 
primary endpoint is significant. One hundred imputations will be generated using PROC MI of 
SAS. The imputation at Month 12 will be imputed using the MNAR ADJUST statement within 
SAS to shift the imputed values for the increase in nSEBs for subjects randomized to the 
Patidegib arm by different values until the p-value changes from significant to non-significant. 
The seed to be used is 20180330. 
In order to classify a medication as prior or concomitant or classify an AE as treatment-emergent or not, 
missing or partial dates will be imputed. Please see Appendix D for full details of the imputation of 
missing/partial dates. 
3.3 Pooling of Sites 
Approximately 
 centers are planned in this study in 2 geographic regions: North America (USA and 
Canada), and Europe. ANCOVA analyses of primary and secondary endpoints will include geographic 
region, in addition to other factors, as a covariate. Sub-group analyses of primary efficacy endpoints will 
be done by geographic region in addition to other stratification factors age 
), 
gender, and prior HHI therapy if at least 30 subjects are in a subgroup.  
3.4 Protocol Deviations 
Protocol deviations and violations will be monitored. Before unblinding the study, protocol deviations 
will be classified as minor, or those major deviations that may impact on the interpretation of the results. 
Major protocol deviations in regard to inclusion/exclusion criteria, prohibited concomitant medications, 
or treatment compliance not between 80% – 120% will cause the removal of subjects from the PP 
population. A summary of deviations by impact (major vs. minor) and COVID-19 related deviations will 
be summarized in the ITT Population. All deviations will be provided in a listing. Additionally, a listing 
of missed visits due to COVID-19 will be presented.  


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3.5 Compliance with Study Drug Application 
At each visit when study drug is returned by the subject, returned tubes will be weighed. Compliance 
with study drug application will be calculated from the previous dispensation of study drug. Compliance 
will be calculated using the following formula: 
 
 
 
Where DW represents the dispensed weights and RW represents the returned weights of each kit. If a 
tube is not returned, then it will be assumed that the subject used none of it, i.e. the returned weight 
equals the dispensed weight. An alternative compliance calculation based on the following formula: 
 
 
will be presented. 
Total dose received, duration of treatment, and compliance will be compared between the 2 treatment 
groups using summary statistics. Compliance will also be a factor in defining the PP population as noted 
in Section 2.3. 
Listings of baseline study drug application, study drug accountability, compliance, and study drug 
interruption will be created. 
Compliance will also be calculated based on the cumulative number of days that study drug was 
interrupted. If drug is interrupted for one day it will be assumed that two doses were missed which will 
be a conservative estimate of the number of doses missed.  
4. 
CHANGES FROM THE PROTOCOL 
This section highlights text in the SAP that overrides the cited text in the protocol.  
The protocol (Section 8.2.1) refers to an Imaging Review Charter. In actuality this is an Imaging Review 
Work Instruction. 
In the section on Sample Size Determination (Section 12.9) the protocol states ‘mean number of new 
BCC lesions at 6 months was 0.42’ instead of ‘mean number of new SEB lesions at….’ 
The secondary endpoints for the number of nSEBs at Months 6 and 9 were clarified to reflect that they 
are “by Month” 6 or 9 to bring these endpoints in line with the primary endpoint. Exploratory endpoints 
for the time to first nSEB, Skindex-16, DLQI, and EQ-5D-5L questionnaires were added.  
The primary endpoint analysis distributional assumption was changed from Poisson to Negative 
Binomial based on FDA and EMA feedback, however the primary endpoint remains unchanged.  


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The interim analysis will no longer be performed based on EMA Scientific Advice, dated 26Mar2020, 
and FDA advice during a Type B Meeting held on 11May2020 recommending that the interim analysis 
should not be conducted; only a final analysis will be performed at an alpha level of 0.05 instead of 
0.045 (both primary and secondary endpoints).  
Laboratory test results will be summarized as change from baseline to last result on treatment instead of 
at each visit to provide a more concise, medically relevant summary. 
5. 
REFERENCES 
Chren, M.M., Lasek, R.F., Sahay, A.P, and Sands, L.P. Measurement Properties of Skindex-16: A Brief 
Quality-of-Life Measure for Patients with Skin Diseases. Journal of Cutaneous Medicine and Surgery. 
2001; 105-110. 
Finlay, A.Y. and Khan, G.K. 1992. Cardiff University Department of Dermatology. 
www.dermatology.org.uk. January 21, 2019. 
Mathias, S.D., Chren, M.M., Crosby, R.D., et al. Reliability and validity of the Advanced Basal Cell 
Carcinoma Index (aBCCdex). British Journal of Dermatology. 2015;173:713-719. 
Stokes, M.E., Davis, C.S., and Koch, G.G. (2012), Categorical Data Analysis Using the SAS System, 
Third Edition, Cary, NC: SAS Institute Inc. 
Wilson, E.B, and Hilferty, M.M. 1931. The distribution of chi-squared. Proceedings of the National 
Academy of Sciences. 1931; 16: 219-242. 
 


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APPENDIX A: ABCCDEX SCORING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Items answered as not relevant will be scored as ‘0’ for the purposes of scoring.  
 
 


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APPENDIX B: SKINDEX-16 SCORING  
During the past week, how often have you been bothered by: 
Range 
Scale (Range) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A scale will be set to missing if >25% of the items in the scale were left blank. Individual missing items 
will not be imputed. 
 


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APPENDIX C: DLQI SCORING  
The scoring of each question is as follows: 
Answer 
Score 
 
 
 
 
 
 
 
 
 
 
 
3 
The total score is calculated by summing each question’s score with a score ranging from 0 to 30. The 
higher the score, the more impairment in quality of life. 
 
 


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APPENDIX D: PRESENTATION OF DATA AND PROGRAMMING 
SPECIFICATIONS 
 
General  
 Specialized text styles, such as bold, italics, borders, and shading will not be used in tables, 
figures, and data listings unless they add significant value to the table, figure, or data listing. 
 Only standard keyboard characters are to be used in tables and data listings. 
 Special characters, such as nonprintable control characters, printer-specific, or font-specific 
characters, will not be used on a table, figure, or data listing. 
 Hexadecimal character representations are allowed (eg, µ, , ß). 
 All footnotes will be left justified and at the bottom of a page. Footnotes must be used sparingly 
and must add value to the table, figure, or data listing. 
 Outputs will be numbered in accordance with Synteract’s SAS Programming Standards (WI-
SOP-0205-001) and will follow the listed examples: t14.3.4.x-vs-<yyyy-mm-dd>.rtf, l16.2.4.x-
mh-<yyyy-mm-dd>.rtf, and f14.x.x-ttdis-<yyyy-mm-dd>.rtf. 
 
Tables 
 Formal organization of tabulations may be changed during programming, if appropriate, eg, 
tables for the different variables may be combined into a single table, or tables with more than 1 
variable may be split into several tables. 
 Means and medians will be presented to 1 more decimal place than the raw data. SDs will be 
presented to 2 more decimal places than the raw data. Minimums and maximums will be 
reported with the same number of decimal places as the raw data.  
 Percentages will be presented to the tenths place. 
 For frequency counts of categorical variables, categories whose counts are zero will be displayed 
for the sake of completeness. For example, if none of the subjects discontinue due to “lost to 
follow-up,” this reason will be included in the table with a count of 0. Categories with zero 
counts will not have zero percentages displayed. 
 Lower and upper CI values must be presented to 1 decimal place more than the raw/derived data 
(ie, to the same number of decimal places as the mean). 
 Percentiles (eg, 25%, 75%) must be presented to 1 decimal place more than the raw/derived data. 
 For all inferential analyses, P values will be rounded to 4 decimal places (or at the highest level 
of precision) with a leading zero (0.0001). P values less than 0.0001 will be presented as 
“<0.0001.” 
 The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source table number(s) if applicable (in case aggregated results like 
mean or median are plotted) or the source listing(s) (in case individual responses are plotted) and/or source 
datatset(s) (eg, ADaM).  
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: DDMMYY 
hh:mm”. 
where extract date is the datestamp of the data snapshot used. 
 
 


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Figures 
 Legends will be used for all figures with more than 1 variable or item displayed. Treatment 
group sizes (n=xx) will be included, as appropriate. 
 Figures will be in black and white but can be in color to add value to the clarity and readability 
of a figure. Lines must be wide enough to see the line after being copied. 
 The last footnotes will be 
- 
“Source: xxx”, where xxx indicates the source listing number(s) and/or source datatset(s) (eg, ADaM).  
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: DDMMYY 
hh:mm”. 
where extract date is the datestamp of the data snapshot used. 
 Line graphs over time of change from baseline results will include a horizontal dashed reference 
line at zero. 
 For box plots, the horizontal line will represent the median, + represents the group mean, the 
length of the box represents the interquartile range (25th-75th percentiles), and the whiskers will 
represent the minimum and maximum. 
 
Listings 
 Formal organization of the listing may be changed during programming, if appropriate, eg, 
additional variables may be included, change in the column order, or the listing may be split into 
multiple parts due to space constraints. 
 If not otherwise specified, all data listings will be sorted by treatment, center, subject number, 
visit, and date/time, as appropriate.  
 All date values will be presented in a SAS date (eg, 29AUG2001) format showing actual dates 
entered and not imputed dates.  
 All observed time values will be presented using a 24-hour clock HH:MM:SS format (eg, 
01:35:45 or 11:26). Seconds will only be reported if they were measured as part of the study. 
 The last footnote will be 
- 
“PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN DATE: DDMMYY 
hh:mm”. 
where extract date is the datestamp of the data snapshot used. 
 
 
 


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Missing or incomplete dates (ie, AEs (for determination of treatment-emergence only) and 
concomitant medications) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing/incomplete, it is assumed to have occurred during the study treatment phase (ie, considered a 
TEAE) except if the partial onset date or other data, such as the stop date, indicates differently. 
Similarly, a medication with partial start and stop dates could be considered as both a prior and 
concomitant treatment. 
 
The following algorithms will be applied to missing and incomplete start and stop dates: 
 
Start Dates 
 If the day portion of the start date is missing, then the start date will be estimated to be equal to 
the date of first dose of study drug, provided the start month and year are the same as the first 
dose of study drug and the stop date is either after the first dose of study drug or completely 
missing. Otherwise, the missing day portion will be estimated as “01.” 
 If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the same as 
the first dose of study drug and the stop date is either after the first dose of study drug or 
completely missing. Otherwise, the event will be assumed to start on the first day of the given 
year (eg, ??-???-2013 is estimated as 01-JAN-2013). 
 If the start date is completely missing and the stop date is either after the dose of study drug or 
completely missing, the start date will be estimated to be the day of study drug dosing. 
Otherwise, the start date will be estimated to be the first day of the same year as the stop date. 
All other non-AE and non-concomitant medication day calculations where only partial dates are 
available will be handled as follows: the first day of the month will be used in the calculations if 
the day part of a start date is missing while January 1 will be employed if both the month and day 
parts of a start date are missing. 
 
Stop Dates 
 If only the day of resolution is unknown, the day will be assumed to be the last of the month (eg, 
??-JAN-2013 will be treated as 31-JAN-2013).  
 If both the day and month of resolution are unknown, the event will be assumed to have ceased 
on the last day of the year (eg, ??-???-2013 will be treated as 31-DEC-2013).  
 if the stop date is completely missing or the event is continuing, the event will be assumed to be 
after first dose of study drug and will be imputed using the last known date on the study. 
 
Standard Calculations 
 
Variables requiring calculation will be derived using the following formulas: 
 
Days – A duration expressed in days between 1 date (date1) and another later date (date2) is calculated 
using the formulas noted below: 
duration in days = date2 – date1 + 1 
Months – A duration expressed in months is calculated using the INTCK function of SAS as follows: 
months=intck('month','date1'd,date2'd, 'continuous'). 


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Years – A duration expressed in years between 1 date (date1) and another later date (date2) is calculated 
as follows:  
duration in years = intck(‘year,'date1'd,date2'd, 'continuous'). 
Age – Age is calculated as the number of years from the date of birth (DOB) to the date of informed 
consent (DOIC). If the month of DOIC < month of DOB or the month of DOIC=DOB and the day of 
DOIC < day of DOB, then the following formula is used: 
age (years) = year of DOIC – year of DOB – 1. 
Otherwise, the following formula is used: 
age (years) = year of DOIC – year of DOB. 
Height – Height entries made in inches (in) are converted to centimeters (cm) using the following 
formula: 
height (cm) = height (in) × 2.54. 
Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using the following 
formula: 
weight (kg) = weight (lb)/2.2046. 
Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using the following 
formula: 
BMI (kg/m2) = weight (kg)/[[height (cm)/100]2]. 
Temperature – Temperature entries in degrees Fahrenheit are converted to degrees centigrade using the 
following formula: 
temp (degrees centigrade) = 5/9 × [temp (degrees Fahrenheit) – 32]. 
Change from baseline – Change from baseline will be calculated as: 
Change = postbaseline value – baseline value. 
 
 


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